Harper S Textbook of Pediatric Dermatology Wiley Blackwell 2020 PDF

Harper’s
Textbook of
Pediatric Dermatology
Harper’s
Textbook of
Pediatric
Dermatology
IN TWO VOLUMES
FOURTH EDITION
EDITED BY
Peter Hoeger
Veronica Kinsler
Albert Yan
EDITORIAL ADVISORS
John Harper
Arnold Oranje
ASSOCIATE EDITORS
Christine Bodemer
Margarita Larralde
David Luk
Vibhu Mendiratta
Diana Purvis
This edition first published 2020 © 2020 John Wiley & Sons Ltd
Edition History
Blackwell Publishing Ltd (1e, 2000 2e, 2006; 3e, 2011)
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Library of Congress Cataloging‐in‐Publication Data

Names: Hoeger, Peter H., editor. | Kinsler, Veronica, editor. | Yan, Albert C., editor.
Title: Harper’s textbook of pediatric dermatology / edited by Peter Hoeger, Veronica Kinsler,
Albert Yan ; editorial advisors, John Harper, Arnold Oranje ; associate editors, Christine
Bodemer, Margarita Larralde, David Luk, Vibhu Mendiratta, Diana Purvis.
Other titles: Textbook of pediatric dermatology
Description: Fourth edition. | Hoboken, NJ : Wiley-Blackwell, 2020. | Includes bibliographical
references and index.
Identifiers: LCCN 2019031032 (print) | ISBN 9781119142195 (hardback) | ISBN 9781119142805
(adobe pdf) | ISBN 9781119142737 (epub)
Subjects: MESH: Skin Diseases | Child | Infant
Classification: LCC RJ511 (print) | LCC RJ511 (ebook) | NLM WS 265 | DDC 618.92/5–dc23
LC record available at https://lccn.loc.gov/2019031032
LC ebook record available at https://lccn.loc.gov/2019031033
Cover image: CP Photo Art/Getty Images

Cover design by Wiley
Set in 9.5/11.5 pt Palatino by SPi Global, Pondicherry, India
10 9 8 7 6 5 4 3 2 1
v
Contents
List of Contributors, xi 10 Differential Diagnosis of Neonatal Erythroderma, 121

Hagen Ott & Peter H. Hoeger
Preface to the Fourth Edition, xxiv
11 Vesiculopustular, Bullous and Erosive Diseases
Dedication to Arnold P. Oranje, xxv of the Neonate, 134
Caroline Mahon & Anna E. Martinez
Acknowledgements, xxvi
12 Iatrogenic Disorders of the Newborn, 154
List of Abbreviations, xxvii Elia F. Maalouf & Wilson Lopez
Section 3 Atopic Dermatitis and Related

VOLUME 1 Disorders
Section 1 Development, Structure and 13 Epidemiology of Atopic Dermatitis, 167

Physiology of the Skin Carsten Flohr, Jonathan I. Silverberg, Joy Wan &
Sinéad M. Langan
1 Embryogenesis of the Skin, 1
14 Genetics and Aetiology of Atopic Dermatitis, 184
Lara Wine Lee & Karen A. Holbrook
Elke Rodriguez & Stephan Weidinger
2 Molecular Genetics in Paediatric Dermatology, 36
15 Clinical Features and Diagnostic Criteria of Atopic
Anna C. Thomas & Veronica A. Kinsler
Dermatitis, 193
3 Cutaneous Microbiome, 46 Sinéad M. Langan & Hywel C. Williams
Carrie C. Coughlin & William H. McCoy IV
16 Severity Scoring and Quality of Life Assessment
4 Physiology of Neonatal Skin, 56 in Atopic Dermatitis, 212
Peter H. Hoeger Christian Apfelbacher, Cecilia A.C. (Sanna) Prinsen,
Daniel Heinl & Hywel C. Williams
17 Atopic Dermatitis and Related Disorders:

Section 2 Skin Disorders of the Neonate Special Types of Presentation, 228
and Young Infant Nawaf Almutairi
5 Neonatal Skin Care, 63 18 Atopic Dermatitis: Complications, 245

Peter H. Hoeger Kevin B. Yarbrough & Eric L. Simpson
6 Transient Skin Disorders in the Neonate 19 Management of Atopic Dermatitis, 253

and Young Infant, 72 Lea Solman & Mary Glover
Margarita Larralde & Maria Eugenia Abad
7 Congenital and Acquired Infections in the Neonate, 84

Scott H. James, Nico G. Hartwig, David W. Kimberlin &
Section 4 Other Types of Dermatitis
Peter H. Hoeger
20 Napkin Dermatitis, 265
8 Transplacentally Acquired Dermatoses, 93 Arnold P. Oranje, Ernesto Bonifazi, Paul J. Honig &
Paula Carolina Luna Albert C. Yan
9 Developmental Anomalies, 101 21 Adolescent Seborrhoeic Dermatitis, 279

Marion Wobser & Henning Hamm Roselyn Kellen & Nanette Silverberg
vi Contents
22 Irritant Contact Dermatitis, 287 39 Pitted Keratolysis, Erythrasma and Erysipeloid, 456

David Luk Zhe Xu, Yuanyuan Xiao, Ying Xiu & Lin Ma
23 Allergic Contact Dermatitis, 300 40 Lyme Borreliosis, 463

Sharon E. Jacob, Hannah Hill & Alina Goldenberg Susan O’Connell
24 Hypereosinophilic Disorders, 316 41 Bartonella Infections, 475

Eirini E. Merika & Nerys Roberts Sonia Kamath & Minnelly Luu
25 Juvenile Plantar Dermatosis, 335 42 Mycobacterial Skin Infections, 485

John C. Browning & Margaret Brown G. Sethuraman, Tanvi Dev & V. Ramesh
26 Perioral Dermatitis, 338 43 Rickettsial Disease, 503

Marius Rademaker Arun C. Inamadar & Aparna Palit
44 Endemic Treponematoses: Yaws, Pinta and Endemic

Syphilis, 515
Section 5 Psoriasis Herman Jan H. Engelkens
45 Tropical Ulcer, 523

27 Psoriasis: Epidemiology, 343 Vibhu Mendiratta & Soumya Agarwal
Matthias Augustin & Marc Alexander Radtke
28 Psoriasis: Aetiology and Pathogenesis, 350

Jonathan Barker Section 8 Fungal Skin Infections
29 Psoriasis: Clinical Features and Comorbidities, 354
Derek H. Chu & Kelly M. Cordoro 46 Superficial Fungal Infections, 527
Peter Mayser & Yvonne Gräser
30 Psoriasis: Classification, Scores and Diagnosis, 362
Nirav Patel & Megha Tollefson 47 Deep Fungal Infections, 560
María Teresa García‐Romero
31 Psoriasis: Management, 368
Marieke M.B. Seyger
Section 9 Viral Skin Infections and Opportunistic

Infections
Section 6 Other Papulosquamous Disorders
48 Molluscum Contagiosum, 579
32 Pityriasis Rubra Pilaris, 377 Joachim J. Bugert, Ali Alikhan & Tor Shwayder
Liat Samuelov & Eli Sprecher
49 Human Papillomavirus Infection, 588
33 Lichen Planus, 390 Yun Tong, Stephen K. Tyring & Zsuzsanna Z. Szalai
Vibhu Mendiratta & Sarita Sanke
50 Herpes Simplex Virus Infections, 598
34 Lichen Nitidus, 403 Manuraj Singh, Helen M. Goodyear & Judith Breuer
Jasem M. Alshaiji
51 Varicella Zoster Virus Infections, 612
35 Lichen Striatus, 408 Manuraj Singh & Judith Breuer
Franck Boralevi & Alain Taïeb
52 Poxvirus Infections, 624
36 Pityriasis Rosea, 416 Susan Lewis‐Jones & Jane C. Sterling
Antonio A.T. Chuh & Vijay Zawar
53 HIV and HTLV‐1 Infection, 649
Neil S. Prose, Ncoza C. Dlova, Rosalia A. Ballona &
Coleen K. Cunningham
Section 7 Bacterial Skin Infections 54 Viral Exanthems, 660
Jusleen Ahluwalia, Pamela Gangar & Sheila Fallon
37 Pyodermas and Bacterial Toxin‐mediated Friedlander
Syndromes, 423
James R. Treat, Christian R. Millett, 55 Eruptive Hypomelanosis, 681
Warren R. Heymann & Steven M. Manders Vijay Zawar & Antonio A.T. Chuh
38 Cutaneous Manifestations of Gram‐negative 56 Cutaneous Infections in Immunocompromised

Infections, 434 Children, 684
Saul N. Faust, Diane Gbesemete & Robert S. Heyderman Miriam Weinstein, Hagen Ott & Peter H. Hoeger
Contents vii
Section 10 Parasitic Skin Infestations Section 14 Blistering Disorders

and Sting Reactions
73 Differential Diagnosis of Vesiculobullous Lesions, 859
57 Leishmaniasis, 693 Sharleen F. Hill & Dédée F. Murrell
Bernardo Gontijo & Carolina Talhari
74 Autoimmune Bullous Diseases, 868
58 Helminthic Infections, 702 Nina van Beek & Enno Schmidt
Héctor Cáceres‐Ríos & Felipe Velasquez
75 Childhood Dermatitis Herpetiformis, 898
59 Scabies and Pseudoscabies, 711 Carmen Liy Wong & Irene Lara‐Corrales
Wingfield E. Rehmus & Julie S. Prendiville
76 Epidermolysis Bullosa and Kindler Syndrome, 907
60 Pediculosis and Cimicosis, 723 Jemima E. Mellerio, Anna E. Martinez & Christina Has
Sandipan Dhar & Sahana M. Srinivas
61 Noxious and Venomous Creatures, 733

Kam Lun Ellis Hon, Theresa Ngan Ho Leung & Section 15 Photodermatoses, Photoprotection
Ting Fan Leung and Environmental Skin Disorders
62 Aquatic Dermatoses, 746
77 The Idiopathic Photodermatoses and Skin Testing, 943
Sarah Hill
Erhard Hölzle & Robert Dawe
78 The Porphyrias, 957

Section 11 Urticaria, Erythemas and Drug Jorge Frank
Reactions
79 Photoprotection, 969
Lachlan Warren & Genevieve Casey
63 Urticaria, 751
Bettina Wedi 80 Skin Reactions to Plants, Cold, Heat
and Chemicals, 983
64 Annular Erythemas, 764
Tuyet A. Nguyen, Christopher Lovell &
Kimberly A. Horii
Andrew C. Krakowski
65 Gianotti–Crosti Syndrome, 771
Carlo M. Gelmetti
66 Erythema Multiforme, Stevens–Johnson Syndrome Section 16 Granulomatous Diseases

and Toxic Epidermal Necrolysis, 777
Benjamin S. Daniel, Lizbeth Ruth Wheeler & 81 Sarcoidosis, 995
Dédée F. Murrell Lisa M. Arkin, Julie L. Cantatore‐Francis & Julie V. Schaffer
67 Hypersensitivity Reactions to Drugs, 785 82 Granuloma Annulare, 1006

Mohannad Abu‐Hilal & Neil Shear Annalisa Patrizi & Iria Neri
83 Orofacial Granulomatosis, 1017

Lisa Weibel & Martin Theiler
Section 12 Acne and Acneiform Disorders
68 Acne, 803
Marissa J. Perman, Bodo C. Melnik & Anne W. Lucky Section 17 Neutrophilic Dermatoses
69 Childhood Rosacea, 821
84 Sweet Syndrome, 1023
Clio Dessinioti & Andreas Katsambas
Peter von den Driesch
70 Hidradenitis Suppurativa, 825
85 Pyoderma Gangrenosum, 1027
Peter Theut Riis & Gregor B.E. Jemec
Karolina Gholam
Section 13 Nutritional Disorders

Section 18 Lymphocytic Disorders
71 Skin Manifestations of Nutritional Disorders, 831
Carola Durán McKinster & Luz Orozco‐Covarrubias 86 Pityriasis Lichenoides, 1035
Christine T. Lauren & Maria C. Garzon
72 Skin Manifestations of Paediatric Metabolic
Syndrome, 841 87 Jessner Lymphocytic Infiltrate of the Skin, 1040
Gregor Holzer & Beatrix Volc‐Platzer R.M. Ross Hearn
viii Contents
88 Primary Cutaneous Lymphoma, 1044 102 Panniculitis in Children, 1207

Rebecca Levy & Elena Pope Christine Bodemer
89 Childhood Leukaemias and Lymphomas, 1063 103 Lipodystrophies, 1221

Keith Morley & Jennifer Huang Robert K. Semple
Section 19 Histiocytic Disorders Section 23 Mosaic Disorders, Naevi and

Hamartomas
90 Langerhans Cell Histiocytosis, 1071
Sylvie Fraitag & Jean Donadieu 104 An Introduction to Mosaicism, 1229
Veronica A. Kinsler
91 Juvenile Xanthogranuloma and Other
Non‐Langerhans Cell Histiocytoses, 1078 105 Melanocytic Naevi, 1237
Gudrun Ratzinger & Bernhard W.H. Zelger Veronica A. Kinsler
106 Epidermal Naevi, 1260

Leopold M. Groesser & Christian Hafner
Section 20 Mastocytosis 107 Other Naevi and Hamartomas, 1276
Jonathan A. Dyer
92 Paediatric Mastocytosis, 1097
Laura Polivka & Christine Bodemer 108 Proteus Syndrome and Other Localized Overgrowth
Disorders, 1283
Veronica A. Kinsler
Section 21 Disorders of Connective Tissue 109 Mosaic Disorders of Pigmentation, 1296
Veronica A. Kinsler
93 Ehlers–Danlos Syndromes, 1111
Nigel P. Burrows
Section 24 Nonvascular Skin Tumours
94 Pseudoxanthoma Elasticum and Cutis Laxa, 1125
Sean D. Reynolds & Lionel Bercovitch
110 Differential Diagnosis of Skin Nodules and Cysts, 1313
95 Buschke–Ollendorff Syndrome, Marfan Syndrome Susanne Abraham & Peter H. Hoeger
and Osteogenesis Imperfecta, 1139
111 Adnexal Disorders, 1325
Marc Lacour
Andrew Wang & Robert Sidbury
96 Anetodermas and Atrophodermas, 1151
112 Calcification and Ossification in the Skin, 1338
Marc Lacour
Amanda T. Moon, Albert C. Yan & Eulalia T. Baselga
97 Hyalinoses, Stiff Skin Syndrome and Restrictive
113 Angiolymphoid Hyperplasia with Eosinophilia, 1350
Dermopathy, 1164
Jasem M. Alshaiji
David G. Paige
114 Fibromatoses, 1356
98 Striae in Children and Adolescents, 1172
Jenna L. Streicher, Moise L. Levy & Albert C. Yan
Marcelo Ruvertoni
115 Carcinomas of the Skin, 1370
99 Morphoea (Localized Scleroderma), 1175
Karen Agnew
Despina Eleftheriou & Lindsay Shaw
116 Childhood Melanoma, 1377
100 Systemic Sclerosis in Childhood, 1183
Birgitta Schmidt & Elena B. Hawryluk
Christopher P. Denton & Carol M. Black
117 Other Malignant Skin Tumours, 1382
Index, i1 Andrea Bettina Cervini, Marcela Bocian,
María Marta Bujan & Paola Stefano
Section 25 Vascular Tumours and Malformations

VO L U M E 2
118 Vascular Malformations, 1399
Section 22 Disorders of Fat Tissue Laurence M. Boon & Miikka Vikkula
101 Lipoma and Lipomatosis, 1195 119 Infantile Haemangiomas, 1425

Siriwan Wananukul & Susheera Chatproedprai Anna L. Bruckner, Ilona J. Frieden & Julie Powell
Contents ix
120 Other Vascular Tumours, 1440 135 Focal Dermal Hypoplasia, 1706
Ann M. Kulungowski, Taizo A. Nakano & Bret L. Bostwick, Ignatia B. Van den Veyver &
Anna L. Bruckner V. Reid Sutton
121 Disorders of Lymphatics, 1452 136 Incontinentia Pigmenti, 1718

Arin K. Greene & Jeremy A. Goss Elizabeth A. Jones & Dian Donnai
137 Premature Ageing Syndromes, 1725

Helga V. Toriello & Caleb P. Bupp
Section 26 Disorders of Pigmentation
122 Inherited and Acquired Hyperpigmentation, 1463

Leslie Castelo‐Soccio & Alexis Weymann Perlmutter
Section 29 Genetic Diseases Predisposing
to Malignancy
123 Vitiligo, 1476
Julien Seneschal, Juliette Mazereeuw‐Hautier & 138 Xeroderma Pigmentosum and Related Diseases, 1743
Alain Taïeb Steffen Schubert & Steffen Emmert
124 Albinism, 1486 139 Gorlin (Naevoid Basal Cell Carcinoma) Syndrome, 1769
Fanny Morice‐Picard & Alain Taïeb Kai Ren Ong & Peter A. Farndon
125 Disorders of Hypopigmentation, 1492 140 Rothmund–Thomson Syndrome, Bloom Syndrome,

M.W. Bekkenk & A. Wolkerstorfer Dyskeratosis Congenita, Fanconi Anaemia
and Poikiloderma with Neutropenia, 1786
126 Dyschromatosis, 1499 Lisa L. Wang & Moise L. Levy
141 Other Genetic Disorders Predisposing to Malignancy, 1802
Julie V. Schaffer
Section 27 Disorders of Keratin and

Keratinization Section 30 Neurofibromatosis, RASopathies and
Hamartoma-Overgrowth Syndromes
127 Review of Keratin Disorders, 1515
Maurice A.M. van Steensel & Peter M. Steijlen 142 The Neurofibromatoses, 1823
Amy Theos, Kevin P. Boyd & Bruce R. Korf
128 Mendelian Disorders of Cornification (MEDOC):
The Keratodermas, 1524 143 Tuberous Sclerosis Complex, 1837
Edel A. O’Toole Francis J. DiMario Jr
129 Mendelian Disorders of Cornification 144 Other RASopathies, 1857

(MEDOC): The Ichthyoses, 1549 Fanny Morice‐Picard
Angela Hernández, Robert Gruber & Vinzenz Oji
130 Keratosis Pilaris and Darier Disease, 1599

Flora B. de Waard‐van der Spek & Arnold P. Oranje
Section 31 Vasculitic and Rheumatic Syndromes
131 The Erythrokeratodermas, 1608 145 Cutaneous Vasculitis, 1865

Juliette Mazereeuw‐Hautier, S. Leclerc‐Mercier & Joyce C. Chang & Pamela F. Weiss
E. Bourrat
146 Purpura Fulminans, 1891
132 Netherton Syndrome, 1613 Michael Levin, Brian Eley & Saul N. Faust
Wei‐Li Di & John Harper
147 Kawasaki Disease, 1906
133 Porokeratosis, 1623 Wynnis L. Tom & Jane C. Burns
Leslie Castelo‐Soccio
148 Polyarteritis Nodosa, Granulomatosis with Polyangiitis
and Microscopic Polyangiitis, 1918
Paul A. Brogan
Section 28 Focal or Generalized Hypoplasia 149 Juvenile Idiopathic Arthritis, Systemic Lupus
and Premature Ageing Erythematosus and Juvenile Dermatomyositis, 1933
Elena Moraitis & Despina Eleftheriou
134 Ectodermal Dysplasias, 1629
Cathal O’Connor, Yuka Asai & Alan D. Irvine 150 Behçet Disease and Relapsing Polychondritis, 1952
Sibel Ersoy‐Evans, Ayşen Karaduman & Seza Özen
x Contents
151 Erythromelalgia, 1961 Section 37 Psychological Aspects of Skin

Nedaa Skeik Disease in Children
165 Assessing and Scoring Life Quality, 2241

Section 32 Cutaneous Manifestations of Andrew Y. Finlay
Systemic Disease
166 Coping with the Burden of Disease, 2255
152 Metabolic Disorders and the Skin, 1965 Sarah L. Chamlin
Fatma Al Jasmi, Hassan Galadari, Peter T. Clayton & 167 Physiological Habits, Self‐Mutilation and Factitious
Emma J. Footitt Disorders, 2262
153 Cystic Fibrosis, 1988 Arnold P. Oranje, Jeroen Novak & Robert A.C. Bilo
Roderic J. Phillips
154 Cutaneous Manifestations of Endocrine Disease, 1993

Devika Icecreamwala & Tor A. Shwayder Section 38 Principles of Treatment in Children
155 Autoinflammatory Diseases and Amyloidosis, 2010 168 Topical Therapy, 2275

Antonio Torrelo, Sergio Hernández‐Ostiz & Teri A. Kahn Johannes Wohlrab
156 Immunodeficiency Syndromes, 2028 169 Systemic Therapy in Paediatric Dermatology, 2282
Julie V. Schaffer, Melanie Makhija & Amy S. Paller Blanca Rosa Del Pozzo‐Magana & Irene Lara‐Corrales
157 Graft‐Versus‐Host Disease, 2067 170 New Genetic Approaches to Treating Diseases
John Harper & Paul Veys of the Skin, 2301
Stephen Hart & Amy Walker
171 Surgical Therapy, 2310

Section 33 The Oral Cavity Julianne A. Mann & Jane S. Bellet
158 The Oral Mucosa and Tongue, 2079 172 Laser Therapy, 2319
Jane Luker & Crispian Scully Samira Batul Syed, Maria Gnarra & Sean Lanigan
173 Sedation and Anaesthesia, 2330

Brenda M. Simpson, Yuin‐Chew Chan &
Lawrence F. Eichenfield
Section 34 Hair, Scalp and Nail Disorders
159 Hair Disorders, 2103

Elise A. Olsen & Matilde Iorizzo Section 39 Diagnostic Procedures in
Dermatology
160 Alopecia Areata, 2139
Kerstin Foitzik‐Lau
174 Approach to the Paediatric Patient, 2341
161 Nail Disorders, 2147 Diana Purvis
Antonella Tosti & Bianca Maria Piraccini
175 Dermoscopy of Melanocytic Lesions in the Paediatric
Population, 2357
Maria L. Marino, Jennifer L. DeFazio, Ralph P. Braun &
Section 35 Anogenital Disease in Children Ashfaq A. Marghoob
176 The Role of Histopathology and Molecular Techniques

162 Genital Disease in Children, 2159
in Paediatric Dermatology, 2378
Gayle O. Fischer
Lori Prok & Adnan Mir
163 Sexually Transmitted Diseases in Children
and Adolescents, 2195
Arnold P. Oranje, Robert A.C. Bilo & Nico G. Hartwig
Section 40 Nursing Care of Cutaneous Disorders
in Children
Section 36 Cutaneous Signs of Child 177 Nursing Care of the Skin in Children, 2393
Maltreatment and Sexual Abuse Bisola Laguda, Hilary Kennedy, Jackie Denyer,
Heulwen Wyatt, Jean Robinson & Karen Pett
164 Maltreatment, Physical and Sexual Abuse, 2219
Bernhard Herrmann Index, i1
xi
List of Contributors
Maria Eugenia Abad, MD Ali Alikhan Rosalia A. Ballona

Dermatology Department University of Cincinnati Division of Dermatology
Hospital Alemán Department of Dermatology Instituto del Salud del Niño
Pediatric Dermatology Department Cincinnati, OH, USA Lima, Peru
Hospital Ramos Mejía
Buenos Aires, Argentina Nawaf Almutairi, MD Jonathan Barker, MD, FRCP,
Professor FRCPath
Susanne Abraham, MD Department of Medicine Professor of Dermatology
Department of Dermatology Faculty of Medicine St John’s Institute of Dermatology (King’s
Medical Faculty Carl‐Gustav‐Carus Kuwait University College)
Technical University of Dresden Kuwait Guy’s Hospital
Dresden, Germany London, UK
Jasem M. Alshaiji, MD
Mohannad Abu‐Hilal, MD Head of Dermatology Department Eulalia T. Baselga, MD
Assistant Professor Head of Pediatric Dermatology Unit Pediatric Dermatology Unit
Division of Dermatology Amiri Hospital Hospital de la Santa Creu I Sant Pau
Department of Medicine Kuwait Universitat Autònoma de Barcelona
McMaster University Spain
Hamilton, ON, Canada Christian Apfelbacher, PhD
Medical Sociology M.W. Bekkenk, MD, PhD
Soumya Agarwal, MD Institute of Epidemiology and Preventive Dermatologist
Senior Resident Medicine Netherlands Institute for Pigment Disorders
Department of Dermatology University of Regensburg Amsterdam University Medical Centers
Lady Hardinge Medical College and Regensburg, Germany Amsterdam, The Netherlands
Associated Hospitals
New Delhi, India Lisa M. Arkin, MD Jane S. Bellet, MD
Department of Dermatology Associate Professor of Dermatology and
Karen Agnew, MBChB, FRACP, University of Wisconsin School of Medicine Pediatrics
FNZDS and Public Health Duke University Medical Center
Consultant Dermatologist Madison, WI, USA Durham, NC, USA
Starship Children’s and Auckland City
Hospitals Yuka Asai, MSc, PhD, MD Lionel Bercovitch, MD
Auckland, New Zealand
Assistant Professor Professor of Dermatology
Division of Dermatology Warren Alpert Medical School of Brown
Jusleen Ahluwalia, MD Queen’s University University
Resident Physician Kingston, ON, Canada Director of Pediatric Dermatology
Department of Pediatric and Adolescent Hasbro Children’s Hospital
Dermatology Matthias Augustin, MD Providence, RI, USA
Rady Children’s Hospital Medical Director
Professor
San Diego, CA, USA PXE International, Inc.
Institute for Health Services Research in
Washington, DC, USA
Dermatology and Nursing (IVDP)
Fatma Al Jasmi, MBBS, FRCPC, University Medical Center Hamburg‐
FCCMG Eppendorf (UKE) Robert A.C. Bilo
Associate Professor Hamburg, Germany Department of Forensic Medicine
College of Medicine and Health Science Section on Forensic Pediatrics
United Arab Emirates University Netherlands Forensic Institute
Al Ain, United Arab Emirates The Hague, The Netherlands
xii List of Contributors
Carol M. Black, DBE, MD, FRCP, Ralph P. Braun, MD Jane C. Burns, MD

MACP, FMedSci Dermatology Clinic Professor of Pediatrics
Principal of Newnham College Cambridge, University Hospital Zürich Director, Kawasaki Disease Research Center
Expert Adviser on Health and Work to NHS Zürich, Switzerland University of California, San Diego
England and Public Health England, Chair of Rady Children’s Hospital
Think Ahead, Chair of the British Library Judith Breuer, MBBS, MD, La Jolla, CA, USA
Centre for Rheumatology FRCPath
Royal Free Hospital and UCL Division of
Professor of Virology Nigel P. Burrows, MBBS, MD,
Medicine FRCP
UCL
London, UK
Honorary Consultant Virologist Consultant Dermatologist and Associated
Great Ormond Street Hospital Lecturer
Christine Bodemer, MD, PhD UCL Division of Infection and Immunity Department of Dermatology
Professor of Dermatology London, UK Addenbrooke’s Hospital
Department of Dermatology Cambridge University Hospitals NHS
Imagine Institute Paul A. Brogan, MBChB, Foundation Trust
Necker‐Enfants Malades Hospital Cambridge, UK
Paris, France
FRCPCH, PhD
Professor of Vasculitis and Honorary
Consultant Paediatric Rheumatologist Héctor Cáceres‐Ríos, MD
Marcela Bocian, MD Section Head: Infection and Inflammation and Consultant in Pediatric Dermatology
Assistant Physician Rheumatology Department of Pediatric Dermatology
Dermatology Department Co‐Director of Education (Clinical Academics) Instituto de Salud del Niño
Hospital de Pediatría ‘Prof. Dr. Juan P. Garrahan’ UCL Institute of Child Health Lima, Peru
Buenos Aires, Argentina Great Ormond Street Hospital NHS
Foundation Trust Julie L. Cantatore‐Francis, MD
Ernesto Bonifazi, MD London, UK
Dermatology Physicians of Connecticut
Professor of Dermatology Shelton, CT, USA
Dermatologia Pediatrica Association Margaret Brown, MD
Bari, Italy Division of Dermatology Genevieve Casey
The University of Texas Health Science Center
Specialist Registrar
Laurence M. Boon, MD, PhD at San Antonio
Department of Dermatology
San Antonio, TX, USA
Coordinator of the Center for Vascular Women’s & Children’s Hospital
Anomalies Adelaide, SA, Australia
Division of Plastic Surgery John C. Browning, MD, FAAD,
Cliniques Universitaires Saint Luc and FAAP Leslie Castelo‐Soccio, MD, PhD
Human Molecular Genetics Assistant Professor Professor of Pediatrics and Dermatology
de Duve Institute Baylor College of Medicine Department of Pediatrics
University of Louvain Chief of Dermatology Section of Pediatric Dermatology
Brussels, Belgium Children’s Hospital of San Antonio University of Pennsylvania Perelman School
San Antonio, TX, USA of Medicine and Children’s Hospital of
Franck Boralevi, MD, PhD Philadelphia
Pediatric Dermatology Unit Anna L. Bruckner, MD, MSCS Philadelphia, PA, USA
Hôpital Pellegrin‐Enfants Associate Professor of Dermatology and
Bordeaux, France Pediatrics Andrea Bettina Cervini, MD
University of Colorado School of Medicine Dermatologist, Pediatric Dermatologist
Bret L. Bostwick, MD Section Head Head of Dermatology Department
Assistant Professor Division of Dermatology Hospital de Pediatría ‘Prof. Dr. Juan P.
Department of Molecular and Human Children’s Hospital Colorado Garrahan’
Genetics Aurora, CO, USA Buenos Aires, Argentina
Baylor College of Medicine and Texas
Children’s Hospital Joachim J. Bugert, MD, PhD Sarah L. Chamlin, MD
Houston, TX, USA Lab Group Leader Professor of Pediatrics and Dermatology
Institut für Mikrobiologie der Bundeswehr The Ann and Robert H. Lurie Children’s
E. Bourrat, MD München, Germany Hospital of Chicago and Northwestern
Reference Center for Inherited Skin Disease University
Dermatology Department María Marta Bujan, MD Feinberg School of Medicine
CHU Saint Louis Assistant Physician Chicago, IL, USA
Paris, France Dermatology Department
Hospital de Pediatría ‘Prof. Dr. Juan P. Garrahan’ Yuin‐Chew Chan
Kevin P. Boyd, MD Buenos Aires, Argentina Dermatologist
Clinical Assistant Professor Dermatology Associates
University of Alabama at Birmingham Caleb P. Bupp, MD Gleneagles Medical Centre
Birmingham, AL, USA Medical Geneticist Singapore
Spectrum Health Medical Group
Grand Rapids, MI, USA
List of Contributors xiii
Joyce C. Chang, MD Robert Dawe, MBCh, MD, FRCPE Francis J. DiMario Jr, MD
Instructor Photodermatology Unit Professor of Pediatrics and Neurology
Division of Rheumatology Department of Dermatology University of Connecticut School of Medicine
The Children’s Hospital of Philadelphia Ninewells Hospital and Medical School Farmington, CT, USA
Philadelphia, PA, USA Dundee, UK Associate Chair for Academic Affairs,
Department of Pediatrics,
Susheera Chatproedprai, MD Jennifer L. DeFazio, MD Director, Neurogenetic‐Tuberous Sclerosis Clinic
Division of Pediatric Neurology
Associate Professor of Paediatrics Department of Dermatology
Connecticut Children’s Medical Center
Head of Division of Paediatric Dermatology Memorial Sloan‐Kettering Cancer Center
Hartford, CT, USA
Department of Paediatrics New York, NY, USA
Faculty of Medicine
Chulalongkorn University, Blanca Rosa Del Pozzo‐Magana Ncoza C. Dlova
Bangkok, Thailand London Health Sciences Center and Western Department of Dermatology
University University of Kwazulu‐Natal
Derek H. Chu, MD London, ON, Canada Durban, South Africa
Clinical Assistant Professor of Dermatology

and Pediatrics Christopher P. Denton, PhD, Jean Donadieu, MD, PhD
Stanford University School of Medicine FRCP Service d’Hémato‐Oncologie Pédiatrique
Palo Alto, CA, USA Registre des Histiocytoses
Professor of Experimental Rheumatology
Centre de Référence des Histiocytoses
Centre for Rheumatology
Antonio A.T. Chuh, MD Hopital Trousseau
Royal Free Hospital and UCL Division of
Paris, France
Department of Family Medicine Medicine
and Primary Care London, UK
The University of Hong Kong and Queen Dian Donnai, CBE, FMedSci,
Mary Hospital Jackie Denyer FRCP, FRCOG
Pokfulam, Hong Kong Clinical Nurse Specialist in Paediatric Professor of Medical Genetics
JC School of Public Health and Primary Care Dermatology Manchester Centre for Genomic Medicine
The Chinese University of Hong Kong and the Great Ormond Street Hospital St Mary’s Hospital
Prince of Wales Hospital London, UK Manchester University NHS Foundation Trust
Shatin, Hong Kong Manchester, UK
Division of Evolution and Genomic Sciences
Clio Dessinioti
Peter T. Clayton, BA, MBBS, Department of Dermatology
Faculty of Biology Medicine and Health
MSc, MRCP University of Manchester
Andreas Syggros Hospital
Manchester, UK
Professor University of Athens
Institute of Child Health Greece
University College London with Great Carola Durán McKinster, MD
Ormond Street Hospital for Children Tanvi Dev, MD Paediatric Dermatologist and Professor of
NHS Trust Pediatric Dermatology
Senior Resident (Fellow)
London, UK Universidad Nacional Autonoma de México
Head of the Department of Pediatric
All India Institute of Medical Sciences
Kelly M. Cordoro, MD Dermatology
New Delhi, India
National Institute of Paediatrics of Mexico
Associate Professor of Dermatology and
Mexico City, Mexico
Pediatrics Flora B. de Waard‐van der
University of California San Francisco Spek, MD, PhD
San Francisco, CA, USA Jonathan A. Dyer, MD
Paediatric Dermatologist
Associate Professor of Dermatology and
Carrie C. Coughlin, MD Child Health
Franciscus Gasthuis and Vlietland
Departments of Dermatology and Child Health
Assistant Professor Rotterdam/Schiedam, The Netherlands
University of Missouri
Division of Dermatology
Columbia, MO, USA
Department of Medicine and Department of Sandipan Dhar, MBBS, MD,
Pediatrics
DNB, FRCP(Edin) Lawrence F. Eichenfield, MD
Washington University School of Medicine
Professor and Head
St Louis, MO, USA Professor of Clinical Dermatology
Department of Pediatric Dermatology
Pediatric and Adolescent Dermatology
Institute of Child Health
Coleen K. Cunningham Rady Children’s Hospital
Kolkata, West Bengal, India
San Diego University of California
Department of Pediatrics and Dermatology
San Diego School of Medicine
Duke University Medical Center Wei‐Li Di, MBBS, PhD San Diego, CA, USA
Durham, NC, USA
Associate Professor in Skin Biology
Infection, Immunity and Inflammation
Benjamin S. Daniel Programme
Department of Dermatology Immunobiology Section
St George Hospital and University of New Institute of Child Health
South Wales University College London
Sydney, NSW, Australia London, UK
xiv List of Contributors
Despina Eleftheriou, MBBS, Gayle O. Fischer, MBBS, FACD, Pamela Gangar, MD

PhD, MRCPCH MD Resident Physician
Associate Professor in Paediatric Rheumatology Associate Professor in Dermatology University of Arizona Department of Pediatrics
Infection, Inflammation and Rheumatology The Northern Clinical School Tucson, AZ, USA
Section The University of Sydney
UCL Institute of Child Health Sydney, NSW, Australia María Teresa García‐Romero,
Paediatric Rheumatology Department, Great MD, MPH
Ormond Street Hospital for Children NHS Carsten Flohr, MD, PhD Attending Physician
Foundation Trust
Professor of Dermatology Department of Dermatology
Arthritis Research UK Centre for Adolescent
Unit for Population‐Based Dermatology National Institute for Pediatrics
Rheumatology
Research Member of the National System of Researchers
London, UK
St John’s Institute of Dermatology Mexico City, Mexico
Guy’s and St Thomas’ NHS Foundation Trust
Brian Eley, BSc (Hons) (Med and King’s College Maria C. Garzon, MD
Biochem), MBChB (Cape Town), London, UK
Columbia University Medical Center
FCP (SA) New York, NY, USA
Professor of Paediatric Infectious Diseases Kerstin Foitzik‐Lau, MD
University of Cape Town Physician
South Africa
Diane Gbesemete, BM,
Skin and Vein Clinic Winterhude
Hamburg, Germany
MRCPCH, PGDipID
Clinical Research Fellow
Steffen Emmert, MD
NIHR Southampton Clinical Research Facility
Professor of Dermatology Emma J. Footitt, MB, BS, BSc, University of Southampton and University
Director PhD Hospital Southampton NHS Foundation Trust
Clinic for Dermatology and Venereology
Institute of Child Health Southampton, UK
University Medical Center Rostock
University College London with Great Ormond
Rostock, Germany
Street Hospital for Children NHS Trust Carlo M. Gelmetti
London, UK
Professor of Dermatology and Venereology
Herman Jan H. Engelkens, MD,
Department of Pathophysiology and
PhD Sylvie Fraitag, MD Transplantation
Department of Dermatology and Venereology Dermatopathologie Pédiatrique Università degli Studi di Milano
Ikazia Hospital Service d’Anatomo‐Pathologie Head
Rotterdam, The Netherlands Hôpital Necker‐Enfants Malades Unit of Pediatric Dermatology
Paris, France Fondazione IRCCS Ca’ Granda ‘Ospedale
Sibel Ersoy‐Evans, MD Maggiore Policlinico’
Professor of Dermatology Jorge Frank, MD Milan, Italy
Hacettepe University School of Medicine Professor of Dermatology
Department of Dermatology Department of Dermatology, Venereology Karolina Gholam, MBSS, MSc,
Ankara, Turkey and Allergology FRCPCH, SCEderm
University Medical Center Göttingen Consultant Paediatric Dermatologist
Peter A. Farndon, MSc, MD, Göttingen, Germany Great Ormond Street Hospital
FRCP London, UK
Professor of Clinical Genetics (Retired) llona J. Frieden, MD
University of Birmingham Professor of Dermatology and Pediatrics Mary Glover, MA, FRCP, FRCPCH
Birmingham, UK Division of Pediatric Dermatology Consultant Paediatric Dermatologist
San Francisco School of Medicine Great Ormond Street Hospital for Children
Saul N. Faust, FRCPCH, PhD University of California NHS Foundation Trust
San Francisco, CA, USA London, UK
Professor of Paediatric Immunology and
Infectious Diseases and Director of the NIHR
Southampton Clinical Research Facility Sheila Fallon Friedlander, MD Maria Gnarra, MD, PhD
University of Southampton and University Professor of Dermatology and Pediatrics Research Fellow
Hospital Southampton NHS Foundation Trust Department of Pediatric and Adolescent Paediatric Dermatology
Southampton, UK Dermatology Great Ormond Street Hospital for Children
Rady Children’s Hospital NHS Trust
Andrew Y. Finlay, CBE, FRCP San Diego, CA, USA London, UK
(Lond. and Glasg.)
Professor of Dermatology Hassan Galadari, MD Alina Goldenberg, MD
Division of Infection and Immunity Associate Professor Resident in‐training
Cardiff University School of Medicine College of Medicine and Health Science Department of Dermatology
Cardiff, UK United Arab Emirates University University of California
Al Ain, United Arab Emirates San Diego, CA, USA
List of Contributors xv
Bernardo Gontijo, MD, PhD John Harper, MBBS, MD, FRCP, Bernhard Herrmann, MD
Professor of Dermatology FRCPCH Consultant
Federal University of Minas Gerais Honorary Professor of Paediatric Child Protection Center
Medical School Dermatology Pediatric and Adolescent Gynecology
Belo Horizonte, MG, Brazil Great Ormond Street Hospital for Children Department of Pediatrics
NHS Trust Klinikum Kassel
Helen M. Goodyear, MB, ChB, London, UK Kassel, Germany
FRCP, FRCPCH, MD, MMEd, MA

Health Education England (West Midlands) Stephen Hart, PhD Robert S. Heyderman, PhD,
Associate Postgraduate Dean Professor in Molecular Genetics FRCP, DTM & H
Heart of England NHS Foundation Trust Experimental and Personalised Medicine Professor of Infectious Diseases
Birmingham, UK UCL Great Ormond Street Institute of University College London
Child Health London, UK
Jeremy A. Goss, MD London, UK
Research Fellow Warren R. Heymann, MD

Department of Plastic and Oral Surgery Nico G. Hartwig, MD, PhD Head, Division of Dermatology,
Vascular Anomalies Center Department of Paediatrics Clinical Professor of Dermatology
Boston Children’s Hospital Franciscus Gasthuis & Vlietland University of Pennsylvania School of
Harvard Medical School Rotterdam, The Netherlands Medicine
Boston, MA, USA Professor of Medicine and Paediatrics
Christina Has, MD University of Medicine and Dentistry of
Yvonne Gräser, PhD New Jersey
Consultant Dermatologist and Professor
Robert Wood Johnson Medical School
Professor of Molecular Mycology Molecular Dermatology
Camden, NJ, USA
The National Reference Laboratory for Medical Center
Dermatophytes University of Freiburg
Universitätsmedizin – Charité Freiburg, Germany Hannah Hill, MD
Institute of Microbiology and Hygiene Resident in‐training
Berlin, Germany Elena B. Hawryluk, MD, PhD Department of Dermatology
Mayo Clinic
Arin K. Greene, MD, MMSc Scottsdale, AZ, USA
Massachusetts General Hospital
Professor of Surgery Harvard Medical School;
Department of Plastic and Oral Surgery Dermatology Program Sarah Hill, MBChB, FRACP
Vascular Anomalies Center Division of Allergy and Immunology Paediatric and General Dermatologist
Boston Children’s Hospital Department of Medicine Department of Dermatology
Harvard Medical School Boston Children’s Hospital Waikato Hospital
Boston, MA, USA Harvard Medical School Hamilton, New Zealand
Boston, MA, USA
Leopold M. Groesser, Dr med. Sharleen F. Hill, BM BSc MRCP
Department of Dermatology R.M. Ross Hearn Dermatology Clinical Research Fellow
University of Regensburg Department of Dermatology and St George Hospital
Regensburg, Germany Photobiology Conjoint Associate Lecturer
Ninewells Hospital and Medical School University of New South Wales
Robert Gruber, MD Dundee, UK Sydney, NSW, Australia
Department of Dermatology and Division of

Human Genetics Daniel Heinl, MD Peter H. Hoeger, MD
Medical University of Innsbruck Medical Sociology Professor of Paediatrics and Dermatology
Innsbruck, Austria Institute of Epidemiology and Preventive (University of Hamburg)
Medicine Head, Departments of Paediatrics and
Christian Hafner, Dr med. University of Regensburg Dermatology
Regensburg, Germany Catholic Children’s Hospital, Wilhelmstift
Professor of Dermatology
Hamburg, Germany
University of Regensburg Angela Hernández, MD
Regensburg, Germany Department of Dermatology Karen A. Holbrook, MD
Hospital Infantil del Niño Jesús (Retired)
Henning Hamm, MD Madrid, Spain Department of Physiology and Cell Biology
Ohio State University
Sergio Hernández‐Ostiz, MD Columbus, OH, USA
Department of Dermatology, Venereology and
Allergology Department of Dermatology
University Hospital Würzburg Hospital Infantil del Niño Jesús
Würzburg, Germany Madrid, Spain
xvi List of Contributors
Gregor Holzer, MD Arun C. Inamadar, MD, FRCP Ayşen Karaduman, MD

Department of Dermatology Professor and Head
Donauspital SMZ Ost Department of Dermatology,
Hacettepe University School of Medicine
Vienna, Austria Venereology & Leprosy
Sri B.M.Patil Medical College
Ankara, Turkey
Hospital & Research Centre
Erhard Hölzle, MD BLDE University
Professor of Dermatology Vijayapur, Karnataka, India Andreas Katsambas
Director Professor of Dermatology
Department of Dermatology and Allergology
University Hospital
Matilde Iorizzo, MD Department of Dermatology
Andreas Syggros Hospital
Oldenburg, Germany Private Dermatology Practice
University of Athens
Bellinzona and Lugano
Greece
Switzerland
Kam Lun Ellis Hon, MBBS,
MD, FAAP, FCCM, FHKCPaed, Roselyn Kellen, MD
Alan D. Irvine, MD, FRCPI, FRCP
FHKAM(Paed) Resident Physician
Professor
Honorary Professor Icahn School of Medicine at Mount Sinai
Paediatric Dermatology
Department of Paediatrics, The Chinese New York, NY, USA
Trinity College Dublin and Our Lady’s
University of Hong Kong
Children’s Hospital
Consultant
The Hong Kong Children’s Hospital
Dublin, Ireland Hilary Kennedy
Hong Kong Clinical Nurse Specialist in Paediatric
Sharon E. Jacob, MD Dermatology
Professor Great Ormond Street Hospital
Paul J. Honig, MD London, UK
Loma Linda University
Denver Children’s Hospital
Denver, CO, USA
Loma Linda, CA, USA David W. Kimberlin, MD
Department of Pediatrics Department of Pediatrics
Perelman School of Medicine at the University Scott H. James, MD Division of Infectious Diseases
of Pennsylvania Department of Paediatrics University of Alabama
Philadelphia, PA, USA Division of Infectious Diseases Birmingham, AL, USA
University of Alabama
Kimberly A. Horii, MD Birmingham, AL, USA Veronica A. Kinsler, MA, MB,
Associate Professor of Pediatrics BChir, FRCPCH, PhD
Division of Dermatology Gregor B.E. Jemec, MD, DMSc Professor of Paediatric Dermatology and
University of Missouri‐Kansas City School Department of Dermatology Dermatogenetics
of Medicine Roskilde Hospital Paediatric Dermatology Department
Children’s Mercy‐Kansas City Roskilde, Denmark Great Ormond Street Hospital for Children
Kansas City, MO, USA NHS Foundation Trust
Genetics and Genomic Medicine
Elizabeth A. Jones, MA MB,
UCL Great Ormond Street Institute of
Jennifer Huang, MD BChir, FRCP, PhD Child Health
Assistant Professor of Dermatology Consultant Clinical Geneticist London, UK
Dermatology Program Manchester Centre for Genomic Medicine
Boston Children’s Hospital St Mary’s Hospital
Boston, MA, USA Manchester University NHS Foundation Trust
Bruce R. Korf, MD, PhD
Manchester, UK Professor and Chairman of Department
of Genetics
Devika Icecreamwala, MD Division of Evolution and Genomic Sciences
Faculty of Biology Medicine and Health University of Alabama at Birmingham
Pediatric Dermatology Fellow
University of Manchester Birmingham, AL, USA
Henry Ford Health System Manchester, UK
Detroit, MI, USA Andrew C. Krakowski, MD
Teri A. Kahn, MD, MPH Chief
Ying Liu, MD, PhD Associate Professor
Department of Dermatology St Luke’s University Health Network
Associate Chief Physician
University of Maryland Easton, PA, USA
Beijing Children’s Hospital Baltimore, MD, USA
Capital Medical University Ann M. Kulungowski, MD
National Center for Children’s Health Sonia Kamath, MD Assistant Professor of Surgery and Pediatrics
Beijing, China Resident Physician University of Colorado School of Medicine
Department of Dermatology Surgical Director
Keck School of Medicine of University of Vascular Anomalies Center
Southern California Children’s Hospital Colorado
Los Angeles, CA, USA Aurora, CO, USA
List of Contributors xvii
Marc Lacour, MD Ting Fan Leung, MBChB(CUHK), Pediatrics and Pediatric Dermatology
MD(CUHK), MRCP(UK), FRCPCH, Cincinnati Children’s Hospital
Paediatrician
Cincinnati, OH, USA
Pediatric Dermatology Clinic FAAAAI, FHKCPaed,
Carouge, Switzerland FHKAM(Paediatrics)
David Luk, FHKAM(Paed),
Chairman and Professor
Bisola Laguda Department of Paediatrics FHKCPaed, FRCPCH
Consultant The Chinese University of Hong Kong Consultant Paediatrician
Paediatric Dermatology Hong Kong United Christian Hospital, Hong Kong
Chelsea and Westminster Hospital Hong Kong Children’s Hospital
Honorary Clinical Assistant Professor
London, UK Michael Levin, FRCPCH, PhD The Chinese University of Hong Kong
Professor of Paediatrics and International The University of Hong Kong
Sinéad M. Langan, MD, PhD Child Health President
Associate Professor of Epidemiology Imperial College London Hong Kong Paediatric and Adolescent
Faculty of Epidemiology and Population Health London, UK Dermatology Society
London School of Hygiene and Tropical
Medicine Moise L. Levy, MD Jane Luker, BDS, PhD, FDSRCS
London, UK
Professor Eng @ Edin DDR, RCR
Department of Pediatrics
Consultant Dental Surgeon
Sean Lanigan, MD, FRCP, DCH Texas Children’s Hospital
Bristol Dental Hospital
Regional Medical Director Baylor College of Medicine
University Hospitals Bristol NHS Foundation
sk:n Limited Houston, TX, USA
Trust
Birmingham, UK Department of Pediatrics
Bristol, UK
Dell Medical School/University of Texas and
Dell Children’s Medical Center
Irene Lara‐Corrales, MD Paula Carolina Luna, MD
Austin, TX, USA
Associate Professor of Pediatrics Dermatology Department
Pediatric Dermatology Fellow Hospital Alemán
Section of Dermatology Rebecca Levy, MD, FRCPC
Buenos Aires, Argentina
Division of Paediatric Medicine Clinical Fellow
Hospital for Sick Children Pediatric Dermatology
University of Toronto University of Toronto Minnelly Luu, MD
Toronto, ON, Canada The Hospital for Sick Children Assistant Professor of Clinical Dermatology
Toronto, ON, Canada Department of Dermatology
Keck School of Medicine of University of
Margarita Larralde, PhD, MD
Susan Lewis‐Jones, FRCP, Southern California
Head Los Angeles, CA, USA
Dermatology Department FRCPCH Division of Pediatric Dermatology
Hospital Alemán Honorary Consultant Dermatologist Children’s Hospital Los Angeles
Head Ninewells Hospital & Medical School Los Angeles, CA, USA
Pediatric Dermatology Department Dundee, UK
Hospital Ramos Mejía
Buenos Aires, Argentina Lin Ma, MD, PhD
Carmen Liy Wong Professor, Director
Pediatric Dermatology Fellow Department of Dermatology
Christine T. Lauren, MD Section of Dermatology Beijing Children’s Hospital
Assistant Professor of Dermatology and Division of Paediatric Medicine Capital Medical University
Pediatrics Hospital for Sick Children National Center for Children’s Health
Columbia University Medical Center Toronto, ON, Canada Beijing, China
New York, NY, USA
Wilson Lopez, MBBS, MD, MRCP, Elia F. Maalouf, MBChB, MRCP,
S. Leclerc‐Mercier, MD FRCPCH, DCH, MSc FRCPCH, MD
Reference Center for Rare and Inherited Skin Consultant Neonatologist Consultant in General Paediatrics and
Diseases (MAGEC) Neonatal Unit Neonatal Medicine
Departments of Dermatology and Pathology Barking, Havering and Redbridge University Neonatal Unit
CHU Necker‐Enfants Malades Hospitals NHS Trust Homerton University Hospital NHS
Paris, France UK Foundation Trust
London, UK
Theresa Ngan Ho Leung, Christopher Lovell
MBBS, FRCPCH, FHKCPaed, Consultant Dermatologist Caroline Mahon, MD
FHKAM(Paed) Kinghorn Dermatology Unit Consultant Paediatric Dermatologist
Clinical Associate Professor Royal United Hospital Department of Dermatology
Department of Paediatrics and Adolescent Bath, UK Bristol Royal Infirmary
Medicine University Hospitals Bristol NHS Foundation Trust
The University of Hong Kong Anne W. Lucky, MD Bristol, UK
Hong Kong
Adjunct Professor of Pediatrics and Dermatology
Divisions of General and Community
xviii List of Contributors
Melanie Makhija, MD, MSc Jemima E. Mellerio, MD, FRDP Dermatology

Reference Center for Rare Skin Diseases
Assistant Professor of Pediatrics Consultant Dermatologist and Honorary
Hôpital Saint André
Department of Pediatrics Professor
Bordeaux, France
Northwestern University Paediatric Dermatology Department
Feinberg School of Medicine, Great Ormond Street Hospital for Children
Chicago, IL, USA NHS Trust Keith Morley, MD
and St John’s Institute of Dermatology Paediatric Dermatology Fellow
Steven M. Manders, MD Guy’s and St Thomas’ NHS Foundation Trust Dermatology Program
London, UK Boston Children’s Hospital
Professor of Medicine and Paediatrics
Boston, MA, USA
University of Medicine and Dentistry of New Bodo C. Melnik, MD
Jersey Adjunct Professor of Dermatology Dédée F. Murrell,
Robert Wood Johnson Medical School Department of Dermatology, Environmental MA(Cambridge), BMBCh (Oxford),
Camden, NJ, USA Medicine and Health Theory FAAD(USA), MD (UNSW), FACD,
University of Osnabrück
FRCP(Edin)
Julianne A. Mann, MD Osnabrück, Germany
Head
Assistant Professor of Dermatology Department of Dermatology
Dartmouth‐Hitchcock Medical Center Vibhu Mendiratta, MD St George Hospital
Lebanon, NH, USA Director and Professor Professor of Dermatology
Department of Dermatology University of New South Wales
Lady Hardinge Medical College and Sydney, NSW, Australia
Ashfaq A. Marghoob, MD
associated hospitals
Memorial Sloan‐Kettering Cancer Center
New Delhi, India Taizo A. Nakano, MD
New York, NY, USA Assistant Professor of Pediatrics
Eirini E. Merika, MBBS, iBSc, University of Colorado School of Medicine
Maria L. Marino, MD MRCP Derm Medical Director

Consultant Paediatric Dermatologist Vascular Anomalies Center
Department of Dermatology Children’s Hospital Colorado
Chelsea and Westminster Hospital
Memorial Sloan‐Kettering Cancer Center Aurora, CO, USA
London, UK
New York, NY, USA
Christian R. Millett, MD Iria Neri

Anna E. Martinez, FRCPCH Professor of Dermatology
Forefront Dermatology
Consultant Paediatric Dermatologist Department of Specialized, Diagnostic and
Vienna, VA, USA
Paediatric Dermatology Department Experimental Medicine
Great Ormond Street Hospital for Children Division of Dermatology
NHS Trust Adnan Mir, MD, PhD University of Bologna
London, UK Assistant Professor of Dermatology Bologna, Italy
University of Texas Southwestern Medical
Peter Mayser, MD Center and Children’s Medical Center Dallas
Tuyet A. Nguyen, MD
Dallas, TX, USA
Professor of Dermatology Kaiser Permanente Dermatology
Clinic of Dermatology, Allergology and Los Angeles, CA, USA
Venereology Amanda T. Moon, MD
Justus Liebig University (UKGM) Departments of Pediatrics and Dermatology
Giessen, Germany Jeroen Novak
Perelman School of Medicine at the University
of Pennsylvania GGZ Momentum
Breda, The Netherlands
Juliette Mazereeuw‐Hautier, Philadelphia, PA, USA
MD, PhD Section of Dermatology
Children’s Hospital of Philadelphia Susan O’Connell, MD
Philadelphia, PA, USA Formerly Lyme Borreliosis Unit
Reference Center for Rare Skin Diseases
Department of Dermatology Health Protection Agency Microbiology
CHU Larrey Elena Moraitis, MBBS, PhD Laboratory
Toulouse, France Consultant in Paediatric Rheumatology Southampton University Hospitals NHS Trust
Infection, Inflammation and Rheumatology Southampton, UK
William H. McCoy IV, MD, PhD Section

UCL Institute of Child Health Cathal O’Connor, MD
Resident Physician
London, UK Paediatric Dermatology
Paediatric Rheumatology Department Trinity College Dublin and Our Lady’s
Department of Medicine
Great Ormond Street Hospital for Children Children’s Hospital
Washington University School of Medicine
NHS Foundation Trust Dublin, Ireland
St Louis, MO, USA
London, UK
Vinzenz Oji, MD
Fanny Morice‐Picard, MD, PhD Department of Dermatology
Department of Dermatology and Paediatric University Hospital Münster
Münster, Germany
List of Contributors xix
Elise A. Olsen, MD Aparna Palit, MD Laura Polivka, MD, PhD

Professor of Dermatology and Medicine Professor Department of Dermatology
Director, Cutaneous Lymphoma Research and Department of Dermatology Imagine Institute
Treatment Center Venereology and Leprosy Necker‐Enfants Malades Hospital
Director, Hair Disorders Research and Sri B.M.Patil Medical College Paris, France
Treatment Center Hospital & Research Centre
Director, Dermatopharmacology Study Center BLDE University Elena Pope, MSc, FRCPC
Departments of Dermatology and Medicine Vijayapur, Karnataka, India
Professor of Paediatrics
Duke University Medical Center
University of Toronto
Durham, NC, USA Amy S. Paller, MD, MSc Fellowship Director and Section Head
Walter J. Hamlin Professor and Chair of Paediatric Dermatology
Kai Ren Ong, MD, MRCP Dermatology, Professor of Pediatrics The Hospital for Sick Children
Consultant Clinical Geneticist Departments of Pediatrics and Dermatology Toronto, ON, Canada
West Midlands Regional Clinical Genetics Service Northwestern University
Birmingham Women’s Hospital Feinberg School of Medicine Julie Powell, MD, FRCPC
Birmingham, UK Chicago, IL, USA
Director
Pediatric Dermatology
Arnold P. Oranje, MD, PhD Nirav Patel, MD Professor of Dermatology (Pediatrics)
(Deceased) Departments of Dermatology and Pediatrics Division of Dermatology
Professor of Pediatric Dermatology Mayo Clinic Department of Pediatrics
Kinderhuid.nl, Rotterdam, The Netherlands Rochester, MN, USA CHU Sainte‐Justine
Hair Clinic, Breda, The Netherlands University of Montreal
Dermicis Skin Clinic, Alkmaar, The Netherlands Annalisa Patrizi, MD Montreal, QC, Canada
Professor
Luz Orozco‐Covarrubias, MD Head of Dermatology Julie S. Prendiville, MBBCH,
Paediatric Dermatologist and Associated Department of Specialized, Diagnostic and DCH, BAO, FRCPC
Professor of Pediatric Dermatology Experimental Medicine, Chief
Universidad Nacional Autonoma de México Division of Dermatology Pediatric Dermatology
Attending Physician University of Bologna Sidra Medicine
Department of Pediatric Dermatology Bologna, Italy Doha, Qatar
National Institute of Paediatrics of Mexico
Mexico City, Mexico Marissa J. Perman, MD Cecilia A.C. (Sanna) Prinsen,
Assistant Professor of Pediatrics and PhD
Edel A. O’Toole, MB, PhD, FRCP, Dermatology VU University Medical Center
FRCPI Children’s Hospital of Philadelphia and Department of Epidemiology and Biostatistics
Professor of Molecular Dermatology and The University of Pennsylvania Amsterdam Public Health Research Institute
Honorary Consultant Dermatologist Philadelphia, PA, USA Amsterdam, The Netherlands
Royal London Hospital Karen Pett Lori Prok, MD
Barts Health NHS Trust and Centre for Cell
Clinical Nurse Specialist in Paediatric Associate Professor of Dermatology and
Biology and Cutaneous Research
Dermatology Pathology
Barts and the London School of Medicine
West Hertfordshire Hospitals NHS Trust University of Colorado Denver and Children’s
and Dentistry
St Albans, UK Hospital Colorado
London, UK
Denver, CO, USA
Roderic J. Phillips, BSc(Hons),
Hagen Ott, MD
MBBS, PhD, FRACP, AMAM, CIRF Neil S. Prose, MD
Head of the Division of Pediatric Dermatology
Associate Professor Professor
and Allergology
Paediatric Dermatologist Department of Pediatrics and Dermatology
Epidermolysis Bullosa Centre Hannover
Royal Children’s Hospital Duke University Medical Center
Children’s Hospital AUF DER BULT
Honorary Research Fellow Research Professor of Global Health, Duke
Hannover, Germany
Murdoch Children’s Research Institute Global Health Institute
Adjunct Professor Co‐Director, Duke Health Humanities Lab
Seza Özen, MD Paediatrics Durham, NC, USA
Professor of Pediatrics Monash University
Hacettepe University School of Medicine Melbourne, VIC, Australia
Department of Pediatric Rheumatology
Diana Purvis, MB ChB, MRCPCH,
Ankara, Turkey FRACP
Bianca Maria Piraccini, MD, PhD Paediatric Dermatologist
Dermatology Starship Children’s Hospital
David G. Paige, MBBS, MA, Department of Experimental, Diagnostic and Honorary Senior Lecturer
FRCP Specialty Medicine Department of Paediatrics
Consultant Dermatologist University of Bologna University of Auckland
Department of Dermatology, Bologna, Italy Auckland, New Zealand
Bart’s and The London NHS Trust
London, UK
xx List of Contributors
Marius Rademaker, BM, Marcelo Ruvertoni, MD Julien Seneschal, MD, PhD

FRCP(Edin), FRACP, DM Paediatric Dermatologist and Paediatrician Professor
Clinical Director British Hospital Department of Dermatology and Paediatric
Dermatology Department Montevideo, Uruguay Dermatology
Waikato District Health Board Reference Center for Rare Skin Diseases
Hon Associate Professor Liat Samuelov, MD Hôpital Saint André
Waikato Clinical Campus Bordeaux, France
Vice Chair
Faculty of Medical and Health Sciences
The University of Auckland
Tel Aviv Sourasky Medical Center G. Sethuraman, MD
Hamilton, New Zealand
Tel Aviv, Israel Professor of Dermatology
Marc Alexander Radtke, MD Sarita Sanke, MD All India Institute of Medical Sciences
Professor New Delhi, India
Dermatology and STD
Institute for Health Services Research in
Lady Hardinge Medical College and
Dermatology and Nursing (IVDP)
associated hospitals Marieke M.B. Seyger, MD, PhD
University Medical Center Hamburg‐
New Delhi, India Associate Professor of Dermatology
Eppendorf (UKE)
Hamburg, Germany
Radboud University Medical Center
Julie V. Schaffer, MD Nijmegen, The Netherlands
V. Ramesh, MD Associate Professor of Pediatrics
Division of Pediatric and Adolescent
Dermatology Lindsay Shaw, MBBS, MRCPCH
Hackensack University Medical Center Consultant in Paediatric Rheumatology
Vardhman Mahavir Medical College &
Hackensack, NJ, USA Paediatric Dermatology
Safdarjung Hospital
Great Ormond Street Hospital for Children
New Delhi, India
NHS Foundation Trust
Birgitta Schmidt, MD London and Bristol Children’s Hospital
Gudrun Ratzinger, MD Department of Pathology Bristol UK
Boston Children’s Hospital
Harvard Medical School
Department of Dermatology, Venereology and
Boston, MA, USA Neil Shear, MD, FRCPC, FACP
Allergology
Professor of Medicine and Pharmacology
Medical University Innsbruck
Austria Enno Schmidt, MD, PhD Sunnybrook Health Sciences Center and
Professor of Dermatology University of Toronto
Wingfield E. Rehmus, MD Lübeck Institute of Experimental Toronto, ON, Canada
Dermatology (LIED)
Clinical Assistant Professor
Lübeck, Germany
Department of Pediatrics Tor A. Shwayder, MD
University of British Columbia and British
Director
Columbia’s Children’s Hospital Steffen Schubert Pediatric Dermatology
Vancouver, BC, Canada Department of Dermatology, Venereology Department of Dermatology
and Allergology Henry Ford Hospital
Sean D. Reynolds, MB BCh, BAO University Medical Center Göttingen Detroit, MI, USA
Göttingen, Germany
Warren Alpert Medical School of Brown Brenda M. Simpson
University Crispian Scully, CBE, DSc, DChD, Dermatologist
Providence, RI, USA DMed (HC), Dhc (multi), MD, PhD, El Paso Dermatology Center
PhD (HC), FMedSci, MDS, MRCS, El Paso, TX, USA
Nerys Roberts, MD, FRCP, BSc, FDSRCS, FDSRCPS, FFDRCSI,
MRCPCH, BSc FDSRCSEd, FRCPath, FHEA Robert Sidbury, MD, MPH
Consultant Paediatric Dermatologist (Deceased) Professor
Chelsea & Westminster Hospital Emeritus Professor of Oral Medicine at UCL Department of Pediatrics
London, UK Bristol Dental Hospital Chief
University Hospitals Bristol NHS Division of Dermatology
Jean Robinson Foundation Trust Seattle Children’s Hospital
Bristol, UK University of Washington School of Medicine
Clinical Nurse Specialist in Paediatric
University College London Seattle, WA, USA
Dermatology
London, UK
Royal London Hospital
London, UK Jonathan I. Silverberg, MD,
Robert K. Semple, PhD, FRCP PhD
Elke Rodriguez, PhD Professor of Translational Molecular Medicine
Associate Professor of Dermatology
Centre for Cardiovascular Sciences, Queens
Senior Researcher Northwestern University Feinberg School
Medical Research Institute
Department of Dermatology, Allergology and of Medicine
University of Edinburgh
Venereology Chicago, IL, USA
Edinburgh, UK
University Hospital Schleswig‐Holstein
Campus Kiel
Kiel, Germany
List of Contributors xxi
Nanette Silverberg, MD Peter M. Steijlen, MD, PhD Amy Theos, MD

Clinical Professor of Dermatology Professor of Dermatology and Chair Associate Professor of Department of
Icahn School of Medicine at Mount Sinai Department of Dermatology Dermatology
Chief Maastricht University Medical Center University of Alabama at Birmingham
Pediatric Dermatology Maastricht, The Netherlands Birmingham, AL, USA
Mount Sinai Health System
Director Jane C. Sterling, MB, BChir, MA, Peter Theut Riis, MD
Pediatric and Adolescent Dermatology
FRCP, PhD Department of Dermatology
Consultant Dermatologist Roskilde Hospital
New York, NY, USA
Department of Dermatology Roskilde, Denmark
Cambridge University Hospitals NHS
Eric L. Simpson, MD Foundation Trust Anna C. Thomas, BSc, PhD
Professor of Dermatology Addenbrooke’s Hospital
Post‐doctoral Research Associate
School of Medicine Cambridge, UK
Genetics and Genomic Medicine
UCL Great Ormond Street Institute of Child
Oregon Health and Science University
Portland, OR, USA
Jenna L. Streicher, MD Health
Clinical Assistant Professor London, UK
Department of Pediatrics, Dermatology Section
Manuraj Singh, MBBS, MRCP, Children’s Hospital of Philadelphia Megha Tollefson, MD
PhD, DipRCPath (Dermpath) Departments of Pediatrics and Dermatology
Departments of Dermatology and Pediatrics
Consultant Dermatologist and Perelman School of Medicine at the University
Mayo Clinic
Dermatopathologist of Pennsylvania
Rochester, MN, USA
St George’s University Hospitals Philadelphia, PA, USA
London, UK
Wynnis L. Tom, MD
V. Reid Sutton, MD
Associate Clinical Professor of Dermatology
Nedaa Skeik, MD, FACP, FSVM, RPVI Professor
and Pediatrics
Associate Professor of Medicine Department of Molecular and Human
University of California, San Diego
Section Head, Vascular Medicine Department Genetics
Rady Children’s Hospital
Medical Director, Thrombophilia & Baylor College of Medicine and Texas
San Diego, CA, USA
Anticoagulation Clinic Children’s Hospital
Medical Director, Hyperbaric Medicine Houston, TX, USA
Medical Director, Vascular Laboratories Yun Tong, MD
Minneapolis Heart Institute at Abbott Clinical Research Fellow
Samira Batul Syed, MBBS, DCH,
Northwestern Hospital – part of Allina Health Department of Dermatology, University of
Minneapolis, MN, USA
DCCH, RCPEd, RCGP, FCM, BTEC California San Diego
Adv LASER, DPD San Diego, CA, USA
Associate Specialist in Paediatrics
Lea Solman, MD, FRCPCH Dermatology
Consultant Paediatric Dermatologist Helga V. Toriello, PhD
Department of Paediatric Dermatology NHS Trust Professor
Great Ormond Street Hospital for Children London, UK Department of Pediatrics/Human
NHS Trust Development
London, UK Michigan State University College of Human
Zsuzsanna Z. Szalai, MD Medicine
Professor and Head Grand Rapids, MI, USA
Eli Sprecher, MD, PhD Department of Pediatric Dermatology
Professor and Chair Heim Pál Children’s Hospital
Department of Dermatology and Deputy Antonio Torrelo, MD
Budapest, Hungary
Director General for Patient Safety Head
Tel Aviv Sourasky Medical Center Department of Dermatology
Frederick Reiss Chair of Dermatology Alain Taïeb, MD, PhD Hospital Infantil del Niño Jesús
Sackler Faculty of Medicine Professor of Dermatology Madrid, Spain
Tel Aviv University Department of Dermatology and Paediatric
Tel Aviv, Israel Dermatology, Reference Center for Rare Skin
Antonella Tosti, MD
Diseases
Hôpital Saint André Department of Dermatology and Cutaneous
Sahana M. Srinivas, DNB, DVD, Bordeaux, France Surgery
FRGUHS (Paediatric Dermatology) Miller Medical School University of Miami
Consultant Paediatric Dermatologist Miami, FL, USA
Department of Pediatric Dermatology
Carolina Talhari, MD, PhD
Adjunct Professor of Dermatology
Indira Gandhi Institute of Child Health James R. Treat, MD
Bangalore, Karnataka, India Amazon State University
Manaus, AM, Brazil Associate Professor of Clinical Pediatrics and
Dermatology
Paola Stefano, MD Fellowship Director, Pediatric Dermatology
Martin Theiler, MD Education Director, Pediatric Dermatology
Assistant Physician
Dermatology Department Paediatric Dermatology Department Children’s Hospital of Philadelphia
Hospital de Pediatría ‘Prof. Dr. Juan P. Garrahan’ University Children’s Hospital Zurich Dermatology Section
Buenos Aires, Argentina Switzerland Perelman School of Medicine at the University
of Pennsylvania
Philadelphia, PA, USA
xxii List of Contributors
Stephen K. Tyring, MD, PhD Peter von den Driesch, MD Miriam Weinstein, BSc, BScN,
Clinical Professor Professor of Dermatology MD, FRCPC (Paediatrics) FRCPC
Department of Dermatology Head (Dermatology)
University of Texas Health Science Center Center for Dermatology Department of Paediatrics
at Houston Klinikum Stuttgart Hospital for Sick Children
Houston, TX, USA Stuttgart, Germany Toronto, ON, Canada
Nina van Beek, MD Amy Walker, MRes, BSc Pamela F. Weiss, MD, MSCE
Department of Dermatology Experimental and Personalised Medicine Associate Professor of Pediatrics and
University of Lübeck UCL Great Ormond Street Institute of Epidemiology
Lübeck, Germany Child Health Divison of Rheumatology
London, UK Children’s Hospital of Philadelphia
Ignatia B. Van den Veyver, MD Center for Clinical Epidemiology and
Professor Lachlan Warren Biostatistics
Departments of Obstetrics and Gynecology Consultant Dermatologist University of Pennsylvania
and Molecular and Human Genetics Department of Dermatology Philadelphia, PA, USA
Director of Clinical Prenatal Genetics Women’s & Children’s Hospital
BCM and Texas Children’s Hospital Pavilion Adelaide, SA, Australia Alexis Weymann Perlmutter,
for Women MD
Investigator Joy Wan, MD, MSCE Resident
Jan and Dan Duncan Neurological Research
Postdoctoral Fellow of Dermatology Department of Dermatology
Institute at Texas Children’s Hospital
Department of Biostatistics and Epidemiology Geisinger Medical Center
Baylor College of Medicine
University of Pennsylvania Perelman School PA, USA
Houston, TX, USA
of Medicine
Philadelphia, PA, USA Lizbeth Ruth Wheeler
Maurice A.M. van Steensel,
MD, PhD Siriwan Wananukul, MD St George Hospital and University of New
Professor of Dermatology and Skin Biology South Wales
Professor of Paediatrics
Lee Kong Chian School of Medicine Sydney, NSW, Australia
Head of Department of Paediatrics
Singapore
Faculty of Medicine
Research Director
Skin Research Institute of Singapore
Chulalongkorn University Hywel C. Williams, MD, PhD
Bangkok, Thailand
Singapore Director of the NIHR Health Technology
Assessment Programme
Andrew Wang, MD Co‐Director of the Centre of Evidence Based
Felipe Velasquez, MD Dermatology
Brookline Dermatology Associates
Consultant in Pediatric Dermatology University of Nottingham
West Roxbury
Department of Pediatric Dermatology Nottingham, UK
MA, USA
Instituto de Salud del Niño
Lima, Peru
Lisa L. Wang, MD Lara Wine Lee, MD, PhD
Associate Professor Departments of Dermatology and Pediatrics
Paul Veys Medical University of South Carolina
Department of Pediatrics
Director Charleston, SC, USA
Texas Children’s Hospital
Bone Marrow Transplantation Unit
Baylor College of Medicine
NHS Trust
Houston, TX, USA Marion Wobser, MD
London, UK Department of Dermatology, Venereology and
Bettina Wedi, MD, PhD Allergology
Professor of Dermatology University Hospital Würzburg
Miikka Vikkula, MD, PhD Würzburg, Germany
Department of Dermatology and Allergology
Head of Laboratory of Human Molecular
Hannover Medical School
Genetics
de Duve Institute
Hannover, Germany Johannes Wohlrab, MD
University of Louvain Professor of Dermatology
Brussels, Belgium Lisa Weibel, MD Department of Dermatology and Venereology
Paediatric Dermatology Department and Institute of Applied Dermatopharmacy
University Children’s Hospital Zurich Martin‐Luther‐University Halle‐Wittenberg
Beatrix Volc‐Platzer, MD Halle (Saale), Germany
Switzerland
Donauspital SMZ Ost Stephan Weidinger, MD A. Wolkerstorfer, MD, PhD
Vienna, Austria Professor of Dermatology Netherlands Institute for Pigment Disorders
Deputy Head Amsterdam University Medical Centers
Department of Dermatology, Allergology and Amsterdam, The Netherlands
Venereology
University Hospital Schleswig‐Holstein
Campus Kiel
Kiel, Germany
List of Contributors xxiii
Heulwen Wyatt Albert C. Yan, MD, FAAP, FAAD Bernhard W.H. Zelger, MD,
Clinical Nurse Specialist in Paediatric Section of Dermatology MSc
Dermatology Children’s Hospital of Philadelphia Professor of Dermatology
Dermatology Unit Philadelphia, PA, USA Department of Dermatology, Venereology and
St Woolos Hospital, Departments of Pediatrics and Dermatology Allergology
Newport, UK Perelman School of Medicine at the University Medical University Innsbruck
of Pennsylvania Austria
Yuanyuan Xiao, MD Philadelphia, PA, USA
Associate Chief Physician

Department of Dermatology Kevin B. Yarbrough, MD
Beijing Children’s Hospital Staff Physician
Capital Medical University Department of Pediatric Dermatology
National Center for Children’s Health Phoenix Children’s Hospital
Beijing, China Phoenix, AZ, USA
Zhe Xu, MD, PhD Vijay Zawar, MD

Chief Physician Skin Diseases Centre
Department of Dermatology Nashik, India
Beijing Children’s Hospital Professor
Capital Medical University Department of Dermatology
National Center for Children’s Health MVP’s Dr Vasantrao Pawar Medical College
Beijing, China and Research Centre
Nashik, Maharashtra, India
xxiv
Preface to the Fourth Edition
It is with much delight and pride that we present the The fourth edition appears at a time when digital instant
fourth edition of this textbook. The new edition continues access to information, retrievable anywhere and at anytime,
to provide state‐of‐the‐art information on all aspects of is the norm. Nevertheless, the value of having a physical
skin disease in children. Existing content has been textbook to read and study remains an integral part of clini-
refreshed and fully updated to reflect emerging thinking cal practice and academia; but, in order to keep up to date,
and to incorporate the latest in research and clinical the book will also be accessible online on an interactive plat-
data – especially at the genetic level. The three Editors, form via laptops and smartphones. The book’s virtue is, in
two Editorial Advisors and five Associate Editors from our opinion, its comprehensiveness and in‐depth informa-
across the world bring a truly global perspective to the tion written by international experts on each subject.
work. Some 31 countries are represented by 313 We hope that this fourth edition will be as warmly
contributors, of whom 192 are new contributors, who received as its three predecessors and will contribute to
have extensively updated or completely rewritten the 177 the improved care of children with skin diseases.
chapters. The book represents a definitive reference text PH
for dermatologists, paediatricians, clinician scientists, VK
research workers and all other individuals involved in the AY
care of children with skin disease. JIH
xxv
Dedication
In memory of Arnold P. Oranje, 1948–2016
This 4th edition of the textbook is dedicated to my dear friend and colleague Arnold Oranje. Arnold’s untimely death
shocked us all and is a great loss to the world of paediatric dermatology. He was one of the three original editors of this
book, with Neil Prose and myself, and was working on this edition at the time of his death.
On a personal note, my collaboration with Arnold was unique: his enthusiasm, passion for the subject, expertise and exuber-
ant laughter made him a joy to work with. I hope that Arnold would be immensely proud of this new edition.
John Harper
Taïeb A, Stalder J‐F, de Waard‐van der Spek F, Harper J. In Memoriam: Arnold P. Oranje. Pediatr Dermatol 2017; 34: 231–4.
xxvi
Acknowledgements
We wish to thank the following people: the Associate However, the biggest thank you has to be to our patients
Editors and chapter authors for their invaluable contri- who provide the inspiration and motivation for our work
bution to the book; the editorial staff and production on a daily basis.
staff at Wiley‐Blackwell, freelance project editor, Alison PH
Nick, project manager, Nik Prowse, and the copy-editors VK
for their tireless efforts; the families who gave permis- AY
sion for the photographs of their children to be used in JIH
this book and our own families for their understanding
and support.
xxvii
List of Abbreviations
AA alopecia areata AMMoL acute myelomonocytic leukaemia

AA amyloid A AMN acquired melanocytic naevi
AAD American Academy of Dermatology AMoL acute monocytic leukaemia
AAV adeno‐associated virus AMP antimicrobial peptide
AAV antineutrophil cytoplasmic antibody (ANCA)‐ AMPK adenosine monophosphate‐activated protein kinase
associated vasculitides AN acanthosis nigricans
ABC ATP‐binding cassette ANA antinuclear antibody
ACA acrodermatitis chronica atrophicans ANCA antineutrophilic cytoplasmic antibody
ACA anticentromere antibodies AP actinic prurigo
ACC aplasia cutis congenita AP adaptor protein complex
ACD allergic contact dermatitis AP anteroposterior
ACD amyloidosis cutis dyschromica APC antigen‐presenting cell
ACE angiotensin‐converting enzyme APECED autoimmune polyendocrinopathy–candidiasis–
aCGH array‐comparative genomic hybridization ectodermal dystrophy (syndrome)
ACR American College of Rheumatology APL acquired partial lipoatrophy
ACS Aicardi–Goutiéres syndrome APL atrichia with papular lesions
ACTH adrenocorticotropic hormone APP atrophoderma of Pasini and Pierini
AD atopic dermatitis APS antiphospholipid antibody syndrome
AD autosomal dominant APSS acral peeling skin syndrome
ADA adenosine deaminase AR androgen receptor
ADCL autosomal dominant cutis laxa AR autosomal recessive
ADCL anergic diffuse cutaneous leishmaniasis ARC arthrogryposis–renal dysfunction–cholestasis
ADHD attention deficit hyperactivity disorder (syndrome)
ADR adverse drug reaction ARCI autosomal recessive congenital ichthyosis
ADM atypical dermal melanocytosis ARCL autosomal recessive cutis laxa
ADULT acro‐dermato‐ungual‐lacrimal‐tooth ARD adult Refsum disease
ADWH autosomal‐dominant woolly hair AR‐HIES autosomal recessive hyperimmunoglobulin E
AEC ankyloblepharon, ectodermal defects and cleft lip/ syndrome
palate ARKID autosomal recessive keratoderma ichthyosis and
AEDS atopic eczema/dermatitis syndrome deafness (syndrome)
AEI annular epidermolytic ichthyosis ARMS amplification‐refractory mutation system
AFB acid‐fast bacilli ASD autism spectrum disorders
AGA androgenetic alopecia ASM aggressive systemic mastocytosis
AGEP acute generalized exanthematous pustulosis ASO antistreptolysin O
aGVHD acute GVHD ASPS alveolar soft part sarcoma
AGL acquired generalized lipoatrophy ASST autologous serum skin test
AGM acrylate gelling material AST aspartate transaminase
AHA American Heart Association AST aspartate aminotransferase
AHA antihistone antibody AT ataxia telangiectasia
AHEI acute haemorrhagic oedema of infancy ATG anti‐thymocyte globulin
AHO Albright hereditary osteodystrophy ATGL adipose triglyceride lipase
AHT abusive head trauma ATP adenosine triphosphate
AID autoinflammatory disease ATPase adenosine triphosphatase
AIDS acquired immune deficiency syndrome ATS arterial tortuosity syndrome
AIP acute intermittent porphyria ATT antitubercular therapy
ALHE angiolymphoid hyperplasia with eosinophilia AUC area under the concentration‐time curve
ALL acute lymphoblastic leukaemia AUG acute ulcerative gingivitis
ALN actinic lichen nitidus AV arteriovenous
ALP actinic lichen planus AVF arteriovenous fistula
ALT alanine transaminase AVM arteriovenous malformations
ALU aphthous‐like ulceration AV atrophoderma vermiculata
AML acute myeloid leukaemia AZA azathioprine
xxviii List of Abbreviations
BAL bronchoalveolar lavage CFU colony‐forming unit

BB β‐blockers CGD chronic granulomatous disease
BCC basal cell carcinoma CGH comparative genomic hybridization
BCG bacillus Calmette–Guérin CGL congenital generalized lipodystrophy
BCIE bullous congenital ichthyosiform erythroderma CGRP calcitonin gene‐related product
BD Behçet disease CGS contiguous gene syndrome
BDCS Bazex–Dupré–Christol syndrome cGVHD chronic graft versus host disease
BDD blistering distal dactylitis CH congenital haemangiomas
BDNG British Dermatological Nursing Group CHAND curly hair, ankyloblepheron, nail dysplasia
BER base excision repair (syndrome)
BGS Baller–Gerold syndrome CHCC Chapel Hill Consensus Conference
BHDS Birt–Hogg–Dubé syndrome CHH Conradi–Hünermann–Happle syndrome
BHPR British Health Professionals in Rheumatology CHH cartilage hair hypoplasia
BMD bone mineral density CHIKV Chikungunya virus
BMI body mass index CHILD congenital hemidysplasia with ichthyosiform
BMP bone morphogenetic protein erythroderma and limb defect (syndrome)
BMT bone marrow transplantation CHIME colobomas, congenital heart disease, early‐onset
BO branchio‐otic ichthyosiform dermatosis, mental retardation and ear
BOR branchio‐oto‐renal abnormalities
BOS Buschke–Ollendorff syndrome CHP cytophagic histiocytic panniculitis
BP blood pressure CHRPE congenital hypertrophy of the retinal pigment
BP bullous pemphigoid epithelium
BRBN blue rubber bleb naevus CHS Chédiak–Higashi syndrome
BRRS Bannayan–Riley–Ruvalcaba syndrome CI congenital ichthyoses
BS Bloom syndrome CIAD Childhood Impact of Atopic Dermatitis
BSA body surface area CID combined immunodeficiency
BSCL Berardinelli–Seip congenital lipodystrophy CIE congenital ichthyosiform erythroderma
BSI bathing suit ichthyosis CIL‐F congenital infiltrating lipomatosis of the face
BSLE benign summer light eruption CL cutaneous leishmaniasis
BSR British Society for Rheumatology CLM cutaneous larva migrans
BSS Brooke–Spiegler syndrome CLOVE congenital lipomatous overgrowth, vascular
BTK Bruton tyrosine kinase malformations and epidermal naevi (syndrome)
BV bacterial vaginitis CLQI Children’s Life Quality Index
BWS Beckwith–Wiedemann syndrome CLSM confocal laser scanning microscopy
CA condyloma acuminata CM capillary malformation
CAD chronic actinic dermatitis CM cutaneous mastocytosis
CADIS Childhood Atopic Dermatitis Impact Scale CM‐AVM capillary malformation‐arteriovenous malformation
C‐ALCL cutaneous anaplastic large cell lymphoma CMC chronic mucocutaneous candidiasis
CALM café‐au‐lait macules CML chronic myeloid leukaemia
CAM cell adhesion molecule CMN congenital melanocytic naevi
CA‐MRSA community‐associated meticillin‐resistant CMN congenital mesoblastic nephroma
Streptococcus aureus CMO carotenoid 15,15′‐mono‐oxygenase
CAN child abuse and neglect CMRDS constitutional mismatch repair deficiency syndrome
c‐ANCA cytoplasmic antineutrophil cytoplasmic antibody CMTC cutis marmorata telangiectatica congenita
CANDLE chronic atypical neutrophilic dermatosis with CMV cytomegalovirus
lipodystrophy and elevated temperature CNS central nervous system
CAPS cryopyrin‐associated autoinflammatory syndromes CNTP connective tissue naevus of the proteoglycan type
CAT cutaneovisceral angiomatosis with thrombocyopenia CNV copy number variations
CAVB complete atrioventricular block CoA co‐enzyme A
CAVM capillary–arteriolovenular malformations C1‐INH C1‐esterase inhibitor
CBCL cutaneous B‐cell lymphoma CoNS coagulase‐negative Staphylococcus
CBS cystathionine β‐synthase COFS cerebro‐oculo‐facio‐skeletal
CCA congenital contractural arachnodactyly CPAP continuous positive airway pressure
CCC congenital cutaneous candidiasis CRP C‐reactive protein
CCTN cerebriform connective tissue naevi CRIE congenital reticular ichthyosiform erythroderma
CD coeliac disease CRISPR clustered regularly interspaced palindromic repeats
CDLQI Children’s Dermatology Life Quality Index CPD cyclobutanepyrimidine dimers
CDP chondrodysplasia punctata CS Cockayne syndrome
CDPX2 X‐linked dominant chondrodysplasia punctata CS Costello syndrome
CDS Chanarin–Dorfman syndrome CSA child sexual abuse
CE cell envelope CSD cat scratch disease
CEA carcinoembryonic antigen CSF cerebrospinal fluid
CEDNIK cerebral dysgenesis, neuropathy, ichthyosis, CSMH congenital smooth muscle hamartoma
keratoderma (syndrome) CST Christ–Siemens–Touraine
CEP congenital erythropoietic porphyria CT Chlamydia trachomatis
CEVD congenital erosive and vesicular dermatosis (with CT computed tomography
reticulated supple scarring) CTCL cutaneous T‐cell lymphoma
CFCS cardiofaciocutaneous syndrome CTGF connective tissue growth factor
CFTR cystic fibrosis transmembrane conductance regulator CTN connective tissue naevi
List of Abbreviations xxix
CTL cytotoxic T‐lymphocyte ECM1 extracellular matrix protein 1

CTLA‐4 cytotoxic T‐lymphocyte antigen‐4 ECP eosinophil cationic protein
CVG cutis verticis gyrata ECP extracorporeal photopheresis
CVID common variable immunodeficiency ED ectodermal dysplasia
CVS chorionic villus sampling EDA ectodysplasin‐A
CVS congenital varicella syndrome EDP erythema dyschromicum perstans
CVST cerebral venous sinus thrombosis EDS Ehlers–Danlos syndrome
Cx connexin EDTA ethylenediaminetetraacetic acid
DADA2 deficiency of adenosine deaminase type 2 EDV epidermodysplasia verruciformis
DASI Dyshidrotic Eczema Area and Severity Index EEC ectrodactyly, ectodermal dysplasia and cleft lip/
DBPCDC double‐blind placebo‐controlled drug challenge palate
DBS DeBarsy syndrome EED erythema elevatum diutinum
DC dyskeratosis congenita EEG electroencephalogram
DCM diffuse cutaneous mastocytosis EF eosinophilic fasciitis
dcSSc diffuse cutaneous systemic sclerosis EGA estimated gestational age
DD Darier disease EGF epidermal growth factor
DDD Dowling–Degos disease EGFR epidermal growth factor receptor
DDEB dominant dystrophic epidermolysis bullosa EGPA eosinophilic granulomatosis with polyangiitis
DE dermoepidermal EGW external genital wart
DEB dystrophic epidermolysis bullosa EH eczema herpeticum
DEJ dermoepidermal junction EH epithelioid haemangioma
DEPPK diffuse epidermolytic palmoplantar keratoderma EHK epidermolytic hyperkeratosis
DFA direct fluorescent antibody EI epidermolytic ichthyosis
DFI Dermatitis Family Impact EIA enzyme immunoassay
DFSP dermatofibrosarcoma protuberans EIB erythema induratum of Bazin
DG1 DGI disseminated gonoccocal infection EKA erythrokeratoderma with ataxia
DGS DiGeorge syndrome EKC erythrokeratoderma en cocardes
DH dermatitis herpetiformis EKV erythrokeratoderma variabilis
DHEA dihydroepiandrosterone EKVP erythrokeratoderma variabilis progressiva
DHEAS dihydroepiandrosterone sulphate ELISA enzyme‐linked immunosorbent assay
DI dentinogenensis imperfecta EM erythema migrans
DIF direct immunofluorescence EM erythema multiforme
DIHS/AHS drug‐induced or anticonvulsant hypersensitivity EMG electromyogram
syndrome EMLA eutectic mixture of local anaesthetics
DIRA deficiency of the IL‐1 receptor antagonist EMS electromagnetic spectrum
DKS dyskeratosis congenita EN epidermal naevus
DLE discoid lupus erythematosus EN erythema nodosum
DMARD disease modifying antirheumatic drugs EN‐D epidermal naevus – Darier type
DMEG dysplastic megalencephaly ENDA European Network for Drug Allergy
DMSA dimercaptosuccinic acid ENS epidermal naevus syndrome
DMSO dimethyl sulphoxide ENT ear, nose and throat
DNEPPK diffuse nonepidermolytic palmoplantar keratoderma EORTC European Research and Treatment of Cancer
DOC disorders of cornification EOS early‐onset sarcoidosis
DOPA dihydroxyphenylalanine EP eccrine poroma
DP dyschromatosis ptychotropica EPDS erosive pustular dermatosis of the scalp
DPR dermatopathia pigmentosa reticularis EPI eosinophilic pustulosis of infancy
DRESS drug rash with eosinophilia and systemic symptoms EPF eosinophilic pustular folliculitis
DSAP disseminated superficial actinic porokeratosis EPP erythropoietic protoporphyria
DSH dyschromatosis symmetrica hereditaria ER endoplasmic reticulum
DSP disseminated superficial porokeratosis ERA enthesitis‐related arthritis
DTE desmoplastic trichoepithelioma ES epithelioid sarcoma
DUH dyschromatosis universalis hereditaria ESPD European Society of Pediatric Dermatology
DVA developmental venous anomaly ESR erythrocyte sedimentation rate
DVT deep vein thrombosis ESRD end‐stage renal disease
EAACI European Academy of Allergy and Clinical ET exfoliative toxin
Immunology ETN erythema toxicum neonatorum
EASI Eczema Area and Severity Index EULAR European League Against Rheumatism
EB epidermolysis bullosa EV eczema vaccinatum
EBA epidermolysis bullosa acquisita EV enteroviruses
EBP emopamil binding protein EV epidermodysplasia verruciformis
EBV Epstein–Barr virus EV‐HPV epidermodysplasia verruciformis‐associated human
EBS epidermolysis bullosa simplex papillomavirus
EBS‐DM epidermolysis bullosa simplex Dowling–Meara FADH fatty alcohol dehydrogenase
EBS‐MP epidermolysis bullosa simplex with mottled FAE fumaric acid ester
pigmentation FALDH fatty aldehyde dehydrogenase
ECCL encephalocraniocutaneous lipomatosis FAP familial adenomatous polyposis
ECF eosinophil chemotactic factor FAO fibroadipose hyperplasia or overgrowth
ECG electrocardiogram FATP fatty acid transport protein
ECHO enteric cytopathic human orphan FC familial cylindromatosis
xxx List of Abbreviations
FDA US Food and Drug Administration HCC harlequin colour change

FDE fixed drug eruptions HCG human chorionic gonadotropin
FDEIA food‐dependent exercise‐induced urticaria/ HCP hereditary coproporphyria
anaphylaxis HCT haemopoietic cell transplantation
FDH focal dermal hypoplasia HDL high‐density lipoprotein
FFD Fox–Fordyce disease HDN haematodermic neoplasm
FFDD focal facial dermal dysplasias HE hypereosinophilia
FFM focus‐floating microscopy HED hypohidrotic ectodermal dysplasia
FFP fresh frozen plasma HEP hepatoerythropoietic porphyria
FFPE formalin‐fixed paraffin‐embedded HES hypereosinophilic syndrome
FGFR fibroblast growth factor receptor HFMD hand, foot and mouth disease
FH familial hypercholesterolaemia HFS hyaline fibromatosis syndrome
FHL familial haemophagocytic lymphohistiocytosis HGA homogentisic acid
FII fabricated or induced illness HGPS Hutchinson–Gilford progeria syndrome
FISH fluorescence in situ hybridization HHD Hailey–Hailey disease
FITC fluorescein isothiocyanate HHML hemihyperplasia–multiple lipomatosis syndrome
5‐FU 5‐fluorouracil HHT hereditary haemorrhagic telangiectasia
FMF familial Mediterranean fever HHV human herpesvirus
FML familial multiple lipomatosis HI haemangioma of infancy
FNAC fine needle aspiration cytology HI harlequin ichthyosis
FOP fibrodysplasia ossificans progressiva HI hypomelanosis of Ito
FPHH familial progressive hyperpigmentation and HID hystrix‐like ichthyosis with deafness (syndrome)
hypopigmentation HIES hyperimmunoglobulin E syndrome
FPLD familial partial lipodystrophies HIF hypoxia inducible factor
FSH follicle‐stimulating hormone HIMS hyperimmunoglobulin M syndrome
FTC familial tumoural calcinosis HIP helix initiation peptide
FTG full‐thickness skin graft HIV human immunodeficiency virus
FTI farnesyltransferase inhibitors HJMD hypotrichosis with juvenile macular dystrophy
FVC forced vital capacity HLA human leucocyte antigen
GA granuloma annulare HLH haemophagocytic lymphohistiocytosis
GABA γ‐aminobutyric acid HLRCC hereditary leiomyomatosis and renal cell cancer
GACI generalized arterial calcification of infancy HMG high mobility group
GAS Group A Streptococcus HMS Haim–Munk syndrome
GBFDE generalized bullous fixed drug eruption HOME Harmonising Outcome Measures for Eczema
GCDFP gross cystic disease fluid protein HOPP hypotrichosis–osteolysis–periodontitis–palmoplantar
GCS Giannott—Crosti syndrome keratoderma
GD Gaucher disease HP hydroxylysylpyridinoline
GFR glomerular filtration rate HPC haemangiopericytoma
GGR global genome repair HPS Hermansky–Pudlak syndrome
GGT gamma‐glutamyl transpeptidase HPETE hydroperoxyeicosatetraenoic acid
GH growth hormone HPV human papillomavirus
GI gastrointestinal HR H1‐receptor
GLA generalized lymphatic anomaly HRCT high resolution computed tomography
GM‐CSF granulocyte macrophage colony‐stimulating factor HRM high‐resolution melt PCR
GMS Gomori’s methenamine silver HS hidradenitis suppurativa
GNCST granular nerve cell sheath tumour HSCT haematopoietic stem cell transplantation
GO geroderma osteodysplastica HSD holocarboxylase synthetase deficiency
GOSH Great Ormond Street Hospital for Children HSP heat shock proteins
GPA granulomatosis with polyangiitis HSP Henoch–Schönlein purpura
GPP generalized pustular psoriasis HSV herpes simplex virus
GPS Griscelli–Prunieras syndrome HTLV human T‐lymphotropic virus
GS Griscelli syndrome HTP helix termination peptide
GSD Gorham–Stout disease HUV hypocomplementemic urticarial vasculitis
GSE gluten‐sensitive enteropathy HUVS hypocomplementemic urticarial vasculitis syndrome
G6PD glucose‐6‐phosphate dehydrogenase HV hydroa vacciniforme
GSS granulomatous slack skin IA infantile acropustulosis
GVHD graft‐versus‐host disease IBD inflammatory bowel disease
GVHR graft‐versus‐host reaction IBIDS ichthyosis, brittle hair, intellectual impairment,
GVL graft‐versus‐leukaemia decreased fertility and short stature
GVM glomuvenous malformation IBS ichthyosis bullosa of Siemens
GWAS genome‐wide association study ICAM intracellular adhesion molecule
HAART highly active antiretroviral therapy ICD irritant contact dermatitis
HAE hereditary angioedema IC1/IC2 imprinting centre 1/2
HA‐MRSA hospital‐associated meticillin‐resistant Streptococcus ID infective dermatitis
aureus IDQoL Infants’ Dermatitis Quality of Life Index
H&E haematoxylin and eosin IEM inborn errors of metabolism
HBD human β‐defensin IF immunofluorescence
HBT hereditary benign telangiectasia IF infantile fibrosarcoma
HBV hepatitis B virus IF intermediate filament
List of Abbreviations xxxi
IFA indirect fluorescence assay KS Kindler syndrome

IFAP ichthyosis follicularis, alopecia and photophobia KTS Klippel–Trenaunay syndrome
IFM immunofluorescence mapping KWE keratolytic winter erythema
IFN interferon LABD linear immunoglobulin IgA bullous dermatosis
Ig immunoglobulin LAD leucocyte adhesion deficiency
IgA1 IgA subtype 1 LAD linear IgA dermatosis
Ig ε RI high‐affinity IgE receptor LAH localized autosomal recessive hypotrichosis
IGF insulin‐like growth factor LAM linear atrophoderma of Moulin
IGFBP insulin‐like growth factor binding protein LAM lymphangiomyomatosis
IgM immunoglobulin M LAS loose anagen syndrome
IGRA interferon‐γ release assay LB Lyme borreliosis
IH infantile haemangiomas LCD liquor carbonis detergens
IHCM ichthyosis hystrix of Curth–Macklin LCH Langerhans cell histiocytosis
IHS ichthyosis hypotrichosis syndrome LCR locus control region
IHSC ichthyosis–hypotrichosis–sclerosing cholangitis lcSSC limited cutaneous systemic sclerosis
(syndrome) LED light‐emitting diode
IIF indirect immunofluorescence LIC localized intravascular coagulopathy
IL interleukin LD linkage disequilibrium
ILAR International League of Associations for LD lymphoedema‐distichiasis
Rheumatology LDF laser Doppler flowmetry
ILC ichthyosis linearis circumflexia LDH lactate dehydrogenase
ILVEN inflammatory linear verrucous epidermal naevus LDL low‐density lipoprotein
IMF immunofluorescence LDS Loeys–Dietz syndrome
IM infectious mononucleosis LE lupus erythematosus
IM intramuscular LEC lymphatic endothelial cells
IP incontinentia pigmenti LEKTI lymphoepithelial Kazal‐type inhibitor
iPCS inducible pluripotential stem cells LET lidocaine/epinephrine/tetracaine
IPEX immune dysregulation, polyendocrinopathy, LFA‐3 lymphocyte function‐associated antigen‐3
enteropathy, X‐linked LH luteinizing hormone
IPP infantile perineal protrusion LI lamellar ichthyosis
IPS ichthyosis prematurity syndrome LJ Lowenstein–Jensen (medium)
IR insulin resistance LM lymphatic malformation
IRAK‐4 IL‐1 receptor associated kinase‐4 LMP last menstrual period
IRIS immune reconstitution inflammatory syndrome LMP1 latent membrane protein 1
IS infantile spasms LMS Lenz–Majewski syndrome
ISAAC International Study of Asthma and Allergies in LMS limb–mammary syndrome
Childhood LMX liposomal lidocaine
ISD infantile seborrhoeic dermatitis LN lichen nitidus
ISH infantile systemic hyalinosis LOH loss of heterozygosity
ISM indolent systemic mastocytosis LOSSI localized scleroderma severity index
ISSVA International Society for the Study of Vascular LOX lipoxygenase
Anomalies LP lichen planus
ISU idiopathic solar urticaria LP lupus panniculitis
IV ichthyosis vulgaris LP lysylpyridinoline
IVF in vitro fertilization LPL lipoprotein lipase deficiency
IVIG intravenous immunoglobulin LPP lichen planopilaris
JAK janus kinase LPS lipopolysaccharide
JDM juvenile dermatomyositis LS lichen sclerosus
JEB junctional epidermolysis bullosa LS lichen scrofulosorum
JHF juvenile hyaline fibromatosis LS lichen striatus
JIA juvenile idiopathic arthritis LSC lichen simplex chronicus
JLI Jessner lymphocytic infiltrate LSc localized scleroderma
JPD juvenile plantar dermatosis LT‐β lymphotoxin‐β
JSPD Japanese Society for Pediatric Dermatology LTT lymphocyte transformation test
JSLE juvenile systemic lupus erythematosus LV lentiviral vector
JSSc juvenile‐onset systemic sclerosis LV livedoid vasculopathy
JXG juvenile xanthogranuloma LV lupus vulgaris
KD Kawasaki disease LyP lymphomatoid papulosis
KEN keratinocytic epidermal naevus MAC membrane attack complex
KFSD keratosis follicularis spinulosa decalvans MACS macrocephaly‐alopecia‐cutis laxa‐scoliosis
KHE kaposiform haemangioendothelioma MACS magnetic‐activated cell sorting
KID keratitis, ichthyosis and deafness (syndrome) MAD mandibuloacral dysplasia
KIF keratin intermediate filaments MAIC M. avium‐intracellulare complex
KLA Kaposiform lymphangiomatosis MALDI‐TOF matrix‐assisted laser desorption/ionization
KLICK keratosis linearis‐ichthyosis congenita‐keratoderma time‐of‐flight
KLK kallikrein MALT mucosa‐associated lymphoid tissue
KMP Kasabach–Merritt phenomenon MAPK mitogen‐activated protein kinase
KPI keratinopathic ichthyoses MAS macrophage activation syndrome
KS Kaposi sarcoma MAS McCune–Albright syndrome
xxxii List of Abbreviations
MBL mannose‐binding lectin NBCC naevoid basal cell carcinoma

MBP major basic protein NBD nucleotide‐binding domain
MBTPS2 membrane‐bound transcription factor protease, site 2 NBS Nijmegen breakage syndrome
MC mast cells NBT nitroblue tetrazolium
MC molluscum contagiosum NB‐UVB narrow‐band UVB
MCAS mast cell activation symptoms NC naevus comedonicus
MC&S microscopy, culture and (antibiotic) sensitivity NCAM neural cell adhesion molecule
MCL mast cell leukaemia NCIE nonbullous congenital ichthyosiform erythroderma
MCL mucocutaneous leishmaniasis NCP neonatal cephalic pustulosis
M‐CM megalencephaly‐capillary malformation NCV nerve conduction velocity
MCS mast cell lymphoma ND naevus depigmentosus
MCV molluscum contagiosum virus Nd:YAG neodymium:yttrium aluminium garnet
MDM minor determinant mixture NEP neonatal eosinophilic pustulosis
MDP mandibular hypoplasia, deafness and progeria NEPPK nonepidermolytic palmoplantar keratoderma
(syndrome) NER nucleotide excision repair
MDR multidrug‐resistant NET neutrophil extracellular trap
MED minimal erythema dose NF necrotizing fasciitis
MEDNIK mental retardation, enteropathy, deafness, peripheral NFJ Naegeli‐Franceschetti‐Jadassohn (syndrome)
neuropathy, ichthyosis, keratoderma NF‐κB nuclear factor κB
MeDOC mendelian disorders of cornification NF1 neurofibromatosis type 1
MEN‐1 multiple endocrine neoplasia type‐1 NGCO non‐gestational ovarian choriocarcinoma
MetS metabolic syndrome NGF nerve growth factor
MF mycosis fungoides NGFR nerve growth factor receptor
MFS Marfan syndrome NGS next‐generation sequencing
MFT multiple familial trichoepitheliomas NHL non‐Hodgkin lymphoma
mHA minor histocompatibility antigen NICE National Institute for Health and Care Excellence (UK)
MHC major histocompatibility complex NICH noninvoluting congenital haemangioma
MIDAS microphthalmia, dermal aplasia and sclerocornea NICU neonatal intensive care unit
(syndrome) NIH National Institutes of Health (USA)
MKD mevalonate kinase deficiency NISCH neonatal ichthyosis‐sclerosing cholangitis
MLPA multiplex ligation‐dependent probe amplification (syndrome)
MLT multifocal lymphangioendotheliomatosis with NK natural killer (cell)
thrombocyopenia NL necrobiosis lipoidica
MMA methylmalonic acidaemia NL neonatal lupus
MMF mycophenolate mofetil NLCH non‐Langerhans cell histiocytosis
MMP matrix metalloproteinases NLCS naevus lipomatosus cutaneous superficialis
MMP mucous membrane pemphigoid NLD necrobiosis lipoidica
MMPH multifocal micronodular pneumocyte hyperplasia NLP nail lichen planus
MMR mismatch repair NLS naevus lipomatosus superficialis
MODY maturity‐onset diabetes of the young NLS Neu‐Laxova syndrome
MPA microscopic polyangiitis NLSD neutral lipid storage disease
MPCM maculopapular cutaneous mastocytosis NLSDI neutral lipid storage disease with ichthyosis
MPDE maculopapular drug eruptions or exanthems NMF natural moisturizing factor
MPE maculopapular exanthems NOMID neonatal onset multisystemic inflammatory disorder
MPNST malignant peripheral nerve sheath tumour N2O nitrous oxide
MPO myeloperoxidase NPSA National Patient Safety Agency (UK)
MPS mucopolysaccharidoses NP‐SLE neuropsychiatric systemic lupus erythematosus
MRA magnetic resonance angiography NPY neuropeptide Y
MRI magnetic resonance imaging NS naevus sebaceus
MRSA meticillin‐resistant Staphylococcus aureus NS Netherton syndrome
MRSS modified Rodnan skin score NS Noonan syndrome
MSD multiple sulphatase deficiency NSML Noonan syndrome with multiple lentigines
MSF Milton sterilizing fluid NSAIDs nonsteroidal anti‐inflammatory drugs
MSH melanocyte‐stimulating hormone NSIP nonspecific interstitial pneumonia
MSL multiple symmetric lipomatosis NSV nonsegmental vitiligo
MSS Mulvihill–Smith syndrome NTM nontuberculous mycobacteria
MSUD maple syrup urine disease NUV normocomplementemic urticarial vasculitis
MTC Mycobacterium tuberculosis complex OA ocular albinism
mtDNA mitochondrial DNA OC osteoma cutis
mTOR mammalian target of rapamycin OCA oculocutaneous albinism
MTS Muir–Torre syndrome OCCS oculocerebrocutaneous syndrome
MTX methotrexate OES oculoectodermal syndrome
MUGA multiple uptake gated acquisition angiography OFC oral food challenge
MUHH Marie–Unna hereditary hypotrichosis OFG orofacial granulomatosis
MVP mitral valve prolapse OI osteogenesis imperfecta
MWS Muckle–Wells syndrome OL‐EDA‐ID osteopetrosis, lymphoedema, anhidrotic ectodermal
NA naevus anaemicus dysplasia and immune deficiency
NAC N‐acetylcysteine OMIM Online Mendelian Inheritance in Man
NADPH nicotinamide adenine dinucleotide phosphate OODD odonto‐onycho‐dermal dysplasia
List of Abbreviations xxxiii
OPG optic pathway glioma PKDL post‐kala‐azar dermal leishmaniasis

OPK osteopoikilosis PKS Pallister–Killian syndrome
ORF open reading frame PKU phenylketonuria
OS Omenn syndrome pI isoelectric point
OSD occult spinal dysraphism PI3 proteinase inhibitor 3
OTU operational taxonomic unit PIP proximal interphalangeal
O/W oil in water PL pityriasis lichenoides
PA pityriasis alba PLC pityriasis lichenoides chronica
PA phytanic acid PLCA primary localized cutaneous amyloidosis
PABA para‐aminobenzoic acid PLE polymorphous light eruption
PAF platelet‐activating factor PLEVA pityriasis lichenoides et varioliformis acuta
PAH phenylalanine hydroxylase PLS Papillon–Lefèvre syndrome
PAHX phytanoyl CoA hydroxylase PM porokeratosis of Mibelli
PAI‐1 plasminogen activator inhibitor 1 PML progressive multifocal leucoencephalopathy
PAN polyarteritis nodosa PMLE polymorphous light eruption
p‐ANCA perinuclear antineutrophilic cytoplasmic antibody PMN polymorphonuclear cell
PAP peak arterial pressure PN poikiloderma with neutropenia
PAPA pyogenic arthritis, pyoderma gangrenosum and acne PN prurigo nodularis
PAR2 protease‐activated receptor 2 PNET peripheral neuroectodermal tumour
PAS periodic acid–Schiff PNF plexiform neurofibroma
PASI Psoriasis Area and Severity Index POC point of care
PC pachyonychia congenita P1cp procollagen type 1 carboxy‐terminal peptide
PCFCL primary cutaneous follicle‐centre lymphoma PNT papulonecrotic tuberculid
PCFH precalcaneal congenital fibrolipomatous hamartoma POEM Patient‐Oriented Eczema Measure
PCL primary cutaneous lymphoma POEMS polyneuropathy, organomegaly, endocrinopathy,
PCLBCL primary cutaneous diffuse large B‐cell lymphoma M protein, skin changes (syndrome)
PCMZL primary cutaneous marginal zone B‐cell lymphoma POH progressive osseous heteroplasia
PCNA proliferating cell nuclear antigen PP prurigo pigmentosa
PCOS polycystic ovarian syndrome PPAR peroxisome proliferator‐activated receptor
PCR polymerase chain reaction PPGSS papular‐purpuric gloves‐and‐socks syndrome
PCT porphyria cutanea tarda PPi inorganic pyrophosphate
PCT primary care trust PPK palmoplantar keratoderma
PDGF platelet‐derived growth factor PPK phacomatosis pigmentokeratotica
PDL pulsed‐dye laser PPKN palmoplantar keratoderma Nagashima
PDT photodynamic therapy PPL penicilloyl‐polylysine
PE pulmonary embolism PPP palmoplantar pustulosis
PEG polyethylene glycol PPV phakomatosis pigmentovascularis
PEH palmoplantar eccrine hidradenitis PPPD porokeratosis palmaris et plantaris disseminata
PELVIS perianal haemangioma, external genitalia PPT positive patch test
malformations, lipomyelomeningocoele, vesicorenal PPTR positive patch test reaction
abnormalities, imperforate anus and skin tags PR pagetoid reticulosis
PEP postexposure prophylaxis PRES Paediatric Rheumatology European Society
PEPD paroxysmal extreme pain disorder PRINTO Paediatric Rheumatology International Trials
PEN porokeratotic eccrine naevus Organization
PENS papular epidermal naevus with skyline basal cell layer PRIS propofol‐related infusion syndrome
PEODDN porokeratotic eccrine ostial and dermal duct naevus PRNT plaque‐reduction neutralization test
PET positron emission tomography PRO patient‐reported outcome
PF pemphigus foliaceus PROM patient‐reported outcome measure
PFT pulmonary function tests PROS PIK3CA‐related overgrowth spectrum disorders
PG pyoderma gangrenosum PRP pityriasis rubra pilaris
PG pyogenic granuloma PRR pathogen recognition receptors
PGA Physician Global Assessment PR3 proteinase 3
PGD preimplantation genetic diagnosis PS Proteus syndrome
PGP 9.5 protein gene product 9.5 PSEK progressive symmetric erythrokeratoderma
PGRP peptidoglycan recognition protein PSH premature sebaceous hyperplasia
PH palmoplantar hidradenitis PSS peeling skin syndromes
PH pulmonary hypertension PT prothrombin time
PHA phytohaemagglutinin PTC premature termination codon
PHACES posterior fossa brain malformations, large or PTEN phosphatase and TENsin homologue
complex haemangiomas of the face, arterial PTH parathyroid hormone
anomalies, cardiac anomalies and eye abnormalities PTHrP parathyroid‐hormone‐related peptide
PHP pseudo‐hypoparathyroidism PTT partial thromboplastin time
PHTS PTEN hamartoma tumour syndrome PUVA psoralens plus UVA
PhyH phytanoyl‐CoA2‐hydroxylase PV pemphigus vulgaris
PICH partially involuting congenital haemangioma PV psoriasis vulgaris
PID pelvic inflammatory disease PVL Panton–Valentine leukocidin
PID primary immunodeficiency PWS port wine stain
PILA papillary intralymphatic angioendothelioma PXE pseudoxanthoma elasticum
PJS Peutz–Jeghers syndrome QoL quality of life
xxxiv List of Abbreviations
qPCR quantitative polymerase chain reaction SFT solitary fibrous tumour

qRT‐PCR quantitative real‐time PCR SGC Shprintzen–Goldberg craniosynostosis
QUADAS Quality Assessment of Diagnostic Accuracy tool SHBG sex hormone‐binding globulin
RAK reticulate acropigmentation of Kitamura SHCB self‐healing collodion baby
RAMBA retinoic acid metabolism blocking agent SHH Sonic Hedgehog
RAS recurrent aphthous stomatitis SHFM split hand–split foot syndrome
RAST radio‐allergosorbent test SHP Schönlein–Henoch purpura
RBP retinol‐binding protein SIB self‐injurious behaviour
RCC renal cell carcinoma SICI self‐improving congenital ichthyosis
RCDP rhizomelic chondrodysplasia punctata SID sudden infant death (syndrome)
RCT randomized controlled trial sIgE drug‐specific IgE antibodies
RD restrictive dermopathy siRNA small interfering RNA
RDD Rosai–Dorfman disease SIRS systemic inflammatory response syndrome
RDEB recessive dystrophic epidermolysis bullosa 6‐4PP pyrimidine‐6,4‐pyrimidone photoproducts
RICH rapidly involuting congenital haemangioma SJIA systemic juvenile idiopathic arthritis
RF rheumatoid factor SJS Stevens–Johnson syndrome
RF rib fracture SLADP Latin American Society for Pediatric Dermatology
RFC replication factor C S‐LAM spontaneous lymphangiomyomatosis
RFLP restriction fragment length polymorphism SLC27 solute carrier family 27
RH retinal haemorrhage SLE systemic lupus erythematosus
RMH rhabdomyomatous mesenchymal hamartoma SLICC Systemic Lupus International Collaborating Clinics
RMS rhabdomyosarcoma SLN speckled lentiginous naevus
RNP ribonucleoprotein SLOS Smith–Lemli–Opitz syndrome
ROAT repeated open application test SLPI secretory leucocyte protease inhibitor
ROS reactive oxygen species SLS Sjögren–Larsson syndrome
RP relapsing polychondritis SLS sodium lauryl sulphate
RPA replication protein A SM systemic mastocytosis
RPE recurrent toxin‐mediated perineal erythema SM‐AHN systemic mastocytosis with an associated
RRP recurrent respiratory papillomatosis haematological neoplasm
RSC respiratory syncytial virus SMO smoothened
RT‐PCR reverse transcription polymerase chain reaction SNA spherical nucleic acid
RTS Rothmund–Thomson syndrome SNP single nucleotide polymorphism
RTX rituximab SNV single nucleotide variant
RV retroviral vector SP syringocystadenoma papilliferum
RXLI recessive X‐linked ichthyosis SPD Society for Pediatric Dermatology
SA Streptococcus aureus SPECT single‐photon emission computed tomography
SAA serum amyloid A SPF sun protection factor
SAM severe dermatitis, multiple allergies and metabolic SPINK serine protease inhibitor Kazal type
wasting SPRR small proline‐rich proteins
SAPHO synovitis, acne, pustulosis, hyperostosis and osteitis SPTCL subcutaneous panniculitis‐like T‐cell lymphoma
SASSAD six‐area, six‐sign atopic dermatitis (score) SR systemic retinoids
SC stratum corneum SS Sézary syndrome
SC subcutaneous SS Sjögren syndrome
SCALP sebaceous naevus, central nervous system SS Sweet syndrome
abnormalities, aplasia cutis, limbal dermoid and SSc systemic sclerosis
pigmented naevus (syndrome) SSG split‐thickness skin graft
SCAP syringocystadenoma papillifera SSKI saturated solution of potassium iodide
SCC squamous cell carcinoma SSLR serum sickness‐like reaction
SCCE stratum corneum chymotryptic enzyme SSM smouldering systemic mastocytosis
SCE sister chromatid exchange SSP Schöpf–Schulz–Passarge
SCF stem cell factor SSPE subacute sclerosing panencephalitis
SCFN subcutaneous fat necrosis SSRI selective serotonin reuptake inhibitors
SCH spindle cell haemangioma SSS stiff skin syndrome
SCID severe combined immunodeficiency SSSS staphylococcal scalded skin syndrome
SCLE subacute cutaneous lupus erythematosus SSTI skin and soft tissue infection
SCORAD SCORing Atopic Dermatitis STD sexually transmitted disease
SCT stem cell transplantation STI sexually transmitted infection
SCTE stratum corneum tryptic enzyme STS sodium thiosulfate
SD seborrhoeic dermatitis STS steroid sulphatase
SDA Sabouraud dextrose agar STS soft tissue sarcoma
SDH subdural haematoma STSS streptococcal toxic shock syndrome
SEGA subependymal giant cell astrocytoma SWS Sturge–Weber syndrome
SegPD segmental pigmentary disorder TA tufted angioma
SEI superficial epidermolytic ichthyosis TA teichoic acid
SEN scalp–ear–nipple (syndrome) TAC tetracaine/adrenaline/cocaine
SEN subependymal nodules TBE tickborne encephalitis
SERCA2 sarco/endoplasmic reticulum ATPase type 2 TBSA total body surface area
SFD scrofuloderma TCC triple‐combination cream
List of Abbreviations xxxv
TCI topical calcineurin inhibitors US/LS upper to lower segment

TCR T‐cell receptor UTR untranslated region
TCS topical corticosteroids UV ultraviolet
TDO trichodento‐osseous UVA ultraviolet A
TEN toxic epidermal necrolysis UVB ultraviolet B
TEWL transepidermal water loss UV‐DDB UV‐damaged DNA‐binding
TFIIH transcription factor IIH UVSS UV‐sensitive syndrome
TG transglutaminase UVR ultraviolet radiation
TG triacylglycerol VACTERL vertebral anomalies, anal atresia, congenital cardiac
TGF transforming growth factor anomalies, tracheo‐oesophageal fistula and/or
TG1 transglutaminase‐1 oesophageal atresia, renal anomalies, radial dysplasia
TIMP tissue inhibitor of metalloproteinase and other limb defects
TJ tight junction VDLR Venereal Disease Research Laboratory
TLR toll‐like receptor VEGF vascular endothelial growth factor
TMD transmembrane domains VEGFR3 vascular endothelial growth factor receptor 3
TMEP telangiectasia macularis eruptiva perstans VIG vaccinia immune globulin
TMP‐SMX trimethoprim‐sulfamethoxazole VIT venom immunotherapy
TND twenty‐nail dystrophy VL visceral leishmaniasis
TNF tumour necrosis factor VL visible light
TNFR tumour necrosis factor receptor VLBW very low birthweight
TNPM transient neonatal pustular melanosis VLCFA very‐long‐chain fatty acid
tPA tissue plasminogen activator VLDL very low‐density lipoproteins
TPM transient pustular melanosis VM venous malformation
TPMT thiopurine methyltransferase VMCM cutaneomucosal venous malformation
TPN total parenteral nutrition VS Vohwinkel syndrome
TRAPS TNF receptor superfamily 1A‐associated periodic VZIG varicella zoster immunoglobulin
fever syndrome VZV varicella zoster virus
TREC T‐cell receptor excision circle WAO World Allergy Organization
TRPS trichorhinophalangeal syndrome WAS Wiskott–Aldrich syndrome
TRT thermal relaxation time WGS whole‐genome shotgun
TS tuberous sclerosis WHO World Health Organization
TSC tuberous sclerosis complex W/O water in oil
TSC‐IS TSC‐associated infantile spasms WPWS Wolff–Parkinson–White syndrome
TSH thyroid‐stimulating hormone WRS Wiedemann–Rautenstrauch syndrome
TSS toxic shock syndrome WS Werner syndrome
TST tuberculosis skin test XD X‐linked dominant
TTD trichothiodystrophy XLA X‐linked agammaglobulinaemia
TU tropical ulcer XLI X‐linked ichthyosis
TV Trichomonas vaginalis XLMR X‐linked mental retardation
UD unrelated donor XP xeroderma pigmentosum
uE3 unconjugated oestriol XPV xeroderma pigmentosum variant
UNT unilateral naevoid telangiectasia XR X‐linked recessive
UP urticaria pigmentosa YNS yellow nail syndrome
UPD uniparental disomy ZIKV Zika virus
URDS Urban–Rifkin–Davis syndrome ZNS Zunich neuroectodermal syndrome
US ultrasound
1
C HA PTER 1
STRUCTURE AND PHYSIOLOGY

SECTION 1: DEVELOPMENT,
Embryogenesis of the Skin
Lara Wine Lee1 & Karen A. Holbrook2
Departments of Dermatology and Pediatrics, Medical University of South Carolina, Charleston, SC, USA
1
Formerly Department of Physiology and Cell Biology, Ohio State University, Columbus, OH, USA
2
Introduction, 1 Embryonic–fetal transition, 10 Conclusion, 35

Time‐scale of skin development, 2 Fetal skin, 16
Embryonic skin, 3 Unique features of developing human skin, 20
Abstract gene regulation; apoptosis; differentiation (structural, biochemical

and functional); and certain longstanding basic p henomena
of development such as induction, pattern formation and dif-
The skin is a large and complex organ. While skin development be-
ferentiation. Rigorous understanding of embryogenesis allows
gins during early embryogenesis, full development is not complete
definition of critical periods when the skin may be more vulner-
until well into the postnatal years. Studies of skin development
able to developmental errors. Further understanding of these
can shed light on a number of basic problems in c ontemporary bi-
critical processes advances the study of developmental d isorders
ology: epithelial–mesenchymal interactions that establish organs
of the skin with the promise of improving therapeutic options for
(in skin, these tissue interactions occur in follicle, sweat gland and
these disorders.
nail formation); cell–cell interactions through soluble mediators;
Introduction in a continuum of events that modifies the skin. It is

The skin is an ideal organ in which to study development c haracterized by morphogenetic processes, activation of
because it is readily accessible for observation, sampling new genes and gain of function. In contrast, ageing may
and evaluation. As an interface, it straddles the internal, involve morpholytic processes in which genes are turned
systemic world of the individual and the external environ off, resulting in a loss of function. Consideration of this
ment and is modified by both. The skin itself is a compli continuum, and the genetic and environmental interac
cated and complex organ, with the normal structure and tions that come into play throughout life, provides a con
function of each ‘part’ highly dependent upon what ceptual framework for discussing the place and role of the
happens in other parts of the skin. In other words, one events in skin morphogenesis.
cannot understand, for example, changes that occur in the Understanding the stages and events of normal human
epidermis without understanding the nature of the der skin development is also important from a biomedical
mis since the dermis has major influences on the activities perspective. Skin embryogenesis allows the definition of
and functions of the epidermis. This is the case for each critical periods when the skin may be more vulnerable to
region or structure of the skin. developmental errors. It provides an opportunity to study
Development offers an opportunity to study skin the evolution of skin function, establishing a background
structure and function under more controlled conditions for understanding the natural history of expression of
because the environment of the developing skin is rea genetic skin disease in its earliest form. Moreover, advances
sonably constant (controlled light, temperature, pressure, in gene therapy may provide intervention rooted in
etc.). It is therefore possible to investigate how the prop understanding normal morphological processes.
erties of the different regions and structures of the skin The unique morphological properties of developing
are coordinately established, presumably under the human skin have always intrigued investigators.
directions of a genetic programme. Specific aspects of the skin that are found only in the
Some of the structures of the skin may be fully formed fetus, such as the periderm, and specific events that
early in the fetal period whereas other structures or result in the formation of complex structures, such as
regions are not complete until well into the postnatal follicle or sweat gland, were often described for specific
years. Full establishment of adult functions of the skin ages only (reviewed in [1–4]). Expansion of studies to
always requires an extended period of development characterize the complete ontogeny of the tissue, region
beyond the stages in utero. Development is the first period or structure then began to include data derived from
Harper’s Textbook of Pediatric Dermatology, Fourth Edition. Edited by Peter Hoeger, Veronica Kinsler and Albert Yan.
© 2020 John Wiley & Sons Ltd. Published 2020 by John Wiley & Sons Ltd.
2 Section 1 Development, Structure and Physiology of the Skin
iochemical or immunohistocytochemical assays for the

b fetal period. Histogenesis of all skin regions is initiated
expression of specific molecules that were known to in the embryo, and differentiation of some of those tis
correlate with the state of differentiation or with a sues begins to occur in the first trimester [2]. The boundary
specific property such as barrier function adhesion. between the first and second trimesters, at 3 months of
Culturing and grafting human embryonic and fetal skin age, is based only on fetal age and not on any specific
(reviewed in [5–8]) and skin‐derived cells [9,10] and changes in structure, composition or function of any
evaluation of skin from fetuses affected with genoder region of the skin.
matoses (reviewed in [11–13]), or under conditions of The second trimester includes many important
growth retardation, have also provided insight into events in skin development. Morphogenesis of new
human skin development. Our understanding of skin structures is initiated and there is terminal differentia
development continues to increase as we apply tion of others. During the third trimester, all parts of
more modern tools of biology to study the skin at all the skin are assembled and the functions of each of
stages of life. them are unfolding. The end of this period is not the
final state of the skin, as there is significant reorganiza
References tion of certain units of the skin (e.g. the vasculature),
1 Holbrook KA. Structure and function of the developing human skin. additions to the skin in volume (e.g. the dermal matrix)
In: Goldsmith LA (ed.) Physiology, Biochemistry and Molecular
and functional maturation of many structures of the
Biology of the Skin, 2nd edn. Oxford: Oxford University Press,
1991:63–110. skin (e.g. nerves, sweat glands and stratum corneum)
2 Holbrook KA. Structural and biochemical organogenesis of skin and after birth [3–7].
cutaneous appendages in the fetus and neonate. In: Polin RA, Fox Other important times that should be recognized in
WW (eds) Neonatal and Fetal Medicine Physiology and
Pathophysiology. New York: Grune & Stratton, 1992:527–51.
skin development are the ages at which diagnostic proce
3 Holbrook KA, Wolff K. The structure and development of skin. In: dures are performed for the purpose of evaluating the
Fitzpatrick TB, Eisen AZ, Wolff K et al. (eds) Dermatology in condition of a fetus at risk for a genetic skin disease
General Medicine, 6th edn. New York: McGraw‐Hill, 1993:97–144. (reviewed in [8]). Fetal deoxyribonucleic acid (DNA)
4 Holbrook KA, Sybert VP. Basic science. In: Schachner L, Hansen R
(eds) Pediatric Dermatology, 2nd edn. New York: Churchill can be extracted from chorionic villi sampled around
Livingstone, 1995. 10 weeks EGA and amniotic fluid cells can be obtained at
5 Holbrook KA, Minami SA. Hair follicle morphogenesis in the human: around 14–16 weeks EGA. Fetal skin can be sampled as
characterization of events in vivo and in vitro. NY Acad Sci 1991;
642:167–96.
early as 16 weeks EGA, however this technique is largely
6 Zeltinger J, Holbrook KA. A model system for long term, serum‐free, obsolete and has been replaced by more advanced diag
suspension organ culture of human fetal tissues: experiments using nostic and genetic methods. Newer technology allows
digits and skin from multiple body regions. Cell Tissue Res 1997; isolation of fetal DNA from maternal plasma as early as
290:51–60.
7 Lane AT, Scott GA, Day KH. Development of human fetal skin trans 9 weeks EGA. The cell‐free DNA testing is currently not
planted to the nude mouse. J Invest Dermatol 1989;93:787–91. widely used for microdeletion syndromes but offers
8 Gilhar A, Gershoni‐Baruch R, Margolis A et al. Dopa reaction of fetal promising noninvasive first‐trimester testing in the
melanocytes before and after skin transplantation onto nude mice.
future. In addition, preimplantation genetic diagnosis has
Br J Dermatol 1995;133:884–9.
9 Oliver AM. The cytokeratin expression of cultured human foetal been used successfully for diagnosis of severe skin d isease
keratinocytes. Br J Dermatol 1990;123:707–16. (reviewed in [8]).
10 Scott G, Ewing J, Ryan D et al. Stem cell factor regulates human
melanocyte–matrix interactions. Pigment Cell Res 1994;7:44–51.
11 Holbrook KA, Smith LT, Elias S. Prenatal diagnosis of genetic skin References
disease using fetal skin biopsy samples. Arch Dermatol 1993; 1 Holbrook KA, Odland GF. The fine structure of developing human
129:1437–54. epidermis: light, scanning and transmission electron microscopy of
12 Sybert VP, Holbrook KA, Levy M. Prenatal diagnosis of severe the periderm. J Invest Dermatol 1975;65:16–38.
dermatologic diseases. Adv Dermatol 1992;7:179–209. 2 Holbrook KA, Dale BA, Smith LT et al. Markers of adult skin expressed
13 Sybert VP, Holbrook KA. Antenatal pathology of the skin. In:
in the skin of the first trimester fetus. Curr Prob Dermatol
Claireaux AE, Reed GB (eds) Diseases of the Fetus and Newborn: 1987;16:94–108.
Pathology, Radiology and Genetics. New York: Cockburn, Chapman 3 Holbrook KA. Structure and function of the developing human skin.
& Hall, 1995:755–68. In: Goldsmith LA (ed.) Physiology, Biochemistry and Molecular
Biology of the Skin, 2nd edn. Oxford: Oxford University Press,
1991:63–110.
Time‐scale of skin development 4 Holbrook KA. Structural and biochemical organogenesis of skin
and cutaneous appendages in the fetus and neonate. In: Polin RA,
There are several schemes for categorizing stages of Fox WW (eds) Neonatal and Fetal Medicine Physiology and
skin development (Fig. 1.1) [1]. Development is defined 5 Holbrook KA, Wolff K. The structure and development of skin. In:
by estimated gestational age (EGA) starting at the time Fitzpatrick TB, Eisen AZ, Wolff K et al (eds) Dermatology in General
of fertilization, which differs from calculations based on Medicine, 6th edn. New York: McGraw‐Hill, 1993:97–144.
the last menstrual period (LMP). Fertilization occurs on 6 Holbrook KA, Sybert VP. Basic science. In: Schachner L, Hansen R
(eds) Pediatric Dermatology, 2nd edn. New York: Churchill
average 2 weeks after the LMP. Human development is Livingstone, 1995.
separated into the embryonic period, before the onset of 7 Holbrook KA. A histologic comparison of infant and adult skin. In:
bone marrow function, which corresponds to fertiliza Boisits E, Maibach HI (eds) Neonatal Skin: Structure and Function.
New York: Marcel Dekker, 1982:3–31.
tion to 2 months EGA, and the fetal period from 8 Luu M, Cantatore‐Francis L, Glick S. Prenatal diagnosis of
2 months EGA until birth. The first trimester includes genodermatoses: current scope and future capabilities. Int J Derm
the entire embryonic period and the first stages of the 2010;49:353–61.
Chapter 1 Embryogenesis of the Skin 3
*Organogenesis

Histogenesis
Maturation
Amniocentesis: Fetal skin

Chorionic villus biochemical, biopsy:
sampling: DNA chromosomal morphological
analysis analysis analysis
1 2 3 4 5 6 7 8 9
Months
First trimester Second trimester Third trimester
Embryonic Fetal
Fig. 1.1 Time‐scale diagram identifying specific Embryonic-fetal Follicular Interfollicular

stages of skin development and identifying the transition keratinization epidermal
ages at which prenatal diagnosis can be performed keratinization
using each of the various methods currently
employed. Source: Adapted from Polin RA, Fox *Dashed lines suggest that the starting/ending point
WW. Fetal and Neonatal Physiology, 2nd edn. Vol. for these events is uncertain
1. Philadelphia: W.B. Saunders, 1998:730.
Embryonic skin
The primitive ectoderm of the developing blastocyst is
established at 1 week EGA, and by 20–50 days EGA the
development of major organs and organ systems of the
human embryo is initiated. The integumentary system
exhibits characteristics of the skin at 30 days EGA. The
epidermis, dermoepidermal junction (DEJ) and dermis
are well delineated and the tissue is innervated and vas
cularized (Fig. 1.2). The boundary between the dermis
and subcutaneous tissue is not clearly defined in all body
sites, but in some regions these two zones are distinct
from one another on the basis of a greater density of cells
and matrix in the dermis compared with the hypodermis.
The skin is closely associated with the underlying devel
oping striated muscle or cartilage on the appendages. (a)
There is no morphological evidence that epidermal
appendages have begun to form.
In most regions of the embryo, the epidermis is a sim
ple, flat, two‐layered epithelium consisting of basal and
periderm cells (Figs 1.2 and 1.3). The periderm is a dis
tinct embryonic layer that is eventually shed. Both types
of cells are mostly filled with glycogen, a molecule that
is characteristic of the cytoplasm of developing and
regenerating tissues, where it most likely serves as a
(b)
source of energy [1] (Fig. 1.3). Microvilli project from
the peridermal surface into the amniotic fluid (Figs 1.3b Fig. 1.2 (a) Tissue of the body wall of a 36‐day EGA human embryo and
and 1.4). The nucleus is centrally located in periderm (b) the skin from a 45‐day EGA human embryo. Note the two‐layered epidermis,
dermis and subcutaneous tissue and the more linear orientation of dermal cells
and basal cells, and the cytoplasmic organelles are
in contrast to the pleomorphic shapes of the subcutaneous mesenchyme. In
sparse and distributed either around the nucleus or at (b) note the periderm and basal cells of the epidermis, the closely associated
the periphery of the cell (Fig. 1.3b). Both layers contain fibroblastic cells in the dermis proximal to the epidermis and a nerve–vascular
distinct keratin intermediate filament proteins (Fig. 1.5) plane separating the dermis from the subcutaneous tissue (×200).
Fig. 1.3 Transmission electron micrographs of the embryonic epidermis. In

(a) note the glycogen (G)‐filled basal (B) and periderm (P) layer cells.
Desmosomes are evident between basal cells and between basal cells and
periderm cells. The DEJ is flat and shows few sites of increased density,
suggesting sites of desmosome formation. In (b) one periderm cell and
P portions of two basal cells are shown. Note the nature and disposition of
cytoplasmic organelles within both cell types, the keratin filaments
associated with desmosomes (arrow) and the microvilli extending from the
periderm surface (a, ×11 525; b, ×25 000).
(a)
Fig. 1.4 Scanning electron micrograph of the surface of 55‐day EGA

embryonic skin from the surface of the developing foot. The layer of cells
shown is the periderm. Note the microvilli and the variable size and shape
of the cells (×1000).
(50 kDa), that are characteristic of adult basal layer

keratinocytes [2,3] and additional keratin polypep
tides, K19 (40 kDa) and K8 (52 kDa), that are specific to
embryonic/fetal basal cells and periderm cells [2,3]. At
least one keratin polypeptide expressed in periderm
cells is different from those in the basal cells, K18
(45 kDa), although it is a marker for Merkel cells [5]. In
contrast to the adult tissue, the filaments in fetal
embryonic epidermis are dispersed in the cytoplasm
or assembled in small, seemingly short, bundles
that are associated primarily with desmosomes and
hemidesmosomes (see Fig. 1.3b). Periderm cells and
basal cells also differ in the expression of many growth
factors, growth factor receptors (Fig. 1.6), cell adhesion
(b)
molecules and other cytoplasmic and cell‐surface
molecules [6–8].
Two of the immigrant cells that are prominent in
adult epidermis, melanocytes (neural crest in origin)
[2,3], and unique cell‐surface molecules [4]. The latter and Langerhans cells, are present in the embryonic
markers may reflect the differences in environments epidermis among basal cells and associated with
surrounding each layer. the basement membrane. Sheets of embryonic epider
The columnar‐shaped basal cells of the embryonic mis immunostained with an antibody that recognizes
epidermis express the keratins, K5 (58 kDa) and K14 m elanocytes specifically (HMB‐45, an inducible,


(a)
Fig. 1.6 Section of skin from a 78‐day EGA human fetus showing
differential expression of the A‐chain of platelet‐derived growth factor
(PDGF) in the basal and intermediate cell layers (green) and an absence of
staining in peridermal cells. The receptor for PDGFA, PDGFR‐α (red), is
expressed by cells in the dermis (×350).
(b)
(c)
(d)
Fig. 1.5 Immunostained samples of (a) early (∼50‐day EGA) and (b–d)
later (∼60‐day) human embryonic epidermis showing positive staining of
both periderm and basal layers with the AE1 (a) and AE3 (d) monoclonal
antibodies that recognize keratins. Both layers are negative when reacted
with the AE2 (c) antibody, which recognizes the differentiation‐specific
keratins (×350).
(a)
cytoplasmic antigen common to melanoma and embryonic/

fetal melanocytes [9,10]) show a remarkably high den
sity (∼1000 cells/mm2) of these cells organized in a
regular pattern of distribution (Fig. 1.7). They are den
dritic as early as 50 days EGA in general body skin but
there is no evidence of melanosomes in the cytoplasm
[11]. Langerhans cells are recognized in embryonic skin
as early as 42 days EGA on the basis of a reaction prod
uct for membrane‐bound Mg2+ adenosine triphos
phatase (ATPase) and histocompatibility locus antigen
(HLA‐DR) on the plasma membrane [12–14]. Their
truncated or dendritic morphology is also apparent (b)
(Fig. 1.8). Interestingly, they are present in skin before
Fig. 1.7 Embryonic skin from a 54‐day EGA human embryo immunostained
the bone marrow begins to function leading to a with the HMB‐45 monoclonal antibody, which recognizes an antigen in the
hypothesis that they are derived from the yolk sac or melanocyte. (a) Section of skin. Note the abundance and position of these
fetal liver at this age. At 7 weeks EGA, the density of cells within the two‐layered epidermis. (b) Epidermal sheet. Note the density,
Langerhans cells is about 50 cells/mm2 [13,14]. spacing and dendritic morphology of these cells (a, ×350; b, ×25).
A continuous basal lamina (lamina densa) underlies the

two‐layered epidermis and defines, morphologically, one

structural component of the basement membrane zone

[25–27]. The basal lamina is patchy, however, in regions of
the body where the epidermis may be only a single layer,
for example, superior to the spinal cord. The molecules and
antigens characteristic of all basal laminae (type IV colla
gen, laminin, heparan sulphate proteoglycan, nidogen/
entactin) are present in the earliest recognized basal lamina
of the skin; skin‐specific molecules are recognized later
during the first trimester in accord with the more promi
nent development of the attachment structures [28,29].
A thin, mat‐like layer of microfilaments lies just inside the
Fig. 1.8 Epidermal sheet from a 53‐day EGA human embryo immunostained
to recognize HLA‐DR antigen in epidermal Langerhans cells (×400). basal plasma membrane of the basal cell keratinocytes
Source: Micrograph courtesy of Dr Carolyn Foster. (Fig. 1.9). It may reinforce this surface of the epidermis and
add to the strength of the DEJ at this stage when the struc
tural modifications associated with dermoepidermal adhe
sion (hemidesmosomes, anchoring filaments, anchoring
The third immigrant cell, the Merkel cell, can be rec fibrils) are rudimentary [30]. The same organization of fila
ognized in embryonic palmar skin as early as 55–60 ments is observed in cultured keratinocytes, which do not
days EGA (see Eccrine sweat gland formation) at a den typically form hemidesmosomes and anchoring fibrils in
sity of ∼130 cells/mm2 [15], using as a marker any one vivo, and in basal keratinocytes under pathological situa
of the set of keratins expressed by Merkel cells (K8, K18, tions, such as junctional epidermolysis bullosa, in which
K10 and K20) [5,16–18]. K20 is the only keratin found the epidermis separates from the dermis.
exclusively in Merkel cells [18]. At this embryonic age, The antigens associated with the attachment structures
they are distributed randomly and in a suprabasal posi (laminin 5/epiligrin/kalinin and 19 DEJ‐1 for hemides
tion. Merkel cells are neuroendocrine cells that were mosomes and anchoring filaments [31–34]; type VII
originally thought to function primarily as slow‐adapting collagen for anchoring fibrils [35]) are not seen by light
mechanoreceptors. Studies that have found soluble microscopic immunostaining methods until early in the
mediators produced by these cells such as nerve growth fetal period. It is likely, however, that keratinocytes begin
factor (NGF) and brain‐derived neurotrophic factor to synthesize these proteins in the embryonic period but
[19,20] suggest that it is likely that Merkel cells are tar that the methods used for detection are not sensitive
gets for ingrowing nerve fibres or other cells such as the enough to demonstrate their low levels of expression.
smooth muscle cells of the arrector pili muscle [21,22]. The dermoepidermal boundary is flat in the embryonic
Their presence in selected sites of developing epidermal skin (Figs 1.2, 1.3 and 1.9) and thus presents a limited
appendages (e.g. sweat glands and hair follicles) has surface area for nutrients to traverse between the dermis
also been suggested to stimulate or to correlate with and the epidermis. This may be relatively less important
active proliferation of the tissue. It is generally accepted in the developing skin than in infant and adult skin
that Merkel cells are derived from keratinocytes in situ because the dermis is thin and the small, dispersed bun
[16,18,21,23,24]. dles of dermal matrix proteins and the hydrated condition
Fig. 1.9 Enlarged view of the DEJ of human embryonic epidermis showing the microfilament network within the basal epidermal cell (arrows), sites where
desmosomes are forming (arrowhead) and the lamina densa. Note collagen fibrils (C) surrounding the dermal fibroblastic cells (×11 625).
of the interstitial matrix permit more rapid diffusion of

substances than the mature skin.
The dermis in the embryo is highly cellular (Figs 1.2
and 1.10), but it also contains the extracellular fibrous
matrix proteins, types I, III, V and VI interstitial collagens,
characteristic of adult dermis [30,36–43]. Small bundles of
collagen accumulate in a thin, dense layer, called the retic
ular lamina, immediately beneath the dermoepidermal
interface (Figs 1.2b, 1.5 and 1.9). They are also dispersed
throughout the dermis in varying densities according to
the collagen type and age of the embryo. Types I, III and
VI collagen are distributed uniformly throughout the
dermis. Type V collagen is concentrated primarily along
basement membranes (at the DEJ and around blood ves
sels) and surrounding cells (Fig. 1.11). Fibre bundles
within the interstitial spaces are widely dispersed by a
hydrated, hyaluronic acid‐rich proteoglycan matrix
(a) [44,45] (Figs 1.11 and 1.12). The fluidity of the matrix at
this stage permits migration of mesenchymal cells to sites
of active tissue morphogenesis.
A broader zone of sulphated proteoglycan‐rich matrix,
called the compact mesenchyme, is delineated beneath
the epidermis on the basis of its rich concentration of cells
that express growth factor receptors – the platelet‐derived
growth factor receptor β (PDGFR‐β) and PDGFR‐α (see
Fig. 1.6), nerve growth factor receptor (NGFR) – and cell
adhesion molecules (e.g. neural cell adhesion molecule,
NCAM) [44,45]. Evidence from the skin of non‐human
species during development has shown enlargement of
the composition of growth factors and receptors and
adhesion molecules that are included in this dermal zone
(reviewed in [44] and [46–48]). The compact mesenchyme
may be involved in the exchange of signals between the
epidermis and dermis and may be very important in
stimulating the onset of appendage formation. Many of
the growth factors that correspond to the receptors on the
mesenchymal cells are produced by cells of the develop
ing epidermis (e.g. PDGF‐AA, PDGF‐BB and NGF)
(Fig. 1.6). The compact mesenchyme may also be the earli
est evidence of a papillary dermis. In the adult, the modi
fied composition and structure of the papillary dermis
probably reflects molecular interactions between the epi
dermal and dermal cells, similar to the situation of the
compact mesenchyme.
Elastic fibres are not formed in the embryonic skin, but
fibrillin (the microfibrils of elastic fibres) (Fig. 1.13) and
elastin proteins of the elastic fibre can be identified immu
nohistochemically [30,36–40,42] and microfibrils can be
seen by electron microscopy [30].
Fine nerve fibres and capillaries are present within the
compact mesenchyme and deeper dermis (Fig. 1.14a),
and large nerve trunks and vessels are readily apparent in
the subcutaneous region. Reconstructions of vessels from
(b)
serial sections of developing first‐trimester skin have
Fig. 1.10 Transmission (a) and scanning (b) electron micrographs of the
shown that the basic pattern of cutaneous vasculature is
embryonic dermis at 48 days EGA beginning at the DEJ. The matrix is less
evident in the sectioned sample (a) than in the whole‐mount specimen (b)
established in the first trimester [49]. New vessels pre
(a, ×4500; b, ×1500). sumably both form de novo from dermal mesenchyme
and sprout from deeper, established vessels through a
process that includes endothelial cell migration, capillary
budding and vessel remodelling [50]. Pieces of full‐thickness
(a) (b)
(c) (d)
Fig. 1.11 Samples of embryonic skin immunostained with antibodies that recognize type I (a), III (b), V (c) and VI (d) collagens. Note that all of the collagens
are concentrated beneath the DEJ but types III and V, especially, are found in association with all basement membranes. Types I, III and VI are found in the
matrix throughout the dermal and subcutaneous tissue (a–c, ×150; d, ×300). Source: Immunostaining courtesy of Dr Lynne T. Smith.
Fig. 1.12 Section of the body wall from a 57‐day EGA embryo treated
with the Alcian blue/periodic acid–Schiff (PAS) histochemical stains. The
bright pink staining of the epidermis (glycogen) and DEJ (glycoproteins)
indicates a PAS‐positive reaction. The blue dermis reflects the high content
of hyaluronic acid. The dermal–subcutaneous boundary is marked by a
transition to a lighter slightly purple reaction indicating more of the
collagen–glycosaminoglycan complex (×300). Source:
Immunohistochemistry courtesy of Dr Richard Frederickson.
Fig. 1.13 Section of skin from a 57‐day EGA human embryo immu-
nostained with an antifibrillin antibody. Note staining throughout the
dermis (×200). Source: Immunostaining courtesy of Dr Lynne T. Smith.

(a)
Fig. 1.15 Nerves and vessels in the skin of a 79‐day EGA human fetus
immunostained with an anti‐neurofilament antibody. Note the positively
stained nerve network, the immunopositive cells (presumably Merkel cells)
and the vascular network (clear) (×25). Source: Immunostaining courtesy
of Dr Mark Bressler.
fibres become organized in networks throughout the

ermis and in relation to developing epidermal append
d
ages [53]. At 7 weeks EGA, a few calcitonin gene‐related
product (CGRP)‐immunopositive fibres, denoting sen
sory fibres, are also evident [53], but autonomic nerves
are not yet recognized in the skin. Staining the tissue with
the p75 low‐affinity NGFR antibody also reveals the pat
terns of nerve fibres and specific concentrations of mesen
chymal cells (e.g. around developing hair follicles) [54].
(b) Both nerves and vessels are visible in stained, full‐thickness
samples of the nearly transparent skin (Fig. 1.15).
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24 Tilling T, Wladykowski E, Failla AV et al. Immunohistochemical anal enchymal interaction and order of molecular reappearance. J Invest
yses point to epidermal origin of human Merkel cells. Histochem Cell Dermatol 1996;107:639–46.
Biol 2014;141:407–21. 48 Widelitz RB, Jiang T‐X, Noveen A et al. FGF induces new feather
25 Marinkovich MP, Keene DR, Rimberg CL. Cellular origin of the der buds from developing avian skin. J Invest Dermatol 1996;107:
mal–epidermal basement membrane. Dev Dyn 1993;196:255–67. 797–803.
26 Christiano AM, Uitto J. Molecular complexity of the cutaneous base 49 Johnson CL, Holbrook KA. Development of human embryonic and
ment membrane zone: revelations through the paradigms of epider fetal dermal vasculature. J Invest Dermatol 1989;93:10S–17S.
molysis bullosa. Exp Dermatol 1996;5:1–11. 50 Karelina TV, Goldberg GI, Eisen AZ. Matrix metalloproteinases in
27 Uitto J, Pulkkinen L. Molecular complexity of the cutaneous basement blood vessel development in human fetal skin and in cutaneous
membrane zone. Mol Biol Rep 1996;23:35–46. tumors. J Invest Dermatol 1995;105:411–17.
28 Fine JD, Smith LT, Holbrook KA et al. The appearance of four base 51 Dalsgaard CJ, Rydh M, Haegerstrand A. Cutaneous innervation in
ment membrane zone antigens in developing human fetal skin. man visualized with protein gene product 9.5 (PGP 9.5) antibodies.
J Invest Dermatol 1984;83:66–9. Histochemistry 1989;92:385–9.
29 Smith LT, Sakai LY, Burgeson RE et al. Ontogeny of structural compo 52 Gulbenkian S, Wharton J, Polak JM. The visualisation of cardiovascu
nents at the dermal–epidermal junction in human embryonic and lar innervation in the guinea pig using an antibody to protein gene
fetal skin: the appearance of anchoring fibrils and type VII collagen. product 9.5. J Autonom Nerv Syst 1987;18:235–47.
J Invest Dermatol 1988;90:480–5. 53 Terenghi G, Sundaresan M, Moscoso G et al. Neuropeptides and a
30 Holbrook KA. Structure and function of the developing human skin. neuronal marker in cutaneous innervation during human foetal
In: Goldsmith LA (ed.) Physiology, Biochemistry and Molecular development. J Comp Neurol 1993;328:595–603.
Biology of the Skin, 2nd edn. Oxford: Oxford University Press, 54 Holbrook KA, Bothwell MA, Schatteman G et al. Nerve growth factor
1991:63–110. receptor labelling defines developing nerve networks and stains
31 Hopkinson SB, Riddelle KS, Jones JCR. Cytoplasmic domain of the follicle connective tissue cells in human embryonic and fetal skin.
180‐kD bullous pemphigoid antigen, a hemidesmosomal component: J Invest Dermatol 1988;90:609A.
molecular and cell biologic characterization. J Invest Dermatol
1992;99:264–70.
32 Ishiko A, Shimizu H, Kikuchi A et al. Human autoantibodies against Embryonic–fetal transition
the 230 kD bullous pemphigoid antigen (BPAG1) bind only to the
intracellular domain of hemidesmosome, whereas those against the The most remarkable time in skin development is the
180 kD bullous pemphigoid antigen (BPAG2) bind along the plasma embryonic–fetal transition, which occurs at approxi
membrane of hemidesmosome in normal human and swine skin.
J Clin Invest 1993;91:1608–15. mately 2 months’ gestation, when the embryo measures
33 Verrando P, Blanchet‐Bardon C, Pisani A et al. Monoclonal antibody about 31 mm in length (crown–rump), weighs about 2.5 g
GB3 defines a widespread defect of several basement membranes and and has a humanoid appearance. The skin and the under
a keratinocyte dysfunction in patients with lethal junctional epider
molysis bullosa. Lab Invest 1991;64:85–92.
lying tissues of the body wall are translucent, revealing
34 Fine J‐D, Horiguchi Y, Couchman JR. 19‐DEJ‐1, a hemidesmosomal– the ribs and solid organs. The skin has a mucoid quality
anchoring filament complex associated monoclonal antibody: definition (Fig. 1.16). In spite of this structural simplicity, the cells in

c
n c
n
(a)
M
Fig. 1.16 Sample of human fetal skin of 80 days EGA held at the tips of a
forceps and demonstrating the mucoid quality of the tissue.
the skin begin to express characteristics of adult skin. The

2‐month age is thus identified as an important landmark
in skin development (see Fig. 1.1). Since this period of
development begins the establishment of adult character
istics of the skin, it is a stage that is vulnerable to errors in
n
development. The most apparent change in the skin is the
stratification of the epidermis from two to three cell layers
(Fig. 1.17a and b). An intermediate cell layer is added as
the product of basal cell mitoses. Basal cells divide asyn (b)
chronously to produce an epidermis that, initially, remains
Fig. 1.17 Skin from a human fetus of approximately 70–89 days EGA
two‐layered at some sites and at others becomes three lay
shown at the light (a) and electron (b) microscopic levels. Note the
ers thick. intermediate layer of cells between basal and periderm epidermal layers,
Intermediate cells are both similar to and distinct from the distinction between dermis and subcutaneous tissue based on
basal and periderm cells. Keratins are more abundant differences in the orientation of fibroblastic cells, the density of collagenous
and distributed in a more specific distribution than in matrix and the subcutaneous vascular plane. Small nerves (n) and
the cells in the basal and periderm layers; small bundles capillaries (c) are evident in the dermis. Segments of melanocytes (M)
of keratin filaments associated with desmosomes outline are evident within the basal layer and collagen is accumulated beneath
the DEJ (×3675).
the boundaries of the intermediate cells (Fig. 1.17b). The
expression of the major keratin pairs in both basal‐ and
intermediate‐layer keratinocytes in the early fetal epi on the surface of intermediate‐layer cells. Like the peri
dermis is now identical to the expression of the keratins derm and basal cells, the first intermediate cells still con
in the fully keratinized adult epidermis. The K5 and K14 tain glycogen as the primary cytoplasmic component
basal cell keratins are downregulated in the intermedi (Fig. 1.17a and b). Thus, at this stage, when the epidermis
ate cells and a new keratin pair, K1 (56.5 kDa) and K10 is only a few cell layers thick, and has few similarities in
(67 kDa), the high‐molecular‐weight differentiation‐ morphology to adult epidermis, it possesses all of the
specific keratins, is synthesized [1,2] (Fig. 1.18). Other keratins and many of the other markers that are typical
markers of keratinocyte differentiation (e.g. pemphigus of the epidermis throughout life. Therefore, genetic
antigen [3], cornified cell envelope proteins [4,5], blood diseases that involve mutations in keratin proteins have
group antigens [6] and cell‐surface glycoproteins [7]; the potential of being expressed as early as the first
reviewed in [8–11]) are also expressed in the cytoplasm or trimester in development.
(a)
(b)
Fig. 1.18 Keratin filaments in the cells of the intermediate layer of 77‐day
EGA fetal skin stain positively with the AE2 monoclonal antibody, which
recognizes the K1 and K10 differentiation‐specific keratins (a). The reaction
pattern is even stronger when a second intermediate layer is added at the
beginning of the second trimester (b) (a, ×120; b, ×120).
Fig. 1.20 Scanning electron micrograph of the periderm of a 60‐ to
70‐day EGA human fetus showing the blebs and microvilli that modify the
amniotic surface (×8000).
Fig. 1.19 Skin from a 72‐day EGA fetus immunoreacted with an anti‐epidermal
growth factor receptor showing a reaction pattern on the membranes of
basal and intermediate layer cells and on the basal and lateral borders of
periderm cells (×120).
Fig. 1.21 Section of skin from an 82‐day EGA fetus immunostained with
Initially, the keratinocytes of both basal and intermediate the HMB‐45 antibody, which recognizes melanocytes. Note the high density
cell layers express epidermal growth factor (EGF) recep of the cells and their position within the basal epidermal layer (×200).
tors [12] (Fig. 1.19), respond to EGF and retain the ability
to proliferate [13,14]. Near the end of the first trimester, ifferentiation. There must be more processes involved,
d
however, the proliferative cells become restricted primar however, than simply the addition of cell layers because
ily to the basal layer [13,14]; only the basal cells express embryonic skin maintained in suspension organ culture
P‐cadherin [15], a marker of proliferative ability. Basal stratifies to become several layers thick but will not dif
cells change in morphology and cell‐surface properties ferentiate in the manner characteristic of early fetal skin
after stratification. A greater volume of the cytoplasm is in vivo [18,19].
occupied by organelles and keratin filaments than with Melanocytes are easily recognized in sections of fetal
glycogen, and cell‐surface carbohydrates that correlate epidermis at 8 weeks EGA by their position along the
with stratification and differentiation are differentially basement membrane, dense cytoplasm, an absence of
expressed by cells of the basal and intermediate layers glycogen and a heterochromatic nucleus [20]. Around
[7,16]. Selected basal‐ and intermediate‐layer keratino 80 days EGA, they are present in the epidermis in maxi
cytes participate in the formation of the epidermal mal density (∼3000 cells/mm2) [20] compared with all
appendages: the pilosebaceous structures, nails and teeth, other stages of skin development, and in a nonrandom
and the eccrine sweat glands in thick skin. The morpho distribution among cells of the basal layer (Fig. 1.21). The
genesis of these structures is described under Unique fea numbers decrease towards birth then continue to decline
tures of developing human skin. over the decades of postnatal life. The high numbers of
The cells of the periderm increase in size and develop melanocytes around the embryonic–fetal transition may
microvilli‐covered blebs that extend from the outermost reflect the fact that these cells arrive early in the skin, pro
surface of the cell into the amniotic cavity (Fig. 1.20). The liferate and remain close together before there is substan
molecular species of keratins remain the same as they tial growth of the fetus. The labelling index of keratinocytes
were in the embryonic periderm cells, but the cells lose is also high [13] at this stage, suggesting that the paracrine
their ability to divide and to express P‐cadherin [13,17]. interactions between melanocytes and keratinocytes that
Because the epidermal cells that are located in the more occur in the adult skin may be established early in devel
superficial layers express differentiation‐related antigens, opment [20]. Melanosomes are recognized late in the
it is appealing to link stratification and the onset of third month of development (Fig. 1.22) and show some

Fig. 1.24 Section of skin from the palm of an 83‐day EGA fetus
immunostained to recognize keratin 18 (green), an antibody that
recognizes Merkel cells within the basal layer. Note the regular distribution
of cells, presumably marking the sites of primary epidermal ridge location.
The skin of the hand is more advanced in development than that of the
trunk at an equivalent age (×300). Source: Immunostaining courtesy of
Fig. 1.22 Section through late embryonic–early fetal skin showing Dr Dong‐Kun Kim.
developing melanosomes in a melanocyte positioned between keratino-
cytes in the basal layer. The early age of the tissue is confirmed by the
immature structure of the DEJ (×25 000). however, by about 13 weeks EGA Langerhans cells seem
to express both markers with reasonable consistency.
By the end of the first trimester, Merkel cells are located
along the primary epidermal ridges of palmar skin in
regular alignment relative to the sites of origin of the
sweat duct primordia and at a maximum density of ∼1400
cells/mm2 [25,26] (Fig. 1.24). In hair‐bearing skin, they
first become evident in association with the developing
hair germs. At later stages in follicle development, they
concentrate in the infundibulum and bulge regions of the
hair pegs and bulbous hair pegs [27,28]. It is likely that the
dermal Merkel cells originate in the follicular or interfol
licular epidermis and migrate into the dermis, where they
are suggested to play a role at early stages of develop
ment in attracting and organizing nerve fibres in the
upper dermis and around developing appendages [29].
Merkel cells in the interfollicular epidermis lack NGF
Fig. 1.23 Epidermal sheet from an 80‐day EGA fetus reacted to demonstrate receptors (and produce NGF [30]), but dermal Merkel
ATPase. Note the regular distribution and density of these highly dendritic cells and Merkel cells of the developing follicle are immu
cells (×120). nopositive when the tissue is reacted with the p75 NGF
antibody [29]. It must be recognized, however, that nerve
evidence of pigment formation in selected sites of the fibres are already apparent in the embryonic dermis
body. Understanding the density of melanocytes and the before dermal Merkel cells are detectable; thus, other fac
onset of pigment synthesis had been previously useful in tors must also attract or direct nerves into the skin. Other
prenatal diagnosis of tyrosinase‐negative oculocutaneous morphological markers that are characteristic for Merkel
albinism, a technique no longer used [15,21]. cells in postnatal skin, such as dense core granules, are
Langerhans cells are also abundant in the epidermis at not apparent in dermal Merkel cells at this stage. Merkel
this stage (∼50/mm2) [22,23]. Unlike melanocytes, which cells decrease in number during the later stages of fetal
migrate into the epidermis only during the embryonic development [29].
period, the bone marrow‐derived Langerhans cells The DEJ has acquired all of the adult features that are
migrate into the epidermis continually throughout life; characteristic for this region (Fig. 1.25). Hemidesmosomes,
their numbers do not increase significantly, however, until anchoring filaments and anchoring fibrils are structurally
the third trimester and after birth [22,23]. Langerhans cells complete, and the antigens related to these attachment
at 80 days EGA are highly dendritic (Fig. 1.23), begin to structures, the skin‐specific markers of the DEJ, are also
express CD1a at the surface [22–24] and develop Birbeck expressed [31–33]. Immunostaining with an antibody to
granules in the cytoplasm, suggesting that they may be type VII collagen outlines the DEJ with high intensity [32]
capable of processing and presenting antigen in utero. The and stains basal cell cytoplasm (the primary source of this
number of cells that are HLA‐DR positive is significantly protein) with low intensity. Nonetheless, the structural
greater than the number that express CD1a at this stage; organization of the DEJ appears delicate in contrast to the
(a)
Fig. 1.25 Transmission electron micrograph of the DEJ of a 78‐day EGA
human fetus. Note the well‐formed hemidesmosomes and associated
keratin filaments, anchoring filaments within the lamina lucida and fine
anchoring fibrils (×47 500).
(b)
Fig. 1.27 Light micrograph of 78‐day EGA human skin showing the
vascular pattern organized in a series of horizontal plexuses and vertical
connecting vessels (a, b). Note that the diameters of the vessels become
increasingly smaller towards the epidermal surface. In the higher‐magnifi-
cation image, the rounder cells of the papillary dermis are distinct from the
more elongated fibroblastic cells of the reticular dermis and subcutaneous
region (a, ×25; b, ×100). Source: Micrographs courtesy of Dr Greg Hébert.
subcutaneous mesenchymal cells still retain glycogen in

the cytoplasm, but they have assumed a distinctly fibro
blastic morphology and are responsible for the synthesis
of all of the matrix molecules that are characteristic of
adult dermis. There is accumulation of small bundles of
fibrous proteins within the interstitial space and papillary
and reticular regions of the dermis are demarcated on the
Fig. 1.26 Light micrograph of 72‐day EGA fetal dermis stained with the
basis of increased cell density proximal to the epidermis
Alcian blue/periodic acid–Schiff (PAS) histochemical stain. The low‐
magnification image shows the clear demarcation between the dermal
(the papillary region) and larger collagen fibril diameter
and subcutaneous tissue and the different concentrations of fibrous and and fibre bundle size in the reticular region [9,34–36]
glycosaminoglycan matrix proteins in the two regions. A vascular plane (Fig. 1.27b). The position of the subpapillary vascular
also demarcates the two regions. Skeletal muscle is evident in the lower plexus of arterioles and postcapillary venules also forms
right corner of the micrograph (×200). Source: Histochemical staining an approximate boundary between these two dermal
courtesy of Dr Richard Frederickson. zones. In spite of the significant accumulation of matrix
protein, the dermis remains highly cellular, with the
robust structure of the basal lamina and anchoring fibrils matrix accounting for substantially less of the bulk of the
in adult skin. The dermoepidermal interface is still flat skin than it does in the postnatal infant and the adult.
although modifications of individual basal cells begin to The skin is still transparent enough to permit the net
alter the smoothness of this junction. works of vessels and nerves to be seen through the body
The dermis and subcutaneous tissue are distinguished wall of the fetus (Fig. 1.28). The vessels are organized in
on a morphological basis by differences in the organiza the dominant pattern of adult skin, with one plexus
tion and composition of the matrix (Fig. 1.26). Dermal and located at the dermosubcutaneous boundary and another
lumina of some of these structures suggest that they may

belong to the venous side of the vasculature although the
simplicity of the wall structure would suggest they could
be lymphatics.
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1995;104:411–16. in the second trimester include completion of the forma
28 Narisawa Y, Hashimoto K, Nakamura Y et al. A high concentration of tion of the lanugo hair follicle and synthesis of the hair
Merkel cells in the bulge prior to the attachment of the arrector pili (around 17–19 weeks EGA), completion of the formation
muscle and the formation of the perifollicular nerve plexus in human
fetal skin. Arch Dermatol Res 1993;285:261–8.
of the nail (around 20–22 weeks EGA) and keratinization
29 Narisawa Y, Hashimoto K, Pietruk T. Biological significance of der- of the interfollicular epidermis (around 22–24 weeks
mal Merkel cells in development of cutaneous nerves in human EGA). The timing is variable because the formation of the
fetal skin. J Histochem Cytochem 1992;40:65–71. hair follicle and epidermal keratinization are regionally
30 Vos P, Stark F, Pittman RN. Merkel cells in vitro: production of nerve
growth factor and selective interactions with sensory neurons. Dev dependent. Sweat glands on the general body surface
Biol 1991;144:281–300. only begin to form around 17–18 weeks EGA (see Unique
31 Fine JD, Smith LT, Holbrook KA et al. The appearance of four base features of developing human skin). The 24‐week‐old
ment membrane zone antigens in developing human fetal skin.
J Invest Dermatol 1984;83:66–9.
fetus is fully formed and has hair on the scalp and body
32 Smith LT, Sakai LY, Burgeson RE et al. Ontogeny of structural compo surface. The length is about 228 mm (crown–rump).
nents at the dermal–epidermal junction in human embryonic and One or two additional intermediate cell layers are
fetal skin: the appearance of anchoring fibrils and type VII collagen. added to the epidermis by proliferation of basal keratino
33 Hertle MD, Adams JC, Watt FM. Integrin expression during human cytes and upward migration of the first intermediate cells.
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112:193–206. sal, intermediate cell layers, which become progressively
34 Smith LT, Holbrook KA, Byers PH. Structure of the dermal matrix
more flattened towards the epidermal surface (Fig. 1.30).
during development and in the adult. J Invest Dermatol 1982;
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35 Smith LT, Holbrook KA, Madri JA. Collagens types I, III and V in of keratin filaments, which can be seen in stained specimens
human embryonic and fetal skin. Am J Anat 1986;175:507–22. at the light microscopic level as a reticulate cytoskeleton
36 Smith LT, Holbrook KA. Embryogenesis of the dermis. Pediatr

Dermatol 1986;3:271–80.
(Fig. 1.30). Glycogen is still a major constituent of the
37 Holbrook KA, Bothwell MA, Schatteman G et al. Nerve growth factor cytoplasm.
receptor labelling defines developing nerve networks and stains As the epidermis thickens, the interface it forms with
follicle connective tissue cells in human embryonic and fetal skin. the dermis becomes less flattened and smooth, due largely
J Invest Dermatol 1988;90:609A.
38 Terenghi G, Sundaresan M, Moscoso G et al. Neuropeptides and a to changes in the basal surface of each keratinocyte rather
neuronal marker in cutaneous innervation during human foetal than to convolutions of the layer itself. Basal cells stain
development. J Comp Neurol 1993;328:595–603. with less intensity than the intermediate‐layer cells
because there is less glycogen, the bundles of keratin
filaments are smaller and the cytoplasm is more ribosome
Fetal skin
rich, dense and organelle filled (Fig. 1.30). At the end of
Conclusion of the first trimester the second trimester, the five‐layered interfollicular
The first stages of fetal skin development occur from the epidermis keratinizes. Skin of the trunk shows signs of
time of the embryonic–fetal transition at 2 months to the keratinization around 21 weeks EGA in the uppermost
end of the first trimester at 3 months, when a template of intermediate cell layers and the overlying periderm
the adult skin is established. There are notable features of (Fig. 1.31).
adult skin that are still lacking. The epidermis has yet to Changes in the structure and composition of the plasma
keratinize and one of the key proteins of keratinization, membrane mark the formation of a cornified cell enve
filaggrin, is not yet expressed in any region of the skin. lope [1,2], and lamellar granules are identified in the cyto
The dermoepidermal interface lacks rete ridges and rete plasm (Fig. 1.31) and in the spaces between intermediate
pegs. The dermis lacks fully formed elastic fibres and an and periderm layers. The modified intermediate cells
elastic fibre network. Ectodermal appendages are just remain associated with the overlying periderm cells by
starting formation in limited areas; for example, sweat infrequent and tenuous‐appearing desmosomal attach
gland development is initiated only on the palms and ments. Cells are also evident in which the nucleus is pyk
soles and apocrine glands have not begun to develop. notic and the cytoplasm contains dense bundles of
Hair and nails are not synthesized. Adipose tissue has not filaments, vacuoles and other remnants of the cytoplasm.
differentiated within the mesenchyme of the hypodermis. Cells beneath these seemingly incompletely keratinized

(a) (b)
Fig. 1.30 Light (a) and electron (b) micrographs of a section of skin from a 104‐day EGA human fetus showing additional intermediate cell layers, changes
in periderm morphology, the reticulate keratin cytoskeleton in upper intermediate cells, less intense staining of basal cells (a, b) and the smaller bundles of
collagen fibrils in the papillary dermis (a). A melanocyte is evident (a, arrow). Several capillaries (a) and nerves (b, n) lie within the papillary region (a, ×300;
b, ×3500).
squames contain very small, stellate keratohyalin gran although the adult level of approximately 650 cells/mm2,
ules and react immunopositively with an antibody that or about 8500 cells/mm3, is not achieved until after birth
recognizes profilaggrin and filaggrin proteins of the gran [7]. Melanosomes are transferred to keratinocytes in the
ule [3] (Fig. 1.31). The two or three subjacent intermediate fifth month of gestation.
cell layers can now be called spinous cells. At this stage, All of the structures of the DEJ were formed in the first
periderm cells are very large in diameter, flattened and trimester, and only a few antigens of the DEJ (AF‐1 and
also display a thickened cell envelope. Each cell covers a AF‐2 associated with anchoring fibrils) remain to be rec
cluster of underlying epidermal cells. The periderm stains ognized at this age [8]. By 19–21 weeks EGA, the hemides
differently from the underlying epidermal cells, probably mosomes are present at the basal keratinocyte plasma
owing to a lesser amount of structural protein within the membrane with adult‐like frequency and show a strong
cytoplasm. association with basal cell keratin filaments. Anchoring
A few layers of thin, flattened, keratinized cells, organ filaments and banded anchoring fibrils are well formed
ized in the manner of a true stratum corneum, are first (reviewed in [9–12]).
apparent around 22–24 weeks EGA (Fig. 1.32). The granu Small bundles of interwoven, fibrous connective tissue
lar cell layer is now more typical of an adult granular occupy the interstitial space within the dermis (Fig. 1.33a),
layer in that keratohyalin granules are larger and the although they remain loosely organized because the sul
cytoplasm contains less glycogen. The numbers of layers phated proteoglycans and fibrous proteins of the intersti
of the stratum corneum continue to increase in the third tial matrix are still very hydrated. Elastin is detectable
trimester to reach a more mature appearance by 34 weeks biochemically, and elastic fibres can be recognized as
gestation [4]. Of note, premature birth hastens develop granular‐appearing structures along the borders of
ment of mature stratum corneum and epidermal thick collagen fibre bundles in immunostained samples of skin
ness with histologically similar appearance to term infants and by electron microscopy. The structure of the elastic
seen within 2–3 weeks after birth regardless of gestational fibres, however, even in the deepest portions of the reticu
age [4]. lar dermis, is similar to that of the elaunin fibres of adult
By 22–24 weeks EGA, 1700 Merkel cells/mm2 can be skin, which have only sparse amounts of elastin associ
measured in the epidermis [5,6] and the number of ated with the microfibrillar bundles. The extent to which
Langerhans cells begins to increase (∼200 cells/mm2), elastic fibres are developed is dependent upon the region
(a)
Fig. 1.32 Electron micrograph of the keratinized epidermis from a fetus at

the end of the second trimester. There are a few layers of cornified cells, a
single granular cell layer and three layers of spinous cells, which retain a
significant quantity of glycogen. Note the greater irregularity in the basal
border of the basal cells at the DEJ (×3000).
Third‐trimester fetal skin

The skin in the third trimester appears structurally similar
to postnatal skin (reviewed in [9–13]) (Fig. 1.34). The
epidermis is fully keratinized, contours are beginning to
(b) form at the DEJ, the regions of the dermis are well defined,
Fig. 1.31 Electron micrographs of the skin from two 21‐week EGA fetuses
the adnexa are fully formed and reside deeply in the
showing early (a) and late (b) changes in the upper intermediate layers dermis, and large fat lobules fill the hypodermis. There
(spinous) at the onset of keratinization. Note the regressed periderm are, however, some notable differences in structure in all
separating from the upper epidermal layers (a), lamellar granules in the top regions: suprabasal epidermal cells retain a significant
few layers (arrows), the small particulate (a) then stellate (b) keratohyalin amount of glycogen in the cytoplasm and the dermis
granules, and the few layers of incompletely keratinized cells (black remains relatively thin. The bundles of collagen matrix
material) to demonstrate the permeability of the epidermis to tracers
are small elastic fibres and are immature in structure and
(a, ×12 150; b, ×9500). Source: Micrograph (b) courtesy of Dr Richard
Frederickson.
composition, and the stratum corneum has fewer cell
layers than infant or adult skin.
Studies of the function of skin of the premature infant
provide some understanding of the status of the skin dur
of the skin. In addition to fibroblasts, mast cells, mac ing the third trimester. In general, various functions of the
rophages and smooth muscle cells are present in the skin, such as barrier properties, temperature regulation,
dermis [9–12]. sweating, response to tactile and mechanical stimuli [14],
The hypodermis remains distinct from the dermis by its that have been measured reflect the gestational age more
less dense matrix and cellularity. Around 15–16 weeks than the birthweight.
EGA, mesenchymal cells collect in globular arrays sur The epidermis, even though keratinized and possessing
rounded by a capsule‐like assembly of matrix (Fig. 1.33b). several layers of stratum corneum cells, is a less effective
This is the first stage of adipose tissue formation. Small barrier than the infant epidermis. Transepidermal water
vessels are present within these cellular aggregations. By loss, for example, decreases in a steep slope from 26 weeks
18 weeks EGA, lipid droplets are evident within some of EGA to 38 weeks EGA. It decreases even further and with
the mesenchymal cells, and by 20 weeks lobules of fat are a similarly rapid decline over the first 10–15 postnatal
established. days (reviewed in [15,16]). Disorders of keratinization or

(a)
Fig. 1.34 A section through skin obtained from a third‐trimester (34‐week)

human fetus showing all regions of the skin and the presence of hair
follicles and eccrine sweat glands (×40).
(reviewed in [15,16]). These compromised epidermal

arrier properties, coupled with the fact that the preterm/
b
neonatal infant’s body surface‐to‐volume ratio is very
high, can place the premature infant at significant risk.
Although the structure and cellular differentiation of
the sweat glands in the preterm infant and term newborn
(see Unique features of developing human skin) appear
little, if any, different from those of the infant, the sweat
ing function requires a period of maturation after birth,
presumably for the innervation to become fully estab
lished. The sweating response is limited or absent in the
preterm infant to an extent that correlates with the gesta
tional age (reviewed in [13]). Apocrine glands begin to
secrete during this trimester [9–12].
Some aspects of the vasculature are less organized in
the third‐trimester fetus and the newborn than is charac
(b)
teristic in the infant. The marked redness of the newborn
Fig. 1.33 Scanning electron (a) and light (b) micrographs of the human reflects the high density of superficial vessels in the der
fetal dermis at 15 weeks EGA showing the density of the fibrous matrix,
mis and the thinness of the epidermis. Remodelling of the
the differences in textures between papillary and reticular regions (a), and
the boundary between the dermis and subcutaneous regions (a, b). The
microcirculation occurs as appendages and regions of the
developing hair follicles are evident in cross‐section in (a) and in longitudinal skin are completed. At birth, the capillary network is still
section in (b). A lobule of subcutaneous fat (arrows) is evident in (b) disorganized and will stabilize only after birth (reviewed
(a, ×80; b, ×100). in [9–12]).
References
infection of the skin may give an even greater disadvan 1 Holbrook KA, Underwood RA, Dale BA et al. Formation of the
tage to the premature newborn in its ability to regulate cornified cell envelope in human fetal skin: presence of involucrin,
substances crossing the skin. The stratum corneum of the keratolinin, loricrin and transglutaminase correlated with the onset
of transglutaminase activity. J Invest Dermatol 1991;96:542A.
preterm infant is more permissive to absorption of sub 2 Akiyama M, Smith LT, Yoneda K et al. Expression of transglutaminase
stances from the external environment and those applied 1 (TG1) and cornified cell envelope (CCE) proteins during human epi
to skin to protect, treat or cleanse it in the neonatal nursery dermal development. J Invest Dermatol 1997;108:598 (Abstract).
3 Dale BA, Holbrook KA, Kimball JR et al. Expression of the epidermal The most remarkable features of the periderm are the
keratins and filaggrin during fetal human development. J Cell Biol
morphological changes that the periderm cells undergo

1985;101:1257–69.
4 Evans NJ, Rutter N. Development of the epidermis in the newborn. with progressive stages of development [8]. Studies of the
Biol Neonate 1986;49:74–80. surface of the developing skin using scanning electron
5 Moll R, Moll I, Franke W. Identification of Merkel cells in human skin microscopy, and of corresponding tissue sections exam
by specific cytokeratin antibodies: changes in cell density and distri
bution in fetal and adult plantar epidermis. Differentiation
ined by light and transmission electron microscopy from
1984;28:136–54. consistent regions of the body, have established the stages
6 Kim D‐G, Holbrook KA. The appearance, density and distribution of of human skin development [8] (Fig. 1.35).
Merkel cells in human embryonic and fetal skin: their relation to The early embryo is covered by a thin, flattened pave
sweat gland and hair follicle development. J Invest Dermatol
1995;104:411–16. ment epithelium that is the periderm (Fig. 1.4). Around
7 Foster CA, Holbrook KA. Ontogeny of Langerhans cells in human 8–11 weeks, when the epidermis stratifies, the periderm
embryonic and fetal skin: cell densities and phenotypic expression cells increase in volume and develop a rounded external
relative to epidermal growth. Am J Anat 1989;84:157–64.
8 Lane AT, Helm HF, Goldsmith LA. Identification of bullous pemphig
surface. By 10–14 weeks, single blebs extend from the
oid, pemphigus, laminin and anchoring fibril antigens in human fetal amniotic surface of each cell and the cell increases in
skin. J Invest Dermatol 1985;84:27–30. diameter (see Fig. 1.20). All of the cell surface, including
9 Holbrook KA. Structure and function of the developing human skin. the blebs, is modified by microvilli. A network of micro
In: Goldsmith LA (ed.) Physiology, Biochemistry and Molecular
Biology of the Skin, 2nd edn. Oxford: Oxford University Press, filaments is organized beneath the plasma membrane.
1991:63–110. Later in the second trimester, the surfaces of the peri
10 Holbrook KA. Structural and biochemical organogenesis of skin
derm cells project multiple blebs, the larger of which
and cutaneous appendages in the fetus and neonate. In: Polin RA,
have the configuration of a blackberry (Figs 1.30 and
Fox WW (eds) Neonatal and Fetal Medicine Physiology and
Pathophysiology. New York: Grune & Stratton, 1992:527–51. 1.36). The cell diameter continues to increase as the cells
11 Holbrook KA, Wolff K. The structure and development of skin. In: become thinly stretched over the epidermis. By 16–23
Fitzpatrick TB, Eisen AZ, Wolff K et al. (eds) Dermatology in General weeks EGA, the blebs flatten and the periderm regresses
Medicine, 6th edn. New York: McGraw‐Hill, 1993:97–144.
(Fig. 1.37). It once again becomes a very thin layer of
(eds) Pediatric Dermatology, 2nd edn. New York: Churchill cells, which, at this stage, rarely contain a nucleus, have
Livingstone, 1995. few if any organelles and are composed largely of disor
13 Holbrook KA. A histologic comparison of infant and adult skin. In: ganized, fine filaments [8].
Boisits E, Maibach HI (eds) Neonatal Skin: Structure and Function.
New York: Marcel Dekker, 1982:3–31. The periderm cells do not undergo the events of dif
14 Andrews K, Fitzgerald M. The cutaneous withdrawal reflex in human ferentiation that are typical for the keratinocyte. The
neonates: sensitization, receptive fields, and the effects of contralat composition of keratins in the periderm cells remains
eral stimulation. Pain 1994;56:95–101.
15 Cartlidge PAT, Rutter N. Skin barrier function. In: Polin RA, Fox WW
unchanged throughout development and, since neither
(eds) Fetal and Neonatal Physiology, Vol. 1. Philadelphia: W.B. the K1/K10 keratin proteins nor profilaggrin are present
Saunders, 1992:3133–42. in the periderm cells of any stage, it is clear that they do
16 Chiou YB, Blume‐Peytavi U. Stratum corneum maturation. A review not undergo full keratinization. The plasma membrane of
of neonatal skin function. Skin Pharmacol Physiol 2004;17:57–66.
the early second‐trimester fetal periderm cell, however,
appears similar to a cornified envelope (Fig. 1.38a) and
the presence of several cornified cell envelope proteins,
nique features of developing human
U
involucrin, loricrin, keratolinin (cystatin), small proline‐
skin
rich proteins (SPRR) 1 and 2, and the transglutaminase 1
Periderm (TG1) enzyme, in the cytoplasm [9,10] of these cells has
The periderm is the outermost, transient cellular layer of been demonstrated (Fig. 1.38b–d). The expression of
the developing skin of some mammals and birds. These cornified envelope proteins in conjunction with ultras
embryonic epidermal cells are larger than basal keratino tructural studies suggests that periderm cells do contrib
cytes and cover the entire surface of the early epidermis. ute to the cornified envelope.
The origin of the periderm is not fully elucidated in humans Towards the end of the second trimester, individual
but mouse studies may give some clue to its development. periderm cells loosen from the underlying epidermal cells
It is possible that the amnion contributes cells to periderm and are desquamated over the sites of elevated and
that grow over the single‐layered epidermis. This is sup exposed hair canals (follicular epidermis). They remain
ported by the fact that the amnion and periderm are similar associated, however, with the interfollicular epidermis
in keratin composition [1,2] and surface morphology and until the stratum corneum is formed. At this time, the
in the expression of other antigens [3,4]. Studies from early periderm is mostly gone from the skin surface. The events
mouse embryos, however, suggest that a continuous sheet that lead to disengagement of this layer are not known.
of tissue may not cover the epidermis as proposed by this Abnormality of periderm shedding is hypothesized to
model, because patches of periderm cells are present in contribute to collodion formation.
some sites [5]. The single, ectodermal layer of the early The structural properties of periderm cells may provide
embryo may divide and give rise to a second cell layer that clues as to the function of the layer. The blebs and micro
becomes superficial to the basal layer [6]. This is supported villi increase the surface area of the periderm as it faces
by whole‐mount studies showing expression of basal‐layer the amniotic fluid, suggesting that these cells may be
keratinocytes K5 and K14 in both the single‐layer ectoderm important in the exchange of substances between the
and the periderm [7]. fetus and the amniotic fluid, across the skin, in one or

<36 days
35–55 days
95–120 days
55–75 days
110–160 days
65–95 days
Fig. 1.35 Stages of epidermal development

proposed on the basis of periderm structure. 85–110 days >160 days
Fig. 1.36 Scanning electron micrograph of the periderm from a mid‐second‐ Fig. 1.37 Scanning electron micrograph of the surface of the flexor
trimester fetus showing multiple, complex blebs and microvilli extending forearm of a late‐second‐trimester fetus showing the large, thin, regressed
from the amniotic surface (×1500). periderm cells (×800).
both directions. Direct evidence for this role in humans is fetus, the periderm has been shown to be involved in the
limited. A morphological study of the intramembranous uptake of drugs from the amniotic fluid [13]. It has also
modifications of the periderm plasma membrane sug been postulated that the periderm is a secretory epithe
gests that the cells have a role in regulating water trans lium that adds material to the amniotic fluid [14] and that
port [11], and Koren [12] has suggested that the skin it serves as a protective layer for the developing epidermis
absorbs nicotine dissolved in amniotic fluid; in the sheep (also reviewed in [15–17]). In mouse models of aberrant
(a) (b)
(c)
(d)
Fig. 1.38 Transmission image of the periderm cornified cell envelope from fetal skin of 21 weeks EGA (a). The periderm expresses involucrin early in the
first trimester. (b) Data from a 98‐day EGA fetus. Epidermal transglutaminase (c) is also expressed early in the periderm but does not appear to function
until the end of the first trimester, when it first demonstrates cross‐linking of dansyl cadaverine to substrate in the tissue (d) (a, ×41 250; b, ×300; c, ×300;
d, ×300).
or absent periderm development, pathological adhesions periderm cells. Keratin filaments are aggregated in the
developed at sites of apposed tissues [18]. This is likely second‐trimester skin of fetuses affected with epidermo
the mechanism behind popliteal pterygium syndrome lytic hyperkeratosis (EHK) [20] and epidermolysis bullosa
and cocoon or fetal encasement syndrome. simplex Dowling–Meara (EBS‐DM) [21], but none of the
The periderm is regionally variable in its properties filaments clump in periderm cells, nor are there other
and timing of development [2]. Periderm of the plantar consequences for the periderm layer. The absence of
surface of the toe, for example, shows a very late stage of clumping would be expected in the case of EHK since the
development at 70 days compared with trunk skin. At keratins involved in this disorder are not keratins that are
this time, the epidermis of the appendage is thicker and present in periderm cells, but basal cells and periderm
more differentiated than trunk skin. This suggests that the cells do share keratins in common. The persistence of
nature of the underlying epidermis determines the rate periderm cells with no adverse outcome in an environ
of modification of the periderm. This is supported by ment of severe cell destruction in layers proximal to the
similarities in keratin patterning between the basal periderm in EHK is surprising and argues for autonomy
keratinocytes and the periderm cells [7]. The pattern of of this layer. To the contrary, however, animal models of
development of the mature stratum corneum follows disorders where mature epidermal barrier function is not
periderm disaggregation, suggesting a functional achieved (e.g. ichthyosis) show incomplete shedding of
relationship between these two processes which coin the periderm suggesting a complex interplay that is not
cides with the limits of fetal viability between 22 and yet understood fully [22].
26 weeks EGA [19].
The periderm is thus a distinct layer of cells that is defined Regionalization in developing skin
early in development from the remainder of the epidermis. Regional differences in properties of the skin are well
Many genetic disorders, for example, that modify cells of documented in adult skin. Regionalization is also a
the basal and intermediate layers during development phenomenon of developing skin even at very early ages
appear to have no direct or indirect consequences for of gestation. Few systematic studies have been done to
document these regional differences consistently through

out development [8,23]. Without a clear appreciation and
accurate knowledge of differences in normal morphology
at various sites, structural evaluation of skin samples that
may be from unknown regions can be difficult. At the
same time, it is essential to appreciate whether the disease
of concern is also expressed with regional variation not
only in the adult but also at the onset of expression of the
disease during development [24,25]. In at least one situa
tion, the understanding of regional variability of expres
sion of a disease at its first presentation was gained from
samples obtained for prenatal diagnosis [26] (Fig. 1.39).
Systematic studies of affected fetal skin from multiple
regions are valuable to undertake when tissue becomes
available. Such efforts also expand our knowledge of the (a)
natural history of the disorder.
Keratinization
Keratinization of the nails, hair follicles (follicular epider
mis), intraepidermal sweat ducts and the interfollicular
epidermis occurs at different times during gestation. The
nails are the earliest structures of the skin to keratinize
in utero, with the appearance of cornified cells as early as
11–12 weeks EGA. The timing of keratinization of follicu
lar epidermis is consistent with the cephalocaudal direc
tion of follicle morphogenesis [25]; the interfollicular
epidermis keratinizes first in thick skin and then in thin
skin, with the latter also proceeding in a regionally
dependent manner. The timing of keratinization for a
given region appears to follow a rigidly specified pro
gramme during development. The molecular mediators
of keratinization are beginning to be elucidated and in (b)
many instances disruption of these pathways causes Fig. 1.39 Sections of skin obtained in utero by fetal skin biopsy from a
diseases of abnormal keratinization [26]. Even in these fetus at risk of lamellar ichthyosis. Note the difference in morphology
situations of abnormal keratinization, for example in between the two samples. One sample shows an epidermis of normal
fetuses affected with lamellar ichthyosis, harlequin ich thickness and state of development for 19 weeks EGA (a). The second
thyosis and EHK, there is no evidence for early or delayed sample shows a thickened epidermis, still covered by periderm (b). In both
samples, hair canals were excessively keratinized. This disorder is expressed
onset of the keratinization process in either the follicular
in utero with regional variation (a, ×300; b, ×300).
or interfollicular epidermis (reviewed in [27–30]).
Appendage formation After the embryo–fetal transition, around 10–11

The embryonic epidermis gives rise to diverse structures weeks EGA, basal epidermal cells, through various
collectively known as the ectodermal appendages. molecular events, undergo proliferation at specifically
Despite their diverse structure and function in the mature patterned sites to form buds that grow down into the
skin, the hair follicles, nails, sweat glands, mammary dermis as hair germs and sweat ducts, or as a fold of
glands and teeth have similar early inductive events. tissue that establishes the nail fold. These earliest induc
Interactions between the embryonic ectoderm and under tive events lead to the formation of an epidermal thick
lying dermis are important in the development of the skin ening, the placode. The epithelial layers then proliferate
appendages. Experimental studies of appendage forma with growth into the mesenchyme, forming a bud. After
tion have revealed the early molecular events that occur bud formation, specific characteristics of the diverse
stepwise to control various aspects of appendage forma appendages emerge. Nerves and vessels, cell adhesion
tion (reviewed in [31]). Epithelial and mesenchymal cells molecules (CAMs), soluble mediators and homeobox
lie in close proximity at the sites of appendage formation, genes (homeoproteins) have been implicated in the pat
and in some cases make physical contact (Fig. 1.40). These tern formation of certain appendages (reviewed in [32–37).
structures are thought to develop in response to epithe Several molecular pathways, including Wnt/β‐catenin,
lial–mesenchymal interactions that initiate the process fibroblast growth factor (FGF), transforming growth
through instructive messages, sustain the process through factor (TGF)β/bone morphogenetic protein (BMP) and
permissive interactions and then support differentiation hedgehog pathways, are well established as mediators
and maintenance of the fully developed appendage. of these early interactions (reviewed in [31]). The
(a)
Fig. 1.40 Developing hair germ showing the close proximity between the
epithelial cells of the germ and the mesenchymal cells of the dermis, which
will follow the developing appendage and influence its development and
differentiation (×8250).
e vidence for these interactions in the development of

the epidermal appendages in human skin is best docu
mented for formation of the pilosebaceous apparatus
[38–40].
Nail formation
(b)
The formation of the nail unit is highly dependent on dor
sal–ventral patterning of the limb bud. As with other ecto Fig. 1.41 Developing nail. (a) Scanning electron micrograph of a digit from
dermal appendages, epithelial–mesenchymal pathways an 85‐day EGA fetus showing the boundaries of the nail field recognized
by proximal (identifying the position of the nail fold), lateral and distal
are critical for proper patterning (reviewed in [41]).
folds. (b) A section through the digit of a 70‐day EGA fetus shows the
Mutations in factors critical in dorsal–ventral patterning position of the nail fold and the thicker and more advanced epidermis over
of the mammalian limb, such as Wnt7a, engrailed 1 (EN1) the nail bed (a, ×100; b, ×150).
and LIM homeobox transcription factor 1β (LMX1B), give
rise to developmental nail anomalies such as nail–patella
syndrome. By 90 days EGA, the dorsal ridge is evident superfi
The distal rays of the digit are evident on the hand of cially and is delineated from the plantar surface of the
the 50‐day EGA embryo, and within the next 7 days the digital pad by a deep constriction (Fig. 1.42a). The nail
digits separate [42]. Formation of the nail on the dorsal fold has invaginated deeply into the dermis and
surface of the digits and the eccrine sweat glands on organized into dorsal (roof of the fold) and ventral
the ventral surface is initiated at approximately the (floor of the fold) layers that are distinguished from
same time after embryo–fetal transition. By 70 days’ one another morphologically and functionally
gestation, the boundaries of the nail field are estab (Fig. 1.42b). The ventral fold becomes the nail matrix,
lished externally by proximal, lateral and distal folds which is primarily responsible for the synthesis of the
(Fig. 1.41a) and sections through the digit reveal a shal nail plate.
low nail fold (Fig. 1.41b). Development of the epider The earliest nail, which is formed late in the first trimes
mis over the nail bed is furthest advanced at its ter, consists of several layers of keratinized cells that are
distal‐most margin [43,44]. evident primarily at the distal margin of the nail bed and

(b)
(a)
(c)
(d)
Fig. 1.42 Developing digit and nail. (a) Scanning electron micrograph of the ventral surface of the developing digit of an 80‐day EGA fetus showing the
dorsal ridge and the large volar pads. (b) Transverse section through the nail fold of a digit from an 85‐day EGA fetus showing the distinction between
dorsal and ventral (presumptive nail matrix) surfaces of the nail fold. The higher‐magnification section shows more detail of the epidermal surface and the
mesenchyme beneath the nail fold. (c) Transverse sections through the digit and distal‐most tip of the nail bed of a digit from a 105‐day fetus showing
keratinization of the superficial cells forming the ‘preliminary’ nail. (d) Scanning electron micrograph of a nail of a 140‐day EGA fetus showing the fragile
nature of the nail plate (a, ×60; b, ×100; c, ×200; d, ×100).
over the dorsal ridge. By 15 weeks EGA, a thick cornified Eccrine sweat gland formation
layer covers the nail bed (Fig. 1.42c). This ‘preliminary’ Human skin has the highest density of eccrine sweat
nail is easy to slough from the surface and thus may be glands amongst mammals. The development of the digits
composed to a greater extent of keratinized epidermal and the morphogenesis of eccrine sweat glands and nails
cells from the nail bed rather than derived from the matrix occur on the hand in advance of the foot and on the distal
of the nail fold. The nail of a 19‐week EGA fetus is estab pads ahead of the middle and proximal phalanges and
lished by both the nail matrix and the nail‐bed epidermis, the palm [32,42]. Eccrine sweat glands form on the gen
although the nail is still fragile (Fig. 1.42d). The nail that is eral body surface at least 4–6 weeks later than on the
present at birth is actually a composite of layers of cells palms and soles. They are the last of the epidermal
derived from the dorsal nail fold (contributes the outer appendages to be formed (reviewed in [32]). The struc
most layer of the nail) and the nail matrix (contributes the tural events have been much better characterized for the
intermediate layer of the nail); the distal half to two‐thirds ridged skin of the palmar plantar and digital skin than for
of the nail bed contributes the inner layer of the nail. The trunk skin (reviewed in [15–17]). About 8.5–9 weeks EGA,
layers are more evident in the fetus than in the postnatal the shape of the terminal digit is evident. Volar pads, tran
individual [45]. sient mounds of mesenchyme that accumulate beneath
the epidermis on the ventral surface of the digits, are well

formed (Fig. 1.42a). Their presence in the first trimester

is presumed to influence the dermatoglyphic patterns

[46,47] and the development of those flexion creases that
are not considered to be dependent upon movements of
the hand [42,48,49]. Interest in the development of flexion
creases relates to the aberrant patterns they assume in cer
tain congenital disorders. Volar pads begin to regress
around 10.5–11 weeks EGA and are nearly gone by 12.5–
13 weeks EGA [42] when, presumably, their influence is
no longer needed for morphogenesis.
The primary epidermal ridges are first formed around
10–11 weeks EGA [50]. They are recognized in sectioned
specimens as localized aggregations of basal epidermal (a)
cells on the digits, palms and soles (Fig. 1.43a); in sheets of
epidermis viewed basally, they appear first as discontinu
ous then as continuous ridges [51]. At this stage, the epi
dermis on the plantar surface consists of five or six layers
of intermediate cells and the periderm. Merkel cells con
taining the characteristic granules are distributed along
the primary epidermal ridges, where they may attract
periglandular nerve fibres to this position of the structure
[52] (Fig. 1.43b). Electron microscopy has revealed nerve
fibres associated with basal laminae underlying the ridges
and Merkel cells, and occasionally extending into the
epidermal tissue [32]. Merkel cell–nerve complexes are
evident in digital skin before the primary ridges begin to
(b)
form, and remain prominent in the primary ridges after
the appearance of the sweat gland anlagen (Fig. 1.43a).
They do not appear to migrate, however, into any region
of the developing appendage.
The sweat gland primordia are recognized around
13–14 weeks at regular sites along the now flattened
ridges as narrowed, solid, epithelial cords of cells that
contain basal cell keratins and express classical carci
noembryonic antigen (CEA) on all cells [50,52]. There is
no evidence of condensed mesenchyme associated with
the onset of sweat gland development as there is in fol
licle development, thus suggesting that other sources of
signalling molecules, possibly the volar pad mesenchyme,
or nerves and/or other cell–cell interactions (perhaps
within the epithelium) may instruct the sites for appendage
formation and trigger the onset of gland development.
As the cords of epithelial cells elongate into the der
mis, a thickening at the terminus defines the glandular
segment from the duct [53] (Fig. 1.44a). Ductal, secre (c)
tory, myoepithelial and acrosyringial cell types differ Fig. 1.43 Developing sweat glands on the ventral surfaces of the digit.
entiate in the dermal and intraepidermal regions of the (a) Cross‐section through the digit of a 95‐day EGA fetus showing the
gland and duct, and are easily distinguished from one primary epidermis ridges organized from the basal layer of the epidermis.
another by light and electron microscopy (Fig. 1.44) Note the abundance of nerves and vessels in the proximal dermis.
(b) Immunolabelled section through the palm of a 105‐day fetal hand
and by immunostaining patterns using antibodies to
showing the position of Merkel cells (green) marked by an antibody that
keratin intermediate filament proteins [53]. All cells recognizes keratin 18. The red labelling recognizes neurofilaments in
continue to express CEA [52]. The secretory cells bor dermal nerve fibres. (Source: Micrograph courtesy of Dr Dong Kun Kim.)
der a central lumen within the gland; myoepithelial (c) Immunolabelled section through the palm of a 163‐day fetal hand
cells are evident at the periphery of the structure. Cells showing the position of Merkel cells (green) marked by an antibody that
of layers of the duct and of the gland are distinct from recognizes keratin 20. The red labelling recognizes neurofilaments in
one another at 15 weeks EGA by their morphological dermal nerve fibres. Note the well‐established sweat ducts and the
secondary epidermal ridges alternating with the primary ridges from which
properties and by differences in expression of keratins
the ducts are formed. (Source: Micrograph courtesy of Dr Dong‐Kun Kim.)
(duct) and vimentin (gland) and CAMs [53,54]. (a, ×300; b, ×300; c, ×100.)
Coexpression of the two intermediate filament proteins

(a) (c)
(d)
(b)
Fig. 1.44 Developing sweat glands and ducts. (a) Scanning electron micrograph of the palm of a 19‐week EGA fetus showing the elongated ducts and the
club‐like terminal gland. (b) A section through the palm of a 147‐day EGA fetus shows the position of the duct and gland in the dermis and the canalization
(keratinization) of the intraepidermal portion of the duct. A higher‐magnification image of the gland and duct in the palmar dermis of a 126‐day EGA fetus
(c) shows the cell layers of the duct and the cells of the gland (arrows). (d) Scanning electron micrograph of the undersurface of palmar epidermis of a
19‐week EGA fetus showing the primary epidermal ridges with the remnants of torn sweat ducts spaced periodically and the secondary ridges that do not
give rise to sweat ducts (a, ×80; b, ×120; c, ×300; d, ×80).
in the same cells of the secretory segment of the devel Secondary ridges form between the primary ridges (see
oping gland is unique to this appendage, but it is char Figs 1.43c and 1.44d). They do not give rise to sweat glands
acteristic of other glandular tissues such as mammary or contain Merkel cells. Globular keratohyalin granules
and salivary glands [53]. are evident in the cytoplasm of the circumferentially
organized cells of the intraridge, the intraepidermal por Pilosebaceous apparatus formation
tion of the duct (the acrosyringium) at about 15 weeks The pilosebaceous apparatus is best described as a com
EGA, signalling the onset of canalization in the acrosyrin posite epithelial–mesenchymal structure with critical
gium (Fig. 1.45). The lumen of the duct forms by the molecular ‘cross‐talk’ between the two. Morphogenesis of
fusion of cytoplasmic vesicles within ductal cells. The the hair follicle begins on the head and face at around
duct remains partially occluded even in the third trimes 70–80 days EGA, shortly after the epidermis stratifies,
ter [55]. By 22–24 weeks EGA, the sweat glands on the then proceeds in a cephalocaudal direction [20]. The pro
palms and soles have attained the structure of the adult cess is completed at around 19–20 weeks EGA, when
glands, with a coiled secretory gland. hairs extend from the lanugo follicle through the peri
The absence of sweat glands is a hallmark of the derm‐covered surface of the skin. Follicles form in regular
ectodermal dysplasias due to mutations in ectodysplasin patterns in all body regions, with the distances separating
pathway genes [56]. The ectodysplasin pathway interacts each dependent upon the specific site (Fig. 1.46). The
with the Wnt/β‐catenin pathway, amongst others, to con stages of follicle development, including hair germ, hair
trol eccrine gland formation from induction through peg, bulbous hair peg and lanugo follicle stages of follicle
secretory duct differentiation [57]. While these pathways formation (Fig. 1.47), are based on the vellus hairs on the
are shared with other skin appendages, the molecular trunk [58]. Follicles form only during development and
mechanisms leading to specification of eccrine glands decline in numbers as a function of ageing.
specifically is not well established. The induction of follicles, their stages of development,
maintenance in the adult and the cyclical growth and
regression of the scalp follicles are all dependent upon an
association of the follicle epithelium with dermal mesen
chymal cells that form a cellular and matrix sheath
around the developing and mature follicle and establish
the dermal papilla as a special collection of mesenchymal
cells that modulate the production and elongation of
hairs [59].
(a)
(b)
Fig. 1.45 Formation of the intraepidermal sweat duct by the development
and coalescence of vesicles and subsequent keratinization of the lining Fig. 1.46 Scanning electron micrograph of the undersurface of the
cells (a). Note the globular keratohyalin granules that are characteristic of epidermis from a 15‐week EGA fetus showing the pattern of hair follicles
acrosyringial keratinization (×9100). Source: Micrograph originally in the hair peg and hair germ stages of development. Note the longitudinal
published in Odland G, Holbrook K. Curr Prob Derm 1981;9:29–49. grooves in the epidermis that mark the position of intraepidermal hair
Reproduced with permission of Karger Publishers. canals (×100).

Fig. 1.47 Diagram of the stages of hair follicle
formation including the prefollicle two‐layered
epidermis, pregerm, hair germ, early hair peg,
late hair peg/early bulbous hair peg and
lanugo follicle stages.
The epithelial and mesenchymal cells have been exten At around 13–14 weeks EGA, the hair germs elongate
sively characterized at each stage of follicle formation into the dermis as cords of cells called hair pegs (Figs 1.46
with regard to the expression of growth factors, growth and 1.50). The hair peg consists of an inner core of cuboi
factor receptors, cytokines, other signalling molecules dal cells and outer layer of columnar cells that is associ
and growth regulators, and structural proteins and ated with the basal lamina surrounding the follicle and
enzymes (reviewed in [60–63]). Experimental studies in continuous with that of the interfollicular epidermis.
animal models, transgenic animals, tissue recombination Cells of the outer layer contain the same keratins as the
preparations and various cell and organ culture systems basal epidermal keratinocytes and the cells of the inner
have revealed the functions of specific populations of core contain intermediate cell keratins (Fig. 1.50a), thus
cells in developing follicles (e.g. dermal papilla and cells implicating the origins of follicle cells from two epider
of the bulge) and events that signal early and sequential mal layers. Merkel cells are distributed among the outer
steps in the induction of other appendage primordia root sheath keratinocytes.
[31,36,37]. Thus, the data can be used only to infer what Early hair pegs are cylindrical, but as they elongate
may be occurring in utero at the time the human follicles further they develop three regions: (i) a constricted, neck‐
form de novo as most studies are done on postnatal like connection with the epidermis (the presumptive
human hair follicles. infundibulum); (ii) a central, cylindrical region (the
The sites of follicle formation can be recognized, even presumptive isthmus); and (iii) a terminal zone that

before the hair germs are visible, in sections of fetal skin by becomes widened at its most distal end (the lower follicle
immunostaining the tissue with an antibody that recog and the presumptive bulb) (Fig. 1.50). The length of
nizes the matrix molecule tenascin [33,34]. Patches of reac the hair peg and the three zones of the developing follicle
tion product at the basement membrane zone correspond are exaggerated in some regions of the skin but more
to pregerms, or sites where basal keratinocyte nuclei are subtle in others.
closely spaced and mesenchymal cells are aggregated Changes occur in all three regions, with the first notable
(Fig. 1.48) [64,65]. Cells from the basal epidermal layer bud events taking place at the proximal and distal ends.
into the dermis to become hair germs (Fig. 1.48b). Elongated core cells in the neck of the follicle continue
Condensed mesenchymal cells associate closely with the into the epidermis, where they form a strand of cells that
germs, often extending processes that contact the basal lies between the basal and intermediate cell layers (see
lamina (Fig. 1.40); this collection of mesenchymal cells is Fig. 1.50). This is the hair tract that marks the position and
intensely immunoreactive with antibodies to NGFR (p75) pathway of the presumptive hair canal (Fig. 1.50c) [66].
(Fig. 1.49), NCAM and other growth factor receptors. The distal end of the hair peg flattens and the epithelial
Little if any collagenous matrix is present around the cells cells along this basal border elongate to form a distinct
as a consequence of either downregulated production or layer that establishes the matrix (Fig. 1.50a and b). The
enhanced degradation (reviewed in [33,34]). Merkel cells flattened end of the follicle begins to invaginate into
are recognized in some of the developing germs. As is the the cord, shaping the bulb with the matrix as the roof of
case with the other appendages in which Merkel cells are the bulb. Mitotic figures are evident in matrix cells, and lon
prominent, they may play a role in targeting nerve fibres gitudinally orientated cells, presumably the progeny of
towards the developing appendage. the dividing matrix cells, move out of the matrix into the
(a)
(b)
Fig. 1.48 Immunolabelled section of human fetal skin at 70–75 days EGA
showing tenascin‐positive sites where hair germs have formed or are (a) (b)
expected to form (a and b). The clustering of basal keratinocytes is
apparent at sites where tenascin is strongly expressed in the basement
membrane zone (a) (a, ×100; b, ×350). Source: Micrograph courtesy of
Dr Beth Kaplan.
(c)
Fig. 1.50 Late‐stage hair pegs (a, b) showing the continuity of the
intermediate‐layer keratins into the upper core cells of the follicle (a), the
regions of the peg and the mesenchymal cells surrounding the peg and
aggregated at its tip (the presumptive dermal papilla) in association with
the presumptive matrix of the follicle. Note the differences in cell
Fig. 1.49 Hair germs in the skin of a 97‐day fetus immunostained to orientation in the inner and outer and the distal and proximal regions of
recognize the p75 neurotrophic receptor, which recognizes NGFR. Note the the peg (b). (c) Section through the upper end of a hair peg showing the
concentration of this immunoreactive material within the mesenchymal continuation of cells into the epidermis as the hair track (a, ×300; b, ×300;
cells surrounding the hair germ (×120). c, ×300).
centre of the cord, thereby establishing the first layers of

the inner root sheath and the hair (the hair cone). Cells of in [27]) (Fig. 1.51). Such samples can be induced to syn
the outer layer of the follicle located adjacent and lateral thesize melanin by the dihydroxyphenylalanine (DOPA)
to the matrix appear to become more loosely associated reaction if the fetus is normal [67,68].
with one another, perhaps permitting the inward migra During these events, the cord is surrounded in its
tion of the cells derived from the matrix. Melanocytes entirety by several layers of elongated mesenchymal cells
aggregate in the matrix and produce melanin ahead of that form a sheath. The connective tissue matrix is sparse
melanocytes in the general body skin, thus making the within this cellular sheath and appears to be devoid of
bulbs of developing hair follicles ideal sites to examine the fibrillar collagens that are present in the surrounding
when evaluating skin biopsy samples from a fetus at risk subepidermal and interstitial matrix (Fig. 1.52). Diffe
of tyrosinase‐negative oculocutaneous albinism (reviewed rences in matrix molecules are observed at different levels

(a)
(a)
(b)
(b)
Fig. 1.51 The bulb of a hair peg (a) and lanugo follicle (b) in skin from
different regions obtained at ages 115 days and 125 days EGA. Note the
concentration of melanocytes in the matrix of the follicle (a, ×300;
b, ×300).
of the hair peg and when comparing the dermal papilla

with the follicle sheath [33,34].
Between 15 and 17 weeks EGA, bulges of epithelial
cells begin to grow out from the epithelial cord on the
posterior surface of the follicle and the adult layers of the
follicle differentiate into the hair and internal root sheath.
Once these bulges form, the follicle is called a bulbous
hair peg (Fig. 1.53a). The factors that stimulate the devel
opment of these structures to arise from the follicle, at a
precise stage in the hair peg formation and at precise sites
along the hair peg, are unknown. There are no obvious
landmarks along the hair peg that provide morphological (c)
clues as to how the bulges might originate. Fig. 1.52 Sections of fetal skin immunolabelled with antibodies to
The most superior bulge is the primordium of the collagens of the dermis. Note the decreased staining for types I (a),
sebaceous gland (Fig. 1.53a). Cells begin to produce III (b) and V (c) collagens in the developing hair germs (a, ×300;
sebum soon after this structure is evident. Analysis of b, ×300; c, ×300). Source: Immunolabelling studies by Dr Lynne T.
Smith.
epidermal lipids from fetal skin at this stage reveals a
sterol/wax ester content, which suggests that the mate
rial is similar to adult sebum [69]. The second bulge, the
‘true bulge’, forms concurrently with and slightly distal
to the sebaceous gland. It is the site of follicular stem cells
(a)
(b)
Fig. 1.54 The hair canal. (a) Section through the skin of a 138‐day EGA
fetus showing the floor of an opened hair canal. Keratinization of this
structure stands out in contrast to the non‐keratinized epidermis.
(b) Scanning electron micrograph of the skin of a 21‐week EGA fetus
(a) (b) showing hair canals within (beneath the surface of) the epidermis. Note
that one hair has emerged and others are evident through the thinned
Fig. 1.53 Bulbous hair peg in the skin of a 15‐week EGA fetus. (a) In the epidermal layers above the canal (a, ×100; b, ×185).
longitudinal section through the follicle, note the sebaceous gland, the
bulge located just distal to the sebaceous gland, the cell layers of the inner
root sheath (inner bar) and the outer layers of the outer root sheath (outer (axilla, areola, scalp, external eyelid, auditory meatus
bar). The infundibulum is the region of the follicle that lies between the and anogenital regions).
sebaceous gland and the epidermis. Note the cells of the dermal papilla
The cylindrical layers of the follicle differentiate and
within the bulb. (b) A cross‐section through a region between the two bars
shows the layers of the outer root sheath and the inner root sheath (a,
keratinization begins in several different structures of the
×300; b, ×300). follicle concurrently: the outer layer of cells of the inner
root sheath (layer of Henle); the cuticle and cortex of the
hair (Fig. 1.53b); the sebaceous duct; and the hair canal.
[70] and the point of attachment of the arrector pili mus Continued production of cells of the three layers of the
cle (Fig. 1.53a). Multipotent epithelial stem cells reside in inner root sheath and the hair gradually creates the kerati
the bulge [71]. The stem cell population is maintained nized tube of the inner root sheath and the hair.
throughout development and postnatal life, giving rise Keratinization within the hair tract canalizes the cord of
to the cells responsible for regenerating the cycling folli cells and forms a keratin‐lined channel that courses diag
cle as well as having an important role in wound healing. onally through the epidermis (Figs 1.50c and 1.54a) [69].
Merkel cells also concentrate in the bulge at early stages The granular and cornified cell layers of the hair canal
of bulge formation. They may be important in establish form a sharp contrast with the remainder of the, as yet
ing this structure, stimulating proliferation or attracting non‐keratinized, epidermis (Fig. 1.54a). The angle of the
nerve fibres and smooth muscle cells to the site. A third canal with the epidermis and the intraepidermal length of
bulge may form superior to the sebaceous gland as the the canal are regionally variable. On the eyebrow, for
primordium of the apocrine sweat gland. These struc example, the hair canals are closely spaced and their
tures are located in the restricted sites of the body where paths are very short. In other regions of the body, such as
apocrine sweat glands are present in the postnatal infant the appendages, the canals can be very long. By examining

Fig. 1.55 Cross‐section of the hair canals from a fetal skin sample
obtained at 23 weeks EGA from a fetus affected with harlequin ichthyosis.
Keratinization of these structures is extraordinarily thick (×300).
Fig. 1.57 Skin from a 117‐day EGA fetus, immunostained with the AE13
antibody, which recognizes a hair keratin (×120).
whole‐mount preparations of tissue at this stage by the

presence of melanin‐producing melanocytes in the
matrix and the melanin pigment in the hair (Fig. 1.51b).
Antibodies to hair keratins also highlight the forming
hair in sections of skin (Fig. 1.56). The first hairs of the
fetus are in the anagen phase of the hair cycle. By 24–28
weeks EGA, the fetal follicles enter catagen and then
telogen phase. There is shedding of the first lanugo hairs
into the amniotic fluid prior to re‐entry into second
anagen. Due to synchronous cycling in newborns, a sig
nificant number of follicles will enter telogen postna
tally and be shed, creating alopecia that can last up to
6 months.
Fig. 1.56 A lanugo follicle associated with an epidermal sheet from a
126‐day EGA fetus. Note the hair, sebaceous gland, bulge and sebum‐ References
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eruption of hair in the human fetus. J Invest Dermatol 1978;71:385–90. data also provide information about composition, and
67 Eady RAJ, Gunner DB, Garner A et al. Prenatal diagnosis of oculocu thus the morphological approaches have allowed a rea
taneous albinism by electron microscopy. J Invest Dermatol
1983;80:210–12.
sonable story of skin development to unfold. Continuing
68 Kikuchi A, Shimizu H, Nishikawa T. Epidermal melanocytes in nor advances in molecular techniques and animal models
mal and tyrosinase‐negative oculocutaneous albinism fetuses. Arch have further contributed to understanding the pathways
Dermatol Res 1995;287:529–33. and interactions needed for normal skin development.
69 Williams ML, Hincenbergs M, Holbrook KA. Skin lipid content dur
ing early fetal development. J Invest Dermatol 1988;91:263–8. In addition, advancing knowledge of genetic skin dis
70 Cotsarelis G, Sun T‐T, Lavker RM. Label‐retaining cells reside in ease continues to shed further light on these pathways
the bulge area of pilosebaceous unit: implications for follicular and how perturbations in developmental pathways lead
stem cells, hair cycle and skin carcinogenesis. Cell 1990;61:1329–37.
to cutaneous disease. Further advances in understand
71 Akiyama M, Dale BA, Sun T‐T et al. Characterization of hair follicle
bulge in human fetal skin: the human fetal bulge is a pool of undif ing skin development will undoubtedly lead to new
ferentiated keratinocytes. J Invest Dermatol 1995;105:844–50. therapeutic approaches.
36
CHA PTER 2
Molecular Genetics in Paediatric Dermatology

Anna C. Thomas1 & Veronica A. Kinsler1,2
1
Genetics and Genomic Medicine, UCL Great Ormond Street Institute of Child Health, London, UK
2
Paediatric Dermatology Department, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK
Introduction, 36 Which samples to take for genetic Concept of personalized medicine, 39

Genetics and inheritance in brief, 36 testing, 39 Molecular genetics techniques, 40
Consent for genetic testing and incidental How to interpret genetic results, 39
findings, 38 What to do with a genetic result, 39
Abstract volume of genetic data generation, and have made the transition
from the research sphere to the diagnostic laboratories. The iden-
tification of disease‐causing genetic mutations in both inherited
Molecular genetics is the study of the structure of genes at molecu-
and sporadic paediatric dermatological conditions has begun to
lar level, and the impact of gene expression and regulation on the
influence clinical management, allowing preimplantation genetic
biology of the organism. The interplay between these two fields,
diagnosis, stratification for targeted personalized medical therapies,
genetics and biology, is a burgeoning area in all disease. In recent
or gene therapy in some cases. This chapter reviews the essential
years the process of disease gene identification and clinical genetic
terminology, key techniques and important advances needed to
diagnostic reporting has been revolutionized by the technologies
update paediatric dermatologists in this field, forming a basis for
discussed in this chapter, most prominently next‐generation
the detailed disease‐specific chapters that follow.
sequencing (NGS). These techniques have increased the speed and
Introduction confirm a diagnosis or to subclassify disease, the

identification of disease‐causing genetic mutations in
Molecular genetics is the study of the structure of genes at both inherited and sporadic paediatric dermatologi-
a molecular level, and the impact of gene expression and cal conditions has begun to be clinically relevant in
regulation on the biology of the organism. The interplay clinical management. Preimplantation genetic diagno-
between these two fields, genetics and biology, is a bur- sis (PGD) as part of the in vitro fertilization (IVF) pro-
geoning area in all disease. For essential terminology in cess can be offered for future pregnancies where there is
molecular genetics, see Table 2.1. a family history and the genetic defect is known, for
A large number of skin conditions have now had their example in epidermolysis bullosa and the autosomal
genetic aetiology identified and this information can be recessive ichthyoses. In other instances the genetic
easily accessed through many of the online curated defect will stratify patients towards targeted medical
databases available, for example Online Mendelian therapies, such as in the vascular overgrowth disorders.
Inheritance in Man (www.omim.org) and the Decipher In addition, paediatric dermatology is now in the era
database (https://decipher.sanger.ac.uk), as well as from of personalized genetic therapy, and this will surely
published literature. be an area of tremendous growth in the decade to come.
In recent years, the process of disease gene identifica- Techniques of gene therapy will be discussed in
tion and clinical genetic diagnostic reporting has been Chapter 170.
revolutionized by the technologies discussed in this chap-
ter, most prominently next‐generation sequencing (NGS).
These techniques have increased the speed and volume of
genetic data generation, and have made the transition
Genetics and inheritance in brief
from the research sphere to the diagnostic laboratories. The human genome is comprised of deoxyribonucleic acid
Storage and analysis of this data however, is still fraught (DNA) neatly contained within 23 pairs of chromosomes
with difficulties, not least in the interpretation of novel in the human, one of each pair inherited maternally and
(undescribed) variants. In addition, functional analysis of one paternally. The sex chromosomes are inherited XX for
the implications of any novel findings still requires vali- a female and XY for a male, and the other 22 pairs are
dation by cell biology and animal model generation. described as autosomes. It should also be noted that cel-
The implications of genetic diagnosis have changed lular mitochondria house 37 genes within a circular
in recent years. Whereas this used to serve only to genome that is inherited maternally. DNA is transcribed
Chapter 2 Molecular Genetics in Paediatric Dermatology 37
Table 2.1 Essential terminology in molecular genetics

Allele The alternative form of a gene’s sequence
Allele‐specific A test or treatment directed at only one allele
Array An ordered arrangement of probes on a solid surface
Base/nucleotide A DNA or RNA nucleotide (ACTG or ACUG)
Biallelic mutations Two different mutations at the same site in a gene
Chimaera An organism resulting from the fusion of two or more zygotes
Compound heterozygous mutations Two different mutations at different sites in a gene
Copy number Number of copies of a DNA sequence, usually at chromosomal or gene level but can be applied to
repeats in the DNA sequence
Copy number variation A change in the copy number of a portion of DNA, which is described in the normal population and
therefore considered to be a variant rather than pathogenic
De novo mutation Not inherited from either parent, but arisen for the first time in the patient
Digenic mutation A condition which is caused by mutations in two different genes
Exons The parts of the DNA sequence that code for proteins
Frameshift mutation A mutation that causes a shift in the reading frame of the DNA sequence
Gain‐of‐function/activating mutation A mutation that increases the function of the gene
Germline mutation A mutation that affects all the cells of an organism including the gametes
Hemizygous mutation Having only a single copy of a gene, which results in monoallelic expression
Heterozygous mutation The occurrence of a mutation in one copy of a gene but not in the other
Homozygous mutation The occurrence of the same mutation in both copies of a gene
Hybridization Binding of DNA or RNA to complementary strands or probes
Imprinting Natural silencing of one allele, leading to monoallelic expression
Introns The parts of the DNA sequence of the genome that do not code for proteins
In silico The analysis of the effects of a mutation using bioinformatics rather than laboratory experiments
Knockdown The deliberate reduction in expression of a gene (e.g. in an experiment to see what it does)
Knockout The deliberate obliteration of expression of a gene (e.g. in a mouse model)
Ligation Joining together of fragments of DNA
Loss‐of‐function mutation A mutation that reduces or obliterates the function of a gene
Missense mutation A single base change in the DNA sequence that alters an amino acid in the protein but does not
truncate it
Monoallelic expression Expression of only one allele instead of two. This occurs with X inactivation and with imprinted genes
Mosaicism The presence of two or more genotypes in an organism arising from a single zygote
Mutant or minor allele frequency The proportion of a sample or a population affected by a mutation
Mutation A change in the DNA sequence that is thought or known to be pathogenic. Non‐synonymous
mutations are those that alter the amino acid code in an exon whereas synonymous mutations do
not
Nonsense mutation A mutation that truncates the protein product
Novel A mutation that has not previously been described in the literature or in public databases
Oligonucleotide A short synthetic sequence of DNA or RNA bases
Overexpression Increased expression of a gene, usually deliberately to analyse the effects
Panel/targeted panel A selected set of genes for DNA sequencing
Polymorphism A change in the sequence of DNA that is commoner than 1% frequency in a population, and
therefore considered to be a variant rather than pathogenic
Post‐zygotic A mutation that occurs in utero
Segregation The co‐occurrence of a phenotype in members of a family who are affected by a particular genotype,
and the absence of that phenotype in unaffected family members
Sequencing Elucidation of the sequence of the bases in DNA or RNA
Single nucleotide polymorphism (SNP) or variant A single base pair change in DNA that is seen in more than 1% of a normal population
(SNV)
Somatic mutation A mutation within a tissue
Splice site A sequence of DNA that indicates the junction of an exon and intron
Sporadic A disorder that does not appear to be inherited or passed on
Transcription The process of making RNA from a DNA template
Translation The process of making protein from an RNA template
Uniparental disomy (UPD) The inheritance of two copies of a gene or genes from one parent
Validation The use of secondary or functional tests to confirm a DNA mutation
into messenger ribonucleic acid (mRNA) and mRNA is The genetic code of DNA occurs in the form of four
translated into protein. Proteins are the molecules in each chemicals or ‘bases’, namely cytosine (C), thymine (T),
cell that perform the vital functional tasks required in the guanine (G) and adenine (A). Complementary pairing
human body. It is the chemical properties of the amino occurs between C bases and G via three hydrogen bonds,
acids and the exact order in which they are aligned that and between T with A via two hydrogen bonds, at the
causes the protein to fold into a particular shape, and centre of the famous DNA double helix [1,2]. Long runs of
therefore determines its functional properties. these four bases are grouped into regions known as exons
and introns. Exons are known to be the regions that ‘code’ or disrupted, and on a larger scale there can be chromo-
for RNA and therefore for protein products, and they somal structural aberrations such as translocations and
make up only around 1% of the whole DNA sequence. inversions.

Introns make up the rest of the sequence and their func- In many cases a disease manifests itself because the
tion is still not completely understood. Early on in the flow of molecular information from DNA to RNA to pro-
study of molecular genetics they were considered to be tein contains a mutation, usually originating from the
‘junk DNA’, however it is now well established that DNA code. Many diseases can be described as ‘dominant’
intronic sequences are crucial for the functioning and con- or ‘recessive’ in inheritance pattern, where either one or
trol of the exonic areas and their protein products. The both copies of the gene are required to be faulty respec-
four bases of the exons and their flanking sequences are tively in order to cause the resultant disease. As males
‘transcribed’ into RNA by the process of transcription. In have one copy of the X chromosome, all genes in males
this process an RNA molecule is made from the DNA that do not lie on the pseudoautosomal regions of the X/Y
sequence transcript, with the intronic sequences removed, chromosomes cannot be described as heterozygous or
and the thymine base of DNA replaced by the uracil base homozygous and in this situation are referred to as
of RNA. The four RNA molecule bases (UCGA) can be ‘hemizygous’. X‐linked disorders in general are therefore
arranged into groups of three in 64 different ways, called more likely to be severe in males as there is only one copy
codons. Sixty one of these codons code for one of 20 amino of the gene.
acids, and three code for a so‐called stop codon. This is A disease is described as monogenic if there is only one
known as the genetic code, and the excess of codons for gene involved in the phenotype; however this is a rapidly‐
amino acids is known as the redundancy or degeneracy of disappearing concept, as the background genotype of the
the genetic code. Amino acids are the building blocks patient will almost inevitably have some phenotype‐
of proteins, and stop codons tell the protein when the modifying effect in any disease situation. Polygenic disor-
exonic instructions are finished. The process of forming a ders are those in which more than one gene is known to
string of amino acids from the RNA code is known as be involved in the phenotype. Mosaic disorders are dealt
translation. with in Section 23.
DNA mutations can occur anywhere in the human
genome, and in some cases lead directly to or contribute References
to disease. Broadly speaking the most damaging muta- 1 Watson JD, Crick FH. Molecular structure of nucleic acids; a structure
for deoxyribose nucleic acid. Nature 1953;171:737–8.
tions are found within exons, however they are increas-
2 Watson JD, Crick FH. Genetical implications of the structure of deox-
ingly being discovered outside coding regions, for yribonucleic acid. Nature 1953;171:964–7.
example in important regulatory regions outside the
gene itself such as the promoter. Mutations can be clas-
onsent for genetic testing and
C
sified into (i) point mutations, similar to a spelling mis-
incidental findings
take where a single base is replaced by another, and (ii)
insertions or deletions, where part of the DNA message Individual hospitals usually have their own standards
is missing or a part is added. Point mutations can be and protocols for obtaining consent for genetic testing.
subdivided into synonymous or non‐synonymous and, This will vary depending on the method to be used, and
where non‐synonymous, into missense or nonsense. whether the test is a diagnostic laboratory test or being
Synonymous mutations are base changes that do not done on a research basis. Oral consent for genetic testing
change the amino acid which is coded for and therefore may be sufficient for established diagnostic tests, but any
the protein product remains the same. These are usually research testing should have fully informed written con-
but not always benign, and therefore usually without sent recorded in the hospital and research notes.
apparent functional consequence. Non‐synonymous In most diagnostic tests the issue of incidental find-
mutations are those that alter the amino acid code in an ings does not arise as only a single gene is being tested.
exon. Within this group missense mutations are those However, with the increase in gene panel testing and of
that change the amino acid but not to a stop codon, clinical exome testing there may be genes being tested
producing a protein, although this protein is abnormal which are known to affect clinical outcome in other
in sequence. Nonsense mutations on the other hand diseases, such as tumour suppressor genes or onco-
lead to an absent or truncated protein product by chang- genes. In these cases, there is no international consen-
ing the codon to a stop codon. For mutations that are sus as yet for whether specific consent needs to be
deletions or insertions of sequence this can be ′in‐frame’ taken in advance, however, a gradual consensus is
or leading to a ′frameshift’. In‐frame insertions or dele- emerging, and in general it is good practice to inform
tions lead to one codon being changed, either to a dif- families that there is a possibility that other mutations
ferent codon or a stop codon, and frameshift alter the may be uncovered which could affect their health in
reading frame of the gene – in other words the three‐ other areas. Ideally there is a specific option after
letter codons are no longer read in the correct groups of informed consent for the patient/family to choose
three, which leads to a nonsense protein product and whether they would like to be told of incidental find-
sometimes to a premature stop codon. Large deletions, ings. Recent US and European publications in this area
duplications and insertions can also occur at gene level, may help with consideration of issues around consent
causing whole exons or multiple exons to be removed for incidental findings [1–6].
References result as reported should be inserted into the patient’s

1 Evans BJ. Minimizing liability risks under the ACMG recommenda-

medical notes, as the exact mutation may be extremely
tions for reporting incidental findings in clinical exome and genome
sequencing. Genet Med 2013;15:915–20. important. Reading the results of a DNA sequence muta-
2 Green RC, Berg JS, Grody WW et al. ACMG recommendations for tion is explained in Table 2.2.
reporting of incidental findings in clinical exome and genome
sequencing. Genet Med 2013;15:565–74.
3 Hehir‐Kwa JY, Claustres M, Hastings RJ et al. Towards a European What to do with a genetic result
consensus for reporting incidental findings during clinical NGS
testing. Eur J Hum Genet 2015;23:1601–6. In general terms it is best to refer the family to Clinical
4 May T. On the justifiability of ACMG recommendations for report- Genetics for the result to be given. Even if the paediatric
ing of incidental findings in clinical exome and genome sequencing.
J Law Med Ethics 2015;43:134–42. dermatologist feels confident of their knowledge in the
5 Anderson JA, Hayeems RZ, Shuman C et al. Predictive genetic testing area, they are not trained in genetic counselling and may
for adult‐onset disorders in minors: a critical analysis of the arguments not be aware of all the implications for all family mem-
for and against the 2013 ACMG guidelines. Clin Genet 2015;87:301–10.
6 Kalia SS, Adelman K, Bale SJ, et al. Recommendations for reporting of
bers. In referral of the family, mention that the whole fam-
secondary findings in clinical exome and genome sequencing, 2016 ily may need to attend, and certainly both parents where
update (ACMG SF v2.0): a policy statement of the American College of possible, and warn that further testing may be required.
Medical Genetics and Genomics. Genet Med 2017;19:249–55. Clinical geneticists can also deal with the issues surround-
ing incidental findings where relevant.
hich samples to take for genetic
W
testing Concept of personalized medicine
Blood DNA A rapidly evolving area of science is that of personalized
Methods of DNA extraction from whole blood can vary medicine, or precision medicine [1,2]. This is a broad term
dependent on the local laboratory, and it is always worth to describe the use of genetic data on an individual to tai-
checking before obtaining a sample. Very commonly lor the treatment of a disorder to that individual. There
1–5 mL is sufficient from children, collected into an EDTA‐ are two principal ways in which this research is being
containing vial. The sample is safe overnight at room tem- driven. First, genetic information is being analysed retro-
perature if need be. spectively from cohorts of patients who have had success-
ful or unsuccessful responses to therapy to create a model
Cheek swab or saliva DNA of genotypic association with outcomes including side‐
Increasingly it is possible to get good‐quality DNA from effects. Second, where disorders are found to be caused
a cheek swab, however this will also depend on the local by or driven by a specific mutation, researchers and clini-
laboratory. These samples require a specialized swab (not cians are prescribing therapies targeted to these mutations
a normal skin swab), and instructions for collection or to the known effects of these mutations. In paediatric
should be followed. Generally lower quantities of DNA dermatology this is currently being used in trials such as
are obtainable than from blood. The method is, however, of AKT1 inhibitors in Proteus syndrome, rapamycin in the
particularly suitable for young babies if it is difficult to PIK3CA‐related overgrowth spectrum, and collagen VII
obtain a blood sample, or from family members who are
not able to attend clinic to have blood taken, when a cheek Table 2.2 Terminology used in genetic testing results
swab or saliva sample can be sent remotely by following
the manufacturer’s instructions. _ (Underscore) is a range (e.g. c.76_78delACT)
> Indicates a substitution at DNA level (e.g. c.76A>T)
Skin DNA c. Position of base pair in cDNA
Skin biopsy is required for DNA extraction where it is c.(83G=/83G>C) Describes the two genotypes of a mosaic case
del Indicates a deletion (e.g. c.76delA)
possible that the mutation is not present in the germline
dup Indicates a duplication (e.g. c.76dupA)
and therefore not detectable in blood but only in affected fs Frameshift
tissue. A skin biopsy for DNA extraction must not be put fs*# *# Indicates at which codon position the new
into formalin. It can be transported fresh to the laboratory reading frame ends in a stop codon (*). The
on a saline‐soaked gauze, or snap‐frozen in liquid nitro- position of the stop in the new reading frame is
gen, or placed in a medium that stabilizes nucleic acids. calculated starting at the first amino acid that is
Most diagnostic laboratories when presented with a skin changed by the frameshift, and ending at the first
stop codon (*#)
sample for DNA extraction will culture fibroblasts from it
g. Position of base pair in genomic DNA
by default, and then extract DNA from the fibroblasts. This ins Indicates an insertion (e.g. c.76_77insG)
may not be appropriate in a mosaic disorder as the muta- inv Indicates an inversion (e.g. c.76_83inv)
tion may not be present in that cell type, and therefore DNA m. Position in mitochondrial DNA
extraction from whole skin should be specifically requested. n. Position in noncoding RNA
p. Position of amino acid in protein
p.(Arg97Profs*23) Frameshifting change with arginine‐97 as the first
How to interpret genetic results affected amino acid, changing into a proline, and the
new reading frame ending in a stop at position 23
Once a clinical or research test has been ordered it is use- r. Position in RNA (e.g. r.76a>u)
ful to be able to understand the result. The full genetic
replacement therapy in recessive dystrophic epidermoly- of complementary sequence in the gene of interest.
sis bullosa. This personalized medicine approach will Polymerase chain reaction (PCR) is then performed to
change the face of medicine and is likely to improve amplify DNA fragments followed by dideoxynucleotide
patient outcome in response to drug therapies, reducing chain termination sequencing to obtain a sequencing
the requirement for multiple therapies and avoidable readout that can be compared to the known ‘wild‐type’
side‐effects. reference version. An example is shown in Fig. 2.1.
References Next‐generation sequencing (NGS) of DNA [3]

1 Ashley EA. Towards precision medicine. Nat Rev Genet 2016;
NGS is the best way to sequence DNA on a large scale.
17:507–22.
2 Collins DC, Sundar R, Lim JS, Yap TA. Towards precision medicine
Sequencing that would previously have taken years
in the clinic: from biomarker discovery to novel therapeutics. Trends can now be done in around a week by hand or 3 days
Pharmacol Sci 2017;38:25–40. when using a robotic automated system. Over the years
there have been different technologies for NGS, and
there are still a wide variety of methods available.
Molecular genetics techniques
However, the principles behind NGS are similar in all
Key reviews are referenced for further reading. cases, and there are also certain major categories of
experiment. These categories vary in how the DNA of
Karyotype interest is captured:
A karyotype test is used to determine chromosomal num- 1 Whole exome: all predicted coding regions of the genome
ber, structure and integrity. The test has to be performed are sequenced.
on actively dividing live cells, and therefore the speci- 2 Whole genome: all DNA regardless of its known function
mens need to be freshly delivered to the laboratory. is sequenced.
Karyotyping can be performed on blood or skin. Single 3 Targeted capture: only preselected DNA is enriched for
nucleotide polymorphism (SNP) arrays are increasingly and sequenced. This is often in the form of a set of
replacing karyotyping for the assessment of chromosomal known and/or candidate genes added to a screening
number and integrity (detection of duplications and dele- panel or it could be a region on a particular chromo-
tions); however if structural rearrangements are to be some. This is the most commonly used type within a
detected (for example inversions or translocations) then diagnostic context, where only known genes are being
karyotyping is still required. investigated. NGS panels are now validated in many
paediatric dermatology diseases [4–7].
Mutation identification by DNA sequencing There are a number of different protocols available
All methods of DNA sequencing rely on the existence of depending on the concentration of DNA collected, for
what is known as the reference sequence, which is the example a total concentration of 3 μg or as low as 200 ng.
accepted and curated version of the human genome. There This is extremely helpful if there are only small quantities
are various version of the reference sequence, and new of material to begin with. Recently adapted protocols
‘builds’ of these become available at intervals of a few have been optimized to obtain good‐quality sequencing
years, when the current version is updated with the latest data from DNA extracted from formalin‐fixed paraffin‐
data. The reference sequence can be found at various web- embedded (FFPE) blocks. This is advantageous as it
sites such as the University of California Santa Cruz means archived pathology samples can be analysed from
(UCSC) genome browser, https://genome.ucsc.edu. The skin samples (as well as other tissues). This has previ-
production of the reference sequence was made possible as ously been difficult as DNA extracted from FFPE blocks is
a result of the revolutionary Human Genome Project [1]. often of lower quality and often more fragmented than a
fresh sample.
Sanger sequencing How NGS works:
Sanger sequencing is a technique of sequencing DNA that 1 A ‘library’ is prepared by randomly fragmenting a
was discovered by Frederick Sanger and coworkers [2]. genomic DNA sample.
The method is to design numerous pairs of oligonucleo- 2 Ligation adapters are then added to both ends of each
tide DNA ‘primers’ that cover the coding region of the DNA fragment.
gene of interest. Primers are essentially small pieces of 3 Adapter‐ligated fragments are PCR amplified and
DNA of around 20 base pairs in length that bind to DNA subjected to purification.
#70 #80
G C T G C G G G T C C G C G T G C C C A C C A C
C G A C G C C C A G G C G C A C G G G T G G T G
#130 #130
Fig. 2.1 A typical Sanger sequencing trace after importing the data into an appropriate analysis software tool. Bases are represented in different colours.
4 At this stage the library is loaded onto a flow cell so that 7 Data analysis is then carried out by sequence‐read

the DNA fragments can hybridize to the surface of the alignment to a selected reference genome with the use
flow cell via surface‐bound oligonucleotides that are of specialized software. After alignment, any differ-
complementary in sequence to the attached adapters. ences between patient samples and the reference
5 Each bound fragment goes through an amplification genome are identified (Fig. 2.2).
process to produce a cluster that becomes clonally If hunting for new genes on a research basis, the ideal
identical. scenario is to find gene variants in all/most of the affected
6 Sequencing reagents, including a differently labelled individuals that are not present in the reference genome
fluorescent nucleotide for each base, are used to iden- and other control populations and, if looking for an inher-
tify each base. ited disease, are present in the parental DNA where the
Library preparation Cluster amplification
Genomic DNA
Fragmentation
Row cell
Adapters
Bridge amplification
cycles
Ligation
Sequencing
library
2 4
1 3
Clusters
NGS library is prepared by fragmenting a gDNA sample and Library is loaded into a flow cell and the fragments hybridize
ligating specialized adapters to both fragment ends. to the flow cell surface. Each bound fragment is amplified into
a clonal cluster through bridge amplification.
(a) (b)
Sequencing Alignment & data anaylsis
A
T
C
2 4 G
1 3
ATGGCATTGCAATTTGACAT
TGGCATTGCAATTTG
AGATGGTATTG
Reads GATGGCATTGCAA
Sequencing cycles
GCATTGCAATTTGAC
ATGGCATTGCAATT
AGATGGCATTGCAATTTG
T A
G C
Reference
Digital image AGATGG TATTGCAATTTGACAT
genoma
Data is exported to an output file
Cluster 1 > Read 1: GAGT...

Cluster 2 > Read 2: TTGA...
Cluster 3 > Read 3: CTAG...
Cluster 4 > Read 4: ATAC... Text file
Sequencing reagents, including fluorescently labelled nucleo- Reads are aligned to a reference sequence with bioinformatics
tides, are added and the first base is incorporated. The flow software. After alignment, differences between the reference
cell is imaged and the emission from each cluster is recorded. genoma and the newly sequenced reads can be identified.
The emission wavelength and intensity are used to identify
the base. This cycle is repeated ”n” times to create a read
length of “n” bases.
(c) (d)
Fig. 2.2 Overview of the workflow of an Illumina next‐generation sequencing (NGS) method. Source: Courtesy of Illumina, Inc.
p15.31 p15.1 p14.1 p13.2 p12 q11.2 q12.2 q13.2 q14.1 q14.3 q15 q21.2 q22.2 q23.2 q31.1 q31.3 q33.1 q34 q35.2
41 bp
140,207,950 bp 140,207,960 bp 140,207,970 bp 140,207,980 bp
T
T
C
C
C
Typical representation of the output of NGS, with 'reads' represented as grey horizontal bands aligned with the reference
genome build using Integrative Genomics Viewer (Broad Institute). Each of these is the equivalent to one of the Sanger
sequencing traces shown in Figure 2.1. A heterozygous mutation is demonstrated by the blue cytosine change.
(e)
Fig. 2.2 (Continued)
inheritance can be explained. However, we also know Copy number changes

that diseases can be sporadic and mutations can appear Copy number mutations or copy number variations
de novo so this has to be considered during the analysis (CNVs) can be challenging to identify when using DNA
phase. sequencing methods, especially if they occur in heterozygous
At this point there is still a requirement for DNA varia- form. CNVs occur if a copy of all or part of a gene is either
tions within candidate genes to be validated by Sanger deleted or duplicated by one or more copies. There are a
sequencing. It is always important to ensure that any number of different methods by which to identify CNVs.
result is not due to an NGS artefact that has happened by
chance. Array techniques [8–14]
One preferred method of detection is array‐comparative
Other types of NGS genomic hybridization (aCGH). In simple terms aCGH
In the last few years NGS protocols have been adapted to has RNA oligonucleotides or ‘oligos’ spaced at specific
perform sequencing of RNA in a process known as RNA‐ distances along the human genome that bind DNA
seq. This has the huge advantage of being able to analyse complementary in sequence. In each case a patient DNA
the sequence of alternatively spliced mRNA transcripts. sample under investigation is labelled with a red fluo-
Splicing is the editing of an early mRNA into a mature rescent dye and a reference DNA sample is labelled
form, where introns (noncoding DNA) are removed and with a different dye which fluoresces green. Differentially
exons (protein‐coding parts of DNA) are joined together. labelled samples are mixed 50 : 50 and then hybridized
In this manner a single gene can give rise to different pro- to the array surface. After a time of hybridization, sam-
teins depending on the composition of the exons ligated ples can be analysed for CNVs. In areas of normal copy
together during the splicing stage. Different tissues of the number, equal binding of red and green labelled DNA
body can contain differentially spliced forms of the same is assumed. However, in cases of a patient deletion the
mRNA. RNA‐seq can capture this information and addi- software would detect more or all green fluorescence
tionally gather quantitative information on how highly a compared with red in a genomic location depending on
particular transcript is expressed at a given time point. the presence of a homozygous or heterozygous dele-
There are different types of RNA that have specialized tion. Conversely, in the case of a patient duplication
biological functions and, depending on the precise meth- there would be a higher detection of red fluorescence
ods used, small RNAs, microRNA (miRNA) and transfer than green, depending on the number of duplicated
RNA (tRNA) as well as total RNA can be analysed using copies (Fig. 2.3).
RNA‐seq. SNP DNA arrays can also be used to read copy number.
Other types of NGS include chromatin immunopre- These work by fragmentation of the patient DNA and
cipitation sequencing (CHIP‐seq), which extracts data labelling with fluorescent dye, and then hybridization
on protein interactions with DNA (DNA‐binding sites), onto a solid surface peppered with allele‐specific oligo-
and methylated DNA immunoprecipitation (MeDIP‐seq), nucleotide probes. These probes are allele‐specific at sites
which extracts data on DNA methylation. of known common variation in the population, and are
Ratio plot 143.39 Mbp. 9q34.3, no genes, no CNVs

4.00

3.75
3.50
3.25
3.00
2.75
2.50
2.25
2.00
1.75
1.50
1.25
1.00
0.75
0.50
0.25
0.00
–0.25
–0.50
–0.75
–1.00
–1.25
–1.50
–1.75
–2.00
–2.25
–2.50
–2.75
–3.00
–3.25
–3.50
–3.75
–4.00
24.3
24.2
24.1
23
22.3
22.1
21.3
21.2
21.1
13.3
13.2
13.1
12
11.2
11.1
12
13
21.11
21.12
21.13
21.2
21.31
21.32
21.33
22.1
22.31
22.32
22.33
31.1
31.2
31.3
32
33.1
33.2
33.3
34.11
34.13
34.3
Fig. 2.3 Array comparative genomic hybridization ratio plot depicting a deletion of a large part of chromosome 9p (shown in red), and two small areas of
closely related deletion/duplication (red and green). The chromosomal bands are laid out at the bottom of the figure.
therefore able to give information not only on copy (cDNA). cDNA contains all the relevant information on
number but also on genotype at these loci, and on large expression level and is preferable to work with as it is
areas of homozygosity or hemizygosity. more stable than mRNA and therefore less likely to
degrade during the handling process.
Multiplex ligation‐dependent probe It is now possible to extract mRNA directly from blood
amplification [15] using specialized kits, however this is only useful if the
Often the results of aCGH require validation by another gene of interest is expressed in white blood cells and this
method; the gold standard here is multiplex ligation‐ is not always the case. Luckily for dermatologists, skin
dependent probe amplification (MLPA). There are com- can be easily biopsied. Different cell types such as fibro-
panies that provide validated and optimized panels with blasts and keratinocytes can be extracted from a fresh skin
probes annealing at many points along a certain gene. biopsy and then cultured to obtain a large number of cells
MLPA works on a multiplex PCR basis after specific to work with. Additionally, the skin biopsy as a whole can
probes have annealed to the designated DNA regions. be used to extract mRNA, resulting in mRNA from all the
Using specialized analysis software the designed probes cell populations in the skin in one sample.
can identify CNVs in the gene under investigation. A Two methods are used, differing in how the experiment
schematic showing the interpretation of MLPA results is technically works: an intercalated dye method such as
explained in Fig. 2.4. MLPA is the preferred method for SYBR® green, or a probe method such as TaqMan® where
diagnostic reporting where pathological CNVs are known a fluorescent reporter dye is analysed. Both obtain data
to be causative of a particular disease. on the basis that the amount of cDNA (equating to the
original relative amounts of mRNA) can be quantified as
Quantitative real‐time PCR [16] each round of PCR cycle causes the amount of cDNA to
Expression analysis of a particular gene can be extremely double during the exponential amplification phase. By
useful for validating involvement in a particular disease, comparing to the expression of a gene that is expressed to
and quantitative real‐time PCR (qRT‐PCR) is often used. the same level in all cells, known as a ‘housekeeping
Put simply, this works by obtaining mRNA and using the gene’, such as glyceraldehyde‐3‐phosphate dehydroge-
retroviral enzyme reverse transcriptase to convert RNA nase (GAPDH) or beta‐actin (ACTB), the expression level
back to DNA to a form known as complementary DNA of the gene of interest can be calculated. For example, if
2.5
1.5
Peak ratio
0.5
100 150 200 250

(a) Size (bps)
2.5
1.5 Fig. 2.4 Schematic representation of multiplex

Peak ratio
ligation‐dependent probe amplification (MLPA) data.

Blue squares on the right are reference probes showing
1 normal copy number over different chromosomes.
Squares on the left indicate probes for a particular
gene. (a) In this case the gene under investigation
0.5 shows probes in red and above the cut‐off for normal
copy number (depicted by the green lines). This
indicates a duplication of the whole gene. (b) Shows
0 partial deletion of the same gene as five probes are in
green and below the normal cut‐off, but the rest of the
100 150 200 250 gene is of normal copy number as shown by three blue
(b) Size (bps) squares within the lines.
the gene of interest has a significantly lower level of

expression or lacks detectable expression in patient sam-
ples compared to control samples, this can provide fur-
ther evidence that the mutation is causative of the disease
under investigation.
Fluorescence in situ hybridization [17]

Fluorescence in situ hybridization (FISH) is another
method that can be used for copy number variations of
genes or indeed whole chromosomes. This works via the
attachment of fluorescently labelled probes to a specified
chromosomal location in an individual cell where the
chromosomes can be visualized microscopically. Fig. 2.5
shows the presence of three copies of chromosome 21,
which is the karyotype of an individual with Down syn-
drome, in a cell during metaphase of cell division.
Genome‐wide association studies [18]

Sometimes it is extremely challenging to find specific
gene candidates associated with a disease. This is espe-
cially the case for disorders that are likely to be polygenic. Fig. 2.5 Fluorescence in situ hybridization showing three copies of
In these cases a genome‐wide association study (GWAS) chromosome 21 during metaphase as depicted by the red fluorescent probe
may be helpful. This works by analysing the genotype of in a single cell of an individual with Down syndrome. The two control green
a set of patients with a particular condition, for example probes are hybridized to chromosome 13. Chromosomes are stained in blue.
psoriasis, compared to a control cohort without clinical creating double‐stranded RNA. Owing to a n atural

signs or a family history of psoriasis. By genotype in this mechanism within cells this double‐stranded RNA is then
example we are interested in single base variations at degraded by the cell. This therefore prevents translation
locations throughout the genome known as SNPs. If there of the RNA into protein, and effectively stops or reduces
is an association with a particular set of SNPs in the dis- expression of the protein. This molecular genetic tech-
ease cohort compared to the control cohort, this may give nique is therefore useful for studying the effects of
valuable information regarding areas of the genome that removal of the protein product from the cell, and by infer-
require further investigation. ence can help with working out what that gene usually
does. Alternatively, siRNA has been suggested to be used
Other commonly‐encountered techniques as therapy for diseases in paediatric dermatology where a
Polymerase chain reaction (PCR) mutation is leading to overexpression of a protein. This is
PCR is a technique whose discovery revolutionized therefore a type of gene therapy for skin disease and is
molecular biology [19,20], earning its inventor Kary being researched in paediatric dermatology conditions.
Mullis a Nobel Prize in 1993. It forms the basis of many
other techniques in molecular genetics. It exploits a class References
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in DNA by primed synthesis with DNA polymerase. J Mol Biol
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duced. Taq polymerase is combined with the DNA tem- years of next‐generation sequencing technologies. Nat Rev Genet
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4 Lai‐Cheong JE, McGrath JA. Next‐generation diagnostics for
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reaction involves multiple rounds of increasing the tem- 6 Bhoj EJ, Yu Z, Guan Q et al. Phenotypic predictors and final diagnoses
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plate DNA denaturation (separation of the two strands), sequencing. Genet Med 2017;19:715–8.
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ers to stick to their relevant complementary strands, and and other skin diseases. J Invest Dermatol 2013;133:573–6.
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on clinical diagnosis. Genet Med 2007;9:600–6.
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46
CHA PTER 3
Cutaneous Microbiome
Carrie C. Coughlin1 & William H. McCoy IV2
Division of Dermatology, Department of Medicine, and Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, USA
1
Division of Dermatology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA
2
Introduction, 46 Methods of collection and analysis, 50 Fungal microbiota, virome and parasites, 54
Evolution of the cutaneous microbiome, 47 Cutaneous diseases and the microbiome, 51 Conclusion, 55
Abstract This chapter investigates the composition of the microbiome

throughout childhood, interactions of the microbiome with the skin
Bacteria, fungi and viruses comprise the cutaneous microbiome. barrier and immune system, and microbial contributions to health
Exposures starting in utero shape our initial microbiome, which then and disease. Current skin microbiome research related to several
evolves over time through exposure to external microbial communi- common diseases (atopic dermatitis, acne, psoriasis) suggests that
ties (delivery method, close contacts, environment) and changes in incorporation of this information may be beneficial in disease treat-
our skin’s biochemical nature (adrenarche, hygiene, skin disease). ment, thus underscoring the need for further studies in this field.
Key points • Different skin environments (sebaceous, moist, dry) harbour

distinct microbial communities.
• The composition of the cutaneous microbiome changes from
• The cutaneous microbiome encompasses bacteria, viruses, fungi
infancy to adulthood.
and parasites living on and in the skin.
• Microbes provide targets to influence disease states, as well as
• The microbiome has many different influences, and starts
substrates of potential therapies.
developing in utero.
Introduction (human β‐defensins [HBDs] and cathelicidins), and

The cutaneous microbiome made up of bacteria, fungi, adaptive responses, with the latter potentially depend
parasites and viruses evolves over time and differs by ent on the commensal microbiota [4]. These host–
body site. Epithelial bacteria on skin and mucosal sur microbe interactions are the subject of investigations
faces have been shown to be important contributors to into the effect of the microbiome on cutaneous disease
health and illness [1–3]. This chapter will discuss changes states (see, for example, Atopic dermatitis). Conceivably,
in cutaneous bacterial microbiota from infancy to adoles patients with impaired immune systems may have dif
cence. Specifically, we will explore its establishment, ferent responses to the bacteria they encounter and
general composition, changes in response to external and different microbiome compositions than those with
internal pressures, variations with disease states, interac intact immune systems. To investigate the microbiota
tions with the gut microbiome, and relation to the virome of patients with primary immunodeficiencies, research
and fungal microbiota. ers have studied primary immunodeficiency patients
Though the classification of many types of bacteria has with eczematous dermatitis and compared them to
changed with the availability of new research techniques, patients with atopic dermatitis. Patients with primary
there are four phyla and a subset of their representative immunodeficiency had decreased site‐to‐site variation
genera that are commonly referenced in discussions of the of bacteria [5]. These authors have postulated that ‘eco
cutaneous microbiome (Table 3.1). Familiarity with these logical permissiveness” may contribute to the recurrent
bacteria helps frame discussions of their contributions to infections of patients with primary immunodeficiencies [5].
cutaneous health and disease. To understand how these interactions occur and change
Bacteria on the skin play an important role in host over time, we will examine how a human infant is colo
immunity, affecting both skin barrier function and nized by microbes and how this microbial community
immunological defences. These defences involve both is moulded by the host, environment and exposures
innate mechanisms, such as antimicrobial peptides (Fig. 3.1; see Table 3.2 for definitions of terminology).
Chapter 3 Cutaneous Microbiome 47
Table 3.1 Commonly encountered cutaneous bacteria

Phyla Gram staining Common cutaneous genera
Actinobacteria Gram positive Actinomyces

Corynebacterium
Cutibacterium
Micrococcus
Propionibacterium
Bacteroidetes Gram negative Prevotella
Firmicutes Gram positive (predominantly) Enterococcus
Lactobacillus
Staphylococcus
Streptococcus
Proteobacteria Gram negative Escherichia
Pseudomonas
Table 3.2 Common terms used in discussions of the microbiome
Term Definition
General
Metaorganism Microbes and host organism (e.g. human)
Microbiome The microbes and their genes in a particular environment
Microbiota The microbes living in a particular environment
Prebiotics Chemical/nutrient supplementation that selectively stimulates growth/activity of one or more microbes of a
metaorganism to benefit the host organism [43]
Probiotics Microbe supplementation to selectively modify a microbiome of a metaorganism to benefit the host organism [44]
Synbiotics Combinations of prebiotics and probiotics
Virome The viruses living on or with a host
Statistics and methods of identification
Alpha diversity The mean species diversity (Chao1 Index, Simpson’s Diversity, Shannon Index, etc.) in a habitat on a local scale
Beta diversity The differentiation between habitats based on species diversity
Colony‐forming unit (CFU) A measure of viable bacteria or fungi in a sample
Gamma diversity Total species diversity across a landscape (human)
Next‐generation sequencing ‘High‐throughput DNA sequencing’ performed on a variety of platforms. Faster and more comprehensive than the
(NGS) older Sanger sequencing method
Metagenome Set of genes and genomes from a sample. Usually restricted to microbiota
Operational taxonomic units Groups (‘clusters’) of bacteria with similar (often 97% similarity when compared pairwise) 16S rRNA sequences, with
(OTUs) one representative sequence representing the group for analysis
Quantitative PCR (qPCR) Amplification of nucleic acids (DNA or RNA) by polymerase chain reaction that is monitored in real time for quantification
Relative abundance Amount of one organism as compared with other similar organisms.
16S ribosomal RNA (rRNA) Sequencing a portion of a bacterium’s 16S ribosomal subunit to allow identification of the bacterium. This technique
sequencing does not distinguish organism status (alive/dead), unlike culture techniques used to identify bacteria
Relationships between organisms
Colonization Organisms living on/within a host or surface
Commensalism Two separate organisms living in contact with one another where one organism benefits from this interaction without
affecting the other organism
Dysbiosis A change in normal microbial ecology on/inside a host or surface due to microbial community imbalance/
maladaptation leading to disease (opposite of symbiosis)
Mutualism Two separate organisms living in contact with one another where both derive benefit from this interaction
Parasitism Two separate organisms living in contact with one another where one organism benefits from this interaction at the
expense of the other organism
Symbiosis Two separate organisms living in close association with one another (commensalism, mutualism, parasitism)
Evolution of the cutaneous been identified by quantitative PCR (qPCR) from surface

microbiome swabs from the endometrium and upper endocervix [6].
First exposures contribute Further, Lactobacillus and several other species have been
to the microbiome identified in cultured curettings from the endometrium [7].
The dogma that fetuses develop in a sterile environment Interestingly, Propionibacterium spp. have been grown by
has recently been challenged, as bacteria similar to those culture‐based methods from the upper genital tract [6].
found in the vagina (Prevotella and Lactobacillus spp.) have Multiple studies have now shown bacteria in the placenta
Exposure Microbiome Immunity

Prenatal exposure
vs. Immune response

development
Delivery method
‘NATURAL’
microbiome
Home environment
TPN
Nutrition
Microbiome-related
diseases
Hygiene Dysbiosis
Gastrointestinal
• Clostridium difficile colitis
Antibiotics • Inflammatory bowel disease (CD, UC)
ALTERED Cutaneous Mucosal
microbiome • Atopic dermatitis • Bacterial vaginosis
• Acne • Candidiasis
• Psoriasis • Chronic periodontitis
Urbanization
Fig. 3.1 Exposures affecting the human microbiome. Upper panel: exposures proposed to mould the ‘NATURAL’ microbiome of an individual without
clearly favouring development of disease. Lower panel: exposures known to or proposed to perturb established microbial communities to create an
ALTERED microbiome that favours the development of various diseases.
[8–10], but the validity of a ‘placental microbiome’ has bacteria [16]. Samples taken less than 5 minutes after birth
been challenged due to methodological concerns in these from neonates’ skin, oral mucosa and nasopharyngeal
studies, specifically the concern for contamination during aspirate in the study by Dominguez‐Bello et al. showed
sample acquisition [11,12]. Amniotic fluid [8] and meco similar microbial composition [15]. This is in contrast to
nium [13,14] also harbour bacteria. Thus, neonates have the diversity that develops later (see the next section,
several potential influences on their microbiome even Neonates and infants). However, in other work, bacteria
before birth. from stool in the first 1–2 days of life were different than
Method of delivery has a clear impact on an infant’s cuta those of the oropharynx [16]. Thus, the lower gut flora
neous microbiome. Neonates born via vaginal delivery may be distinct from other sites starting from birth.
have early skin colonization by vaginal flora (Lactobacillus Regardless of the human microenvironment, it appears
and Prevotella spp.), while infants born via caesarean section that initial external exposure has a profound effect on
are colonized by typical skin flora including Staphylococcus, microbial colonization, which may dictate susceptibility
Corynebacterium and Propionibacterium spp. [15]. Further, the to a variety of diseases.
bacterial composition of a mother’s vaginal flora was more A number of studies have demonstrated an association
similar to the microbiome of her vaginally delivered baby between caesarean section delivery and increased risk for
than to other vaginally delivered infants. The uniqueness of allergies [18], asthma [19,20], immunodeficiency [20] and
an infant’s cutaneous microbiome transmitted via vaginal obesity [21] (though there are mixed results in the litera
delivery was not observed in caesarean deliveries, as there ture [19,22]), thus leading to a recent investigation dem
was no difference between the skin floras of infants born via onstrating that infants born via caesarean section but
caesarean section [15,16]. While microbial colonization of intentionally exposed to vaginal fluids can be colonized
the skin would seem to be the most pertinent to dermatolo by bacteria from these fluids [23]. While this study estab
gists, the intestinal flora may also affect allergic and inflam lishes how a ‘normal’ microbiome can be fostered in an
matory reactions in patients [3,17], thus an examination of infant born via caesarean section through the introduc
the oropharyngeal and intestinal flora of infants is relevant tion of an available probiotic source, the link between dis
to paediatric dermatologists. tinct microbiome communities and/or specific bacteria
Much as observed for cutaneous microbial colonization, with inflammatory skin disease requires further study.
the mode of delivery has been shown to dictate oropharyn Another external source supporting maintenance and
geal microbial colonization with infants born vaginally expansion of a physiological microbiome is breast milk.
having increased Firmicutes (trending to more Lactobacillus) Diversity of the infant gut microbiome is proportional to
and infants born via caesarean section having increased the amount of daily breast milk intake even after intro
Actinobacteria (Propionibacterium, notably) and Proteo duction of solid foods [24].
The potential links between skin inflammation and cuta paralleling the increased sebaceous gland activity seen in

neous bacteria include both intrinsic host–microbe and adolescents and adults [35].
extrinsic microbe–microbe interactions. While the intrinsic
link between a specific bacterial strain and a disease state Adults
may seem straightforward (see Atopic dermatitis), extrin After the hormonal shifts of adolescence, adults have dis
sic effects can be less clear. Extrinsic links may include the tinct sebaceous, moist and dry zones on their skin [37,38].
influence of one type of bacteria on the colonization of Researchers have compared the bacterial composition of
[25,26], virulence of [27] and/or host response to [28] an these sites with an aim to inform work on diseases such as
unrelated bacterium. The last link is particularly concern acne and atopic dermatitis that tend to have site predilec
ing in the setting of increasing emergence of multidrug‐ tions [34]. Propionibacteria dominate the microbial com
resistant organisms, leaving some patients with limited or munities of sebaceous sites, such as the face [38,39]. Of
no therapeutic options. Of note, antibiotic resistance genes note, P. acnes has been reclassified under the genus
carried by maternal bacteria can transfer to neonates and Cutibacterium (C. acnes), which is important when com
the mode of delivery influences this transfer [14,29]. Thus, paring older and more recent research. Moist locations,
the transfer of bacteria from one host to another can affect such as the axilla and antecubital fossa, harbor corynebac
the ability of the new host to fight infection. teria and staphylococci [38,39]. Flavobacteria and
Proteobacteria are found at dry sites [38]. Not only the
Neonates and infants dominant phyla, but also the diversity of the microbial
After delivery, environment is the next major influence on community correlates with skin microenvironment, as
a neonate’s microbiome. Broadly, for neonates, environ sebaceous sites have the least, and dry sites have the most,
ment can be split into hospital/nursery and home set community diversity [38].
tings. Infants requiring prolonged hospital stays have In contrast to the changes seen in the microbiome from
different influences on their microbiota than children dis infancy to maturation, recent work shows the adult cuta
charged to home [30]. Incubators, cribs, bedding, moni neous microbiome is relatively constant over time [34].
tors, leads, tubes, catheters, gloves, nutrition, medications, Bacterial communities are maintained by the host, rather
caregivers, family and more all contribute to the environ than reacquired over time, and remain particular to the
ment encountered by a hospitalized infant. Due to individual. Cutaneous sites with lower diversity (such as
changes in the epidermal barrier over time, the effects of the face) were more stable than sites with higher diversity
these influences can also change. Infant skin evolves in (such as the feet). Moreover, left/right symmetry of the
structure and barrier function over weeks to months cutaneous microbiota has been noted [39,40], which could
[31,32]. Consideration of these exposures is important have implications for interventional trials. However,
when seeing neonates in the hospital, as their microbial studies looking specifically at the axillae show differences
flora can be quite different from that encountered in the in bacteria at left versus right sites, with handedness
outpatient setting. potentially influencing these results [41,42]. The microbi
The cutaneous microbiome starts to change within the ome differences revealed through studies of life stage and
first 3 months of life and continues to evolve over the first body site have begun to reveal important considerations
year of life, as shown by Capone et al. [33]. Diversity for therapeutic targets for diseases associated with per
increases and, in contrast to the uniformity in oral and turbations in the microbiome (see Cutaneous diseases
skin samples at birth [15], skin flora evolves to be site‐ and the microbiome).
specific. This evolution also is in contrast to the relative
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Allergy 2013;43:198–211. Staphylococcus and Corynebacterium clusters in the human axillary
14 Gosalbes MJ, Valles Y, Jimenez‐Hernandez N et al. High frequencies region. PloS One 2013;8:e70538.
of antibiotic resistance genes in infants’ meconium and early fecal 42 Egert M, Schmidt I, Hohne HM et al. rRNA‐based profiling of bacteria
samples. J Dev Orig Health Dis 2016;7:35–44. in the axilla of healthy males suggests right‐left asymmetry in bacte
15 Dominguez‐Bello MG, Costello EK, Contreras M et al. Delivery rial activity. FEMS Microbiol Ecol 2011;77:146–53.
mode shapes the acquisition and structure of the initial microbiota 43 Gibson GR, Roberfroid MB. Dietary modulation of the human colonic
across multiple body habitats in newborns. Proc Natl Acad Sci U S A microbiota: introducing the concept of prebiotics. J Nutr 1995;125(6):
2010;107:11971–5. 1401–12.
16 Brumbaugh DE, Arruda J, Robbins K et al. Mode of delivery deter 44 Fuller R. Probiotics in man and animals. J Appl Bacteriol 1989;66(5):
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colonization. J Pediatr Gastroenterol Nutr 2016;63:320–8.
17 West CE, Ryden P, Lundin D et al. Gut microbiome and innate
immune response patterns in IgE‐associated eczema. Clin Exp Allergy Methods of collection and analysis
2015;45:1419–29.
18 Papathoma E, Triga M, Fouzas S, Dimitriou G. Cesarean section When evaluating a microbiome investigation, it is impor
delivery and development of food allergy and atopic dermatitis in
early childhood. Pediatr Allergy Immunol 2016;27:419–24.
tant to review the experimental design of the authors, as
19 Cuppari C, Manti S, Salpietro A et al. Mode of delivery and risk for this field lacks standardization, leading to varying results
development of atopic diseases in children. Allergy Asthma Proc from different investigators. Identifying the sample
2015;36:344–51. source is the first step in this process, as it will dictate the
20 Sevelsted A, Stokholm J, Bonnelykke K, Bisgaard H. Cesarean section
and chronic immune disorders. Pediatrics 2015;135:e92–8. overall microbial community being assessed. As reviewed
21 Rutayisire E, Wu X, Huang K et al. Cesarean section may increase earlier in the chapter, the skin microbiome community
the risk of both overweight and obesity in preschool children. BMC profiles of the three main skin environments (sebaceous,
Pregnancy Childbirth 2016;16:338.
moist, dry) are quite distinct [1,2]. Recent work has also
22 Robson SJ, Vally H, Abdel‐Latif ME et al. childhood health and devel
opmental outcomes after cesarean birth in an Australian cohort. shown that fungal colonization is affected by site with
Pediatrics 2015;136:e1285–93. feet harbouring more diversity than the rest of the body
23 Dominguez‐Bello MG, De Jesus‐Laboy KM, Shen N et al. Partial resto [3]. Cutaneous disease at the sites sampled can also affect
ration of the microbiota of cesarean‐born infants via vaginal microbial
transfer. Nat Med 2016;22:250–3.
the microbial community even if that is not the focus of
24 Pannaraj PS, Li F, Cerini C et al. Association between breast milk the investigation.
bacterial communities and establishment and development of the While body site can have a profound effect on the study,
infant gut microbiome. JAMA Pediatr 2017;171:647–54. the method of skin sampling (cutaneous swab, scrape and
25 Bomar L, Brugger SD, Yost BH et al. Corynebacterium accolens
releases antipneumococcal free fatty acids from human nostril and biopsy) has generally been found to be equivalent on a
skin surface triacylglycerols. mBio 2016;7:e01725–15. ‘phylotype level’ (operational taxonomic units, OTUs)
26 Christensen GJ, Scholz CF, Enghild J et al. Antagonism between between samples when examining skin microbes [4].
Staphylococcus epidermidis and Propionibacterium acnes and its
genomic basis. BMC Genomics 2016;17:152.
However, more recent work has found differences in
27 Lo CW, Lai YK, Liu YT et al. Staphylococcus aureus hijacks a skin bacteria isolated from the epidermis, dermis and adi
commensal to intensify its virulence: immunization targeting beta‐ pose tissue [5]. Unlike pilosebaceous units, the dermis
hemolysin and CAMP factor. J Invest Dermatol 2011;131:401–9. and subcutis are not in direct communication with the
28 Cogen AL, Nizet V, Gallo RL. Skin microbiota: a source of disease or
defence? Br J Dermatol 2008;158:442–55. skin surface, and demonstration of varied bacterial com
29 Alicea‐Serrano AM, Contreras M, Magris M et al. Tetracycline resist munities in different levels of biopsy specimens broadens
ance genes acquired at birth. Arch Microbiol 2013;195:447–51. the potential impact of sampling technique. When look
30 Hartz LE, Bradshaw W, Brandon DH. Potential NICU environmental
ing at the acne microbiome, an alternative method to
influences on the neonate’s microbiome: a systematic review. Adv
Neonatal Care 2015;15:324–35. these three commonly used sampling techniques is the
31 Evans NJ, Rutter N. Development of the epidermis in the newborn. use of pore strips to selectively sample pilosebaceous
Biol Neonate 1986;49:74–80. units [6]. Further, hair‐specific studies have sampled indi
32 Nikolovski J, Stamatas GN, Kollias N, Wiegand BC. Barrier function
and water‐holding and transport properties of infant stratum corneum
vidual follicular units (‘plucked hairs’) and found higher
are different from adult and continue to develop through the first year amounts of human papillomavirus (HPV) than skin biop
of life. J Invest Dermatol 2008;128:1728–36. sies [7]. Beyond reviewing sample site and acquisition,
33 Capone KA, Dowd SE, Stamatas GN, Nikolovski J. Diversity of the critically assessing sample preparation and the use of
human skin microbiome early in life. J Invest Dermatol 2011;131:
2026–32. appropriate negative controls (background microbial signal)
34 Oh J, Byrd AL, Park M et al. Temporal stability of the human skin is critically important, as contaminants can skew results.
microbiome. Cell 2016;165:854–66. The sensitivity of next‐generation sequencing (NGS) tech
35 Oh J, Conlan S, Polley EC et al. Shifts in human skin and nares micro
biota of healthy children and adults. Genome Med 2012;4:77.
niques can often reveal microbial signal from even classi
36 Shi B, Bangayan NJ, Curd E et al. The skin microbiome is different cally ‘sterile’ techniques, such as sterile cotton swabs used
in pediatric versus adult atopic dermatitis. J Allergy Clin Immunol for skin swabs (personal data). Cleaning and sterilizing the
2016;138:1233–6. skin to avoid introducing surface contaminants when
assessing the microbiome of deeper structures and changing difference in staphylococcal colonization at other sites

gloves between sample sites can be crucial. (popliteal fossa, nasal tip, cheeks) and no difference at
Beyond sample collection and basic preparation, the other time points in the first year of life. Older patients with
techniques used to analyse the microbial community AD are more often Staphylococcus aureus carriers [2,3].
structure should be considered as well. While culture‐ Staph. aureus can produce toxins that affect mast cell
based methods previously dominated the literature, they degranulation and drive atopic disease, thus mechanisti
have now largely taken a secondary role. Investigators cally linking the presence of bacteria and the maintenance
are using more powerful techniques, such as 16S ribo of disease [2]. In addition, Staph. aureus is associated with
somal DNA (rDNA) sequencing and whole‐genome Th2 inflammation and immunoglobulin E (IgE) response [4].
shotgun (WGS) metagenomic sequences. NGS uses The benefit of commensal bacteria is exemplified by data
hypervariable rDNA regions to differentiate OTUs instead that Staph. epidermidis has counter‐regulatory effects on
of the full rDNA sequence, as was used in classical Sanger cutaneous inflammation [4] and can interfere with Staph.
sequencing. The choice of which hypervariable region to aureus biofilms [5].
use as a proxy for the sequence can affect the data, as In an attempt to utilize bacteria to modify inflamma
the V1–V3 region was found to be more accurate (closer tion in patients with AD, one group has investigated
to whole metagenomic data) for skin samples than V4, applying lysates of Vitreoscilla filiformis, a bacterium found
which is more helpful in gut microbiome studies [8,9]. in some thermal springs, directly to the skin in a com
Further, species discrimination for various microbes may pounded cream [6]. Both AD disease activity and pruritus
require particular hypervariable region primer sets or decreased in the intervention group treated with the
may not be able to be resolved using standard 16S rDNA compound versus controls treated with vehicle only. The
NGS. It is important to consider that as techniques evolve, authors then investigated the mechanism behind this
results from studies using different methodologies may improvement using a mouse model, which showed that
no longer be comparable. this treatment resulted in high levels of interleukin (IL)‐10
in dendritic cells via toll‐like receptor (TLR)2 leading
References to increased regulatory T‐cell activity [7]. This study
1 Grice EA, Kong HH, Conlan S et al. Topographical and temporal proposes that AD therapy could utilize disease‐modifying
diversity of the human skin microbiome. Science 2009;324:1190–2.
bacteria that are not typical cutaneous colonizers or
2 Perez Perez GI, Gao Z, Jourdain R et al. Body site is a more determinant
factor than human population diversity in the healthy skin microbiome. commensals.
PloS One 2016;11:e0151990. Microbial diversity differs between affected and normal
3 Findley K, Oh J, Yang J et al. Topographic diversity of fungal and skin. In patients with AD, microbial diversity decreases at
bacterial communities in human skin. Nature 2013;498:367–70.
4 Grice EA, Kong HH, Renaud G et al. A diversity profile of the human
an affected site during a flare and increases (improves,
skin microbiota. Genome Res 2008;18:1043–50. approaching levels seen in control patients) with treat
5 Nakatsuji T, Chiang HI, Jiang SB et al. The microbiome extends to ment [8]. Additionally, even intermittent treatment of
subepidermal compartments of normal skin. Nat Commun 2013;4:1431. a site before a flare can affect microbial diversity [8].
6 Craft N, Li H. Response to the commentaries on the paper:
Propionibacterium acnes strain populations in the human skin micro Moreover, Staph. aureus as well as Staph. epidermidis are
biome associated with acne. J Invest Dermatol 2013;133:2295–7. over‐represented during flares, showing how dysbiosis
7 Schneider I, Lehmann MD, Kogosov V et al. Eyebrow hairs from actinic can contribute to disease.
keratosis patients harbor the highest number of cutaneous human
papillomaviruses. BMC Infect Dis 2013;13:186.
Manipulating the microbiome of these patients is seen
8 Kong HH. Details matter: designing skin microbiome studies. J Invest as a possible new way to treat and/or prevent AD. Dilute
Dermatol 2016;136:900–2. bleach baths are commonly recommended to decrease
9 Meisel JS, Hannigan GD, Tyldsley AS et al. Skin microbiome surveys Staph. aureus counts in children with AD [9–11]. Topical
are strongly influenced by experimental design. J Invest Dermatol
2016;136:947–56. antibiotics such as mupirocin are used to treat infection or
decrease colonization, as well. The effect of topical corti
costeroids on the microbiome has been investigated more
recently. Early work showed a reduction of Staph. aureus
Cutaneous diseases and the
with topical corticosteroid use [12], and more recently
microbiome
treatment with fluticasone cream was shown to normalize
The contribution of bacteria and fungi to cutaneous the microbiome at lesional sites [13]. As topical corticos
disease is a booming field of research. Here, we review teroids do not directly target bacteria, this work demon
the links between atopic dermatitis (AD), acne and psoria strates the intimate cross‐talk between an inflammatory
sis to bacterial communities on the skin. dermatosis and the cutaneous flora that can drive disease.
These studies support the use of topical corticosteroids
Atopic dermatitis even on overtly infected lesions.
Bacterial colonization and bacterial/viral superinfection There is an inverse correlation between AD severity
of AD are recognized as challenges in the management and skin colonization with Streptococcus salivarius [14].
of this disease. Interestingly, Kennedy et al. found that Interestingly, regular use of emollients in infants at risk of
infants without staphylococcal colonization of the antecu developing AD was associated with a lower skin pH and
bital fossa at 2 months were more likely to have AD at increased skin colonization with Strep. salivarius [14].
12 months, raising the possibility of early bacteria modu These two effects are thought to contribute to the preven
lating the risk for AD [1]. However, this study showed no tive effect of emollients in high‐risk infants.
The role of dysbiosis in AD has been investigated level is downregulated in C. acnes from acne skin and
by multiple groups leading to attempts to modify the that host supplementation with B12 can further modify
development and course, and/or improve treatment of AD C. acnes transcription of multiple genes possibly leading
through prebiotics [15,16], probiotics [15,17,18] and synbi to skin inflammation via increased porphyrin production
otics [19]. One such study is investigating the effect of sup [30]. These initial investigations are beginning to illumi
plementing pregnant women with probiotics to decrease nate the specific role(s) that the cutaneous microbiome
risk of atopy [18]. Unfortunately, these investigations have plays in acne, but further research is required before these
not yielded consistent results nor have they improved care findings can be translated to clinical treatments.
recommendations. At this point, there is not sufficient evi
dence to recommend routine pre‐/pro‐/synbiotic supple Psoriasis
mentation for patients with or at risk for AD. Acute flares of psoriasis can be triggered by infections,
Clothing materials have also been studied as means to including streptococcal infections of the oropharynx or
change the microbiome in patients with AD. For example, perianal skin. In fact, the strength of this association has
chitosan (a biopolymer derived from crustacean shells led to the proposal that the potential life‐threatening
with inhibitory properties against Staph. aureus) was sequelae of streptococcal infections have exerted evolu
explored as a coating on cotton to alter the microbiome. In tionary pressure to select for the psoriasis phenotype
one study, there was no difference in Staph. aureus between (Fig. 3.2) [31,32], though an alternative evolutionary argu
participants who slept in chitosan‐coated pyjamas and ment has also been proposed for Mycobacterium leprae
those who did not, but the amount of coagulase‐negative [33]. The potential link between the microbiome and
Staphylococcus (CoNS) increased in the chitosan group [20]. chronic psoriasis is under investigation, with only a
While this might appear to be a negative result, the increased limited number of studies published. Researchers are
CoNS may help to control Staph. aureus (as described previ examining psoriasis in relation to both the cutaneous and
ously) and thus decrease disease activity. Additionally, fab gut microbiomes at least in part due to the finding that
rics incorporating silver have been investigated for patients with Crohn disease are more likely to develop
treatment of AD. Silver dressings and topical preparations psoriasis. In addition, these diseases have overlapping
have long been used in wound care for their broad antimi genetic associations and immune activation pathways,
crobial properties. More recently, fabrics made with silver which has led some authors to suggest that both psoriasis
mesh [21] and cellulose fibres of seaweed‐impregnated sil and Crohn’s are related to alterations in immune toler
ver [22–24] have been shown to decrease microbial counts ance to the microbiota (Fig. 3.2) [31]. This proposed dys
in patients with AD. Pruritus [24] and disease severity biosis must be differentiated from true infection, as
[21,23,24] also decreased in patients wearing the fabrics. psoriatic lesions have a very low incidence of infection
These studies were performed with small numbers of due to high expression of antimicrobial peptides such as
patients, which limits the ability to generalize the findings. HBDs 2/3 and cathelicidin LL‐37 [31]. Alekseyenko and
Investigations of antimicrobial fabrics are representative of colleagues have recently published microbiome data
ongoing research to further manipulate microbial dysbio suggesting that there are distinct cutaneotypes associated
sis, infection and inflammation in AD. with normal skin (cutaneotype 1: Proteobacteria) versus
psoriatic lesional skin (cutaneotype 2: Firmicutes,
Acne Actinobacteria), with the latter carrying an odds ratio for
The predominant bacterium found at sebaceous sites asso psoriasis of 3.52 (95% confidence interval [CI] 1.44 to 8.98,
ciated with acne in adults is Cutibacterium acnes (formerly P <0.01). Notably, their work suggested generalized
Propionibacterium acnes) [25,26]. This bacterium has long dysbiosis was present on both lesional and nonlesional
been linked to acne, and the amount of C. acnes recovered skin from psoriatics (decreased alpha diversity), but
from these sites changes over time [27,28]. More recently, that cutaneotype was only informative when sampled
distinct C. acnes ribotypes (RT; a surrogate descriptor for from a lesional site, as nonlesional skin could be either
C. acnes strains) have been significantly associated with cutaneotype [34]. Others have investigated the gut micro
acne skin (RT4, 5, 8, 10) or normal skin (RT6) [29], which biome link to psoriasis, thinking of it more as a systemic
suggests dysbiosis of the C. acnes community may lead to disease. In a mouse model, gut bacteria can increase
clinically apparent acne. Interestingly, though, younger inflammation and increase the Th17 response of the skin,
children have comedonal acne and more Streptococcus producing psoriasis‐like inflammation [35]. Further,
than C. acnes (personal data), which correlates with their ingestion of a poorly absorbed carbohydrate analogue
tendency to have less sebaceous gland activity. Though (acarbose) in an imiquimod‐based mouse model of
antibiotics have been a mainstay to treat inflammatory psoriasis can reduce skin inflammatory markers (tumour
acne for generations of dermatologists, the increasing necrosis factor [TNF]‐α, IL‐1β, IL‐6, IL‐17A, IL‐22) and
incidence of antibiotic resistance and general movement clinical findings associated with psoriasis [36], thus sug
to increased antimicrobial stewardship has led some gesting that manipulation of the mouse gut microbiome
researchers to investigate more specific treatment targets. through acarbose can modulate the psoriatic skin pheno
Understanding the drivers behind bacterial activity type. While this type of research provides evidence for a
may help us better understand acne pathogenesis and link between alterations in both the skin/gut flora and
develop such treatments. To this end, it has been shown cutaneous disease, confirmatory studies are required
that the vitamin B12 synthesis pathway at the mRNA prior to being useful in clinical practice.
Tonsillar microbiota Evolving pathogens

Evolutionary pressure?

Mycobacterium leprae?
Strep pyogenes?
Microbe–host
interactions
Gene mutations
Skin microbiota CARD14 IL-23 Intestinal microbiota
IL-23 NFκB
NFκB NOD2/CARD15
PGRP-3, -4
PG + TLR2 PG + NOD2
(Staph, Strep) LPS + TLR4
Innate immunity
ACTIVATION
IL-17, IL-23
Immune
IL-23
Adaptive immunity
Th1 cells Th17 cells
IFN-γ IL-17, IL-22
Keratinocyte proliferation
phenotype
Clinical
Psoriasis Crohn disease
Fig. 3.2 Comparison of microbiota influences on psoriasis and Crohn disease. Proposed evolutionary pressures favouring the development of a psoriasis
phenotype and proposed pathways for the triggering of autoimmune disease (psoriasis by the skin microbiota, Crohn’s by intestinal microbiota) in
genetically predisposed individuals. IFN, interferon; IL, interleukin; LPS, lipopolysaccharide; NF, nuclear factor; PG, peptidoglycan; PGRP, PG recognition
protein; Th, T‐helper; TLR, toll‐like receptor. Source: Adapted from Fry et al. 2013 [31], McFadden et al. 2009 [32] and Bassukas et al. 2012 [33].
Research into the importance of the microbiome to cuta 8 Kong HH, Oh J, Deming C et al. Temporal shifts in the skin microbi
ome associated with disease flares and treatment in children with
neous diseases is providing more insight into pathogenesis
atopic dermatitis. Genome Res 2012;22:850–9.
and treatment. Additionally, recent studies are advancing 9 Huang JT, Rademaker A, Paller AS. Dilute bleach baths for
investigations into the relationship between the skin and Staphylococcus aureus colonization in atopic dermatitis to decrease
other organs (the gastrointestinal tract, most commonly). disease severity. Arch Dermatol 2011;147:246–7.
10 Huang JT, Abrams M, Tlougan B et al. Treatment of Staphylococcus
The ideas that ingested prebiotics and probiotics can aureus colonization in atopic dermatitis decreases disease severity.
affect AD, diet influences acne, and microbial‐induced Pediatrics 2009;123:e808–14.
signalling in the gastrointestinal tract can manifest on the 11 Eichenfield LF, Boguniewicz M, Simpson EL et al. Translating atopic
skin as psoriasis are advancing research into novel ways dermatitis management guidelines into practice for primary care pro
viders. Pediatrics 2015;136:554–65.
to prevent and treat skin disease. 12 Nilsson EJ, Henning CG, Magnusson J. Topical corticosteroids and
Staphylococcus aureus in atopic dermatitis. J Am Acad Dermatol
1992;27:29–34.
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Staphylococcus aureus and Staphylococcus epidermidis secretomes tered Lactobacillus rhamnosus GG with skin and gut microbiota and
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21 Gauger A, Mempel M, Schekatz A et al. Silver‐coated textiles reduce present on infected skin, but it is not typically present on
Staphylococcus aureus colonization in patients with atopic eczema.
healthy skin [4]. Researchers have proposed Malassezia as

Dermatology 2003;207:15–21.
22 Hipler UC, Elsner P, Fluhr JW. Antifungal and antibacterial properties the triggering agent for neonatal cephalic pustulosis, but
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23 Fluhr JW, Breternitz M, Kowatzki D et al. Silver‐loaded seaweed‐based
cellulosic fiber improves epidermal skin physiology in atopic derma
in the proportions of Malassezia species, with M. globosa
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single‐blinded exploratory in vivo study. Exp Dermatol 2010;19:e9–15. In Chinese and French patients with dandruff, though,
24 Juenger M, Ladwig A, Staecker S et al. Efficacy and safety of silver M. restricta is more abundant [7]. Malassezia was found in
textile in the treatment of atopic dermatitis (AD). Curr Med Res Opin
2006;22:739–50. greater amounts and had greater diversity in 1‐month‐
25 Grice EA, Kong HH, Conlan S et al. Topographical and temporal olds with seborrhoeic dermatitis compared with those
diversity of the human skin microbiome. Science 2009;324:1190–2. without seborrhoea [8]. In this population, M. sympodialis
26 Bek‐Thomsen M, Lomholt HB, Kilian M. Acne is not associated with
yet‐uncultured bacteria. J Clin Microbiol 2008;46:3355–60.
and M. restricta were the dominant species. Thus, similar
27 Leyden JJ, McGinley KJ, Mills OH, Kligman AM. Propionibacterium to previously described bacterial studies, the fungal
levels in patients with and without acne vulgaris. J Invest Dermatol microbiota changes with maturation of the human host,
1975;65:382–4. which requires longitudinal studies to ascertain the role
28 Leyden JJ, McGinley KJ, Mills OH, Kligman AM. Age‐related changes
in the resident bacterial flora of the human face. J Invest Dermatol of various fungal community members in skin disease.
1975;65:379–81. Compared to the bacterial and fungal components of
29 Fitz‐Gibbon S, Tomida S, Chiu BH et al. Propionibacterium acnes the cutaneous human microbiome, work on the cutane
strain populations in the human skin microbiome associated with
ous human virome is in its infancy. Notably, viruses have
acne. J Invest Dermatol 2013;133:2152–60.
30 Kang D, Shi B, Erfe MC et al. Vitamin B12 modulates the transcrip been linked with multiple skin cancers, including HPV
tome of the skin microbiota in acne pathogenesis. Sci Transl Med and squamous cell carcinoma [9], Merkel cell polyomavirus
2015;7:293ra103. and Merkel cell carcinoma [10] and human herpesvirus 8
31 Fry L, Baker BS, Powles AV et al. Is chronic plaque psoriasis triggered
by microbiota in the skin? Br J Dermatol 2013;169:47–52.
(HHV8) and Kaposi sarcoma [11]. While these skin
32 McFadden JP, Baker BS, Powles AV, Fry L. Psoriasis and streptococci: cancers can occur in children, more often as paediatric
the natural selection of psoriasis revisited. Br J Dermatol 2009; dermatologists we deal with acute viral infections, such
160:929–37. as those in children with eczema (eczema herpeticum
33 Bassukas ID, Gaitanis G, Hundeiker M. Leprosy and the natural selec
tion for psoriasis. Med Hypotheses 2012;78:183–90. [HSV] and eczema coxsackium [coxsackie virus, often A6
34 Alekseyenko AV, Perez‐Perez GI, De Souza A et al. Community dif or A16]) or those with verrucae (HPV). Interestingly
ferentiation of the cutaneous microbiota in psoriasis. Microbiome enough in the latter case, work on adult skin has revealed
2013;1:31.
35 Zakostelska Z, Malkova J, Klimesova K et al. Intestinal microbiota
multiple HPV strains on normal skin [4]. While a viral
promotes psoriasis‐like skin inflammation by enhancing Th17 cause has been established for a small subset of skin
response. PloS One 2016;11:e0159539. diseases, far less is known about the normal viral ecology
36 Chen HH, Chao YH, Chen DY et al. Oral administration of acarbose of human skin.
ameliorates imiquimod‐induced psoriasis‐like dermatitis in a mouse
model. Int Immunopharmacol 2016;33:70–82. One reason that viral cutaneous microbiome research
has lagged behind is that the majority of viruses are not
catalogued in genomic databases, thus making compu
tational analyses of untargeted DNA sequences that
Fungal microbiota, virome
identify unique genomes particularly challenging. Similar
and parasites
to other microbiome efforts, more is currently known
Studies of cutaneous fungal species show site‐specific about the gut virome than the cutaneous virome [12].
diversity similar to that described for bacteria and viruses Recent work has delineated the composition of the cuta
[1]. Feet have the most diverse fungal community, with neous double‐stranded (ds) DNA virome at multiple sites
Malassezia and many environmental fungi identified [1]. in adults, thus allowing the investigators to investigate
Knowledge of typical fungal species resident on the skin viral diversity and virulence factors [13]. While cutaneous
can aid investigations of infections with opportunistic viromes were found to be stable over a 1‐month time
fungi. For example, Trichosporon asahii is an uncommon period, diversity over this time was present within the
pathogen of immunocompromised/immunosuppressed metagenomes and site diversity was seen [13]. This work
hosts. T. asahii can be found on normal skin, thus provid has also provided data allowing the authors to hypoth
ing a source for this opportunistic infection [2]. Work on esize how the dsDNA virome interacts with other
cutaneous fungal colonization is essential to understand members of the microbiota [13]. Delineation of the typical
ing overall cutaneous microbial ecology (bacteria/fungi/ paediatric virome (both healthy and disease‐associated)
viruses), which will advance the treatment of both fungal will be essential as we investigate the causes of both infec
skin disease and other dermatoses. tious and malignant skin disease.
Similar to bacterial microbiome colonization with par Recently there has been more interest in skin ectopara
turition, colonization of the skin with fungi is present on sites, with Demodex mites implicated by some authors in
day 0 of life with maternal transfer of Malassezia to infants the pathogenesis of adult rosacea, though causation is not
[3]. Studies of the fungal microbiota often centre on confirmed [14–16]. However, in keeping with the thought
Malassezia, a lipophilic yeast, present as a colonizer and in of one microbial community influencing another, Murillo
disease states. Another common yeast, Candida, can be et al. found differences in the local microbiota associated
with Demodex in patients with papulopustular rosacea 10 Feng H, Shuda M, Chang Y, Moore PS. Clonal integration of a polyoma
virus in human Merkel cell carcinoma. Science 2008;319:1096–100.

(less Actinobacteria, and more Proteobacteria and
11 Chang Y, Cesarman E, Pessin MS et al. Identification of herpesvirus‐
Firmicutes) versus patients with erythematotelangiectatic like DNA sequences in AIDS‐associated Kaposi’s sarcoma. Science
rosacea and controls [17]. Demodex is not seen as often on 1994;266:1865–9.
paediatric skin, but immunosuppressed patients (spe 12 Lim ES, Wang D, Holtz LR. The bacterial microbiome and virome
milestones of infant development. Trends Microbiol 2016;24:801–10.
cifically those with acute lymphoblastic leukaemia) are 13 Hannigan GD, Meisel JS, Tyldsley AS et al. The human skin double‐
at risk for eruptions triggered by this mite [18,19]. More stranded DNA virome: topographical and temporal diversity,
work is needed to evaluate the potential influence of genetic enrichment, and dynamic associations with the host micro-
Demodex on paediatric rosacea, and its presence on the biome. mBio 2015;6:e01578–15.
14 Holmes AD. Potential role of microorganisms in the pathogenesis of
skin of different immunosuppressed and immunodefi rosacea. J Am Acad Dermatol 2013;69:1025–32.
cient patients. 15 Brown M, Hernandez‐Martin A, Clement A et al. Severe demodexfol
liculorum‐associated oculocutaneous rosacea in a girl successfully
treated with ivermectin. JAMA Dermatol 2014;150:61–3.
References 16 Gupta G, Daigle D, Gupta AK, Gold LS. Ivermectin 1% cream for
1 Findley K, Oh J, Yang J et al. Topographic diversity of fungal and bac rosacea. Skin Therapy Lett 2015;20:9–11.
terial communities in human skin. Nature 2013;498:367–70. 17 Murillo N, Aubert J, Raoult D. Microbiota of Demodex mites from
2 Zhang E, Sugita T, Tsuboi R et al. The opportunistic yeast pathogen rosacea patients and controls. Microb Pathog 2014;71‐72:37–40.
Trichosporon asahii colonizes the skin of healthy individuals: analysis 18 Hitraya‐Low M, Ahmad RC, Cordoro KM. Facial eruption in a
of 380 healthy individuals by age and gender using a nested polymer 5‐year‐old child with acute lymphoblastic leukemia. Pediatr Dermatol
ase chain reaction assay. Microbiol Immunol 2011;55:483–8. 2016;33:671–2.
3 Nagata R, Nagano H, Ogishima D et al. Transmission of the major 19 Ivy SP, Mackall CL, Gore L et al. Demodicidosis in childhood acute
skin microbiota, Malassezia, from mother to neonate. Pediatr Int lymphoblastic leukemia; an opportunistic infection occurring with
2012;54:350–5. immunosuppression. J Pediatr 1995;127:751–4.
4 Foulongne V, Sauvage V, Hebert C et al. Human skin microbiota: high
diversity of DNA viruses identified on the human skin by high
throughput sequencing. PloS one 2012;7:e38499.
5 Bergman JN, Eichenfield LF. Neonatal acne and cephalic pustulosis: is Conclusion
malassezia the whole story? Arch Dermatol 2002;138:255–7.
6 Sugita T, Suzuki M, Goto S et al. Quantitative analysis of the cutane The cutaneous microbiome is made up of a diverse array
ous Malassezia microbiota in 770 healthy Japanese by age and gender
of bacteria, fungi, viruses and parasites. These micro
using a real‐time PCR assay. Med Mycol 2010;48:229–33.
7 Wang L, Clavaud C, Bar‐Hen A et al. Characterization of the major scopic passengers may colonize or infect the skin depend
bacterial‐fungal populations colonizing dandruff scalps in Shanghai, ing on natural virulence, host maturation or environment
China, shows microbial disequilibrium. Exp Dermatol 2015;24:398–400. pressures. While the general contribution of microbes to
8 Yamamoto M, Umeda Y, Yo A et al. Utilization of matrix‐assisted laser
desorption and ionization time‐of‐flight mass spectrometry for
both healthy and defective skin barriers is well appreci
identification of infantile seborrheic dermatitis‐causing Malassezia ated in dermatology, specific host–microbe and microbe–
and incidence of culture‐based cutaneous Malassezia microbiota of microbe interactions are still largely unknown. Research
1‐month‐old infants. J Dermatol 2014;41:117–23. into the ‘normal’ microbiome and how dysbiosis contrib
9 Euvrard S, Chardonnet Y, Pouteil‐Noble C et al. Association of skin
malignancies with various and multiple carcinogenic and noncarcino utes to skin disease is leading to seminal investigations
genic human papillomaviruses in renal transplant recipients. Cancer that will undoubtedly change how we treat, and hope
1993;72:2198–206. fully in the future prevent, cutaneous diseases.
56
CHA PTER 4
Physiology of Neonatal Skin

Peter H. Hoeger
Department of Paediatric Dermatology, Catholic Children’s Hospital Wilhelmstift, Hamburg, Germany
Introduction, 56 Epidermis, 57 Dermis and skin appendages, 61

Vernix caseosa, 56 Transepidermal water loss, 58
Abstract in premature babies leads to potentially life‐threatening water loss

and enhances the risk of infections. It takes more than 12 months
While the skin of the neonate appears to be ‘mature’ with regard for the intraepidermal concentrations of natural moisturizing fac-
to its anatomical appearance, many physiological functions of the tors (NMF) and, hence, the transepidermal water loss (TEWL), to
skin undergo postnatal maturation. Insufficient interlacement normalize. The threshold for eccrine sweating remains elevated
between epidermis and dermis leads to increased susceptibility for months. Conversely, due to stimulation by maternally derived
towards shearing forces. Immaturity of the epidermal lipid barrier androgens, sebum production is increased.
Key points maturation in terms of increasing hydration and concentrations

of water‐binding natural moisturizing factors (NMF).
• Vernix caseosa is a mixture of water, protein and lipids whose • In premature babies, transepidermal water loss (TEWL) is
composition reflects epidermal barrier maturation. It protects inversely proportional to gestational age. In very low birthweight
the epidermis from water (amniotic fluid) exposure and has infants (VLBW) TEWL can be as high as 100 g/m2/h which, if
antimicrobial and hydrating properties. not immediately compensated for (by humidified incubators,
• Epidermis and dermis along with its appendages (sweat glands, plastic wraps, topical emollients), is incompatible with life. Poor
sebaceous glands, hair follicles) are fully developed in a term integrity of the stratum corneum puts premature infants at risk
neonate. During the first year of life the skin undergoes functional of mechanical trauma and transcutaneous infections.
Introduction Vernix caseosa

The transition from an aqueous, but sterile, environment During the last trimester of gestation, the fetus is covered
to a dry one rich in pathogens represents a dramatic by a protective biofilm called vernix caseosa. It forms a
challenge to the skin of the newborn infant. Intactness of mechanical ‘shield’ against maceration by amniotic fluid
the epidermal barrier is of utmost importance both for the and bacterial infection. Vernix is composed mainly of
prevention of water loss and for the defence against water (80.5%), proteins and lipids (8–10%) (Fig. 4.1) [1,2].
microorganisms that start to colonize the neonatal skin These lipids are derived from two sources: wax esters
from the moment of birth. The efficacy of this barrier formed in sebaceous glands [3] and epidermal barrier
is proportional to its thickness and lipid composition. lipids derived from keratinocytes [2]. Vernix contains all
During late gestation, the number of epidermal layers major stratum corneum lipids, including ceramides [4],
and the thickness of the stratum corneum increase with which are not synthesized by sebaceous glands. Similar
fetal age. The extent of transepidermal water loss (TEWL) to postnatal skin, sebum and epidermal lipids apparently
and the risk of infections with skin‐colonizing microor- mix within vernix in order to provide on the fetal skin
ganisms in preterm infants are thus directly proportional surface what has been referred to as the skin surface lipid
to the infant’s degree of prematurity. Although the gross film [5]. Interestingly, the lipid composition of vernix
anatomy of epidermal and dermal structures in neonatal closely resembles that found in fetal skin [2]. Composition
skin is similar to that in older skin (Table 4.1), the process of vernix lipids was found to reflect epidermal barrier
of postnatal maturation and adaptation affects virtually maturation and correlates with gestational age, sex and
all compartments and structures of the skin. maternal diet [6].
Chapter 4 Physiology of Neonatal Skin 57
Table 4.1 A comparison of skin anatomy between preterm and term neonates and older children

Premature baby Full‐term neonate Infants/children
Skin thickness (mm) 0.9 1.2 2.1

Diameter of epidermis (μm) 20–25 40–50 >50
Diameter of stratum corneum (μm) (number of layers) 4–5 (5 or 6) 9–10 (≥10–15) 10–15 (≥10–15)
Dermoepidermal junction Flat, no rete ridges Rete ridges start to form Deep rete ridges
Eccrine sweat glands Upper dermis, inactive Upper dermis, barely active Deeper dermis, fully active
Elastic fibres Microfibrils, no elastin Elastic fibre network, immature Elastic fibre network, mature
Water 80.5% Epidermis

Proteins 10.3%
The epidermis protects against evaporation, percutaneous
Other lipids 6.4% absorption of toxic substances, physical damage and
microbial infection. These properties depend largely on the
Barrier lipids 2.72% thickness and barrier lipid content of the epidermis, both of
which are directly related to gestational age [1,2]. As shown
Cholesterol 1.1% in Fig. 4.2, the number of epidermal cell layers and, from
about the beginning of the third trimester, the thickness
FFA 0.6%
of the stratum corneum increase progressively with age.
Phospholipids 0.4%
Scanning electron microscopy of the epidermal surface
Ceramides 0.7% showed high anisotropy with irregular corneocyte clusters
in young infants indicating a poorly controlled process of
Fig. 4.1 Composition of human vernix caseosa. FFA, free fatty acid.
Source: Adapted from Pickens et al. 2000 [1] and Hoeger et al. 2002 [2]. corneocyte desquamation while in older children the dis-
tribution of superficial corneocytes was more regular [3].
The most important lipids required for barrier function
Unlike postnatal skin, sebum and keratinocytes are (i.e. ceramides, cholesterol and free fatty acids) are syn-
not shed in the fetal period but adhere to the skin; accu- thesized in the lamellar bodies within the granular layer.
mulation of vernix might thus compensate for the relative There is a patterned succession of epidermal expression of
lack of barrier lipids in fetal skin. Application of vernix to mRNA and of enzymes involved in lipid synthesis preced-
normal adult skin has been shown to increase surface ing the formation of an effective epidermal barrier [4,5].
hydration [7]. Vernix contains antimicrobial peptides, e.g. Among the most important factors regulating the sequence
cathelicidin, lysozyme and lactoferrin, which along with of epidermal differentiation and stratum corneum forma-
free fatty acids provide antimicrobial protection against tion is the peroxisome proliferator‐activated receptor‐α
fungi, bacteria and parasites [8,9]. (PPAR‐α). PPARs are expressed abundantly in early fetal
epidermis; they regulate the activity of key enzymes
required for barrier ontogenesis (e.g. β‐glucocerebrosidase
References and steroid sulphatase) [5,6]. Similar to what happens in
1 Pickens WL, Warner RR, Boissy YL et al. Characterization of vernix
maturation of the lung, glucocorticoids, thyroid hormones
caseosa: water content, morphology, and elemental analysis. J Invest
Dermatol 2000;115:875–81. and oestrogens accelerate barrier formation, while andro-
2 Hoeger PH, Schreiner V, Klaassen IA et al. Epidermal barrier lipids in gens retard it [5]. Initiation of skin barrier formation in the
human vernix caseosa: corresponding ceramide patterns in vernix and human fetus starts at around 20–24 weeks’ gestation [7].
fetal epidermis. Br J Dermatol 2002;146:194–201.
3 Stewart ME, Quinn MA, Downing DT. Variability in the fatty acid com- The process of keratinization reveals an interesting tempo-
position of wax esters from vernix caseosa and its possible relation to ral and spatial pattern, starting at and spreading from dis-
sebaceous gland activity. J Invest Dermatol 1982;78:291–5. tinct epidermal initiation sites such as forehead, palms and
4 Oku H, Mimura K, Tokitsu Y. Biased distribution of the branched‐
soles [7,8]. Filaggrin – derived from profilaggrin in the
chain fatty acids in ceramides of vernix caseosa. Lipids 2000;35:
373–81. keratohyalin granules – aggregates keratin filaments in the
5 Sheu H‐M, Chao S‐C, Wong T‐W et al. Human skin surface lipid film: stratum corneum. Small molecules known as natural mois-
an ultrastructural study and interaction with corneocytes and inter- turizing factor (NMF) are proteolytically cleaved from
cellular lipid lamellae of the stratum corneum. Br J Dermatol
1999;140:385–91.
filaggrin. They are responsible for hydration and plasticity
6 Checa A, Holm T, Sjödin MOD et al. Lipid mediator profile in vernix (flexibility) of the skin surface and help to prevent TEWL
caseosa reflects skin barrier development. Sci Rep 2015;5:15740. [9]. Forty percent of the NMF are formed by hygroscopic
7 Bautista MIB, Wickett RR, Visscher MO et al. Characterization of free amino acids such as urocanic acid; their concentration
vernix caseosa as a natural biofilm: comparison to standard oil‐based
ointments. Pediatr Dermatol 2000;17:253–60. at birth is extremely low, and increases slowly over the first
8 Akinbi HT, Narendran V, Pass AK et al. Host defense proteins in months in parallel with stratum corneum hydration [10,11].
vernix caseosa and amniotic fluid. Am J Obstet Gynecol 2004; Intraepidermal concentrations of the pro‐inflammatory
191:2090–6.
9 Tollin M, Bergsson G, Kai‐Larsen Y et al. Vernix caseosa as a multi‐
cytokine interleukin 1‐alpha (IL‐1α) are higher in infants
component defence system based on polypeptides, lipids and their than in adults, and higher in premature than in mature
interactions. Cell Mol Life Sci 2005;62:2390–9. infants. Its release is stimulated by the rapid transition
(a)
(b)
(c) (d)
Fig. 4.2 Embryonic, fetal and neonatal skin: (a) at 13 weeks’ gestation; (b) at 18 weeks’ gestation; (c) at 25 weeks’ gestation; (d) in a mature neonate.
from high to low humidity at birth, and in response to epi- 80

dermal damage in order to induce the recovery process
[12,13]. The same applies to the antimicrobial peptides
60
(human β‐defensins [HBD] and cathelicidins) which are
TEWL (g/m2/hr)
reduced in neonates [14] while the antimicrobial proteins

lysozyme and lactoferrin are present in neonatal epider- 40
mis at levels five times higher than in adults [15].
20
Transepidermal water loss
The intactness of the epidermal barrier can be assessed by
0
measuring the TEWL. The TEWL is proportional to the
0 5 10 15 20
vapour pressure gradient measured with an evaporimeter
Postnatal age (days)
[16,17]. It is influenced by gestational age, site and ambi-
ent humidity [16–18]. In term neonates, the TEWL ranges Fig. 4.3 The effect of gestational age on transepidermal water loss
(TEWL). Serial measurements from abdominal skin in 17 infants of 25–29
from 4 to 8 g/m2/h. This is slightly lower than in adults
weeks’ gestation. Shaded bar represents TEWL in term infants. Source:
[19] owing to the fact that eccrine sweating is low or absent Cartlidge and Rutter 1998 [18]. Reproduced with permission of Elsevier.
in the newborn infant. In the premature infant, TEWL is
inversely proportional to gestational age (Fig. 4.3). In very
immature infants (24–26 weeks’ gestation), it can be as along a water vapour gradient, it can be prevented by rais-
high as 100 g/m2/h, which means that these infants, if left ing the ambient humidity. It is now common practice to
in a dry atmosphere, could lose 20–50% of their body humidify incubators for premature babies, particularly
weight within 24 hours. This degree of TEWL would rap- those of less than 32 weeks’ gestation [20]. Humidity needs
idly lead to hypernatraemia, polyglobulia and hypother- to be as high as 80–90% within the first days in order to
mia, resulting eventually in periventricular haemorrhage prevent heat and fluid loss. Prevention of hypothermia
and death. As TEWL represents passive diffusion of water and TEWL can also be ascertained by using polyethylene
caps or wraps immediately after delivery [21]. Randomized infants should therefore be adequately increased during

controlled trials in Pakistan and India where incubators phototherapy. Neonatal epidermis can easily be damaged
are not readily available have demonstrated that postnatal (e.g. by removal of plastic adhesives), which induces a
application of topical emollients (sunflower seed oil, coco- measurable disruption of the skin barrier function [29].
nut oil or mineral oils [petrolatum]) can (i) reduce TEWL Interestingly, air exposure leads to acceleration of post-
in VLBW preterm babies [22] and (ii) improve skin integ- natal barrier maturation. As depicted in Fig. 4.3, TEWL in
rity and reduce the risk of bloodstream infections in pre- most premature infants approaches that of term infants
term infants [23] if started immediately after birth [24]. within 10–15 days. Studies in rodents have shown that
The effectiveness of this approach in primary care settings this functional maturation is paralleled by an increase in
needs to be further explored since a meta‐analysis of pre- stratum corneum thickness, the number of lamellar bod-
vious reports could not demonstrate benefits of topical ies in stratum granulosum cells and the barrier lipid con-
emollients with respect to infection rate and mortality [25]. tent of the stratum corneum [30,31]. In ultra‐low‐birthweight
There is a striking regional variability on the skin surface infants (23–25 weeks of gestational age), this process can,
regarding TEWL; it is usually highest through the abdomi- however, take significantly longer [32]. As demonstrated
nal skin, where maturation of the epidermal barrier occurs recently, even in mature babies it takes up 12 months until
latest [7,8]. Preterm infants nursed under a radiant heater TEWL normalizes to levels seen in older children and
exhibit higher rates of evaporation because the level of adults; this process is paralleled by a constant increase of
ambient water vapour is lower [26]. It is likewise increased NMF levels within the epidermis [33].
(by 20%) during phototherapy, even if relative humidity
and ambient temperature are tightly controlled; this is Skin surface pH
probably caused by increased dermal blood flow during Acidification of the skin surface is effected by acidic compo-
phototherapy [27,28]. Maintenance fluid intake of preterm nents in the sweat, sebum and horny layer (Fig. 4.4a) [34].
7.5 140
7.0 120
6.5 100
Corneometer units
6.0 80
pH
5.5 60
5.0 40
4.5 20
4.0 0
3 30 90 3 30 90
(a) RZ Din (b) Ra
160 30
140
25
120
20
100
80 15
μm
μm
60
10
40
5
20
0 0
3 30 90 3 30 90
(c) Age (days) (d) Age (days)
Fig. 4.4 Development of skin surface parameters in neonates and young infants (n = 180 healthy neonates). (a) Skin surface pH. (b) Stratum corneum hydration (both
measured on the frontal area). (c and d) Microtopography (parameters of skin roughness). Rz Din, mean depth of roughness; Ra, arithmetic mean surface roughness.
Three classes of molecules are considered to be the most 15 Walker VP, Akinbi HT, Meinzen‐Derr J et al. Host defense pro-
teins on the surface of neonatal skin: implications for innate
likely sources of protons in the epidermis [35]: some

immunity. J Pediatr 2008;152:777.
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α‐hydroxy acids such as lactic acid; and acidic lipids age in appropriate and small for gestational age. Acta Paediatr
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eds. Textbook of Fetal and Neonatal Physiology, 2nd edn. Philadelphia:
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20 Harpin VA, Rutter N. Humidification of incubators. Arch Dis Child
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Dermis and skin appendages is hastened postnatally so that nearly all preterm infants

are able to sweat at the age of 13 days, although the ther-
The dermis supplies sweat, sebum and, most impor- mal stimulus required is higher and sweat output lower
tantly, nutrients to the epidermis. Dermal vessels are than in term neonates [10]. Emotional sweating, which is
most important for the regulation of skin and body particularly prominent on the palmoplantar regions, rep-
temperature. The dermis connects the epidermal sheath resents a response to hunger or pain independent of
with the underlying fatty tissue and, through a network ambient temperature. It is not present before 36–37 weeks’
of collagenous and elastic fibres, provides stability and gestation [12]. Functional immaturity of the sweat glands
protection against trauma to the skin. With its papillary appears to be without clinical significance in the neonatal
ridges, the epidermis is intertwined with the dermis, thus period. Even in children with anhidrotic ectodermal dys-
protecting against shearing or abrasive forces. The basal plasia, who are completely unable to sweat, hyperpyrexia
cell layer to surface length ratio gives an indication of the does not occur until late infancy/early childhood.
undulation of the epidermal–dermal interface [1]. In term
infants, it increases from 1.07 ± 0.07 to 1.2 ± 0.13 within the Percutaneous respiration
first 4 months [1]. As long as the rete ridges are not or only The absorption of oxygen and excretion of carbon dioxide
incompletely formed, the epidermis is prone to abrasive through the skin is an often quoted and much overrated
injuries caused for instance by shearing movements of phenomenon. In adults and mature neonates, it accounts
the patients’ own hands or by the removal of plasters. for <2% of total respiration. In premature infants of
This effect is augmented by the relative thinness of the <30 weeks’ gestation, however, transcutaneous gas
epidermis. exchange is 6–11 times higher than in term infants. In par-
allel with the postnatal maturation of the transepidermal
Sebaceous gland activity lipid barrier, it tends to normalize within 2–3 weeks after
Sebum is composed of squalenes and monoester waxes
birth [13]. Interestingly, prolonged skin‐to‐skin contact
[2]. Sebum levels during the first month tend to be as
(‘kangarooing’) between premature babies (gestational
high as those in adults [3,4], but they decline significantly
age 30 weeks) and their mothers has been shown to
towards the end of the first trimester and remain low
improve gas exchange independent of postnatal age [14].
until the beginning of puberty. Stimulation of sebaceous
glands by maternal androgens starts before birth [3].
Accordingly, transient sebaceous gland hypertrophy is a
Wound healing
Scars result from cutaneous damage involving the basal
common finding in term neonates. Rates of maternal and
layer and dermis. Scarless wound healing is a much debated
neonatal sebum secretion are correlated [4].
phenomenon associated with fetal skin. During the first and
Thermoregulation second trimester, skin and bone wounds heal in a regenera-
Neonates, and particularly premature babies, are at an tive manner [15]. Cutaneous wound healing in the fetus
increased risk of heat loss. Heat loss is largely caused by differs in many ways from that in children or adults. The
evaporative rather than radiative loss during the first most striking difference is the absence of an acute inflam-
week of life [5]. In term infants thermogenesis is largely matory response to trauma. Degranulation and aggregation
driven by brown adipose tissue which is located around of fetal platelets and the production of fibrogenic platelet‐
the kidney and in the interscapular areas and represents derived growth factor (PDGF), transforming growth factor
about 1% of fetal weight at term [6]. Regional heat loss is (TGF)‐β1 and TGF‐β are decreased. As very few neutrophils
closely related to the external temperature. The vaso- are attracted to the wound site, devitalized tissue is mainly
constrictive response to reduced temperature, which cleared by macrophages and wound fibroblasts instead of
can be assessed by laser Doppler flowmetry, appears to neutrophils [16]. While healing of postnatal wounds involves
be diminished in the newborn infant [7]. Occlusive coordinated activity of chemokines, cytokines, growth
wrapping of VLBW infants has been shown to prevent factors and other soluble mediators [17], pro‐inflammatory
the dangerous postnatal evaporative heat loss [8]. chemokines, such as interleukins (IL)‐6 and 8, are dimin-
Although their density of sweat glands is even higher ished while IL‐10 is increased [18].
than that in adults, thermal sweating is reduced in the The number of stem cells is increased in fetal wounds
term neonate (i.e. the induction threshold for sweating is as well as in unwounded fetal skin [19]. They may be
higher than in adults) [9,10]. Sweating occurs first on the ‘educating’ the stromal cells [15] towards regeneration
forehead and later on the trunk and extremities. The instead of scarring. Proliferation and migration rates of
intensity of sweating in response to a thermal stimulus fetal fibroblasts as well as their rate of synthesis of colla-
depends on gestational age [10]. Unlike term neonates, gen are indeed increased as compared to adults. There are
preterm babies are usually unable to sweat in response also differences in the type of collagen (collagen III > I = 3 : 1
to heat during the first days of life. On the other hand, instead of 1 :3) synthesized [20].
sweating can be induced chemically as early as 32 weeks’
gestation, suggesting that hypohidrosis results from References
immaturity of neurological regulation rather than ana- 1 Evans NJ, Rutter N. Development of the epidermis in the newborn.
Biol Neonate 1986;49:74–80.
tomical immaturity [11]. Similar to their adaptation 2 Nikkari T. Comparative chemistry of sebum. J Invest Dermatol 1974;
regarding TEWL, however, the development of sweating 62:257–67.
3 Agache P, Blanc D, Barrand C et al. Sebum levels during the first year 13 Cartlidge PHT, Rutter N. Percutaneous respiration in the newborn
of life. Br J Dermatol 1980;103:643–9. infant: effect of gestation and altered ambient oxygen concentration.
4 Henderson CA, Taylor J, Cunliffe WJ. Sebum excretion rates in

Biol Neonate 1987;52:301–6.
mothers and neonates. Br J Dermatol 2000;142:110–11. 14 Föhe K, Kropf S, Avenarius S. Skin‐to‐skin contact improves gas

5 Hammarlund K, Strömberg B, Sedin G. Heat loss from the skin of exchange in premature infants. J Perinatol 2000;5:311–15.
preterm and full term newborn infants during the first weeks after 15 Yates C, Hebda P, Wells A. Skin wound healing and scarring: fetal
birth. Biol Neonate 1986;50:1–10. wounds and regenerative restitution. Birth Defects Res C Embryo
6 Hillman N, Kalapur SG, Jobe A. Physiology of transition from Today 2012;96:325–33.
intrauterine to extrauterine life. Clin Perinatol 2012;39:769–83. 16 Coolen NA, Schouten KC, Middelkoop E et al. Comparison between
7 Karlsson H, Hänel SE, Nilsson K et al. Measurement of skin tempera- human fetal and adult skin. Arch Dermatol Res 2010;302:47–55.
ture and heat flow from skin in term newborn babies. Acta Paediatr 1 7 Wulff BC, Parent AE, Meleski MA et al. Mast cells contribute to
1995;84:605–12. scar formation during fetal wound healing. J Invest Dermatol
8 Rohana J, Khairina W, Boo NY, Shareena I. Reducing hypothermia in 2012;132:458–46.
preterm infants with polyethylene wrap. Pediatr Int 2011;53:468–74. 18 Kiechty KW, Adzick NS, Crombleholme TM. Diminished interleukin
9 Mancini AJ, Lane AT. Sweating in the neonate. In: Polin RA, Fox WW, 6 (IL‐6) production during scarless human fetal wound repair.
eds. Textbook of Fetal and Neonatal Physiology, 2nd edn. Philadelphia: Cytokine 2000;12:671–6.
W.B. Saunders, 1998:767–70. 19 Wagers AJ, Christensen JL, Weissman IL. Cell fate determination from
10 Harpin VA, Rutter N. Sweating in preterm babies. J Pediatr 1982; stem cells. Gene Ther 2002;9:606–12.
100:614–18. 20 Merkel JR, DiPaolo BR, Hallock GG et al. Type I and Type III collagen
11 Behrendt H, Green M. Nature of the sweating deficit in prematurely content of healing wounds in fetal and adult rats. Proc Soc Exp Biol
born neonates. N Engl J Med 1972;286:1376–9. Med 1988;187:493–7.
12 Harpin VA, Rutter N. Development of emotional sweating in the
newborn infant. Arch Dis Child 1982;57:691–5.
63
C HA PTER 5
Neonatal Skin Care

Peter H. Hoeger
SECTION 2: SKIN DISORDERS

OF NEONATES AND INFANTS
Introduction, 63 Skin care of the premature infant, 66 Percutaneous absorption, 71

Skin care of the neonate, 63 Skin care of the term neonate and infant, 67
Abstract The benefits of emollient care need to be weighed against poten-

tial side‐effects. Anionic detergents such as sodium lauryl sulfate
Due to its structural and functional immaturity, the skin of neo- and emollients containing emulsifiers can emulsify stratum
nates is more susceptible to mechanical damage and chemical corneum lipids, thus increasing permeability and skin dryness.
irritation. Neonatal skin care aims at preventing physical injury, Common ingredients such as lanolin can cause contact a llergies,
minimizing transepidermal water loss and avoiding infection. others such as parabenes or triclosan can act as endocrine
The optimal emollient for skin care remains to be determined. disrupting agents.
Key points • The rate of inadvertent percutaneous absorption of many agents

applied to the skin surface is increased in infants, but largely
• Due to its immature epidermal barrier, neonatal skin is highly unexplored for cosmetic ingredients.
sensitive to physical and chemical damage. • Commonly used ingredients can lead to contact sensitization.
• Infants are exposed to many cosmetic ingredients at an early • These aspects need to be considered for all aspects of skin care in
age. the neonate and young infant.
Introduction however not easily answered as there are very few rand-
omized controlled trials (RCTs) addressing these issues.
Due to its structural and functional immaturity, the skin In the absence of scientific evidence, many recommenda-
of full‐term and preterm neonates and infants is different tions are rather based on common sense, traditional prac-
from that of older children. Epidermal barrier and ther- tice or ‘experts’ opinions’, some of which are more or less
moregulatory mechanisms are immature; the skin is thin- openly sponsored by the cosmetic industry.
ner and more susceptible to mechanical damage and
chemical irritation; and the skin surface of neonates is
References
larger (in proportion to their body mass) than in adults. 1 Nikolovski J, Stamatas GN, Kollias N et al. Barrier function and
As outlined in Chapter 4, these structural and develop- water‐holding and transport properties of infant stratum corneum
mental differences are associated with decreased epider- are different from adult and continue to develop through the first
year of life. J Invest Dermatol 2008;128:1728–36.
mal concentrations of natural moisturizing factors (NMF) 2 Chittock J, Cooke A, Lavender T et al. Development of stratum cor-
and increased transepidermal water loss (TEWL) [1,2]. neum chymotrypsin‐likeprotease activity and natural moisturizing
As a consequence, the skin surface pH is increased and factors from birth to 4 weeks of age compared with adults. Br J
epidermal proteases are activated [2,3]; both factors Dermatol 2016;175:713–20.
3 Hachem JP, Man MQ, Crumrine D et al. Sustained serine proteases
plus decreased epidermal concentrations of antimicro- activity by prolonged increase in pH leads to degradation of lipid pro-
bial lipids [4] facilitate bacterial colonization and trans- cessing enzymes and profound alterations of barrier function and stra-
cutaneous infections, particularly in preterm infants. tum corneum integrity. J Invest Dermatol 2005;125:510–20.
4 Drake DR, Brogden KA, Dawson DV et al. Thematic review series: skin
Furthermore, the immature epidermal barrier allows eas- lipids. Antimicrobial lipids at the skin surface. J Lipid Res 2008;49:
ier transcutaneous penetration of allergens and chemi- 4–11.
cals. In conjunction with the larger skin surface of neonates
this transforms into an increased risk for systemic toxicity
Skin care of the neonate
from topically applied substances. Maturation of the bar-
rier takes at least 12 months [1]. It is therefore obvious that Aims of neonatal skin care
the skin of neonates and young infants requires specific Neonatal skin care aims at:
care in order to avoid damage and, ideally, to compensate • minimizing transepidermal water loss
for the immaturity of the epidermal barrier. The questions • prevention of physical injury and
if, when and how neonates should receive skin care are • avoiding infections.
64 Section 2 Skin Disorders of the Neonate and Young Infant
Environmental factors affecting epidermal As bathing can lead to neonatal hypothermia (<36.5 °C),
integrity which in itself carries the risk of intraventricular haemor-
The abrupt switch from 100% humidity within the rhage, the first bath should be delayed until the neonate’s
amniotic fluid to the relatively dry ambient atmosphere vital signs and body temperature have remained stable
represents a maximal challenge to the adaptability of for at least 4–6 hours [7,11,12]. For rewarming after
the neonatal skin. Various environmental factors can the first bath, close skin‐to‐skin contact (under protec-
adversely affect the epidermal integrity and should be tive covering) is preferred by most mothers and has been
avoided wherever possible (Table 5.1). shown to be safe and effective [13]. In resource‐poor
Soap and anionic detergents such as sodium lauryl sul- countries neonatal mortality can be reduced significantly
fate (SLS) lead to an immediate increase of the skin sur- by postponing the first bath for 72 hours post partum [14].
face pH which in turn activates proteases capable of Blood and meconium should however be gently removed
disturbing the epidermal barrier. ‘Hard’ tap water which after birth.
contains high levels of free calcium is prevalent in many
areas. In these areas, the incidence of atopic dermatitis Washing and bathing
(AD) is increased [1]. Hard water can induce skin irrita- Immersion (tub) bathing is not only a means of cleansing,
tion [2], particularly so because it requires increased use but also a moment of close tactile interaction between
of soap. High levels of free calcium have been shown to baby and parent(s). In an RCT comparing sponge and tub
inhibit skin barrier repair in vitro [3]. immersion bathing in a cohort of late preterm infants, tub
Skin irritation can likewise be induced by too‐frequent bathing was shown to significantly improve thermoregu-
washing, synthetic or inflexible garments causing abra- lation [15]. The water should cover the infant’s entire
sions, or the removal of adhesives [4]. body in order to decrease evaporative heat loss. The opti-
It is well known that disruption of the normal skin mal water temperature is 37–38 °C. Water temperature
microbiome by antibiotic treatment during the first weeks should always be accurately measured before immersion
of life increases the risk to develop AD [5]. Recent evi- as tests just by touch have proved inaccurate to avoid
dence using whole‐metagenome sequencing [6] suggests scalds. Since hyperhydration of the epidermis would ren-
that skin bacteria can influence the skin surface microen- der the skin more fragile, the duration of the bath should
vironment, for instance by production of excessive be limited to 5–10 minutes every other day [9,16].
amounts of ammonia which adds to the increased skin Immediately after bathing, the infant’s skin should be
surface pH in children with AD. gently towelled and a head covering applied [7]. There is
no evidence that delaying the first bath until the umbilical
Skin care immediately after birth cord has separated prevents umbilical cord infection
and in the first 2–3 days [8,9,17].
Immediately after delivery, the neonate should be Surfactants in skin cleansers are tensioactive agents
wrapped in a towel and gently rubbed. The baby should capable of removing fatty substances from the skin sur-
be kept in a room of at least 25–28 °C ambient temperature face by emulsifying them into fine droplets, which can
and no draught. Any remaining vernix should be left in then be rinsed away. Anionic detergents contain mole-
place and allowed to dry and peel off naturally [7–9]. cules with a negatively charged hydrophilic end (e.g.
Owing to its antimicrobial property and its capacity to SLS). They create a foaming effect which is associated
diminish TEWL, vernix would in fact be an ideal emol- with a cleansing action on the stratum corneum. Cationic
lient for the neonate [10], and there is some evidence that detergents such as quaternary ammonium salts contain
retention of vernix is associated with better skin hydra- molecules with a positively charged end. Skin cleansing
tion and lower skin surface pH as compared to newborns with soaps leads to alkalization of the skin surface and
whose vernix was removed immediately after birth [10]. can cause irritation [17,18].
However, in case of maternal human immunodeficiency Surfactants can emulsify stratum corneum lipids, thus
virus (HIV) or hepatitis B infection, early removal is increasing permeability and dryness of the skin surface
advisable due to the risk of transmission of infectious [19]. Detergents should therefore be used cautiously in
agents via maternal blood [7]. neonates, and the skin should be rinsed with water fol-
lowing their use. Although frequently recommended by
Table 5.1 Environmental factors exerting negative effects on the epider- various sponsored panels, the evidence in favour of the
mal barrier use of liquid (or gel) cleansers with or without emollient
is inconclusive. A comparative study in neonates indi-
Factor Effect on epidermal barrier cated that liquid cleansers plus emollients might lead to
increased TEWL as compared to rinsing with water alone
Hard water Hydration of SC↓, skin barrier repair↓ [20]; opposite results were found in another study [21]. It
Detergents Skin surface pH↑, activation of proteases
is strongly advisable to use only mild, non‐irritating liq-
Too‐frequent washing Hydration of SC↓, skin dryness↑
Adhesive plasters Destruction of corneal layer uid cleansers able to maintain the normal surface pH [17];
Synthetic garments Skin irritation in order to minimize their irritation potential, cleansers
Altered skin flora Formation of ammonia, skin surface pH↑ should be fragrance‐free and dye‐free and contain the
least possible concentration of preservatives [8]. The same
↑, increase; ↓, decrease; SC stratum corneum. cleansers can be used for the scalp and hair. Alternatively,
Chapter 5 Neonatal Skin Care 65
shampoos containing very mild surfactant complexes

Box 5.1 List of common potential allergens in baby wipes causing
and buffers in order to achieve a pH and saline concentra-
allergic contact dermatitis [36,37]
tion similar to those of tears have been specifically
designed for infant care [16,22]. • Botanical extracts, including members of the Compositae family
• α‐tocopherol
Umbilical cord care • Fragrances

The umbilical cord stump dries out and falls off between • Propylene glycol
5 and 10 days after birth. In countries with poor hygienic • Parabens
standards, the cord stump represents an important focus • Iodopropynyl butylcarbamate
• Lanolin
for neonatal infection and mortality. Umbilical cord care
• Methylchloroisothiazolinone/methylisothiazolinone
varies widely around the world [23–27]. General recom-
• Formaldehyde releaser
mendations issued by the WHO in 2004 [23] include:
• proper hand hygiene
• cutting the cord with a sterile instrument
• washing the cord stump with clean water or soap. to maintain an acidic skin surface pH [34]. This is in
Several agents formerly recommended for cord care accordance with the results of a prospective study show-
(isopropyl alcohol, hexachlorophene, neomycin) can have ing that a higher skin pH in neonates is a predisposing
serious adverse effects and should be avoided [9]. Alcohol factor for napkin dermatitis [35]. However, preservatives
or topical antiseptics delay cord separation by 2 days and fragrances in baby wipes can lead to allergic contact
[23,24]. Meta‐analyses of controlled studies indicate that sensitization which is an underrecognized cause of per-
the application of 4% chlorhexidine solution to the umbil- ineal dermatitis [36,37] (Box 5.1).
ical stump is non‐hazardous and can reduce the risk of
omphalitis by up to 50% and of neonatal mortality by 12% References
[25–27]. However, in a large randomized study from 1 Ewence A, Rumsby P, Rockett L et al. A review of skin irritation and
France with 8698 participants published in 2017, dry care tap water quality. Swindon: WRc. Drinking Water Inspectorate Ref.
DWI8375, 2011:1–149.
of the cord proved non‐inferior to the use of antiseptics 2 Warren R, Ertel KD, Bartolo RG et al. The influence of hard water
[28]. Both approaches may have their justification; how- (calcium) and surfactants on irritant contact dermatitis.Contact
ever, antiseptic prophylaxis may be preferable for deliver- Dermatitis 1996;35:337–43.
3 Lee SH, Elias PM, Proksch E et al. Calcium and potassium are impor-
ies outside a hospital setting and in resource‐limited
tant regulators of barrier homeostasis in murine epidermis. J Clin
populations [29]. Invest 1992;89:530–8.
There is currently no good evidence favouring full‐ 4 Lund CH, Nonato LB, Kuller JM et al. Disruption of barrier function
body skin cleansing with chlorhexidine as a prophylactic in neonatal skin associated with adhesive removal. J Pediatr 1997;131:
367–72.
skin disinfectant in neonates [26]. The same applies to 5 Tsakok T, McKeever TM, Yeo L, Flohr C. Does early life exposure to
maternal vaginal chlorhexidine washes compared to antibiotics increase the risk of eczema? A systematic review. Br J
usual care [26]. Underdeveloped countries with poor Dermatol 2013;169:983–91.
hygienic conditions might nevertheless benefit from these 6 Chng KR, Tay ASL, Li C et al. Whole metagenome profiling reveals
skin microbiome‐dependent susceptibility to atopic dermatitis flare.
approaches to reduce neonatal mortality [9]. All antisep- Nat Microbiol 2016;1:1–10.
tic solutions required for sterile procedures should be 7 Lund CH, Osborne JW, Kuller J et al. Neonatal skin care: clinical out-
applied only to the immediate skin area and in very small come of the AWHONN/NANN evidence‐based clinical practice
guideline. J Obstet Gynecol Neonatal Nurs 2001;30:41–51.
amounts. They should be removed with water‐soaked 8 Dyer JA. Newborn skin care. Semin Perinatol 2013;37:3–7.
gauze after the procedure to prevent unnecessary absorp- 9 Ness MJ, Davis DMR, Carey WA. Neonatal skin care: A concise
tion due to prolonged exposure in order to avoid serious review. Int J Dermatol 2013;52:14–22.
complications [30]. In neonates, alcohol used as a topical 10 Visscher MO, Barai N, LaRuffa AA et al. Epidermal barrier treatments
based on vernix caseosa. Skin Pharmacol Physiol 2011;24:322–9.
antiseptic is nearly completely absorbed percutaneously 11 Blume‐Peytavi U, Lavender T, Jenerowicz D et al. Recommendations
with a potential for systemic toxicity. It is also drying and from a European Roundtable Meeting on Best Practice Healthy Infant
painful to abraded skin and can cause skin necrosis [31]. Skin Care. Pediatr Dermatol 2016;33:311–21.
12 WHO. Pregnancy, Childbirth, Postpartum and Newborn Care: A
Its use should be completely abandoned in this age group.
guide for essential practice, 3rd edn. Geneva: WHO, 2015.
13 George S, Phillips K, Mallory S et al. A pragmatic descriptive study of
Napkin/diaper care rewarming the newborn after the first bath. J Obstet Gynecol Neonatal
Since permanently moist skin leads to maceration, and Nurs 2015;44:203–9.
14 Akter T, Dawson A, Sibbritt D. What impact do essential newborn
macerated skin is more susceptible to irritation and injury, care practices have on neonatal mortality in low and lower‐middle
napkins should be changed frequently, i.e. every 3–4 income countries? Evidence from Bangladesh. J Perinatol 2016;36:
hours, at least after each feed. Superabsorbent napkins 225–30.
are clearly superior to cloth napkins with respect to sur- 15 Loring C, Gregory K, Gargan B et al. Tub bathing improves ther-
moregulation of the late preterm infant. J Obstet Gynecol Neonatal
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(Chapter 20). Although water and a wash cloth are the 16 Gelmetti C. Skin cleansing in children. J Eur Acad Dermatol Venereol
traditional standard of care for rinsing the napkin area 2001;15:12–15.
17 Blume‐Peytavi U, Cork MJ, Faergemann J et al. Bathing and cleansing
[8,9], disposable infant wipes have become a popular
in newborns from day 1 to first year of life: recommendations from a
alternative. Comparative studies suggest that they may European round table meeting. J Eur Acad Dermatol Venereol
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18 Visscher MO, Adam R, Brink S. Newborn infant skin: Physiology, humidity of ≥80%. Ambient humidity is usually reduced
development and care. Clin Dermatol 2015;33:271–80.
stepwise after a week because of concerns about an
19 Lodén M, Buraczewska I, Edlund F. The irritation potential and reser-
voir effect of mild soaps. Contact Dermatitis 2003;49:91–6. increased risk of infection [2]. Conventional phototherapy
20 Roberta R, Patrizi A, Cocchi G et al. Comparison of two different neo- can increase TEWL, while modern LED phototherapy
natal skin care practices and their influence on transepidermal water units do not [3].
loss in healthy newborns within first 10 days of life. Minerva Pediatr
2014;66:369–74.
Various emollients have been shown to improve the
21 Garcia Bartels N, Scheufele R, Prosch F et al. Effect of standardized immature epidermal barrier function in premature
skin care regimens on neonatal skin barrier function in different body infants. Since the first randomized controlled study in
areas. Pediatr Dermatol 2010;27:1–8. 60 premature infants (<33 weeks of gestation) demon-
22 Walters RM, Fevola MJ, LiBrizzi JJ et al. Designing cleansers for the
unique needs of baby skin. Cosm Toil 2008;123:53–60. strated decreased TEWL, improved skin scores and
23 Zupan J, Garner P, Omari AA. Topical umbilical cord care at birth. decreased colonization and infection rates in those treated
Cochrane Database Syst Rev 2004;CD001057. with a preservative‐free petrolatum ointment versus an
24 Ahn Y, Sohn M, Jun Y et al. Two methods of cord care in high‐risk
newborns: their effects on hydration, temperature, pH, and floras of
untreated control group [4], about 20 similar studies with
the cord area. J Child Health Care 2015;19:118–29. various emollients (mineral oil, lanolin cream, oils from
25 Mullany LC, Shah R, El Arifeen S et al. Chlorhexidine cleansing of sunflower seed, olive, almond, vegetable or coconut) and
the umbilical cord and separation time: a cluster‐randomized trial. involving a total of >3000 infants have confirmed the orig-
Pediatrics 2013;131:708–15.
26 Sinha A, Sazawal S, Pradhan A et al. Chlorhexidine skin or cord inal findings [e.g. 5–9]. There are however concerns about
care for prevention of mortality and infections in neonates. an increased risk of coagulase‐negative staphylococcal
Cochrane Database Syst Rev 2015;(3):CD007835. infection, nosocomial infection and systemic candidiasis
27 Karumbi J, Mulaku M, Aluvaala J et al. Topical umbilical cord care for
in premature infants treated with topical emollients
prevention of infection and neonatal mortality. Pediatr Infect Dis J
2013;32:78–83. [10,11]. A meta‐analysis of 18 studies published between
28 Gras‐Le Guen C, Caille A, Launay E et al. Dry care versus antisep- 1993 and 2015 revealed no benefit in terms of significant
tics for umbilical cord care: A cluster randomized trial. Pediatrics reduction of mortality in the emollient‐treated groups of
2017;139:e20161857.
29 Stewart D, Benitz W. Umbilical cord care in the newborn infant.
preterm infants [12]. This was probably due to methodo-
Pediatrics 2016;138:e20162149. logical weakness of many studies, specifically uncertainty
30 Upadhyayula S, Kambalapalli M, Harrison CJ. Safety of anti‐infective about adequate allocation concealment methods in many
agents for skin preparation in premature infants. Arch Dis Child and lack of blinding in all of the trials [12].
2007;92:646–7.
31 Harpin VA, Rutter N. Percutaneous alcohol absorption and skin
Therefore, preventive application of ointments to
necrosis in a premature infant. Arch Dis Child 1982;57:477–9. improve the immature epidermal barrier cannot be rec-
32 Heimall LM, Storey B, Stellar JJ, Davis KF. Beginning at the bottom: ommended at present. However, this simple and low‐
evidence‐based care of diaper dermatitis. MCN Am J Matern Child
Nurs 2012;37:10–16.
cost approach to reduce infectious complications and
33 Tüzün Y, Wolf R, Bağlam S, Engin B. Diaper (napkin) dermatitis: A mortality of premature infants has great potential, par-
fold (intertriginous) dermatosis. Clin Dermatol 2015;33:477–82. ticularly for low‐income countries, and deserves further
34 Visscher M, Odio M, Taylor T et al. Skin care in the NICU patient: well‐designed RCTs.
effects of wipes versus cloth and water on stratum corneum integrity.
Neonatology 2009;96:226–34.
35 Yonezawa K, Haruna M, Shiraishi M et al. Relationship between skin Avoidance of mechanical damage
barrier function in early neonates and diaper dermatitis during the Patients undergoing neonatal intensive care are exposed to
first month of life: a prospective observational study. Pediatr Dermatol
2014;31:692–7.
many diagnostic and therapeutic procedures. Neonates are
36 Yu J, Treat J, Chaney K, Brod B. Potential allergens in disposable particularly susceptible to iatrogenic injury, the incidence
diaper wipes, topical diaper preparations, and disposable dia- of which was calculated in a prospective study at 25.6 per
pers: under‐recognized etiology of pediatric perineal dermatitis. 1000 patient days [13]. Among 267 iatrogenic events
Dermatitis 2016;27:110–18.
37 Chang MW, Nakrani W. Six children with allergic contact dermatitis observed, cutaneous injuries were the most frequent
to methylisothiazolinone in wet wipes (baby wipes). Pediatrics 2014; (35.2%), but they were mild in 95% [13]. In a more detailed
133:e434–8. analysis in 113 premature infants <33 weeks of gestation,
16.8% of all infants were affected by iatrogenic cutaneous
Skin care for the premature infant injuries [14]. These were mainly induced by ventilation
equipment, intravenous catheters, electrodes, dressings,
As outlined in Chapter 4, the thickness of the epidermis disinfectants and pressure sores. The main risk factors
correlates inversely with gestational age. In a 25‐week‐ were low birthweight and duration of ventilation [14].
old premature baby, it is only 25 μm instead of 50 μm in a Implementation of a systematic quality improvement
neonate at term. The skin of premature infants is thus approach can lead to a significant reduction in device‐
even more susceptible to trauma, TEWL and transepider- related pressure ulcers on the NICU [15]. This approach
mal intoxication than that of a mature neonate. includes preventive skin care, early detection of immi-
nent damage through systematic assessment of the skin,
Control of transepidermal water loss and identification of strategies to mitigate device‐related
In premature infants younger than 30 weeks of gesta- injury to further reduce ulcer rates [15]. Nasal continuous
tion, transepidermal and evaporative water loss is exces- positive airway pressure frequently (20–60%) leads to
sive and life‐threatening. Immediately after birth, babies nasal injury and trauma secondary to tight‐fitting nasal
are wrapped in polyurethane foil [1] and then placed interfaces [16]. Nasal injury can be reduced using rotating
in a humidification incubator with an initial ambient mask/prong nasal interfaces [17].
Table 5.2 Recommendations for skin care in premature infants 4 Nopper AJ, Horii KA, Soodeo‐Drost S et al. Topical ointment therapy
benefits premature infants. J Pediatr 1996;128:660–9.
5 Darmstadt GL, Badrawi N, Law PA et al. Topically applied sunflower
Problem Recommendation
seed oil prevents invasive bacterial infections in preterm infants in
Egypt: a randomized, controlled clinical trial. Pediatr Infect Dis J
Bathing • No full‐immersion bathing until ≥32 weeks of 2004;23:719–25.
gestation and stable body temperature 6 Darmstadt GL, Ahmed S, Ahmed NU, Saha SK. Mechanism for pre-
• No cleansing agent in the first 2 weeks vention of infection in preterm neonates by topical emollients. A ran-

• Surface cleansing with a cotton cloth twice a week domized, controlled clinical trial. Pediatr Infect Dis J 2014;33:1124–7.
Adhesives • Avoid adhesives wherever possible 7 Erdemir A, Kahramaner Z, Yuksel Y et al. The effect of topical oint-
• Place protective barrier (pectin hydrocolloid) between ment on neonatal sepsis in preterm infants. J Matern Fetal Neonatal
Med 2015;28:33–6.
skin and sites of frequent taping (e.g. nose for
8 Salam RA, Darmstadt GL, Bhutta ZA. Effect of emollient therapy on
nasogastric tubes, continuous positive airway pressure) clinical outcomes in preterm neonates in Pakistan: a randomized con-
• Use silicone adhesives wherever possible trolled trial. Arch Dis Child Fetal Neonatal Ed 2015;100:F210–15.
• Use nonadhesive probes 9 Nangia S, Paul VK, Deorari AK et al. Topical oil application and trans‐
Topical agents • Be aware of percutaneous absorption epidermal water loss in preterm very low birth weight infants—a ran-
• Never use alcohol or alcoholic solutions domized trial. J Trop Pediatr 2015;61:414–20.
• Never use triclosan, hexachlorophene and other 10 Conner JM, Soll RF, Edwards WH. Topical ointment for preventing
potentially toxic agents (see Table 5.4) infection in preterm infants. Cochrane Database Syst Rev 2004;(1):
Emollients • Consider preventive/protective skin care with CD001150.
11 Campbell JR, Zaccaria E, Baker CJ. Systemic candidiasis in extremely
emollients when humidified incubators for premature
low birth weight infants receiving topical petrolatum ointment for
infants are not available skin care: A case‐control study. Pediatrics 2000;105:1041–5.
Phototherapy • Use LED phototherapy only 12 Cleminson J, McGuire W. Topical emollient for preventing infection
in preterm infants. Cochrane Database Syst Rev 2016;(1):CD001150.
13 Ligi I, Arnaud F, Jouve E et al. Iatrogenic events in admitted neonates:
a prospective cohort study. Lancet 2008;371:404–10.
14 Roche‐Kubler B, Puzenat E, Mariet AS et al. Lésions cutanées

Adhesive tapes should be used only sparingly. Removal iatrogènes: étude prospective chez les prématurés de moins de 33
semaines de l´hôpital universitaire de Besançon. Ann Dermatol
requires a special technique with one hand holding the Venereol 2015;142:3–9.
underlying skin while the other peels off the adhesive. 15 Visscher M, King A, Nie AM et al. A quality‐improvement collabora-
The application of a hydrocolloid (pectin) barrier between tive project to reduce pressure ulcers in PICUs. Pediatrics 2013;
131:e1950–60.
the adhesive surface of a temperature probe and the neo-
16 Newnam KM, McGrath JM, Estes T et al. An integrative review of
nate’s skin or under tape minimizes the trauma of strip- skin breakdown in the preterm infant associated with nasal continu-
ping when the probe is removed [18,19]. The pectin‐based ous positive airway pressure. J Obstet Gynecol Neonatal Nurs
barrier under tape held probes and appliances safely for 2013;42:508–16.
17 Newnam KM, McGrath JM, Salyer J et al. A comparative effectiveness
an average of 5–6 days, and the skin condition remained study of continuous positive airway pressure‐related skin break-
normal in 97% after barrier removal [18]. down when using different nasal interfaces in the extremely low birth
Use of soft silicone adhesives was shown to reduce pain weight neonate. Appl Nurs Res 2015;28:36–41.
severity scores during dressing changes and was atrau- 18 Lund C, Kuller JM, Tobin C et al. Evaluation of a pectin‐based barrier
under tape to protect neonatal skin. J Obstet Gynecol Neonatal Nurs
matic in >99% [20]. For full‐thickness and exudative 1986;15:39–44.
wounds, polyurethane foam may likewise be suitable as 19 OʼNeil A, Schumacher B. Application of a pectin barrier for medical
an atraumatic wound dressing. Silver alginate, however, adhesive skin injury (epidermal stripping) in a premature infant.
J Wound Ostomy Continence Nurs 2014;41:219–21.
is not advisable in premature infants because it can lead 20 Morris C, Emsley P, Marland E et al. Use of wound dressings with soft
to systemic absorption of silver [21]. silicone adhesive technology. Paediatr Nurs 2009;21:38–43.
Pulse oximetry has largely replaced transcutaneous 21 Khattak AZ, Ross R, Ngo T, Shoemaker CT. A randomized controlled
oxygen monitoring. If transcutaneous oxygen monitors evaluation of absorption of silver with the use of silver alginate
(Algidex) patches in very low birth weight (VLBW) infants with cen-
are still required, electrodes should be adjusted to the tral lines. J Perinatol 2010;30:337–42.
lowest effective temperature; in order to prevent skin burns, 22 Villarroel M, Guazzi A, Jorge J et al. Continuous non‐contact vital sign
electrode positions should be changed every 4 hours. monitoring in neonatal intensive care units. Healthc Technol Lett
2014;1:87–91.
An ideal goal for the (near) future is the continuous moni-
toring of vital signs (heart and respiratory rate, oxygen
saturation) in preterm infants with non‐contact methods
such as a digital video camera [22]. kin care of the term neonate
S
Table 5.2 summarizes basic recommendations for skin and infant
care in premature infants. Infants and young children have become a major target of
the cosmetics industry. The use of cosmetic products has
References increased significantly in this age group over the past
1 Bhandari V, Brodsky N, Porat R. Improved outcome of extremely low years [1–3]. Regular use of ‘leave‐on’ products such as
birth weight infants with Tegaderm application to skin. J Perinatol
2005;25:276–81. facial cream and body lotion is very common in children
2 Lund CH, Osborne JW, Kuller J et al. Neonatal skin care: clinical out- from 0 to 4 years [1,3]. The newborn infant is exposed to
come of the AWHONN/NANN evidence‐based clinical practice an average of 8 ± 3 different skin care products containing
guideline. J Obstet Gynecol Neonatal Nurs 2001;30:41–51.
3 Bertini G, Perugi S, Elia S et al. Transepidermal water loss and cerebral
48 ± 18 different environmental chemicals. On average,
hemodynamics in preterm infants: conventional versus LED photo- infants are bathed four times per week and shampooed
therapy. Eur J Pediatr 2008;167:37–42. three times [4]. Many cosmetic products carry a risk of
percutaneous absorption, irritation or sensitization, and TEWL, and hence increased dryness. Maturation of the
the mere fact that they are advertised for children does epidermal barrier extends throughout the first year of life
not necessarily imply that they are free of these risks [1–4]. and beyond [7]. The extent of skin dryness varies widely
Baby powder containing talcum or corn starch was part of between neonates; if marked and persistent it can be an
the traditional care of infants. However, it neither pos- early sign of dominantly inherited filaggrin deficiency.
sesses moisturizing properties nor is it suitable for the Emollients are cosmetic products intended to make the
treatment of oozing umbilical stump infections. Powders skin softer (Latin: mollis) since sufficient hydration is
should be completely abolished from infant care because essential for softness and flexibility of the skin. Some work
of the risk of accidental aspiration with potentially life‐ by reducing dehydration through an occlusive effect and
threatening respiratory disease [5,6]. create a film, thus decreasing imperceptible water loss.
The most occlusive emollients are derivatives of mineral
Emollients oil (Vaseline, liquid paraffin) or those containing waxes
Dry skin is a common phenomenon in term and post‐ (mainly beeswax). More physiological lipid film compo-
term neonates. The instantaneous transition from 100% nents are lanolin, plant oils (evening primrose, sunflower
humidity in utero to a comparatively dry ambient atmos- seed, jojoba, wheat germ, avocado and others) and cera-
phere is frequently followed by a period of transitory mides. Fatty, cetyl or stearyl alcohols are frequently required
postnatal desquamation (Fig. 5.1) which can be quite pro- due to their emulsifying capacity. In addition to lipids,
nounced and is sometimes mistaken for the manifestation many emollients contain humectants (mainly glycerol,
of a keratinization disorder. As outlined previously, urea). In a direct comparison, emollients containing humec-
immaturity of the epidermal barrier leads to increased tants exhibit a greater and more sustained improvement of
(a) (c)
(b)
Fig. 5.1 Postnatal desquamation in 2‐ to 8‐day‐old neonates. (a) Abdomen, (b) upper arm, (c) foot.
Table 5.3 Potentially irritant or hazardous components of emollient • Vegetable oils: Vegetable oils share the benefit of being
creams ‘natural’ and are commonly used in baby skin care.
However, owing to different ratios of saturated/unsat-
Component Hazard
urated fatty acids, the physicochemical properties of
vegetable oils on the skin surface are quite different.
Detergents (e.g. SLS) Damage of epidermal barrier, TEWL↑
Emulsifiers Emulsification of endogenous epidermal
Olive oil, with a high percentage of saturated fatty

lipids, TEWL↑ acids, is prone to oxidation on the skin surface, which
Lanolin Contact allergy; low‐level contamination with leads to increased formation of reactive oxygen radi-
organophosphates from pesticides cals. As a consequence, and in contrast to sunflower
Mineral oils (petrolatum, Accumulation of mineral oil saturated and seed oil, olive oil was found to damage the epidermal
paraffin) aromatic hydrocarbons in fatty tissue barrier and cause skin irritation and exacerbation of
Olive oil Damage of epidermal barrier, TEWL↑
AD [11]. However, in an RCT in 115 healthy, full‐term
Polyethylene glycols (PEG) Percutaneous absorption in burns patients,
serum osmolarity ↑, high calcium gap,
neonates, both olive and sunflower seed oil treated
imminent renal failure infants had significantly improved hydration but sig-
Propylene glycol Serum hyperosmolarity after excessive use in nificantly less improvement in lipid lamellae structure
burns patients or patients with toxic compared to the no oil group. There were no significant
epidermal necrolysis differences in TEWL, pH or erythema/skin scores
Urea Skin irritation in children <2 years (‘stinging between treated and untreated neonates [19].
effect’)
• Emulsifiers: Emulsifiers are required to link the lipo-
philic and hydrophilic components in creams. They
↑, increase; SLS, sodium lauryl sulfate; TEWL, transepidermal water loss.
permeate through the stratum corneum into deeper
layers of the epidermis where they can interact with
the epidermal barrier function [8]. However, all emollients epidermal lipids [20]. Long‐term use of creams con-
currently available have only transient effects and need to taining high concentrations of emulsifiers can lead to
be applied repeatedly over the day [8]. irritational dermatitis and paradoxically increase skin
Emollients are generally perceived as ‘inert’, and poten- dryness [20,21].
tial side‐effects are neither expected nor systematically • Polyethylene glycols (PEG) are widely used in cosmetic
investigated. However, several reports highlight negative applications because of their emulsifying and viscous
effects of commercially available skin care products on properties and low toxicity. In patients with wide-
the epidermal barrier [9–11]. Potential hazards of emol- spread burns, however, percutaneous absorption of
lients (Table 5.3) should therefore be borne in mind, par- ethylene glycol after topical treatment with a PEG‐
ticularly in infants and young children: based burn cream was described, leading to increased
• Mineral oils (petrolatum, paraffin) contain variable serum osmolalities and a high ‘calcium gap’, i.e.
amounts of mineral oil saturated hydrocarbons and increased serum calcium with a concomitant decrease
mineral oil aromatic hydrocarbons, some of which are in the ionized calcium likely attributable to binding of
strongly accumulated in fatty tissue and can lead to calcium by dicarboxylic acid metabolites of PEG [22].
granuloma formation [12,13]. Mineral oil hydrocarbons All three patients died in acute renal failure. Similar
are considered the greatest contaminant of the human findings were obtained in rabbits treated with PEG.
body, amounting to approximately 1 g per person. Caution is advised with PEG‐containing emollients not
Routes of contamination include inhalation, food only in burn patients but also in children with wide-
intake (e.g. breast milk [12], baby food contaminated by spread barrier defects, e.g. premature babies and epi-
packaging [14]), and dermal absorption from moistur- dermolysis bullosa patients. Hyperosmolarity was
izers or lipsticks. likewise observed after excessive topical use of PEG in
• Lanolin: Lanolin is a component of many ‘natural’ skin burns or toxic epidermal necrolysis patients [23].
care products. With a prevalence of up to 3.8% [15], it is • Urea: Emollients containing urea frequently cause skin
also one of the most common contact allergens. irritation In infants described as a ‘stinging effect’.
Children with AD are particularly prone to develop Glycerol (5–20%) is well tolerated and therefore the
contact allergy to skin care components, most com- preferred moisturizer up to the age of 2 years.
monly to cocamidopropyl betaine, lanolin, tixocortol There are very few RCTs dealing with regular skin care in
pivalate and parthenolide [16]. Since lanolin is derived neonates [24], and virtually all were sponsored by pro-
from sheep wool, low‐level contamination of lanolin ducers of baby skin care products. In a small RCT with 64
wool grease with organophosphates such as diazinon neonates assigned to different skin care modalities and
derived from insecticides is still detectable with highly followed up for 2 months, babies who were bathed twice
sensitive methods [17,18]. a week with a wash gel followed by application of a skin
• Sodium lauryl sulfate (SLS): Detergents such as SLS are care cream were found to have lower TEWL than those
known to exert negative effects on the intactness of the bathed in water alone; not surprisingly, cream application
epidermal barrier. A widely used emollient, aqueous was associated with higher stratum corneum hydration
cream BP, was found to increase TEWL in volunteers [25]. The significance of these findings is limited by the
prone to AD; this effect was attributed to the presence small group of infants studied and the short period of
of 1% SLS in the emollient [10]. follow‐up.
Emollients for primary prevention 5 Silver P, Sagy M, Rubin L. Respiratory failure from corn starch aspi-
ration: a hazard of diaper changing. Pediatr Emerg Care 1996;12:
of atopic dermatitis 108–10.
Although AD rarely manifests before the age of 3–4 6 Matina F, Collura M, Maggio MC et al. Inhaled surfactant in the treat-
months, recent evidence suggests that asymptomatic neo- ment of accidental talc powder inhalation: a new case report. Ital J
nates who later develop AD have an elevated TEWL as Pediatr 2011;37:47.
7 Nikolovski J, Stamatas GN, Kollias N et al. Barrier function and
early as 2 days and 2 months of life [26]. In filaggrin‐defi- water‐holding and transport properties of infant stratum corneum
cient infants, early transcutaneous sensitization to food are different from adult and continue to develop through the first
allergens is a common phenomenon [27]. Correspondingly, year of life. J Invest Dermatol 2008;128:1728–36.
8 Danby SG, Chalmers J, Brown K et al. A functional mechanistic
early elevation of TEWL also correlates with the presence study of the effect of emollients on the structure and function of the
of food sensitization/food allergy at the age of 2 years skin barrier. Br J Dermatol 2016;175:1011–19.
[28]. It would therefore make perfect sense to prevent AD 9 Man MQ, Sun R, Man G et al. Commonly employed african neonatal
and food allergy by improving the defective skin barrier skin care products compromise epidermal function in mice. Pediatr
Dermatol 2016;33:493–500.
in presymptomatic neonates immediately after birth. The 10 Danby SG, Al‐Enezi T, Sultan A et al. The effect of aqueous cream BP
effectiveness of a preventive barrier therapy in neonates on the skin barrier in volunteers with a previous history of atopic der-
at high risk of developing AD – as deduced from the fam- matitis. Br J Dermatol 2011;165:329–34.
11 Danby SG, Al‐Enezi T, Sultan A et al. Effect of olive and sunflower
ily history – was studied in two RCTs from Japan [29] and
seed oil on the adult skin barrier: implications for neonatal skin
the UK [30], with 118 and 108 healthy neonates, respec- care. Pediatr Dermatol 2013;30:42–50.
tively, who were randomized to either receive daily emol- 12 Concin N, Hofstetter G, Plattner B et al. Evidence for cosmetics as a
lient care for 6 months, or not. The primary endpoint was source of mineral oil contamination in women. J Womens Health
(Larchmt) 2011;20:1713–19.
the cumulative incidence of AD at week 32 and 24, respec- 13 Niederer M, Stebler T, Grob K. Mineral oil and synthetic hydrocar-
tively. This was 32% less in the treated group (P = 0.12) in bons in cosmetic lip products. Int J Cosmet Sci 2016;38:194–200.
the first [29], and 50% less (OR 0.50, CI 0.28–0.9, P = 0.17) 14 Mondello L, Zoccali M, Purcaro G et al. Determination of saturated‐
in the second [30] study. No effect on food sensitization hydrocarbon contamination in baby foods by using on‐line liquid‐gas
chromatography and off‐line liquid chromatography‐comprehensive
could be demonstrated. gas chromatography combined with mass spectrometry. J Chromatogr
The results of these pilot studies have been received A 2012;1259:221–6.
with enthusiasm. However, many questions still need to 15 Miest RY, Yiannias JA, Chang YH, Singh N. Diagnosis and preva-
lence of lanolin allergy. Dermatitis 2013;24:119–23.
be answered before preventive barrier therapy can and 16 Jacob SE, McGowan M, Silverberg NB et al. Pediatric Contact

should be recommended for all newborns at risk: Dermatitis Registry Data on Contact Allergy in Children With Atopic
• Type of emollient: Different emollients have been used in Dermatitis. JAMA Dermatol 2017;153:765–70.
the studies mentioned. With respect to potential haz- 17 Copeland CA, Raebel MA, Wagner SL. Pesticide residue in lanolin.
JAMA 1989;261:242.
ards associated with the long‐term use of emollients as 18 Wester RC, Sedik L, Melendres J et al. Percutaneous absorption of
outlined previously, the risks of unnecessarily exposing diazinon in humans. Food Chem Toxicol 1993;31:569–72.
many asymptomatic neonates to agents that can be sen- 19 Cooke A, Cork MJ, Victor S et al. Olive oil, sunflower oil or no oil for
baby dry skin or massage: a pilot, assessor‐blinded, randomized con-
sitizing, accumulate or induce paradoxical skin dry-
trolled trial (the Oil in Baby SkincaRE [OBSeRvE] Study). Acta Derm
ness must be weighed up against noticeable long‐term Venereol 2016;96:323–30
benefits which still need to be demonstrated. 20 Wohlrab J, Klapperstück T, Reinhardt HW, Albrecht M. Interaction of
• Definition of risk group: It is obvious that the more spe- epicutaneously applied lipids with stratum corneum depends on the
presence of either emulsifiers or hydrogentated phosphatidylcholine.
cifically risk group(s) can be defined, the more effective Skin Pharmacol Physiol 2010;23:298–305.
(and justifiable) are the preventive measures. Based on 21 Wolf G, Höger PH. [Hypoallergenic and non‐toxic emollient therapies
recent studies [26,28], it is likely that early assessment for children.] J Dtsch Dermatol Ges 2009;7:50–60.
of TEWL in addition to a positive family history would 22 Bruns DE, Herold DA, Rodeheaver GT, Edlich RF. Polyethylene gly-
col intoxication in burn patients. Burns 1982;9:49–52.
significantly enhance the predictive power and thus 23 European Medicines Agency (EMA). Propylene glycol in medicinal
limit the number needed to treat (number of neonates products for children. Assessment report EMA/175205/2014. London:
needed to receive preventive barrier therapy in order to EMA, 2014.
24 Irvin EJ, Miller HD. Emollient use in the term newborn: a literature
reduce the incidence of AD and food allergy). review. Neonatal Network 2015;34:227–30.
• Duration of protective effects: It is unclear at present 25 Garcia Bartels N, Scheufele R, Prosch F et al. Effect of standardized
whether preventive barrier therapy indeed reduces the skin care regimens on neonatal skin barrier function in different body
manifestation rate of AD or just postpones it to a later areas. Pediatr Dermatol 2010;27:1–8.
26 Kelleher M, Dunn‐Galvin A, Hourihane JO et al. Skin barrier dys-
stage. function measured by transepidermal water loss at 2 days and 2
months predates and predicts atopic dermatitis at 1 year. J Allergy
Clin Immunol 2015;135:930–5.
References 27 Brown SJ, Asai Y, Cordell HJ et al. Loss‐of‐function variants in the
1 Gomez‐Berrada MP, Gautier F, Parent‐Massin D, Ferret PJ.
filaggrin gene are a significant risk factor for peanut allergy. J Allergy
Retrospective exposure data for baby and children care products: an Clin Immunol 2011;127:661–7.
analysis of 48 clinical studies. Food Chem Toxicol 2013;57:185–94. 28 Kelleher MM, Dunn‐Galvin A, Gray C et al. Skin barrier impairment
2 Ficheux AS, Dornic N, Bernard A et al. Probabilistic assessment of at birth predicts food allergy at 2 years of age. J Allergy Clin Immunol
exposure to cosmetic products by French children aged 0‐3 years. Food 2016;137:1111–16.
Chem Toxicol 2016;94:85–92. 29 Horimukai K, Morita K, Narita M et al. Application of moisturizer to
3 Manová E, von Goetz N, Keller C et al. Use patterns of leave‐on per- neonates prevents development of atopic dermatitis. J Allergy Clin
sonal care products among Swiss‐German children, adolescents and Immunol 2014;134:824–830.
adults. Int J Environm Res Publ Health 2013;10:2778–98. 30 Simpson EL, Chalmers JR, Hanifin JM et al. Emollient enhancement of
4 Cetta F, Lambert GH, Ros SP. Newborn chemical exposure from over‐ the skin barrier from birth offers effective atopic dermatitis preven-
the‐counter skin care products. Clin Pediatr (Phila) 1991;30:286–9. tion. J Allergy Clin Immunol 2014;134:818–23.
Percutaneous absorption the endocrine disrupting actions of triclosan, parabenes

and several chemical ultraviolet (UV) filters [3–6] which
Immaturity of the epidermal barrier in infants is not only have been shown to exert mainly oestrogenic activity in
associated with increased TEWL and skin dryness but vitro. Early (or even prenatal) exposure to triclosan, para-
also brings an increased risk of percutaneous resorption benes, phthalates and other chemical compounds can
of toxic substances applied to the skin surface. Skin per- contribute to premature puberty [7]. In addition to avoid-
meability is inversely proportional to gestational age [1].

ance of high‐level UV exposure and appropriate clothing,
Even in the term infant, transcutaneous absorption is UV protection in young children should preferably be
more readily achieved because the body surface area to based on mineral agents such as micro‐ (not nano‐) molec-
weight ratio is two‐ to threefold higher than in older chil- ular titanium dioxide and zinc dioxide.
dren and adults [2]. Low‐molecular‐weight chemicals
(<800 Da) penetrate more easily. Topical antiseptics (hexa- References
chlorophene, iodine) and antibiotics (particularly neomy- 1 Barker N, Hadgraft J, Rutter N. Skin permeability in the newborn.
cin, which is highly ototoxic), alcohol dressings, salicylates, J Invest Dermatol 1987;88:409–11.
urea and others have all been associated with neonatal 2 Rutter N. Percutaneous drug absorption in the newborn: hazards and
uses. Clin Perinatol 1987;14:911–30.
toxicity caused by transcutaneous resorption, particularly 3 Diamanti‐Kandarakis E, Bourguignon JP, Giudice LC et al.

in the preterm infant [1]. The likelihood of percutaneous Endocrine‐disrupting chemicals: an Endocrine Society scientific
absorption is higher in areas with high numbers of seba- statement. Endocr Rev 2009;30:293–342.
4 Schlumpf M, Cotton B, Conscience M et al. In vitro and in vivo estro-
ceous glands per cm2 (head, napkin area) and in intertrigi- genicity of UV screens. Environ Health Perspect 2001;109:239–44.
nous areas due to the occlusive effect. The vehicle also 5 Ozáez I, Martínez‐Guitarte JL, Morcillo G. Effects of in vivo exposure
affects percutaneous absorption. Lipophilic agents can to UV filters (4‐MBC, OMC, BP‐3, 4‐HB, OC, OD‐PABA) on endocrine
penetrate the lipid bilayer better than water‐soluble com- signaling genes in the insect Chironomus riparius. Sci Total Environ
2013;456‐457:120–6.
pounds. Their occlusive effects lead to enhancement of 6 Schreurs RH, Sonneveld E, Jansen JH et al. Interaction of polycyclic
epidermal hydration which in turn widens the intracellu- musks and UV filters with the estrogen receptor (ER), androgen recep-
lar bonds and facilitates absorption. The risk of toxicity is tor (AR), and progesterone receptor (PR) in reporter gene bioassays.
Toxicol Sci 2005;83:264–72.
further compounded by immature metabolic mechanisms
7 Harley KG, Berger KP, Kogul K et al. Association of phthalates, para-
of detoxification. Table 5.4 summarizes potential hazards bens and phenols found in personal care products with pubertal tim-
of common topically applied drugs. Of particular note are ing in girls and boys. Human Reproduction 2019;34:109–17.
Table 5.4 Potential hazards of percutaneously absorbed agents
Compound Function Toxicity
Alcohols Topical antiseptic Cerebral and hepatic damage, cutaneous haemorrhagic necrosis
Benzocaine Topical anaesthetic Methaemoglobinaemia
Calcipotriol Topical vitamin D3 analogue Hypercalcaemia
Clioquinol Topical antiseptic Neurotoxicity (subacute myelo‐ophthalmoneuritis, SMON)
Diphenhydramine Topical antipruritic Sedation, central anticholinergic syndrome
EMLA Topical anaesthetic mixture Methaemoglobinaemia
Gentamicin Topical antibiotic Neuro‐, oto‐, nephrotoxic
Lindane Topical scabicide Neurotoxic
Neomycin Topical antibiotic Neuro‐, oto‐, nephrotoxic
Contact allergen
N,N‐dimethyl‐m‐toluamide (DEET) Insect repellant Neurotoxicity
Parabene Preservative Endocrine disrupting agent
Phenolic compounds (pentachlorophenol, Topical antiseptic Neurotoxicity, tachycardia, metabolic acidosis,
hexachlorophene, resorcinol) methaemoglobinaemia, death
Povidone–iodine Antiseptic Hypothyroidism
Prilocaine Topical anaesthetic Methaemoglobinaemia
Salicylic acid Keratolytic Metabolic acidosis, seizures
Silver sulfadiazine Topical antibiotic Kernicterus, agranulocytosis, argyria
TCS (potent) Anti‐inflammatory Adrenal suppression, Cushing’s syndrome, skin atrophy, acne
Triclosan Antiseptic Endocrine disrupting agent
UV filtersa UV protection Endocrine disrupting agents
TCS, topical corticosteroid.

a
UV filters with potential oestrogenic side‐effects: benzophenone‐3, ethylhexyl‐methoxy‐cinnamate (EHMC), octocrylene.
72
CHA PTER 6
Transient Skin Disorders in the Neonate

and Young Infant
Margarita Larralde1,2 & Maria Eugenia Abad1,2

1
Dermatology Department, Hospital Alemán, Buenos Aires, Argentina
2
Pediatric Dermatology Department, Hospital Ramos Mejía, Buenos Aires, Argentina
Introduction, 72 Transient vesicopustular eruptions, 76 Miscellaneous, 80

Physiological skin findings, 72 Oral lesions, 77
Transient vascular physiological changes, 75 Pigmentary skin lesions, 79
Abstract (erythema toxicum neonatorum and transient neonatal pustular

melanosis), oral lesions (Epstein pearls, Bohn nodules, dental
lamina cysts, natal and neonatal teeth, eruption cyst and sucking
Cutaneous lesions are common in the neonatal period. Most are
pads of the lips), pigmentary lesions (Mongolian spots or congeni-
physiological, transient and benign. Transient skin disorders may
tal dermal melanocytosis, pigmentary lines of the newborn and
be classified as physiological skin disorders (vernix caseosa, phys-
periungual hyperpigmentation) and miscellaneous lesions (subcu-
iological desquamation, lanugo, sebaceous gland hyperplasia,
taneous fat necrosis, sucking blisters and erosions, adnexal polyps,
milia, physiological jaundice, and the collective effects of maternal
pedal papules of infancy and perineal groove). In this chapter we
or placental hormones resulting in what has been referred to as
discuss the categories mentioned above and also consider that
miniature puberty), transient vascular physiological changes (cutis
serious and potentially life‐threatening diseases or associations
marmorata, salmon patch, harlequin colour change, erythema
should sometimes be ruled out.
neonatorum and acrocyanosis), transient vesicopustular eruptions
Key points eruptions, oral lesions, pigmentary lesions and miscellaneous

lesions.
• Transient skin disorders should be differentiated from serious
• Most cutaneous lesions in the neonatal period are physiological,
and potentially life‐threatening diseases, e.g. infections or
transient and benign.
genodermatoses.
• Transient skin disorders include physiological skin disorders,
transient vascular physiological changes, transient vesicopustular
Introduction Most cutaneous lesions in neonates represent transient

skin disorders characterized by benign and self‐limiting
Cutaneous lesions are common in the neonatal period. conditions (Box 6.1).
Most are benign, transient or physiological conditions
that should be differentiated from serious and potentially
Physiological skin findings
life‐threatening diseases that carry more significant risks
of morbidity or mortality, as might be seen with infections Vernix caseosa
or genodermatoses. For this reason, initial evaluation This white, greasy and lipophilic natural skin barrier is
should include a careful physical examination and a present at birth. It is synthesized by fetal keratinocytes
complete clinical history focusing on family and prenatal and sebaceous glands in late pregnancy, and formed by
history, pregnancy, delivery, gestational age, birthweight, sebaceous secretions and shed epithelial cells and lanugo
and the presence of general symptoms and specific [4]. It may cover the entire cutaneous surface of full‐term
anomalies. When needed, useful diagnostic tools include babies or may be found concentrated in skin folds and on
routine laboratory (blood chemistry and haematological the back. After a few hours or days of life, it disappears.
profile) testing; screening for infections through bacterial, Vernix caseosa may be brownish‐yellow if there was
viral and mycological smears, cultures, antibody detec contact with meconium or as might be seen in cases of
tions and polymerase chain reaction (PCR); skin biopsy; haemolytic disease. Vernix caseosa may have a noticeable
and genetic testing [1–3]. typical odour in a case of neonatal sepsis [4–6]. It consists
Chapter 6 Transient Skin Disorders in the Neonate and Young Infant 73
Box 6.1 Transient skin disorders
Physiological skin disorders • Eosinophilic pustular folliculitis

• Vesiculopustular eruption in neonatal transient myeloproliferative disorder
• Vernix caseosa
• Physiological desquamation
Oral lesions

• Lanugo

• Sebaceous gland hyperplasia • Epstein pearls
• Milia • Bohn nodules
• Miniature puberty • Dental lamina cysts
• Physiological jaundice • Natal and neonatal teeth
• Eruption cyst
Transient vascular physiological changes • Sucking pads of the lips
• Cutis marmorata
Pigmentary skin lesions
• Salmon patch
• Harlequin colour change • Mongolian spots
• Erythema neonatorum and acrocyanosis • Pigmentary lines of the newborn
• Periungual hyperpigmentation
Transient vesicopustular eruptions
Miscellaneous
• Erythema toxicum neonatorum
• Transient neonatal pustular melanosis • Subcutaneous fat necrosis
• Miliaria • Sucking blisters, erosions and calluses
• Benign neonatal cephalic pustulosis • Adnexal polyp
• Neonatal acne • Pedal papules of infancy
• Infantile acropustulosis • Perineal groove
mainly of water (81%), but also contains lipids (9%) and

proteins (10%) [7,8]. Vernix caseosa protects neonatal skin
and facilitates the transition from intrauterine to extrau
terine life. Other functions are skin surface adaptation
after birth, temperature regulation, skin hydration,
wound healing, prevention of water loss and antimicro
bial action. Vernix caseosa contains several antimicrobial
peptides and proteins (lysozyme, lactoferrin, cathelici
dins and defensins) that may protect the fetus prenatally
and also facilitate postnatal skin colonization by non
pathogenic bacteria [4,5,8,9]. Vernix caseosa also acts as a
lubricant to facilitate passage through the birth canal.
Although the traditional practice has been to wipe off the
vernix caseosa after birth, more current recommendations
advocate leaving it in place and avoidance of removal by
wiping or bathing [5,10].
Physiological desquamation
A fine desquamation that occurs in most newborns may Fig. 6.1 Lanugo on the dorsum.
persist during the first 3 months of life [11]. In healthy
full‐term neonates this process begins on the first or second Lanugo is often located on the dorsum, shoulders, face
day of life and in preterm infants it starts at 2–3 weeks of and scalp (Fig. 6.1). The first coat of lanugo normally
age. Desquamation is more evident on hands, feet and sheds in utero during the last trimester of gestation, and
ankles. In post‐term newborns it tends to be more gener consequently it is more prominent in preterm newborns
alized and thicker [2,11]. In extreme cases in which des [8,12]. Lanugo must be differentiated from congenital
quamation is persistent or severe, consideration should hypertrichosis lanuginosa, gingival fibromatosis with
be given to evaluation for other underlying disorders hypertrichosis, Cornelia de Lange syndrome and other
such as congenital syphilis or ichthyosis [11,12]. rare disorders associated with excess body hair [4,6,8,12].
Lanugo Sebaceous gland hyperplasia

Newborn skin is often covered by fine, soft, nonpig Sebaceous gland hyperplasia is found at birth in 50–89%
mented and unmedullated immature hair termed lanugo. of newborns, especially full‐term neonates [10,13,14].
It is replaced by vellus hair during the first months of life. Both sexes are affected equally, with the highest incidence
in African Americans and the lowest in Asians [10,15].

Box 6.2 Genodermatoses associated with milia
It is produced by the increased activity of the sebaceous
gland stimulated by transplacental transfer of maternal
Primary congenital milia
androgens. It is characterized by multiple tiny whitish‐
yellow papules located at the opening of pilosebaceous • Orofaciodigital syndrome type 1
follicles in areas in which sebaceous glands are prominent • Familial milia with absent dermatoglyphics (Basan syndrome)
• Familial profuse congenital milia

such as around the nose, cheeks, forehead and upper lip

[6,7,13]. No treatment is needed since it generally resolves
spontaneously within the first few weeks after birth. Primary milia developing later in life
Differential diagnosis includes milia, miliaria cristallina • Basal cell naevus syndrome (Gorlin syndrome)
and neonatal acne [10]. • Generalized basaloid follicular hamartoma syndrome
• Brooke–Spiegler syndrome
Milia • Basex–Dupré–Christol syndrome
Milia are small superficial keratinous cysts found com • Rombo syndrome
monly on newborn skin, produced by retention of keratin • Pachyonychia congenita
within the superficial dermis. They originate from the • Atrichia with papular lesions
pilosebaceous apparatus of vellus hair [6,13]. Milia may • Nicolau–Balus syndrome
be divided into two categories: primary milia which arise • Keratitis–ichthyosis–deafness syndrome (KID syndrome)
spontaneously, and secondary milia due to medications,
Secondary milia
diseases and cutaneous healing after trauma. Neonatal
milia are included in the first subtype [16,17]. They occur • Epidermolysis bullosa
in 40–50% of neonates, with no racial or gender prepon • Porphyria
derance. Milia are multiple superficial pinpoint white‐
yellowish papules 1–2 mm in diameter located on the
face, especially the nose, but also cheeks, forehead and
chin (Fig. 6.2). Scalp, upper trunk and upper limbs may
also be affected. There may be single or multiple lesions.
In some cases, a solitary and usually larger milium may
be present on the areola, genitalia or foreskin [13]. They
disappear spontaneously, usually within a few weeks of
life without scarring, although they may persist for several
months. In cases where profuse and persistent milia are
noted or associated with other anomalies, an underlying
genodermatosis must be suspected (Box 6.2) [6,13,17–19].
Miniature puberty
Maternal hormones, especially androgens, are acquired
transplacentally, producing a neonatal transient hormo
nal elevation that normalizes by 6–8 weeks of age.
Miniature puberty comprises a group of spontaneously
resolving manifestations secondary to this phenomenon
[6,13,20]. Darkening of the linea alba (linea nigra), areolas
and external genitalia is frequently seen, especially in Fig. 6.3 Miniature puberty: hypertrophic and darkened genitalia in a
female newborn.
non‐Caucasian infants [21]. Breast hypertrophy may
occur in both sexes, as may neonatal acne and sebaceous

gland hyperplasia [20]. The enlarged breast gland may
secrete a colostrum‐like substance. Male genitalia may
appear well‐developed with hyperpigmentation of scro
tum. Female genitalia may appear full with clitoral hyper
trophy and darkening of the labia and vulva (Fig. 6.3).
Within a few days after birth, a whitish, creamy vaginal
discharge can be seen. Rarely, on the third to fourth day of
life, bleeding similar to menses may occur [6,13,20,21].
Hyperpigmentation of labia may occasionally be misdi
agnosed as naevi.
Physiological jaundice
Jaundice is produced by the accumulation of bilirubin in
Fig. 6.2 Milia: tiny whitish cysts. the skin, mucous membranes and sclerae that causes a
yellowish colouration. Physiological jaundice refers to the Adams–Oliver syndrome, phakomatosis pigmentovas
common and in general harmless jaundice seen in babies cularis and van Lohuizen syndrome [24,25]. Rarely,
during the first days of life, with no significant underly neonatal lupus erythematosus may present with cutis
ing disease. It is common in the first week, affecting marmorata telangiectatica congenita‐like lesions. Reticu
60% of term and 80% of preterm newborns. Up to 30% late capillary malformations (port wine stains) may also
of predominantly breastfed babies are still jaundiced at resemble cutis marmorata; however, these reticulate cap

1 month of age [4,6,22]. illary malformations are persistent. Extensive reticulate
Red blood cell breakdown produces unconjugated or capillary malformations or congenital livedo reticularis‐
indirect bilirubin which is mostly bound to albumin as it like findings in conjunction with overgrowth or macro
circulates. Unconjugated bilirubin is metabolized in the cephaly represent some of the cutaneous hallmarks of
liver to produce conjugated or direct bilirubin which macrocephaly–capillary malformation [26,27] and other
passes into the gut and is excreted in stool. Hepatic PIK3‐related overgrowth syndromes.
immaturity associated with a shorter lifespan and higher
concentration of red blood cells is responsible for hyper Salmon patch
bilirubinaemia [22]. Also known as naevus simplex, Unna naevus, ‘angel kiss’
Early‐onset or prolonged jaundice may be a sign of or ‘stork bite’, this is the most common vascular stain pre
pathological jaundice. Pathological jaundice has many sent at birth. It affects almost half of newborns with no
aetiologies including blood group incompatibility gender predilection. It involves the median part of the
(Rhesus or ABO incompatibility), as well as other causes face (glabella, forehead, eyelids, nasal alae and philtrum),
of haemolysis, such as large haematomas (hepatic sub the nape and occipital area and in some cases the sacral
capsular or cephalohaematoma), sepsis, in addition region (Fig. 6.4) [26]. Its colour typically varies from pale
to primary liver disease (Gilbert and Crigler–Najjar pink to bright red with undefined borders that become
syndrome), biliary atresia and glucose‐6‐phosphate more prominent with heat, crying and physical activity.
dehydrogenase deficiency [4,22,23]. Facial lesions usually fade within the first 2 years of life.
Lesions involving the nape may persist [28,29]. Patients
with lumbosacral naevus simplex should have imaging
Transient vascular physiological performed to rule out underlying spinal dysraphism if
changes the naevus is extensive or atypical, or other cutaneous
Cutis marmorata anomalies such as lipoma, hypertrichosis or dermal sinus,
Cutis marmorata is a frequent, benign and generalized among others, are also present [12,29].
cutaneous vasomotor phenomenon induced by hypother
mia. The immature autonomic nervous system is respon
Harlequin colour change
This transient and sudden, uncommon phenomenon
sible for an irregular distribution of superficial capillary
consists of sharply demarcated erythema on one half of
blood flow [6,8]. Although it is more common in preterm
the body with simultaneous blanching on the contralat
infants, full‐term babies may also be affected. It is charac
eral half. A line of demarcation along the midline is well‐
terized by a transient, blanchable, bluish‐red, reticulated
defined. The change of colour, which generally fades
mottling that in general lasts minutes, aggravated by cold
within 30 seconds to 20 minutes, appears between the
and abated by warm temperatures. Physiological cutis
second and fifth days after birth, but may occur up to the
marmorata improves spontaneously within the first few
third week [8,30,31]. Although harlequin colour change
weeks [4,6,8].
may arise as a single episode, it sometimes reappears. It is
Persistent or severe cutis marmorata has been reported
in several diseases including Down syndrome, trisomy
18, congenital hypothyroidism, homocystinuria, Divry–
Van Bogaert syndrome and Cornelia de Lange syndrome
[4,24,25].
Cutis marmorata telangiectatica congenita is a rela
tively uncommon capillary malformation that can mimic
physiological cutis marmorata but does not disappear
with warming. It is characterized by deep purple reticular
or stellate areas of mottling, is present at or shortly after
birth, and may have a localized, segmental or generalized
distribution. Atrophy or skin ulceration and loss of
underlying subcutaneous fat, as well as prominent
veins, telangiectasias and hyperkeratosis may be seen.
Extracutaneous findings such as growth and develop
mental delay, discrepancies in length and circumference
of limbs, glaucoma, macrocephaly, neurological abnor
malities and other vascular anomalies have been reported
in 20–80% of patients. Cutis marmorata telangiectatica
congenita may be present in some disorders such as Fig. 6.4 Salmon patch: erythematous macules on the nose and philtrum.
most commonly observed when the baby is in a lateral

decubitus position. The colour characteristically changes
location when the baby is rotated [6,30]. Newborns with
harlequin colour change are in good general condition
with no other signs or symptoms associated. Although it
is observed in healthy newborns, it has also been reported
in the context of hypoxia, such as prematurity or low

birthweight. Exacerbation of the phenomenon has been
reported in patients with congenital cyanotic cardiomyo
pathy receiving prostaglandin E1 treatment [30,32]. Its
aetiopathogenesis is poorly understood, but it has been
suggested that hypothalamic immaturity produces a
transient imbalance in cutaneous vessel regulation [30,32].
Erythema neonatorum and acrocyanosis

Generalized erythema or rubor neonatorum is a physio
logical condition present from the first hours until the sec Fig. 6.5 Erythema toxicum neonatorum: erythematous macules and
ond day of life. Its mechanism is related to cutaneous pustules.
vasodilation and hyperaemia. Neonatal polycythaemia is
an associated factor that contributes to erythema [4,6]. Although this rash may be present at birth, it usually
Acrocyanosis is characterized by bilateral and symmet begins 2–3 days after birth. Typical lesions consist of
rical purple‐bluish colouration of hands and feet as well erythematous macules 2–3 cm in diameter with a central
as the perioral area. It is intermittent, may intensify with papule or pustule. Lesions can vary in number from one
vigorous crying, cold, polycythaemia or other hypervis to several and be located on the face, trunk and proximal
cosity syndromes, and may revert with warmth. In gen extremities, without involvement of palms and soles
eral it resolves within the first week of life [4,6,8]. Its (Fig. 6.5). The lesions are highly evanescent and usually
pathogenesis is not well understood, but it is proposed evolve in crops that wax and wane, with spontaneous
that cutaneous vasomotor instability related to immatu resolution of individual lesions within hours to days.
rity is involved. Blood flow is reduced in dilated subpap Spontaneous involution of the eruption occurs within
illary and papillary venous vessels favouring oxygen 1–2 weeks without sequelae, although lesions may recur
release in peripheral tissues and subsequent formation of [3,34,36,38].
desaturated haemoglobin [4]. It should be distinguished Diagnosis is made clinically. Cytological examination
from Raynaud’s phenomenon and other disorders associ of a pustular smear with Giemsa or Wright staining dem
ated with central cyanosis such as congenital cardiac dis onstrates eosinophilia. Skin biopsy, if performed, shows a
ease or respiratory diseases [33]. Since this condition is dense inflammatory infiltrate around hair follicles com
benign and self‐healing, no treatment is required. posed mostly of eosinophils and subcorneal pustules.
Peripheral eosinophilia may be present [34,37]. Differential
diagnosis includes transient neonatal pustular melanosis,
Transient vesicopustular eruptions miliaria and eosinophilic pustular folliculitis, as well as
Erythema toxicum neonatorum infections including congenital candidiasis, staphylococ
Erythema toxicum neonatorum is a benign and self‐ cal impetigo and neonatal herpes simplex [3,34,36].
limited condition with no racial, gender or seasonal As erythema toxicum neonatorum is a self‐limiting
predilection. Its incidence varies from 16.7% to 55% in condition, no treatment is required. However, atypical
different reports [34,35]. Higher incidence rates are seen presentations often appropriately prompt further evalua
in term neonates with birthweight over 2500 g. It is rarely tion to rule out an underlying infection.
seen in preterm infants and its presence in this population
should prompt an evaluation for underlying infection. Transient neonatal pustular melanosis
Different hypotheses have been proposed to explain This benign, transient disorder is found in 0.2‐–4% of full‐
the pathogenesis of erythema toxicum, including allergic term neonates. It is more common in more dark‐skinned
response to transplacental or environmental allergens; infants, but there is no sex predilection. It is characterized
response to mechanical, chemical or thermal irritation; by fragile pustules or vesicles without surrounding ery
hormonal influences on the extracellular matrix; and a thema that are almost always present at birth. Lesions
graft‐versus‐host reaction triggered by maternal lympho measure 1–5 mm in diameter, are single or grouped in
cytes transferred to the infant before or during delivery clusters, and may occur anywhere but are commonly seen
[3,34,36]. Currently it is accepted that pro‐inflammatory on the forehead, mandibular area, neck, trunk, buttocks,
mediators (IL‐1, IL‐8, eotaxin, aquaporins 1 and 3, psoria thighs, palms and soles (Fig. 6.6). The vesicopustules are
sin, nitric oxide synthases 1, 2 and 3) identified in the very fragile and break down easily, leaving pigmented
erythema toxicum infiltrate reflect an immunological macules surrounded by fine, white collarettes of scale.
cutaneous reaction to microbial skin colonization of hair Brownish macules may persist for months, but in general
follicles from birth [37]. fade spontaneously within a few weeks. In some cases,
Epstein pearls
Epstein pearls are single or multiple, small (1–3 mm),
whitish keratin‐filled cysts, located at the junction of the
hard and soft palates or at the palatal midline (Fig. 6.7).
They have been reported in 65–85% of newborns, and
arise from epithelial remnants along the line of fusion of

palatal components during embryogenesis. No treatment
is indicated, as they regress spontaneously within the first
several weeks after birth. They are considered analogous
to milia [10,44,45].
Bohn nodules
Bohn nodules are isolated or multiple firm small white
cystic structures located on the vestibular and lingual
surface of the alveolar ridges (Fig. 6.8). The maxillary arch
is more commonly affected than the mandibular. These
lesions are very common, reported in 85% of neonates.
They are keratin cysts derived from epithelial remnants of
minor salivary glands or from remnants of odontogenic
Fig. 6.6 Transient neonatal pustular melanosis: grouped pustules without

surrounding erythema on the scalp.
the vesicular stage develops in utero and the newborn

presents with only hyperpigmented macules at birth
[3,36,39,40].
The differential diagnosis includes erythema toxicum
neonatorum, staphylococcal pustulosis, congenital can
didiasis, syphilis, herpes simplex and acropustulosis of
infancy.
Giemsa or Wright staining of pustular content reveals
neutrophils and occasional eosinophils. No organism is
observed and cultures are negative. Skin biopsy of pustu
lar lesions shows an intracorneal or subcorneal collection
of neutrophils; in contrast to classical erythema toxicum,
there are few eosinophils [3,7,36].
Based on similarities in clinical findings and the pres
ence of both neutrophils and eosinophils in the skin
biopsy, as well as the coexistence of lesions of erythema
toxicum neonatorum and transient neonatal pustular
melanosis in the same patient, it has been postulated that Fig. 6.7 Epstein pearls: multiple small whitish palatal cysts.
these disorders may be variations of the same disease.
The term sterile transient neonatal pustulosis was pro
posed by Ferrandiz et al. to include these overlapping
conditions [41,42].
Oral lesions
Lesions affecting the oral cavity of infants may vary from
benign transient lesions to tumours. Knowledge of these
common conditions is important for appropriate manage
ment of patients and their families.
Transient inclusion cysts or developmental nodules of
the oral mucosa are very frequent, affecting almost 80% of
newborns. They represent the most common oral disor
der in infants, and are located in the alveolar ridges or on
the palate. Based on histological origin and location in the
oral cavity, they can be classified as Epstein pearls, Bohn Fig. 6.8 Bohn nodules: small white cystic structures on the surface of
nodules or dental lamina cysts [43,44]. alveolar ridges.
epithelium over the dental lamina [43,46]. Differential

diagnosis includes Epstein pearls, natal or neonatal teeth
and dental lamina cysts. Spontaneous rupture and sub
sequent involution of the cysts within a few weeks is the
rule. No treatment is needed [43,45–47].
Dental lamina cysts

Also known as gingival cysts of the newborn, they occur

on the crest of alveolar ridges, and derive from remnants
of the dental lamina. They may be single or multiple, and
are located mainly on the maxilla. Clinically, they are
small (1–3 mm), pearly, firm papules observed in 25–53%
of newborns [44,48]. These keratin‐filled cysts disappear
within the first weeks of life.
Natal and neonatal teeth

Normal eruption of primary teeth usually occurs around Fig. 6.9 Partially erupting natal tooth and ulceration of the tongue (Riga–
6 months of age. Premature eruption of teeth is a rare Fede disease).
condition; depending on the time of eruption such teeth
are defined as natal teeth when present at birth, and neo Clinically, natal and neonatal teeth are typically poorly
natal teeth when they erupt during the first month. The developed, loose and conical, with yellowish‐brown or
incidence of natal and neonatal teeth varies from 1 : 716 whitish opaque discolouration, and have hypoplastic
to 1 : 3500 live births, with no gender predilection [49,50]. enamel. Occasionally they are normal in size, shape and
Natal teeth are approximately three times more frequent colour (Fig. 6.9). Natal and neonatal teeth may be classi
than neonatal teeth. Most natal and neonatal teeth repre fied as mature when they are nearly or fully developed
sent early eruption of the normal primary deciduous den and immature when their structure is incomplete, leading
tition, whereas less than 10% are supernumerary teeth to a poor prognosis [49,50]. The most common location of
[45,49,51]. The exact pathogenesis is not known, but it has natal and neonatal teeth is mandibular central incisors
been suggested that premature eruption of primary teeth (85%), followed by maxillary incisors (11%), mandibular
may be related to superficial location of the developing canines or molars (3%) and maxillary canines or molars
tooth germ in the alveolar bone [51]. It has also been (1%) [45,50,52].
hypothesized that increased resorption of overlying bone Radiographic examination helps to differentiate between
results in premature tooth eruption [49,52]. Autosomal supernumerary primary teeth and teeth of the normal
dominant inheritance has been reported in some cases, dentition, as well as Bohn nodules and dental lamina
as have several predisposing factors such as hormonal cysts, the major differential diagnosis.
disturbances (pituitary, thyroid), poor maternal health, Extraction is the treatment of choice in the case of
febrile episodes during pregnancy and environmental supernumerary teeth as they may interfere with normal
factors (including polyhalogenated aromatic hydrocar tooth eruption. Excessively mobile teeth should be
bons) [49–52]. Some syndromes are associated with natal extracted to prevent the risk of exfoliation and subse
and neonatal teeth (Table 6.1) [10,45,49,51,53]. Natal and quent swallowing or aspiration [45,49]. A major compli
neonatal teeth have been reported in infants with con cation is the development of a traumatic ulceration on
genital hypothyroidism and in the context of cleft lip the ventral surface of the tongue, lips or mother’s breast,
and palate [54,55]. which represents a sign of Riga–Fede disease and associ
ated pain insensitivity. The lesion begins as an eroded
area, evolving into an enlarged granulomatous ulcerated
Table 6.1 Syndromes associated with natal and neonatal teeth
mass. Discomfort during breastfeeding with subsequent
refusal to eat, malnutrition and dehydration may be asso
Syndrome Inheritance
ciated. A conservative approach is the first treatment
Pachyonychia congenita AD
option for Riga–Fede disease. Sharp tooth edges may be
Ellis–van Creveld syndrome AR polished using a finishing burr or covered with compos
Hallermann–Streiff syndrome Isolated cases ite resin. In some cases tooth extraction may be required
Wiedemann–Rautenstrauch syndrome (neonatal AR [49,50,52,56].
progeroid syndrome)
Short‐rib thoracic dysplasia 13 with or without AR Eruption cyst
polydactyly Eruption cyst is characterized by circumscribed fluctuant
Restrictive dermopathy AR
mucosal swelling overlying a tooth during the eruption
Raine syndrome (osteosclerotic bone dysplasia) AR
Osteopathia striata with cranial sclerosis XLD process. Given that eruption cysts are related to both pri
Epidermolysis bullosa, lethal acantholytic AR mary and permanent tooth eruption, they are rarely
observed in the neonatal period, in which case they are
AD, autosomal dominant; AR, autosomal recessive; XLD, X‐linked dominant. secondary to natal or neonatal teeth [45]. The eruption

Fig. 6.10 Eruption cyst: bluish, dome‐shaped lesion on the alveolar ridge
of the mandible. Fig. 6.11 Mongolian spots: aberrant and superimposed.
cyst appears as a translucent, flesh‐coloured or bluish, in early to mid childhood. Superimposed darker spots on
dome‐shaped, compressible lesion on the alveolar ridge classic Mongolian spots may be present [61–64].
of the mandible or maxilla (Fig. 6.10) [45,57,58]. The Histopathology reveals the presence of scattered mel
differential diagnosis includes mucocoele, lymphatic anocytes in the lower dermis associated with occasional
malformation, congenital epulis, dental lamina cysts, melanophages [62].
teratoma and Bohn nodules [58]. Radiological examina Rarely, Mongolian spots may be associated with lysoso
tion shows a natal or neonatal tooth. Cystic content mal storage diseases. In these cases Mongolian spots are
obtained by needle aspiration has a yellowish colouration persistent, aberrant in appearance and extensive, affecting
and low viscosity and presents cholesterol crystals. not only the dorsum but also the ventral aspect of the
Although treatment options include marsupialization or trunk, with darker and progressive pigmentation. An
surgical removal, most eruption cysts resolve spontane extensive confetti appearance has also been observed in
ously within several weeks [45,58]. some patients. The most common lysosomal storage
disease associated with Mongolian spots is GM1 gangli
Sucking pads of the lips osidosis 1, followed by mucopolysaccharidosis type 1
Sucking pads or sucking calluses on the lips are present (Hurler disease) and, to a lesser degree, mucopolysaccha
in both term and preterm neonates, and are considered ridosis type 2 (Hunter disease), mucolipidosis, Niemann–
a physiological adaptive reaction of lip structures to Pick disease and mannosidosis [61,65–68]. Phakomatosis
sucking. They are characterized by painless, whitish and pigmentovascularis consists of the association of a vascu
hyperkeratotic swelling of the lips, predominantly in the lar malformation and a cutaneous melanocytic lesion.
middle of the upper lip. Skin biopsy, if performed, shows Persistent Mongolian spots are part of phakomatosis
hyperkeratosis, epidermal hyperplasia and intracellular pigmentovascularis types II, IV and V, also known as
oedema. They disappear spontaneously after 3–6 months, phakomatosis cesioflammea and phakomatosis cesio
when breastfeeding is stopped [45,59,60]. marmorata [61,62,65,69].
Pigmentary lines of newborns

Pigmentary skin lesions This rare, transient, pigmentary dermatosis is character
Mongolian spots ized by horizontal linear hyperpigmentation on the skin
Mongolian spots (congenital dermal melanocytosis) are folds of the abdomen, back and extremities from birth.
congenital homogeneous greyish macules located on Spontaneous resolution occurs between 2 and 6 months
sacral and gluteal areas, resulting from the aberrant pres of age. Most reported cases were darkly‐pigmented male
ence in the lower dermis of melanocytes that failed to newborns. Pathogenesis is thought to be nonhormonal,
migrate from the neural crest to the epidermis during possibly induced by mechanical trauma related to flexion
fetal life. The prevalence varies with race, affecting around in utero, which produces slight hyperkeratosis within the
90–100% of Africans and Asians, 50% of Hispanics, and skin folds resulting in postinflammatory hyperpigmenta
10% of Caucasians [61,62]. tion [70–72].
Clinically Mongolian spots are characterized by single
or multiple grey, blue‐grey, blue‐green or dark blue mac Periungual hyperpigmentation
ules of varying sizes and shapes, with irregular borders, Hyperpigmentation of the distal phalanges and the proxi
located mainly on the sacrogluteal area. Aberrant extrasa mal nail fold is an occasional clinical finding in dark‐
cral locations include the lower and upper extremities, skinned newborns, although it has also been described
upper back and shoulders (Fig. 6.11). They typically fade in Caucasian babies. Pigmentation is uniform in each
patient: light‐brown in fair‐skinned patients and intensely

hyperpigmented in dark‐skinned neonates. It occurs in
both fingers and toes, is present at birth in full‐term
neonates, and fades spontaneously within the second
year of life [73,74]. Its pathogenesis is unclear, although it
is speculated to be a result of melanocyte‐stimulating
hormone in utero [71,73].
Miscellaneous
Subcutaneous fat necrosis
Subcutaneous fat necrosis of the newborn is a rare and
transient disorder of fat tissue that affects term and post‐
term babies. It is a lobular form of panniculitis that
appears in the first week of life, few cases developing as
late as 6 weeks of age. It has been associated with various
physiological stressors as risk factors, including maternal
factors (gestational diabetes, pre‐eclampsia, smoking or
exposure to passive smoking, intake of calcium channel
blockers, cocaine abuse) and neonatal factors (perinatal
asphyxia, meconium aspiration, umbilical cord prolapse,
hypothermia, obstetrical trauma, Rhesus incompatibility)
[75–79]. Subcutaneous fat necrosis was reported in 1–3%
of neonates managed with moderate therapeutic hypo Fig. 6.12 Subcutaneous fat necrosis: erythematous plaques on the back.
thermia for hypoxic ischaemic encephalopathy. Lesions
may develop in areas directly exposed to the cooling
blanket. Induction of therapeutic cooling improves sur
vival and reduces neurological sequelae in newborns
with hypoxic ischaemic encephalopathy, and has become
common practice in these cases [80–82]. Subcutaneous fat
necrosis was also documented in infants who underwent
whole‐body cooling before cardiovascular surgery [82].
Perinatal asphyxia induces blood shunting from skin and
spleen to brain, heart and adrenal glands, producing
impaired tissue perfusion with local hypoxia [78,82].
Neonatal adipose tissue has a relatively high concentra
tion of saturated fatty acids (stearic and palmitic acids)
with a high melting point that makes them more prone to
solidify and crystallize under cold stress, resulting in adi
pocyte necrosis and subsequent formation of granuloma
tous inflammation [75,76,82]. Also, enzymes involved in
fatty acid metabolism are immature [83].
This condition is characterized by multiple indurated, Fig. 6.13 Subcutaneous fat necrosis (H&E): radially arranged needle‐
shaped birefringent crystals.
erythematous or violaceous painful plaques and nodules
located on the back, shoulders, extremities, buttocks and
cheeks (Fig. 6.12). Some lesions may become fluctuant Skin biopsy in subcutaneous fat necrosis demonstrates
with drainage of liquefied fat from nodules [75,78,82]. lobular panniculitis with fat necrosis, mixed inflammatory
Lesions resolve spontaneously within a few weeks, infiltrate with abundant histiocytes, giant multinucleated
leaving on rare occasions atrophy, fibrosis, scarring, cells with granuloma formation and adipocytes with
ulcers or necrosis. radially arranged needle‐shaped birefringent crystals and
The differential diagnosis most commonly includes, clefts (Fig. 6.13) [75,77]. Fine‐needle aspiration is an
but is not limited to, infection (cellulitis, abscess) and option for diagnosis.
tumours (such as infantile myofibromatosis, rhabdo Although subcutaneous fat necrosis is a benign condi
myosarcoma and deep haemangioma of infancy). tion, complications such as transitory hypoglycaemia,
Sclerema neonatorum is the main differential diagnosis, hypertriglyceridaemia and thrombocytopenia have been
though it is encountered uncommonly. The latter appears reported [75,76,78,79]. Hypercalcaemia is a potentially
in preterm infants with sepsis or underlying disease in life‐threatening complication found in 25–56% of patients.
the first week of life, with generalized hardening of the It usually appears when the cutaneous lesions start to
skin except on palms, soles and genitalia. Its prognosis is regress [75,84]. Although the first 6 weeks of life is the
poor [75,77]. period of highest risk for developing hypercalcaemia,
calcium should be evaluated periodically up to 6 months

of age. The pathogenesis of hypercalcaemia is not fully
understood. The mechanism involved includes increased
prostaglandin E2 activity leading to osteoclast activation,
direct calcium release from necrotic fat tissue and secre
tion of 1,25‐dihydroxyvitamin D3 from granulomas

which produces increased intestinal calcium absorption
[76,78,83,85]. Infants with hypercalcaemia present with
irritability, lethargy, hypotonia, vomiting, polyuria, poly
dipsia, dehydration, constipation and failure to thrive.
Persistent moderate‐to‐severe hypercalcaemia may result
in metastatic calcification of skin, myocardium, falx cer
ebri, liver, gastric mucosa and kidney, leading to nephro
calcinosis, nephrolithiasis and, rarely, renal failure [76,78].
Treatment of hypercalcaemia includes conservative
management with formulas that are low in calcium and
vitamin D, increased hydration, calcium‐wasting diuretics Fig. 6.14 Adnexal polyp: small pedunculated flesh‐coloured lesion.
and corticosteroids. In cases of refractory hypercalcaemia,
treatment with pamidronate has been reported as being
effective. Differential diagnostic considerations should include
Treatment of subcutaneous fat necrosis in most cases is skin tags, accessory auricles and supernumerary nipples.
unnecessary because it is a self‐limited condition. Severe Skin tags are multiple acquired tumours common in
fluctuant abscess‐like nodules or plaques should be adults but rare in infants, often located on axilla, groin
aspirated to prevent rupture and infection, and to mini and neck. Histologically, adnexal structures are absent in
mize pain and skin sequelae. It is important to prevent skin tags [88,90].
and manage complications [76,82]. Cooled neonates
should be turned regularly to prevent prolonged contact Pedal papules of infancy
with the cooling interface [82]. Pedal papules, also known as precalcaneal congenital
fibrolipomatous hamartomas or benign anteromedial
plantar nodules, were first described by Larralde et al. in
Sucking blisters, erosions and calluses 1990 [91]. They are present at birth and consist of bilateral,
Sucking blisters and erosions are the result of repetitive symmetrical, asymptomatic, subcutaneous flesh‐coloured
vigorous fetal sucking. They occur in 0.4–2% of healthy nodules located on the plantar region of the heel. As only
newborns at birth [86,87]. They present as an intact flaccid relatively few case series have been reported in the lit
bulla or erosion on non‐inflamed skin of the dorsal aspect erature, the natural history of this entity is unclear.
of forearms, wrists and fingers (thumb and index) and However, one group reported an incidence rate of 5.9% in
rarely on the feet. Although a solitary lesion is the most newborns and 39.4% among infants, with the majority of
common form of presentation, multiple and bilateral lesions lesions appearing by 2–3 months of age and largely
have also been reported. Calluses are the result of chronic showing spontaneous regression by 3 years of age [92].
and less intense sucking [13,86,87]. They spontaneously The pathogenesis is not yet understood. Histopathological
regress without sequelae within a few days to 2 weeks study shows mature adipose tissue enveloped in pre
after birth. The differential diagnosis with serious neonatal dominantly collagenous fibrous sheaths. Differential
blistering diseases such as bullous impetigo, herpes diagnostic considerations include other lipomas, naevus
simplex, congenital syphilis, mastocytosis or epidermolysis lipomatosus and childhood fibrous hamartoma. They are
bullosa should be effected [13,86,87]. Observation of focal an entity distinct from piezogenic pedal papules, whose
sucking of the area involved as well as failure to develop onset is more frequently in adulthood [91–94].
new lesions postnatally aids diagnosis.
Perineal groove
Adnexal polyp This rare and benign congenital anomaly of the perineum
Adnexal polyp of neonatal skin is a solitary, small, con occurs mostly in females, with only one male reported.
genital polypoid tumour occurring most frequently on It is characterized by a wet groove that extends from the
the areola of the nipple (Fig. 6.14). It may also develop in posterior fourchette to the anus with a normal vestibule.
other sites such as eyelid, cheek, scapula, arm, axilla, labia On rare occasions an anogenital or urogenital anomaly
majora and scrotum. Although it usually falls off sponta may be associated. It is an asymptomatic lesion, with few
neously within a few days, persistent lesions in a 53‐day‐ reported complications such as constipation or infection.
old and a 2‐year‐old infant have been reported. Its Given that complete epithelialization is achieved by 1–2
incidence is estimated between 0.7 and 4%. years of age, treatment is not generally necessary. Although
Histopathology demonstrates the presence of hair fol its pathogenesis remains unclear, some embryological
licles, eccrine glands and vestigial sebaceous glands in the mechanisms have been proposed such as failure to fuse of
centre of the tumour [11,88–90]. the midline perineal raphe [95,96].
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84
CHA PTER 7
Congenital and Acquired Infections

in the Neonate
Scott H. James1, Nico G. Hartwig2, David W. Kimberlin1 & Peter H. Hoeger3

1
Department of Pediatrics, Division of Infectious Diseases, University of Alabama, Birmingham, AL, USA
2
Department of Paediatrics, Franciscus Hospital, Rotterdam, The Netherlands
3
Department of Paediatrics and Paediatric Dermatology, Catholic Children’s Hospital Wilhelmstift, Hamburg, Germany
Introduction, 84 Congenital infections, 84 Acquired neonatal infections, 86
Abstract anifestations. Viral, bacterial, fungal and parasitic aetiologies are

m
reviewed for common congenital, perinatal and postnatal infec-
This chapter provides a brief overview of congenital and neonatal tions in neonates. Diagnostic evaluation and clinical management
infections, with particular consideration given to cutaneous are also discussed.
Key points • Due to the potential for significant clinical sequelae, timely
diagnostic evaluation is crucial for the appropriate identification
and management of congenital, perinatal and postnatal
• Cutaneous findings in the neonate may be a sign of an underlying
infections presenting during the neonatal period.
infectious process, but they are often nonspecific.
• Clinicians should maintain a broad differential diagnosis,
including viral, bacterial, fungal, parasitic and noninfectious
aetiologies, when evaluating neonates.
Introduction growth restriction, decrease in muscle tone, hepatosple-

nomegaly, lymph node enlargement, pale skin colour or
Consideration of infectious diseases presenting at or neurological findings. The skin may be involved, but
soon after birth is an important aspect of neonatal care. diagnosis of congenital infections should not be based on
Cutaneous findings can be a sentinel for an underlying cutaneous findings alone.
infectious process, but clinicians should also be aware During the neonatal period, defined as the age from birth
that many unrelated skin disorders can mimic infectious to 4 weeks (the first month of life), postnatally acquired
diseases. Pustules in the neonate, for instance, can repre- infections may present with systemic symptoms and can
sent self‐limiting noninfectious processes such as erythema lead to serious sequelae, depending upon the pathogen.
toxicum, infantile acropustulosis, transient neonatal The skin is frequently involved and may show petechiae,
pustular melanosis, acne and miliaria, or they may be purpura, vesicles, pustules or a maculopapular rash.
indicative of potentially life‐threatening diseases such as This chapter provides an overview of congenital,
bacterial sepsis (Listeria, group B Streptococcus) or herpes perinatal and postnatal infections, with particular
simplex virus (HSV) and varicella zoster virus (VZV) consideration given to cutaneous manifestations.

infections [1,2]. Although some cutaneous findings more Diagnostic evaluation and clinical management are
specifically point to an infectious aetiology (e.g. oral vesi- also discussed. Many of the topics addressed here are
cles in HSV infections, scarring after intrauterine VZV also discussed more extensively in other chapters.
infection, or ‘blueberry muffin’ lesions), the clinician must
maintain a broad differential diagnosis when evaluating
neonates.
Congenital infections are transmitted from mother to
Congenital infections
fetus in utero and include a wide range of aetiologies Congenital infections may be due to viral, bacterial, fun-
and clinical presentations. While some congenital infec- gal or protozoal microorganisms. Many of these infec-
tions are asymptomatic, many infants will be born with tions are associated with cutaneous findings, which may
clinically apparent signs of systemic involvement such as aid in diagnosis.
Chapter 7 Congenital and Acquired Infections in the Neonate 85
Box 7.1 Causes of blueberry muffin rash
Dermal erythropoiesis
• Congenital infections
Toxoplasmosis

Rubella

Cytomegalovirus
Herpes simplex virus
Coxsackie B2 virus
• Haemolytic disease of the newborn
Rhesus and ABO incompatibility
Hereditary spherocytosis
Twin–twin transfusion syndrome
Neoplastic diseases
• Transitory myeloproliferative disease

• Neuroblastoma
• Langerhans cell histiocytosis
• Congenital leukaemia
One notable cutaneous finding relevant to several con-

genital infections is a blueberry muffin rash. Blueberry
Fig. 7.1 Congenital varicella zoster virus infection with widespread
muffin rash was first described in congenital rubella with
papulovesicles.
thrombocytopenia [3]. It is characterized by bluish‐red
macules representing sites of dermal erythropoiesis,
which occur after intrauterine infections with rubella
virus, cytomegalovirus (CMV), Toxoplasma, or other seri- sequelae are common in infants with severe involvement,
ous systemic illnesses including congenital leukaemia but 6 months of oral valganciclovir has been shown to
[4–7]. A cutaneous biopsy is helpful for rapid diagnosis of improve hearing and neurodevelopmental outcomes in
the underlying disease (Box 7.1). symptomatic congenital CMV infection [11].
Molluscum contagiosum can be transmitted vertically
Viral infections and presents with characteristic umbilicated papules
Except for HSV, VZV and rubella, few congenital viral either at birth or within 6 weeks of age [6]. These and
infections are associated with specific cutaneous signs; in other congenital viral infections associated with cutaneous
fact, many newborns with congenital viral infections are manifestations are listed in Table 7.1.
asymptomatic.
Grouped vesicles on an erythematous base are typical Bacterial infections
of HSV. Congenital HSV infections likewise can present Bacterial infections present at birth can directly cause
with widespread scarring or erosions without any vesi- skin lesions, most commonly pustules (e.g. Staphylococcus
cles or vesiculopustules [8]. Congenital VZV can present aureus, β‐haemolytic streptococci), but also macules, pap-
with disseminated vesicles, vesiculopustules and papules ules and others. Widespread macules and scaly papules
(Fig. 7.1) or, if transmission occurs early during the course are often seen in congenital syphilis. Most of these skin
of gestation, with limb hypoplasia and significant cutane- changes are directly attributable to the presence of bacte-
ous scarring. Disseminated vesicles have been reported ria in the skin and are therefore contagious themselves.
with coxsackievirus infections, which may ultimately This is particularly true for congenital syphilis, which
ulcerate or become nodular [9,10]. classically presents with a papulosquamous rash and
CMV is the most common congenital infection, occur- coryza. Erythema multiforme‐like target lesions have
ring in approximately 0.5–2% of live births. Skin abnor- also been described as a presenting sign; Treponema
malities include petechiae, purpura, maculopapules pallidum DNA can be detected within these lesions [21].
and papulonodules. Vesicles and pustules are unusual Erythema multiforme‐like lesions have also been reported
but have been described. The clinical presentation of as a presenting sign of congenital tuberculosis [22], which
‘blueberry muffin rash’ (dermal extramedullary erythro- is very rare and usually characterized by disseminated
poiesis) can be observed. Diagnosis of congenital CMV papulopustules and cutaneous abscesses not responding
infection often is based on viral urine culture or the detec- to routine antibiotics.
tion of CMV DNA via polymerase chain reaction (PCR) in Bacterial toxins, mainly produced by Staph. aureus
saliva, peripheral blood, cerebrospinal fluid (CSF) or (exfoliative toxin, toxic shock syndrome toxins [23]) or
urine within the first 3 weeks after birth. Long‐term pyogenic streptococci (streptococcal toxic shock syndrome
Table 7.1 Cutaneous signs of congenital viral infection
Infectious agent Time of Cutaneous signs Diagnosis Comments References

maternofetal
transmission
Coxsackievirus A4, Any time Herpangina (A5, B2, B3); mostly Culture, ELISA–IgM Types B5 and B1 [4,5]
B1–6 transient maculopapular rash, most commonly

occasionally petechial; vesicular associated with
lesion on erythematous base, cutaneous
ulcerate or become nodular symptoms
Cytomegalovirus Any time Petechiae (76%), jaundice (67%), PCR or culture (urine, saliva), – [12]
(CMV) purpura (13%); blueberry Tzanck smear, CMV IgM/IgE
muffin lesions
Echovirus (types 4, 5, Any time Maculopapular rash, petechiae Culture, ELISA–IgM Rash often very mild [12,13]
7, 9, 11, 16–19, after perinatal
21–22, 33) infection
Herpes simplex virus Any time Vesicles (single, grouped or PCR or culture (vesicles, CSF, – [14]
(HSV) types I and II disseminated), scars. conjunctivae, skin), Tzanck
Widespread erosions smear, direct
immunofluorescence
Human Any time Generalized macular rash (‘acute PCR, serology, viral load – [12]
immunodeficiency retroviral syndrome’)
virus (HIV)
Molluscum Birth to Typical skin‐coloured papules Clinical Vertical transmission [15]
contagiosum 6 weeks with central umbilication likely in early‐onset
lesions
Papillomavirus At birth Condylomata acuminata, Cervical smear (mother), PCR – [12]
laryngeal papilloma (laryngeal swab)
Parvovirus B19 Intrauterine, Transient or recurrent macular PCR, parvovirus IgM – [12]
at birth erythematous rash
Rubella virus Any time Dermal erythropoiesis (blueberry Maternal: four‐fold rise in – [16–18]
muffin syndrome); generalized antibody (HI, CF, LA); fetal:
brown macules and papules; positive rubella IgM (ELISA)
persistent facial rash
Varicella zoster virus Intrauterine, Generalized varicelliform blisters PCR – [19,20]
at birth (Fig. 7.1) or scars; grouped
zosteriform vesicles
CF, complement fixation text; CSF, cerebrospinal fluid; ELISA, enzyme‐linked immunosorbent assay; HI, haemagglutination inhibition; HSV, herpes simplex
virus; IgE and IgM, immunoglobulin E and M; LA, latex agglutination; PCR, polymerase chain reaction.
toxin [24]), can equally cause exanthematous diseases. and upper torso (Fig. 7.2). These pustules have in the
Staphylococcal scalded skin syndrome, which usually past mistakenly been referred to as ‘neonatal acne’ [30].
presents during the neonatal period or later, has been While infection with Malassezia spp. may or may not
reported to start in utero during late gestation. Toxic shock be attributable to immaturity of the neonatal cutane-
syndrome can also induce rashes in the early neonatal ous defence system, widespread cutaneous infections
period [25]. Bacterial pathogens associated with congeni- with Candida spp. or Aspergillus spp. are almost exclu-
tal and neonatal rashes are listed in Table 7.2. As seen in sively observed in premature infants or term neonates
this table, the timing of acquisition of bacterial infections with an underlying immunodeficiency disorder
(intrauterine vs. peri‐ or postnatal) varies widely and, in (Fig. 7.3) [31,32].
certain cases, many of the microorganisms covered here Toxoplasma gondii is a protozoan that can lead to congen-
could rightly be classified as neonatal rather than congenital infection in the event of primary maternal infection
ital infections. during the course of gestation. Congenital toxoplasmosis
can be associated with petechiae, maculopapular or pur-
Fungal and protozoal infections puric lesions, or a blueberry muffin rash [33]. Additional
It is often very difficult to decide whether an infection considerations of fungal and protozoal congenital infec-
observed in a young neonate results from intrauterine tions can be found in Table 7.3.
or early postnatal transmission. Given their ubiquitous
distribution, this is particularly difficult with fungal
Acquired neonatal infections
infections. Malassezia spp. can be isolated from the
scalp region of 30–40% of adults and are readily trans- As opposed to congenital infections, which are acquired
mitted to the newborn infant either at or shortly after in utero, the infections considered in this section are
birth, frequently leading to pustules in the facial area transmitted to the newborn infant in the perinatal and
Table 7.2 Cutaneous signs of congenital bacterial infection
Infectious agent Time of Cutaneous signs Diagnosis Comments References

maternofetal
transmission
Gram‐negative septicaemia At birth or Petechiae; erythematous Culture (blood, CSF, – [1]

(Escherichia coli, Klebsiella after PRM, macules; occasionally small urine)
spp., Pseudomonas perinatal nodules or vesicles;
aeruginosa, Haemophilus Pseudomonas aeruginosa:

influenzae) ecthyma gangrenosum (rare)
Borrelia burgdorferi Intrauterine May have vasculitis or ‘skin rash’ PCR, specific IgM Congenital infection rare [12]
Listeria monocytogenes Perinatal Pustular petechial lesions Stool microscopy, culture [26]
Mycobacterium Intrauterine, Erythematous papulopustules Microscopy and culture Fundoscopy recommended [22]
tuberculosis diaplacental, with central crusting, multiple from multiple sites (chorioretinitis frequent);
at birth abscesses, multiform lesions (including gastric lavage), maternal infection often
placenta histology subclinical; skin lesions rare
Mycoplasma hominis, Perinatal Subcutaneous abscess Cervical/vaginal swabs Preterm babies at risk [12]
M. pneumoniae formation
Neisseria gonorrhoeae At birth Ophthalmia neonatorum, Microscopy, culture, PCR – [27]
occasionally pustules
Staphylococcus aureus At birth Impetigo bullosa, toxic shock Culture, assays for toxin – [23,25]
syndrome, staphylococcal production
scalded skin syndrome
Streptococcus pyogenes At birth Impetigo, streptococcal toxic As above – [24]
shock syndrome
Group B streptococci Perinatal; rarely Blisters, impetigo, erosions, Culture Skin lesions rare [28,29]
intrauterine superficial blisters
Treponema pallidum Intrauterine, Papulosquamous rash; Microscopy, TPHA, FTA – [21]
diaplacental, desquamation over palms and
at birth soles; EM‐like targetoid lesions
CSF, cerebrospinal fluid; EM, erythema multiforme; FTA, fluorescent treponemal antibody; IgM, immunoglobulin M; PCR, polymerase chain reaction; PRM,
premature rupture of membranes; TPHA, Treponema pallidum haemagglutination test.
Fig. 7.2 Neonatal cephalic pustulosis due to Malassezia spp.

Fig. 7.3 Primary cutaneous aspergillosis.
Table 7.3 Cutaneous signs of congenital fungal and protozoal infection
Infectious agent Time of maternofetal Cutaneous signs Diagnosis References

transmission
Candida albicans Perinatal Congenital cutaneous candidiasis: widespread erythema/ Skin swabs, KOH [32]
erythroderma or localized thrush preparation, culture
Malassezia spp. At birth Folliculitis As above [30]
(Pityrosporum spp.)
Aspergillus spp. At birth, post partum Pustules, necrotic ulceration As above [32,34]
Trichophyton rubrum At birth, post partum Scaling, erosion As above [35]
Sarcoptes scabiei At birth, post partum Generalized papulopustules (including face, palms, soles) KOH, microscopy [36]
Toxoplasma gondii Intrauterine erythropoiesis Petechiae, purpura, jaundice Toxoplasma IgM ELISA [33]
ELISA, enzyme‐linked immunosorbent assay; IgM, immunoglobulin M; KOH, potassium hydroxide.

Varicella is caused by VZV, a member of the herpes-

Box 7.2 Common acquired infections in the neonate
virus family. Its normal route of transmission is airborne.
Viral infections
The incubation time for varicella is approximately
2 weeks (range 10–23 days). Perinatal varicella is poten-
• Herpes simplex infection tially dangerous in the neonate, especially when primary
• Cytomegalovirus infection maternal infection develops any time from 5 days before
• Varicella to 2 days after delivery. In this setting, mother‐to‐child

• Enteroviral infections transmission can occur haematogenously or via the air-
Bacterial infections
borne route in a newborn with no protective maternal
antibodies. Haematogenous transmission may shorten
• Pustular staphylococcal infections the incubation period and some children may present
• Neonatal impetigo with vesicles at birth [40].
• Omphalitis Mild prodromal symptoms such as fever, malaise and
• Cellulitis
upper respiratory symptoms may precede the onset of
• Neonatal abscesses
rash by 1–2 days but are generally absent in neonates. The
• Circumcision infections
skin lesions erupt over 1 week and evolve within 12–24 h
Yeast infections of eruption from small red macules to papules, vesicles
and pustules on an erythematous base. The vesicular
• Neonatal candidiasis
lesions are typically umbilicated and differ in their stage
• Malassezia furfur pustulosis
of development. Crusting occurs 1–3 days following the
• Neonatal pityriasis versicolor
appearance of an individual lesion.
Parasitic infections Diagnosis is usually by observation of typical signs.
Tzanck smears from the base of an intact vesicle are no
• Scabies
longer commonly performed. Cytology and histopathol-
ogy are identical to those seen in HSV infections.
Definitive evidence of VZV usually is obtained via a
positive PCR from a swab of the base of one or more
postnatal periods. Common neonatal infections are listed unroofed fresh lesions. Newborns of mothers who
in Box 7.2. developed clinical varicella from 5 days before to 2 days
after delivery should be treated with varicella zoster
Viral infections immunoglobulin (VariZIG) intramuscularly as soon as
Viral exanthemas are discussed in detail elsewhere. Brief possible, preferably within 72 h. If VariZIG is not avail-
mention is made here of neonatally acquired HSV, VZV able, intravenous immune globulin may be used [41].
and enteroviral infections. In addition, administering parenteral aciclovir may
Neonatal HSV infection is a potentially serious disease reduce symptoms. Mortality in untreated perinatally
that manifests in the first 4–6 weeks of life. Based on the acquired varicella can approach 30%.
incubation period, the onset rarely occurs before the age Enteroviruses include RNA viruses such as groups A
of 1 week. Transmission occurs perinatally during pas- and B coxsackieviruses, echoviruses, and enteroviruses
sage through the birth canal in 85% of infected infants. (types 68–71), which may cause a variety of illnesses in
The risk of transmission is greater than 50% in women neonates. Enteroviral infections are frequently observed
with first‐episode primary genital infections at the time of in infants and children. Parechoviruses, a recently
delivery, whereas women with recurrent genital lesions described genus of viruses, were previously classified
carry a 2% risk increase [37]. In an effort to prevent among the enteroviruses as echovirus 22 and 23, which
mother‐to‐child transmission of HSV, women with active have similar features to other enteroviral infections.
recurrent genital herpes should be offered suppressive These viruses are spread via faecal–oral and oral–oral
antiviral therapy beginning at 36 weeks of gestation and routes. Faecal viral excretion and transmission may
caesarean delivery should be performed in women with continue for weeks or months. The incubation time is
active genital lesions at the time of delivery (whether pri- 3–6 days.
mary or recurrent) [38]. It should be noted, however, that Common skin manifestations of neonatal enteroviral
mother‐to‐child transmission can also occur in asympto- infections include maculopapular, petechial and vesic-
matic women with no reported history of genital herpes, ular rashes. These skin manifestations are frequently
as well as those with a history of genital herpes who are accompanied by a sepsis‐like syndrome and/or respir-
receiving antiviral suppressive therapy [39]. Medical per- atory problems. Gastrointestinal symptoms such as
sonnel and family members with herpetic infection on the stomatitis, vomiting, abdominal pain and diarrhoea

fingers or around the mouth also can transmit HSV, and may occur. In rare cases neonates develop pericarditis,
therefore should take appropriate measures to prevent myocarditis, (meningo‐)encephalitis, hepatitis and
transmission. In 45% of cases skin lesions are observed, disseminated intravascular coagulopathy. Diagnosis is
usually vesicles or petechiae. Disseminated disease has a aided by PCR of blood, CSF, saliva and stool. There cur-
high mortality. Treatment with parenteral aciclovir is rently are no licensed antiviral agents for neonatal
advised when neonatal HSV infection is suspected. enteroviral infections.
Bacterial infections Box 7.3 Neonatal pustular eruptions

Newborns are susceptible to a number of bacterial infec-
tions, many of which are associated with cutaneous Infectious
findings (Table 7.2). Particular infections are covered in
greater detail elsewhere, but the following represents an • Bacterial
overview of common neonatally acquired bacterial • Staphylococcus aureus (bullous impetigo)

• Listeria monocytogenes

infections.
• Streptococcus (group B β‐haemolytic)
Pustular eruptions in the neonate are most commonly
• Pseudomonas aeruginosa
caused by Staphylococcus aureus. Skin lesions may appear
• Haemophilus influenzae
as early as the second or third day of life. Clinical pres-
entation ranges from vesicles to pustules on an erythe- Viral
matous base. The condition may evolve into honeycomb
• Herpesvirus infections (HSV, CMV, VZV)
crusts or into bullous lesions, so‐called bullous impetigo
(Fig. 7.4). The intertriginous and napkin areas are sites Fungal
of predilection. The same symptoms are caused rarely
by group B streptococci, which are of a more invasive • Candidiasis (congenital, neonatal)
nature [29]. • Malassezia furfur folliculitis
In addition to Staphylococcus, pustular eruptions in the Parasitic

neonate include a large range of infectious and nonin-
fectious causes (Box 7.3). Final diagnosis is obtained after • Scabies
culturing for Staph. aureus. Cytological smears and histol-
Noninfectious
ogy may also show polymorphic neutrophils and Gram‐
positive cocci in clusters. Local therapy such as mupirocin • Erythema toxicum neonatorum
is sufficiently effective for limited lesions in an other- • Infantile acropustulosis
wise well‐appearing neonate with no fever. If lesions • Transient neonatal pustular melanosis
are accompanied by lymphadenopathy or fever, empiric • Neonatal acne
systemic antibiotics and further evaluation for dissemi- • Pustular miliaria
• Eosinophilic pustular folliculitis of infancy
nated disease are warranted.
• Incontinentia pigmenti
Neonatal impetigo is another possible manifestation of
• Congenital self‐healing Langerhans cell histiocytosis
staphylococcal infection. Some strains of Staph. aureus
produce an exfoliative exotoxin, which is able to split the Source: Adapted from Praag et al. 1997 [1]. Reproduced with permission
superficial epidermis at the level of the granular layer. from John Wiley & Sons.
When the exotoxins enter the blood circulation, involve-
ment of the entire skin is possible and can lead to staphy-
lococcal scalded skin syndrome (SSSS) [42]. At present,
three exfoliative exotoxins have been described but only impetigo may occur on the second or third day of life,
two, exfoliatin A and B, are associated with neonatal starting with pustules that develop into flaccid bullae
impetigo and SSSS [43,44]. The higher potential for devel- filled with yellow fluid. The bullae burst easily, leaving a
oping disseminated and even systemic disease in neo- circular erosion with a peripheral collarette of scale. The
nates is brought about by less efficient metabolism and infection is limited to the epidermis but may extend very
excretion of the toxin [45]. easily and may result in SSSS.
Cytological smears and histology for neonatal impetigo Neonatal impetigo is treated in the same way as pustu-
are identical to those of pustular infection. Neonatal lar staphylococcal infection, but systemic treatment may
be required more often to prevent the development of
SSSS. However, the infection is mainly limited to the
epidermis and generally does not result in systemic dis-
ease. Localized infections are treated topically, whereas
widespread infection requires systemic treatment with a
penicillinase‐resistant penicillin, a cephalosporin or van-
comycin, depending on drug susceptibility. SSSS is always
treated systemically via intravenous therapy. It is some-
times lethal, especially in the neonatal period.
Omphalitis neonatorum has a low incidence in devel-
oped countries (about 0.7%) but is more frequently
encountered in underdeveloped countries (about 6%)
[46]. Improper severing of the umbilical cord, application
of oily substances to the umbilical stump and other unhy-
gienic practices during the neonatal period are important
predisposing factors. Late separation of the umbilical
Fig. 7.4 Bullous impetigo in the neonate. cord may also lead to infection and inflammation.
In most cases, Gram‐negative organisms are responsible The treatment of choice is the parenteral combination of
for omphalitis, particularly Escherichia coli and Klebsiella ampicillin with an aminoglycoside. Listeria is not sensi-
pneumoniae. Infections with group A streptococci and tive to cephalosporins.
staphylococci have also been observed. Polymicrobial
infection is common. Gram staining is a reliable and easy Fungal infections
method for initial identification of the microorganism. Yeast infections of the neonate are common and include
A persistent omphalitis may indicate immunodeficiency thrush, neonatal candidiasis (napkin eruption, paronych-
[47]. Cellulitis occurs when inflammation spreads ium) and Malassezia furfur pustulosis. Greater detail on
beyond the umbilicus. When the inflammation extends each of these can be found elsewhere in this book.
to the subcutaneous tissue and underlying fascia, Two types of Candida infection are seen in neonates:
necrotizing fasciitis develops [48]. Necrotizing fasciitis superficial infections and disseminated infections.
is associated with a mortality rate of 50%. Thus, early Disseminated Candida infections are rare but the incidence
diagnosis is strongly indicated, and should be followed appears to be increasing because of higher survival rates
by surgical debridement. of premature and very‐low‐birthweight neonates [53].
Neonates have a high risk of cellulitis and abscess These disseminated infections may manifest as vesicu-
formation following skin injury. Scalp abscesses are asso- lobullous, pustular or a burn‐like exfoliative dermatitis.
ciated with the use of scalp electrodes. Also, puncture Superficial infections such as oral candidiasis (thrush)
wounds from blood sampling or intravenous catheters and Candida napkin dermatitis are common diseases in
are sites where cellulitis or abscesses are found. The neonates, especially when broad‐spectrum antibiotics
microorganisms involved are those that colonize the neo- have been administered.
nate during passage through the birth canal: Staph. aureus, Superficial candidiasis is seen after 1–2 weeks of life,
E. coli and group A and B streptococci. Gram stain and presenting first as oral thrush and then as perianal napkin
culture of the abscess content will typically reveal the dermatitis. Candida species, usually C. albicans, can be iso-
aetiology. Antimicrobial therapy should be tailored to the lated from the lesions and faeces. Neonatal superficial
causative organism and surgery should be considered candidiasis is characterized by a moist erythematous
when fluctuation or abscesses are diagnosed. (‘beefy red’) napkin dermatitis, located near the anus,
Breast abscess is a special entity that appears in full‐ surrounded by satellite lesions. Pustules and vesicles
term neonates within the first 8 weeks. Usually, unilateral may develop. Inner folds such as the intergluteal fold,
swelling of the breast in combination with redness and perineum and inner thighs are often involved. Direct
warmth appears about 1 week after birth. Transplacentally potassium hydroxide smears show the presence of
acquired maternal hormones stimulate the glandular Candida pseudohyphae. Cultures yield mostly Candida
breast tissue causing it to be more susceptible to infec- albicans and rarely another species. Therapy of superfi-
tions. The disease is seen more often in girls than in boys. cial candidiasis includes local antifungal therapy for
Diagnostic procedures and treatment are the same as 7–10 days. Therapy of disseminated candidiasis requires
described previously [49]. a longer course of a parenteral antifungal agent.
Circumcision has proven to have preventive effects on Neonatal M. furfur pustulosis is another common fungal
the development of penile cancer [50] and also leads to a infection. M. furfur is associated with a nonfollicular
lower risk of urinary tract infections as well as a decreased pustulosis on the face and neck of a neonate. This disease
likelihood of acquisition of human immunodeficiency frequently is misdiagnosed as neonatal acne. Identification
virus (HIV). Pathological phimosis and paraphimosis of M. furfur can be made by direct microscopy of pustular
induce inflammation of the glans penis and the prepuce material with May–Grünwald–Giemsa stain. If treatment
(balanitis, posthitis, balanoposthitis). These infections are is warranted, pustules typically respond to topical keto-
extremely painful and primarily affect uncircumcised conazole therapy. A disseminated M. furfur fungaemia
male babies. Chronic balanoposthitis may result in scar- may occur in rare circumstances, usually in premature
ring and secondary phimosis [51]. The circumcision of a neonates who receive parenteral nutrition [54].
neonate is a low‐risk procedure. The most common com- Pityriasis versicolor can be acquired from the mother in
plications are local infections and bleeding. Any infection the neonatal period, often diagnosed in the first 2 weeks
that develops should be treated immediately. of life. The differential diagnosis of multiple depigmented
Listeriosis is a septicaemic disease caused by Listeria lesions in a neonate may include tuberous sclerosis, nae-
monocytogenes, which is a small aerobic non‐spore‐forming vus anaemicus and naevus depigmentosus (achromic
Gram‐positive rod. Transmission occurs via contami- naevus) [55].
nated food, especially products made from unpasteur-
ized milk. Early‐onset infection is acquired in utero; Parasitic infections
late‐onset infection may be acquired after birth. Late‐ Scabies is a parasitic infection caused by Sarcoptes scabiei.
onset infection usually affects full‐term healthy infants. Scabies in infancy is different from scabies in children and
The infection develops soon after birth to weeks there- adults (Fig. 7.5). Pruritus is often subtle or nonexistent.
after [52]. The infection is accompanied by grey‐white Neonatal scabies presents with papules, vesicles, vesicu-
maculopapules with vesicles or pustules. The organism lar burrows and very typical vesicles on palms and soles
can be recovered in routine cultures, but special tech- [36]. Eczematization and impetiginization are common
niques may be necessary to isolate and identify Listeria. and sometimes lead to misdiagnosis. Mites, ova and faeces
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93
C HA PTER 8
Transplacentally Acquired Dermatoses

Paula Carolina Luna

Hospital Alemán, Buenos Aires, Argentina
Neonatal lupus erythematosus, 93 Transplacental melanoma, 98

Transplacentally acquired neonatal bullous autoimmune Transplacental Behçet disease, 99
disorders, 97
as maternal antibodies wane from the neonatal circulation. This

Abstract group includes neonatal lupus erythematosus and transplacentally
acquired autoimmune bullous diseases (pemphigoid gestationis,
Transplacentally acquired dermatoses are a group of rare diseases pemphigus vulgaris and foliaceus and epidermolysis bullosa acquisita).
that affect the skin and are due to the action of maternal anti- Although Behçet disease has no recognizable antibodies, it shows
bodies that cross the placenta. They all behave in a similar way, a similar behaviour. Transplacental metastasis of maternal melanoma
being present at birth (or developing shortly after) and resolving will also be briefly addressed.
Key points maternal antibody (SSA/Ro, SSB/La or U1RNP). It may affect

the neonatal skin, heart, liver, blood, brain and even the bones.
• Transplacentally acquired dermatoses are rare and typically Cardiac manifestations can be severe and life‐threatening and
caused by transplacental passage of maternal autoantibodies. are the only manifestation that may persist through life.
• Neonatal lupus (NL), being the most frequent of this group, • Manifestations are transient and resolve as maternal antibodies
represents a syndrome caused by the tranplacental passage of clear from the infant’s blood.
Neonatal lupus erythematosus Pathogenesis

According to current knowledge, NL is due mainly to the
Introduction transplacental passage of maternal antibodies, although
Neonatal lupus (NL) is a disease that was first described
several other factors, both maternal and fetal, have also
by McCuiston et al. in 1954. It represents a model of pas-
been implicated [3].
sive autoimmune disease in which pathogenic maternal
The main antibody associated with NL is anti‐Ro/SSA,
antibodies (mainly SSA/Ro, SSB/La and less frequently
followed by anti‐La/SSB, and rarely anti‐U1 RNP [4]. It
U1RNP) are transmitted through the placenta. It is
has been hypothesized that it is the titre of maternal anti-
reported to affect 1% to 2% of children born to mothers
bodies rather than their presence that is associated with
with these antibodies and is characterized by the variable
cardiac injury. Approximately 15% of NL patients with
presence of dermatological, cardiac, haematological or
cardiac issues had Ro‐values of ≥50 U/mL while 85% had
hepatic manifestations. Aside from heart block, most
≥100 U/mL; overall, the rate of complete heart block was
manifestations are transient and completely resolve as the
5%. Those with low titres of antibodies had a 0% rate of
passive antibodies clear from the newborn’s blood.
complete heart block. High anti‐La levels (≥100 U/mL)
Cardiac manifestations are the exception; these may be
were also more related to noncardiac features of NL [5].
life‐threatening and can persist throughout life.
Anti‐U1‐RNP antibodies are less commonly seen,
although they have been reported in around 5% of patients.
Epidemiology
These neonates may develop cutaneous, haematological,
NL has an estimated incidence of around 1 in 12 500 to
hepatic or osteoarticular manifestations, but have never
20 000 live births [1] although this number is probably
been reported to develop cardiac manifestations [6,7].
underestimated because of the self‐healing nature of the
While all these antibodies are necessary to the develop-
extracardiac manifestations that are only diagnosed when
ment of NL, they are not the only determinant of the
there is a high degree of suspicion. It is considered to be
development of NL. Fetal susceptibility may be influ-
the most frequent transplacental immune‐mediated
enced by specific HLA alleles, mainly DQB1*02, DRB1*03
dermatosis [2] as well as the most frequent cause of con-
and a polymorphism in the promoter region of the gene
genital heart block.
for tumour necrosis factor‐α [8]. Discordance in identical Lesions tend to develop around the sixth week after
twins raises concern about other possible in utero factors. birth, although some cases present as early as at birth or
Animal models have revealed that reactivity to the shortly thereafter. Reports exist that document the skin
p200 region of the Ro52 protein and antibody targeting of findings being triggered following exposure to photo-
L‐type calcium channels seem to be relevant in the devel- therapy for neonatal hyperbilirubinaemia [1].
opment of cardiac NL. In vitro studies support a protec- The most typical lesions are erythematous, arcuate,
tive role of β2 glycoprotein 1 (by preventing anti‐Ro

polycyclic or annular macules, patches and papules.

binding to apoptotic cells) and pathological roles of the Lesions typically show slight central atrophy, with or
urokinase–plasminogen activator/receptor system (lead- without a fine scale, appearing mainly on the scalp and
ing to activation of transforming growth factor [TGF]‐β) periorbital area with a tendency to be confluent around
and endothelin‐I secretion by macrophages in mediating the eyes giving the baby an ‘owl eyes’, ‘raccoon eyes’ or
tissue injury. Genetic studies highlight the fetal major his- ‘owl mask’ appearance [15] (Figs 8.1 and 8.2). These
tocompatibility complex (MHC) in the development of lesions show some clinical and histological similarity to
disease, and a multigenerational study demonstrated that subacute cutaneous lupus erythematosus (SCLE) with
mothers of NL children accumulate genetic risk factors interface changes, vacuolar alteration in the basement
preferentially from the NL child’s grandparents [9]. membrane and dermoepidermal junction, along with epi-
Mothers of patients with NL may suffer from systemic dermal atrophy and perivascular inflammatory infiltrates
lupus erythematosus (SLE) [10], Sjögren syndrome, SLE/ with lymphocyte dominance [16].
SS, undifferentiated connective tissue disease or leukocy- Urticaria‐like lesions (Fig. 8.3) are characterized by
toclastic vasculitis [11], or be completely asymptomatic, polycyclic erythematous plaques that mainly affect the
although when tested mothers always show positive anti- scalp and face but can also appear on the trunk or limbs.
bodies. Although asymptomatic, mothers with positive On histology these lesions may also show interface
antibodies will need to be followed up. Progression to SLE changes or a superficial and deep perivascular and inter-
and SS does not invariably occur. In fact, only about 10% stitial lymphocytic infiltrate [16].
of mothers developed SLE and 14% developed SS during Atrophic lesions [17] (Fig. 8.4), bullae, telangiectasia
a 15‐year follow‐up period. [12]. [18], purpura, erythema multiforme‐like lesions (Fig. 8.5),
Maternal hypothyroidism has been suggested to widespread erosions [19], cutis marmorata telangiectatica
increase the risk nine‐fold of having an affected fetus with congenita (CMTC)‐like [20,21] (Fig. 8.6) lesions as well as
congenital heart block compared to mothers without
hypothyroidism [13].
Clinical manifestations
Neonatal lupus may show a spectrum of clinical manifes-
tations. Affected organs include the skin, the heart, the
blood, the liver, the brain and the bones. Most of the lit-
erature reports a similar incidence of around 50% for both
skin and heart and 15% for all the other symptoms col-
lectively. Any individual patient may show one to several
of these manifestations. According to the Research
Registry for Neonatal Lupus (RRNL; a nationwide US
registry of NL patients), 61% of NL patients present with
cardiac disease alone, 26.9% with cutaneous manifesta-
tions, 8.7% with both cutaneous and cardiac, and 3.2%
with hepatic or haematological abnormalities [3].
Cutaneous manifestations
Cutaneous lesions are highly variable and polymorphous
[14]. The different morphologies are listed in Box 8.1.
Box 8.1 Dermatological manifestations of neonatal lupus
• ‘Raccoon eye’ or ‘owl mask’ erythema

• Erythema multiforme
• Cutis marmorata telangiectatica‐like skin changes
• Bullous skin changes
• Eczematous skin changes
• Telangiectasias
• Extensive capillary malformation
• Targetoid lesions
• Varicelliform lesions Fig. 8.1 Erythematous arcuate plaques over the forehead and around the
eyes, with the typical ‘owl mask’ appearance.
Chapter 8 Transplacentally Acquired Dermatoses 95

Fig. 8.2 Scaly circinate plaques around the eyes, with the typical
‘owl‐mask’ appearance.
Fig. 8.5 Erythema multiforme‐like lesions over the face.
Fig. 8.3 Urticarial lesions over the chest of a newborn.

Fig. 8.6 Cutis marmorata telangiectatica congenita‐like lesions over the
abdomen.
Fig. 8.4 Congenital atrophic lesions over the face.

Fig. 8.7 Erosions in the napkin area, showing that non‐photo‐exposed
lesions mimicking an extensive capillary malformation [22] areas can also be affected.
have all been described more rarely in affected patients.
A report of one patient that presented with alopecia, atro- Although these lesions tend to be aggravated with sun
phy and erosions has also been published [23]. exposure or phototherapy, they can appear in non‐exposed
In addition to the cutaneous eruption, mucosal ulcera- areas such as the feet or napkin area (Fig. 8.7) [24] and
tion has been documented in several patients. even be present at birth, before there is any sun exposure.
The clinical differential diagnosis includes but is not Haematological manifestations

limited to: a drug eruption, urticaria, bullous pemphi- Any haematological lineage can be affected by the
goid, congenital syphilis, erythema multiforme, cutis maternal passage of antibodies. Thrombocytopenia,
marmorata telangiectatica congenita, tinea corporis and haemolytic or aplastic anaemia and neutropenia have all
annular erythema of infancy, among many others. been described in NL patients. These manifestations
Most of the lesions tend to resolve completely, paralleling tend to appear in 10% [29] of patients and rarely lead to
the decline in maternal antibodies around 6–9 months [25] complications such as bleeding or sepsis [14]. Although
although in some instances some residual hypo‐ or hyper- lymphopenia is a relatively common manifestation of
pigmentation, atrophic scars or telangiectasias may remain. lupus in adults, it is not a feature of NL [15].
Cardiological manifestations Neurological manifestations

More than half of the affected patients present different Hydrocephalus and macrocephaly have been described
types of cardiac manifestations. NL accounts for 80–95% in patients with NL. Some degree of neuropsychiatric
of the cases of congenital complete atrioventricular block dysfunction, compared with normal controls, has also
(CAVB) diagnosed in utero [26]. This alteration develops been reported. Abnormal computed tomography (CT)
usually during a vulnerable period from weeks 18 to 24 findings have been reported in affected patients, including
and rarely arises after week 30. Binding of autoantibodies nonspecific white matter changes, calcification of the basal
to the cardiac conduction system at this early stage of ganglia and subependymal cysts [30]. A case of transient
development results in cardiac dysfunction that does not myasthenia gravis has also been reported [31]. These
undergo spontaneous regression. findings are also thought to be transient and reverse as
Although the precise pathogenic mechanism of the the antibodies clear from the neonatal circulation.
cardiac injury remains unknown, it is thought to be a In a study evaluating the potential neurotoxic effect
two‐stage process. First, maternal anti‐Ro antibodies of autoantibodies from NL, no statistical difference in
bind to fetal cardiomyocytes leading to apoptosis. The attention and behavioral problems, depression, anxiety,
subsequent binding of anti‐La antibodies to the apop- developmental delays, learning, hearing, and speech prob-
totic cardiomyocytes starts the inflammatory cascade lems was noted among patients and their siblings [32].
that finally leads to fibrosis and calcification of the
conducting tissue and surrounding myocardium.
In addition to CAVB, several other electrophysiological Chondrodysplasia punctata
abnormalities have been described, including transient The term chondrodysplasia punctata (CDP) describes a
and persistent sinus node dysfunction, long QT interval, heterogeneous group of disorders characterized by the
ventricular and atrial ectopy, ventricular and junctional radiological finding of punctuate calcification of cartilage
tachycardia and atrial flutter. [33]. The different aetiologies responsible for these find-
A more diffuse myocardial disease with ventricular ings include disorders of peroxisome biosynthesis,
dilation, myocardial hypertrophy or endocardiofibroelas- maternal conditions (including anti‐SSA/Ro, SSB/La and
toidosis [27] has also been described. anti‐U1RNP), and teratogens, especially anticoagulants
Structural congenital heart disease including persistent [34]. Several patients with CDP and maternally derived
ductus arteriosus, atrial and ventricular septal defects, antibodies (mainly anti‐U1RNP) have been described.
semilunar and atrioventricular valve abnormalities has These patients may present only with CDP or may also
been reported in 16–42% of patients. These alterations develop cutaneous or haematological manifestations. No
may also present in patients in the absence of CAVB, patient with CDP and associated cardiac manifestations
suggesting the possibility that maternal autoimmune‐ has been reported to date.
mediated pathology may also play a role in other forms of The proposed mechanism for the bony defects and
congenital heart disease. stippling in CDP‐associated maternal lupus is immune‐
Most children with CAVB will require permanent mediated, attributed to maternal autoantibodies crossing
heart pacing before adulthood with 60% paced during the placenta in early to mid gestation, and may involve
the neonatal period [28]. the inhibition of a high‐affinity calcium‐binding protein,
calreticulin, which is a multifunctional protein of the
Liver disease endoplasmic reticulum. Ro/SSA is an autoantigen com-
Liver involvement is said to occur in approximately plex that may include calreticulin.
15% of patients with NL, but its incidence is probably As with other extracutaneous manifestations, the
underestimated [14]. In many patients, liver disease is stippling of the bones can disappear with time.
asymptomatic and transient or may be misdiagnosed as
physiological jaundice [1]. It usually presents as asympto- Other manifestations
matic transaminitis, hepatomegaly, transient hepatitis, Pulmonary complications of NL such as transient self‐
hyperbilirubinaemia or, rarely, liver failure [29]. Most of limited pneumonitis and pulmonary capillaritis and
these manifestations (except that of fulminant liver failure) haemorrhage have been described although they are
are transient and, as seen in the other noncardiac organs exceedingly rare [35]. Nephritis has rarely been described
affected in NL, resolve spontaneously concurrent with [36]. A rare case with unilateral pectoris major atrophy has
waning of maternally derived antibodies. also been reported [37].
Diagnosis recurrence rate can be unusually high in some families: in

As there are no diagnostic criteria for NL, the diagnosis is one case report four affected siblings were documented [25].
made in a newborn presenting with one or more of the It is suggested that all pregnant women with autoim-
previously described clinical findings (cutaneous, car- mune symptoms should undergo early first‐trimester
diac, haematological, hepatic, osseous) in the context of screening for SSA/Ro and SSB/La antibodies. If they are
positive antibodies (anti‐SSA/Ro, SSB/La or anti‐U1RNP) positive, fetal PR interval should be monitored by

both in the patient and the mother. echocardiogram weekly between weeks 16 and 26 and
biweekly between weeks 26 and 32 [45].
Evaluation All patients should have long‐term follow‐up, because
Once the diagnosis is established, affected patients should although extracardiac manifestations resolve spontane-
be evaluated for other manifestations of NL. A cardiologi- ously early in life, these patients seem to be at a higher
cal evaluation with an electrocardiogram (ECG) and an risk of developing other autoimmune diseases during
echocardiogram should be performed in every patient. A their childhood. A long‐term follow‐up study of NL
blood test including platelet count and liver function is patients and their unaffected siblings [42] showed that six
also advisable at the time of diagnosis. If the patient is out of 49 patients had a definite rheumatic/autoimmune
U1RNP positive, a radiological evaluation is also advisa- disease (two had juvenile rheumatoid arthritis, one had
ble. Neurological evaluation should be suggested if there Hashimoto thyroiditis, one had psoriasis and iritis, one
are clinical symptoms of neurological involvement. had psoriasis and diabetes, and one had diabetes and
nephrotic syndrome) by the age of 8 years or older.
Treatment
As cutaneous lesions are usually transient, sun avoidance
is the only recommended intervention. Under some spe- Transplacentally acquired neonatal
cial circumstances topical calcineurin inhibitors or topical bullous autoimmune disorders
corticosteroids might be considered [38]. Transplacental passage of maternal antibodies to several
Given that complete heart block is irreversible and can autoimmune blistering diseases has been reported to
currently only be treated with a pacemaker, prevention is affect newborns. Neonatal blisters or erosions (or lesions
the most promising strategy. The use of prophylactic developing shortly after birth) have been documented in
intrapartum hydroxychloroquine has been evaluated the infants of mothers with pemphigus vulgaris, pemphi-
through a case‐control study. In this study, exposure to gus foliaceus, gestational pemphigoid and epidermolysis
hydroxychloroquine during pregnancy was demon- bullosa acquisita [46–48] (Table 8.1). Although the true
strated to decrease the risk of fetal cardiac NL among neo- incidence of transplacentally acquired neonatal bullous
nates born to mothers with these antibodies [39]. autoimmune disorders is unknown [49], they seem to be
Hydroxychloroquine inhibits the endosomal acidification exceedingly rare.
required for optimal toll‐like receptor (TLR) signalling, The presumed mechanism of disease is passive transfer
whose activation is known to promote cardiac inflamma- of maternal IgG autoantibodies across the placental tis-
tion and scarring. sues. Hormonal changes of pregnancy can modulate
Systemic fluorinated steroids administered to the mother autoimmune bullous diseases. Vertically transmitted
have been widely used, with questionable efficacy and autoimmune conditions are caused by passive transfer of
risks [3]. When first‐ or second‐degree heart block is IgG antibodies, which are able to cross the placenta begin-
detected in utero, systemic fluorinated steroids (dexameth- ning at week 13 and are present at highest levels in the
asone and betamethasone) may help reverse the cardiac third trimester [50].
alteration. In utero treatment with glucocorticosteroids for Management of these diseases during the neonatal
these degrees of heart block is generally not advised unless period usually involves use of bland emollients and topi-
the patient also presents with myocarditis [28]. cal corticosteroids, if needed, because disease activity will
As it is well known that the rate of recurrence in moth- probably wane as maternal autoantibodies are cleared
ers with a previous affected child rises dramatically, the from the affected neonate. New blisters rarely develop
use of prophylactic intravenous immunoglobulin (IVIG) past the newborn period [50].
in subsequent pregnancies has been evaluated, but
proved not to be as effective as prophylactic therapy for
CAVB in high‐risk mothers [40,41].
Table 8.1 Targets of different immunologically‐mediated bullous neonatal
Long‐term follow‐up diseases
The risk of a second affected neonate after the first NL
child is about 17–36% [42,43]. Cardiac NL recurrence is Type of immune bullous disorder Target
thought to be approximately 17% and seems to be
unaffected by maternal health, use of steroids, antibody Pemphigoid gestationis BP180
Neonatal pemphigus Desmoglein 3
status, severity of cardiac disease in the first affected child
Neonatal epidermolysis bullosa 145‐kDa NC1 domain of
or gender of the fetus [44]. For these reasons, subsequent acquisita collagen VII
pregnancies should be strictly monitored and maternal Neonatal pemphigus foliaceus Desmoglein 1
prophylactic systemic therapy may be considered. The
Gestational pemphigoid keratinocytes [56]. The frequency of neonatal PF is exceed-

Pemphigoid gestationis, previously known as herpes ges- ingly low and this is thought to be due to the fact that in
tationis, is a rare pregnancy‐associated immunobullous neonatal epidermis (in contrast to adult epidermis),
disease. Affected mothers usually develop the skin condi- desmoglein 3 is coexpressed in the superficial epidermis
tion during the second or third trimester of pregnancy and together with desmoglein 1. Therefore, the lack of des-
findings resolve within a few weeks after labour. It has moglein 1 is compensated by desmoglein 3, providing a
been shown that the pathogenic antibody to BP180 certain degree of protection [55]. Confirming this, a study
increases immediately before and after delivery in patients of 19 neonates born to mothers with active fogo selvagem
with gestational pemphigoid, presumably in response to (endemic PF) showed that no skin disease was manifested
the release of the BP180 antigen from the chorionic mem- in the neonates despite positive Dsg1 autoantibodies in
brane. The exact role of hormones in accelerating bulla 9 of 19 neonates.
formation or pathogenic antibody titre is unknown. Very few cases of neonatal PF have been reported in the
Pemphigoid gestationis is exceedingly rare, with an literature. In all of them maternal antibody titres against
estimated incidence of 1 in 50 000 pregnancies. Neonatal desmoglein 1 were very high (1 : 320 and 1 : 640) [57]. Clinical
bullous pemphigoid has been rarely reported in around manifestations included superficial erosions and crusts
5–10% of newborns of affected mothers [51]. There is a with no mucosal involvement. Management with topical
strong male predominance with a male : female ratio of corticosteroids seems to be sufficient and lesions have been
4.6, in contrast to adult bullous pemphigoid which has reported to be completely resolved at 2 weeks of age.
female : male ratios ranging from 1.01 to 2.00 [49].
Lesions in newborns can appear as blisters, erosions, Epidermolysis bullosa acquisita
vesicles, urticarial plaques or reticular eruptions [49] and Epidermolysis bullosa acquisita (EBA) is an extremely
yellow plaques with erythematous bases. Lesions typi- rare autoimmune bullous disorder caused by circulating
cally spontaneously resolve within 1–3 weeks [52], with IgG autoantibodies directed against the 145‐kDa NC1
antibody negativization by around 1 month [53]. Babies domain of collagen VII. Only one case of transplacentally
are affected due to transfer of pathogenic antibodies to a acquired EBA has been reported in the literature to date.
subunit of bullous pemphigoid antigen (180 kDa). Apart This patient, born to a mother with a well‐known history
from the rare occurrence of neonatal blistering, pemphig- of EBA, presented at birth with generalized blisters and
oid gestationis has occasionally been associated with other erosions including nares and lips, while sparing the
complications such as adverse birth outcomes, including mucous membranes. At 2 months of age, lesions were
miscarriage, low birthweight and prematurity [48]. completely re‐epithelialized with the development of
numerous milia [46].
Neonatal pemphigus vulgaris
Neonatal pemphigus vulgaris is a rare transient autoim-
Transplacental melanoma
mune blistering disorder caused by the transfer of mater-
nal IgG autoantibodies against desmoglein 3 to the neonate Malignancies during pregnancy are calculated to occur
born from a mother with pemphigus vulgaris [54]. in one every 1000 pregnancies, with a frequency that
Antibody titres in the mother have ranged from 1 : 20 to parallels that of age‐matched nonpregnant women.
1 : 640, and several authors suggest that neither antibody These include breast, cervix, lung, melanoma and hae-
titres nor the clinical severity of the mother’s findings matological malignancies [58]. The estimated incidence
predict the severity of disease in the child. In fact, of all of melanoma during pregnancy is 0.1 to 2.8 per 1000
reported transient bullous transplacentally acquired pregnancies. Fetal metastases are rare, with around 100
dermatoses, only neonatal pemphigus has been reported in cases reported in the literature [59]. Melanoma is the
neonates born from clinically asymptomatic mothers [55]. most common neoplasm with transplacental transmission
It is clinically characterized by transient flaccid blisters to the fetus [60]. Given that 45% of melanoma patients
and erosions on the skin and, very rarely, the mucous are diagnosed in the first four decades of life, and with
membranes because of the compensatory expression of rates of melanoma rising over the last two decades, this
desmoglein 1 in infant mucous membranes. It may be incidence may rise [61].
present at birth or develop during the first 2 weeks of life. Lesions have been identified between birth and 8
It has never been reported to persist beyond the neonatal months of age [62], and they may appear as cutaneous
period or progress to adult disease [47]. Cutaneous lesions pigmented lesions or as internal metastases.
regress in less than 3 weeks and circulating antibodies are Although exceptional cases of spontaneous regression
not detected longer than 2 months after birth [53]. have been reported [58], most neonates with clinical evi-
Treatment may consist of supportive measures alone, dence of maternal metastasis at time of delivery have an
emollients or topical corticosteroids, depending on exceedingly poor prognosis. Death typically occurs before
severity. the age of 3 months. Placental involvement seems to be a
key risk factor among patients with no clinical evidence
Neonatal pemphigus foliaceus of metastasis at birth [62]; for that reason, the placenta
Pemphigus foliaceus (PF) is an autoantibody‐mediated should be evaluated in these cases, and all children born
epidermal blistering disease caused by antibodies against to mothers with evidence of placental involvement should
desmoglein 1 with loss of adhesion between superficial be evaluated and strictly monitored [58].
The diagnosis of metastatic melanoma in a child born Given that all cases of neonatal BD have been reported
to a mother with known metastatic melanoma seems among symptomatic mothers, and colchicine reduces the
straightforward when there are pigmentary lesions evi- risk of severe BD flares, the use of this drug could be
dent in a newborn from a mother with known metastatic considered as prophylactic therapy during pregnancy.
melanoma. In some circumstances where congenital Colchicine has an antimitotic effect and crosses the pla-
melanocytic naevi may appear clinically atypical and centa. The safety of this drug was evaluated in one study

might even show benign proliferative nodules with high in which 238 colchicine‐exposed pregnancies showed no
mitotic rates on the biopsy, the diagnosis of transplacental increase in teratogenicity or congenital abnormalities [67].
melanoma may be confirmed with the use of modern
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101
C HA PTER 9
Developmental Anomalies
Marion Wobser & Henning Hamm

Department of Dermatology, Venereology and Allergology, University Hospital Würzburg, Würzburg, Germany
Introduction, 101 Other abnormalities of the breast and Rudimentary (atretic, sequestrated)
Cutis verticis gyrata, 101 nipple, 107 meningocele, 112
Accessory tragi, 103 Developmental abnormalities of the Nasal glioma (nasal cerebral heterotopia), 112
Congenital cartilaginous rests of the neck umbilicus, 107 Congenital inclusion dermoid cysts, 113
(wattles), 103 Median raphe cysts and canals of the Cutaneous signs of occult spinal
Preauricular cysts and sinuses, 104 penis, 108 dysraphism, 114
Branchial cysts, sinuses and fistulae, 104 Infantile perineal (perianal) protrusion, 108 Aplasia cutis congenita (congenital
Congenital midline cervical cleft, 105 Precalcaneal congenital fibrolipomatous absence of skin), 116
Thyroglossal duct cysts, 105 hamartoma, 109 Amniotic constriction band (amnion
Cutaneous bronchogenic cysts, 105 Congenital smooth muscle rupture sequence), 118
Skin dimples, 106 hamartoma, 110 Congenital abnormalities of
Transverse nasal line, 106 Rhabdomyomatous mesenchymal dermatoglyphics, 119
Congenital lip pits, 106 hamartoma, 110
Supernumerary nipples (polythelia), 106 Cutaneous signs of cranial dysraphism, 111
Abstract of nature. However, some developmental abnormalities may be as-

sociated with severe underlying conditions, such as cranial or spi-
nal dysraphism, or complex syndromes, for example branchial arch
A multitude of developmental anomalies may affect the skin.
malformations. Hence, the purpose of the chapter is to enable the
Some of them are easily visible; others are unimpressive or hidden
specialist to differentiate between harmless variations and cutane-
and can therefore remain overlooked for a while. A few anoma-
ous markers of serious developmental failures. This knowledge is
lies, such as the transverse nasal line and precalcaneal congenital
of ultimate clinical importance as the latter may require rapid di-
fibrolipomatous hamartoma, are merely an insignificant variation
agnostic evaluation and treatment to prevent grave consequences.
• Early recognition of conspicuous cutaneous signs may help to

Key points prevent severe complications as is evidenced by spinal dysraphism.
• Cutaneous malformations often demand an interdisciplinary
• Developmental anomalies of the skin may be associated with diagnostic and therapeutic approach involving radiologists,
further clinical findings within a syndromal context. pathologists and surgeons.
Introduction of the brain. It has an estimated prevalence of 1 in 100 000

of the male and 0.026 in 100 000 of the female general pop-
Developmental anomalies of the skin comprise a rela- ulation. In psychiatric patients and mentally handicapped
tively large group of conditions that are caused by errors persons the condition is far more frequent with a reported
in embryonic development [1]. Fig. 9.1 demonstrates the prevalence of 0.2–12.5%.
typical site of some important anomalies on the head and
neck. Most of them are apparent at birth. This chapter Aetiology. CVG is not a disease entity but originates
focuses on characteristic minor abnormalities. Major from a multitude of diverse aetiologies. In primary (‘true’)
defects forming part of more complex malformation types underlying soft‐tissue abnormalities are lacking,
syndromes are mentioned in connection with particular apart from hypertrophy of connective tissue and adnexal
cutaneous features but are not presented in detail. structures [2]. The alteration may occur as an independ-
ent condition (primary essential CVG) or in association
Cutis verticis gyrata with a wide range of neurological and psychiatric disor-
ders, such as mental retardation, developmental delay,
Definition. Cutis verticis gyrata (CVG) is a descriptive cerebral palsy, epilepsy, microcephaly and schizophrenia
term that refers to the clinical appearance of ridges and (primary nonessential CVG) with or without ophthalmo-
furrows on the scalp resembling the convoluted surface logical changes (cataract, strabismus, blindness, retinitis
10
9 Predilection sites of
1 Accessory tragus
2 Preauricular sinus
3 4 3 Dermoid cyst
2 4 Nasal glioma
5
1 5 Transverse nasal line
6 Congenital lip pits
6 7 Congenital midline cervical cleft
8 Branchial cysts/sinus/fistulae
9 Aplasia cutis congenita
7 10 Cutis verticis gyrata
8
Fig. 9.1 A schematic diagram showing various sites of
developmental abnormalities over the face and neck.
pigmentosa) [3]. There is a strong association between dermal oedema, elastic fibre degeneration and hypertro-
CVG and chromosomal abnormalities and genetic phy of sebaceous glands are present within the context
syndromes (Turner syndrome, Klinefelter syndrome, of pachydermoperiostosis, possibly as a result of prosta-
Noonan syndrome, fragile chromosome syndromes, glandin‐mediated tissue effects due to mutations in pros-
Beare–Stevenson cutis gyrata syndrome, Ehlers–Danlos taglandin‐catalysing enzymes [5]. Histological changes in
syndrome, tuberous sclerosis, insulin resistance syndrome, secondary types depend on the underlying condition.
Apert syndrome and primary hypertrophic osteoar-
thropathy/pachydermoperiostosis) [4]. CVG in Turner
Clinical features. Primary CVG usually presents with
and Noonan syndrome is believed to result from regress-
symmetrical folds that run from anterior to posterior and
ing lymphoedema present in utero.
involve the vertex and occiput, only occasionally the
Secondary types (‘pseudo‐CVG’) result from local
entire scalp. Male patients are affected considerably more
inflammation (eczema, psoriasis, folliculitis, impetigo,
often with a ratio of 4–5 : 1. Onset is usually postpubertal
erysipelas, pemphigus, acne keloidalis, acne inversa),
with the vast majority developing after the third decade
neoplastic processes and hamartomas of the scalp (con-
of life. Congenital occurrence of primary CVG is extremely
genital or acquired intradermal melanocytic naevus,
rare [6]. If an underlying genetic abnormality is suspected,
sebaceous naevus, naevus lipomatosus, connective tissue
molecular genetic or cytogenetic studies are advised.
naevus, neurofibroma, fibroma, cylindroma) or from
In secondary types the clinical appearance is much
systemic illnesses (acromegaly, myxoedema, acanthosis
more variable, and the folds usually do not run in a
nigricans, diabetes mellitus, misuse of anabolic substances,
sagittal direction. Systemic and inflammatory conditions
amyloidosis, syphilis, chronic pulmonary diseases, con-
may present with mild corrugation of the entire scalp
genital cyanotic heart disease, hepatobiliary disorders,
whereas local neoplasms may produce irregular, cerebri-
leukaemia, paraneoplastic syndromes) or certain drugs.
form folding in a circumscribed area. Secondary types
occur at any age, reflecting the manifold causes. Cranial
Pathology. Histopathological examination of a scalp biopsy computed tomography (CT) or magnetic resonance
is mandatory to distinguish between primary and sec- imaging (MRI) may be indicated to rule out a pituitary
ondary types, especially to exclude neoplastic causes. adenoma and acromegaly or involvement of deeper
Findings in primary types range from essentially normal structures. Congenital secondary CVG is mainly caused
skin to thickened connective tissue with hypertrophy or by benign neoplasms such as an intradermal melano-
hyperplasia of adnexal structures. Mucin deposition, cytic naevus (see Table 9.1).
Table 9.1 Differences between primary and secondary cutis verticis gyrata
Primary cutis verticis gyrata Secondary cutis verticis gyrata
Clinical features Furrows and ridges in sagittal orientation Irregular furrows and ridges
Associated conditions • Genetic defects including chromosomal aberrations • Local inflammatory diseases
• Neurological/psychiatric disorders • Local hamartomas/neoplasias
• Sporadic • Systemic illnesses
Pathology Hypertrophy of connective tissue and adnexal structures Variable, depending on aetiology
Time of onset Second decade of life to adulthood, rarely congenital Variable, depending on aetiology
Sex Male predominance Equal sex distribution
Chapter 9 Developmental Anomalies 103
CVG is asymptomatic in most cases but may cause pru-

ritus, burning, tenderness, unpleasant odour or recurrent
infection. The texture and amount of hair are usually
unaffected in primary types whereas neoplastic lesions
may show progressive alopecia.

Treatment. Good skin and scalp hygiene with optional
application of topical antiseptics to deep furrows is rec-
ommended to avoid intertrigo and bacterial or mycotic
infection. Many conservative treatments have proved
ineffective in flattening the uneven surface. In spite of the
benign nature of CVG, elective surgery may be indicated
for psychological or aesthetic reasons. Possible interven-
tions include excision with primary closure or local flaps
in small lesions or partial resection, serial excision or tissue
expansion procedures for larger areas. In CVG within
the context of pachydermoperiostosis, inhibition of the
underlying pathogenetically relevant prostaglandin syn-
thesis may show benefit if carried out in early childhood.
Accessory tragi
Aetiology. Accessory tragi are minor developmental

abnormalities of the dorsal portion of the first (mandibu-
lar) branchial arch, which explains their location between
the pretragal and sternoclavicular areas.
Fig. 9.2 Accessory tragi in typical preauricular location.
Pathology. There is histological similarity to the normal

radial dysplasia and other limb defects) syndromes [8].
anatomy of the external ear. Numerous mature vellus hair
Multiple accessory tragi are a relatively constant finding
follicles are present in various phases of the hair cycle.
in the oculo‐auriculo‐vertebral (Goldenhar) syndrome
A prominent connective tissue framework encloses aggre-
featuring ear malformations, hemifacial microsomia, epi-
gates of mature adipose tissue. A central core of cartilage is
bulbar (lipo)dermoids and vertebral anomalies.
occasionally present, helping to distinguish an accessory
The accessory tragus should be differentiated from a
tragus from hair follicle naevus and trichofolliculoma.
macrotragus which shares its histopathological charac-
teristics but represents an enlarged, mostly anteriorly
Clinical features. Accessory tragi present as congenital displaced tragus in a normal anatomical position.
roundish, skin‐coloured papules or nodules, usually
located in front of the auricle (Fig. 9.2). Less common sites Treatment. Accessory tragi can easily be treated by surgical
include the cheek along the line of the mandible to the excision. Pedunculated papules may even be removed by
angle of the mouth, and the lateral neck anterior to the ligation or application of a titanium clip flush to the skin.
sternocleidomastoid muscle down to the suprasternal Care must be taken to remove any protuberant portion of
region. In a cervical location, they may be called wattles the underlying cartilage. Some authors advocate treat-
or congenital cartilaginous rests of the neck (see ment under local anaesthesia in the first days of life.
Congenital cartilaginous rests of the neck (wattles)).
The skin tags may be solitary or multiple, unilateral or
ongenital cartilaginous rests
C
bilateral, soft or cartilaginous, sessile or pedunculated.
of the neck (wattles)
They are often covered by vellus hairs. The incidence is
approximately 1 in 500–600 live births. Congenital cartilaginous rests of the neck (wattles) are
Usually, accessory tragi are isolated congenital defects rare, uni‐ or bilateral branchiogenic surplus malforma-
[7]. Familial occurrence has been reported. In rare tions that may be considered the cervical variant of acces-
instances, especially if multiple, they are associated with sory tragi [9]. An irregular, often pedunculated, papule or
other first branchial arch abnormalities, including cleft nodule of ‘springy’, cartilaginous texture is located over
lip, cleft palate, branchial fistulae and hypoplasia of the or near the lower half of the sternocleidomastoid muscle
mandible, and are an inconstant feature of the Treacher– (Fig. 9.3). Other malformations, such as microtia, stenosis
Collins, Wolf–Hirschhorn (4p deletion), Townes–Brocks, of the external ear canal and branchiogenic fistulae, are
Delleman and VACTERL (vertebral anomalies, anal atre- rarely associated. Differential diagnosis includes sentinel
sia, congenital cardiac anomalies, tracheo‐oesophageal tags associated with branchial sinuses or fistulae, simple
fistula and/or oesophageal atresia, renal anomalies, skin tags and benign papillomas. As congenital cartilaginous
Fig. 9.3 Bilateral congenital cartilaginous rests of the neck (‘wattles’). Fig. 9.4 Inflamed preauricular cyst and sinus.
homologue of the Drosophila eye absent (EYA1) gene.

rests of the neck are not cystic or fistulous, they can easily
Therefore, auditory testing and renal ultrasound are
be excised for cosmetic reasons.
regarded as imperative if a preauricular sinus is accompa-
nied by one or more of the following: other malformations
Preauricular cysts and sinuses or dysmorphic features, a family history of deafness,
auricular and/or renal malformations or a maternal history
Aetiology. Preauricular cysts and sinuses are believed to of gestational diabetes.
be the result of imperfect fusion of the sixth auditory In most cases preauricular sinuses remain asymptomatic,
hillocks of the first two branchial arches. Global preva- at least until adulthood. However, the seemingly trivial
lence seems to differ considerably (India, 0.17%; USA, and often unnoticed anomaly can give rise to troublesome
0.1–0.9%; England, 0.9%; China, 1.4%; Taiwan 1.6–2.5%; symptoms if infection occurs (Fig. 9.4). In this case, recur-
some areas of Africa, 4–10%) [10,11]. rent purulent discharge and preauricular abscesses causing
oedema, erythema and pain may develop.
Pathology. The cysts and sinuses are lined by stratified Ultrasound of underlying tissue is helpful to confirm
squamous epithelium. The adjacent connective tissue fre- the diagnosis and to determine the extent of the sinus and
quently contains skin appendages. After severe inflam- cysts and their relation to adjacent anatomical structures.
mation, the lining is often replaced by granulation tissue.
Treatment. If asymptomatic, a preauricular sinus does not
Clinical features. Preauricular sinuses usually present as require intervention. Cure of symptomatic sinuses is only
tiny pits or indentations at the anterior margin of the achieved by often difficult, meticulous complete excision
ascending limb of the ear helix (Fig. 9.4). Much less com- of the entire tract and its associated cysts. Thus, most
mon sites are the lateral surface of the helicine crus and authors recommend surgery only after preoperative anti-
the superior posterior margin of the helix, tragus or lob- biotic treatment. Nevertheless, postoperative recurrences
ule [12]. The sinuses may be unilateral, more frequently are reported to occur in 9–42% of cases. General anaesthe-
on the right side, or bilateral; they can be sporadic or sia, magnification employed during surgery, wide local
inherited. Bilateral occurrence is more likely to be heredi- excision with removal of cartilage at the base of the tract,
tary and transmitted as an autosomal dominant trait with demonstrating the sinus with dye injection, and probing
reduced penetrance and variable expression. The narrow at the time of surgery help to reduce the recurrence risk.
sinuses have a cutaneous opening and a blind inner end,
almost always connecting to the perichondrium of the
auricular cartilage. They may arborize, with a subcutane- Branchial cysts, sinuses and fistulae
ous network of cysts arranged around their tracts, and
rarely extend into the parotid gland. Aetiology. Branchial cysts, sinuses and fistulae result from
In 3–10% of cases, they are associated with deafness maldevelopment of the branchial apparatus, most often
and with several complex developmental defects, pre- the second branchial arch, during embryonic develop-
dominantly branchio‐oto‐renal (BOR) syndrome and ment. Familial occurrence has repeatedly been reported.
branchio‐otic (BO) syndrome. BOR and BO syndromes
are autosomal dominant conditions characterized by Pathology. The sinus tracts of branchial anomalies are
preauricular pits, conductive, sensorineural or mixed lined by stratified squamous epithelium, which may in
hearing loss, structural defects of the outer, middle or part be replaced by respiratory (ciliated columnar) epi-
inner ear, lateral cervical fistulae, cysts or sinuses, and thelium. There is often abundant subepithelial lymphoid
nasolacrimal duct stenosis or fistulae. Renal anomalies tissue. Thymic or thyroid tissue points to derivation from
are additional features of BOR syndrome [12]. Both syn- the third or fourth branchial arch, respectively. The pres-
dromes are frequently caused by mutations in the human ence of smooth muscle, cartilage and seromucous glands
in branchial arch remnants may lead to confusion with a Thyroglossal duct cysts
bronchogenic cyst (see Cutaneous bronchogenic cysts).
Thyroglossal duct cysts develop as a result of mucus pro-
Clinical features. External branchial sinuses and fistulae duction within an incompletely obliterated thyroglossal
are detectable as openings located on the lateral neck, at duct [16]. Most often, these cysts lie close to the hyoid
the anterior border of the sternocleidomastoid muscle. bone in or near the midline of the neck, but they may be
located at any site along the pathway of the thyroid

Sinuses end blindly in the deep neck tissue, while fis-
tulae have a continuous communication between skin anlage. They are the commonest cause of midline neck
and mucosa and may drain into the tonsillar area of the swellings in childhood and adolescence although a signifi-
pharynx. Cysts present as painless, mobile swellings and cant minority of cysts are not diagnosed before adulthood.
have neither a cutaneous nor a mucosal opening. The Typically, a painless soft mass of 1–2 cm diameter moves
external orifice of sinuses and fistulae may exude a upwards on swallowing and on protrusion of the tongue.
mucous secretion. Early secondary infection is frequent Less often, there may be a discharging sinus occurring
and may cause significant morbidity. Because of their spontaneously or after incomplete excision. Infection
obvious skin opening and associated drainage and infec- occurs with increasing frequency with age. To avoid infec-
tion, branchial sinuses and fistulae are usually diagnosed tious complications and malignant change, thyroglossal
much earlier than branchial cysts, most often in the first duct cysts should be excised early in life by resection of
few years of life [13]. the mid‐portion of the hyoid bone and en bloc cystectomy
Bilateral lesions are rare; preauricular pits may be an with a cuff of muscle around the duct to the base of the
associated finding. Branchial anomalies may form part of tongue (Sistrunk’s operation) [17]. Postoperative recur-
complex hereditary conditions, such as BOR syndrome, rence rates are in the range of 3–4%. Prior to surgery, the
branchio‐oculo‐facial syndrome and others. normal thyroid gland should be identified by appropriate
Diagnosis of branchial sinuses and fistulae is obvious imaging. On ultrasound, the cysts themselves show an
in light of the cutaneous opening in a typical location. unechoic, hypoechoic, pseudosolid or heterogeneous
In contrast, branchial cysts are part of the extensive pattern. CT, MRI and radioisotope thyroid scanning offer
differential diagnosis of lateral neck masses including more precise information about location, size and relation
lymphadenitis, abscess, lipoma, cystic hygroma, hae- to adjacent structures and together with fine‐needle
mangioma, lymphangioma, lymphoma, ectopic thyroid aspiration help to exclude differential diagnoses such
cyst, thyroglossal duct cyst and cervical thymic cyst [14]. as ectopic thyroid tissue, lipoma, lymphadenopathy
Radiographic imaging may be indicated to establish the and carcinoma. The ducts are frequently multiple and
diagnosis and assess the extension. branched. There are numerous cases reporting malig-
nancy arising in thyroglossal duct remnants with thyroid
Treatment. Due to the lack of spontaneous regression of
papillary carcinoma being by far the most common type
branchial anomalies and common recurrent infections, of associated neoplasm.
complete surgical removal under general anaesthesia
during the first year of life is the treatment of choice. Cutaneous bronchogenic cysts
The precise aetiology of cutaneous bronchogenic cysts
Congenital midline cervical cleft
is disputed. The more common cysts inside the thoracic
This rare congenital anomaly, most likely related to aber- cage are believed to originate from accessory buds that
rant fusion of the first or second branchial arches, is became sequestrated from the primitive tracheobron-
located in the anterior midline of the neck at any point chial tree or primitive foregut. This concept also fits for
between the mandible and the sternum [15]. The charac- presternal cysts that may develop after the intervention
teristic clinical presentation consists of a cephalic nipple‐ of fusing sternal bars, but it is unlikely for bronchogenic
like projection (‘skin tag’) with the inferior margin being cysts in ectopic locations such as the shoulder and scap-
formed by a short sinus of about 1 cm length and an ular regions. Transplantation via lymphatic or haematog-
atrophic mucosal surface dividing the two. An underly- enous routes, metaplasia and maldifferentiation of
ing fibrous cord may impair the movement of the head epithelial components to ciliated epithelium are other
and neck and cause webbing. The cleft is covered by possibilities.
stratified squamous epithelium lacking skin append- In most cases, the lesion becomes evident within the
ages while the sinus tract is usually lined by pseu- first days of life as a swelling or as discharge on the lower
dostratified columnar epithelium and often contains neck, the anterior upper chest near the suprasternal notch
seromucinous salivary glands. The abnormality may be or over the manubrium sterni. Chin, shoulder, scapular
isolated or associated with a broad spectrum of midline region, back and abdomen are less common sites [18].
defects, such as median cleft of the mandible, tongue There is no connection to underlying structures. Males are
and lower lip. Complete excision of the anomaly with predominantly affected. Histological examination of
the underlying fibrous tract within the first year of life is bronchogenic cysts typically reveals a lining of ciliated
critical to avoid scarring contracture and mandibular and mucin‐producing pseudostratified columnar epithe-
deformities. The surgical defect is usually closed with lium of respiratory type. Excision is recommended to pre-
multiple Z‐plasties. vent infection and malignant transformation.
Skin dimples within the oral cavity at the angle of the mouth and rep-
resent the openings of bilateral, short and blind‐ending
Skin dimples are unilateral or more often bilateral deep sinuses. They are frequently inherited as an isolated
cutaneous depressions commonly seen over bony autosomal dominant anomaly, but may be a feature of
prominences, such as the acromial process of the scapula, the BOR syndrome, associated with branchial, hearing
os sacrum, elbow, patella and tibia [19]. They are thought and renal anomalies. Furthermore, commissural lip
to be caused by early entrapment‐induced fixation of the
pits have been described in association with alveolar

skin to the underlying bony prominence, thus preventing synechia, ankyloblepharon filiforme adnatum and
the development of subcutaneous tissue. ectodermal defects.
Usually, skin dimples are an isolated congenital finding In midline sinus of the upper lip, the opening of a
and, as in the case of bilateral acromial or shoulder blind‐ending sinus tract is seen in the midline of the
dimpling, also known as ‘supraspinous fossae’, may upper‐lip philtrum. Hypertelorism, nasal fistula and lip
represent a harmless autosomal dominant anomaly. fistula may be associated.
However, bilateral acromial dimples have also been Congenital lower‐lip pits result from a fusion defect of
reported as a relatively constant feature of the 18q dele- the lower part of the first branchial arch. They usually
tion syndrome, and as an occasional finding in trisomy 9p present as bilateral, symmetrical depressions on the ver-
syndrome, Russell–Silver dwarfism and Say syndrome. milion portion of the lower lip on each side of the midline.
An association of subacromial dimples with recurrent The orifices represent the endpoints of blind sinuses that
posterior dislocation of the shoulder has been postulated. extend inwards into the orbicularis oris muscle to a depth
Dimples overlying the tibia are seen in camptomelic of up to 20 mm or more and may bifurcate. The tracts are
dwarfism, oral–facial–digital syndrome and osteoglo- lined by stratified squamous epithelium. If there is a com-
phonic dysplasia. Dimples over elbows and knees have munication with the ducts of the nearby minor salivary
been observed in prune belly syndrome, Joubert syndrome glands, saliva or mucus may be discharged. Occasionally,
and facial clefting syndrome. Midline sacral dimples only a single paramedian or median sinus may be pre-
are an inconstant minor feature of various congenital sent. Labial conical elevations without fistulous ostia are
malformation syndromes including spinal dysraphism, believed to represent the microform of the anomaly.
especially when they are large, more than 2.5 cm away Congenital lower‐lip pits are the hallmark of Van der
from the anus or combined with other lesions. Sporadic Woude syndrome, an autosomal dominant craniofacial
cases of skin dimpling have been described in association disorder with high penetrance and variable expressivity
with congenital rubella, hypophosphatasia and misoprostol characterized by lower‐lip pits, cleft lip/palate and
exposure in utero. Dimple‐like scars are not uncommon other inconstant features such as hypodontia or diverse
after amniocentesis. malformations [24]. They are also a characteristic
feature of the popliteal pterygium syndrome (popliteal
Transverse nasal line webs, cleft lip and/or cleft palate and anomalies of the
genitourinary system). Van der Woude syndrome and
The transverse nasal line runs transversely across the skin popliteal pterygium syndrome are allelic conditions
between the upper two‐thirds and lower third of the caused by diverse mutations of the gene encoding the
nose. The clinical appearance varies from a faint reddish interferon regulatory factor 6 (IRF6) [25]. Therefore,
to hyperpigmented line to a more visible groove or crease genetic counselling has to respect the considerable
with a depth and width of up to several millimetres [20]. phenotypic variation and overlap of the two conditions.
It appears early in life and often remains indefinitely. Furthermore, lower‐lip pits are a facultative sign of the
There is a clear familial predisposition, and females seem orofaciodigital syndrome type 1 and the Kabuki make‐
to be affected more often. up syndrome.
Distinct growth kinetics of the alar and triangular The only treatment for symptomatic or unpleasant lip
cartilages of the nose are presumed to be pathogeneti- pits is surgical excision, ensuring complete removal of the
cally relevant. The transverse nasal line may be associ- often bifurcating tracts.
ated with milia, cysts and comedones. Inflammation may
lead to ‘pseudoacne of the nasal crease’ [21].
The transverse nasal line has to be distinguished from Supernumerary nipples (polythelia)
the nasal crease or wrinkle developing in patients with With a prevalence of 0.2–5.6%, supernumerary nipples
allergic rhinitis as a response to frequently rubbing the (polythelia) are the most frequently encountered congeni-
nose upward for relief of itching (the ‘allergic salute’) [22]. tal abnormality of the breast. They are remnants of the
embryological milk line which runs from the anterior
axillary fold to the inner thigh. Most often, they are
Congenital lip pits
located on the chest wall and upper abdomen and present
Congenital lip pits can be divided into three types: com- as small brown or pink, umbilicated or elevated papules
missural pits, midline sinuses of the upper lip, and lower surrounded by a pigmented areola (Fig. 9.5) [26]. A nipple
lip pits (lip sinuses) [23]. may also be seen without an areola, and vice versa.
Commissural pits are the commonest type of lip pits, Usually there is only a single lesion, but multiple and
found in about 0.5–2% of neonates. They are located bilateral nipples are possible.
include ectodermal dysplasia, Al Awadi–Raas‐Rothschild

syndrome (absence or severe hypoplasia of skeletal parts
of the limbs), Poland syndrome choanal atresia–athelia
syndrome, scalp–ear–nipple syndrome, and ADULT
(acro‐dermato‐ungual‐lacrimal‐tooth) syndrome [28].
Athelia is believed to be caused by a failure in parathy-

roid hormone‐related protein production.
Unilateral absence (amastia) or hypoplasia (hypomastia)
of the breast and nipple is most often a feature of Poland
syndrome. This congenital anomaly consists of a spec-
trum of congenital deformities of the chest wall, breast
and upper extremity. Unilateral absence of the sternocos-
tal head of the pectoralis major muscle is the indispensa-
ble prerequisite for diagnosis. In addition, amastia or
mild hypoplasia of the breast, athelia or abnormal nipple,
scarcity of subcutaneous tissue over the pectoral region,
absence of the pectoralis minor muscle, deficiency of
additional chest wall muscles, aplasia/deformity of costal
cartilages or anterior ribs II–V, alopecia of axillary and
mammary regions, and ipsilateral hand anomalies (brach-
ysyndactyly, syndactyly, hypoplasia of middle phalan-
ges) may be present. Less frequent associated defects
include renal malformations, dextrocardia and vertebral
abnormalities. Poland syndrome is thought to be caused
Fig. 9.5 Supernumerary nipple in a male adolescent. by interruption of the embryonic blood supply to the
upper limb bud in the sixth week of gestation with
Familial occurrence without further anomalies suggest- consecutive hypoplasia of the subclavian artery. It occurs
ing autosomal dominant transmission has been observed. in about 1 out of 25 000 live births, mostly sporadically
Polythelia may present within a syndromal context, such and mainly in males. Evaluation of the vascular status is
as part of the Becker naevus syndrome, the X‐linked mandatory prior to reconstructive breast surgery.
Simpson–Golabi–Behmel syndrome or in association Ipsilateral hypoplasia of the breast, areola and/or
with malformations of the urinary tract or with haemato- nipple is the most frequent anomaly in Becker naevus
logical disorders. syndrome. Other associated features include supernumer-
Accessory nipples are occasionally mistaken for mel- ary nipples, scoliosis, vertebral anomalies and shortening
anocytic naevi [27]. They should also be differentiated or other forms of asymmetry of the upper limbs due to
from unilateral or bilateral intra‐areolar polythelia with hypoplastic soft tissue [29]. Hypomastia has also been
two or more nipples located within the areola, caused observed in conjunction with naevus depigmentosus and
by intrauterine division (dichotomy) of the developing phacomatosis cesioflammea in individual cases.
nipple. Excision may be indicated for diagnostic or While functional deficits of the breast and nipple
cosmetic reasons. deformities may need early intervention, final aesthetic
surgery should be postponed until after puberty to obtain
an optimal cosmetic outcome respecting the symmetry of
ther abnormalities of the breast
O
the chest anatomy.
and nipple
Accessory breast tissue (polymastia) may underlie a super-
numerary nipple and usually becomes evident only after
Developmental abnormalities
hormonal stimulation at puberty or in pregnancy.
of the umbilicus
Supernumerary breasts are located along the primitive A variety of congenital umbilical lesions result from
milk line with the axilla being a particularly common site complete or partial failure of obliteration of two embryo-
where they can be mistaken for lymphadenopathy or logical structures: the omphalomesenteric (vitelline) duct
lipoma. Comparable to polythelia, polymastia can be and the urachus. The clinical features depend upon the
associated with other, especially renal, anomalies. Fine‐ site and extent of patency of these structures [30].
needle aspiration may serve as a useful tool for diagnosis. A completely patent omphalomesenteric duct is exceed-
Complete excision of ectopic breast tissue is recom- ingly rare and leads to a fistula between the ileum and
mended due to the risk of malignant transformation [27]. umbilicus. The anomaly is noted soon after birth by faecal
Athelia is defined as congenital complete absence of the discharge severely irritating the adjacent skin. Infections
nipple–areola complex and may be unilateral or bilateral. and sudden ileal prolapse through the umbilicus may
The rare anomaly is almost always combined with complicate the anomaly; the latter represents a surgical
amastia (absence of the breast and nipple) within the emergency because of the danger of strangulation and
frame of syndromic developmental disorders. These necrosis of the affected bowel.
A partially patent omphalomesenteric duct gives rise

to an umbilical polyp of bright‐red colour (remnant
of the peripheral portion), an umbilical sinus (patency of
the peripheral portion) or a vitelline cyst (patency
of the intermediate portion). The last is usually
asymptomatic whereas polyps and sinuses mostly dis-
charge serous or mucinous fluid shortly after birth.

This distinguishes the umbilical polyp from the most
important differential diagnosis, granuloma pyogeni-
cum, which usually has no secretion. Polyps and cysts
are frequently accompanied by potentially serious
internal omphalomesenteric remnants, such as Meckel’s
diverticulum attached to the umbilicus by obstructing
fibrous bands.
A completely patent urachus leads to fistula between
the urinary bladder and umbilicus. It presents soon after
birth by leakage of urine from the abnormal‐appearing Fig. 9.6 Median raphe cyst.
umbilicus, which may cause irritation of periumbilical
skin. An umbilical tumour that may be confused with
pyogenic granuloma and infection of the genitourinary edian raphe cysts and canals
M
tract may occur. of the penis
A partially patent urachus may result in an umbilical Median raphe cysts and their more elongated variants,
urachal sinus (patency of the peripheral portion) or a ura- called raphe canals, are located in a midline position
chal cyst (patency of the intermediate portion). Unless along the genitoperineal raphe anywhere from the ure-
large or infected, they present as asymptomatic cystic thral meatus to the anus but most commonly on the distal
swellings. Adenocarcinoma of the urachus may rarely portion of the penis (Fig. 9.6) [32]. They present as well‐
occur in later life and has a poor prognosis. circumscribed, freely mobile, solitary or multiple cystic
The diagnosis of developmental anomalies can be veri- lesions. On rare occasions, they may be pigmented or
fied by radiographic imaging, especially ultrasound and appear as a perianal polyp. Histologically, they are lined
sinography, and histological demonstration of ectopic with pseudostratified columnar or less often stratified
gastrointestinal or bladder transitional epithelium cover- squamous epithelium, mimicking the epithelial lining of
ing polyps or lining sinuses and cysts. the male urethra and suggesting derivation from urethral
Umbilical enteric and urinary fistulae are absolute or genital folds [33]. Mucous glands may be present.
indications for surgical intervention [31]. Simple exci- Most median raphe cysts and canals remain asympto-
sion of umbilical polyps should be performed only if matic. Medical attention is sought in the first three
underlying intestinal and urinary tract anomalies are decades of life for secondary infections of staphylococcal
ruled out. More often, the lesion has to be completely or gonococcal origin, injury or discomfort upon inter-
excised together with the attached part of the bladder course, or for cosmetic reasons. Simple excision with
or bowel. Total resection of the umbilicus is usually not primary closure is effective because there is no communi-
required. cation with the urethra.
Umbilical anomalies may also form part of complex
malformation syndromes. Redundant periumbilical skin
extending along the cord for an excessive distance is a Infantile perineal (perianal) protrusion
characteristic feature of Rieger syndrome, an autosomal
dominant disorder of morphogenesis. Recognition of Definition. Infantile perineal protrusion (IPP) is a harm-
the umbilical stump abnormality enables early diagno- less, often congenital, soft‐tissue lesion on the perineal
sis of associated glaucoma due to goniodysgenesis median raphe of prepubertal children, mostly girls [34].
(abnormal development of the anterior chamber angle of
the eye) and may prevent blindness. Lozenge‐shaped Aetiology. Classification into three different types has
diastasis around the umbilicus and umbilical depression been proposed. The constitutional type is considered to
occur within the scope of the autosomal recessive so‐ result from constitutional weakness of the median raphe
called 3MC syndrome (Malpuech–Michels–Mingarelli– or perineum of females or a remnant of a projected tip of
Carnevale syndrome). Umbilical hernia and abnormal the urogenital septum; it may be familial and/or congeni-
umbilicus are signs of the autosomal dominant Robinow tal. The functional type is related to bowel irregularities
syndrome. Ventral developmental defects, such as (diarrhoea, constipation) or other irritant exposure. A
sternal clefting or supraumbilical abdominal raphe, may third type is associated with genitoanal lichen sclerosus.
be associated with posterior fossa brain malformations,
large or complex haemangiomas of the face, arterial Pathology. The epidermis and dermis are essentially
anomalies, cardiac anomalies and eye abnormalities normal. Inflamed lesions may show acanthosis, vacuo-
(PHACES association). lar changes in basal keratinocytes, thickening and/or
Precalcaneal congenital
fibrolipomatous hamartoma
Definition. Precalcaneal congenital fibrolipomatous

hamartoma (PCFH) is a harmless nodular anomaly on
the medial plantar aspects of infants’ feet. It has been

described under various terms, including bilateral con-
genital adipose plantar nodules, benign anteromedial
plantar nodules of childhood, bilateral congenital fatty
heel pads, pedal papules in the newborn, congenital pie-
zogenic‐like pedal papules, hypertrophic infantile pedal
papules and congenital fibrolipomata.
Aetiology. The exact aetiology is unknown. PCFH has

been speculated to result from hamartomatous formation
of fat and connective tissue, secondary to incomplete
involution of the physiologically abundant fetal subcu-
taneous plantar tissue, or from herniation of fatty tissue
through congenital defects in the plantar fascia and the
trabecular fibroconnective system of the sole [36]. Rare
familial observations favour a genetic cause.
Fig. 9.7 Infantile perineal protrusion. Although PCFH is considered to be uncommon, a
systematic investigation found an incidence of 5.9% in
newborns and of 39.4% in infants [37]. Underreporting
elongation of the rete ridges, upper dermal oedema,
may be attributed to the small size and the lack of symp-
dilatation of capillary and lymph vessels and mild infil-
toms in most cases.
tration of neutrophils and eosinophils. Histological
signs of lichen sclerosus may be associated.
Pathology. Histological examination reveals lobulated,
Clinical features. The anomaly presents as a single, soft, mature adipose tissue protruding into the reticular
skin‐coloured or reddish papule or nodule with a smooth dermis, enveloped by fibrous septa. Blood vessels may
or slightly velvety surface and resembles an outward probe prominent. Mucinous deposits have been described
jection of essentially normal, redundant skin (Fig. 9.7). It at the periphery of the lesion and within fat lobules.
is usually located along the midline of the perineum ante-
rior to the anus, only exceptionally posterior to it or both. Clinical features. PCFH usually presents as soft, flesh‐
IPP is almost exclusively seen in girls [35]. Mechanical coloured, painless nodules of 5–10 mm symmetrically
irritation of wiping after defaecation and constipation located on the medial posterior aspects of the soles, just
may cause swelling, inflammation or fissuring, and anterior to the heels of an infant (Fig. 9.8) [38]. Unilateral
induce pain. Spontaneous regression is common in the occurrence and extension onto the heel area are rare. The
functional type, in contrast to only gradual involution in lesions are present at birth or appear in the first few
the constitutional and lichen sclerosus‐associated types. months of life, grow in proportion to the growth of the
infant and are most prevalent at about 1 year of age. They
Differential diagnosis. Skinfolds, haemorrhoids, acro- tend to disappear at 2–3 years of age, but can persist
chordons, midline malformations, genital warts, sentinel
tag of anal fissure, granulomatous lesions of inflamma-
tory bowel disease, haemangioma and rectal prolapse
may be considered in the differential diagnosis [35].
Misinterpretation as a sign of sexual abuse has to be
avoided.
Treatment. The child’s anal region should be wiped

clean from anterior to posterior to avoid inflammation.
Inflamed lesions respond rapidly to topical corticosteroids
whereas the outcome of the lichen sclerosus‐associated
type is determined by the course of the underlying der-
matosis. A fibre‐rich diet and hydration are recommended
in case of associated constipation. As most lesions are
asymptomatic and tend to regress spontaneously, surgical
excision is rarely required. Fig. 9.8 Precalcaneal congenital fibrolipomatous hamartoma.
considerably longer. They almost never cause functional

Differential diagnosis. The clinical diagnosis is difficult
problems, such as interference with standing and walking.
as specific diagnostic criteria are lacking and clinical
There are no reports of associated malformations.
findings are nonspecific. However, histology allows clari-
fication. CSMH should be suspected in any congenital
Differential diagnosis. In contrast to PCFH, piezogenic hairy lesion, especially in the lumbosacral area. Differential
papules usually develop in adulthood, are multiple and diagnosis includes congenital melanocytic naevus, Becker
smaller, and accentuate with standing. Further differen- naevus, connective tissue naevus, epidermal naevus, café‐
tial diagnoses include juvenile plantar fibromatosis, au‐lait spot, leiomyoma and mastocytoma.
fibrolipomatous hamartoma of the plantar nerve, lipoma,
naevus lipomatosus, haemangioma, neurofibroma, con-
genital solitary histiocytoma, lymphatic malformation, Treatment. No treatment is necessary.
calcified nodules after repeated heel sticks and focal
dermal hypoplasia [36]. Rhabdomyomatous mesenchymal
hamartoma
Treatment. In almost all instances treatment is not
required and parents should be reassured about the harm- Definition. Rhabdomyomatous mesenchymal hamartoma
less finding with high propensity for rapid spontaneous (RMH), originally termed striated muscle hamartoma, is
involution. Surgical excision should be confined to cases a rare congenital lesion of the dermis and soft tissues con-
of persistent tenderness or impairment of walking. sisting of a disordered and varied collection of mature
skeletal muscle and other mesenchymal tissues.
Congenital smooth muscle hamartoma
Aetiology. The aetiology is unknown. Aberrance in the
Definition and aetiology. Congenital smooth muscle embryonic migration of mesodermally derived tissues, in
hamartoma (CSMH) originates from smooth muscle particular skeletal muscle, has been suggested. RMH pre-
fibres of the musculi arrectores pilorum. dominantly affects areas of superficially located striated
muscles that are derived from the second branchial arch.
Pathology. Histological examination shows a focal prolif-
eration of large, mature, well‐demarcated bundles of Pathology. The central part of the lesion contains dermal
smooth muscle fibres in the reticular dermis which may and subcutaneous bundles of haphazardly arranged stri-
extend to the subcutaneous tissue. The bundles are ated muscle fibres admixed with varying amounts of fat,
haphazardly arranged and interwoven. fibrous tissue, blood vessels and nerves. It is surrounded
by multiple adnexal elements, such as vellus hair follicles
and sebaceous and eccrine glands.
Clinical features. CSMH is usually present at birth or
noted shortly thereafter with an estimated prevalence of
0.5–1 per 1000–2700 live births. Clinical features. Most often, RMH is noted at birth as a
The most frequent presentation of the congenital variant solitary, sporadic lesion in or near the midline of the head
is a single skin‐coloured or slightly hyperpigmented, or neck, in sites where striated muscles are superficially
indurated plaque, often with prominent vellus hairs. It located. Unusual sites include oral cavity, perianal or
occurs on the trunk, particularly the lumbosacral area, or genital area, and digit. The flesh‐coloured, firm, non-
the extensor surfaces of the thighs, more rarely on arms, tender lesion may present as a papillomatous, polypoid
face or mammary region. Another manifestation is an or pedunculated papule or nodule or, less commonly, as a
area of studded follicular papules without prominent sessile plaque or subcutaneous mass. It hardly changes
hairs. Occasionally, large areas may be involved. Stroking in size and appearance over time. Rarely, spontaneous
the lesion often produces transient elevation with pilo- telescopic and retractile movements of the ‘skin tag’ may
erection (pseudo‐Darier sign) [39]. Sometimes, worm‐like be noted. There are few cases with multiple lesions.
movements owing to involuntary contraction of the In about one‐quarter of reported RMH cases associ-
arrector pili muscles may be elicited (myokymia) [40]. ated congenital abnormalities have been observed.
Multiple lesions are rare. Generalized forms may These include ocular abnormalities, preauricular sinuses,
present with follicular dimpling and excess skin folds, nasofrontal meningocoele, dermoid cyst, thyroglossal
representing one of the causes of the striking ‘Michelin duct sinus, haemangioma, cleft lip and palate, and more
tyre baby’ phenotype. They may be associated with complex malformation syndromes such as amniotic
psychomotor and growth retardation, epilepsy, ingui- band syndrome and oculocerebrocutaneous (Delleman)
nal hernia, joint hypermobility, skeletal, dental and syndrome (absent corpus callosum, colobomas, orbital
other anomalies [41]. cysts, porencephalic cysts and facial skin tags) [42].
The clinical course of CSMH is benign. In most lesions,
induration, hyperpigmentation and hypertrichosis Differential diagnosis. RMH lesions may be clinically or
diminish with age. Malignant transformation has not pathologically mistaken for accessory tragi, congenital
been observed. midline cervical cleft, nasal glioma, fibrous and other rare
hamartomas of infancy, fetal rhabdomyoma, naevus

lipomatosus superficialis, benign Triton tumour, acro-
chordon, infantile myofibromatosis and smooth muscle
hamartoma [43]. Histological examination establishes
the correct diagnosis.

Treatment. Simple excision is sufficient. Removal of
plaque‐type variants or other atypical presentations is not
obligatory because malignant transformation has never
been observed. Systemic evaluation of patients is advisable
because of possible associated anomalies.
Cutaneous signs of cranial dysraphism
Definition. The terms cranial dysraphism and cranial

neural tube defect summarize developmental defects of
Fig. 9.9 Hair collar sign, associated with rudimentary meningocoele.
the central nervous system due to failure of normal
midline fusion [44]. Neural tube defects may occur as
an isolated anomaly but also form part of many syn- of congenital nontraumatic scalp nodules are supposed to
dromes and chromosomal aberrations. connect to the underlying central nervous system.
Cephalocoele is the general term for a congenital herni- Additional cutaneous stigmata of cranial dysraphism
ation of intracranial structures through a scalp defect. [3,45] include capillary malformations and large haeman-
An encephalocoele or meningoencephalocoele contains giomas, cutaneous dimples, dermoid cysts and dermal
both meninges and brain tissue, and the sac content sinuses. The latter are 1–5 mm tracts in the midline of the
communicates with cerebrospinal fluid through the bony nose (see Nasal glioma (nasal cerebral heterotopia)) or
defect. A meningocoele is a scalp herniation in which the occipital scalp, connecting a dermoid cyst to the skin sur-
sac contains only meninges and cerebrospinal fluid. For face. They may not be noticed until infection occurs and
neural tube defects in which the central nervous system pus drains from the orifice. Communication with the
connection has been ablated and the underlying bone central nervous system implies the risk of meningitis.
defect has healed, various terms are in use including cuta- Of special significance are circumscribed abnormalities
neous neural heterotopia, heterotopic or ectopic brain tis- of hair growth. The so‐called hair collar sign (Fig. 9.9) is
sue and rudimentary, atretic or vestigial encephalocoele/ characterized by a ring of coarse, long, dark hair encircling
meningocoele. a bald nodule, plaque or patch [46]. It is found around
encephalocoeles and meningocoeles as well as around
Aetiology. Cranial and spinal dysraphism result from their rudimentary counterparts. A tuft of hair may have the
genetic, environmental and dietary factors. In contrast to same implication. Lesions surrounded by a hair collar are
what was formerly believed, neural tube closure initiates most often located at the vertex or parietal regions. About a
at several, probably five, separate sites representing the third of them are associated with an underlying skull defect
clinical ‘hotspots’ of dysraphism. Specific genes may con- [47]. Coexistence of the hair collar sign and a capillary
trol individual closure sites. Reduced red blood cell folate malformation around a congenital scalp lesion is a highly
levels are associated with a higher risk of open neural indicative cutaneous marker of cranial dysraphism [48].
tube defects. Rudimentary meningocoele and nasal glioma are dis-
cussed in more detail later in the chapter.
Clinical features. Large encephalocoeles and meningo-
coeles are noted at birth and usually do not come to the Differential diagnosis. Cephalocoeles may be mistaken
attention of dermatologists. for dermoid and epidermoid cysts, a haemangioma, lipo-
Smaller or rudimentary encephalocoeles and menin- blastoma or lipoma, naevus psiloliparus, pilomatricoma,
gocoeles may be mistaken for cutaneous tumours or may eosinophilic granuloma or cephalohaematoma. The exact
be inconspicuous enough to go unnoticed for a time. nature of the cephalocoele has to be defined by cranial
Usually, minor forms of cranial dysraphism present as a imaging, especially MRI. Bony defects vary greatly in size
soft, cystic, compressible nodule of variable size with a from large, obvious defects easily demonstrated radiologi-
bluish translucent or glistening surface in the midline of cally to small defects evident only on surgery. Elevation of
the frontal, parietal or occipital scalp or 1–3 cm lateral to α‐fetoprotein in maternal serum, a well‐established marker
it. The base of the nodule often has an oval shape and of neural tube defects, is found only in open subtypes.
smooth boundaries. The malformation increases in size
on agitation of the neonate. Occasionally, the lesion may Treatment. Surgical correction of neural and – if necessary –
flatten to an atrophic, parchment‐like, well‐marginated bony structures with plastic reconstruction is the treatment
scar during the first months of life. Between 20% and 37% of choice for all cephalocoeles.
udimentary (atretic, sequestrated)

R evaluation including appropriate radiological imaging
meningocoele is required.
Definition. Rudimentary meningocoele is a develop-

mental anomaly in which meningothelial elements are asal glioma (nasal cerebral
N
found ectopically in the skin or subcutis without an heterotopia)
overt underlying bone defect.

Definition. Nasal cerebral heterotopia denotes a benign
mass of heterotopic, mainly glial, brain tissue at the nasal
Aetiology. As discussed previously, rudimentary menin- root thought to arise from the abnormal extracranial
gocoele is regarded as a remnant of a neural tube defect sequestration of neural elements during embryogenesis
with abnormal attachment of the developing neural tube to [50]. The term ‘nasal glioma’ is sensu stricto a misnomer in
the skin [49] displaying a continuous spectrum with true that it implies an underlying neoplastic condition with
meningocoele. A few familial cases have been observed. malignant potential.
Pathology. Histological diagnosis is difficult as changes Aetiology. In most cases, a portion of neuroectodermal
are often subtle and meningothelial cells may be mistaken tissue is sequestrated by closure of the craniofrontal
for vascular elements or connective tissue. In the dermis sutures, equivalent to an encephalocoele that has lost
and subcutis a variably dense collagenous stroma con- its intracranial attachment. If closure is incomplete, as
tains scattered strands and small aggregates of menin- it is in 15–25% of cases, a vestigial stalk of fibroglial tissue
gothelial cells lining pseudovascular spaces. The ovoid to remains attached to the neuroectodermal mass through
spindle‐shaped cells have a scant eosinophilic cytoplasm the foramen caecum.
with indistinct cell borders and small oval nuclei with
finely stippled chromatin. Calcification may be present.
Immunohistochemical examination applying a panel of Pathology. Histologically, nasal gliomas are composed
antibodies is necessary to assess lineage and confirm the of nonencapsulated islands of astrocytes and neuroglial
meningothelial derivation. fibres, embedded in varying amounts of fibrovascular
connective tissue stroma [51]. The glial cells stain posi-
tively with antibodies to glial fibrillary acidic protein
Clinical features. The congenital malformation is and S100 protein. Multinucleated giant astrocytes and
observed at birth or in the first few months of life. The gemistocytic astrocytes are often present with a variable
clinical presentation is highly variable, ranging from a inflammatory infiltrate. Occasionally, focal calcifications
dimple, a bald patch, a pink papule or a soft cystic are present. In some cases, definitive distinction from
nodule to an exophytic mass up to several centimetres in encephalocoele is not possible on histological grounds.
diameter. However, most lesions are small and are usu-
ally located over the posterior scalp or cranial suture
lines. The posterior trunk axis and forehead are less Clinical features. Nasal gliomas are slightly more
common sites. Rarely, more than one lesion is noted. common in boys than in girls. There is no familial pre-
Rudimentary meningocoele may be accompanied by disposition and malignant degeneration has never been
abnormalities of hair growth, such as a ‘hair collar’ (see reported.
Fig. 9.9), hair tuft or (annular) alopecia. In the majority of Extranasal (60%), intranasal (30%) and combined cases
cases, no underlying skull defect is present. However, (10%) can be distinguished. Extranasal gliomas are
minor rudimentary bony defects, a fibrous tract connect- usually recognized at birth. They present as a smooth,
ing to the dura or other evidence of residual communica- firm, nontender, noncompressible, nontransilluminating
tion to the meninges may occasionally be identifiable in nodule or mass at the root of the nose, often located to
imaging studies or during surgery and point to their one side of the midline. More unusual sites include the
pathogenetic mechanism. junction of the bony and cartilaginous portions of the
nose, and between the frontal, nasal, ethmoid and lacri-
mal bones [50]. The overlying skin may be red, bluish or
Differential diagnosis. Clinically, other types of cranial telangiectatic. In contrast to encephalocoeles, the bulge
dysraphism, aplasia cutis congenita, congenital dermal does not pulsate or expand with straining and crying, or
sinus, dermoid cyst, epithelial and sebaceous naevus, when the jugular vein is compressed (negative Furstenberg
vascular naevi and tumours, lipoblastoma and lipoma, test) [52]. Bilateral occurrence is very exceptional.
neurofibroma and meningioma may be taken into account. Intranasal gliomas are seen as a polypoid mass pro-
Histological differential diagnosis mainly includes classical truding from a nostril or, more commonly, within the
meningocoele, secondary cutaneous meningioma, endothe- nasal cavity or nasopharynx. Nasal obstruction with
lial neoplasms and giant cell fibroblastoma. breathing and feeding difficulties and rhinorrhoea may
result [53].
Treatment. Rudimentary meningocoele is usually cured Although benign, the mass may cause substantial
by complete local excision. To exclude any communica- deformity and displacement of the nasal skeleton.
tion to the central nervous system, careful preoperative In cases with intracranial communication, leakage of
cerebrospinal fluid with consecutive meningitis or Congenital inclusion dermoid cysts

encephalitis may occur.
Aetiology. Congenital inclusion dermoid cysts result
Differential diagnosis. Congenital midline nasal masses from the entrapment of skin and adnexal structures along
occur in one in about 20 000–40 000 live births. Differential the lines of embryonic fusion. Although usually sporadic,
diagnosis includes numerous lesions (Box 9.1), of which several familial cases in frontonasal, epibulbar and exter-

dermoid cysts, haemangiomas, nasal gliomas and enceph- nal angular sites have been reported. Inclusion dermoid
alocoeles are the most frequent [54]. cysts have to be distinguished from epidermoid and
trichilemmal cysts, and from the more complex ovarian
Treatment. Biopsies and any partial nasal interven- ‘dermoids’, which represent benign cystic teratomas com-
tions should be avoided. Prior to surgery, a thorough prising entodermal, ectodermal and mesodermal tissue.
radiological evaluation is mandatory, also for differ-
entiation from other congenital nasal masses [55]. Pathology. Dermoid cysts are located in the subcutis
Ultrasound and Doppler flow studies help to rule out but are known to form deep tracts that may adhere to
haemangioma. CT scans are useful in visualizing bony subjacent periosteum and erode or penetrate the bony
defects, whereas MRI is better suited to rule out intrac- calvarium. The skin‐like (‘dermoid’) cyst wall is lined
ranial extension. by keratinizing stratified squamous epithelium. The
The treatment of choice is complete surgical resection adjacent dermis may contain all elements of the skin
early in life to prevent facial deformities, secondary vis- including hair follicles, smooth muscle, sebaceous and
ual impairment, meningitis and other complications eccrine sweat glands, and fibroadipose tissue. In contrast
[52]. Owing to intracranial extension of the sequestered to the clinical presentation, many dermoid cysts show
glial tissue in 15–25% of cases, the therapeutic approach signs of inflammation on histological grounds, mainly
is often multidisciplinary and requires the collaboration due to leakage of the keratin contents.
of otorhinolaryngologists and neurosurgeons. Excision
of the skin overlying the tumour may avoid recurrences Clinical features. Most external dermoid cysts are noticea-
if the glial tissue infiltrates the dermis. Endoscopic ble at birth or early in life. If small, the manifestation may
resection of the nasal glioma with immediate repair of be delayed until inflammation and subsequent enlarge-
the skull base defect may be a reliable technique in ment occur. Typically, they present as a firm, roundish,
selected cases. slowly growing, asymptomatic, subcutaneous nodule or
mass of variable size on the head or neck and are nonpul-
sating, nontransilluminating and noncompressible [56].
Box 9.1 Differential diagnosis of congenital midline nasal The orbital and periorbital areas, in particular the lateral
masses eyebrow (Fig. 9.10), are by far the most common sites.
Lateral eyebrow dermoid cysts often adhere to the under-
Benign lying bone but do not exhibit intracranial invasion [57].
• Epidermoid cyst Nasal dermoid cysts appear as a pale, flesh‐coloured,
• Glioma (ectopic neuroglia) sometimes pearly or erythematous nodule or mass located
• Encephalocoele in the midline close to the glabella or on the bridge of the
• Meningocoele nose [50]. In about half of the cases, they are associated
• Dermoid cyst with a sinus tract of variable length connecting the der-
• Juvenile xanthogranuloma moid cyst to the surface of the skin (nasal dermoid sinus
• Haemangioma cyst). The sinus ostium presents as a small punctum or pit
• Lymphangioma anywhere on the midline of the nose between glabella and
• Meningioma
• Neurofibroma
• Teratoma
Malignant
• Rhabdomyosarcoma
• Olfactory neuroblastoma
• Lymphoma
• Metastatic tumour
• Teratoma
Infectious
• Subcutaneous abscess
• Dacryocystitis
Facial trauma
Source: Adapted from Julapalli MR et al. 2006 [54].

Fig. 9.10 Dermoid cyst underlying the lateral eyebrow.
base of the columella, most frequently on the distal two‐ bony or neural elements of the spine in the dorsal midline
thirds of the dorsum of the nose, and may intermittently of the back. Open spinal dysraphism, with non‐neurulated
discharge. A small tuft of hair emerging from the pit is a neural tissue exposed to the environment, is distinguished
characteristic sign. The sinus is mostly confined to superfi- from closed or occult spinal dysraphism, which is cov-
cial structures but may also extend deeply, penetrate the ered by intact skin. The latter may be further subdivided
nasal septum and the base of the skull and – with a reported based on whether a subcutaneous mass is present on
incidence of 6–45% – even reach intracranial structures [58]. the lower back or not. Closed spinal dysraphisms with
In these cases, it most often passes through the foramen associated mass comprise lipomyelocoele, lipomye-
caecum or cribriform plate to the base of the frontal fossa lomeningocoele, meningocoele and myelocystocoele.
and adheres to the leaves of the falx cerebri extradurally. Closed spinal dysraphisms without mass include simple
Patients with a clinically evident sinus opening are sug- dysraphic states, such as tight filum terminale, intradural
gested to have a higher risk of intracranial extension. lipoma and dermal sinus, and complex dysraphic states,
Other dermoid cysts are found overlying the anterior such as diastematomyelia (split spinal cord).
fontanelle, in submental, suprasternal and suboccipital
regions. When located on the scalp, there may be focal Aetiology. Separation of the neuroectoderm from the
alopecia surrounded by a collar of hypertrophic hair. epithelial ectoderm occurs between the third and fifth
Dermoid cysts may gradually flatten and resolve over a weeks of intrauterine life. Lack of separation of germi-
number of years leaving behind a scar. nal layers and failure of closure of the caudal and
Common complications of dermoid cysts include cephalic neuropores result in neural tube defects which
recurrent inflammation, e.g. secondary to trauma, and often involve tissues overlying the spinal cord, such as
bacterial infection, particularly if the cyst is connected to meninges, vertebral arches and skin. Most combined
the skin surface via a sinus. Infection may result in local defects are located on or near the midline in the lum-
abscesses, periorbital and mid‐facial cellulitis, and osteo- bosacrococcygeal and suboccipital regions in which
myelitis. Recurrent inflammation and expansion of the fusion of neural folds occurs last. The recurrence risk in
cyst may cause bone atrophy and skeletal distortion. In subsequent pregnancies is increased, however it is less
cases of intracranial connection, brain abscesses, menin- than 25%.
gitis and meningoencephalitis may develop. In submen-
tal and anterior neck locations the cysts may compromise Clinical features. Overt forms of spinal dysraphism
swallowing, speech and respiration. Malignant degener- are easily recognized, whereas occult forms may be
ation is extremely rare. overlooked until neurological deficits occur. A variety of
congenital cutaneous signs which are associated in about
Differential diagnosis. Differential diagnosis essentially three‐quarters of cases (43–95% in different series) may
depends on the location of the dermoid cyst. Other types serve as early clues to the diagnosis of occult spinal
of cyst, such as epidermoid, trichilemmal, glandular and dysraphism [59]. Lesions with a high and low index of
other developmental cysts, are the most frequent simula- suspicion may be differentiated (Box 9.2 and Fig. 9.11)
tors. When located on the neck, dermoid cysts may be [60,61]. In general, a combination of two or more con-
mistaken for thyroid neoplasms or enlarged lymph nodes. genital midline skin lesions constitutes a much higher
Box 9.1 provides a comprehensive list of congenital mid- degree of suspicion than isolated anomalies.
line nasal masses. Lipomatous swellings, either isolated or in conjunction
with other suggestive lesions, especially overlying a
Treatment. Complete excision under general anaesthesia vascular naevus, are the most common midline cutane-
is performed to prevent inflammation and for cosmetic ous markers of occult spinal dysraphism. They present
reasons. Endoscopic approaches have been introduced to as soft, nontender, poorly circumscribed masses of fat
avoid prominent scars in aesthetically challenging sites. The of considerably varying size in the lumbosacral area.
best time for intervention is considered to be early child- Histologically, they are not encapsulated and are finely
hood, around 2 years of age. The surgeon should be aware lobulated, much like mature adult fat. The fatty tissue
that dermoid cysts are often fixed to the surrounding tissue. may penetrate through a vertebral defect into the
Prior to surgery, radiological studies are mandatory to visu- intraspinal canal causing a tethered cord (lipomye-
alize putative intracranial and intraorbital extension. CT is lomeningocoele). Deviation of the gluteal furrow is an
best suited to detect bony alterations while MRI is the pre- important feature suggesting an underlying mass.
ferred method for evaluating the anatomy of the cyst and Dorsal dermal sinuses are deep tracts that may connect
sinus tract and potential intracranial connection. In case of the skin directly to the spinal canal. The sinus opening may
the latter, craniotomy is required for adequate resection. be located off the midline. Epidermoid cysts lined by strati-
fied squamous epithelium or dermoid cysts containing, in
utaneous signs of occult spinal
C addition, cutaneous appendages in association with the
dysraphism cyst wall may form at any depth along a sinus. Their cuta-
neous openings, usually located in the midline of the
Definition. The term spinal dysraphism encompasses a suboccipital and lumbosacral areas, are often accompanied
spectrum of developmental abnormalities caused by by other skin lesions, such as dimpling, hypertrichosis or
incomplete fusion or malformation of mesenchymal, vascular naevus. There is a considerable risk of infection,
Box 9.2 Cutaneous signs of spinal dysraphism
Depressed lesions • Congenital melanocytic naevus

• Teratoma
• Congenital absence of skin*
• Neurofibroma
• Sinus tract (with or without dermoid cyst)*

• Atypical dimple* (see text)

Polypoid lesions
• Simple dimple (see text)
• True (persistent vestigial) tail*
Dermal lesions • Pseudotail*
• Congenital scar* • Acrochordon*
• Connective tissue naevus
• Hypertrophic skin Subcutaneous masses
• Lipoma*
Dyschromic lesions
• Dermoid cyst*
• Hyperpigmentation • Neural tissue* (ependymoma, lipomeningocoele, lipomyelomeningo-
• Hypopigmentation coele, occult meningocoele)
Hairy lesions Vascular lesions

• ‘Faun tail’* • Infantile haemangioma
• ‘Silky down’* • Vascular naevus
• Other forms of hypertrichosis* • Telangiectasia*
Neoplasms
• Hamartoma, unclassifiable
* Lesions marked with an asterisk are those with a high index of suspicion.
Source: Adapted from Davis et al. 1994 [59].
Neurosurgical
Overt protrusion Open spinal dysraphism intervention,
of neural tissue supportive therapy
Cutaneous signs
if indicated
• ≥ 2 of the following
findings
• Congenital scar/sinus
High index of suspicion of Imaging
• Hypertrichosis occult spinal dysraphism (ultrasound, magnetic
• Vestigial tail/acrochordon resonance tomography)
• Lipoma
• Haemangioma
• Dermoid cyst
• Hyper-/hypopigmentation
Low index of suspicion of
Fig. 9.11 An algorithm describing the approach • Nevus, hamartoma Watch & wait
occult spinal dysraphism
to a child with spinal dysraphism. • Telangiectasia
including meningitis and epidural, subdural or spinal localized just above the gluteal furrow can be considered
cord abscesses. Inflammatory enlargement of cysts and as harmless.
sinuses may exert pressure on neural structures. Abnormal lumbosacral hair growth present at birth is
Skin dimples are roundish depressions caused by fixa- commonly associated with other indicative stigmata of
tion of the skin to underlying fibrous or bony structures. spinal dysraphism and frequently associated with tethered
They are usually located in the midline of the postanal cord and diastematomyelia. A ‘faun tail’, a broad lozenge‐
area. This common finding presents in about 4% of new- shaped patch of coarse terminal hair, and a ‘silky down’, a
borns and is rarely associated with underlying anomalies. line of soft lanugo hairs limited to a discrete midline area,
Only ‘atypical’ dimples that are deep, large (≥ 5 mm), high may be differentiated from other forms of hypertrichosis.
on the back (≥2.5 cm from the anus) or combined with The hairy lesion may hide a dermal sinus opening.
other lesions are associated with a considerable risk of A human tail is a rare, finger‐like, cutaneous appendage
spinal dysraphism. In contrast, ‘simple’ dimples up to protruding from the lumbosacrococcygeal area. It is
5 mm in diameter and 2.5 cm or closer to the anus and believed to represent a persistent caudal vestigium.
Histologically, it contains a central core of mature fat

Treatment. Undetected spinal dysraphism often gives
and bundles of muscle and nerve fibres. In contrast, a
rise to severe orthopaedic (abnormal gait, clubfoot,
pseudotail is a stump‐like projection that may contain
inequality of the lower limbs, scoliosis), neurological
cartilage.
(urinary and faecal incontinence, muscle weakness and
An acrochordon is a small sessile or pedunculated skin
atrophy, awkwardness, paresis, back pain, pain or sen-
tag composed of epidermis and a fibrovascular core. In all
sory deficits in the legs with resultant trophic changes,
developmental abnormalities mentioned here, appropri-

recurrent meningitis) and urological complications (uri-
ate radiological imaging is mandatory prior to removal
nary tract infections) in infancy or childhood [58,62]. The
since these findings may be associated with an underlying
sequelae develop insidiously and are often permanent.
dysraphic state, even in the absence of further cutaneous
As posterior midline cutaneous abnormalities are usually
markers.
present at birth, attentive paediatricians and dermatologists
Among vascular lesions, haemangiomas are the most
have the opportunity to forestall irreversible damage.
important cutaneous signs indicating spinal dysraphism.
Early neurosurgical intervention can prevent deteriora-
They may be large and tend to ulcerate. The so‐called
tion, or even improve symptoms. High‐resolution spinal
PELVIS syndrome indicates perianal haemangioma,
ultrasonography is an easy screening method for early
external genitalia malformations, lipomyelomeningo-
detection of occult dysraphic lesions, even prenatally, but
coele, vesicorenal abnormalities, imperforate anus and
its use is limited to the first 4–6 months of life owing to
skin tags. Telangiectasias or vascular naevi, whether in a
skeletal maturation and a relatively high rate of false neg-
nuchal or sacral location, are of minor significance.
ative findings. MRI is accepted as the best noninvasive
Further lesions associated with spinal dysraphism
technique for the detection of occult spinal dysraphism
include congenital absence of skin or scar‐like defects
[59]. Therefore, spinal MRI has to be performed in every
(‘cigarette burn marks’) in the lumbosacral region, tera-
case where there is a high degree of suspicion, even if ultra-
tomas, melanocytic naevi and unusual pigmentation.
sound examination is unremarkable. Plain radiographs
Other occasionally associated cutaneous stigmata are
are not sufficiently sensitive.
listed in Box 9.2.
Differential diagnosis. A variety of other tumours may be plasia cutis congenita (congenital
A
located in the lumbosacrococcygeal area, such as naevus absence of skin)
lipomatosus (Fig. 9.12), rectal duplication, chordoma,
pacinioma and astrocytoma. In contrast to dorsal dermal Definition. The term aplasia cutis congenita (ACC) is
sinuses, pilonidal sinuses represent tracts superficial to used for a heterogeneous group of disorders in which the
the sacral fascia. They are not connected with the spinal skin is absent at birth or a congenital scar is present. In
canal and rarely appear before adulthood. most cases, this condition is localized and solitary, how-
ever multiple or widespread areas may be affected.
Aetiology. Congenital absence of skin areas has an esti-

mated incidence of 1–3 in 10 000 births. It is not attributable
to a single cause. Exogenous factors, such as detached
amniotic adherences, intrauterine trauma, viral infections
and teratogens, as well as endogenous factors such as
vascular abnormalities, associated fetus papyraceus and
genetic factors can be causative. Genetic causes of ACC are
heterogeneous and mutations have been found in genes
previously not known to regulate skin morphogenesis [63].
Numerous familial cases, most of them compatible with
autosomal dominant transmission, have been reported.
The most popular classification of ACC distinguishes nine
groups according to the site involved and the presence or
absence of associated abnormalities [64] (Table 9.2).
Pathology. Healed areas show a flattened re‐epithelialized

epidermis and an underlying dermal fibrosis with absence
of adnexal structures and variable reduction of elastic
fibres.
Clinical features. About 80% of lesions are located on the

scalp, most of them in the midline in close proximity to
the parietal hair whorl [4] (Fig. 9.13). Scalp lesions are
Fig. 9.12 Naevus lipomatosus in the lumbosacral area. single in about 75% of cases, double in about 20% and
Table 9.2 Frieden’s classification of aplasia cutis congenita (ACC)
Group Specification Body areas affected Associated abnormalities and syndromes Inheritance
1 Scalp ACC without Scalp, particularly vertex Without associations Sporadic or autosomal
multiple anomalies In association with isolated abnormalities including: dominant
• Cleft lip and palate

• Tracheo‐oesophageal fistula
• Double cervix and uterus
• Patent ductus arteriosus
• Heart disease
• Omphalocoele
• Polycystic kidneys
• Mental retardation
• Cutis marmorata telangiectatica congenita
2 Scalp ACC with limb Midline scalp Adams–Oliver syndrome Autosomal dominant
reduction abnormalities
3 Scalp ACC with associated Scalp Linear epidermal naevus Sporadic
epidermal and organoid Linear sebaceous naevus (didymosis aplasticosebacea)
naevi Schimmelpenning syndrome
SCALP syndrome
4 ACC overlying Abdomen, posterior axis, Meningomyelocoele Variable, depending on
embryological scalp Cranial stenosis underlying condition
malformations Congenital midline porencephaly
Leptomeningeal angiomatosis
Spinal dysraphism
Omphalocoele
Gastroschisis
5 ACC with associated fetus Multiple, symmetrical Single umbilical artery, developmental delay, spastic Sporadic
papyraceus or placental areas paralysis, nail dystrophy, clubbed hands and feet,
infarcts amniotic constriction band, gastrointestinal atresia
6 ACC associated with Extremities, rarely trunk Blistering of skin and/or mucous membranes, absent or Autosomal dominant or
epidermolysis bullosa (EB) deformed nails, metatarsus varus, congenital absence of recessive, depending
kidney, pyloric or duodenal atresia, abnormal ears and on type of EB
nose, ureteral stenosis, renal abnormalities, arthrogryposis
7 ACC localized to Pretibial areas, dorsal None Autosomal dominant or
extremities without aspects of hands and recessive
blistering feet, extensor areas of
wrists
8 ACC caused by specific Any area Drugs: methimazole, misoprostol, cocaine, valproic acid, Sporadic
teratogens benzodiazepines, heparin
Intrauterine herpes simplex infection
Intrauterine varicella zoster infection
9 ACC associated with Scalp, any area Trisomy 13 (Patau syndrome) Variable, depending on
malformation 4p syndrome (Wolf–Hirschhorn syndrome) underlying condition
syndromes Xp deletion syndromes
Oculocerebrocutaneous syndrome (Delleman–Oorthuys
syndrome)
Johanson–Blizzard syndrome
Focal dermal hypoplasia
Focal facial dermal dysplasia
Bitemporal ACC syndrome (Setleis syndrome)
Oculoectodermal syndrome
Rodrigues syndrome
SCALP, sebaceous naevus syndrome, central nervous system malformations, aplasia cutis congenita, limbal dermoid and pigmented naevus (giant
congenital melanocytic naevus) with neurocutaneous melanosis.
Source: Adapted from Frieden 1986 [64].
triple in about 8%. Typically, they are 1–3 cm in diameter, with areas of preserved skin appendages (nonmembra-
round or oval in shape, sharply marginated and hairless. nous ACC). In approximately 20% of cases lesions extend
At birth, they often show an atrophic, shiny, membrane‐ to the bone, dura or meninges, with possible complica-
like surface, with or without a hair collar (membranous tions of haemorrhage from the eroded sagittal sinus, sinus
ACC). In contrast, larger lesions tend to have an irregular, thrombosis and meningitis. Even if the skull is involved,
stellate outline and to be deeply ulcerated. Healing leaves ulcers tend to heal spontaneously within several months.
a sclerotic, sometimes hypertrophic surface intermingled Membranous ACC has been suggested to result from
larger defects are recommended to be closed early by skin

grafts or local flaps. Application of cultured dermal and
epithelial autografts as a minimally invasive method has
been used to accelerate healing. Bone grafts may be
needed for closure of cranial defects. If acute intervention
is not required, an unsightly scar may later be excised or
hidden by hair transplants. Tissue expansion of the adja-

cent hair‐bearing scalp can help to close larger surgical
defects resulting from scar removal.
mniotic constriction band

A
(amnion rupture sequence)
Definition. Amniotic constriction band comprises an

extremely varied group of sporadic congenital birth
defects characterized by fibrous constriction bands,
limb deformities and amputations, acrosyndactyly and
multiple craniofacial, visceral and body wall defects. It is
supposed to be secondary to a disruption process of the
amniotic membrane.
Fig. 9.13 Aplasia cutis congenita on the vertex healed with atrophic scarring.
Aetiology. The condition is believed to arise from early
incomplete or faulty closure of ectodermal fusion lines rupture of the amniotic sac, leading to inhibition of its
whereas nonmembraneous ACC appears to have a differ- growth and formation of mesodermic fibrous strands
ent pathogenesis. between the outer surface of the amnion and the denuded
Lesions on the trunk and limbs are often large, irregular chorion (‘extrinsic theory’) [65]. When passing through
in shape and symmetrical in distribution. This unusual the defect in the amniotic membrane, fetal parts may be
pattern may indicate the presence of a fetus papyraceus entangled by these inelastic fibrous strands, resulting in
and also occurs in association with certain severe types of ring constrictions and even amputation of limbs or digits.
epidermolysis bullosa. Healing may lead to dermatogenic Temporary oligohydramnios due to increased amniotic
contractures, especially in the vicinity of the joints. fluid absorption by the bared chorion gives rise to com-
Elevated levels of α‐fetoprotein in midtrimester pression and decreased movement of the fetus. If early
maternal serum and amniotic fluid as well as elevated and acute, this may cause haemorrhage and necrosis,
acetylcholinesterase levels in amniotic fluid may result whereas during organogenesis compression may lead to
from widespread ACC. visceral and neural tube defects and later to clubbing of
In the majority of cases, further abnormalities are the feet, scoliosis and joint contractures. Other, particu-
lacking. However, congenital absence of skin may rarely larly craniofacial, defects may result from vascular dis-
be associated with a large number of anomalies, such as ruption with or without amniotic adhesion to the embryo.
transverse limb malformations (Adams–Oliver syndrome), Early rupture of the amniotic membrane before 45 days
epidermal and organoid naevi, overt or occult develop- gestational age is claimed to produce the most severe
mental abnormalities, fetus papyraceus, epidermolysis defects and even spontaneous abortion. Maternal abdom-
bullosa, specific teratogens (methimazole), intrauterine inal trauma, uterine malformations, dietary deficiencies,
infections, chromosomal abnormalities, ectodermal dys- teratogens and the use of oral contraceptives shortly
plasias and other malformation syndromes [1] (Table 9.2). before conception have all been incriminated in causing
amnion rupture.
Differential diagnosis. Lesions of congenital absence of As the extrinsic theory does not readily explain all pos-
skin have to be differentiated from iatrogenic injuries by sible manifestations, an ‘intrinsic theory’ has been intro-
forceps or scalp electrodes. Further differential diagnoses duced advocating alterations in key germline genes
include congenital abscess of the scalp, encephalocoele implicated in normal development. More probably, dif-
and meningocoele. Healed areas may be mistaken for ferent patterns of presentation result from different aeti-
other causes of cicatricial alopecia, sebaceous naevus, ologies. For example, certain combined defects featuring
naevus psiloliparus or, if hypertrophic, scalp tumours. congenital skin pedicles and cleft lip and palate may cor-
respond to mutations in the mutant mouse ‘disorganiza-
Treatment. There is no general consensus on the manage- tion gene’ [66].
ment of ACC. In most cases, conservative management of Amniotic band syndrome occurs in approximately 1 in
the wound with antiseptics and appropriate dressings is 1200–15 000 live births. Females outnumber males by
sufficient. Deeper lesions require radiological evaluation about 3 : 2. The prevalence has been reported to be 1.76
of the underlying bone. To prevent serious complications, times higher in African Americans than in Caucasians.
such as haemorrhage, local infection and meningitis, Familial occurrence is extremely rare [67].
dermatoglyphics has also been observed in Kindler

Clinical features. Anomalies occurring within the scope
syndrome.
of amniotic constriction band may be divided into three
Ridge hypoplasia (poorly formed dermal ridges) can
types: disruptions, deformations and malformations.
occur as an isolated autosomal dominant defect or in
They are highly variable and assumed to depend upon
association with chromosomal abnormalities and congen-
the time of amnion rupture. Early rupture is thought to
itally deformed limbs.
give rise to severe craniofacial (encephalocoele, meningo-

In ridge dissociation, the dermal ridge is broken into
coele, anencephaly, cleft lip and palate, nasal deformity,
short segments instead of being continuous. This pattern
microphthalmia), visceral and body wall defects and can
can occur sporadically, as an autosomal dominant condi-
be inconsistent with life. More often, constriction bands
tion, or in association with other diseases, such as hypohi-
circumferentially encircle the distal limbs and may be
drotic ectodermal dysplasia, chromosomal abnormalities
deep enough to cause distal lymphoedema, compression
and cystic fibrosis.
of sensory and motor nerves, and ischaemia with result-
The ridges‐off‐the‐end pattern, which is characterized
ant deficits, atrophy and amputations at any level of an
by ridges running off the fingertip instead of looping
extremity or digit. Further defects include hand deformi-
around it, is usually not associated with other anomalies.
ties, clubfoot (talipes equinovarus), atypical syndactyly
Punctate interruptions of the skin ridges indicating
predominantly involving the distal portions of the digits
pitting are a well‐known manifestation of Darier disease.
(acrosyndactyly, or fenestrated syndactyly), absence of
Unusual dermatoglyphic patterns also occur in the
skin or alopecia at sites of band attachment, abnormal
Kabuki make‐up syndrome, a multiple congenital anom-
palmar creases and altered dermatoglyphic pattern.
alies/mental retardation syndrome.
Asymmetrical involvement of multiple extremities to var-
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121
C HA PTER 10
Differential Diagnosis of Neonatal

Erythroderma

Hagen Ott1 & Peter H. Hoeger2
Division of Pediatric Dermatology and Allergology, Epidermolysis bullosa Centre Hannover, Children’s Hospital AUF DER BULT, Hannover, Germany
1

2
Introduction, 121 Adverse drug reactions, 129 Diagnostic work‐up of neonatal

Cutaneous disorders, 123 Immunological disorders, 130 erythroderma, 133
Infections and toxicities, 128 Inborn errors of metabolism, 132
Abstract critically depends on swift diagnosis and early therapeutic inter-

vention. Therefore, this chapter focuses on clinical clues and further
Neonatal erythroderma occurs during the first 28 days of life and diagnostic steps that are helpful in the differentiation of conditions
is defined as a generalized erythema covering more than 90% of regularly associated with neonatal erythroderma. For practical rea-
body surface area. It can be the manifestation of various clinical sons, these are classified into acquired and hereditary skin diseases,
syndromes ranging from benign, transient skin diseases to poten- infections, immunodeficiency disorders, drug reactions and inborn
tially fatal systemic disorders. The prognosis of affected patients errors of metabolism.
Key points • Irrespective of its cause, neonatal erythroderma is associated

with complications due to impaired epidermal barrier function
such as hypothermia, dehydration or infection.
• Neonatal erythroderma is characterized by a generalized
• To differentiate nonsyndromic forms with good prognosis from
erythema covering more than 90% of the neonate’s body
more severe variants of neonatal erythroderma, a thorough
surface area.
diagnostic work‐up is mandatory in every affected patient.
• The underlying illnesses range from benign, erythematosquamous
• Besides routine laboratory tests such as whole blood count, total
disorders such as atopic dermatitis to fatal diseases such as
serum IgE and blood gas analysis, further molecular genetic and
severe combined immunodeficiencies.
other analyses are often required.
Introduction
increased transcutaneous loss of fluid leading to hyper
By definition, neonatal erythroderma has its onset during natraemic dehydration, increased energy consumption
the first 28 days of life and refers to a generalized ery and hypothermia.
thema with or without scaling that covers more than 90% Thus, in order to avoid a critical delay in diagnosis,
of the newborn’s body surface area [1]. Although reliable definitive identification of the underlying condition is
epidemiological data are still not available, neonatal imperative and often requires further laboratory, histologi
erythroderma can be considered a rare disorder as dem cal, microbiological or molecular genetic analyses [3–5]
onstrated by a single‐centre study of 19 000 paediatric (Fig. 10.1). The historical term ‘Leiner’s disease’ (synonyms:
dermatology patients yielding a 0.11% incidence of eryth erythrodermia desquamativa Leiner, Leiner–Moussous
rodermic neonates and infants during a 6‐year period [2]. syndrome) originally denoted infants with exfoliative
Neonatal erythroderma can be the manifestation of erythroderma, diarrhoea and failure to thrive. Because this
various clinical syndromes ranging from benign, tran condition can be attributed to a wide range of different dis
sient skin diseases to potentially fatal systemic disorders. eases it is recommended that the term be abandoned.
The prognosis of affected patients is serious due to a per Many of the diseases that need to be considered in this
sistence of severe skin symptoms in 70% after 3 years and, context are discussed in detail elsewhere in this textbook.
more importantly, a mortality rate of up to 25%. Therefore, the focus of this chapter is on clinical clues and
Irrespective of its cause, erythroderma per se is a life‐ further diagnostic steps that are helpful in the differentia
threatening condition in neonates, mainly due to an tion of conditions regularly associated with neonatal
Basic diagnostic work-up

- Patient history
- Clinical examination Neonatal/infantile erythroderma
- Skin smear
- Capillary blood gas analysis
CSF, blood, urine + Congenital cutaneous

Candida?
cultures candidiasis
no
Blood ammonia level, Molecular

Ketoacidosis? + + Holocarboxylase synthetase def.
HLCS-activity genetics (HLCS)
no
+ Re-exposure, if + Red man syndrome

Vancomycin? Discontinue
indicated
Ophthalmology, Molecular + Chondrodysplasia punctata II

+
no
BERA/audiometry genetics (EBP)
Immunohistochemistry, Mol. genetics

+ + Netherton syndrome
trichogram (SPINK5)
Ichthyosîs?
Mol. genetics
Electron microscopy + + NCIE/BCIE
(TGM1, K1/10)
Funduscopy, FALDH- Mol. genetics

no
+ + Sjögren–Larsson syndrome
activity (fibroblasts) (ALDH3A2)
Exfoliation? Histology (cleavage level) Subepidermal? Toxic epidermal necrolysis
no
Subcorneal? PCR
+ SSSS
(sea, seb)
no
Total lgE, Mol. genetics

+ + Omenn syndrome
lymphocyte typing (RAG1/2, others)
Dystrophy,
Alopecia?
Histology, Chimerism
+ + Maternofetal GvHD
lymphocyte typing analysis
no
Atopic dermatitis
Consider Psoriasis vulgaris
‘transient erythroderma’ Seborrheic dermatitis
Pityriasis rubra pilaris
Fig. 10.1 Proposal for a diagnostic algorithm to be followed in the management of neonatal and early infantile erythroderma. Source: Ott et al. 2008 [1].
Reproduced with permission of John Wiley & Sons. EBP, emopamil‐binding protein; FALDH, fatty aldehyde dehydrogenase; NCIE/BCIE, nonbullous
congenital ichthyosiform erythroderma/bullous congenital ichthyosiform erythroderma; PCR, polymerase chain reaction.
Chapter 10 Differential Diagnosis of Neonatal Erythroderma 123
Box 10.1 Neonatal erythroderma: differential diagnosis

Cutaneous disorders
Retrospective hospital‐based investigations have identified
Cutaneous disorders primary skin diseases as the most common cause of
Erythematosquamous skin diseases neonatal and infantile erythroderma, accounting for as
• Seborrhoeic dermatitis many as 80% of all cases. The underlying cutaneous
disorders comprise erythematosquamous diseases, geno

• Atopic dermatitis

• Psoriasis dermatoses and further skin diseases, particularly scabies
• Pityriasis rubra pilaris and generalized cutaneous mastocytosis [1–3].
Genodermatoses
• Nonsyndromic ichthyosis (nonbullous congenital ichthyosiform Erythematosquamous skin diseases
erythroderma, epidermolytic ichthyosis) Seborrhoeic dermatitis (see Chapters 15 and 21)
• Syndromal ichthyosis (Chanarin–Dorfman syndrome, Conradi– Infantile seborrhoeic dermatitis (SD) represents a tran
Hünermann–Happle syndrome, Sjögren–Larsson syndrome) sient skin disease of good prognosis affecting up to 70%
• Disorders of epidermal homeostasis (Netherton syndrome, peeling of newborns and infants during the first months of life [4].
skin syndrome type B, SAM syndrome) While pruritus is usually mild or completely absent, skin
• Ectodermal dysplasia lesions typically correspond to erythematous patches
with a yellowish hue and greasy scaling which are most
Other skin diseases prominent on the scalp (cradle cap), the napkin (diaper)
• Diffuse cutaneous mastocytosis area and other intertriginous zones [5]. In most patients,
• Scabies skin symptoms respond rapidly to topical treatment with
low‐potency glucocorticoids or antifungal agents, but in
Infections and toxicities
some cases neonatal and infantile SD may develop into
• Staphylococcal scalded skin syndrome erythroderma.
• Congenital and neonatal candidiasis As pathognomonic laboratory parameters or histological
features do not exist, the diagnosis of infantile SD is
Adverse drug reactions established on clinical grounds. In contrast to atopic
• Stevens–Johnson syndrome, toxic epidermal necrolysis
dermatitis, erythematous patches in SD are clearly demar
• Red man syndrome cated, usually less pruritic, and tend to predominate in
the flexural folds including the anogenital area.
Immunological disorders In patients with systemic symptoms such as diarrhoea
or failure to thrive, skin biopsy and further diagnostic
• Omenn syndrome
steps are warranted to rule out more severe conditions
• Graft‐versus‐host disease
such as immunodeficiencies or metabolic defects.
• Other primary immunodeficiencies (DiGeorge syndrome,
Wiskott–Aldrich syndrome, IPEX syndrome)
Atopic dermatitis (see Chapter 15)
Inborn errors of metabolism Despite a period prevalence of up to 28% within the first
• Holocarboxylase synthetase deficiency year of life, atopic dermatitis (AD) does not usually occur
• Amino acid disorders (maple syrup urine disease, methylmalonic in infants younger than 3 months of age and only very
acidaemia) rarely causes severe skin symptoms or even erythroderma
in neonates [6]. If present, however, acute lesions are char
acterized by widespread pruritic erythematous papules
and patches, often with marked exudation. Infantile AD
typically involves the scalp, the face, the trunk and the
erythroderma. For practical reasons, these can be classified
extensor surfaces of the extremities whereas, in contrast
into cutaneous disorders, infectious diseases, immunode
to infantile psoriasis and seborrhoeic dermatitis, the nap
ficiency disorders, drug reactions and inborn errors of
kin area is frequently spared (Fig. 10.2) [7]. Moreover, in
metabolism (Box 10.1).
contrast to more serious causes of neonatal erythroderma,
newborns affected by AD without concurrent food allergy
References
1 Ott H, Hutten M, Baron JM et al. Neonatal and infantile erythrodermas.
usually thrive well and do not exhibit persisting alopecia
J Dtsch Dermatol Ges 2008;6:1070–85. or additional clinical signs of extracutaneous pathology
2 Sarkar R, Basu S, Sharma RC. Neonatal and infantile erythrodermas. (e.g. lymphadenopathy, diarrhoea, atypical infections).
Arch Dermatol 2001;137:822–3. The lesions respond rapidly to topical therapy with cor
3 Al‐Dhalimi MA. Neonatal and infantile erythroderma: a clinical and
follow‐up study of 42 cases. J Dermatol 2007;34:302–7. ticosteroids, calcineurin inhibitors and emollients. Due to
4 El Euch D, Zeglaoui F, Benmously R et al. Erythroderma: a clinical a considerable clinical overlap and rather uncharacteristic
study of 127 cases and review of the literature. Exog Dermatol 2003;2: histological findings upon skin biopsy, differentiation of
234–9.
5 Pruszkowski A, Bodemer C, Fraitag S et al. Neonatal and infantile
erythrodermic AD from other causes of neonatal erythro
erythrodermas: a retrospective study of 51 patients. Arch Dermatol derma is challenging. Although elevated total serum IgE
2000;136:875–80. levels indicate early‐onset AD, they are nonspecific and
Fig. 10.2 Erythroderma sparing the napkin (diaper) area in an otherwise

healthy male infant with atopic dermatitis.
may also be associated with more serious disorders such

as Omenn syndrome, Wiskott–Aldrich syndrome or
Netherton syndrome. Conversely, normal total serum IgE
levels do not rule out neonatal or infantile AD due to a
high prevalence of the intrinsic variant of AD in this age
group [8]. Likewise, recent prospective birth cohort
studies have disclosed that the presence of food‐specific
IgE is not a reliable indicator of infantile AD (as was
previously postulated), because it can be detected equally
often in affected and healthy children [9–11]. Hence, if
severe AD with concurrent cow’s milk allergy is sus Fig. 10.3 Noncongenital psoriasis with widespread lesions in the napkin
pected in a non‐breastfed neonate with erythroderma, the and abdominal area of a male infant revealing sharply demarcated,
patient should first be fed with an extensively hydrolysed infiltrated, bright red plaques.
milk‐ or amino acid‐based formula for a limited period of
time, e.g. 2 weeks. Likewise, in breastfed infants, maternal
avoidance of potential food allergens may be considered, ichthyosiform erythroderma, severe AD or Netherton
but only after adequate dietary counselling. If a clear syndrome. Hence, correct diagnosis may require skin
amelioration is achieved by allergen avoidance, the infant biopsy that reveals a psoriasiform reaction pattern with
should undergo an oral food challenge (OFC) with the laminated parakeratosis, elongated rete ridges often con
incriminated allergen. If symptoms recur upon OFC, the taining neutrophils and little or no dermal lymphocytic
diagnosis of food allergy in the context of severe AD is infiltrate while LEKTI staining is negative [15]. Once the
highly probable. diagnosis of psoriasis is safely established, systemic
treatment with acitretin (0.5–1 mg/kg/day) has proved to
Psoriasis (see Chapter 30) be well‐tolerated and effective even in young infants and
Up to 37.5% of children suffering from plaque psoriasis children with GPP [16–18].
and up to 50% of children with pustular psoriasis develop
symptoms during the first year of life [12]. Neonatal or Pityriasis rubra pilaris (see Chapter 32)
congenital psoriasis is, however, very rare. Neonatal Pityriasis rubra pilaris (PRP) represents a rare papulo
erythroderma due to psoriasis is likely to evolve into squamous disorder of unknown origin which can mani
generalized pustular psoriasis (GPP). Erythrodermic fest at any age. In the first month of life, PRP is almost
GPP requires a thorough diagnostic work‐up in order to exclusively encountered in those extremely rare patients
exclude other serious differential diagnoses, especially with congenital disease onset. These individuals may be
infections with herpes simplex virus (HSV), varicella zoster affected by familial PRP, which accounts for about 5% of
virus (VZV), Staphylococcus aureus or Candida spp. More all PRP cases and has recently been shown to be due to
over, GPP demands immediate treatment to avoid poten activating mutations in CARD14, the gene encoding
tially severe complications such as sterile lytic bone caspase recruitment domain family member 14, a known
lesions, bacterial superinfection or sepsis [13,14]. activator of nuclear factor kappa B (NF‐κB) signalling [19].
Infantile psoriasis often starts with an unusually severe Clinically resembling atypical juvenile PRP (Griffiths
napkin rash that is better demarcated and brighter red than classification type V), skin lesions consist of widespread
that of seborrhoeic dermatitis (Fig. 10.3). Subse quently, follicular, keratotic papules and erythematous patches
rapid dissemination leads to generalized erythemato coalescing into erythroderma. As in typical juvenile PRP,
squamous skin lesions, but in neonates and young infants neonates display salmon‐coloured erythema with islands
psoriatic erythroderma may also mimic nonbullous of unaffected skin (‘nappes claires’) (Fig. 10.4) whereas

(a)
Fig. 10.4 Atypical juvenile pityriasis rubra pilaris in a male infant with
follicular, erythematous papules and patches coalescing into erythroderma.
Of note, the typically salmon‐coloured erythema reveals islands of
unaffected skin (‘nappes claires’) and marked palmar hyperkeratosis.
palmoplantar keratoderma is usually discrete or com

pletely lacking. Histological features of neonatal PRP have
only been reported casuistically and consist of alternating
ortho‐ and parakeratosis with lipping of follicular ostia
and associated follicular plugging [20,21].
Genodermatoses
Neonatal erythroderma is a presenting sign of several
(b)
monogenic skin diseases, particularly ectodermal dyspla
sia and hereditary disorders of keratinization. The latter Fig. 10.5 (a) Collodion baby phenotype in a female neonate with
nonbullous congenital erythroderma.Source: Ott et al. 2008 [24].
include nonsyndromic ichthyoses with exclusively cutane
Reproduced with permission of John Wiley & Sons. (b) Same patient as in
ous symptoms as well as syndromic ichthyoses associated (a) who reveals ‘self‐improving’ ichthyosiform erythroderma with fine
with potentially severe metabolic, neurological, ophthal scaling and discrete palmoplantar hyperkeratosis after shedding of the
mological or other abnormalities [22,23]. If suspicion arises, collodion membrane.
skin biopsy is mandatory and further diagnostic steps
(e.g. molecular genetics, immunohistochemistry) should
optimally be coordinated in cooperation with national ischaemia due to constricting skin bands [26]. At first
reference centres such as the Network for Ichthyoses and presentation, it is important to rule out syndromic
Related Keratinization Disorders: NIRK (https://www. differential diagnoses of the collodion baby phenotype
medizin.uni‐muenster.de/nirk/network‐for‐ichthyoses‐ such as Sjögren–Larsson syndrome, Netherton syndrome,
and‐related‐keratinization‐disorders/willkommen/) or the trichothiodystrophy, Chanarin–Dorfman syndrome or
Centre de référence des maladies rares de la peau et des type 2 Gaucher disease [25].
muqueuses d’origine génétique, MAGEC (http://www. Autosomal dominant epidermolytic ichthyosis (EI, OMIM
maladiesrares‐necker.aphp.fr/magec/), for example. #113800), also designated as bullous congenital ichthy
osiform erythroderma or epidermolytic hyperkeratosis,
Nonsyndromic ichthyoses (see Chapter 129) belongs to the group of keratinopathic ichthyoses and is
Nonbullous congenital ichthyosiform erythroderma (NCIE, caused by mutations in genes encoding the suprabasal
OMIM #242100) is an autosomal recessive keratinization keratins 1 and 10 (KRT1, KRT10) [27]. Clinical presenta
disorder that is caused by mutations in various genes tion varies greatly, but affected patients usually suffer
(ABCA12, ALOXE3, ALOX12B, CERS3, CYP4F22, LIPN, from severe blistering immediately after birth, sometimes
NIPAL4/ICHTHYIN, PNPLA1, TGM1) [22]. As a clinical with widespread erosions, accompanied by variously
hallmark, up to 90% of affected patients present with a severe ichthyosiform erythroderma. During the following
collodion membrane directly post partum which is shed weeks, hystrix‐like hyperkeratoses appear. Interestingly,
during the neonatal period, revealing erythroderma with marked palmoplantar hyperkeratosis is characteristically
generalized fine scaling (Fig. 10.5a and b) [24,25]. While encountered in patients with KRT1 mutations, although
systemic symptoms are usually absent, further cutaneous individuals with EI due to KRT10 mutations may also be
symptoms can include ectropion or eclabium, obstruction of affected. Initially, other bullous disorders of neonatal onset
the external auditory canal, scarring alopecia or peripheral have to be considered as possible differential diagnoses,
especially epidermolysis bullosa hereditaria, superficial oligodendrocytes, retinal cells), resulting in the character
epidermolytic ichthyosis (formerly ichthyosis bullosa istic clinical triad of ichthyosis, psychomotor retardation
Siemens), staphylococcal scalded skin syndrome and and spastic diplegia. In neonates and young infants, SLS
diffuse cutaneous mastocytosis [28]. Affected family tends to manifest as ichthyosiform erythroderma while
members may also facilitate diagnosis, although a nega the full clinical picture is usually not apparent until early
tive family history does not rule out EI because >50% childhood. Definitive diagnosis can be established by the
of patients have spontaneous mutations that are readily assessment of FALDH activity in cultured fibroblasts,
detected in EDTA blood samples or skin biopsy specimens. the characteristic elevation of leukotriene B4 (LTB4) in
urine specimens and, finally, targeted sequencing of the
Syndromic ichthyoses (see Chapter 129) ALDH3A2 gene. Pathognomonic crystalline deposits
Autosomal recessive Chanarin–Dorfman syndrome (CDS, within the retina (‘glistening dots’) and reduced levels of
OMIM #275630), also referred to as neutral lipid storage mean foveal macular pigment are seen upon funduscopy
disease with ichthyosis, represents a multiorgan disorder and macular pigment reflectometry, respectively [33,34].
elicited by mutations in the CGI85 (ABDH5) gene. These
induce pathological alterations in the metabolism of Disorders of epidermal homeostasis
endogenous triglycerides leading to the accumulation of The autosomal recessive Netherton syndrome (NS, OMIM
neutral lipids in multiple cell types, particularly leuko #256500), a syndromic ichthyosis, is caused by inactivat
cytes, myocytes, hepatocytes, fibroblasts and keratino ing mutations in the epidermal serine protease inhibitor
cytes. The resulting cutaneous phenotype resembles Kazal‐type 5 (SPINK5) gene which codes for the lym
other forms of congenital ichthyosiform erythroderma phoepithelial Kazal‐type 5 related inhibitor (LEKTI). As a
only occasionally associated with the presenting sign of result, severe defects in epidermal barrier function and a
a collodion membrane. Systemic manifestations in neo persistent inflammatory reaction lead to severe neonatal
nates and infants may consist of liver involvement such erythroderma (Fig. 10.6) while the typical polycyclic, ser
as hepatosteatosis or cirrhosis in 70% of patients, whereas piginous plaques with erythematous borders and double‐
ocular symptoms (e.g. cataract, nystagmus, myopia) and edged scaling (ichthyosis linearis circumflexa) usually do
sensorineural deafness can occur in about 40% and 25% of not manifest before early childhood. Affected neonates
patients, respectively. Additionally, developmental delay and infants often have bacterial skin infections which are
and growth retardation are frequently observed in CDS also due to an underlying immunodeficiency associated
patients. Lipid vacuoles are present in numerous organs
and can be seen in a skin biopsy specimen or in granulo
cytes and monocytes of a peripheral blood smear on
Pappenheim staining (Jordan sign) [29,30].
Also known as Conradi–Hünermann–Happle syndrome,
type 2 chondrodysplasia punctata (CDPX2, OMIM #302960)
is an X‐linked dominant disorder caused by mutations in
the emopamil‐binding protein (EBP) gene. These entail
increased serum levels of pathological cholesterol metabo
lites due to an impaired function of 8‐7‐sterol isomerase.
CDPX2 is nearly always fatal for male fetuses. In contrast,
affected female neonates suffer from severe ichthyosiform
erythroderma immediately post partum which is usually
associated with hyperkeratosis and scaling following
Blaschko’s lines. Extracutaneous features which may not
become apparent until later in childhood include short stat
ure and kyphoscoliosis, hearing loss, sectorial cataracts,
punctate bone calcifications and mild‐to‐moderate mental
retardation. Moreover, asymmetrical shortening of the
limbs is observed in up to 80% of affected girls. While
elevated serum levels of 8‐dehydrocholesterol and a dimin
ished stratum granulosum with cytoplasmic vacuoles upon
skin biopsy hint at CDPX2, definitive diagnosis is reached
by molecular genetic analysis of the EBP gene [31,32].
As a severe neurocutaneous disease, the autosomal
recessive Sjögren–Larsson syndrome (SLS, OMIM #270200)
is caused by mutations in the ALDH3A2 gene that codes
for fatty aldehyde dehydrogenase (FALDH), an enzyme
of crucial importance for cutaneous and extracutaneous
lipid metabolism. Diminished FALDH activity leads
to a pathological accumulation of essential fatty acids Fig. 10.6 Severe ichthyosiform erythroderma, hypotrichosis and failure
in the membrane of various cell types (keratinocytes, to thrive in an infant with Netherton syndrome.
with an immature natural killer cell phenotype and a Severe dermatitis, multiple allergies and metabolic wasting
decrease of nonswitched memory B cells or CD27+ mem syndrome (SAM, OMIM #615508) has recently been shown
ory B cells [35]. The clinical distinction of NS from other to be caused by homozygous mutations in DSG1, the
causes of ichthyosiform erythroderma is facilitated by desmoglein‐1‐encoding gene (DSG1). These mutations
microscopy of hair shafts (scalp hair, eyebrows, eyelashes) lead to desmosome dysfunction, impaired cell adhesion
revealing trichorrhexis invaginata (‘bamboo hair’) and and aberrant epidermal differentiation. As a consequence,

hypotrichosis. Skin biopsy with immunohistochemical affected neonates reveal early‐onset, ichthyosiform eryth
staining reveals a psoriasiform epidermal hyperplasia roderma, multiple food allergies and a severe failure to
with absence of the stratum granulosum, a mixed perivas thrive. Additional clinical features consist of recurrent
cular infiltrate and reduced or absent LEKTI expression. skin or pulmonary infections, hypotrichosis and palmo
Additionally, total and allergen‐specific IgE levels are fre plantar keratoderma, which may help to distinguish SAM
quently elevated while other traits of atopic disease such syndrome from NS and PSS‐B clinically. While histology
as bronchial asthma or allergic rhinitis do not become reveals subcorneal separation associated with acantholysis,
apparent until late infancy or early childhood. Associated a definitive diagnosis can be established by DSG1
systemic symptoms are subject to marked phenotypic sequencing [38].
variability and include hypernatraemic dehydration, failure
to thrive and chronic diarrhoea which are responsible for Ectodermal dysplasia (see Chapter 134)
a fatality rate of up to 20% in the first year of life [35,36]. Erythroderma can also be seen in neonates suffering from
Peeling skin syndrome type B (PSS‐B, OMIM #270300), a ectodermal dysplasias, a heterogenous group of inherited
nonsyndromic ichthyosis, results from loss‐of‐function disorders involving absence or dysplasia of the ectodermal
mutations in CDSN, the gene encoding for corneodes appendages. In particular, neonates with ankyloblepha
mosin. Phenotypically, neonates and infants with PSS‐B ron, ectodermal dysplasia and cleft lip/palate syndrome
develop a clinical picture mimicking NS with ichthyosi (AEC, OMIM #106260), a very rare autosomal dominant
form erythroderma, recurrent staphylococcal skin infec genodermatosis caused by TP63 mutations, may present
tions, severe pruritus and frequent food anaphylaxis in with widespread erythema. In these patients, neonatal
the context of elevated total and food allergen‐specific erythroderma with extensive erosions and diffuse depig
serum IgE levels. However, unlike in NS, hair shaft abnor mented patches in previously eroded areas can be observed
malities are absent and, even more importantly, PSS‐B besides further clinical signs of ectodermal dysplasia such
patients show increased skin fragility and spontaneous as palmoplantar keratoderma, partial anhidrosis, nail
peeling (Fig. 10.7) corresponding to subcorneal cleavage dystrophy, patchy alopecia and hypodontia [39,40].
upon skin biopsy [37,38].
Other skin diseases
Diffuse cutaneous mastocytosis (see Chapter 92)
As the rarest subtype of cutaneous mastocytosis (CM),
diffuse cutaneous mastocytosis (DCM) affects up to 5% of
CM patients and usually manifests with a peculiar type
of neonatal erythroderma either at birth or shortly there
after. Characteristically, infiltration of mast cells through
out the entire cutis leads to widespread, yellow‐reddish
erythema accompanied by extensive bulla formation.
Other skin manifestations attributable to mediator release
from mast cells comprise flushing, urticaria or pachyder
mia. Extracutaneous symptoms occur in virtually all
affected patients and may consist of abdominal pain,
diarrhoea, headache or even anaphylaxis. Hence, erythro
dermic neonates with DCM require interdisciplinary
management including bone marrow biopsy if suspicion
of systemic mastocytosis arises, as in patients with hepat
osplenomegaly, lymphadenopathy, abnormal blood count
and/or serum tryptase levels above 100 ng/mL [41–43].
Scabies (see Chapter 59)

Neonatal erythroderma due to infestation with the mite
Sarcoptes scabiei hominis has only been very rarely reported.
In these cases, physical examination revealed scaly
erythroderma, multiple micropustules and papules on
the trunk, extremities, scalp, face and the palmoplantar
region with secondary eczematization and bacterial super
Fig. 10.7 Severe erythroderma and spontaneous, superficial exfoliation in infection. Peripheral blood cell counts showed marked
a newborn with peeling skin syndrome type B. eosinophilia. In a recent multicentre trial, anamnestic
relapse, the presence of skin nodules and the involvement 28 Avril M, Riley C. Management of epidermolytic ichthyosis in the
newborn. Neonatal Netw 2016;35:19–28.
of soles and scalp were found to be highly characteristic
29 Emre S, Unver N, Evans SE et al. Molecular analysis of Chanarin‐
signs of scabies infestation in infants and young children. Dorfman syndrome (CDS) patients: Identification of novel mutations
Extracutaneous features such as hepatosplenomegaly or in the ABHD5 gene. Eur J Med Genet 2010;53:141.
lymphadenopathy were not observed [44–46]. 30 Nur BG, Gencpinar P, Yuzbasıoglu A et al. Chanarin‐Dorfman
syndrome: genotype‐phenotype correlation. Eur J Med Genet 2015;
58:238–42.
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2012;91:163–70. Staphylococcal scalded skin syndrome
20 Thomson MA, Moss C. Pityriasis rubra pilaris in a mother and two (see Chapter 37)
daughters. Br J Dermatol 2007;157:202–4.
21 Allison DS, El‐Azhary RA, Calobrisi SD, Dicken CH. Pityriasis rubra Staphylococcal scalded skin syndrome (SSSS), also known
pilaris in children. J Am Acad Dermatol 2002;47:386–9. as Ritter disease, staphylogenic Lyell syndrome or
22 Takeichi T, Akiyama M. Inherited ichthyosis: Non‐syndromic forms. pemphigus acutus neonatorum, is caused by phage group
J Dermatol 2016;43:242–51.
2 staphylococci that produce the exfoliative toxins A or B
23 Yoneda K. Inherited ichthyosis: Syndromic forms. J Dermatol 2016;
43:252–63. (ETA, ETB). As epidermotropic serine proteases, ETA and
24 Ott H, Hutten M, Baron JM et al. Neonatal and infantile erythroder ETB induce subcorneal cleavage by proteolysis of the
mas. J Dtsch Dermatol Ges 2008;6:1070–85. desmosomal adhesion protein desmoglein‐1, thereby
25 Prado R, Ellis LZ, Gamble R et al. Collodion baby: an update with a
focus on practical management. J Am Acad Dermatol 2012;67:
causing exfoliative dermatitis.
1362–74. The disease tends to affect neonates, infants and young
26 Craiglow BG. Ichthyosis in the newborn. Semin Perinatol 2013;37: children because of immature renal toxin clearance
26–31. and low serum levels of toxin‐neutralizing antibodies.
27 Hotz A, Oji V, Bourrat E et al. Expanding the clinical and genetic spec
trum of KRT1, KRT2 and KRT10 mutations in keratinopathic ichthyosis. Following a superficial staphylococcal infection (e.g.
Acta Derm Venereol 2016;96:473–8. purulent conjunctivitis, omphalitis), patients exhibit
paronychia has also frequently been reported. Unlike

neonatal candidiasis, which is acquired during passage
through the birth canal, the oral cavity and nappy area are
usually spared.
In neonates with CCC, further diagnostic and therapeu
tic measures are determined by the patient’s gestational

stage. In full‐term infants the disease is generally benign,
running a self‐limiting course without complications.
Oral fluconazole (3–6 mg/kg/day) is a safe option; in
milder cases, the condition can be treated with topical
agents alone (clotrimazole, miconazole) under careful
clinical surveillance. In contrast, premature infants with
CCC, especially those born before 27 weeks’ gestation
and/or a birthweight of <1000 g, may develop invasive
candidal infections that are associated with a mortality
rate of up to 40%. Therefore, a thorough diagnostic work‐up
Fig. 10.8 Widespread erythema with flaccid, rapidly eroding bullae in a should be performed in these high‐risk patients includ
male neonate with staphylococcal scalded skin syndrome (SSSS). ing blood, urine and cerebrospinal fluid (CSF) cultures.
Depending on test results, systemic antimycotic therapy
with liposomal amphotericin B or fluconazole should be
flexural and facial erythema which may eventually initiated under close clinical surveillance. Moreover, vari
coalesce into erythroderma. Other symptoms include ous transient and infectious pustular diseases of the new
extremely tender skin, fever and a rapid decline of the born must be considered as possible differential diagnoses
infant’s general condition. Sepsis‐like symptoms are not (see Chapters 6 and 11). In particular, Listeria monocytogenes
uncommon in this initial erythematous stage of the infection should be excluded as it may also present with
disease. Shortly thereafter, large, flaccid, rapidly eroding vesiculopustular eruptions in the n eonate and whitish
bullae appear over the entire body (Fig. 10.8). A positive macules on the umbilical cord and placenta [4,5].
Nikolsky sign can regularly be elicited in this exfoliative
stage of SSSS, whereas the mucous membranes are usually References
spared. 1 Handler MZ, Schwartz RA. Staphylococcal scalded skin syndrome:
Neonates and especially preterm infants with sus diagnosis and management in children and adults. J Eur Acad
Dermatol Venereol 2014;28:1418–23.
pected SSSS should be hospitalized, especially because 2 Aalfs AS, Oktarina DM, Diercks GF et al. Staphylococcal scalded skin
there is a reported mortality risk of about 2.5–11% in this syndrome: loss of desmoglein 1 in patient skin. Eur J Dermatol
age group [1]. If exfoliation is extensive, affected neonates 2010;20:451–6.
3 Saida K, Kawasaki K, Hirabayashi K et al. Exfoliative toxin A staphy
and infants should be treated with nonadhesive, polyure
lococcal scalded skin syndrome in preterm infants. Eur J Pediatr
thane wound dressings in analogy to burn care or epider 2015;174:551–5.
molysis bullosa patients. In addition, after microbiological 4 Darmstadt GL, Dinulos JG, Miller Z. Congenital cutaneous candidia
samples have been obtained, systemic antibiotic treatment sis: clinical presentation, pathogenesis, and management guidelines.
Pediatrics 2000;105:438–44.
is warranted, preferably consisting of penicillinase‐resistant 5 Aguin TJ, Sobel JD. Vulvovaginal candidiasis in pregnancy. Curr Infect
penicillins. For definitive diagnosis, isolated Staph. aureus Dis Rep. 2015;17:462.
strains may be sent for molecular genetic analysis of the
genes sea and seb. If other blistering or exfoliative skin
disorders such as toxic epidermal necrolysis, epidermolysis
Adverse drug reactions
bullosa hereditaria or ichthyosis bullosa of Siemens cannot Stevens–Johnson syndrome and toxic epidermal
be ruled out with certainty, a lesional skin biopsy should necrolysis (see Chapters 66 and 67)
be taken. Subcorneal acantholysis is the characteristic Stevens–Johnson syndrome (SJS) and toxic epidermal
feature of SSSS and distinguishes it from toxic epidermal necrolysis (TEN) represent a spectrum of severe, usually
necrolysis with subepidermal blistering [1–3]. drug‐induced skin changes that arise from massive apop
tosis of epidermal keratinocytes and an interaction of
Congenital cutaneous candidiasis (see Chapter 7) additional pathogenetic factors which are discussed more
Candidal chorioamnionitis, which occurs more often in thoroughly in Chapters 66 and 67. Both entities are
pregnant women who have had cerclage or placement of extremely rare during the first 2 months of life and only a
an intrauterine pessary, can manifest immediately post few cases of neonatal or very early infantile TEN have
partum as congenital cutaneous candidiasis (CCC). been published so far.
Whitish macules appear on the placenta and umbilical These neonates and young infants revealed irritability,
cord whereas the affected neonate has a maculopapular, poor feeding and hypothermia as nonspecific prodromal
sometimes pustular or bullous exanthema that may rap symptoms before the onset of cutaneous lesions. As in adults,
idly evolve into exfoliative erythroderma (‘white dots on skin involvement consisted of rapidly coalescing, tender,
the placenta, red dots on the baby’). Characteristically, the erythematous macules progressing to extensive exfoliative
palmoplantar and umbilical regions are involved initially; erythroderma with pluriorificial mucosal involvement.
Histopathological analysis of lesional skin revealed Immunological disorders (see Chapters

characteristic subepidermal blistering and complete 53 and 56)
necrosis of the epidermis, whereas the main differential
diagnosis SSSS was ruled out by the absence of subcorneal Omenn syndrome
splitting. In contrast, concurrent systemic infection with Omenn syndrome (OS, OMIM #603554) represents a
Klebsiella pneumoniae could be diagnosed in two individ genetically heterogeneous, autosomal recessive primary
immunodeficiency characterized by lymphadenopathy,
uals, whereas Candida albicans/dubliensis, Escherichia coli

and coagulase‐negative streptococci were found to be hepatosplenomegaly, elevated serum IgE and eosinophilia.
relevant pathogens in other affected individuals. Thus, It is caused predominantly by mutations in the recombi
the majority of patients had received multiple antimicro nation activating genes 1 and 2 (RAG‐1/RAG‐2), the
bial and other medications prior to the onset of blistering interleukin‐7Rα chain or the nonhomologous end‐joining
which hampered the identification of a single culprit factor Artemis, which interfere with somatic diversifica
drug. Unfortunately, all reported patients died despite tion of T‐ and B‐cell receptor‐encoding genes. This leads
the limitation of applied medications to vitally indicated to oligoclonal expansion of autoreactive T cells and a
drugs and intensive care support [1–4]. However, whether marked reduction in circulating B cells (‘T+B‐ SCID’,
neonatal TEN generally carries a fatal prognosis and ‘leaky SCID’).
whether concurrent sepsis is a relevant co‐factor or even Affected neonates and infants initially reveal severely
the main prerequisite for TEN in newborns remains to be pruritic eczematous lesions resembling atopic dermatitis,
elucidated. which can coalesce to form erythroderma, pachydermia,
onychodystrophy and alopecia while eyebrows and eye
Red man syndrome lashes may appear normal (Fig. 10.9a and b). Over the
Rapid intravenous administration (<60 min) of vancomy course of the disease, the majority of patients develop
cin and other antimicrobial agents, such as rifampicin, lymphadenopathy, hepatosplenomegaly, profuse diar
teicoplanin, ceftriaxone, amphotericin B or ciprofloxacin, rhoea and failure to thrive. Furthermore, patients often
can lead to nonspecific histamine release in up to 14% of present in a reduced general state with hypothermia,
treated patients. Within seconds to several minutes after hypernatraemic dehydration and clinical signs of bacte
the initiation of therapy, patients of any age may develop rial infection, particularly pneumonia, or even sepsis.
generalized flushing, with or without anaphylactoid More than 90% of children show a massive increase in
symptoms, and consecutive transient erythroderma giving total serum IgE levels and nearly all patients display
patients a ‘red man’ appearance. Studies of vancomycin marked peripheral eosinophilia. Lesional skin biopsies
have also shown that the most severe reactions tend usually show epithelial hyperplasia, spongiosis, focal
to occur in younger patients, particularly children. Further basal vacuolation and parakeratosis as well as an inflam
more, concomitant application of further histamine liber matory infiltrate in the upper dermis mainly consisting of
ators such as opioid analgesics or radiological contrast lymphocytes with few interspersed eosinophils.
media may enhance the risk of vancomycin‐induced red OS is known to have a lethal outcome if left untreated,
man syndrome. mostly due to recurrent severe infections. In the presence
The syndrome is easily recognizable, given the short of the characteristic clinical triad of erythroderma, hepat
interval between drug administration and onset of initial osplenomegaly and lymphadenopathy in conjunction
symptoms. As in other immediate‐type reactions, acute with typical laboratory changes such as marked eosino
therapy consists of intravenous administration of an philia and elevated total IgE levels, immunomodulatory
antihistamine and, if necessary, epinephrine in patients therapy with ciclosporin (cyclosporine) can be initiated
with circulatory disturbances. As a preventive measure, rapidly to suppress autoreactive T‐cell clones. This has
vancomycin should be given in an adequate dilution been shown to provide quick symptom relief, particularly
and the infusion rate should be less than 10 mg/min. In with regard to the often debilitating pruritus. Nevertheless,
the absence of alternative agents and if vancomycin is curative therapy can only be achieved with bone marrow‐
urgently indicated, desensitization with the culprit drug or umbilical cord blood‐derived haematopoietic stem cell
is possible but requires close clinical surveillance [5,6]. transplantation yielding survival rates that range from
less than 50% (haploidentical donor) to 75% (HLA‐identical
References
donor) [2–5].
1 de Groot R, Oranje AP, Vuzevski VD, Mettau JW. Toxic epidermal

necrolysis probably due to Klebsiella pneumoniae sepsis. Dermatologica
1984;169:88–90.
Graft‐versus‐host disease
2 Hawk RJ, Storer JS, Daum RS. Toxic epidermal necrolysis in a 6‐week‐ Along with Omenn syndrome, there are several other
old infant. Pediatr Dermatol 1985;2:197–200. severe combined immunodeficiencies (SCID) that are
3 Lohmeier K, Megahed M, Schulte KW et al. Toxic epidermal necrolysis inherited in an autosomal recessive or X‐linked pattern
in a premature infant of 27 weeks’ gestational age. Br J Dermatol
2005;152:150–1.
and are very rare with an estimated incidence of 1 in
4 Islam S, Singer M, Kulhanjian JA. Toxic epidermal necrolysis in a 50 000 to 1 in 500 000 live births. Owing to variable defects
neonate receiving fluconazole. J Perinatol 2014;34:792–4. in both T‐ and B‐cell immunity, classic symptoms such as
5 Myers AL, Gaedigk A, Dai H et al. Defining risk factors for red man profuse diarrhoea, failure to thrive, mucocutaneous can
syndrome in children and adults. Pediatr Infect Dis J 2012;31:464–8.
6 Wazny LD, Daghigh B. Desensitization protocols for vancomycin
didiasis and orogenital ulcerations can occur as early as
hypersensitivity. Ann Pharmacother 2001;35:1458–64. the first 4 weeks of life.
Upon analysis of the affected baby’s peripheral blood,

the identification of accessory HLA haplotypes, high
numbers of maternal lymphocytes or an XX genotype in a
male neonate are highly suggestive of GVHD. Interest
ingly, skin histopathology in neonates with SCID and
maternal engraftment has been reported to differ from

that obtained in patients with SCID after bone marrow
transplantation or after transplant for other diseases.
Whereas a vacuolar interface pattern is usually observed
in the latter disorders, GVHD due to maternal engraft
ment is characterized by psoriasiform epidermal hyper
plasia, dermal lymphocytic infiltrates, parakeratosis and
variable spongiosis [8].
Given the otherwise grave prognosis, haematopoietic
(a) stem cell transplantation should be performed promptly,
as it allows full recovery in 52% (HLA‐different, nonre
lated donors) to 92% (HLA‐identical, related donors) of
patients [6].
Other primary immunodeficiencies

While OS and GVHD due to maternal engraftment are
regularly associated with neonatal erythroderma, other
primary immunodeficiencies only occasionally induce
widespread erythema in newborns or very young
infants.
For example, patients with DiGeorge syndrome (DGS,
OMIM #188400), which is caused by a hemizygous
deletion of chromosome 22q11.2, suffer from conotrun
cal cardiac defects, hypoparathyroidism and immune
dysfunction due to thymic hypoplasia. Additionally,
affected infants and children frequently develop eczem
atous skin lesions closely resembling those of atopic
dermatitis. Nevertheless, generalized eczematous erup
tions have only very rarely been observed in newborns
with DGS [9,10].
Wiskott–Aldrich syndrome (WAS, OMIM #301000), an
X‐linked immunodeficiency with thrombocytopenia,
recurrent infections and secondary autoimmune disorders,
is associated with recalcitrant eczematous dermatitis in
nearly 90% of affected patients. However, only very few
WAS cases have been reported to present with neonatal
erythroderma [11–13]. Besides inflammatory skin lesions
and recurrent cutaneous infections, petechiae and ecchy
(b) mosis in a boy with eczema should raise the suspicion
Fig. 10.9 (a) Ichthyosiform erythroderma, pachydermia and alopecia in a of WAS [14,15].
female infant with Omenn syndrome. (b) Same patient as in (a) after The immune dysregulation, polyendocrinopathy, enteropathy,
5 days of incubator care, intravenous rehydration and topical therapy with
X‐linked syndrome (IPEX, OMIM #304790) represents a
panthenol ointment.Source: Ott et al. 2008 [1]. Reproduced with
permission of John Wiley & Sons.
very rare disorder caused by mutations in the FOXP3
gene, the master transcriptional regulator for the devel
opment and function of CD4+ regulatory T cells. IPEX
In addition, up to 50% of patients with T‐ SCID have patients reveal disrupted immune homeostasis resulting
maternal T cells in the peripheral blood leading to graft‐ in early‐onset autoimmunity with neonatal diabetes mel
versus‐host‐disease (GVHD) in nearly 60% of these cases. litus and hypothyroidism, recurrent infections, cytope
Affected infants may develop alopecia and severe neona nias and villous atrophy leading to enteropathy and
tal erythroderma with a scaly erythematous rash spread severe failure to thrive. Cutaneous symptoms include
ing craniocaudally, often also affecting the palms and eczematous skin lesions in up to 65% of patients that may
soles [6,7]. appear as severe and generalized ichthyosiform dermatitis.
If suspicion arises, a comprehensive immunological Additionally, serum total IgE levels are clearly elevated in
work‐up including differential blood counts, lymphocyte the majority of neonates and infants with IPEX who also
phenotyping and chimerism analysis should be performed. have marked peripheral eosinophilia [16–18].
References with the disease also have eczematous erythroderma with

1 Ott H, Hutten M, Baron JM et al. Neonatal and infantile erythroder
marked periorificial involvement and alopecia. IF HSD is
mas. J Dtsch Dermatol Ges 2008;6:1070–85.
2 Cassani B, Poliani PL, Moratto D et al. Defect of regulatory T cells in not included in the neonatal screening programme, rapid
patients with Omenn syndrome. J Allergy Clin Immunol 2010;125: diagnosis and effective therapy may be missed unless
209–16. carboxylase activity is analysed in cultured fibroblasts.
3 Bai X, Liu J, Zhang Z et al. Clinical, immunologic, and genetic charac
teristics of RAG mutations in 15 Chinese patients with SCID and
On the other hand, if a high clinical index of suspicion is
Omenn syndrome. Immunol Res 2016;64:497–507. supported by characteristic laboratory parameters such as
4 Caglayan Sozmen S, Isik S, Arikan Ayyildiz Z et al. Cyclosporin treat severe ketoacidosis, hyperammonaemia and hypoglycae
ment improves skin findings in omenn syndrome. Pediatr Dermatol mia, neonatal intensive care including biotin substitution
2015;32:e54–7.
5 Sharapova SO, Guryanova IE, Pashchenko OE et al. Molecular
at an oral dose of 10 mg daily is mandatory [1–3].
Characteristics, Clinical and Immunologic Manifestations of 11 Methylmalonic acidaemias (MMA, OMIM #251110,
Children with Omenn Syndrome in East Slavs (Russia, Belarus, #243500 and others) represent genetically heterogeneous
Ukraine). J Clin Immunol 2016;36:46–55.
6 Muller SM, Ege M, Pottharst A et al. Transplacentally acquired mater
disorders of methylmalonate and cobalamin metabolism.
nal T lymphocytes in severe combined immunodeficiency: a study of Patients affected by the infantile, non‐vitamin B12‐responsive
121 patients. Blood 2001;98:1847–51. subtype may appear healthy at birth, but rapidly develop
7 Wahlstrom J, Patel K, Eckhert E et al. Transplacental maternal engraft severe symptoms such as muscular hypotonia, respira
ment and posttransplantation graft‐versus‐host disease in children
with severe combined immunodeficiency. J Allergy Clin Immunol tory distress and encephalopathy which are associated
2017;139:628–33. with marked metabolic ketoacidosis, hyperammonaemia
8 Leclerc‐Mercier S, Bodemer C, Bourdon‐Lanoy E et al. Early skin and hyperglycinaemia. Cutaneous symptoms are initially
biopsy is helpful for the diagnosis and management of neonatal and
similar to the rash observed in acrodermatitis enteropathica
infantile erythrodermas. J Cutan Pathol 2009;37:249–55.
9 Archer E, Chuang TY, Hong R. Severe eczema in a patient with comprising acrofacial, psoriasiform dermatitis and alope
DiGeorge’s syndrome. Cutis 1990;45:455–9. cia. However, untreated infants may develop widespread
10 Minakawa S, Nakano H, Takeda H et al. Chromosome 22q11.2 dele erythema and, finally, exfoliative erythroderma [4–6].
tion syndrome associated with severe eczema. Clin Exp Dermatol
2009;34:410–11.
Similar acrodermatitis‐like eruptions have been
11 Sarkar R, Basu S, Sharma RC. Neonatal and infantile erythrodermas. encountered in newborns and infants suffering from
Arch Dermatol 2001;137:822–3. maple syrup urine disease (MSUD, OMIM #248600), another
12 Al‐Dhalimi MA. Neonatal and infantile erythroderma: a clinical and organic aminoacidopathy elicited by an impaired
follow‐up study of 42 cases. J Dermatol 2007;34:302–7.
13 Pruszkowski A, Bodemer C, Fraitag S et al. Neonatal and infantile branched‐chain alpha‐keto acid dehydrogenase complex
erythrodermas: a retrospective study of 51 patients. Arch Dermatol (BCKD). MSUD is characterized by elevated tissue, blood
2000;136:875–80. and urine concentrations of valine, leucine and isoleucine
14 Massaad MJ, Ramesh N, Geha RS. Wiskott‐Aldrich syndrome: a com
prehensive review. Ann N Y Acad Sci 2013;1285:26–4.
which are responsible for potentially severe symptoms
15 Loyola Presa JG, de Carvalho VO, Morrisey LR et al. Cutaneous such as respiratory distress, muscular hypotonia and
manifestations in patients with Wiskott‐Aldrich syndrome submit seizures. The only effective therapy currently consists of
ted to haematopoietic stem cell transplantation. Arch Dis Child restricted dietary intake of branched‐chain amino acids.
2013;98:304–7.
16 Chen CA, Chung WC, Chiou YY et al. Quantitative analysis of tissue Interestingly, generalized erythematous eruptions have
inflammation and responses to treatment in immune dysregulation, only been described in treated neonates, so far, and have
polyendocrinopathy, enteropathy, X‐linked syndrome, and review of been attributed to extremely low plasma levels of iso
literature. J Microbiol Immunol Infect 2016;49:775–82.
leucine. Accordingly, neonatal erythroderma resolved
17 Bin Dhuban K, Piccirillo CA. The immunological and genetic basis
of immune dysregulation, polyendocrinopathy, enteropathy, X‐linked after supplementation of the deficient amino acid in the
syndrome. Curr Opin Allergy Clin Immunol 2015;15:525–32. majority of affected patients [7,8].
18 Xavier‐da‐Silva MM, Moreira‐Filho CA, Suzuki E et al. Fetal‐onset
IPEX: report of two families and review of literature. Clin Immunol
2015;156:131–40.
References
1 Donti TR, Blackburn PR, Atwal PS. Holocarboxylase synthetase

Inborn errors of metabolism deficiency pre and post newborn screening. Mol Genet Metab Rep
2016;7:40–4.
(see Chapter 152)
2 Van Hove JL, Josefsberg S, Freehauf C et al. Management of a patient
Case studies have reported a number of hereditary meta with holocarboxylase synthetase deficiency. Mol Genet Metab 2008;95:
201–5.
bolic disorders that present with cutaneous symptoms in 3 Tammachote R, Janklat S, Tongkobpetch S et al. Holocarboxylase
neonates and infants. Of these, only holocarboxylase synthetase deficiency: novel clinical and molecular findings. Clin
synthetase deficiency, methylmalonic acidaemia and Genet 2010;78:88–93.
4 Fraser JL, Venditti CP. Methylmalonic and propionic acidemias: clinical
maple syrup urine disease appear to be frequently asso management update. Curr Opin Pediatr 2016;28:682–93.
ciated with neonatal erythroderma. 5 Sasaki M, Aikoh H, Sugai K et al. Picture of the month. Cutaneous
Holocarboxylase synthetase deficiency (HSD, OMIM lesions associated with isoleucine deficiency. Arch Pediatr Adolesc
#253270) is a very rare autosomal recessive metabolic Med 1998;152:707–8.
6 Bodemer C, De Prost Y, Bachollet B et al. Cutaneous manifestations
disorder arising from a defect in incorporation of biotin of methylmalonic and propionic acidaemia: a description based on
(vitamin B7 or H) as a prosthetic group in biotin‐dependent 38 cases. Br J Dermatol 1994;131:93–8.
enzymes such as acetyl‐CoA carboxylase and pyruvate 7 Koch SE, Packman S, Koch TK, Williams ML. Dermatitis in treated
maple syrup urine disease. J Am Acad Dermatol 1993;28:289–92.
carboxylase. While the major clinical findings include
8 Flores K, Chikowski R, Morrell DS. Acrodermatitis dysmetabolica
severe neurological symptoms such as lethargy and sei in an infant with maple syrup urine disease. Clin Exp Dermatol
zures as well as potentially lethal ketoacidosis, infants 2016;41:651–4.
iagnostic work‐up of neonatal

D (blood culture) should be performed to detect the exfo
erythroderma liative toxins A and B.
Whitish maculae on the placenta and umbilical cord
So far, no prospective multicentre studies of neonatal or warrant mycological investigation for Candida. Very pre
infantile erythroderma have been performed and, there mature infants who are diagnosed with congenital cutane
fore, evidence‐based diagnostic algorithms are still not ous candidiasis should be tested for an invasive candidal
available.

infection (CSF/blood culture).
However, even in the case of a complex differential If a clearly elevated serum IgE level is observed in a
diagnosis, a thoughtful stepwise approach to neonatal neonatal patient or a young infant with erythroderma,
erythroderma will lead to a straightforward clinical lymphocyte phenotyping is warranted. In patients with
diagnosis in most cases (see Fig. 10.1). The first step is to B‐lymphocytopenia, a mutation analysis, especially of
determine whether the physical examination and history the RAG‐1/RAG‐2 gene loci, should be obtained; in T‐cell
are consistent with psoriasis, atopic or seborrhoeic der immunodeficiency, a chimerism analysis should be per
matitis and, if so, to treat appropriately. If the answer to formed to detect engraftment of maternal T‐lymphocytes.
the first step is ‘no’ or there is no or insufficient response If the results of immunological tests are normal and
to therapy, the next step is to consider alternative diagnoses, hair shaft anomalies such as trichorrhexis invaginata
i.e. pustules with candidiasis, periorificial distribution in are not present, epidermal LEKTI expression should be
metabolic disorders. The third step is to assess whether determined by immunohistochemistry so as to exclude
the patient is ill or exhibits failure to thrive. If so, the Netherton syndrome.
patient is more likely to have an underlying infectious, A blood gas analysis showing ketoacidosis with con
immunological or metabolic disorder. comitant hypoglycaemia and hyperammonaemia has to
Irrespective of the underlying disease, neonates and be considered a metabolic emergency. Thus, patients
young infants with erythroderma are at greater risk of should be referred to a specialized centre for substitution
potential complications due to impaired epidermal barrier therapy or dietary counselling and further diagnostic
function such as hypothermia, hypernatraemia, dehydra testing (holocarboxylase‐synthetase activity in cultured
tion or hypoproteinaemia. Therefore, at the initial visit, fibroblasts, organic acids in urine).
these patients need to undergo a thorough clinical paedi Ichthyosiform erythroderma is particularly difficult
atric examination including neurological assessment and to distinguish from other diagnoses. The previously‐
measurement of bodyweight and core body temperature. mentioned molecular genetic and hair shaft analyses as
Initial capillary blood gas analysis and assessment of well as ophthalmological examinations, including fundus
serum electrolytes in combination with a limited number copy (glistening dots, sectoral cataract?), and if necessary,
of other screening tests such as differential blood count assessment of sterol isomerase and fatty aldehyde dehy
and serum total IgE level are also advisable. In desquama drogenase activity in cultured fibroblasts are needed.
tive and bullous erythrodermas affecting neonates, a skin
biopsy should be taken to locate the cleavage level and Reference
exclude toxic epidermal necrolysis. If subcorneal blister 1 Ott H, Hutten M, Baron JM et al. Neonatal and infantile erythrodermas.
ing is present, polymerase chain reaction (PCR) analysis J Dtsch Dermatol Ges 2008;6:1070–85.
134
CHA PTER 1 1
Vesiculopustular, Bullous and Erosive Diseases

of the Neonate
Caroline Mahon1 & Anna E. Martinez2

1
Department of Dermatology, Bristol Royal Infirmary, University Hospitals Bristol NHS Foundation Trust, Bristol, UK
2
Paediatric Dermatology Department, Great Ormond St Hospital for Children NHS Trust, London, UK
Introduction, 134 Autoimmune causes of vesicular and Other causes of neonatal blistering, 149
Benign and/or physiological neonatal bullous lesions in the neonate, 146 Erosive lesions in the newborn infant, 150
vesiculopustular and bullous skin Genodermatoses associated with neonatal
lesions, 134 blistering, 147
Abstract becomes accustomed to a low‐humidity environment, is colonized

with commensal organisms and matures as an environmental barrier.
The skin of the neonate must make a rapid adaptation to extrau- Distinguishing between cutaneous eruptions that represent benign
terine life. A number of benign physiological vesiculopustular and or transient physiological cutaneous phenomena, infections, inflam-
bullous skin lesions present in the newborn period and these matory dermatoses and genodermatoses is essential to guide clinical
probably represent adaptive events as the skin of the neonate management.
Key points • Most transient and benign vesiculopustular eruptions require

no intervention when typical clinical features present in a well
• Self‐limiting physiological and benign vesiculopustular skin newborn infant, however there should be a low threshold for
eruptions are very common in the neonatal period. further investigation if lesions progress.
• Blistering and erosions are most commonly due to infectious
causes, however genodermatoses and autoimmune skin disorders
should be considered in the differential diagnosis.
Introduction Benign and/or physiological

The skin of the neonate must make a prompt adaptation neonatal vesiculopustular
to extrauterine life. A number of benign and physiological and bullous skin lesions
vesiculopustular and bullous skin lesions may present Milia (see also Chapter 6)
in the newborn period. These eruptions probably rep- Milia are 1‐ to 2‐mm firm, pearly‐white papular lesions
resent adaptive physiological events while the skin with a pseudopustular appearance.
of the neonate becomes accustomed to a low‐humidity
environment, is colonized with commensal organisms
and matures to establish itself as an environmental barrier. Epidemiology and pathogenesis. In prospective
Distinguishing between skin eruptions that represent observational studies documenting cutaneous lesions
benign and/or transient physiological phenomena, in otherwise well full‐term neonates the incidence of
infections, inflammatory dermatoses and genodermatoses primary or congenital milia ranged between 7.5%
is essential to avoid the unnecessary investigation and and 50% [1–4]. One study found that milia were
treatment of newborn infants with benign skin lesions, significantly more common in male than female infants
to appropriately investigate those with likely signifi- at less than 48 hours of age [4]. Milia are subepidermal
cant pathology and to counsel parents appropriately keratin‐containing cysts that represent an accumula-
(Tables 11.1 and 11.2). For further differential diagnoses tion of keratin within vellus hair‐associated sebaceous
please refer to Chapter 73. glands.
Chapter 11 Vesiculopustular, Bullous and Erosive Diseases of the Neonate 135
Table 11.1 Differential diagnosis of vesiculopustular and bullous eruptions in the neonate
Pathophysiology Typical age of onset Clinical features Typical distribution Diagnostic investigations and
pathological features
Benign, self‐limiting and/or physiological vesiculopustular and bullous disorders

Milia At birth Pinpoint 1‐ to 2‐mm milky Cheeks, nasal bridge and Clinical diagnosis

papules alae, forehead Histopathology shows inclusion
cysts containing keratinized
stratum corneum
Miliaria crystallina At birth, or days to Confluent sheets or clusters of Forehead and trunk are most Clinical diagnosis
weeks of age 1‐ to 2‐mm fragile watery commonly involved Histopathology shows sub‐or intra‐
vesicles without inflammatory corneal eccrine duct obstruction
component
Erythema toxicum Typical onset at 1–2 days Small pinhead‐sized pustules Trunk and limbs excluding Clinical diagnosis
neonatorum (ETN) of age. May be seen as and vesicles associated with acral skin and mucous Pustule smear microscopy reveals
late as 2 weeks of age diffuse erythematous flares membranes predominant eosinophils
Miliaria rubra First days to weeks of Localized crops of erythematous Forehead, posterior neck, Clinical diagnosis
age papules and pustules trunk and proximal limbs Histopathology as for miliaria crystallina
Benign (or transient) Usually after the first Scattered superficial fragile Trunk, limbs, hands and feet Clinical diagnosis
neonatal pustular week of life and up pustules which erode leaving Mucous membranes are not Wright‐stained pustule smear
melanosis to 6 weeks of age a characteristic collarette of involved microscopy reveals predominant
fine scale and macular May infrequently occur on neutrophils (in contrast to ETN)
hyperpigmentation acral surfaces
Benign cephalic Onset within 1–2 Crops of fragile pustules and Face and scalp predominate. Clinical diagnosis
pustulosis weeks of age, up to vesicles associated with May occur over the neck
6 weeks of age erythema and often fine scale and upper chest
Neonatal eosinophilic At birth or weeks to Recurrent, intensely pruritic Scalp and acral sites Clinical diagnosis
pustulosis/pustular months of age pustulovesicular eruption Giemsa‐ or Wright‐stained smear
folliculitis microscopy of pustule contents
reveals abundant eosinophils
Acropustulosis of Typical onset within the Crops of inflammatory pustules Palmoplantar surfaces Clinical diagnosis
infancy first 8 weeks of age predominate Smears of pustule contents reveal
Occasionally present Dorsa of the hands and feet either neutrophil‐ or eosinophil‐
from birth may be involved predominant infiltrate
Infantile acne Onset usually from weeks Crops of comedonal and small Cheeks, chin and forehead Clinical diagnosis
to months of age cystic lesions.
Scarring may occur
Infective causes of vesiculopustular and bullous lesions in the neonate
Staphylococci At birth, or days to Superficial flaccid or fragile May occur at any site. Skin swab bacterial culture
(bullous impetigo and weeks of age blisters associated with The umbilical stump is a
staphylococcal desquamation and crusting common focus of bacterial
scalded skin May present as an exfoliative infection/colonization
syndrome) erythroderma with flexural
accentuation (staphylococcal
scalded skin syndrome)
Streptococcus At birth, or days to Superficial bullae and erosions May occur at any site Skin swab bacterial culture
pyogenes weeks of age associated with yellow crusts
Congenital or neonatal At birth, or days to Pustules and/or erosive skin Pustular lesions are generalized Skin swab microscopy and culture
candidiasis weeks of age lesions Congenital candidiasis may Microscopic examination of the
May be complicated by present as an erosive placenta and umbilical cord
pneumonia erythroderma The presence of microabscesses is
Skinfolds and the napkin highly suggestive of Candida
area are common sites of placentitis
involvement
Herpes simplex virus At birth, or days to Presents with either congenital Vesicles, bullae and erosions Viral swab HSV DNA PCR
(HSV) (types 1 and 2) weeks of age erythroderma and extensive may occur anywhere on Tzanck smear of blister base: balloon‐
skin loss or, in cases of the body and be localized like multinucleated giant cells and
postnatal infection, multiple or generalized eosinophilic inclusion bodies
clusters of monomorphic Mucosal lesions are common Direct immunofluorescence assay
vesicles and necrotic erosions (DFA) smear of vesicle contents or
on a background erythema mucocutaneous lesions
Histopathology shows acantholysis,
Infants may present with solitary keratinocytes within an
disseminated HSV infection intradermal blister cavity and viral
without skin lesions nuclear inclusion bodies
Clinical diagnosis
(Continued )
Table 11.1 Continued
Neonatal varicella At birth or within days Polymorphous fragile May occur at any site Viral swab VZV DNA PCR from skin
zoster virus (VZV) to 2 weeks of age (if haemorrhagic vesicles and Neonatal VZV infection is lesions or CSF
mother develops superficial erosions on an generally associated with Tzanck smear of blister base reveals
primary varicella erythematous base disseminated disease and multinucleate giant cells in the
infection 1 week may be severe and epidermis with marginated
before or after life‐threatening chromatin
delivery) DFA testing of smear of vesicle
contents
Histopathology reveals intraepidermal
vesiculation, multinucleated giant
cells and nuclear inclusions
Congenital Listeria At birth Haemorrhagic and purpuric skin Generalized skin lesions Bacterial skin swabs and blood
monocytogenes lesions with associated associated with sepsis is cultures
pustular and necrotic lesions typical
Congenital syphilis At birth Generalized and nonspecific Palmoplantar pustules and T. pallidum observed in skin
annular, erythematous or desquamation are classical scrapings or skin biopsy by
purpuric lesions when present dark‐field microscopy, Giemsa or
Localized pustules, blisters and silver staining
erosions (‘pemphigus Serological testing has variable
syphiliticus’) sensitivity and specificity
Rhinitis, periostitis metaphyseal Serum VDRL is nonspecific and may
erosions, hepatosplenomegaly be falsely positive
and lymphadenopathy Placental histology may be helpful
Scabies Days to weeks of age Urticated papules and plaques, Scalp typically involved in Clinical diagnosis
pustules and vesicles infants as well as trunk, Microscopy of skin scraping reveals
Absence of excoriation in limbs, palms and soles scabies mites and/or ova
neonates is characteristic Examination of close Dermoscopy reveals linear scabetic
May present with nodules and contacts is mandatory burrows
may mimic urticaria Skin biopsy reveals intraepidermal
pigmentosa and subcorneal pustules
associated with eosinophils
Coxsackie‐type Typically after the first Crops of acral perioral and genital Oral mucosa, perioral skin, Clinical diagnosis
enterovirus week to 1 month papules and grey‐blue vesicles palms and soles as well as Viral swab enterovirus DNA PCR
of age on an erythematous base dorsal hands and feet
May be koebnerized to flexural Not infrequent in the genital
skin, especially in infants with skin, buttocks and
eczema inguinal folds
Autoimmune causes of vesiculopustular and bullous lesions in the neonate
Maternally‐transmitted autoimmune blistering diseases
Pemphigus vulgaris Onset at birth or during Flaccid bullae and erosions Typically generalized Histopathology reveals
(PV) and pemphigus the first 2 weeks of associated with crusting affecting the skin and the intraepidermal blister
foliaceus (PF) age affecting the skin and mucous mucous membranes Direct IF: intercellular deposits of
membranes in both PV and PF (neonates in contrast to IgG and/or C3 in the epidermis
adults have diffusely Indirect IF: may be performed on
distributed desmoglein‐3 serum
in both the skin and
mucous membranes)
Bullous pemphigoid Onset within days or Urticated plaques and tense Widespread tense vesicles Histopathology shows eosinophilic
(BP) weeks of age serous fluid‐filled or and bullae spongiosis with subepidermal
haemorrhagic bullae on an Mucous membranes are not blistering/clefting
inflammatory base affected Direct IF: linear deposition of IgG and/or
C3 along the basement membrane
Indirect IF: may be performed on
serum or blister fluid
NaCl salt‐split skin reveals IgG
deposition on the epidermal side
(blister roof)
Pemphigoid gestationis Within the first week of Annular crops of vesicles and Blistering may occur Direct IF: linear deposition of IgG and
(PG) age bullae on a background of anywhere C3 along the basement membrane
Neonates affected in polycyclic or urticarial Mucous membranes are not NaCl salt‐split skin reveals IgG
3–5% of pregnancies erythema affected deposition on the epidermal side
complicated by PG (blister roof)
(Continued )
Linear immunoglobulin Onset of blistering Crops of tense vesicles and Generalized blistering Skin biopsy reveals subepidermal
A bullous dermatosis reported as early as bullae Mucosal involvement is blistering with linear IgA
1–10 days of life common in neonates and deposition along the epidermal
may lead to life‐threatening basement membrane

aerodigestive complications
Paraneoplastic causes of vesiculopustular and bullous lesions in the neonate
Pustular dermatosis of First weeks to the first Crops of superficial Facial rash is commonly Histopathology reveals infiltrate of
myelodysplasia in month of life pustulovesicular lesions on a described but may occur immature myeloid cells within
Down syndrome background urticated anywhere epidermal spongiotic
erythema vesiculopustular cavities
Other causes of vesiculopustular and bullous lesions in the neonate
Langerhans cell At birth, or within the Multiple haemorrhagic Lesions usually are Histopathology reveals dense dermal
histiocytosis (LCH) first days of life papulovesicles generalized with infiltrate of Langerhans cells
May mimic miliary predominance of lesions Staining for CD1a, S100 and
haemangiomatosis in the scalp, inguinal folds Langerin are classically positive
Solitary congenital LCH tumours and genital areas Histopathology as above
or ulcers have been described May occur anywhere on the
and are frequently self‐resolving body
Bullous mastocytosis At birth, or within days Sparse or generalized bullae Lesions may occur anywhere Histopathology reveals dense
to weeks of life associated with widespread on the body dermal mast‐cell infiltrate with
red‐brown plaques and plane of blister cleavage through
macules the lamina lucida
CD117 positive
Bullous neonatal lupus At birth or at days to Bullae on an inflammatory base May occur anywhere on the Histopathology reveals subepidermal
erythematosus (NLE) weeks of age healing with milia body blistering and vacuolar
Sun‐exposed sites are degeneration of the basal layer
thought to be more prone Maternal anti‐Ro/SSA and/or
to NLE lesions anti‐La/SSB antibody positive
Hyperimmunoglobulin At birth, days, weeks or Generalized sterile papulopustular Face and scalp involvement Histopathology reveals eosinophil‐
E syndrome (HIES) months of age eruption occurring within 2 initially, progressing in rich infiltrate similar to that
months of life in 67% of cephalo‐ caudal direction seen in EPF
infants with HIES Markedly elevated serum IgE levels
Mucocutaneous candidiasis and Three known gene mutations
fungal paronychia are common (TYK2, STAT3, DOCK8)
Deficiency of At birth or days to Sheet‐like micropustular eruption Usually generalized pustular Due to deficiency of interleukin‐1
interleukin‐1 weeks of age on background erythema lesions scattered anywhere receptor antagonist (DIRA)
receptor antagonist resembling pustular psoriasis on the body Skin biopsy shows neutrophilic
(DIRA) Fever, arthritis and/or subcorneal pustules
osteomyelitis may be Molecular genetic testing for
associated mutations in ILRN1
Neonatal bullous At 1–2 months of age Multiple indurated annular May be localized or Histopathology reveals a dense
neutrophilic plaques associated with generalized dermal neutrophilic infiltrate
dermatosis vesicles and bullae or A florid peripheral neutrophilia is
(Sweet syndrome) pustulation on an common
erythematous base Often heralds an immunodeficiency
syndrome, leukaemia or
autoimmune/inflammatory disorder
Genodermatoses associated with neonatal blistering
Epidermolysis bullosa At birth, or within days Bullae, erosions and/or May occur anywhere, but IF of the skin biopsy may be
(EB) or weeks of age ulceration extremities and sites of diagnostic; confirm with genetic
May present with large areas trauma most common testing if available; rarely EM may
of congenital skin loss Aplasia cutis congenita may be required
(aplasia cutis) occur in all forms of EB
Congenital At days to weeks of Generalized severe Skin fragility, bullae and Histopathology reveals
erythropoietic age photosensitivity superficial erosions in subepidermal blistering with
porphyria Severe blistering may result from light‐exposed areas of skin cleavage within the lamina lucida
phototherapy treatment for May be associated with Markedly decreased erythrocyte
neonatal jaundice profound haemolytic uroporphyrinogen synthase
anaemia activity and/or markedly increased
Pink urine and urinary levels of urinary uroporphyrin I
fluorescence under and coproporphyrin I isomers
Wood’s lamp is Detection of biallelic pathogenic
characteristic variant in UROS, or rarely GATA1
(Continued )
Incontinentia pigmenti At birth or up to 6 Blaschkolinear crusted May occur anywhere on the Histopathology shows
weeks thereafter vesicopustules on an body, although the face is intraepidermal blistering with an
(skin lesions may first inflammatory base almost always spared eosinophilic infiltrate
present as late as 1 Cicatricial scalp alopecia is Molecular genetic testing: IKBKG
year of age) not infrequent reveals deletion of exons 4–10 in
80% of cases
Superficial At birth or within a few Bullae and erosions with Intermittent blistering and Skin biopsy reveals hyperkeratosis,
epidermolytic days of age minimal associated desquamation may occur vacuolated keratinocytes and
ichthyosis (previously background erythema anywhere on the body keratohyalin granules in the
ichthyosis bullosa of Superficial erosions and No mucosal involvement epidermal granular and spinous
Siemens) desquamation, so‐called layers
‘Mauserung phenomenon’ No associated acral Molecular genetic testing of KRT2
keratoderma
Epidermolytic At birth or within a few Congenital erythrodema and Generalized erythema and Clinical diagnosis
ichthyosis (previously days of age fragile superficial bullae blistering resulting in Skin swab bacterial culture
called epidermolytic appearing at or within days superficial erosions with Molecular genetic testing of
hyperkeratosis or of birth desquamation KRT1 and KRT10
bullous congenital Annular subtype described Secondary bacterial infection Skin biopsy shows variable
ichthyosiform May be confused with is common hyperkeratosis and acanthosis
erythroderma) staphylococcal scalded skin No mucosal involvement with vacuolar change and
syndrome and suprabasal Palmoplantar keratoderma thickening of the epidermal
forms of EB may be present from birth granular layer
(more commonly
associated in infants with
mutations in KRT1)
CSF, cerebrospinal fluid; DEJ, dermoepidermal junction; DFA, direct fluorescent antibody; IF, immunofluorescence; NaCl, sodium chloride; PCR, polymerase
chain reaction (in vitro nucleic acid amplification); VDRL Venereal Disease Research Laboratory (serological treponemal antibody test).
Table 11.2 Differential diagnosis of erosive or ulcerative skin lesions in the neonate
Pathophysiology Age at onset Clinical features Typical distribution Pathological features and
diagnostic investigations
Mechanical and/or iatrogenic causes of erosions in the neonate

Iatrogenic scalp At birth Localized erosions on the Anywhere on the scalp Clinical diagnosis
birth injuries vertex of the scalp due to Usually linear or crescenteric lesions
pH scalp electrode, ventouse
or forceps placement
May be confused with aplasia
cutis capitis
Sucking blisters At birth Isolated annular erosions, Typically present on the thumb, fingers or Clinical diagnosis
usually solitary medial aspect of the forearms
Infective causes of erosions in the neonate
Staphylococcal At birth or days to Erythroderma with widespread Generalized desquamation Skin swab bacterial culture
scalded skin weeks of age superficial desquamation Perioral, genital and flexural accentuation Skin biopsy shows subcorneal plane
syndrome (SSSS) classical of cleavage
The umbilical stump is a common focus of
infection
Congenital or At birth, days to Erythema associated with May be present with erythroderma, Clinical diagnosis
neonatal weeks of life generalized pustules and generalized micropustulation, scaling Skin swab bacterial culture
candidiasis genital erosions with or without ulceration (congenital
candidiasis) or be localized to the
napkin area, trunk and/or the skinfolds
Herpes simplex virus At birth or at a few Erythroderma with erosions May present with either localized Tzanck smear
(HSV) infection days of age and ulceration ulceration or extensive areas of DFA testing of skin smear
(types 1 and 2) denuded skin Viral swab HSV DNA PCR
from skin lesions or CSF
Skin biopsy
(Continued )
Fetal varicella At birth (if mother Stellate, well‐circumscribed May occur anywhere on the body Clinical diagnosis
(VZV) syndrome infected in the ulcerations (aplasia cutis) May be associated with limb hypoplasia, PCR swab for VZV DNA

first 20 weeks of often in a segmental or microcephaly, ocular abnormalities from skin lesions or CSF
pregnancy) dermatomal distribution (microphthalmia, chorioretinitis, Serum IgM (25% positive)
corneal alterations, cataracts) and
growth retardation
Primary varicella At birth, days or Eroded or ulcerated papules Usually generalized PCR swab for VZV DNA
zoster virus (VZV) weeks of life and vesicles
infection
Ecthyma Days and weeks Necrotic plaques and May be solitary or multiple and occur Bacterial skin swabs/blood cultures
gangrenosum after birth ulceration anywhere on the body for Pseudomonas aeruginosa
localized ulcerations
Congenital Listeria At birth Haemorrhagic areas, May occur anywhere on the skin Bacterial skin swabs/blood cultures
monocytogenes purpura, pustules and
infection bullae
Primary cutaneous Days to weeks after Erosions, ulcerations and Skin may be primarily inoculated Skin biopsy
aspergillosis birth pustulation superimposed through areas of macerated skin, or Fungal hyphae may be visible in
Particularly on background erythema infected at sites of adhesive skin fresh tissue stained with calcofluor
associated with taping or central or peripheral venous Haematoxylin and eosin staining
prematurity and catheter devices variably demonstrates Aspergillus
central venous hyphae
access Period acid–Schiff and Grocott silver
stains may add sensitivity
PCR detection of Aspergillus DNA in
fresh tissue
Autoimmune causes of erosive lesions in the neonate
Maternally‐transmitted autoimmune blistering disease
Pemphigus Onset at birth or In both PV and PF, infants Erosions may involve both the skin and Skin biopsy reveals epidermal
vulgaris during the first 2 present with localized or mucous membranes in neonates with acantholysis with intraepidermal
(PV), pemphigus weeks of life extensive flaccid fragile PF or PV plane of blister cleavage
foliaceus (PF) bullae and crusted erosions IF: intraepidermal IgG antibodies
Other causes of erosive lesions in the neonate
Congenital erosive At birth Mixed erosions, vesicles and Typically generalized skin involvement Clinical diagnosis
and vesicular bullae in early neonatal sparing mucous membranes Almost Skin biopsy findings depend on
dermatosis with period all cases involve >75% of skin surface disease stage
reticulated Reticulated atrophic but
supple scarring subtle scarring evolves over
weeks to months
Langerhans cell At birth, or within Multiple small haemorrhagic Seborrhoeic distribution is classical, but Skin biopsy shows dense dermal
histiocytosis days of life erosions and ulcerations may occur anywhere infiltrate of Langerhans cells
(LCH) CD1a, S100 and Langerin positive
staining
Congenital At birth Solitary eroded or ulcerated May occur at any site Solitary lesions are generally self‐
self‐healing papule and/or nodule healing and regress spontaneously
reticulo- over 3–6 months
histiocytosis
Bullous and At birth, or within Sparse or generalized erosions Lesions may be single or multiple and Skin biopsy reveals a dense dermal
diffuse days to weeks of and ulcers admixed with occur anywhere on the body mast‐cell infiltrate with plane of
cutaneous life bullae and vesicles blister cleavage through the
mastocytosis Skin may thicken markedly in lamina lucida
early postnatal life CD117 positive staining
Aplasia cutis At birth Well‐demarcated, often Localized or widespread ulcers or scars Skin biopsy reveals absence of
congenita stellate areas of absent or May occur anywhere, but most common epidermal and dermal structures
scarred skin on the vertex of the scalp and skin appendages
Lesions may be linear and
appear blaschkoid or
dermatomal in distribution
Methylmalonic At birth or within days Extensive erythema and Marked perioral accentuation Skin biopsy is nondiagnostic
acidaemia of birth superficial erosions Blood count often reveals neutropenia
and thrombocytopenia
Plasma amino acid profile is charac
teristic and confirms the diagnosis
(Continued )
Genodermatoses associated with erosions and ulceration

Epidermolysis At birth, days or Bullae, erosions and/or May present with large areas of Skin biopsy
bullosa (EB) weeks of ulceration, particularly denuded skin or skin loss IF and EM may confirm the
postnatal life extremities Nail changes may be present at birth diagnosis
May present with localized Genetic testing may be appropriate
area of aplasia cutis on one
or more limbs
Epidermolytic At birth Erythroderma with occasional Generalized superficial exfoliation and Clinical diagnosis
ichthyosis fragile bullae and erosions Skin biopsy shows variable
superficial exfoliation Congenital palmoplantar keratoderma hyperkeratosis and acanthosis
Desquamation is often may be evident with vacuolar change and
annular and may mimic thickening of the epidermal
SSSS and other bullous granular layer
disorders Mutational analysis of KRT1 and
KRT10 genes
Superficial At birth Occasional bullae and Intermittent blistering and Skin biopsy
epidermolytic minimal erythema desquamation may occur anywhere Mutational analysis of KRT2 gene
ichthyosis Superficial erosions and on the body
desquamation No mucosal involvement
Incontinentia At birth or up to Blaschkolinear erosions/ May occur anywhere on the body, Clinical diagnosis
pigmenti (IP) 6 weeks ulcerations although face is almost always spared Mutational analysis of IKBKG gene
thereafter
(may first occur as
late as 1 year
of age)
Focal dermal At birth Blaschkolinear aplastic streaks May occur anywhere on the body Clinical diagnosis
hypoplasia and/or dermal hypoplasia Sparse scalp hair and/or patchy Mutational analysis of
(Goltz syndrome) often associated with fat cicatricial alopecia are common PORCN gene
herniation and
telangiectasia
Limb malformations, ocular
abnormalities and
craniofacial dysmorphism
are common
Restrictive At birth Tight, shiny translucent Severe generalized skin restriction Clinical diagnosis
dermopathy skin associated with Erosions typically on extensor surfaces of Skin biopsy reveals hypergranulosis
localized erosions and the joints and absent sebaceous and
ulceration eccrine structures
Joint contractures, pinched Mutational analysis of ZMPSTE24
facial features and or LMNA
microstomia are
characteristic features
CSF, cerebrospinal fluid; DEJ, dermoepidermal junction; DFA, direct fluorescent antibody; EM, electron microscopy; IF, immunofluorescence; PCR,
polymerase chain reaction (in vitro nucleic acid amplification).
bridge. Bohn nodules may be mistaken for natal teeth.

Clinical features. Milia are typically present at birth and
Profuse congenital facial milia are a prominent feature of
their facial distribution is characteristic. Most commonly
Basan syndrome, a rare autosomal dominant dermatosis
they are found on the face, typically on the forehead and
also associated with transient acral bullae, lack of derma-
chin and in the nasolabial folds. Mucosal lesions, either
toglyphs, and palmoplantar hypohidrosis [5]. Other rare
on the palate (Epstein pearls) or alveolar surfaces (Bohn
disorders associated with persistent or widespread milia
nodules) are also common.
include oro‐facial‐digital syndrome, hereditary trichod-
ysplasia (Marie Unna hypotrichosis) (OMIM #146550),
Differential diagnosis. The appearance and distribution Loeys–Dietz syndrome (OMIM #609192) [6], follicular
of milia is usually typical and does not cause diagnostic atrophoderma–basal cell carcinoma (Bazex–Dupré–Christol)
confusion. Milia most closely resemble sebaceous hyper- syndrome (OMIM 301845) and Rombo syndrome (OMIM
plasia, also common in neonates, but in contrast, seba- 180730) characterized by vermiculate atrophoderma, milia,
ceous hyperplasia is almost always confined to the nasal hypotrichosis, trichoepitheliomas and basal cell carcinomas.
adhesive medical monitoring leads and tapes. Congenital

Laboratory/histology findings. The diagnosis is clinical.
lesions are uncommon, but have been reported [10].
The histological appearance of milia is classical. Typically a
In some cases, a history of intrapartum fever is suspected
globular cyst lined with several layers of stratified squa-
to have been the trigger [11].
mous epithelium containing keratinous material is associ-
Miliaria rubra is characterized by crops of nonfolli-
ated with the infundibular portion of a hair follicle or
cular vesicles on an inflammatory base. Most often the
eccrine sweat duct. There is no associated inflammation [7].

flexural skin and sites of friction such as the neck folds
are most prominently affected, but miliaria rubra also
Treatment and prevention. Primary milia in newborns commonly involves the trunk. Type 1 pseudoaldoster-
resolve spontaneously over weeks to months and require onism, a disorder of mineralocorticoid resistance, results
no treatment. in excess loss of salt through eccrine secretions and
appears to characteristically cause a recurrent pustular
Miliaria form of miliaria rubra [12].
Miliaria is a pustulovesicular eruption caused by eccrine
duct obstruction leading to subcutaneous sweat reten- Differential diagnosis. Vesicular lesions may evolve to
tion. Three forms are described: miliaria crystallina become pustular and mimic the infectious lesions of
(sudamina), miliaria rubra and miliaria profunda. These Staphylococcus aureus, Candida albicans and herpes simplex
forms are clinically and histopathologically distinct, the virus (HSV). Miliaria rubra may be mistaken for erythema
appearances depending on the level of eccrine duct toxicum neonatorum, however unlike erythema toxicum
obstruction. miliaria rubra has a predilection for flexural skin and
tends to recur.
Epidemiology and pathogenesis. In a retrospective study
of 5387 Japanese infants examined on a postnatal ward,
Laboratory/histology findings. Miliaria crystallina is
miliaria crystallina was diagnosed in 4.5% of newborns,
characterized by sterile subcorneal vesicles, miliaria rubra
with a peak incidence at 1 week of age [8]. Obstruction of
by intraepidermal vesicles and, in cases of miliaria pustu-
the epidermal component of the sweat ducts leads to
losa, vesicles and pustules are present at the level of the
accumulation of eccrine secretions within the epidermis
dermoepidermal junction. Miliaria can be distinguished
and subsequently superficial vesicle formation.
from infective lesions by the absence of inflammatory
cells, negative bacterial and viral swabs and the presence
Clinical features. Miliaria crystallina is the most super-
of giant keratinocytes on cytological examination of
ficial form of miliaria. Fragile sheets of superficial trans-
vesicle contents.
lucent noninflammatory vesicles measuring 1–3 mm in
diameter and containing watery fluid are most commonly
Treatment and prevention. Cooling measures are gener-
seen in the neck folds and axillae and on the back. Lesions
ally all that is required. Infants should be unwrapped if
on the face are not uncommon (Fig. 11.1). Onset is typically
tightly swaddled and removed from warm or excessively
in the first days of life, and lesions are exacerbated by
humid environments. If care in an incubator is required,
high‐humidity environments, phototherapy and occlusive
the humidity and temperature should be reduced and the
clothing and emollients [9]. Lesions may be found under
infant dressed in loose clothing.
Erythema toxicum neonatorum

(see also Chapter 6)
Erythema toxicum neonatorum (ETN) is characterized by
pinpoint vesicles and pustules appearing on a blotchy
background of ill‐defined macular erythema.
Epidemiology and pathogenesis. The incidence of ETN

in population studies of infants in neonatal units and
postnatal wards varies between 8% and 44% [3,4,11–13].
Incidence is higher in Caucasian infants [10,14] but ETN
is seen in all ethnic groups with incidence rates appearing
to depend on the timing of the neonatal skin examination.
Some authors have reported a preponderance of female
infants [15,16], but others have not [10,11]. The incidence
of ETN appears to increase with gestational age with most
studies [6,11,17–19] reporting a higher incidence in term
Fig. 11.1 Miliaria crystallina on the forehead of a neonate.
infants than in those born prematurely. Associations with
Source: © Crown copyright [2000‐2005] Auckland District Health Board. mode of delivery are unclear: some authors have observed
Image courtesy of Auckland District Health Board, Department of Newborn higher rates of ETN in infants born vaginally [10,11,13]
Services. New Zealand. and others in those born by caesarean section [4,12,20].
The cause of ETN is not known. Many have speculated

that ETN represents a type of cutaneous hypersensitivity
reaction and a normal physiological response to coloni-
zation of neonatal skin with commensal bacteria and
yeasts [21].
Clinical features. Lesions appear as early as day 2 of life

and as late as 10 days. Congenital lesions have rarely been
reported [22,23]. Typically an infant with ETN presents
with multiple macular areas of blotchy ill‐defined ery-
thema with a central 1‐ to 2‐mm papule or pustule, most
commonly on the trunk [10] but possibly involving any
Fig. 11.2 Transient pustular melanosis on the sole of the foot of a
area of the skin except acral sites. Occasionally infants newborn infant.Source: © Crown copyright [2000‐2005] Auckland District
present with florid ETN with marked erythema and urti- Health Board. Image courtesy of Auckland District Health Board,
carial papules or pustules. Infants are characteristically Department of Newborn Services. New Zealand.
asymptomatic. Lesions spontaneously resolve over 2–4 days
and tend not to recur.
Clinical features. Lesions are typically present at birth.
Differential diagnosis. Confusion between the skin Milky‐white to yellow, fragile pustular lesions without
lesions of ETN, miliaria rubra and neonatal cephalic pus- background erythema are most commonly seen on the
tulosis may arise, or they may occur concurrently. The forehead, bitemporal regions, cheeks, neck and back.
lesions of ETN can generally be clinically distinguished Involvement of the palms and soles is less frequent
from those of herpes simplex and varicella zoster virus or (Fig. 11.2). The fragile pustules rupture with minor trauma
Candida albicans. Eosinophilic pustular folliculitis may leaving pea‐sized pigmented macules with a peripheral
closely resemble ETN both clinically and histologically, collarette of fine scale. The hyperpigmentation may
although large pustules rather than papules are the pre- persist for weeks to months. In some cases neonates
dominant morphological finding in eosinophilic pustular present with annular hyperpigmented macules associ-
folliculitis. ated with a peripheral halo of fine scale soon after birth,
having presumably developed pustular lesions in utero.
Laboratory/histology findings. Microscopic evaluation
of a pustule smear stained with Giemsa or Wright stain Differential diagnosis. Infectious diseases, in particular
reveals an eosinophil‐dominant exudate. A peripheral staphylococcal and streptococcal pyoderma, candidiasis,
blood eosinophilia may be observed in 7–15% [24] of primary varicella zoster and herpes simplex virus and
affected neonates. Skin biopsy reveals dermal oedema syphilitic infections may all mimic TNPM. Other benign
with a primarily eosinophilic perivascular infiltrate. In neonatal eruptions confused with pustular melanosis
papular lesions an eosinophilic infiltrate centred in the include eosinophilic pustulosis, benign cephalic pustulosis
pilosebaceous unit may be observed. and ETN.
Treatment and prevention. Parents should be reassured Laboratory/histology findings. Microscopic examination

that the natural history is spontaneous resolution without of a Wright or Giemsa‐stained pustule smear reveals a
specific intervention. No treatment is required. predominance of neutrophils with only occasional eosin-
ophils. A skin biopsy is rarely required for diagnosis.
Transient neonatal pustular melanosis Histopathology reveals epidermal pustules with either
(see also Chapter 6) intra‐ or sub‐corneal collections of neutrophils with scat-
Transient neonatal pustular melanosis (TNPM), also tered eosinophils [22] and a basal and suprabasal increase
called benign pustular melanosis, is a self‐resolving in pigmentation, without pigmentary incontinence.
pustular eruption that typically presents in the first

month of life. Treatment and prevention. TNPM is a self‐limited
disease in newborns, and no treatment is required.
Epidemiology and pathogenesis. TNPM affects both
sexes equally with an overall incidence of approximately Neonatal and infantile eosinophilic
0.5–1% [4] and is more common in Afro‐Caribbean infants, pustulosis
in whom the incidence is 4.4% [25]. The aetiology is Neonatal eosinophilic pustulosis (NEP) is a rare eruption
unclear. It has been speculated that TNPM is a variant that appears to be associated with prematurity [27]. It is
form of ETN, and therefore a physiological response to probably a variant of eosinophilic pustular folliculitis
skin colonization with commensal microorganisms, (EPF), a relapsing and remitting eosinophil‐predominant
because multiple cases of infants with pustular melanosis pruritic pustular dermatosis of unknown aetiology first
followed by the subsequent appearance of classical described in Japanese adults by Ofuji et al. in 1970 [28]
lesions of ETN have been described [26]. (also referred to as Ofuji’s disease), but subsequently also
reported to occur in infancy and childhood [29]. An infan-

tile form of EPF was first described in 1981 [30], followed
by the publication of a case series of five children [31] in
1984. Infantile forms of EPF do not consistently present
with histological evidence of folliculitis. Although the
clinical history, lesion morphology and distribution are

similar in eosinophilic pustulosis of infancy (EPI) [32]
and NEP [33], rather than being distinct disorders, these
entities are likely to fall within the spectrum of EPF.
Additionally, a number of authors have commented on
the clinicopathological similarity between eosinophilic
pustulosis of infancy and acropustulosis of infancy [28,34]
and have suggested that this entity also falls within the
spectrum of EPF.
Epidemiology and pathogenesis. There are a handful

of case reports describing nonfollicular eosinophilic
pustulosis and eosinophilic folliculitis in neonates, all
of which were boys born at 26–28 weeks’ gestation with
onset at between 7 and 13 weeks of age [24,35,36]. Two
infants had a preceding history of Candida sepsis.
A large series of 15 infants with EPI accompanied by a
review of an additional 46 cases from the literature Fig. 11.3 Infantile eosinophilic pustulosis of the scalp in a child aged
found that EPI is more common in boys, with a 36 months.
male : female ratio of 4 : 1, with a mean age of onset
of 6 months with 95% of children presenting before In neonates, NEP is characterized by sterile pustules
14 months of age [37]. There appears to be no racial primarily or exclusively involving the scalp with less
predilection, although EPF appears to be more com- prominent involvement of the face, trunk and extremities.
monly reported and probably more readily recognized Although EPI is characterized by remissions and relapses,
in Japan than in other countries [38]. only one of the neonatal cases described developed
The pathogenesis is unknown. The clinicopathological recurrence.
similarities between hyperimmunoglobulin E syndrome,
EPI and NEP, and the fact that eosinophilic folliculitis is Differential diagnosis. Staphylococcal and streptococcal
well described in patients with human immunodeficiency impetigo should be excluded, as should neonatal herpes
virus (HIV) [39], haematological malignancies [40] and simplex and varicella zoster virus infection. Scabies mites
immunodeficiency syndromes [41] suggests that a dys- commonly infest the head and neck in young infants who
regulated or immature immune response to an as yet may present with a florid vesiculopustular eruption in
unknown trigger is responsible for the vigorous cutane- the scalp. Hyperimmunoglobulin E syndrome may pre-
ous eosinophilic response seen in these infants. In both sent in the neonatal period [42] and this diagnosis,
children and adults EPF should be considered a potential although rare, should also be considered, as there is
cutaneous marker of immunosuppression. considerable overlap in the clinical presentation and labo-
ratory and histopathological findings in both disorders.
Clinical features. Pustular lesions are typically clustered Other diagnoses that may mimic NEP or EPI include
in groups (in contrast to adult EPF in which lesions are Langerhans cell histiocytosis, neonatal pustular melanosis
classically annular) and favour the scalp and bitemporal and neonatal cephalic pustulosis.
areas (Fig. 11.3). In 65% of cases other body sites are
involved and may include the palms and soles. Pruritus Laboratory/histology findings. Eighty percent of EPI
is very common (84%) and many younger infants are cases and all the cases of affected neonates have an
noted to be unsettled and irritable [34]. Crops of pustules associated peripheral eosinophilia with leucocytosis
with an associated erythema mature and crust over a [34]. A Wright‐stained smear of pustular contents dem-
matter of days, then spontaneously heal without scarring onstrates abundant eosinophils. Histopathology reveals
over subsequent weeks. Recurrence is the rule (intervals perifollicular (54%) or interfollicular (32%) inflammatory
between flares ranging from 1 to 12 weeks) with multiple infiltrates in upper and mid dermis, comprising pre-
stereotyped episodes of pustulation occurring over dominantly eosinophils together with neutrophils and
months to years following which there is spontaneous mononuclear cells [33].
resolution in all cases. Eighty percent of infants experi-
ence spontaneous resolution by 3 years of age [34]. Treatment and prevention. Although spontaneous reso-
Affected infants are otherwise well and no systemic lution is the rule, and treatment not necessarily indicated,
involvement, beyond a florid blood eosinophilia with pruritus may be troublesome. Numerous treatments have
leucocytosis, has been reported. been utilized in EPI, including topical corticosteroids [43],
oral antihistamines [26], dapsone [29] and erythromycin

[26] with mixed results. In adult cases, indometacin [44] is
the treatment of choice with response rates of 80–90%,
however in young infants this agent has significant
adverse effects, particularly on renal perfusion. Oral
indometacin has been used successfully in childhood [45].
Topical tacrolimus [46] and indometacin [47] have both

been used successfully, and these may be appropriate
first‐line treatment options.
Infantile acropustulosis
Epidemiology and pathogenesis. Infantile acropustulo-

sis (IA) was first described in 1979 by Kahn et al. [48]
and Jarrat et al. [49] who proposed this term to describe Fig. 11.4 Infantile acropustulosis involving the foot of an 18‐month‐old infant.
a series of 15 infants with recurrent crops of pruritic pap-
ulopustules on acral skin and the distal extremities pre-
treated for scabies prior to presentation, only one infant
senting within the first 2 months of life and responding
having confirmed scabies by microscopic examination of
rapidly to treatment with dapsone. In some cases lesions
a skin scraping. Infants were followed up for 2–24 months,
were present at birth. It appeared initially that acropustulo-
the majority (18) improving significantly with topical
sis was almost exclusively seen in Afro‐Caribbean infants;
corticosteroid therapy alone. A further series of 25 cases
however, not long after, IA was reported in a number of
reported by Dromy et al. reported similar findings
countries in infants of various ethnic groups [50]. Male
although of note two children in this series with very late
infants have predominated in the cases reported in some
onset IA presented at 8 and 9.5 years with classical clinical
[45–47,51] but not all [52,53] of the series reported.
features [53].
A number of authors have highlighted similarities
between scabies infestation and AI because in most cases
Differential diagnosis. The primary differential diagnosis
the clinical findings are indistinguishable [54,55]. Indeed,
of AI is scabies infestation. Other diagnoses to consider
some authors feel that AI does not represent a separate
are pompholyx‐type dyshidrotic eczema, an id dermatitis
clinical entity, and have documented high rates of EPI in
associated with dermatophyte infection. A viral exan-
immigrant children and infants from developing countries
them, such as hand, foot and mouth disease (coxsackie
with high rates of endemic scabies [48,56]. It has been
virus), recurrent herpes simples virus infection or impe-
postulated that in fact most cases of IA are in fact a sequela
tigo should also be considered. In those with involvement
of scabies infestation in which a hypersensitivity reaction
beyond acral surfaces, (particularly if the face and scalp
to the scabies mite and its detritus perpetuates cyclic
are affected), the diagnosis of EPI should be entertained.
recurrent acral pustulation. Diagnostic difficulty is com-
Transient neonatal pustular melanosis and congenital
pounded by the fact that infants are often diagnosed and
cutaneous candidiasis should be considered if onset is
treated empirically for scabies, albeit appropriately, early
at birth.
in the course, and may present to their paediatrician or
dermatologist many months after detection of mites or
ova is possible through skin scrapings. At the same time, Laboratory/histology findings. Direct smears from
there also appears to be considerable clinicopathological pustule contents reveal either neutrophils or eosinophils
overlap between some cases of EPI and IA, leading to fur- although the infiltrate is often mixed. Biopsy of acral sites
ther diagnostic confusion, particularly in infants in whom is rarely performed but, where reported, histopathology
pustular lesions are widespread [26,28,31]. shows intraepidermal vesiculation with either most com-
monly neutrophilic [57] or mixed neutrophil and eosino-
Clinical features. Intensely pruritic palmoplantar papules phil [58] or eosinophil‐predominant infiltrate [50]. Biopsy
evolve into 3‐ to 4‐mm fragile superficial pustules over of a precursor acral lesion has revealed intraepidermal
1–2 days followed by desquamation leaving multiple necrolysis without a cellular infiltrate [59]. A peripheral
collarettes of peeling skin (Fig. 11.4). Typically cyclic recur- eosinophilia may accompany the acral eruption [50,56,60].
rences tend occur 3‐ to 4‐weekly and flares are reported to In general, although the histopathological features are
occur up to the age of 3 years [49]. The dorsal surfaces of distinctive, skin biopsy is not required to make the diag-
the hands and feet are also frequently involved. Some nosis of AI once characteristic lesions are seen and the
infants have generalized involvement including lesions typical clinical course is established.
in the scalp, strongly suggesting overlap with EPI [28,31].
Extreme pruritus is a universal finding and infants are Treatment and prevention. Potent (class I and II) topical
often very unsettled because of itch. In a case series of 21 corticosteroids are the first‐line treatment and effective in
infants diagnosed with AI reported by Mancini et al. [52] aborting an exacerbation if used early and aggressively
lesions were first noted at between 1 and 30 months of during flares [49,50]. Some authors have however
age (mean age 9.7 months). Fourteen infants (70%) were reported poor responses to topical corticosteroids and
questioned their usefulness, although many have not age, 29 of these were culture positive [62]. In a more recent
stated the potency of the corticosteroids used [45,46,54]. similar study of 104 neonates, positive lesional culture
Scabicides are generally not helpful once recurring pustu- was demonstrated in only 6 of 26 infants with cephalic
lation is established and are not indicated unless there is pustulosis [60]. Thus, while there appears to be a strong
documented infection of a first‐degree relative or close association between Malassezia colonization in newborns
contact, the eruption is localized and dermoscopic skin and the development of cephalic pustulosis, a causative

examination and/or scrapings are positive. Dapsone at relationship has not been conclusively demonstrated.
1–2 mg/kg/day has been used with rapid improvement
in pruritus and sustained remission without relapse Clinical features. Infants typically present with non-
[45,54,61] and may be appropriate in severe cases unre- follicular inflammatory papules, pustules and pseudove-
sponsive to topical treatment. A recent case reported com- sicular lesions on a background erythema distributed on
plete responses using a topical D3 analogue, Maxacalcitol the forehead, cheeks and chin. Lesions may less frequently
0.0025% ointment, twice daily in the acute phase, and 3–4 involve the neck and upper chest. The typical age of onset
days per week thereafter [55]. is 2–3 weeks, but infants may present as late as 6–8 weeks
Acropustulosis of infancy eventually remits spontane- of age. Lesions are characteristically asymptomatic, but
ously with less florid and frequent recurrences over time. parents are often very distressed about the appearance.
Parents need to be reassured that this often distressing The natural history is spontaneous resolution over
condition improves gradually with time and does eventu- 7–14 days in the majority of infants [60].
ally remit even without treatment.
Differential diagnosis. Lesions may mimic or indeed
Benign or neonatal cephalic pustulosis
coexist with those of miliaria rubra and seborrhoeic
Benign cephalic pustulosis is a very common self‐resolving
dermatitis. Benign cephalic pustulosis has been called
pustular eruption that favours the face and scalp. Lesions
‘neonatal acne’, causing confusion between this common
consist of inflammatory papules, pustules and pseu-
neonatal eruption and true infantile acne vulgaris, a rela-
dovesicles. The role of Malassezia furfur colonization in
tively rare condition in which children usually present at
causing or perpetuating this inflammatory eruption is
6–9 months of age with comedonal, papulopustular and
unclear. This entity differs both clinically and histopatho-
sometimes cystic lesions typically confined to the cheeks
logically from infantile acne, and the term ‘neonatal acne’
and thought to be primarily androgen‐driven.
should therefore be discouraged.
Epidemiology and pathogenesis. Neonatal cephalic Laboratory/histology findings. Skin scrapings of affected
pustulosis (NCP) is common, the prevalence varying areas or of pustule contents may be examined using
between 10% and 66% of healthy term newborns [62,63]. potassium hydroxide (KOH) or KOH–Calcofluor wet
Clinical overlap with, or concomitant miliaria rubra and mounts. Stains such as Giemsa or periodic acid–Schiff
seborrhoeic dermatitis may be frequently observed. (PAS), Grocott, and Gomori’s methenamine silver may
Infants of all ethnicities are affected and there is no be used to identify yeasts (and dermatophyte fungi, as
gender predilection. indicated). Culture of Malassezia spp. requires specific
Aractingi et al. first described this entity in 1991 [64] in media (Dixon agar) and a positive growth of Malassezia
a 4‐week‐old infant with a cephalic vesiculopustular generally correlates well with positive smear microscopy.
eruption from which M. furfur was isolated. Rapelanoro However the identification of Malassezia species neither
et al. proposed a set of diagnostic criteria in 1996, which confirms nor refutes the diagnosis of NCP, given that
included the isolation of M. furfur from microscopy of colonization is common, and diagnostic swabs or smears
pustular contents [65]. Other criteria were: age at onset, are generally not recommended unless there is a need to
the presence of lesions distributed on the head and neck investigate an alternative infectious diagnosis.
and clearance with topical 2% ketoconazole therapy.
However, in many cases of NCP Malassezia spp. cannot Treatment and prevention. As infants are typically symp-
be detected on microscopy of pustule smear or culture tom‐free and the eruption self‐limiting, no treatment is
leading to uncertainty about whether colonization or required. Parents should be counselled that the eruption is a
indeed infection with this organism is responsible for benign and transient phenomenon thought to be related to
NCP [59,60,66,67]. the colonization of newborn skin with nonpathogenic com-
Malassezia is a dimorphic lipophilic commensal yeast mensal organisms and that it will resolve without scarring.
and can be isolated from 90% of healthy adults [68], If deemed necessary, topical treatment with a combination
11–50% of term infants in the first days of life and 52–80% of an imidazole (such as 2% ketoconazole or clotrimazole)
after 1 week of age [59,69]. Two studies following term and 1% hydrocortisone cream can be applied twice daily for
infants from birth observing Malassezia colonization rates 3–5 days, which typically leads to rapid clearance.
over time and documenting whether the subsequent
development of cephalic pustulosis relates to positive Erosive pustular dermatosis of the scalp
identification of a Malassezia species have been published. Erosive pustular dermatosis of the scalp (EPDS) is a rare
In a study by Bernier et al. of 102 neonates, 56 were cause of scarring alopecia and is primarily reported in
diagnosed with cephalic pustulosis at 3 weeks postnatal elderly patients and associated with chronic sun‐damaged
skin. In most cases a traumatic or topically applied irritant quantities. IgG transfer to the fetus represents an impor-
trigger precedes the eruption [70]. tant adaptive mechanism conferring short‐lived passive
immunity to the neonate. At the same time, placental
Epidemiology and pathogenesis. Pye et al. first described immunoglobulin transfer from mothers with IgG‐mediated
EPDS in 1979 in a series of older women with sterile pus- autoimmune blistering diseases may result in clinical
tules, erosions and scarring alopecia that resolved with expression of these diseases in the infant at birth or
topical corticosteroid therapy [71]. Since then there have during the first days of life. Pemphigus vulgaris (PV),
been multiple case reports and series of adult patients, pemphigus foliaceus (PF), bullous pemphigoid (BP),
and a handful of case reports in neonates with associated pemphigoid gestationis (PG) as well as epidermolysis
scalp trauma sustained during instrumental or difficult bullosa acquisita (EBA) have all been reported in babies
vaginal delivery [72] and in one case of an infant with of affected mothers. In almost all cases blistering has
Klippel–Feil syndrome who at 3 months of age developed developed in babies whose mothers had active disease in
scarring alopecia with chronic scalp ulceration with no pregnancy, however occasionally neonatal disease has
antecedent history of injury to the head [73]. presented in cases in which the mother’s disease was well
controlled, or who had no disease manifestations prior
Clinical features. At birth infants were noted to have to delivery but subsequently developed autoimmune
either annular ulceration or, in one case, necrotic crescen- bullous disease [76].
teric scalp erosion secondary to vacuum extraction and,
in one case, ulceration in the scalp following prolonged Epidemiology and pathogenesis. The autoimmune‐mediated
labour. Days and weeks after the initial injury, a pro- blistering diseases are extremely rare in neonates but
longed chronic phase develops in which inflammation, should be considered in the differential diagnosis of gen-
crust, scaling and an associated alopecia persists for many eralized or localized blistering or erosive lesions present
months. In the case series reported by Siegel et al. [72], either at birth or soon after. Transplacental transfer of
inflammation, crusting and in some cases recurrent pus- maternal IgG results in disease expression in the new-
tulation persisted for between 4 months and 2 years. born infant. There are multiple case reports of neonatal
PV and BP presenting in the newborns of affected moth-
Differential diagnosis. A diagnosis of EPDS is primarily ers [77]. PG is thought to affect 5–10% of infants of affected
clinical as there are no specific histological features. mothers [78]. Reports of maternally transmitted EBA [79]
Dermatophyte infections closely mimic EPDS and these and pemphigus foliaceus (PF) [80] are extraordinarily
should be excluded, particularly in infants presenting rare and the incidence is unknown. Overall, only a minor-
beyond the immediate neonatal period. The differential ity of infants of mothers with an antenatal diagnosis of
diagnosis includes scalp aplasia cutis congenita. Other con- autoimmune blistering disease develop disease manifes-
ditions associated with congenital or early and persistent tations [81].
neonatal scalp ulceration include ankyloblepharon– Male and female infants are affected equally. The
ectodermal defects–cleft lip/palate (AEC) [74] and occurrence and severity of maternally transmitted PV
ectrodactyly–ectodermal dysplasia–cleft lip/palate (EEC). and BP appear to correlate with disease activity and
serum antibody titres during pregnancy, however there
Laboratory/histology findings. Skin biopsy is nonspe- are a number of reports of neonatal PV and BP presenting
cific. Most of the pathological features are consistent with in infants of mothers with well‐controlled or inactive
chronic inflammation and/or scar tissue [68]. disease [82]. Stillbirths and neonatal deaths have been
reported and thus far have occurred exclusively in cases
Treatment and prevention. Bacterial superinfection is of PV, all occurring in infants whose mothers had severe
common, but antibiotic therapy generally fails to result in or poorly controlled disease during pregnancy [83].
healing of the ulceration [68]. Potent topical corticos-
teroids are the mainstay of treatment in most cases Clinical features. Blistering or localized skin erosions are
once fungal and bacterial infection has been treated or usually present at birth or within the first few days of life,
excluded. In adults, topical tacrolimus 0.1%, dapsone 5% although they may first manifest as late as 2 weeks after
gel, calcipotriol, intralesional and oral corticosteroids and birth [84] (Fig. 11.5). The diagnosis is usually straightfor-
oral isotretinoin have all been reported to be helpful in ward once a history of a maternal autoimmune blistering
isolated case reports [75]. A degree of scarring alopecia is disease is established. Blisters are usually generalized and
the inevitable long‐term sequela in most cases. morphologically similar to adult manifestations of the
respective bullous diseases. However, important differ-
ences warrant mentioning. In contrast to adult patients,
Autoimmune causes of vesicular
neonates with PV present with generalized blistering and
and bullous lesions in the neonate
erosions as well as mucosal blistering because neonates
Bullae in the newborn due to maternal have more diffusely distributed desmoglein‐3, the pri-
autoimmune blistering disorders mary target antigen in PV in nonmucosal skin [85].
(see also Chapter 6)
Of the human immunoglobulins, only IgG and its sub- Differential diagnosis. Infections – bacterial, viral and
classes cross the placenta to the fetus in significant fungal – are the important differential diagnoses, followed
problems for the affected neonate [89]. Of the neonatal

cases reported, the age at presentation ranged from 1 to
10 days. Most had a clinical course complicated by signifi-
cant respiratory and/or feeding problems and required
systemic treatment. In one case, severe ocular scarring
resulted in blindness [90]. Although cases described in

the literature have generally been severe, the author has
personal experience of infants in whom blistering was
mild and self‐limiting, requiring only topical treatment.
However, close follow‐up of all infants is advised. In con-
trast to neonatal maternally‐transmitted autoimmune
blistering diseases which spontaneously improve over
weeks, infants with LABD tend to have a prolonged
course, suggesting that the origin of the IgA autoantibodies
Fig. 11.5 Bullous pemphigoid involving the sole of the foot in a 2‐month‐
is not maternal [83].
old infant
Differential diagnosis. Other diagnoses to consider

by toxin‐mediated eruptions such as staphylococcal scalded include staphylococcal and streptococcal pyoderma,
skin. Pemphigus lesions may closely mimic impetigo. bullous pemphigoid, neonatal lupus erythematosus and
bullous erythema multiforme.
Laboratory/histology findings. If autoimmune blistering
is suspected in a neonate, the diagnosis can be confirmed Laboratory/histology findings. LABD is characterized by
by indirect immunofluorescence testing of a cord blood subepidermal blistering with abundant neutrophilic and
sample or by obtaining lesional smear and/or biopsy for eosinophilic dermal infiltrates. The demonstration of lin-
histopathology as well as a biopsy of perilesional fresh ear deposition of IgA along the basement membrane
skin for direct immunofluorescence studies. through immunofluorescence studies is diagnostic.
Treatment and prevention. The prognosis is generally Treatment. Aggressive treatment with systemic corticos-
excellent. The natural history is generally spontaneous teroids is indicated if respiratory, ocular or oesophageal
resolution over 1–3 weeks as maternal IgG is cleared from involvement intercedes. Early ophthalmology assessment
the infant circulation [79]. Neonatal PG typically resolves is strongly recommended. Dapsone is generally consid-
more rapidly than PV, PF and BP; PG generally clears ered the mainstay of therapy for LABD in the longer term,
completely and spontaneously within days of delivery. and is considered an appropriate first‐line steroid‐sparing
Topical therapy with moderate‐potency corticosteroids is agent. Screening for glucose‐6‐phosphate deficiency
usually all that is required. Systemic corticosteroids are should always be performed before commencing therapy.
rarely indicated. In those with localized disease or blistering confined to
the skin, a mild to moderately potent topical corticoster-
Neonatal linear immunoglobulin A (IgA) oid could be safely employed.
bullous dermatosis
Epidemiology and pathogenesis. Linear immunoglobulin

Genodermatoses associated
IgA bullous dermatosis (LABD) is extremely rare in
with neonatal blistering
infancy. There are seven reported cases of LABD presenting Incontinentia pigmenti
in the neonatal period to date [86]. None of the affected
infants had mothers with linear IgA disease. The major Epidemiology and pathogenesis. Incontinentia pigmenti
target antigen of IgA autoantibodies is linear IgA disease (IP, OMIM #308300) is a rare X‐linked dominant genoder-
antigen‐1 (LAD‐1) a component of BP antigen 180 of the matosis resulting from mutations in the inhibitor of the
basement membrane zone [87]. Genetic susceptibility is kappa B kinase gamma (IKBKG) (previously known as
likely as HLA‐DR3, HLA‐B8 and HLA‐DQW2 subtypes NEMO or Nuclear factor kappa B Essential MOdulator)
are found more frequently in patients with LABD [88]. gene. Mutations in IKBKG lead to aberrant expression of
an essential modulator protein NF‐κB in ectodermal tis-
Clinical features. LABD presents at birth or within days sues, resulting in disturbed transcriptional regulation of
of birth as multiple crops of tense, serous, fluid‐filled genes involved in apoptotic pathways and inflammatory
vesicles and bullae. There may be background erythema, as well as immune responses [91].
but this is not seen in all cases. Lesions may be clustered The estimated population prevalence is 0.7 in 100 000
or appear ‘targetoid’, but the classical annular ‘string‐of‐ [92]. IP is seen almost exclusively in females and is usu-
pearl’ lesions associated with linear IgA disease of child- ally lethal in males. Males represent 6% of all reported
hood are usually seen in older children. Neonatal LABD cases (largely due to sex chromosome aneuploidies or
may result in severe and extensive mucosal and respira- somatic mosaicism) and infants of undetermined sex
tory tract involvement and therefore pose life‐threatening make up 2–3% of cases [93]. The phenotypic expression of
IKBKG mutations is highly variable even within families. Other differential diagnoses include the autoimmune
This is thought to be due to skewed X‐chromosome inac- blistering diseases. It is often helpful to properly undress
tivation combined with highly pleiotropic IKBKG expres- the infant with neonatal blistering as the characteristic
sion resulting in generally poor genotypic–phenotypic blaschkoid patterning of the vesicles in IP may not be
correlation [94]. Many cases of IP are sporadic, but 55% immediately obvious if only localized areas of affected
have an affected mother, who is often unaware of her skin are examined.
diagnosis [95].
Laboratory/histology findings. Peripheral blood eosino-
Clinical features. IP may be thought of as a unique form philia is a characteristic finding in the neonatal period.
of ectodermal dysplasia with a characteristic neonatal A skin biopsy may be diagnostic, but is often not neces-
phenotype. The skin is almost invariably involved in sary to make the diagnosis. The classical features are a
neonates with IP and is the defining clinical feature. spongiotic epidermis with intraepidermal eosinophilic
Classical linear vesiculopustular lesions are almost vesiculation, dyskeratotic keratinocytes and pigmentary
always present at birth, although they may first appear incontinence.
as late as the sixth week of life, and represent the first of
four classically‐described phases of cutaneous involve- Treatment and prevention. The natural history is spon-
ment. Blaschkolinear vesiculopustular lesions are most taneous evolution of blistering to warty hyperkeratotic
commonly seen on the arms, legs, trunk and scalp lesions and eventually macular, linear, whorled or retic-
(Fig. 11.6), almost always sparing the face [92]. ulate hyperpigmented streaks over months to years.
IP may be associated with neurological and/or ocular Most adult patients have very subtle skin findings [99].
sequelae. Neurological complications are the most com- No specific intervention is known to modify this course.
mon cause of death and are present in approximately Basic skin care measures may prevent superinfection and
30% of cases. Seizures due to cerebral ischaemia and/or bland emollients may be helpful for crusting and hyper-
structural parenchymal anomalies are the most common keratosis. Ophthalmological assessment in neonates
presentation in the neonatal period [96]. More than 90% with IP is mandatory as sight‐threatening ocular pathology
of neurological problems are evident by the age of 2 years may evolve rapidly after birth [100]. Routine imaging of
[97]. Ophthalmic disease is common, occurring in 36–77% the brain of all neonates with a diagnosis of IP has
of IP patients, and may evolve rapidly in early life. been advocated by some authors [101] but consensus is
Without early intervention almost 60% of these abnor- lacking. Genetic counselling and prenatal molecular
malities may result in irreversible visual loss [98]. genetic testing in subsequent pregnancies should be
offered to parents.
Differential diagnosis. The blistering skin lesions of IP
in newborns are most frequently confused with herpes
simplex infection, but also with congenital varicella. Focal dermal hypoplasia (Goltz syndrome)
Epidemiology and pathogenesis. Focal dermal hypo-

plasia (FDH; OMIM #305600) is a rare X‐linked dominant
multisystem disorder associated with cutaneous, skeletal,
ocular and vascular anomalies. FDH is due to mutations
in PORCN, a gene coding for the PORCN protein, impor-
tant in Wnt signalling pathways involved in the early
fetal development of both mesodermal and ectodermal
tissues [102].
Clinical features. Characteristic cutaneous lesions are

present at birth, and often blaschkolinear typically
atrophic or cicatricial streaks associated with telangiec-
tasia are found on the trunk and limbs (Fig. 11.7). The
streaks may be accompanied by vesicular lesions, fat
herniation through depressed linear areas of atrophic
skin (soft yellow nodules), erosions or areas of frank
aplasia cutis. Macular hypopigmented and/or hyper-
pigmented streaks may coexist, as may other ectodermal,
skeletal and eye abnormalities.
Differential diagnosis. Other X‐linked dominant syn-

dromes in which skin, ocular and distal limb anomalies
are a prominent feature include X‐linked dominant
Fig. 11.6 Incontinentia pigmenti. Blaschkolinear vesiculopustular and chondrodysplasia punctata type 2 (Conradi–Hünermann–
eroded streaks on the arm of a 2‐week‐old infant. Happle syndrome) and congenital hemidysplasia with
typically born prematurely with tight, rigid, shiny and

translucent skin. The facial gestalt is distinctive and char-
acterized by a pinched nose and a fixed open mouth.
Generalized arthrogryposis is common. Erosions and
ulceration of the skin are frequently described, particu-
larly over joint prominences. Pulmonary hypoplasia is

common. Infants are often stillborn or born prematurely,
and die early in the neonatal period, primarily because of
severe pulmonary insufficiency.
Differential diagnosis. The typical clinical features of RD

do not usually cause diagnostic confusion. However the
presence of widespread skin erosions or ulceration in a
low‐birthweight newborn may lead to the consideration
of congenital infection or lethal acantholytic forms of
epidermolysis bullosa in the differential diagnosis.
Laboratory/histology findings. Skin biopsy shows hyper-

granulosis with large keratohyalin granules, a paucity of
dermal elastic fibres and absence of pilosebaceous and
eccrine glands [106].
Treatment and prevention. RD caused by recessive

Fig. 11.7 Focal dermal hypoplasia. Blaschkolinear atrophic and cicatricial (typically null) mutations in ZMPSTE24 causes a severe
streaks associated with telangiectasia.
phenotype and is generally lethal either in utero or early
in the neonatal period [104–106]. Treatment is support-
ichthyosiform erythroderma and limb defects (CHILD ive. Genetic counselling and prenatal molecular genetic
syndrome). testing in subsequent pregnancies should be offered to
parents.
Laboratory/histology findings. FDH may be diagnosed
clinically based on the presence of characteristic major
findings in the skin and skeletal systems. Clinical diag-
Other causes of neonatal blistering
nostic criteria have been established [103]. Molecular Bullous and diffuse cutaneous mastocytosis
genetic testing may be helpful in cases in which the diag-
nosis is uncertain. Skin biopsy is nonspecific. Epidemiology and pathogenesis. Blistering caused by
localized mastocytosis or diffuse cutaneous mast cell
Treatment and prevention. No specific therapy alters the infiltration of the skin rarely manifests as widespread
natural history of FDH. Dressing of eroded areas may be blistering at birth. Classically three forms of cutaneous
required in the newborn period. mastocytosis in children are described: mastocytoma
(solitary or up to three isolated skin lesions), maculopap-
Restrictive dermopathy ular mastocytosis (urticaria pigmentosa), multiple discrete
skin lesions and diffuse cutaneous mastocytosis (DCM).
Epidemiology and pathogenesis. Restrictive dermop- Mastocytosis is caused by clonal mast cell proliferation
athy (RD, OMIM #275210) is a very rare autosomal associated with somatic activating mutations in c‐kit [107].
recessive disorder and typically lethal in the newborn
period. RD results from homozygous null mutations in Clinical features. All forms of cutaneous mastocytosis
ZMPSTE24 which codes for zinc metallopeptidase, a pro- may be associated with blistering in infancy, but DCM,
tease enzyme responsible for cleaving prelamin A to form the rarest subtype, presents with neonatal erythroderma
mature lamin A, and less commonly, heterozygous muta- and generalized bullae [108]. Approximately 25 cases
tions in LMNA coding for proteins lamin A and C. LMNA have been reported. The male : female ratio was 2.5 : 1.
gene mutations and missense ZMPSTE24 appear to con- Almost all infants presented with bullae at birth [109].
fer a milder phenotype [104]. Five infants died before the age of 6 months due to systemic
involvement. Transformation to mast cell leukaemia has
Clinical features. RD results in profound fetal hypokine- been described [110]. Initially the skin is erythematous
sia due to skin restriction in late gestation. There is often a and dermographism is a prominent feature. Gradual
history of polyhydramnios, growth restriction and poor generalized thickening of the skin then develops (pachy-
fetal movements evident after 22 weeks’ gestation. Early dermia). In contrast to urticaria pigmentosa and mastocy-
fetal ultrasound scanning is often unremarkable, and the toma, neonatal DCM is often associated with systemic
severe restrictive effect of the dermopathy not evident symptoms, notably recurrent flushing, dyspnoea, vomit-
until the late second or third trimester [105]. Infants are ing and diarrhoea [94]. Neonates with DCM may present
with prolonged bleeding or develop purpuric lesions, A number of hypotheses have been put forward in an
probably due to heparin release. The tendency to blister attempt to explain nonsyndromic forms of ACC including
usually improves over 3–4 years. incomplete fusion of midline mesodermal tissues [115],
local ischaemic or thrombotic events in utero and focal
Differential diagnosis. Bullous mastocytosis may mimic pressure necrosis. More recently the potential role of genes
all infectious and autoimmune causes of neonatal blister- regulating skin morphogenesis has been emphasized,
ing as well as epidermolysis bullosa. particularly given the very strong association between
ACC and multisystem and dysmorphic syndromes [116].
Laboratory/histology findings. Skin biopsy reveals a This subject is covered in detail in Chapter 9.
plane of blister cleavage within the lamina lucida and a
dense dermal mast cell infiltrate. Serum tryptase is ele- Congenital erosive and vesicular
vated in infants with extensive cutaneous disease as well dermatosis with reticulated supple
as those with systemic involvement and has no utility as scarring
a prognostic marker [111]. Consideration should be given
to investigating infants with extensive or symptomatic Epidemiology and pathogenesis. Congenital erosive and
disease for systemic involvement. vesicular dermatosis with reticulated supple scarring
(CEVD) is very rare. To date 29 cases have been reported.
Treatment and prevention. Antihistamines (both H1 and CEVD affects mostly preterm infants (79%) and neonates
H2 receptor blocking agents) and sodium cromoglicate whose mothers had chorioamnionitis [117]. The cause is
are the cornerstones of treatment. Tyrosine kinase inhibi- unknown.
tors targeting the c‐kit ligand are promising novel thera-
pies for infants with severe systemic manifestations [112]. Clinical features. CEVD often causes diagnostic confu-
Neonates with DCM are at increased risk of developing sion in the neonatal period. Infants present at birth with
anaphylaxis‐like episodes [113] and parents should be widespread vesicles, multiple erosions and/or extensive
informed and educated in managing these. Provision of areas of ulceration. Typically most of the body surface is
an adrenaline autoinjector pen should be considered. involved. Alopecia of the scalp (43%) and nail hypoplasia
Immunization reactions are common and have been (46%) is common. Acral skin involvement is infrequent
reported to trigger systemic symptoms as well as circula- (7%). Reported associated anomalies include seizures,
tory collapse. The administration of routine childhood microcephaly, ocular anomalies, hepatomegaly and
immunizations may require specialist supervision [114]. delayed development. A third of infants develop new
vesicular skin lesions after birth, although in all cases the
eroded and ulcerated areas gradually heal in the months
Erosive lesions in the newborn infant after birth leaving soft, reticulated, often hypopigmented
Aplasia cutis congenita scarring. Hypohidrosis commonly develops due to
Aplasia cutis congenita (ACC) describes any congenital eccrine gland loss secondary to scarring and heat intol-
absence of skin which may be isolated or associated with erance and compensatory hyperhidrosis in non‐scarred
a host of syndromic disorders. The most common presen- areas is well described. In the longer term some (18%)
tation is a localized congenital area of absent skin or scar infants develop recurrent herpes simplex skin infections
on the scalp in an otherwise healthy neonate (Fig. 11.8). to which these children may be vulnerable. There is
emerging evidence to suggest that in utero infection with
herpes simplex virus is the cause of CEVD, which explains
the high incidence of post-natal recurrence.
Differential diagnosis. The primary differential diagnosis

is congenital infection. Lesions may closely mimic those
of disseminated congenital herpes simplex and varicella
zoster virus as well as Candida albicans infection. Eroded
or ulcerated lesions may at birth resemble those seen
in forms of aplasia cutis congenita. Transient bullous
dermolysis of the newborn may present with similar
extensive erosions, but these lesions are superficial
and heal rapidly without scarring.
Laboratory/histology findings. Skin biopsy findings are

very nonspecific and depend on the age of the lesions.
Early histopathological features include dermal oedema
and a mixed infiltrate consisting mainly of neutrophils.
No features of vasculitis or thrombosis have been noted.
Fig. 11.8 Aplasia cutis congenita of the scalp associated with the ‘hair Direct immunofluorescence reveals nonspecific deposits
collar’ sign in a 3‐month‐old infant. of IgG, IgA, IgM, C3 and fibrin [118]. Biopsies of older
lesions show characteristic scarring with either decreased 26 Ferrándiz C, Coroleu W, Ribera M et al. Sterile transient neonatal
pustulosis is a precocious form of erythema toxicum neonatorum.
or absent follicular and eccrine structures [119].
27 Finelt N, Kristal L. Patient characteristics of neonatal eosinophilic
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154
CHA PTER 1 2
Iatrogenic Disorders of the Newborn

Elia F. Maalouf 1 & Wilson Lopez2
1
Neonatal Unit, Homerton University Hospital NHS Foundation Trust, London, UK
2
Neonatal Unit, Barking, Havering and Redbridge University Hospitals NHS Trust, UK
Introduction, 154 Iatrogenic injury during pregnancy, 156 Iatrogenic skin disorders after birth, 159
Iatrogenic disorders of the newborn, 154 Iatrogenic injuries during labour, 157
Abstract profile, weak inflammatory response, unique extracellular matrix

c haracteristics and attenuated biochemical stress.
In spite of significant technical advances in neonatal care, skin
Iatrogenic injuries to the fetus and infant have longlasting
injuries continue to occur. Although severe injuries are less frequent,
consequences. Healing occurs without scar formation during
this is an ongoing problem facing neonatal care, especially as
early gestation as opposed to the postnatal period. Various
greater numbers of very preterm babies are surviving. Adherence to
factors play a role in scarless wound healing during early gestation.
standard neonatal procedures and careful monitoring can prevent
Fetal wound healing involves a distinct growth factor and cytokine
most of these complications.
Key points anti‐inflammatory cytokine profile and distinct extracellular

matrix rich in specific collagen and hyaluronan, and decreased
biochemical stress.
• There are distinct differences between fetal and postnatal
• Different types of iatrogenic injuries occur in the antenatal and
wound healing.
postnatal periods.
• Fetal wound healing has a unique growth factor profile,
weakened inflammatory response with characteristic
Introduction in the next few days. Monocytes differentiate into tissue

macrophages after entering the wound site and subse-
Iatrogenic skin disorders can occur before labour, during quently are important regulators of repair. The inflamma-
delivery or after birth. They are most commonly caused tory stage is responsible for the secretion of numerous
by skin injury, which may lead to infection and scarring. growth factors and cytokines. Cytokines are very impor-
tant in wound healing. Interleukin (IL)‐1β and tumour
necrosis factor (TNF)‐α have been shown to regulate the
Iatrogenic disorders of the newborn
recruitment and function of neutrophils [2].
Scar formation in postnatal skin Tissue macrophages continue the debridement process
Tissue injury initiates bleeding, coagulation, inflamma- begun by granulocytes, but they also secrete substances
tion, cell replication, angiogenesis, epithelialization and that initiate the development of granulation tissue in the
matrix synthesis [1]. Shortly after injury, vessels rapidly next phase of wound repair. If the conditions in the
constrict. Coagulation then limits loss of blood and gener- wound warrant it, macrophages recruit additional inflam-
ates biologically active substances that begin the early matory cells. Lymphocytes contribute in much the same
and late inflammatory phases of tissue repair. Coagulation manner, but probably to a lesser degree. Wound fibro-
also releases biologically active products that convert blasts are derived from cells surrounding the wound that
fibroblasts and endothelial cells into their reparative change their differentiated phenotypes and become
mode. This forms new local tissue and capillary cells. mobile during the process of replication. As they migrate
The next phase of healing, inflammation, begins with into the wound during fibroplasia, they proliferate and
activation of complement and the initiation of the classic secrete extracellular matrix.
molecular cascade, which leads to infiltration of the During angiogenesis, growth and migration of
wound by granulocytes. These cells consume contaminat- cells take place. The growth of vascular endothelial
ing bacteria and debris and are largely replaced by monocytes cells occurs simultaneously with fibroplasia during
Chapter 12 Iatrogenic Disorders of the Newborn 155
granulation tissue formation, stimulated in much the Characteristic features of fetal wound healing include
same manner as fibroblasts, namely by platelets and a weakened inflammatory response, decreased neutrophil
activated macrophage products. Angiogenesis results and macrophage infiltration, poor platelet aggregation
in the rich microvasculature that gives granulation tis- with decreased production of platelet‐derived growth
sue its deep red colour. Granulation tissue is a loose factor (PDGF) and TGF‐β and decreased production
matrix that appears in open wounds and is composed of pro‐inflammatory cytokines such as IL‐6 and IL‐8

of collagen, fibronectin and hyaluronic acid with dense [12,13].

infiltration by macrophages, fibroblasts and capillary Fetal fibroblasts respond weakly to IL‐6 and IL‐8 compared
endothelial cells. In wounds exposed to the external to adult skin [14]. Fetal skin during early gestation
environment, re‐epithelialization begins within min- expresses high levels of IL‐10, which deactivates
utes after injury. Epithelial cells surrounding the defect macrophages and decreases the production of pro‐
become mobile and move into the wound. Within inflammatory cytokines [15].
1–2 days, epithelial cells at the wound edge begin pro- Fetal wound also has an abundance of type III collagen
liferating, and the new cells migrate either along an which is deposited in a fine reticular pattern. There is an
undisrupted basement membrane or across a provisional increased level of high‐molecular‐weight hyaluronan,
matrix of fibrin and fibronectin, which is then replaced which has a suppressive effect on aggregation of platelets
with basement membrane. Necrotic tissue and foreign and their release of growth factors [13,16–18].
bodies are gradually separated from the wound as the Biochemical forces may play a part in wound healing. It
epithelial cells migrate under them. Once epithelial is postulated that increased shear force induces local pro-
integrity is completed, the epithelium becomes attached duction of profibrotic growth factor [19]. The amniotic
to the new basement membrane, thus creating a b arrier fluid provides the fetus with a unique environment. Fetal
to further contamination and water loss. skin wounds are continually bathed in the warm sterile
Repair is not complete for some time after the epithe- amniotic fluid, which is known to be rich in growth fac-
lium covers the wound and there is no longer a risk of tors that are crucial to fetal development [20]. The fluid is
wound separation. Remodelling is largely concerned also a rich source for extracellular matrix components
with the removal of loose extracellular matrix materials such as hyaluronic acid and fibronectin [21–23]. Amniotic
such as fibronectin and the slow deposition of type I col- fluid could modulate fetal skin wound repair simply by
lagen in fibrils, and complete remodelling takes months. allowing hyaluronic acid and fibronectin to come into
During remodelling, the tissue becomes stronger and direct contact with the wounds and by providing growth
more flexible. The end result is scar formation. A scar factors to stimulate fetal wound cells to make a unique
lacks some components of normal tissue and is therefore wound matrix [24].
less functional than the surrounding uninjured area. The Some of the properties of fetal skin wound healing may
major benefit of repair by scar is the rapid return of tissue reflect the development of fetal skin. Between 4 and 24
integrity. weeks’ gestation, the outermost layer of human skin is
called the periderm, which has the appearance of multi-
Fetal wound healing ple microvilli projecting from the surface of the skin. It is
Despite many reports of cutaneous scars caused by possible that the periderm has an absorptive function as
antenatal procedures performed for diagnostic or ther- an amniotic fluid dialysate membrane. What effect the
apeutic purposes [3,4], there have been several obser- changing histology of fetal skin during development has
vations that fetal skin wounds heal without scarring on wound healing remains to be fully determined. The
[5,6]. Recent experimental work demonstrates distinct fetus lies in a sterile environment and has a minimal
differences between fetal and postnatal skin wound inflammatory response to injury. This may play a vital
healing [7–9]. The nature of these differences remains role in the unique fetal repair process, considering the
unknown, but there are two general ideas that could important role that inflammation plays in adult tissue
provide an explanation: differences in fetal wound wound repair.
environment and differences in fetal cells, or a combi- The fetus grows and develops at an astounding rate. It
nation of the two. can be physically wounded but physiologically does not
Fetal wound healing differs from postnatal healing in respond to injury in an adult‐like fashion.
having a unique growth factor profile, weakened inflam- Fetal tissue repair may be a process closely resembling
matory response with characteristic anti‐inflammatory regeneration and growth rather than healing by scar for-
cytokine profile and distinct extracellular matrix rich in mation [25]. Consequent to injury, embryos mount a poor
specific collagen and hyaluronan, and decreased bio- inflammatory response. The levels of TGF‐ β1 and β2 are
chemical stress much lower in embryonic wounds when compared to
A different spectrum of growth factor subgroups is adult wounds [26]. Genetic analysis of fetal and postnatal
believed to be at play in fetal wound healing. Transforming cutaneous wounds sought to identify genes with differen-
growth factor (TGF)‐β and its isoforms secreted by many tial expression and proregenerative function. It was sug-
cell types are involved in tissue repair [10]. The ratio of gested that skin regeneration during wound repair in the
TGF‐β3 expression in a fetal wound is high in comparison fetus may be coordinated by multiple gene products
with TGF‐β1. Exactly the opposite pattern is observed in and that the pattern of expression of these genes declines
adults with hypertrophied scar [11]. with time [27].
Iatrogenic injury during pregnancy Chorionic villus sampling

Chorionic villus sampling (CVS) involves the use of a
Amniocentesis cannula or biopsy forceps under ultrasound guidance to
The aspiration of amniotic fluid is now a common
take a small biopsy of villi from the chorion fundosum.
procedure in obstetric practice. Its regular use was first
The villi are a good source of DNA and are (nearly always)
advocated by Bevis [28] in the management of rhesus
genetically, chromosomally and biochemically identical
disease. Amniocentesis is performed under ultrasound
to the fetus. The procedure can be performed using either

guidance using a 21‐gauge disposable spinal needle
the transcervical or the transabdominal route (Fig. 12.1).
with a stylet and a disposable syringe. Indications for
The main advantage of CVS is that it enables first‐trimester
amniocentesis are shown in Box 12.1 [29].
fetal diagnosis, therefore providing early reassurance,
Early amniocentesis (before 15 weeks of pregnancy) is
termination or treatment [29].
associated with higher fetal loss and increased complica-
As with amniocentesis, the main complication is
tion rates [30]. Direct fetal injury can be minimized by
pregnancy loss, occurring in about 2% [41]. There have
ultrasound‐guided amniocentesis [31]. Skin injuries
been reports of an increased incidence of cutaneous
during amniocentesis have been greatly reduced since
haemangiomas in infants exposed to CVS antenatally.
the introduction of ultrasound guidance. There is an
In one study, the reported incidence was 21%, which
increased risk of fetal injury during transplacental
was three times higher than the incidence in the general
amniocentesis therefore needle site should be selected
population. It was found that the incidence of cutaneous
to avoid the placenta where possible [32–36].
haemangiomas, defined as strawberry birth marks, was
Some studies have suggested that there is increased
significantly higher after CVS compared with second‐
incidence of indirect fetal injuries such as talipes equi-
trimester amniocentesis. This increased incidence was
novarus, congenital dislocation of hips or respiratory
largely confined to patients who underwent a transcer-
problems in infants born after amniocentesis compared
vical CVS procedure [42]. The mechanism by which
with controls who did not undergo amniocentesis
haemangiomas develop in the general population is not
[31,37,38]. A case of patellar disruption following
understood and it would therefore be difficult to explain
amniocentesis has been described [39]. Mid trimester
the above findings.
amniocentesis has been reported to cause fetal injury,
primarily in isolated case reports, and these attributions
Other antenatal procedures
have mostly been based on association rather than
Other procedures that may leave scars or needle marks on
direct evidence. These fetal injuries include exsanguina-
the skin of the newborn include:
tion, skin dimples, ocular injury and intracranial and
• fetal skin biopsies, which may be carried out for prenatal
bowel abnormalities [40].
diagnosis of the severe genodermatoses; with the
The likelihood of injury increases with the number of
development of DNA‐based prenatal diagnosis, this
attempts to obtain fluid [3]. In third‐trimester amnio-
technique is now rarely required
centesis, fetal skin injury has been reported with an
• fetal liver biopsy, which is performed for the diagnosis
incidence of 0.6–2% [3]. Total pregnancy loss has been
of rare inborn errors of metabolism when other tests are
reported to be about 1.9% with a 95% confidence inter-
not suitable, e.g. defects of the urea cycle enzymes
val of 1.4–2.5 [41].
• fetal tumour biopsy, which can be used to confirm the
diagnosis of teratomas or congenital adenomatoid mal-
formations of the lung
Box 12.1 Indications for amniocentesis
Before 20 weeks
• Chromosome abnormalities (maternal age, translocation carrier,

previous affected child)
• Fetal sexing in X‐linked disorders
• Neural tube defects (raised α‐fetoprotein or acetylcholinesterase
levels)
• Inborn errors of metabolism
• DNA analysis
After 20 weeks Syringe

• Bilirubin level estimation
• Phospholipids (for fetal pulmonary maturity)
• Fetal maturity
• Amniography or fetography
Speculum Cervix Portex catheter

Source: Adapted from Rodeck & Pandya 2001 [29].
Fig. 12.1 The transcervical approach for chorionic villus sampling.
• aspiration of fluid collections, such as fetal urine from a involves the breech and scrotum and very unpleasant in a
dilated bladder or a pleural effusion, which can be face presentation. The bruising normally clears sponta-
performed with ultrasound guidance neously in a few days. No specific treatment is needed,
• therapeutic procedures, such as intrauterine shunting but if there is extensive bruising early phototherapy
of obstructive uropathy, hydrocephalus or hydrotho- for hyperbilirubinaemia may be indicated.
rax, and aspiration of fluid from renal cysts, ovarian A cephalhaematoma (Fig. 12.4) is a subperiosteal

cysts or ascites, all of which can be performed antena- haematoma that produces a lump over the scalp limited

tally using ultrasound guidance. by the cranial sutures. Swelling is usually not visible until
several hours after birth, because subperiosteal bleeding
is a slow process. It is of little importance, although it may
Iatrogenic injuries during labour be many months before it finally disappears. The swelling
Fetal monitoring may begin to calcify by the end of the second week and a
Continuous fetal heart rate monitoring is indicated during few may remain for years as bony protrusions. No treat-
labour to monitor fetuses at risk of hypoxia [43]. This is ment is required, although phototherapy may be necessary
achieved by using an ultrasonic transducer placed on the for jaundice.
maternal abdominal wall or by using an electrode Rarely, a bleed may occur under the aponeurosis (sub-
attached to the fetal scalp (Fig. 12.2). The latter method aponeurotic haemorrhage); the bleeding is not confined
may produce bleeding at various levels in the scalp, to a single cranial bone like a cephalhaematoma but
including perforation of the periosteum and subperi- spreads rapidly over the head and down towards the
osteal haemorrhage. Whenever fetal heart rate monitor-
ing is being employed, it is vital that fetal acid–base status
can be established from a scalp blood sample. A falling
blood pH level indicates an impending problem and that
action aimed at delivering the mother will probably be
necessary. Scalp blood samples are obtained by perform-
ing a small incision in the scalp using the instrument
shown in Fig. 12.3. These injuries are a potential site of
serious neonatal infection, which may be acquired during
delivery. Persistent scalp bleeding due to fetal coagulopa-
thy has been reported following fetal blood sampling
[44]. Scalp gonococcal abscess following intrapartum fetal
monitoring is another rare complication [45].
Injuries acquired during normal or

operative deliveries
During labour, a caput succedaneum may develop. This
is defined as soft tissue oedema and bruising of the pre- Fig. 12.3 Lancet used to obtain fetal scalp blood for pH monitoring. The
senting part. The swelling looks uncomfortable when it blade measures 2 mm.
Fig. 12.2 Fetal scalp electrode for heart rate monitoring (note the hook
that penetrates the skin). Fig. 12.4 Left parietal cephalhaematoma in a term baby.
eyes. A significant fraction of the blood volume may be

lost into this haematoma.
Bruising may be seen after manipulative deliveries and
often in preterm infants. Vaginal breech deliveries also
predispose to bleeding into the muscles of the legs and
buttocks resulting from hypoxic capillary damage and
increased hydrostatic pressure in the fetal dependent

parts while awaiting delivery of the head [46].
Forceps deliveries
In addition to the above, forceps deliveries may also
cause erythema, abrasions, ecchymosis and subcutane-
ous fat necrosis of facial or scalp soft tissues. Their loca-
tion depends on the area of application of the forceps.
Moreover, in circumstances in which there is reduced (a)
area of contact, there is a predisposition to slipping of
the forceps, which can result in visible facial and cra-
nial markings [47]. Bruising of the skin after a forceps
delivery may be so extensive as to produce anaemia or
jaundice.
Vacuum extractors
Delivery by the vacuum extractor (ventouse) is occa-
sionally used instead of forceps when there is slow pro-
gress of labour. The vacuum is created using either a
metal or a soft (plastic or silicone rubber) cup applied to
the scalp and the baby is extracted by traction on the
handle (Fig. 12.5). When air is evacuated from the cup,
the scalp is sucked into the space inside the cup, so
producing the chignon, which has a greater diameter
(b)
above the rim than the rim itself (Fig. 12.6). Apart from
Fig. 12.6 (a) Severe skin trauma and chignon following ventouse extraction.
producing jaundice, the chignon is a benign lesion in the
The ventouse is more usually applied over the vertex. (b) Later appearance
majority of cases and it heals over a few days leaving no of the lesion.
scars, but rarely it becomes lacerated and infected.
Neonates delivered by vacuum have a higher incidence
of cephalhaematomas [48].
Abrasions to the scalp may also occur as a result of
34 weeks’ gestation because of a significant incidence of
rotation or movement of the cap on the skin, caused by a
complications [49]. Alopecia is a rare but important
badly placed cap. Sudden detachment of the cap can also
complication of ventouse deliveries [50].
cause skin damage. Ventouse extraction (vacuum
extraction) can be used only for cephalic presentations
Caesarean section
and is contraindicated in preterm deliveries before
Scalpel lacerations occurring during caesarean section
may be deep enough to require suturing and may occa-
sionally become infected.
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VII. Fetal wound healing may be modulated by elevated hyaluronic The widespread availability of intensive care facilities for
acid stimulating activity in amniotic fluid. J Pediatr Surg 1990;25:430–3. the newborn has resulted in the survival of many infants,
25 Adzick NS, Longaker MT. Characteristics of fetal tissue repair. In:
Adzick NS, Longaker MT (eds) Fetal Wound Healing. New York:
particularly preterm babies of low birthweight, who
Elsevier, 1992:53–70. would previously have died. Effective treatment may,
26 Ferguson MW. Wound healing‐scar wars. Ulster Med J 1998;(Suppl unfortunately, bring in its wake serious problems in the
1):37–40. form of iatrogenic disease which may cause or contribute
27 Colwell AS, Longaker MT, Peter Lorenz H. Identification of differ-
entially regulated genes in fetal wounds during regenerative repair. to rapid demise, or whose effects may accompany these
Wound Repair Regen 2008;16:450–9. infants for the rest of their lives.
28 Bevis DC. The antenatal prediction of haemolytic disease of the new- Most reports of iatrogenic damage in the literature
born. Lancet 1952;23:395–8.
29 Rodeck CH, Pandya PP. Prenatal diagnosis. In: Chamberlain G (ed.)
concentrate on tragic accidents which are potentially
Turnbull’s Obstetrics. London: Churchill Livingstone, 2001:169–96. avoidable by more careful use of equipment.
30 American College of Obstetricians and Gynecologists. ACOG Practice Fortunately, however, these major incidents are rare.
Bulletin No. 88, December 2007. Invasive prenatal testing for aneu- The less serious but more common iatrogenic damage,
ploidy. Obstet Gynecol 2007;110:1459.
31 Tabor A, Philip J, Madsen M et al. Randomised controlled trial of mainly to the skin, is usually wrongly considered the
genetic amniocentesis in 4606 low‐risk women. Lancet 1986;1:1287. inevitable price to be paid for survival in some pre-
32 Kappel B, Nielsen J, Brogaard Hansen K et al. Spontaneous abortion term infants.
following mid‐trimester amniocentesis. Clinical significance of pla-
Major risk factors of iatrogenic skin injuries after birth
cental perforation and blood‐stained amniotic fluid. Br J Obstet
Gynaecol 1987;94:50. are low birthweight, lower gestational age, prolonged
33 Bombard AT, Powers JF, Carter S et al. Procedure‐related fetal losses stay in the neonatal intensive care unit, surfactant use,
in transplacental versus nontransplacental genetic amniocentesis. Am mechanical ventilation, insertion of umbilical arterial
J Obstet Gynecol 1995;172:868.
34 Andreasen E, Kristoffersen K. Incidence of spontaneous abortion after
catheters, use of ionotropes for circulatory support, pat-
amniocentesis: influence of placental localization and past obstetric ent ductus arteriosus, bronchopulmonary dysplasia and
and gynecologic history. Am J Perinatol 1989;6:268. positive microbiology culture results [1].
Damage produced in ensuring adequate

respiratory function
The skin of the preterm infant is not as well keratinized as
that of the term infant or adult, and is thus very sensitive
to damage by pressure or friction. Unsightly excoriation
may be produced around the nose or mouth by contact
with endotracheal tubes or facemasks. Although injury of

this sort is not life‐threatening, it may induce considera-
ble parental anxiety. Many infants on neonatal intensive
care units are managed using nasal continuous positive
airway pressure (CPAP), which is delivered via nares‐
occluding prongs or via masks. This mode of respiratory
support has been associated with the development of
columella nasi necrosis [2]. Inappropriately fitted CPAP
devices can cause mild to severe nasal septum damage Fig. 12.7 Gangrene of the toes in a preterm baby who had an umbilical
[3]. Prolonged use of nasal CPAP in preterm babies can catheter.
cause nasal vestibular stenosis, which may require surgi-
cal correction in later life [4].
Newborns who develop a pneumothorax may require
the immediate insertion of a percutaneous drain. Drains
inserted in the second or third intercostal space in the mid-
clavicular line are more effective than those sited in the
anterior axillary line. This is because the tip of the drain is
more likely to be in the anterior third of the hemithorax
(the preferred position) if inserted through the anterior
chest wall [5]. Permanent breast tissue damage is the most
serious complication of anterior chest drains. In one study,
four (three girls) out of nine children in whom chest drains
were inserted in the neonatal period suffered cosmetically
important scars on the anterior chest wall. In the other five
children, mild scars over the anterior chest wall were
related to the site of insertion of the chest drain [6–8]. In
none of these reported patients was there any damage to
the nipple or areola. It is preferable to use the lateral
approach initially, especially in girls, and leave the ante-
rior approach for use if pneumothorax drainage is unsatis-
factory. Just as important as the site of insertion of the
chest drain is the method used to close the wound. Purse‐
string sutures inevitably pucker the skin and result in an
ugly scar that grows with the infant. Another method is to (a)
cover the wound with an occlusive dressing but, because
the wound edges are not apposed, healing is by granula-
tion; thus, the scar is still likely to be marked. The best way
of closing the wound is by apposing the wound edges
using simple suturing or thin strips of adhesive [6].
Conditions related to arterial

catheterization
Catheterization of the umbilical vessels is commonly per-
formed in the sick neonate because of the ready accessibility
of relatively large vessels. Umbilical arterial catheterization
may lead to thrombosis in the abdominal aorta or iliac arter-
ies. Major aortic thrombosis is infrequent but may lead to
serious skin complications such as gangrene of the limbs
(Fig. 12.7). Gluteal skin necrosis has been described as a
complication of umbilical arterial catheterization [9], but
very similar lesions may be produced by pooling of alcohol‐ (b)
containing cleaning solutions used to prepare the skin prior Fig. 12.8 (a) Skin necrosis in a preterm baby caused by alcoholic
to the insertion of the umbilical line (Fig. 12.8). disinfectant solutions. (b) Later appearance of the lesion.
Peripheral arterial catheterization is a widely used the early neonatal period, indicating that their skin is
technique for blood sampling and blood pressure moni- defective as a barrier. Both drug absorption and water
toring in neonatal intensive care units. The brachial artery loss in preterm infants fall steadily and by about 2 weeks
is an end artery to the lower arm, and thus damage or of age the skin of the most immature infants functions like
thrombosis of that artery caused by cannulation may lead that of mature infants. The varying barrier properties can
to ischaemia or gangrene of the lower part of the limb. be explained by the poor development of the stratum cor-

Radial artery sampling or cannulation may be accompa-

neum in the more premature infants at birth, and its rapid
nied by gangrene of the hand but more commonly the maturation after birth [27,28].
ischaemia caused is reversible after removal of the line.
Catheterization of the posterior tibial artery may lead to
the minor complication of cyanosis of the toes, which Extravasation injuries
responds to removal of the catheter [10]. Irreversible Total parenteral nutrition (TPN) consists of solutions con-
ischaemia of the foot following posterior tibial arterial taining a mixture of amino acids, sugar, electrolytes, min-
catheterization leading to gangrene and subsequent erals and trace elements. Intralipid emulsion, a mixture of
amputation has been described [11]. fats and fatty acids suitable for intravenous administra-
tion, can be added to TPN solutions. TPN is used in neo-
nates in whom feeding via the enteral route is impossible,
Complications related to drugs inadequate or hazardous and in whom this state is likely
and nutrients to be prolonged. The preferred route of administration of
Exposure to environmental toxins is also a concern in the TPN is via a central venous catheter placed in the supe-
infant. All infants, regardless of their gestational age at rior vena cava or inferior vena cava outside the cardiac
birth, are uniquely vulnerable to the toxic effects of chem- silhouette. Incorrect placement of the central line may
ical exposure because of the immaturity of their organs lead to serious thrombosis in the large veins of either
and a relatively high surface area to bodyweight ratio. upper or lower limbs. This would in turn lead to swelling
The vulnerability of neonates to cutaneous poisonings is of the affected limb. TPN may also be given via a periph-
thought to be related to their immature hepatic, renal and eral venous catheter. This route may also be used to
central nervous systems and high body surface to volume administer other infusions such as dopamine, which is
ratio, in addition to their accelerated growth and meta- used to improve blood pressure and renal perfusion,
bolic rates [12]. Percutaneous absorption of topical agents, sodium bicarbonate to correct metabolic acidosis or a dex-
while especially hazardous to the preterm baby, remains a trose solution of over 10% concentration to maintain ade-
danger throughout infancy. Conversely, the relative per- quate blood sugar levels. However, these fluids are very
meability of the skin of premature babies makes it a irritant and frequently thrombose the vessels.
potential route for drug delivery [13]. If extravasation occurs, permanent scarring may result.
Methaemoglobinaemia due to aniline dye absorption has Extravasation of lipid‐containing TPN solutions through
been well documented [14]. Percutaneous absorption of neo- a peripheral cannula will initially appear as a white, well‐
mycin has been associated with deafness [15]. Skin sloughing demarcated area over the affected site (Figs 12.9–12.11).
and blister formation with lethal blood ethanol levels have
been reported from the topical application of isopropyl alco-
hol in infants of less than 27 weeks’ gestation [16–19].
Hexachlorophene and iodine absorbed through the
skin are detectable in infant blood [20,21]. These com-
pounds need to be used with great caution in the new-
born because systemic absorption causes toxic side‐effects
[22,23]. Systemic absorption of iodine compounds may
produce metabolic acidosis, hypernatraemia and impair-
ment of renal function. Routine povidone–iodine applica-
tion in the umbilical cord has been reported to interfere
with neonatal screening for hypothyroidism [24]. The use
of iodine alcoholic solutions is contraindicated in very‐
low‐birthweight infants. Systemic absorption of 3% hexa-
chlorophene has been associated with spongiform
changes in the brains of newborn infants [25,26]. The use
of 3% hexachlorophene in the newborn should be avoided.
Ster‐Zac powder, used as an antiseptic applied to the
umbilical cord, contains only 0.33% hexachlorophene.
In general, infants born at 37 weeks’ gestation or later
show little or no drug absorption and have low skin water
losses, indicating that their skin is an effective barrier. By
contrast, infants born at 32 weeks’ gestation or before
show marked drug absorption and high water losses in Fig. 12.9 The acute phase of an extravasation injury.
Area of
chemical burn
Punctures
surrounding Verres
wound site needle
Fig. 12.12 Saline flush‐out technique of chemical burns. Source: Adapted
from Rutter 1987 [13].
plastic surgery. Extravasation from intravenous cannulas

inserted in the scalp may cause alopecia [6]. Extravasation
Fig. 12.10 Later phase of an extravasation injury.
of calcium‐containing TPN solution may lead to subcuta-
neous calcification. Spinal cord compression and necrosis
following TPN extravasation has been reported [29].
Management
Although every effort should be made to detect extrava-
sation injuries early by using clear adhesives to hold
peripheral cannulas in situ and thereby keeping the site of
potential injury in full view, inevitably some injuries may
not become apparent until a late stage. There is a continu-
ing debate about whether treatment of such injuries pro-
duces any long‐term functional or cosmetic benefits. A
final conclusion is difficult without a large controlled trial
to compare the results of treated and untreated groups.
A technique to deal with such injuries has been
described [30] and can be performed by neonatal unit
staff after appropriate training. Under strict aseptic condi-
tions, the discoloured area and surrounding skin are
cleaned and infiltrated with 1% lidocaine. Hyaluronidase,
500–1000 U, is injected into the subcutaneous tissue
beneath the damaged skin. Four small punctures are
made in the tissue plane with a scalpel blade around the
area to be treated. The central blunt cannula of a Verres
needle is inserted subcutaneously through one of the
Fig. 12.11 The granulation stage of an extravasation injury. puncture sites. (This is a needle used most commonly for
insufflation of air at gynaecological laparoscopy; Downes
Surgical Ltd, Sheffield; Rocket London Ltd, Watford.)
This will then gradually develop into a black area of Using a syringe attached to a three‐way tap, saline is
chemical burn. The immediate danger of extravasation injected; this should flow out freely from the other three
injuries is extension of the burn to involve the full thick- incisions (Fig. 12.12). The process is repeated, injecting
ness of the skin and the formation of an abscess, which through each incision and using in total up to 500 mL of
may lead to septicaemia. saline. If during the procedure the limb becomes oedema-
Scars caused by extravasation injuries are typically tous, excess fluid can be removed by gentle massage
larger than needle marks and are most commonly found towards the incisions. The damaged area is then dressed
over the hands and wrists. Extravasation injuries are with Jelonet or a similar dressing and kept covered for
more likely to occur when intravenous cannulas are 24–48 hours. The above technique appeared to be effec-
inserted in the lower limbs, particularly above the ankle. tive in preventing long‐term tissue damage if performed
The majority of extravasation injuries leave minor scars, early (within 24 hours) in a series of 96 patients. There
but some may result in permanent disfiguring scars were no complications reported from the technique in the
and fixed contractures of the limbs which may require study [31,32].
Problems related to intensive care

monitoring
Previously, immature infants survived the first few days
of life only to succumb to overwhelming sepsis and/or
life‐threatening fluid and electrolyte imbalances second-
ary to multiple areas of skin breakdown. Improved sur-

vival rates among smaller and more immature babies and
improving technology mean that more monitoring equip-
ment has to be anchored onto the infant’s fragile skin.
Skin surface probes are widely used to monitor heart rate,
respiratory rate, temperature and blood gases in sick pre-
term infants. Such monitors, although not strictly inva-
sive, need to be secured to the skin with adhesive tape, Fig. 12.13 Scar that resulted from the use of adhesive taping for a
nasogastric tube in the neonatal period.
which strips off the superficial layer of the stratum cor-
neum when it is removed.
Although this is of little consequence in a term infant, it To prevent damage caused by adhesives, the necessity of
is of tremendous importance in the very preterm infant every piece of tape or adhesive should be evaluated care-
below 30 weeks’ gestation, whose stratum corneum is fully, especially if applied directly to the infant’s skin. Skin
thin and poorly developed. Transepidermal water loss protection may be achieved by using a pectin‐based skin
increases, absorption of topically applied chemicals barrier such as the type used in ostomy care. This is applied
occurs more readily and the stripped area may provide a directly to the infant’s skin on all areas where tape will be
site for the entry of microorganisms [33]. The finding of used. For example, in neonatal units, where endotracheal
atrophic macules, possibly secondary to the use of elec- tubes are taped to the skin, protective barriers can be used
trodes or other adhesives in extremely preterm infants, underneath the tape. This will allow the endotracheal tube
has been termed ‘anetoderma of infancy’ [34]. to be changed as often as necessary without removing the
barrier, thereby maintaining skin integrity. Other uses of
skin barriers are underneath the tape used to secure an
Transcutaneous monitoring umbilical catheter, chest drains, nasogastric tubes or a tem-
Transcutaneous electrodes can be used for continuous perature probe from a radiant heater. Pectin‐based skin bar-
monitoring of the partial pressure of oxygen (PO2) and riers can also be used directly over exfoliated skin [35,36].
the partial pressure of carbon dioxide (PCO2). These tech- Another method of preventing skin damage caused by
niques are an invaluable adjunct to intermittent arterial adhesives is the use of karaya gum electrodes, which have
sampling during the acute course of respiratory disease. been demonstrated to be gentle to sensitive skin and very
The monitoring technique employs an electrode, gener- easy to remove or replace, and effectively monitor the cardi-
ally heated to 42–44 °C, which is attached to the skin and orespiratory status. These electrodes should be removed
measures the oxygen and carbon dioxide tensions in the and rotated at least once a day to assess the skin underneath
gas that has diffused from the arterialized capillary bed to and to prevent any damage from the silver chloride gel [37].
the skin surface and through a gas‐permeable membrane. Gentle and careful removal of adhesives is mandatory.
The skin in contact with the heated electrode suffers the Alcohol and/or adhesive removers should be avoided for
changes of an early burn, the surrounding skin is dam- routine use because of their potential for irritation and
aged by stripping when the adhesive ring is removed absorption. A gauze soaked in warm water is effective in
and, as the electrode site is usually changed every 4 hours, gently soaking off adhesives. Alcohol or adhesive remov-
a large area of skin is subject to trauma. In one follow‐up ers should be reserved for emergency situations or when
study, children were found to have lesions on the anterior the adhesives have softened and melted on to the skin. If
abdomen and chest consisting of normally textured skin used, they must be washed off with water [9].
with altered pigmentation caused by transcutaneous
monitors. Most of these lesions were not present at the Transillumination burns
time of discharge from the neonatal unit [30]. Transillumination has been used in neonatology in help-
One method that was described to reduce skin damage ing to identify vascular access and also in the diagnosis of
from transcutaneous oxygen electrodes is the use of plas- pneumothoraces. Blisters secondary to thermal burns
tic spray‐on dressings such as Op‐Site [33]. have been attributed to faulty devices [38,39].
Adhesive tape damage Needle marks

Skin damage may be caused by removal of adhesive tape In a follow‐up study of toddlers who had received neonatal
(Fig. 12.13). This may lead to a highly characteristic lesion intensive care, needle marks consisted of white pinhead‐
that resembles a healed skin graft donor site. Skin slough- sized lesions which individually were barely perceptible
ing, blister formation and haemorrhagic skin necrosis but, where grouped together, gave a speckled appearance.
with lethal blood ethanol levels have been reported after They are principally caused by the insertion of intravenous
attempts to remove adhesive tape using isopropyl alcohol cannulas and less often by venepuncture, arterial cannulas,
in infants of 27 weeks’ gestation or less [17]. arterial puncture and lumbar puncture needles [6].
Heelprick marks References

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Heelprick marks may give the heel a faintly granular and related factors in newborn infants. Paediatr Dermatol 2016;
appearance that most commonly develops months after 33:543–8.
discharge from the neonatal intensive care unit. Some 2 Robertson NJ, McCarthy LS, Hamilton PA et al. Nasal deformities
infants may develop small nodular lesions that intermit- resulting from flow driver continuous positive airway pressure. Arch
Dis Child Fetal Neonatal Ed 1996; 75:F209–12.
tently discharge a white material. These are thought to be 3 McCoskey L. Nursing care guidelines for prevention of nasal break-
implantation dermoid cysts and they rarely interfere with down in neonates receiving nasal CPAP. Adv Neonatal Care 2008;
function, usually disappearing by the age of 2.5 years. 8:116–24.
4 Smith LP, Roy S. Treatment strategy for iatrogenic nasal vestibular
Rarely, infants may have pronounced dimpling of their stenosis in young children. Int J Pediatr Otorhinolaryngol 2006;
heels [36]. 70:1369–73.
5 Allen RW, Lung AL, Lester PD. Effectiveness of chest tube evacuation
Complications of phototherapy of pneumothorax in neonates. J Pediatr 1981;99:629–34.
6 Cartlidge PHT, Fox PE, Rutter N. The scars of newborn intensive
Phototherapy is one of the treatment modalities com- care. Early Hum Dev 1990;21:1–10.
monly used in neonatal jaundice. The principle involved 7 Fox PE, Rutter N. The childhood scars of newborn intensive care.
is transcutaneous photoisomerization of unconjugated Early Hum Dev 1998;51:171–7.
8 Rainer C, Gardetto A, Frühwirth M et al. Breast deformity in adoles-
bilirubin to less toxic polar isomer. A macular erythema- cence as a result of pneumothorax drainage during neonatal intensive
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and minority ethnic babies due to increased melanogen- Arch Dis Child 1980;55:815–17.
10 Sphar RC, Macdonald HM, Holzman IR. Catheterization of the poste-
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Bronze baby syndrome is a rare complication of photo-
12 West D, Worobec S, Solomon L. Pharmacology: toxicology of infant
therapy. Babies with hepatic disease are predisposed to skin. J Invest Dermatol 1981;76:147–50.
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14 Howarth BE. Epidemic of methaemoglobinaemia in newborn infants.
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Broviac catheters may leave horrific scars (Fig. 12.14). 17 Schick J, Milstein J. Burn hazard of isopropyl alcohol in the neonate.
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167
C HA PTER 13
Epidemiology of Atopic Dermatitis

Carsten Flohr1, Jonathan I. Silverberg2, Joy Wan3 & Sinéad M. Langan4
1
Unit for Population‐Based Dermatology Research, St John’s Institute of Dermatology, Guy’s & St Thomas’ NHS Foundation Trust and King’s College, London, UK
2
Northwestern University Feinberg School of Medicine, Chicago, IL, USA
3
Department of Biostatistics and Epidemiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
4
Faculty of Epidemiology and Population Health, London, School of Hygiene and Tropical Medicine, London, UK
Why study the epidemiology of atopic Descriptive epidemiology of atopic Prevention of atopic dermatitis, 182
ATOPIC DERMATITIS
dermatitis?, 167 dermatitis, 171 Conclusion, 183
Defining atopic dermatitis for Specific risk factors, 175
SECTION 3:
epidemiology research, 168
Abstract implications for research findings. We discuss what we currently know

about AD epidemiology, focusing on prevalence, incidence and natu
ral history. In the final sections of the chapter, we assess the evidence
Atopic dermatitis (AD) is a critical disease to study due to its high
for risk factors for AD and what we currently know about preventing
prevalence and morbidity. In this chapter, we review AD definitions
AD. Prevention of disease is the ultimate aim for epidemiology and is
in epidemiology studies, including the challenges of identifying the
a noble ambition for AD, given the rising global prevalence.
disease and the heterogeneity in currently used definitions and their
Key points • Mixed data surround the role of breastfeeding, specialized

formulas and solid foods in the predisposition to AD.
• The ‘hygiene hypothesis’ suggests that AD may be due to lower
Descriptive epidemiology of atopic dermatitis (AD)
exposure to certain viral and bacterial pathogens, but there is no
• Reported prevalence rates of AD vary greatly; surveys suggest current evidence to suggest that exposure to a specific infection
that 10–30% of children in developed countries have AD with reduces the risk of AD.
plateauing prevalence rates in some countries. Lower, but rising, • Irritant exposure can exacerbate AD and increase sensitization,
rates are reported in developing countries. particularly in the context of an impaired skin barrier.
• AD starts in early life in most cases but may begin later in childhood • The strength of association between allergic sensitization and
or adulthood. AD varies widely across studies, and the aetiological role of
• AD is a costly disease that leads to impairments in quality of life. sensitization in AD remains uncertain.
• More recent studies suggest that many patients have persistent • Evidence suggests that specific atmospheric pollutants such as
or relapsed AD in adulthood. Severe childhood disease, early tobacco smoke may be associated with AD.
onset disease and concomitant or family history of atopy are
associated with worsened prognosis. Prevention of AD
• Environmental factors associated with urbanization and socio
• Allergen avoidance may not prevent AD; emerging evidence suggests
economic advantage are thought to contribute to the aetiology of AD.
that early allergenic food exposure may reduce food allergy.
• Prenatal probiotic exposure appears to be associated with a
Specific risk factors
reduction in AD, although further research is required addressing
• Genetic factors that predispose to an impaired skin barrier and timing and formulations.
immune dysregulation are associated with AD. • Limited evidence supports the use of prebiotics, synbiotics
• Environmental influences operating in utero, including maternal and omega‐3 long‐chain polyunsaturated fatty acids although
stress, antibiotic use and allergen exposure, have been proposed prebiotics may be helpful in formula‐fed babies.
to increase the risk of AD. • Emerging evidence suggests that early‐life emollient use may be
• Alterations in gut and skin microflora have been observed in beneficial in the primary prevention of AD.
children with AD; additional studies are needed before a causal • The use of water softeners was tested in a UK‐wide trial in
relationship can be established. children, but showed no benefit over usual care.
Why study the epidemiology of atopic geographical residence. Although this kind of information
dermatitis? may be important in terms of quantifying the burden of
Epidemiology, if mentioned at all in dermatological texts, disease and suggesting hypotheses about disease
is usually confined to brief descriptions of how the causation, it is of little practical use to those who suffer
frequency of skin diseases varies with age, sex and area of from skin diseases such as atopic dermatitis (AD). Modern
168 Section 3 Atopic Dermatitis and Related Disorders
clinical epidemiology goes much further than simply typically flexural, but possibly also limited to extensor
describing the burden of disease. It includes the study of or head and neck areas, or generalized. AD lesions can
causes or risk factors of AD, as well as the evaluation of be challenging to characterize owing to variable mor-
interventions to prevent and treat the disease [1]. Previous phology, including acute oozing and vesicles, subacute
studies relied more on questionnaires and physical exami- scaling, chronic lichenification and prurigo nodules,
nation, whereas more recent work often uses genetic and ill‐demarcated versus more psoriasiform lesions and
immunological tools to better understand the interplay variable intensity. AD is particularly difficult to define in
between genetic and environmental factors. adults because many have a nonflexural distribution of
Interest in the epidemiology of AD has risen in recent lesions, with more involvement of the head/neck and
years because the prevalence of AD is on the increase [2,3], hands, and disease onset in adolescence and adulthood
and because AD can be a very miserable and costly long‐ in a substantial proportion [2,3]. The time course of AD
term condition that may be difficult to treat. Furthermore, is also highly variable, with intermittent or chronic per-
because AD tends to be the first allergic disease to develop sistent disease, seasonal variation, flares secondary to
ATOPIC DERMATITIS
in early life, an increasingly large number of birth cohort emotional factors and episodic exposures. Unfortunately,
studies have investigated AD alongside food allergies, there are no widely accepted biomarkers or objective
SECTION 3:
hay fever and asthma in order to understand the relation- diagnostic tests for AD.
ship between these diseases. This chapter provides an Reliance on flexural dermatitis alone as a defining char-
overview of the basic epidemiology of AD, highlighting acteristic of AD is a reasonable approach to defining AD.
some of the important developments and gaps in current However, this approach would miss a large subset of AD
knowledge. patients with nonflexural disease. The Hanifin and Rajka
criteria are the gold‐standard diagnostic criteria for AD
References [4] and are commonly used in clinical trials, but they are
1 Williams HW. Epidemiology of skin disease. In: Griffiths C, Barker J, too cumbersome for large‐scale population studies and
Bleiker T et al. (eds) Rook’s Textbook of Dermatology, 9th edn. Oxford: were found to have low specificity [5,6]. There are a num-
Wiley‐Blackwell, 2016: vol.1, section 5.1.
2 Williams H, Stewart A, von Mutius E et al. Is eczema really on the
ber of other diagnostic criteria used to define AD interna-
increase worldwide? J Allergy Clin Immunol 2008;121:947–54. tionally (e.g. Japanese Dermatological Association,
3 Williams HC. Is the prevalence of atopic dermatitis increasing? Clin Korean Dermatological Association, American Academy
Exp Dermatol 1992;17:385–91. of Dermatology, etc.). However, these definitions of AD
are not well validated for use in epidemiological research.
Defining atopic dermatitis In 1990, a UK working party (UKWP) of 16 doctors
for epidemiology research selected a minimum list of six reliable diagnostic criteria
for diagnosing AD as a modification to the Hanifin and
• AD is difficult to define for epidemiological study Rajka criteria (shown in Box 13.1) [7]. Visible flexural der-
because of heterogeneity of nomenclature and clinical matitis is required to be ascertained by a trained observer,
manifestations. and a training protocol and quality control test have been
• Survey‐based approaches are relatively low cost, feasible developed for this sign [8] (Fig. 13.1). Nineteen validation
and scalable for population‐based studies. studies of the UKWP diagnostic criteria in both hospital
• There is a lack of consensus as to the best way to define and community populations in a number of different geo-
AD in population surveys. graphical settings, including Romania [9] and China [10],
• Self‐ or caregiver‐reported or healthcare‐diagnosed have found a sensitivity ranging between 10% and 100%
AD, the International Study of Allergies and Asthma and a specificity between 89% and 99% [11].
in Children (ISAAC) criteria and other approaches
may be sufficiently valid definitions of AD for epide-
miological study.
• Physician assessment is often costly, labour‐intensive, Box 13.1 The UK diagnostic criteria for atopic dermatitis for use
not feasible in large‐scale population‐based studies, in epidemiological studies
and might overlook disease activity between visits.
• There are no ‘objective’ tests or biomarkers that are Must have:
sufficiently valid for the epidemiological study of AD. • An itchy skin condition (or parental report of scratching or
AD is difficult to define for epidemiological study rubbing) in the last 12 months
because of the considerable heterogeneity of nomencla- Plus three or more of the following:
ture and clinical manifestations. AD is also referred to as • History of involvement of the skin creases (fronts of elbows,
eczema, atopic eczema, childhood eczema, etc. The term behind knees, fronts of ankles, around neck or around eyes)
eczema has several different uses, including as the most • Personal history of asthma or hay fever (or history of atopic disease
in first‐degree relative if child aged under 4 years)
commonly used lay synonym for AD, as a descriptive
• A history of a generally dry skin in the last year
morphological and/or histological term encompassing
• Onset under the age of 2 years (not used if child aged under 4 years)
multiple aetiologies, and as a diagnostic term for AD [1].
• Visible flexural dermatitis (this includes dermatitis affecting cheeks
The lack of standardized nomenclature for AD interna-
or forehead and outer aspects of limbs in children under 4 years)
tionally makes it difficult to develop consistent and valid
questionnaires for epidemiology research. Moreover, Source: Williams et al. 1994 [7].
there is a variable distribution of AD with lesions being
Chapter 13 Epidemiology of Atopic Dermatitis 169
Several approaches have been used to define AD for sometimes incorporated. In clinical epidemiology
epidemiology research, depending on the study design studies, physical examination and clinical criteria are
and objectives. In population‐based studies, questionnaires more commonly used. The various definitions used
are most commonly used, with physical examination to define AD in different studies make it difficult to
Observer’s protocol for recording the sign of

“visible flexural dermatitis”
A. Subjects aged 4 years and over

Your task is to record as consistently as possible the presence/absence
ATOPIC DERMATITIS
of one physical sign - ‘visible flexural dermatitis’.
To decide whether this sign is present or not, there are two components to consider:
SECTION 3:
Step 1 What dermatitis looks like
Definition of dermatitis: Poorly demarcated erythema (redness) with surface change
‘Surface change’ can mean fine scaling, vesicles, oozing, crusting or lichenification.
Here are some photographs to help you:
1. This is dermatitis. Note it is red, has an indistinct margin 4. This is lichenification in a white skin. Lichenification means
and there is surface change (in this case fine scaling). a thickening of the skin in response to scratching. The skin
markings are exaggerated and the skin feels thickened.
2. This is dermatitis showing another type of surface change, 5. This is lichenification in a black skin. Note the exaggerated
in this case oozing (clear fluid leaking from the skin) and skin creases and post-inflammatory pigmentation.
crusting (scabs).
6. This is also lichenification in a black skin. In this case,

3. These are vesicles (tiny clear “water” blisters). the thickening is comprised of smaller flat topped bumps
corresponding to the hair follicles – so called “follicular
lichenification”.
Fig. 13.1 The photographic protocol to determine the physical sign of visible flexural dermatitis. Source: Adapted from Williams et al. 1995 [8]. See also
https://www.nottingham.ac.uk/~mzzfaq/dermatology/eczema.
compare prevalence estimates and disease associa- diagnostic tests for AD, the best way to define AD for
tions worldwide. epidemiological research remains via clinical diagnostic
The advantages of questionnaires include relatively criteria (e.g. UKWP) or analogous questionnaires, or
low cost to implement, good feasibility and scalability questionnaires assessing for physician‐diagnosed AD or
for population‐based studies. However, there is a lack of eczema. It is imperative that AD be defined using validated
consensus as to the best way to define AD in population assessments that are repeatable, easy to use, acceptable to
surveys. Some studies rely on a single question based on the population under study and correspond well to our
a self‐ or caregiver‐report of ‘eczema’ (the validity of clinical concept of AD [5].
which is usually unknown). Some rely on a history of
healthcare‐diagnosed AD or eczema in the past year. This
approach was previously validated in a dermatology References
1 Kantor R, Thyssen JP, Paller AS, Silverberg JI. Atopic dermatitis,
practice setting and found to have good validity [12]. atopic eczema, or eczema? A systematic review, meta‐analysis, and
However, such questions may underestimate the preva- recommendation for uniform use of ’atopic dermatitis’. Allergy
ATOPIC DERMATITIS
lence of AD because they require access to and utilization 2016;71:1480–5.

2 Katsarou A, Armenaka M. Atopic dermatitis in older patients:
of healthcare, which varies widely between countries
SECTION 3:
particular points. J Eur Acad Dermatol Venereol 2011;25:12–18.

and regions. The ISAAC and National Health and 3 Hanifin JM, Reed ML; Eczema Prevalence and Impact Working
Nutrition Examination Survey in the USA used a com- Group. A population‐based survey of eczema prevalence in the
posite definition of AD based on three questions about United States. Dermatitis 2007;18:82–91.
4 Hanifin J, Rajka G. Diagnostic features of atopic dermatitis. Acta
the presence of an itchy rash for at least 6 months, the Derm Venereol (Stockh) 1980;92(suppl):44–7.
presence of such a rash in the past 12 months, and flex- 5 Williams HC. What is atopic dermatitis and how should it be
ural distribution. These are analogous to having three defined in epidemiological studies? In: Williams HC (ed.) Atopic
Dermatitis: The Epidemiology, Causes and Prevention of Atopic
major Hanifin and Rajka or UKWP criteria for AD. This
Eczema. Cambridge: Cambridge University Press, 2000:3–24.
approach has been previously validated in children from 6 Schultz‐Larsen F. The epidemiology of atopic dermatitis. In: Burr ML
multiple countries and found to have high specificity (ed.) Epidemiology of Clinical Allergy. Basel: Karger, 1993:9–28.
and variable sensitivity [13–17]. However, it has some 7 Williams HC, Burney PG, Pembroke AC, Hay RJ. The U.K. Working
Party’s Diagnostic Criteria for Atopic Dermatitis. III. Independent
limitations as sensitivity has not been adequately tested hospital validation. Br J Dermatol 1994;131:406–16.
in adults [18,19]. 8 Williams HC, Forsdyke H, Boodoo G et al. A protocol for recording
The advantages of physician’s examination include the sign of flexural dermatitis in children. Br J Dermatol 1995;133:
pseudo‐objective assessment and the potential to distin- 941–9.
9 Popescu CM, Popescu R, Williams H, Forsea D. Community valida-
guish between AD and similar‐appearing dermatoses. tion of the United Kingdom diagnostic criteria for atopic dermatitis in
However, there are several limitations of using physician Romanian schoolchildren. Br J Dermatol 1998;138:436–42.
examination in epidemiology studies of AD. Physician 10 Gu H, Chen XS, Chen K et al. Evaluation of diagnostic criteria for
atopic dermatitis: validity of the criteria of Williams et al. in a hospital‐
assessment is often costly and labour‐intensive and not based setting. Br J Dermatol 2001;145:428–33.
feasible in a large‐scale population‐based study. Moreover, 11 Brenninkmeijer EE, Schram ME, Leeflang MM et al. Diagnostic
AD often has a waxing and waning course and active criteria for atopic dermatitis: a systematic review. Br J Dermatol
disease might not be present at a study visit despite mani- 2008;158:754–65.
12 Silverberg JI, Patel N, Immaneni S et al. Assessment of atopic
festing as classic AD at other times. Many of the different dermatitis using self‐report and caregiver report: a multicentre vali-
diagnostic criteria may not be suitable for population‐ dation study. Br J Dermatol 2015;173:1400–4.
based studies because they may not be accurately reflected 13 Strina A, Barreto ML, Cunha S et al. Validation of epidemiological
tools for eczema diagnosis in Brazilian children: the ISAAC’s and UK
in a patient‐ or caregiver‐reported survey, low disease
Working Party’s criteria. BMC Dermatol 2010;10:11.
prevalence may markedly diminish the predictive value 14 Chalmers DA, Todd G, Saxe N et al. Validation of the U.K. Working
of the criteria, and misclassification is common due to an Party diagnostic criteria for atopic eczema in a Xhosa‐speaking
increase in borderline cases [5]. Moreover, formal criteria African population. Br J Dermatol 2007;156:111–16.
15 Yamada E, Vanna AT, Naspitz CK, Sole D. International Study of
are rarely used in routine clinical practice and there is Asthma and Allergies in Childhood (ISAAC): validation of the writ-
considerable heterogeneity about how AD is defined even ten questionnaire (eczema component) and prevalence of atopic
among physicians, depending on their medical back- eczema among Brazilian children. J Investig Allergol Clin Immunol
ground or country of practice [20]. These are particular 2002;12:34–41.
16 Chan HH, Pei A, Van Krevel C et al. Validation of the Chinese
limitations for retrospective studies of health records or translated version of ISAAC core questions for atopic eczema. Clin Exp
claims‐based data [21]. Allergy 2001;31:903–7.
Some ‘objective’ tests such as raised total or specific 17 Firooz A, Davoudi SM, Farahmand AN et al. Validation of the diag-
nostic criteria for atopic dermatitis. Arch Dermatol 1999;135:514–16.
immunoglobulin E (IgE) and positive skinprick tests are 18 Haileamlak A, Lewis SA, Britton J et al. Validation of the International
often included in stricter definitions of ‘atopic’ dermatitis Study of Asthma and Allergies in Children (ISAAC) and U.K. criteria
(e.g. Millennium criteria [22]). However, requirement of for atopic eczema in Ethiopian children. Br J Dermatol 2005;152:
these factors, depending on the population studied, can 735–41.
19 Oien T, Storro O, Johnsen R. Assessing atopic disease in children two
exclude up to about two‐thirds of individuals with the to six years old: reliability of a revised questionnaire. Prim Care
disease phenotype [23,24]. Over‐reliance on laboratory Respir J 2008;17:164–8.
measures that may reflect epiphenomena related to the 20 Williams HC. Diagnostic criteria for atopic dermatitis: where do we
go from here? Arch Dermatol 1999;135:583–6.
study of sick individuals with severe disease in a hospital 21 Dizon MP, Yu AM, Singh RK et al. Systematic review of atopic derma-
setting should be avoided in population studies until titis disease definition in studies using routinely collected health
better disease markers are found. Without any objective data. Br J Dermatol 2018;178:1280–7.
22 Bos JD, Van Leent EJ, Sillevis Smitt JH. The millennium criteria for the Severity
diagnosis of atopic dermatitis. Exp Dermatol 1998;7:132–8.
23 Flohr C, Weiland SK, Weinmayr G et al. The role of atopic sensiti-
In public health terms, the severity distribution of AD is
zation in flexural eczema: findings from the International Study more significant than the total prevalence of AD (which
of Asthma and Allergies in Childhood Phase Two. J Allergy Clin may include many mild cases), as severity is likely to
Immunol 2008;121:141–7. determine those who use or need to use available health
24 Schafer T, Heinrich J, Wjst M et al. Association between severity of
atopic eczema and degree of sensitization to aeroallergens in school- services. Few studies have rigorously examined the severity
children. J Allergy Clin Immunol 1999;104:1280–4. distribution of AD in the community. A population‐based
study conducted in Nottinghamshire, England, found
Descriptive epidemiology of atopic that the severity distribution of AD (defined by a derma-
dermatitis tologist) in 1760 children living around Nottingham,
England, was 84% mild, 14% moderate and 2% severe
Prevalence and incidence [43]. In a US survey of 10 386 children with AD, mild
With so many different time periods and methods of disease accounted for 67% of the cases, moderate 26%
ATOPIC DERMATITIS
measuring AD, making comparisons of the prevalence and severe 7% [35]. Geographical variation in AD sever-
of AD between countries is very difficult. For most ity distribution has also been reported [44].
SECTION 3:
epidemiological studies, the authors recommend that
the 1‐year period prevalence measure is used, in order Morbidity
to reflect the intermittent nature of the disease and to AD ranked first among common skin diseases with
overcome the effect of seasonality. A number of com- respect to disability‐adjusted life‐years and years lived
munity‐based and population‐based prevalence sur- with a disease in the World Health Organization (WHO)
veys have been conducted in various countries around 2010 Global Burden of Disease survey [45,46]. The impact
the world, reporting a wide range of prevalence rates of AD on health‐related quality of life in children is com-
across countries [1–30]. Together, these surveys sug- parable to that of other chronic illnesses such as asthma
gest that around 10–30% of children in developed and diabetes [47]. Furthermore, impairment of quality of
countries suffer from AD, with some studies demon- life appears to be directly related to the severity of AD
strating a plateau in these prevalence estimates over [48]. A US population‐based study found that 25–33% of
recent years [2,4,12,31]. In contrast, the prevalence of adults with AD reported fatigue, daytime sleepiness
AD in developing countries has been generally lower and/or insomnia, which were important predictors of poorer
but is increasing [8,32]. overall health status, number of sick days and doctor visits
To date, the ISAAC has published the most compre- [49]. The psychological morbidity associated with a life-
hensive prevalence and trend data on AD [4,31,33]. The time of scratching, sleep loss and the stigma of a visible
three phases of the ISAAC have included nearly 2 million skin disease can also affect families to a considerable
children from over 100 countries. Using the revised degree [50,51]. Recent studies have found that children
UKWP criteria via questionnaires to identify AD, the and adults with AD are at greater risk for attention‐deficit
ISAAC has found highly variable AD prevalence rates hyperactivity disorder, depression, anxiety and conduct
across different countries, ranging from 0.9% in India to disorder, particularly when AD is severe [52,53]. Children
22.5% in Ecuador among 6‐ and 7‐year‐olds and from with AD also have a greater number of comorbid medical
0.2% in China to 24.6% in Colombia among 13‐ to 14‐year‐ conditions and poorer overall health [35]. In two popula-
olds [31]. Data from ISAAC Phases 1 and 3 have demon- tion‐based surveys in the USA, approximately one in five
strated rising prevalences of AD among 13‐ to 14‐year‐olds adults with AD either met clinical criteria for major
in developing nations over a period of 5–10 years but no depressive disorder or were diagnosed by a physician
significant change or even decreases in prevalence in with depression [54–57]. The association of AD with non-
many developed areas [32]. In contrast, the prevalence of allergic comorbidities is a growing area of investigation.
AD symptoms among 6‐ to 7‐year‐olds has continued to Early studies suggest that AD may be associated with an
increase in both developed and developing nations over increased risk for alopecia areata, vitiligo, rheumatoid
this time period. arthritis, inflammatory bowel disease and extracutaneous
A systematic review of 69 studies examining international infections, but a decreased risk for type 1 diabetes and
trends in AD between 1990 and 2010 also found lifetime selected cancers [58–62].
AD prevalence rates of over 20% in some developed
nations, with increasing rates of AD in Africa, eastern Cost
Asia, western Europe and parts of northern Europe [8]. AD is a costly disease and carries an economic burden
In two population‐based survey studies in the USA, the similar to that of other chronic diseases such as emphy-
mean prevalence rate of AD among children under sema, asthma and epilepsy [63,64]. Although costs‐
18 years of age increased from 10.2% in 2003–2004 to of‐illness studies are relatively few, previous studies from
12.98% in 2007–2008 [34,35], but prevalence estimates also the UK, USA, Germany, Australia and the Netherlands
varied widely, from 8.7% to 18.1%, across different states found highly variable costs across countries, which are
and districts [34]. Finally, prevalence data on adult AD probably due to differences in the study populations
are sparse; to date, studies from the USA, Japan, Australia, (hospital vs. community‐based studies) and the cost com-
Russia and Scotland have found prevalence rates of ponents included [64,65]. In one study, the estimated
2–10% [36–42]. direct costs of AD were nearly 3.8 billion US dollars per
year [64]. Moreover, these estimates often do not include AD‐genetic risk score as well as personal and parental
costs associated with comorbid diseases or indirect costs, history of atopic disease. A newly defined subset of mid‐
both of which can be significant [66,67]. Thus, the eco- onset‐resolving AD, not associated with FLG mutations,
nomic burden of AD is considerable and probably much was strongly associated with asthma [81].
greater than previously reported. Factors that may indicate a worse prognosis include
severe childhood disease, early onset and a concomitant
Age, sex and natural history or family history of asthma or hay fever [77,78,82]. One
Childhood AD starts in early life in the majority of cases birth cohort study of 1314 children followed to the age of
[17,68], but may also begin later in childhood or even 7 years in Germany (The Multicenter Allergy Study)
in adulthood [69,70]. In a sub‐sample of the Avon deserves special mention because it included sequential
Longitudinal Study of Parents and Children (ALSPAC), physical examinations, parental interviews and specific
1509 randomly selected children were followed from IgE levels. Of the 21.5% of children with AD in the first
birth until 5 years of age; 33% had onset of AD before 2 years of life, 43.2% were in complete remission by the
ATOPIC DERMATITIS
18 months of age and 18% had onset after this age [71]. age of 3 years, 38.3% had an intermittent pattern of dis-
Adult‐onset AD is also becoming increasingly recognized ease and 18.7% had symptoms of AD every year. A poorer
SECTION 3:
[69,72]. Two studies in Singapore and Nigeria found that prognosis was related to IgE sensitization (adjusted
13.6–24.5% of AD patients in a tertiary dermatology clinic cumulative odds ratio 2.76; 95% confidence interval [CI],
had onset of AD after the age of 21 years [73,74]. 1.29–5.91) and early disease severity (adjusted cumula-
A systematic review and meta‐analysis showed that tive odds ratio 5.86; 95% CI, 3.04–11.29). Interestingly,
AD characteristics are heterogeneous and vary by region early AD without early wheezing did not increase the risk
and age. The most prevalent AD features were pruritus, of subsequent wheeze at school entry (adjusted odds
lichenification and xerosis. Studies from Africa reported ratio 1.11; 95% CI, 0.56–2.20) [83]. Children with loss‐of‐
more papular lichenoid lesions, palmar hyperlinearity, function mutations in filaggrin, an essential epidermal
ichthyosis and orbital darkening [75]. barrier protein (see Chapter 14), have also been found to
Minor sex differences in AD, namely a slightly higher have earlier onset and more persistent AD [79,84].
prevalence among females, have been noted previously.
The Phase 3 ISAAC evaluated over 1 million children in Ethnic group and migrant studies
two distinct age groups (6‐ to 7‐ and 13‐ to 14‐year‐olds) Several studies have addressed ethnicity as an aetiological
and found slightly higher rates of current eczema symp- factor in AD, and particularly helpful are studies from
toms in girls than boys, especially in the older age group communities of different ethnic origin in the same coun-
[31]. While the ISAAC authors suggested that misclassifi- try. For instance, black Caribbean children born in the UK
cation of irritant or allergic dermatitis might explain and children of Chinese origin born in Australia are at an
their observed gender disparities, another study of 1456 increased risk of developing AD in comparison with their
children in the Isle of Wight birth cohort from the UK also (mainly) white Caucasian peers [85, 86]. As these studies
found higher AD prevalence among girls than boys after recorded point prevalence of AD, it is difficult to say
the age of 10 years [76]. Nevertheless, gender differences whether these differences were due to disease chronicity
have not been a consistent finding across studies [34]. or disease incidence between ethnic groups. Another
Few longitudinal studies have examined the natural study of Asian children in Leicester (UK) found no differ-
history of AD, and it should not be assumed that the ence in the prevalence of AD between different ethnic
prognosis of AD cases studied in a hospital setting (which groups, although Asian children were three times as likely
are usually quite severe by definition) is the same as that to be seen in the local dermatology department, perhaps
for the majority of milder AD cases in the community. reflecting lack of parental familiarity with the condition
Studies of well‐defined AD populations suggest that [87]. In contrast, in a US population‐based study, individ-
patients have a clearance rate of around 60% by the age of uals of black or African‐American race were significantly
16 years [77,78]. True clearance rates are probably even more likely to have AD, even after controlling for socio-
lower, as many individuals relapse at some stage in adult- economic factors [34]. Moreover, AD severity distribution
hood (e.g. by developing irritant hand eczema). In two may also vary with respect to race and ethnicity [44].
studies using a paediatric AD registry, most patients Migrant studies have been helpful in suggesting a
reported active disease at every age of childhood and into strong role for the environment in the aetiology of AD.
early adulthood, suggesting that persistence of mild and Studies of Chinese immigrants in Hawaii and children
moderate paediatric AD into adulthood is not insignifi- from Tokelau who migrated to New Zealand found large
cant [79]. Older patients also sought medical attention increases in the prevalence of AD among migrant children
less often, which may contribute to the erroneous percep- compared with similar genetic groups in their country of
tion that AD tends to resolve with age [80]. origin [88]. Another study found that black Caribbean
In two birth cohort studies, 9894 children from the UK children living in London were around three times more
(ALSPAC) and 3652 from the Netherlands (PIAMA), dis- likely to have AD than similar children living in Kingston,
tinct subclasses were identified. The most prevalent was Jamaica, regardless of the method used to diagnose AD
early‐onset‐early‐resolving AD, which was associated [86]. Findings of lower AD prevalence among immigrants
with male sex. Early‐onset‐persistent and early‐onset‐ versus native‐born persons have been observed in a
late‐resolving AD were most strongly associated with the number of countries [3,89–92]. One US study found that
foreign‐born children, particularly those with parents for studies of skinprick tests, wheezing and hay fever,
who were also foreign‐born, had lower odds of AD com- which may be less prone to diagnostic labels. An increased
pared to US‐born children [93]. However, this protective prevalence of AD has been found in comparative cross‐
effect declined over time, as prolonged residence in the sectional surveys [13,103] and, more convincingly, in
USA for 10 or more years was associated with a greater population‐based longitudinal studies in Japan and the
risk of AD compared to foreign‐born children who had USA [30,104] and two large sequential worldwide eczema
resided in the USA for less than 2 years. Together, these surveys conducted as part of the ISAAC [32]. The ISAAC
migrant studies support the notion that environmental surveys showed that eczema prevalence is still on the rise
factors associated with urbanization and ‘western’ life- among younger children (aged 6–7 years) in both devel-
style are important in the aetiology of AD. oped and developing nations, whereas eczema symptoms
seem to be levelling off in older children (aged 13–14
Social class and family size years) in some countries with previously high rates of
Reported eczema has exhibited a strong positive social AD. In a systematic review examining international time
ATOPIC DERMATITIS
class gradient (i.e. it is more common in higher socio- trends in AD, the prevalence rates of AD in Africa, eastern
economic groups) [94]. Although such a trend could be Asia, western Europe and parts of northern Europe
SECTION 3:
due to enhanced reporting of eczema by mothers in appeared to increase from 1990 to 2010 [8]. The reasons
advantaged socioeconomic groups or increased labelling for this increase in AD are not clear, but environmental
by doctors, an identical trend was found among children factors in genetically predisposed individuals are the
with examined eczema in a UK national birth cohort most likely explanation (see Specific risk factors).
study for children in the 1970s [95]. In further studies, Moreover, the ISAAC survey findings suggest that the
higher household incomes and parental education levels plateauing prevalence rates of AD in some countries may
have continued to be independent risk factors for the soon reach their highest limits [32].
development of AD [34,91,96]. A reduced risk of AD has
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70 Williams HC, Strachan DP. The natural history of childhood eczema: 1987;1:67–79.
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71 Perkin MR, Strachan DP, Williams HC et al. Natural history of atopic cross‐sectional studies conducted in Upper Austria. Pediatr Allergy
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72 Kulthanan K, Samutrapong P, Jiamton S, Tuchinda P. Adult‐onset 98 Schram ME, Tedja AM, Spijker R et al. Is there a rural/urban gradient
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73 Nnoruka EN. Current epidemiology of atopic dermatitis in south‐ 99 Yemaneberhan H, Flohr C, Lewis SA et al. Prevalence and associated
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74 Tay YK, Khoo BP, Goh CL. The profile of atopic dermatitis in a tertiary Clin Exp Allergy 2004;34:779–85.
dermatology outpatient clinic in Singapore. Int J Dermatol 1999;38: 100 Osborne NJ, Ukoumunne OC, Wake M, Allen KJ. Prevalence
689–92. of eczema and food allergy is associated with latitude in Australia.
75 Yew YW, Thyssen JP, Silverberg JI. A systematic review and meta‐ J Allergy Clin Immunol 2012;129:865–7.
analysis of the regional and age‐related differences in atopic dermatitis 101 Silverberg JI, Hanifin J, Simpson EL. Climatic factors are associated
clinical characteristics. J Am Acad Dermatol 2019;80(2):390–401. with childhood eczema prevalence in the United States. J Invest
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18 years of life: results from the Isle of Wight 1989 birth cohort 102 Sargen MR, Hoffstad O, Margolis DJ. Warm, humid, and high sun
study. Clin Exp Allergy 2010;40:1776–84. exposure climates are associated with poorly controlled eczema:
77 Illi S, von Mutius E, Lau S, et al. The natural course of atopic derma- PEER (Pediatric Eczema Elective Registry) cohort, 2004‐2012. J Invest
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J Allergy Clin Immunol 2004;113:925–31. 103 Williams HC. Is the prevalence of atopic dermatitis increasing?
78 Peters AS, Kellberger J, Vogelberg C et al. Prediction of the incidence, Clin Exp Dermatol 1992;17:385–91.
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80 Abuabara K, Hoffstad O, Troxel A et al. Atopic dermatitis disease
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81 Paternoster L, Savenije OEM, Heron J et al. Identification of atopic Genetics
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There is strong evidence to suggest that genetic factors are
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82 Mortz CG, Andersen KE, Dellgren C et al. Atopic dermatitis from important in the predisposition to AD. In addition to fam-
adolescence to adulthood in the TOACS cohort: prevalence, persis- ily studies, twin studies have shown much higher disease
tence and comorbidities. Allergy 2015;70:836–45. concordance for monozygotic than for dizygotic twins [1].
83 Rystedt I. Long term follow‐up in atopic dermatitis. Acta Derm
Venereol Suppl (Stockh) 1985;114:117–20. A systematic review of population‐based twin studies of
84 Rupnik H, Rijavec M, Korosec P. Filaggrin loss‐of‐function mutations AD has estimated the heritability of AD to be approxi-
are not associated with atopic dermatitis that develops in late child- mately 75% [2]. Genome‐wide screens of families with
hood or adulthood. Br J Dermatol 2015;172:455–61.
AD have identified chromosomal regions that overlap
85 Mar A, Tam M, Jolley D, Marks R. The cumulative incidence of atopic
dermatitis in the first 12 months among Chinese, Vietnamese, and with other skin diseases, in particular psoriasis, and with
Caucasian infants born in Melbourne, Australia. J Am Acad Dermatol inflammatory and autoimmune diseases [3]. These,
1999;40:597–602. together with candidate gene studies, suggest that genetic
86 Williams HC, Pembroke AC, Forsdyke H et al. London‐born black
Caribbean children are at increased risk of atopic dermatitis. J Am
predisposition to an impaired skin barrier, for instance
Acad Dermatol 1995;32(2 Pt 1):212–17. due to loss‐of‐function mutations in the filaggrin (FLG)
87 Neame RL, Berth‐Jones J, Kurinczuk JJ, Graham‐Brown RA. gene located within the epidermal differentiation com-
Prevalence of atopic dermatitis in Leicester: a study of methodology plex on chromosome 1q21, is of particular importance for
and examination of possible ethnic variation. Br J Dermatol 1995;
132:772–7. AD pathogenesis [4,5]. Moreover, genetic predisposition
88 Waite DA, Eyles EF, Tonkin SL, O’Donnell TV. Asthma prevalence in to immune dysregulation also contributes to the patho-
Tokelauan children in two environments. Clin Allergy 1980;10:71–5. genesis of AD. To date, genome‐wide association studies
89 Leung RC, Carlin JB, Burdon JG, Czarny D. Asthma, allergy and
atopy in Asian immigrants in Melbourne. Med J Aust 1994;161:
and meta‐analyses have identified a total of 31 suscepti-
418–25. bility loci for AD, many of which are implicated in innate
90 Marcon A, Cazzoletti L, Rava M et al. Incidence of respiratory and immune signalling and T‐cell function [6]. However,
allergic symptoms in Italian and immigrant children. Respir Med genetics alone cannot explain the rise in AD prevalence
2011;105:204–10.
91 Schmitz R, Atzpodien K, Schlaud M. Prevalence and risk factors of over past decades. It is also difficult to explain the ten-
atopic diseases in German children and adolescents. Pediatr Allergy dency of AD to clear spontaneously in genetic terms.
Immunol 2012;23:716–23. Genetic and environmental factors for AD probably work
92 Tedeschi A, Barcella M, Bo GA, Miadonna A. Onset of allergy and
in concert rather than in competition, and the social class
asthma symptoms in extra‐European immigrants to Milan, Italy:
possible role of environmental factors. Clin Exp Allergy 2003;33: gradient, geographical variation and migrant studies
449–54. described earlier all point quite strongly to environmental
factors playing a critical role in the expression of the AD e nvironmental factors other than parasites, one study has
phenotype. (Genetic factors are discussed in more detail suggested that there can be an inverse relationship

in Chapter 14.) between cord blood cat‐specific IgG and cat‐specific IgE
during later childhood [16]. Overall, these observations
Fetal predictors suggest that high allergen exposure in the mother leads to
Care should be taken in distinguishing between genetic low allergy risk in the offspring, but these are probably
factors and environmental factors operating in utero or only some of the factors involved. For instance, little is
during early life. As the vast majority of AD cases present currently known about the role of viral and bacterial
in the first year of life, and heritability is more strongly infections during pregnancy and AD risk in the off-
linked to the maternal side [7], it seems logical to hypoth- spring, and the few studies to date have not shown a con-
esize that environmental influences operating in utero or vincing association [17,18]. However, increased exposure
in early infancy may be important in determining disease to antibiotics in utero is associated with an increased risk
expression. In one systematic review, prenatal maternal of AD in a dose‐related manner [19], and frequent use of
ATOPIC DERMATITIS
stress was found to be associated with a higher risk of AD antibiotics within the first 2 years of life can have a simi-
and other atopy in the offspring [8]. Fetal immunoglobu- lar promoting effect on the clinical expression of allergic
SECTION 3:
lin can be detected as early as 26 weeks’ gestation, and the disease [20,21]. A meta‐analysis of studies examining
house dust mite allergen Der p 1 has been detected in postnatal antibiotic exposure estimated a 40% overall
amniotic fluid [9]. Amniotic fluid levels of IgE are also increased odds of AD in children with antibiotic use
higher in atopic than in nonatopic mothers [9]. Amniotic within the first year of life and observed increasing odds
fluid is predominantly absorbed via the fetal gut [10], and (+7%) with each additional antibiotic course [22].
because the fetal gut, in contrast to the fetal lungs and
skin, has mature antigen‐presenting cells, it is the most The role of the gut microflora and skin
likely site of sensitization [9]. In addition, allergen bound microbiome
to IgG can cross the placenta during the third trimester It has become evident that the commensal microflora of
[11]. It is thought that such early sensitization represents a the gut plays a major role in the ‘education’ of the immune
crucial first step in the development of the child’s immune system of the newborn [23]. Several researchers have
system and its ability to distinguish between friend and suggested that the use of antibiotics both in utero and
foe. In evolutionary terms, helminth parasites are likely to during early life may have a direct influence on the com-
have been important threats to child survival, and human position of the gut microflora. This, in turn, could prevent
host immune responses to parasites are in principle aller- the normal shift from type 2 T‐helper cell dominance at
gic, marked by raised total and specific IgE, overexpres- birth towards a type 1 T‐helper cell‐rich milieu, predispos-
sion of type 2 T‐helper cell cytokines and eosinophilia. It ing to allergic disease [24]. Prenatal factors such as length
has now been shown that in endemic areas fetal exposure of gestation and mode of delivery, as well as other envi-
to helminth antigens occurs in utero through maternal ronmental exposures such as diet and family size, have
infection, and cord blood lymphocytes from babies born also been associated with the altered gut microflora
to helminth‐infected mothers produce parasite‐specific observed in children with AD [25]. Indirect evidence also
immunoglobulins. This not only allows future recogni- comes from studies comparing the gut microflora in chil-
tion of parasite antigen in the host but also generates a dren with and without AD. The latter have significantly
degree of immune tolerance to parasite antigen [12]. more lactobacilli but fewer enterobacteria than their
Through the known cross‐reactivity between certain counterparts with AD, and these changes precede the
helminth antigens and environmental allergens, such as clinical manifestation of AD [26]. Lower bacterial diversity
house dust mites, this may also convey protection against has also been observed in the early gut microbiota of chil-
atopy and allergic disease [13]. Supporting evidence for dren who subsequently develop AD and allergic sensiti-
this hypothesis comes from a birth cohort study among zation [27]. A change in gut microflora composition could
103 mother–infant pairs in Uganda, where cumulative not only change the stimulation of the infant’s immune
eczema risk was decreased by 74% until the age of 15 months system across the intestinal mucosa but also enhance the
among children whose mothers were infected with exposure to allergens, further contributing to the devel-
helminths during the last trimester of pregnancy (adjusted opment of allergic disease. Indeed, there is some evidence
OR = 0.26, 0.08–0.83 [13]). Our reduced exposure to para- that the permeability of the gut mucosa is increased in AD
sites might therefore be one of the reasons why AD has [28]. However, all of these results need to be treated with
become increasingly common over past decades in the caution, and further longitudinal studies that sequen-
developed world [13]. In addition, the fetal immune tially measure gut microflora composition in early life
system is generally biased towards a type 2 T‐helper cell‐ alongside careful phenotyping of AD are still required.
dominated milieu, marked by overexpression of IL‐4, The skin microbiome, which normally consists of
IL‐13 and IL‐10, probably in order to suppress a potential hundreds of different bacterial species but most abundantly
rejection of the fetus by the maternal immune system [14]. Propionibacterium, Staphylococcus and Corynebacterium
In children who develop allergic disease, the type 2 T‐ spp., has also been implicated as a potential driver in AD
helper cell dominance remains postnatally, as decreased pathogenesis (see Chapter 3). There is continuous cross‐
interferon‐γ (IFN‐γ) production is a consistent feature in talk between the skin microbiota and the skin immune system,
neonates born to atopic mothers [15]. With regard to with skin commensal bacteria playing an important role in
host defence pathways, regulatory T‐cell function and A few intervention studies have thus been undertaken in
expression of innate immune factors in the skin [29]. The an attempt to resolve such partially contradicting evi-
composition of the microbiota in AD skin differs signifi- dence. In the Learn Early About Peanut (LEAP) study,
cantly from that of normal skin, particularly with its over 600 infants with severe AD and/or egg allergy were
overgrowth of Staphylococcus aureus [30]. Greater skin randomized to either consume or avoid peanuts until the
colonization with Staph. aureus has been associated age of 5; 17% of the children who avoided peanut devel-
with increased eczema severity and greater skin barrier oped peanut allergy by the age of 5 compared to only 3%
dysfunction as measured by transepidermal water loss of those who consumed peanut [48]. In the Enquire About
[31–33]. Skin dysbiosis and Staph. aureus colonization Tolerance (EAT) study, over 1300 exclusively breastfed
have also been shown to drive eczematous inflammation infants were randomly assigned at 3 months of age to the
in mouse models [34]. More recently, the commensal bac- early introduction of six allergenic foods (peanut, cooked
terium Staph. epidermidis has also been implicated in the egg, cow’s milk, sesame, cod and wheat) or exclusive
development of AD, as AD flares have been associated breastfeeding until 6 months of age; the rate of food
ATOPIC DERMATITIS
with an overabundance of both Staph. aureus and Staph. allergy to one or more of the intervention foods did not
epidermidis in addition to the decreased diversity of other differ between the two arms in the intention‐to‐treat
SECTION 3:
skin microflora [35]. Nevertheless, while these findings analysis but was significantly lower in the early introduc-
suggest an association between the skin microbiome and tion group (2.4%, vs. 7.3% in the standard group) in the
AD, it remains unknown whether dysbiosis of the skin per‐protocol analysis [49]. While these results support the
directly causes AD or simply reflects the impaired epider- notion that early introduction of allergenic foods may
mal barrier and immune dysregulation of AD. induce tolerance, the study found no effect on the risk of
AD development in relation to the length of exclusive
Nursing and infant feeding breastfeeding [49].
Breastfeeding is thought to play an important part in the
establishment of a normal postnatal gut microflora and The hygiene hypothesis
by many is also considered an important strategy to pre- AD is more common among children growing up in
vent AD development, in particular in children from smaller families and families of higher socioeconomic
high‐risk families. However, a meta‐analysis concluded status, and it has been suggested that this may be due to
that there was no convincing evidence for a protective a lower exposure to certain viral and bacterial pathogens
effect of exclusive breastfeeding for at least 3 months on [50]. In other words, allergic disease is thought to occur
AD [36]. For instance, a randomized controlled trial in when the developing immune system is deprived of the
Belarus failed to find any beneficial effect of prolonged or obligatory stimulation through certain microbial antigens
exclusive breastfeeding on the development of AD or [51], and the protective effect on AD development seen
other allergies. Even when comparing only studies that with daycare attendance during infancy, endotoxin expo-
looked at formula versus exclusive breastfeeding, the sure, consumption of unpasteurized farm milk and being
protective effect was negligible [36]. brought up with a dog during early life could all be
There is, however, some evidence from a large German mediated by nonpathological microbial stimulation of the
interventional birth cohort to suggest that certain cow’s infant’s immune system [52]. For instance, a systematic
milk hydrolysates can reduce AD risk in high‐risk children review and meta‐analysis found that farm exposure
[37], but a Cochrane review published prior to the German within the first year of life conferred a significant protec-
report had concluded that there was no such effect, having tive effect on allergic sensitization [53]. Immunologically,
consulted a large body of evidence [38]. There is also no this could be explained by a lack of stimulation of T‐cell‐
evidence to suggest that dietary antigen avoidance during mediated anti‐inflammatory cytokines, such as IL‐10 and
pregnancy or lactation in high‐risk children or soy formula transforming growth factor‐β [54,55]. However, there is
feeding alters the risk of AD [39,40]. Furthermore, there currently no clear epidemiological evidence to suggest
does not appear to be any benefit of an egg‐ and milk‐free that exposure to a specific infection reduces the risk of AD.
diet in unselected children with AD [41]. However, one In fact, there is good evidence from prospective studies
study has suggested that using an egg‐free diet in infants that some childhood infections, such as measles, are
with AD who also have elevated specific IgE levels to egg associated with an increased risk of AD development [52].
may lead to significant improvement in disease severity In addition, the decreased risk of AD seen with increased
[41]. (See Chapter 19 for further details.) number of siblings appears to persist even after adjust-
Two studies have suggested an increased risk for AD in ment for early childhood infections, suggesting that early
infants exposed to solid foods during the first few months postnatal or even prenatal factors play an important role
of life [42,43], but three other studies have found the in allergy development [56]. In this context, alteration of
opposite effect [44–46], i.e. that delayed introduction of the gut microflora, for instance secondary to frequent
solids is associated with AD development. Reverse causa- antibiotic use, has been suggested to programme AD
tion has been proposed as an explanation, but no evidence development [26]. However, the large majority of inter-
of parental allergy playing a role in feeding practices was vention studies with pre‐ and probiotics to prevent and
found [46]. There is also mounting evidence from animal treat AD have been disappointing [57,58], and neither can
research that early introduction of potentially allergenic currently be recommended for routine clinical practice.
foods might induce tolerance rather than allergy [47]. Further research with different probiotic strains is required.
Irritants and washing serum IgE in AD, and in vitro research has shown that
Unlike allergic rhinitis, clinically relevant allergens are eczematous skin is rich in IgE‐bearing antigen‐presenting
seldom documented in AD, and irritants may be more dendritic cells, considered instrumental in the capture of
prominent in triggering skin inflammation [59]. Low environmental allergens [67]. Indeed, inhalation of house
humidity, excessive exposure to soaps and other primary dust mite allergen can provoke eczematous skin lesions in
household irritants, and possibly airborne pollution may predisposed patients, and IgE receptors can act as media-
be important by directly exacerbating skin disease, and tors in the clinical expression of AD following skin
indirectly by increasing vulnerability to sensitization, application of aeroallergens in the atopy patch test [68].
especially in children who are genetically predisposed A systematic review and meta‐analysis of birth cohort
to have an impaired skin barrier [59]. Excessive use of studies also identified a 2.7‐fold increased risk of infantile
chemical household products and frequent washing at eczema among children with food sensitization in the
15 months of age were associated with an increase in AD first 2 years of life [69]. Many therefore see allergic sensi-
at 30 –42 months of age in a birth cohort in the UK [60]. tization as an integral part and potential cause of AD in
ATOPIC DERMATITIS
However, the optimal bathing frequency for children children. However, despite detailed knowledge of the
with AD remains unknown. In a review of the literature, underlying immunological mechanisms in childhood
SECTION 3:
the studies favouring bathing at least once a day outnum- AD, the aetiological role of sensitization in childhood
bered those favouring bathing less than once a day, but eczema remains uncertain [70]. Indeed, a systematic
the evidence still remains limited [61]. More prospective review has shown that the strength of the association
data are also required to see how genetic and environ- between allergic sensitization and AD varies widely
mental factors interact. between studies [65]. Up to 50% of eczema sufferers in
hospital settings are not sensitized, and the proportion of
Pets sensitized individuals tends to be even lower in commu-
Although pets have often been blamed for causing AD nity settings, a finding that is partly explained by differ-
and other allergic diseases, a systematic review of cross‐ ences in disease severity between hospital and community
sectional and cohort studies failed to find any evidence to cases [65]. The strength of the association between allergic
suggest that contact with furry pets before or at birth sensitization and AD phenotype also varies between
increased the subsequent risk of AD. Indeed, another developing countries and industrialized nations.
systematic review and meta‐analysis of birth cohort Population‐based data collected from 31 000 8‐ to 12‐year‐
studies has even shown a protective effect of dogs and old children from 22 countries as part of the ISAAC has
pets overall on the risk of AD in infancy or childhood [62]. shown that even if the same rigid diagnostic criteria and
physical examination are employed across paediatric
Infection populations, the association between allergic sensitiza-
The dry skin and cytokine milieu characteristic of AD tion and flexural eczema is weaker in low‐ versus high‐
patients favours colonization by viruses, such as herpes income countries [71]. One explanation is that the
simplex virus [63], and Staph. aureus, an organism that is association between sensitization and AD in high‐income
implicated in maintaining cutaneous inflammation, as countries is primarily due to shared causes rather than
well as being capable of inciting allergic responses in such direct causality [71]. In addition, an Australian birth
individuals [30]. More than 90% of AD sufferers are colo- cohort study among at‐risk children found that allergic
nized with Staph. aureus compared to 5–30% of the normal sensitization at 18 months was not associated with eczema
population [30]. In addition to increased colonization, at 5 years of age [72]. However, in the same study, AD
about half of the Staph. aureus strains found in AD suffer- phenotype at 18 months was a significant predictor of
ers are toxin producing [30]. Despite this, interventions to skinprick test positivity at 5 years (adjusted OR = 1.67,
reduce Staph. aureus carriage as a treatment of AD have 95% CI [1.20–2.33]), suggesting that sensitization is a
not proven successful to date [64]. However, growing secondary rather than primary phenomenon in AD.
research on the skin microbiome suggests that dysbiosis This idea that allergic sensitization is a secondary phe-
of the skin beyond just increased Staph. aureus may be nomenon in AD is invoked in the concept of the ‘atopic
involved in the pathogenesis of AD. AD flares have been march’, which is characterized by the progression of AD
associated with a significant decrease in overall skin early in life to the subsequent development of asthma and
microbiota diversity as well as increased abundance of allergic rhinitis. It is posited that transcutaneous allergic
Staph. epidermidis [35]. Some studies have also suggested a sensitization occurs through the defective skin barrier in
possible role for Pityrosporum yeasts in inducing exacer- AD, thus invariably leading to the development of the
bations of AD through autoantibody formation [65,66]. other allergic disorders [73]. However, only one‐third of
AD patients develop asthma and two‐thirds develop
Allergic sensitization and the ‘atopic allergic rhinitis, and even among those patients who
march’ appear to follow the atopic march, it remains uncertain
There has been a lot of debate in the dermatological litera- whether the atopic march represents a causal relation-
ture as to whether allergic sensitization, i.e. skinprick test ship, even if atopic dermatitis, rhinitis and asthma often
positivity or elevation of specific IgE levels to common coexist in the same patient [73]. The atopic march
environmental allergens, is an essential feature of AD concept was originally based on cross‐sectional study
[65]. Early studies demonstrated very high levels of total evidence, but its existence has since been questioned as
few prospective cohort studies have been conducted and and carbon monoxide, suggested that air pollution may
the longitudinal studies to date suggest significant heter- contribute to atopic eczema risk, but this association,
ogeneity among AD patients in the development of albeit statistically significant, was very weak with odds
asthma and rhinitis [70,74,75]. For instance, in a study ratios just above 1 (OR = 1.12, 95% CI 1.04–1.22 [81]).
of two UK population‐based birth cohorts, fewer than 7% Similarly, a cohort study among 3000 schoolchildren in
of children had progression of allergic symptoms follow- West Germany with repeat objective pollutant measure-
ing the typical atopic march pattern by the age of 11 [74]. ments suggested that NO2 exposure was positively asso-
Interestingly, of the children who did follow the typical ciated with physician‐diagnosed AD at the age of 6
atopic march, 71% had allergic sensitization on skinprick (OR = 1.18, 95% CI 1.00–1.39 [82]). Furthermore, a French
testing, in contrast to only 14% of children who had only cross‐sectional survey among more than 5000 schoolchil-
eczema without any asthma or rhinitis [74]. Some studies dren in six cities showed a stronger positive relationship
have shown that only children with AD plus sensitization with fine particle pollution (OR = 2.51, 95% CI 2.06–3.06
have a higher risk of allergic respiratory disease [76], but [83]). In a systematic review of birth cohort studies exam-
ATOPIC DERMATITIS
similar observations have also been made in those with ining traffic‐related air pollution and eczema, two of three
allergic sensitization alone [65,72]. These findings are cohorts found increased rates of eczema with exposure to
SECTION 3:
consistent with the idea that skin barrier impairment may NO2 and black carbon and living near a major road, while
be the key primary event that leads to allergic sensitiza- one cohort found no association [84]. Previous question-
tion across a ‘leaky’ epidermis, allowing contact between naire‐based studies from Sweden and East Germany
environmental allergens and antigen‐presenting cells in found that AD risk increased with living close to heavy
the epidermis. FLG loss‐of‐function mutations show traffic [85,86], but similar studies in West Germany, Malta,
much stronger associations with atopic compared to Russia and Japan did not confirm these findings [87–90].
nonatopic eczema, and only skin barrier gene mutation As studies have also shown that allergic sensitization is
carriage in the context of established AD is significantly enhanced in the presence of fine particle pollution [83],
associated with later asthma [4]. it is conceivable that allergic sensitization across the
Well‐conducted large prospective studies with clear epidermis is enhanced in the presence of certain outdoor
diagnostic criteria are needed to demonstrate whether pollutants, and it will be interesting to see whether future
eczema sufferers with allergic sensitization have a differ- studies can explain part of these contradicting results by
ent disease from those without positive skinprick tests differences in skin barrier impairment/skin barrier gene
or elevated specific IgE levels. Disease outcomes, such as status.
prognosis and response to treatment, with adjustment for Some indoor pollutants also appear to be risk factors
disease severity, duration, sex, skin barrier gene/phenotype for AD, including certain types of gas heaters and radia-
as well as early allergic respiratory disease, will be par- tors [91] and pre‐ and post‐natal reported exposure to
ticularly important to study. In addition, further research tobacco smoke [92–94]. One study found a positive
needs to address whether and how allergic respiratory correlation between maternal and cord blood nicotine
disease contributes to AD flares and chronicity. metabolite levels and AD risk [94]. Other indoor environ-
mental factors associated with AD risk are dampness and
Other environmental risk factors moulds [95–98], but all studies were questionnaire‐based
Experimental work with mice has suggested that and allergic sensitization to moulds not tested. More
exposure to atmospheric pollutants may enhance the IgE refined studies are therefore needed to examine the
immune response [77], and passive smoking has also effects of specific environmental pollutants in popula-
been linked with IgE responsiveness and increased allergic tions using standardized disease definitions. Another
airways disease [77]. It has been suggested that pollutants, potentially important risk factor is water hardness. Three
such as passive smoking, cause low‐grade airway inflam- cross‐sectional population‐based studies in the UK, Japan
mation, which enhances sensitization, and this is likely to and Spain have shown a positive association between
be one of the factors accounting for the increase in asthma questionnaire‐diagnosed AD and domestic water hard-
seen over the last 30 years [77]. A meta‐analysis of studies ness [99], but a randomized controlled trial of water
examining exposure to tobacco smoking and AD found softeners for treating established AD (the Softened Water
an association between AD and both active and passive Eczema Trial [SWET] study) did not find any additional
smoking, but not maternal exposure to tobacco smoke improvement in AD severity with the use of water soften-
during pregnancy [78]. Similarly, a meta‐analysis of stud- ers compared to usual care alone [100]. The negative find-
ies examining exposure to tobacco smoking and allergic ings from the SWET trial do not, however, exclude the
conditions has found an association between AD and possibility that domestic water hardness is involved in
both active and passive smoking [79]. Whether atmos- initiating eczematous skin inflammation in early life, and
pheric outdoor pollutants are important in increasing a strong positive association between calcium carbonate
vulnerability to sensitization in AD is less clear, and studies levels and eczema risk at 3 months has been found in a
that employ objective air pollution measures have more population‐based cohort of 1300 children from England
recently been conducted [80]. For instance, a population‐ and Wales, with a stronger effect seen in those carrying an
based cross‐sectional survey among more than 300 000 FLG mutation [101]. A prevention trial is currently under-
Taiwanese schoolchildren with objective measurement of way to test whether fitting a water softener around the
traffic‐related air pollutants, including nitrogen oxides time of birth is able to prevent eczema.
There is also a need to study the potential interaction 22 Tsakok T, McKeever TM, Yeo L, Flohr C. Does early life exposure to
antibiotics increase the risk of eczema? A systematic review. Br J
between indoor and outdoor environmental and climatic
Dermatol 2013;169:983–91.
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sistent evidence for a protective effect with the use of
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A population‐based cross‐sectional study. J Allergy Clin Immunol that warrants further investigation is whether prevention
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of skin barrier breakdown in genetically predisposed
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test the effectiveness of early emollient use in the preven-
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105 Peters TJ, Golding J. The epidemiology of childhood eczema: II.

Statistical analyses to identify independent early predictors. Paediatr tion of eczema. As for secondary prevention, the use of
Perinat Epidemiol 1987;1:80–94. water softeners was tested in a UK‐wide trial in children
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106 Seaton A, Godden DJ, Brown K. Increase in asthma: a more toxic with moderate to severe eczema but did not show a ben-
environment or a more susceptible population? Thorax 1994;49:
171–4. efit over usual care [16] (see also Other environmental
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effect on disease severity but whether such interventions
108 Xu B, Jarvelin MR, Pekkanen J. Prenatal factors and occurrence of
rhinitis and eczema among offspring. Allergy 1999;54:829–36. can alter the natural history of AD. In such a chronic and
intermittent disease, longer‐term studies looking at
disease‐free periods or time series analysis are needed.
Prevention of atopic dermatitis
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ulate the maternal diet during pregnancy and infant diet treatment of atopic dermatitis: a meta‐analysis of randomized clinical
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14 von Berg A, Filipiak‐Pittroff B, Schulz H et al. Allergic manifestation birth cohort studies are not prohibitively expensive to set
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15 Simpson EL, Chalmers JR, Hanifin JM et al. Emollient enhance-
ment of the skin barrier from birth offers effective atopic dermatitis
our understanding of how genetically predetermined skin
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16 Thomas KS, Sach TH. A multicentre randomized controlled trial of to produce the phenotype of AD. We need to understand
ion‐exchange water softeners for the treatment of eczema in chil- better where exactly allergic sensitization comes into this
dren: protocol for the Softened Water Eczema Trial (SWET)
(ISRCTN: 71423189). Br J Dermatol 2008;159:561–6. equation, and it would also be important to know whether
there is a distinct AD phenotype with an underlying immu-
nological defect in the skin and whether its clinical presen-
Conclusion tation differs from AD with a primary skin barrier defect.
ATOPIC DERMATITIS
Over the past few years, the field of AD epidemiology has Understanding these relationships in turn promises new
taken great leaps forward. The information we have opportunities for more intervention studies, which should
SECTION 3:
suggests that environmental factors seem to be critical in not only assess the effect on disease prevention but also
disease expression, which is good news for epidemiolo- evaluate the cost‐effectiveness of preventing disease and
gists as it makes the possibility of disease prevention a reducing the frequency of disease exacerbations.
reality. In addition, the discovery of the filaggrin loss‐
of‐function mutations has rekindled interest in the role of Acknowledgement
skin barrier impairment in the development of AD. Exciting Prof. Hywel Williams cowrote the previous edition of this
new developments in the field of eczema prevention with chapter. We are most grateful for his permission to reuse
barrier enhancement have the potential to transform AD some of this material.
184
CHA PTER 1 4
Genetics and Aetiology of Atopic Dermatitis

Elke Rodriguez & Stephan Weidinger
Department of Dermatology, Allergology and Venereology, University Hospital Schleswig‐Holstein, Campus Kiel, Kiel, Germany
Introduction, 184 Conclusions and future directions, 190

Genes implicated in the aetiology of eczema, 187
ATOPIC DERMATITIS
Abstract by approximately 20% of patients, and they are neither necessary

SECTION 3:
nor sufficient to cause the disease. Most of the other loci harbour
candidate genes with functions related to immune regulation, in
Atopic dermatitis or eczema represents a typical multifactorial dis-
particular innate signalling and T‐cell specification and activation,
ease in that there is an individual hereditary predisposition that is
but the causative genes or gene products as well as the underlying
triggered by environmental and lifestyle factors. The heritability
molecular mechanisms remain to be identified and characterized.
of atopic dermatitis, i.e. the genetically determined proportion of
Together, the established susceptibility loci explain about 20% of
the total variance observed in a population, is estimated to be 70–
the total estimated heritability. This ‘missing heritability’ may be
80%. The possibilities for deciphering inherited risk factors have
explained by gene interactions, rare gene variants not yet discov-
impressively increased during the last years. As a result, more than
ered and epigenetic changes, but may also relate to an overestima-
30 susceptibility loci have been successfully identified. Null vari-
tion of the heritable disease component and the phenotypic com-
ants in the gene encoding the key epidermal barrier protein filag-
plexity of the disease.
grin are the strongest single risk factor, but they are carried only
Key points • Two notable exceptions are loss‐of‐function variants in the gene
FLG, which cause the dry skin condition ichthyosis vulgaris due
to a deficiency of the epidermal structural protein filaggrin, and
• Atopic dermatitis has a very strong heritable component.
infrequent variants in the gene encoding GARP, which lower the
• Genetic risk loci for atopic dermatitis are being discovered
expression of this receptor for latent transforming growth factor
through a range of strategies from linkage studies to genome‐
(TGF)‐β on the surface of regulatory T cells.
wide association studies.
• Known risk loci explain about 20% of the total estimated
• Thus far, more than 30 susceptibility loci for atopic dermatitis
heritability of atopic dermatitis.
have been identified. For most of these regions the causative
genes or gene products remain to be identified and characterized.
been suggested that eczema is part of a syndrome of

Introduction ‘atopic diseases’, in which patients may develop food
Challenges in defining (atopic) dermatitis/ allergy, eczema, asthma and rhinitis in any order and in
eczema any combination over time [4]. Atopy itself is defined as
Eczema (atopic dermatitis, atopic eczema) is the most ‘personal or familial tendency to become sensitized and
common chronic skin disease in infants and children, produce IgE antibodies in response to low doses of
with prevalence rates of up to 30%. It is estimated that allergens, usually proteins’ and to ‘develop typical
approximately 60% of patients with childhood eczema symptoms such as asthma, rhinoconjunctivitis, or
undergo spontaneous remission in early adolescence, but eczema/dermatitis’ [5]. Based on the fact that eczema
up to 50% may have recurrences in adulthood, and the symptoms often precede those of asthma and because
disease can persist into or start in adulthood, making it eczema represents a well‐established risk factor for
one of the most common skin disorders across all ages [1]. asthma, it has been further hypothesized that a suscepti
Eczema, asthma and rhinitis tend to cluster in the ble child commonly passes through a sequential/over
same individuals and families [2], and are often accom lapping series of phenotypes from eczema and food
panied by elevated levels of total serum IgE antibodies allergy to asthma and subsequently allergic rhinitis
and aberrant IgE‐mediated responses to otherwise (‘atopic march”) [6–9]. While allergic sensitization
harmless environmental agents [3]. Therefore it has represents one possible and plausible mechanistic link
Chapter 14 Genetics and Aetiology of Atopic Dermatitis 185
between asthma and eczema, it is notable that a signifi Evidence for a genetic basis for eczema
cant proportion of patients with eczema are not ‘atopic’, There is a longstanding recognition that atopic diseases
i.e. they have normal total serum IgE concentrations and cluster in families and are hereditary disorders [18–20].
no specific IgE responses [3,10]. Furthermore, epidemi Twin studies showed distinctly higher concordance rates
ological research indicates that sensitization might sim among monozygotic than dizygotic twin pairs (for
ply be a shared epiphenomenon and suggests that the eczema 0.23–0.86 vs. 0.15–0.50), and segregation analyses
association between asthma and eczema may occur suggested that genetic factors account for more than 70%
much earlier, i.e. early co‐occurrence of eczema and of the variance in the susceptibility to eczema [21–24].
wheeze progressing to asthma [10–12]. Thus, the role However, unlike monogenic disorders, which are caused
and temporal significance of elevated IgE in eczema is by mutations in a single gene, eczema and atopic disor
as yet unclear, and the concept of an ‘allergic march’ ders are likely to be complex poly‐ or oligogenetic traits,
may represent an oversimplification of complex disease thought to be the result of a complicated network of
co‐associations. Other discovered mechanisms such as numerous susceptibility loci that exert additive or syner
ATOPIC DERMATITIS
epidermally produced thymic stromal lymphopoietin gistic effects but may have only a small role when considered
(TSLP)‐mediated lung inflammation may provide in isolation [25]. In addition, interacting environmental
SECTION 3:
alternative explanations for an early co‐association of factors are thought to precipitate the polygenic risk back
eczema and asthma [13,14]. ground into disease manifestation [26]. The importance
Eczema has a wide spectrum of clinical presentations of environmental influences is emphasized by the wide
and it is unclear whether it is a single disorder with dif ranges in concordance rates, the incomplete concordance
ferent clinical manifestations or a group of syndromes among monozygotic twins and the changing and variable
with unique or overlapping pathophysiological path prevalences of atopic symptoms both between countries
ways that open out into a rather uniform clinical pres with similar ethnic groups and within countries [27,28].
entation. However, a rigorous definition of patient The dissection of complex traits is further hampered by
subgroups is highly desirable in order to facilitate epi phenocopy, incomplete penetrance and genetic heterogeneity
demiological, genetic and clinical investigations. In the [26]. In addition, a set of studies suggested that, particu
absence of a gold standard or adequate laboratory tests larly in atopic disorders such as eczema, inheritance of
to diagnose eczema, numerous lists of diagnostic crite certain polymorphisms from the mother is more likely to
ria have been developed in order to establish a defini be associated with allergic diseases in the child than
tion. At present, the UK diagnostic criteria have been inheritance from the father [29]. This parent‐of‐origin
the most widely validated and appear to be applicable effect is supported by epidemiological studies that indi
and repeatable across all ages and many ethnicities [15]. cate a crucial role of environmental exposures during
However, the ideal set of diagnostic criteria still has to pregnancy [30] and a more close relationship of the
be established [16]. infant’s disease risk to maternal than paternal disease sta
The confusing terminology for atopic diseases, with tus [31–33]. Genomic imprinting is one important epige
terms such as atopic eczema, atopic dermatitis, childhood netic mechanism that might explain such parent‐of‐origin
eczema, atopiform dermatitis and flexural dermatitis fre effects. Imprinting is a phenomenon in which disease‐
quently used synonymously in the literature, reflects the predisposing alleles only show their effects in a particular
complexity of the diseases and the as yet insufficient epigenetic context, for example methylation induced by
knowledge on their pathophysiology. It has previously the parental origin of the variant, leading to mono‐allelic
been suggested that ‘eczema’ be defined as the disease for expression in the somatic cells of the offspring. Differential
merly called ‘atopic eczema’ or ‘atopic dermatitis’, expression can occur in all cells, or in specific tissues or
whereas the term ‘atopic eczema’ be reserved for those developmental stages [34].
patients with eczema and evidence for IgE involvement
[5,17]. However, as pointed out in a review, this division Methods used in the genetic dissection
might not adequately reflect the natural history of this dis of eczema
ease [1], and it has to be considered that so far most, if not For elucidation of the genetic background of complex dis
all, studies on the genetics of eczema were performed eases, genetic association studies and linkage analyses
prior to these suggestions. Also, most existing DNA collec play an important role. The DNA sequence of human
tions have been assembled using older definitions. beings is on average 99.9% identical. The remaining 0.1%
It is anticipated that difficulties in defining eczema and of DNA sequence differences between any two individu
its phenotypes may be overcome or at least improved by als are mainly based on common single nucleotide poly
studying the genetics, and that the results of molecular morphisms (SNPs), in which a single nucleotide within
studies will be of great nosological significance, enabling the DNA sequence is replaced with an alternative one,
a classification of atopic disorders based on the underly and where each variation is present to some appreciable
ing genetic effects rather than on hypothetical concepts degree within a population (e.g. >1%). SNPs have become
and clinical symptoms as is the case today. A similar a favourite genetic tool in the investigation of complex
development has already taken place in other medical diseases, although many are nonfunctional and therefore
fields such as in neurodegenerative diseases, many of result in neutral phenotypic outcomes. However, func
which are now defined by their mutated genes (e.g. spi tional SNPs can predispose individuals to disease, or
nocerebellar ataxias). influence its severity, progression or individual response
to medicine. At the molecular level, these SNPs can affect inadequate assessment of the trait of interest and
the human phenotype by interfering on both levels of the inappropriate controls, variable study designs, inap
protein synthesis machinery: noncoding SNPs may dis propriate statistical modelling and failure to correct
rupt transcription factor binding sites, splice sites and for multiple comparisons, genetic and environmental
other regulatory elements on the transcriptional level, heterogeneity, publication bias (more positive reports
whereas coding SNPs can cause an amino acid change are submitted to and accepted by journals) and lack of
and alter the functional or structural properties of the independent replication [26,41].
translated protein. Since the turn of the millennium, association studies
Whole genome linkage analysis aims at the identifica have been revolutionized through newly developed
tion of chromosomal regions associated with a disease high‐throughput SNP genotyping platforms and
by identifying genetic markers, e.g. microsatellites or knowledge gained from the HapMap project, which
SNPs, co‐segregating with the disease within families. showed that the human genome is organized into
Susceptibility regions identified in such hypothesis‐free blocks of haplotypes with limited diversity within each
ATOPIC DERMATITIS
screens typically encompass several megabases of DNA of these blocks [42]. Association studies aim at the
sequence and might contain hundreds of genes. Thus, detection of proxy variants, which are in linkage dise
SECTION 3:
intensive follow‐up analyses are needed to narrow down quilibrium (LD) with the causal variant. LD refers to
the region of interest and to determine single disease the nonindependent inheritance of alleles, e.g. SNPs, at
genes. While this traditional approach has been extremely two or more loci, which extend over relatively short
successful in the identification of monogenic disease distances and may contain either a single gene or a few
genes [35], it has only limited power to detect risk genes genes only [38]. As a consequence of this genomic
for complex traits due to epistasis, incomplete penetrance, architecture a limited set of SNPs can capture the vast
polygeneity or phenotypic heterogeneity. Very few link majority of common variations and ‘tag’ the haplotype
age approaches have led to the identification of causal pattern sufficiently.
disease variants in this setting. For eczema several link Since 2005, commercial SNP‐typing arrays have been
age studies have identified various putative disease loci available and allow the simultaneous investigation of
in the past [36]. However, with the exception of the filag up to 4 million SNPs. The markers used are selected to
grin (FLG) gene, which partly explains the linkage signal provide maximal coverage of all common variations via
observed on chromosome 1q21 [37], it has not been pos LD‐based tagging, or even spacing within the genome
sible to assign a disease gene to any of the linkage regions [43]. These hypothesis‐free genome‐wide association
identified so far. studies (GWAS) were successfully used to identify com
Association studies are thought to provide a more mon disease‐associated variants (defined as those present
powerful method for detecting complex disease alleles, in more than 5% of the population). Another useful source
in particular alleles that only confer a modest disease for genetic association studies was provided by the
risk. These studies statistically analyse the correlation 1000 Genomes project (http://www.internationalgenome.
between a genetic marker, usually an SNP, and the dis org), which between 2008 and 2015 sequenced the
ease in unrelated individuals (case‐control and case‐ genomes of more than 2500 individuals from 26 different
cohort studies) or their transmission in families populations, thereby providing a comprehensive data set
(family‐based design) [38]. An association between the of common as well as low‐frequency variants.
genotype and the phenotype is assumed if the genetic Technical improvements in recent years have also led
marker and the disease occur together more often than to a substantial decrease in costs of next‐generation
expected by chance. Due to technical limitations, sequencing technologies. In contrast to genetic associa
genetic association studies have been limited to the tion studies that analyse a limited number of prese
study of candidate genes, i.e. genes located in a region lected single nucleotide variants distributed over the
showing linkage in previous screening studies and/or genome, DNA sequencing provides information on
because of their function and expression patterns each single base constituting an individual human DNA
(positional and/or functional candidate genes) [39]. sequence. Whereas whole genome sequencing still is
Based on the assumption that the primary defect in rather costly, whole exome sequencing approaches,
eczema is immunological and prior to the discovery of which exclusively target the coding DNA regions of the
FLG (see Filaggrin), for many years candidate genes human genome, already allow the identification of as
involved in antigen presentation and cell‐mediated/ yet unknown rare functional variants within larger
humoral immune response, and cell signalling/cellular numbers of samples at reasonable costs. This approach
movement have been investigated, as well as genes has already been very successfully applied within fami
that had been associated with asthma and/or atopy. lies affected by rare monogenic diseases, and will
More than 100 associated risk genes for eczema were undoubtedly increase our knowledge of genetic risk
reported up to 2009 by candidate gene association factors for common complex diseases like eczema.
studies [40], but most of these studies lack stringent Due to genetic studies the aetiological concept of
replication and have to be interpreted with caution. eczema underwent a profound change within recent
Potential reasons for irreproducibility of results years from a primarily immune‐mediated disorder to one
include low power (as a result of small sample sizes), that is equally, or may even be primarily, based on a skin
inappropriate selection of candidate loci and markers, barrier malfunction.
Genes implicated in the aetiology highly specific for eczema [48,54–56]. Further, for most of
of eczema these loci the causative gene or gene product as well as
the underlying molecular mechanisms remain to be
Association studies, in particular those using genome‐ identified and characterized. Some notable exceptions are
wide or targeted high‐throughput approaches, have presented here.
robustly identified more than 30 susceptibility regions for
eczema (Table 14.1) [44–52]. These loci together explain
approximately 20% of the estimated heritability. Most of Filaggrin
them harbour candidate genes that contribute to immune Filaggrin (filament aggregating protein; FLG) was first
mechanisms, in particular to innate immune signalling described in 1977 as an insoluble protein purified from rat
and T‐cell activation and specification (Table 14.1, epidermis that interacted with intermediate filaments in
Fig. 14.1), and appear to impact the susceptibility for a vitro [57]. It represents a structural protein with key func
range of immune‐mediated diseases rather than being tions in the formation and maintenance of the cornified
ATOPIC DERMATITIS
SECTION 3:
Table 14.1 Susceptibility loci and most plausible candidate genes identified through genome‐wide association studies for atopic eczema
Associated Candidate gene Known/proposed function

locus
1q21.2 CIART Circadian transcriptional repressor

1q21.3 FLG Terminal epidermal differentiation; aggregation of keratin intermediate filaments
1q21.3 IL6R Subunit of the IL‐6 receptor; differentiation of multiple immune cells, especially B cells
2p13.3 CD207 C‐type lectin with mannose binding specificity; major receptor on Langerhans cells; antigen
uptake, processing and presentation
2p16.1 PUS10 Posttranscriptional modification of structural RNAs; involved in apoptosis
2p25.1 LINC00299 Long noncoding RNA; no known function
2q12.1 IL1RL1 Subunit of the IL‐33 receptor; Th cell function
IL18R1/IL18RAP Subunits of the IL‐18 receptor; regulation of inflammatory response via NF‐κB
2q24.3 XIRP2 Actin cytoskeleton and cell–cell junction organization; protection of actin filaments from
depolymerization
3p21.1 RFT1 Oligosaccharide transporter; protein N‐glycosylation
3p22.3 CCR4 C‐C chemokine receptor; leucocyte trafficking
3q13.2 CCDC80 Cell adhesion and matrix assembly
4q27 IL2/IL21 Differentiation, proliferation and activation of multiple immune cells (T cells, B cells,
macrophages, natural killer cells)
5p13.2 IL7R Subunit of the IL‐7 and TSLP receptor; proliferation of lymphoid progenitors; release of T‐cell‐
attracting chemokines; promotion of Th2‐cell response
5q22.1 TSLP Release of T‐cell‐attracting chemokines; promotion of Th2‐cell response; AMP activity in the oral
cavity and on the skin
5q31.1 IL13/IL4 Mainly produced by activated Th2 cells; B‐cell proliferation; IgE isotype switching
6p21.32 HLA‐DRB Antigen processing and presentation MHC class II
6p21.33 MICB Stress‐induced self‐antigen; activation of cytolytic response of NK cells, αβ T cells, and γδ T cells
7p22.2 CARD11 TCR‐mediated T cell activation; NF‐κB activation
8q21.13 ZBTB10 Transcription regulation
9p21.3 DMRTA1 Transcription regulation
10p15.1 IL15RA/IL2RA IL‐15 and IL‐2 receptor subunits; proliferation and stimulation of different lymphocytes
10q21.2 ZNF365 Mitotic cytokinesis; maintenance of genome stability
11p13‐12 PRR5L Regulation of protein kinase C phosphorylation; survival and organization of the cytoskeleton;
cell migration
11p15.4 NLRP10 Regulation of the innate immune system; pro‐inflammatory cytokine release; inhibition of
apoptosis; anti‐inflammatory activity
11q13.1 OVOL1 Transcription factor; hair formation and spermatogenesis
11q13.5 LRRC32 Regulation of Treg function and TGF‐β activation
11q24.3 ETS1 Transcription factor; direct control of cytokine and chemokine expression
14q13.2 PPP2R3C Regulation of protein phosphatases; activation‐induced cell death of B cells
16p13.13 CLEC16A C‐type lectin; regulation of mitophagy/autophagy and mitochondrial health
17q21.2 STAT3 Signal transducer and transcription activator; mediation of cellular responses to interleukins
17q21.32‐33 ZNF652 Transcription regulation
19p13.2 ACTL9 Cytoskeletal functions
ADAMTS10 Metalloprotease; assembly of extracellular matrix components
20q13.2 CYP24A1 Vitamin D metabolism
20q13.33 TNFRSF6B TNF receptor superfamily; protection against apoptosis
Sorted by chromosome; AMP, antimicrobial peptide; IL, interleukin; MHC, major histocompatibility complex; NF‐κB, nuclear factor ‘kappa‐light‐chain‐enhancer’
of activated B cells; NK cells, natural killer cells; RNA, ribonucleic acid; TCR, T‐cell receptor; TGF‐β, transforming growth factor β; Th cell, T‐helper cell; TNF,
tumour necrosis factor; TSLP, thymic stromal lymphopoietin.
Epidermal barrier Environmental sensing

FLG, OVOL1, CARD11,
ACTL9/ADAMTS10 HLA-DRB, MICB
ATOPIC DERMATITIS
SECTION 3:
Tissue response
Immune regulation CCDC80, CYP24A1,
IL1RL1/IL18R1/IL18RAP LRRC32, NLRP10, PRR5L,
IL2/IL21, IL4/IL13, TNFRSF6B,
IL6R, CLEC16A ZNF365, ZNF652
Fig. 14.1 Functional overview for selected candidate
genes identified through genome‐wide association
studies. Source: Adapted from Weidinger and Novak
(2016) [53].
envelope within the outermost layer of the human reduced in the epidermis of individuals with this disease
epidermis, and is essential for the prevention of penetra [63,64]. However, in‐depth analysis of the protein‐encoding
tion of environmental agents such as microbes or allergens gene transpired to be technically difficult because of its
into the organism and also, on the other hand, for controlling repetitive structural nature, and the sequence of the entire
transepidermal water loss (TEWL) [58,59]. FLG gene was finally published in 2006, identifying two
Profilaggrin is expressed as a large inactive precursor loss‐of‐function variants (p.R501X and c.2282del4) to be
protein of 400 kDa in the stratum granulosum of the epi the cause of IV [65]. Subsequently the same group
dermis, where it represents the main constituent of the detected significant associations between these variants
keratohyalin F granules (Fig. 14.2). It is composed of and eczema [66].
10–12 tandem repeats, each encoding a functionally active Since that time more than 50 recurrent and family‐
FLG monomer. Upon cornification of keratinocytes, pro specific variants have been identified within the FLG
filaggrin is dephosphorylated and proteolytically cleaved gene in European and Asian populations [67]. These are
into its active subunits. These monomers lead to a dense present in up to 10% of the general European population,
bundling of keratin intermediate filaments, leading to and up to 40% of eczema patients are carriers of at least
collapse of the keratinocyte’s cytoskeleton during their one of the five most recurrent null variants (p.R501X,
differentiation into corneocytes, and finally to desquama c.2282del4, p.S3247X, p.R2447X and c.3702delG), which
tion of the stratum corneum. Concurrently, the amino account for about 95% of all known variants within FLG
(N)‐terminus of the protein is translocated into the cell [67]. Interestingly, frequency appears to increase from
nucleus, where it is believed to fulfill an additional but as southern to northern Europe, which might reflect eth
yet unknown role in regulation of terminal differentia nic differences. In populations from UK and Ireland,
tion. Moreover, degradation products of FLG, free hygro FLG loss‐of‐function variants seem to be more prevalent
scopic amino acids and their derivatives, constitute a compared to continental Europe [65,68–72]. Of the more
large part of the pool of so‐called natural moisturizing than 20 described loss‐of‐function variants found in
factors (NMFs) within the skin [61]. NMFs play an impor the European population, the majority could not be found
tant role in regulation of skin hydration and skin pH, the in Asian individuals [65,73,74] and vice versa. Similarly,
latter of which is closely linked to protease activity and no FLG loss‐of‐function variants predominate in
antimicrobial defence [62]. The importance of FLG‐ African‐American children; however, uncommon
derived breakdown products for skin barrier function is FLG loss‐of‐function variants in African‐American chil
supported by the remarkably short half‐life of FLG, dren have been identified and shown to be associated
which exists only for 6 hours before its full proteolysis with more persistent AD [75]. Each ethnic group seems to
into NMFs. have its own exclusive null variants showing the same
FLG was suspected of involvement in keratinization strong impact on the development of eczema. All reported
disorders such as ichthyosis vulgaris (IV) more than variants are frameshift or nonsense variants leading to a
25 years ago, and its expression was found to be clearly premature translation stop and hence truncation of the
Putative filaggrin functions
Outer stratum corneum

Hydration through hygroscopic
amino acids UCA and PCA
Inner stratum corneum Possible contribution to acid mantle
through acid degradation products
Lipid bilayer
Filament binding, barrier integrity
Granular layer Profilaggrin in granular layer:
Pro-protein, nonfunctional
(a) (b)
ATOPIC DERMATITIS
SECTION 3:
PCA
H2O
PADs 1+3 Caspase 14

+PCA
TGMs Profilaggrin A domain
“NMF”
Profilaggrin B domain
Ca2+
Matriptase Profilaggrin tail domain
Dephosphorylation LEKTI
CAP1/Prss Filaggrin
Keratohyalin F granule
Nucleus
Free amino acid
(c)
Fig. 14.2 Filaggrin expression and putative functions in the skin barrier. (a) The precursor pro‐protein profilaggrin is strongly expressed within keratohyalin
granules, tightly limited to and accounting for the typical appearance of the granular layer. The stratum corneum stains strongly positive for filaggrin. (b)
Filaggrin has several proposed site‐specific functions under the influence of the epidermal terminal differentiation programme through the outer granular
layer (cleavage of profilaggrin to filaggrin), lipid bilayer of the inner stratum corneum (filament compaction, contribution to barrier integrity) and during
desquamation of the outer stratum corneum (production of amino acid degradation products that contribute to the hydration of these outer layers and
probably contribute to the ‘acid mantle’). (c) Current knowledge of molecular control of filaggrin homeostasis. Profilaggrin is dephosphorylated in
conditions of increasing calcium concentration and then proteolytically cleaved by the proteases matriptase (inhibited by the protease inhibitor LETKI) and
CAP1/Prss. Post proteolysis, the filaggrin tail domain locates to the nucleus as part of the terminal differentiation process. Free filaggrin protein is cross‐
linked to keratin filaments by transglutaminases (TGMs) and subsequently deiminated by peptidylarginine deiminases (PADs) 1 and 3. Further posttransla-
tional modification is undertaken by caspase 14 to produce the free amino acid hygroscopic degradation products urocanic acid (UCA) and pyrrolidone
carboxylic acid (PCA), collectively known as natural moisturizing factor (NMF), which contributes to stratum corneum hydration. Source: O’Regan et al.
2008 [60]. Reproduced with permission of Elsevier.
profilaggrin molecule. The two most common variants, Th2 cytokine cluster
p.R501X (a nonsense variant of the arginine codon 501 to One of the most consistent associations with eczema and
a stop codon) and c.2282del4 (a frameshift variant at posi a variety of other immune‐related disorders such as
tion 2282 due to a four base pair [bp] deletion), in the first Crohn’s disease, asthma and psoriasis has been observed
repeat of the gene impede any FLG synthesis from these for the T‐helper 2 (Th2) cytokine cluster on chromosome
alleles. As the 3′ gene sequence seems to be important for 5q31 [77,78], a locus that harbours the genes encoding
posttranslational processing into functional FLG subu interleukin (IL)‐3, IL‐4, IL‐5 and IL‐13. These cytokines
nits, even variants located in this region prevent or reduce are mainly produced by differentiated CD4+ Th2 cells
production of free FLG in the stratum corneum [62,69]. that are responsible for the antibody‐mediated immune
Scientific evidence for this gene as one of the strongest response against parasites, allergens and bacteria. Th2
risk factors for eczema is compelling due to numerous cytokines show a great functional overlap and are
replication studies and meta‐analyses, which revealed an involved in Th2 cell development and polarization, B‐cell
overall odds ratio of >3.0 for eczema [76]. Due to the dis proliferation and differentiation, IgE antibody produc
covery of FLG, susceptibility genes for eczema are now tion, and activation and recruitment of certain immune
divided into two major functional groups: genes contrib cell subsets such as mast cells and eosinophils to inflam
uting to epidermal or epithelial structures, and genes matory sites. Different potential risk SNPs have been
encoding immune regulatory proteins. identified throughout the whole region, and functionally
disruptive variants within IL4 and IL13 genes are con by targeted next‐generation sequencing revealed a
vincingly associated with total IgE levels and atopic dis number of low‐frequency variants within the coding
eases including eczema (reviewed in [79]). Additionally, region of LRRC32 to be strongly associated with eczema.
various GWAS identified associated SNPs within RAD50, LRRC32 encodes the protein glycoprotein A repetitions
a gene situated within the cytokine cluster between predominant (GARP), a cell surface receptor mainly
IL4/IL13 and IL5, encoding a DNA repair protein that is expressed on activated regulatory T cells (Tregs), which
ubiquitously expressed and therefore lacks any direct bio binds and activates latent TGF‐β, thereby regulating the
logical connection to eczema. However, in mouse models bioavailability of this multifunctional cytokine [87]. All of
RAD50 has been shown to contain an evolutionarily con the identified variants lead to an amino acid exchange
served locus control region (LCR), which is supposed to within the primary structure of the protein, and structural
tightly control expression of the neighbouring Th2 modelling of GARP predicted a defective posttransla
cytokines [80]. Hence, associated polymorphisms in tional modification due to the identified variants, finally
RAD50 influence regulation of Th2 cytokine gene tran leading to incorrect folding and constrained transporta
ATOPIC DERMATITIS
scription rather than RAD50 gene function itself. tion of GARP to the outer cell membrane. Overexpression
Regulation through the LCR within RAD50 occurs via a experiments of mutated GARP indeed showed reduction
SECTION 3:
complex recruitment of transcription factors and other of the membrane‐bound protein, and a reduced conver
regulatory molecules and includes epigenetic remodelling sion rate of CD4+/CD25− T cells into Tregs was observed
of the three‐dimensional structure of chromatin within when obtained from individuals carrying the identified
this region. An intrachromosomal loop allows direct variants [86]. Tregs are of high importance for suppres
interaction of the transcription factor machinery bound to sion of effector T cells and other leucocytes and for con
the LCR with the Th2 cytokine gene promoter regions in trol of inflammatory immune responses and autoimmunity
order to activate or repress their expression [81,82]. The [88], and experimental deactivation of GARP has been
LCR has also been shown to be rapidly demethylated in shown to lead to a reduction in the suppressor activity of
murine cell lines of stimulated Th2 cells [83], linking the these cells [89]. It is possible to speculate that the missing
epigenetic mechanism of DNA methylation with activa membrane expression of GARP on activated Tregs leads
tion of Th2 cytokine expression. Inactivation of the LCR to a decreased activation rate of TGF‐β and thereby affects
in mice leads to a reduction of Th2 cytokine and IgE levels downstream function of this important cytokine, finally
[84], and variants within the LCR impact its transcrip resulting in an overshooting inflammatory immune reac
tional activity [85]. tion. Moreover, Tregs are suspected to be involved in a
Together, genetic as well as epigenetic elements seem to variety of other diseases, and association of the previ
regulate expression of this important immune gene clus ously mentioned eczema marker has also been detected
ter, and variants might interfere with both mechanisms, in a GWAS on Crohn’s disease, implying that the 11q13.5
thereby promoting Th2‐dominated immune reactions locus and GARP are also important within the disease
characteristically for atopy‐related disorders like eczema. pathophysiology of further (auto)immune diseases.
Given the number of immune‐mediated diseases that
have been linked to the Th2 cytokine cluster, it seems very
Conclusions and future directions
likely that variants within this region are more relevant
for the atopic state sensu lato than for any individual Despite much progress over the past two decades, our
distinct atopic disease. understanding of the complex genetic susceptibility to
Identification of further causal variants that probably eczema is still incomplete. In particular, there is a lack of
exist within this important risk locus is hampered by the follow‐up studies in order to determine affected genes and
complex marker–marker correlation in this genomic downstream mechanisms. Thus far only the 1q21.3, 5q31
region and the gene–gene interactions through overlap and 11q13.5 loci have been functionally explored. The
ping functional pathways. important role of the skin barrier within eczema has been
clearly evidenced with the identification and validation of
GARP (glycoprotein A repetitions FLG variants as the strongest known genetic risk factors for
predominant)/LRRC32 (leucine‐rich the disease. This paradigm change has now also led to early
repeat‐containing protein 32) intervention studies of primary prevention of the disease by
Another consistently‐replicated eczema risk locus has improving the skin barrier function with daily emollient
been identified on chromosome 11q13.5, with the strong applications. The results of these randomized intervention
est association observed for an SNP located in an inter studies have been an approximate 50% reduction of eczema
genic region between the two annotated genes chromosome incidence in high‐risk newborns [90, 91], lending further
11 open reading frame 30 (C11orf30) and leucine rich repeat support for the key importance of a functionally intact skin
containing 32 (LRRC32). Assignment of the signal to one of barrier. Likewise, genetic findings that imply an important
its neighbouring genes could not be accomplished, as role of variation in genes affecting (auto‐)immune regula
both are attractive candidates due to their known func tion, in particular innate signalling and T‐cell activation and
tions in epithelial immunity and differentiation and acti specification, have contributed to the development of drugs
vation of regulatory T cells, respectively, and the causative modifying immune pathways, some of which are already in
risk gene marked by the associated SNP has more recently advanced stages of development and showed encouraging
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ATOPIC DERMATITIS
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193
C HA PTER 15
Clinical Features and Diagnostic Criteria

of Atopic Dermatitis
Sinéad M. Langan1 & Hywel C. Williams2
Faculty of Epidemiology and Population Health, London, School of Hygiene and Tropical Medicine, London, UK
1
The Centre of Evidence Based Dermatology, University of Nottingham, Nottingham, UK

2
ATOPIC DERMATITIS
Clinical features of atopic dermatitis, 194 Diagnostic criteria for atopic dermatitis, 203
SECTION 3:
Abstract define reliably and too infrequent to be of use when examining
groups of individuals, especially when it adds very little to the
This chapter is divided into two sections: the first lists the common predictive ability of existing cardinal features such as flexural
and less common clinical features of atopic dermatitis (AD) with involvement and dry skin. Likewise, diagnostic criteria that may
the aim of helping those less familiar with diagnosing atopic der- produce acceptable results for estimating the prevalence of AD in
matitis in a clinical setting. The second part deals with diagnostic a country may not be suitable when trying to diagnose AD in an
criteria for atopic dermatitis that may be used in research studies. individual, since every set of diagnostic criteria will have limita-
The two sections are set apart deliberately since the requirements tions in sensitivity (proportion of true cases correctly identified)
of a disease definition for making a clinical diagnosis in an individual and specificity (proportion of non‐cases correctly identified). All
may be somewhat different from making a group definition for current diagnostic criteria will therefore misclassify some
research participants. A clinical sign such as thinning of the lateral individuals who have AD as not having AD, and some who do not
eyebrows may be associated with AD, and possibly useful in the have AD as having AD. Such misclassification may be acceptable
context of tipping a clinician to make a diagnosis of AD in a child in research studies, providing the degree of misclassification is
with indeterminate skin inflammation. Yet it is too difficult to understood in relation to the objective of the study.
Key points • Previous definitions of an incident case of AD have paradoxically

included chronicity.
• What is recognized as AD today may turn out to be four or five
Clinical features of atopic dermatitis
different phenotypes (subtypes) in years to come. Any proposals
• Although atopic dermatitis (AD) can affect any part of the body, it has for new subtypes of AD should be based on strong evidence that
a predilection for the skinfolds, the reason for which is still unclear. they increase predictive ability in terms of prognosis, disease
• The distribution of eczema changes from involvement of the face, associations or response to treatments.
scalp and extensor surfaces in infancy to flexural involvement in • While a clinical diagnosis is appropriate in clinical practice,
childhood and later life. standardized diagnostic criteria for AD are essential when
• The morphological appearance of AD can vary greatly from acute comparing groups of people in clinical studies.
red vesicular eczema to chronic thickened purple/grey lichenified • A good disease definition should be valid, reliable, acceptable
patches. to the population, coherent with prevailing clinical concepts and
• AD can be associated with serious complications including comprehensive in its application.
secondary infections and exfoliative dermatitis. • The Hanifin and Rajka list of diagnostic features was an important
• Other differential diagnoses should be considered when infants landmark in suggesting major and minor criteria for AD.
present with a severe eczematous rash with failure to thrive, • A systematic review suggested that the most extensively tested
recurrent infections or petechiae. criteria (the UK Working Party’s refinement of the Hanifin and
Rajka criteria) should be used in future intervention studies,
Diagnostic criteria for atopic dermatitis although there is room for improvement.
• Ideally, diagnostic criteria should be tested beforehand
• AD is a difficult disease to define since it is variable in morphology
for validity in the setting where they are to be used. If
and distribution according to age, skin type and whether the
translation or transcultural interpretation becomes a
skin is acutely or chronically affected.
problem, then question‐free methods of assessing visible
• Although the term ‘atopic dermatitis’ is used throughout this
flexural dermatitis in a standardized way are an option for
book, most cases of ‘atopic’ dermatitis are not atopic when
comparative research.
tested in populations. As a consequence there is debate as to
• It is crucial to consider the type of clinical study before deciding
whether the term ‘atopic dermatitis’ should be reserved for
which diagnostic criteria can be used. Surveys will need a trade‐
cases with evidence of IgE reactivity.
off between sensitivity and specificity whereas clinical trials will
• The positive predictive value of diagnostic criteria will fall with
require specific criteria.
low disease prevalence even though sensitivity and specificity
might appear to be high.
Clinical features of atopic dermatitis

The evidence for the first section of this chapter is largely
based on classical descriptions in textbooks and scholarly
articles by pioneers in the field of atopic dermatitis (AD),
supplemented by clinical experience. An excellent historical
account of the concepts that formed the notion of what
is recognized today as AD may be found elsewhere [1].
Multiple factors including age, ethnic origin, level of
disease activity, therapeutic interventions and infectious
complications influence both distribution and morphology
of AD, leading to variations in disease presentation. The
characteristic clinical features of AD distribution and
ATOPIC DERMATITIS
morphology described here aid clinical diagnosis in the

absence of a specific laboratory test for AD.
SECTION 3:
Distribution
The distribution of AD is dependent on the age of onset
and disease activity. Infantile eczema usually starts at
3 months or younger and typically affects the face and
scalp first (Fig. 15.1a and b), then spreads to involve the
limbs and trunk in a symmetrical distribution (Fig. 15.2)
[2]. Truncal lesions are diffuse while limb lesions tend to
be discrete and localized (Fig. 15.3). The napkin area is
frequently spared for reasons that are unclear, although
local humidity has been suggested.
Fig. 15.2 Facial eczema and diffuse truncal erythema in an infant. Source:
Courtesy of Dr Paula E. Beattie.
(a)
Fig. 15.3 Symmetrical eczema involving the trunk and extensor surfaces
in atopic dermatitis in a child. Source: Courtesy of Professor Hywel C. Williams.
In childhood, AD distribution is seen most commonly in

a flexural pattern. The tendency for skin inflammation and
the effects of chronic rubbing (lichenification) to become
accentuated in the flexures is one of the classical hallmarks
of AD (Fig. 15.4) [3]. Flexures refer to bends in the articular
(b) skeleton where skin apposes skin. What exactly consti-
Fig. 15.1 Scalp involvement in atopic dermatitis in an infant. Source: tutes a flexure varies from text to text, but most agree that
Courtesy of Dr Paula E. Beattie. the fronts of the elbows, backs of the knees, around the
Chapter 15 Clinical Features and Diagnostic Criteria of Atopic Dermatitis 195
neck and in front of the ankles are the commonly affected can affect any part of the body. The fact that a child
flexures. All of the flexure is not always involved – presents with an itchy scalp and diffuse patches of skin
lichenification as a result of prolonged rubbing typically inflammation on extensor parts of the limbs should not
occurs most prominently behind the knees along the most put one off diagnosing AD since it is the most common
prominent tendons (semimembranosus and semitendino- inflamed itchy chronic skin eruption in children in
sus) and likewise overlying the brachioradialis muscle developed countries.
group on the antecubital fossae (Fig. 15.5a and b). From puberty onwards, AD tends to affect the face,
Other affected areas include the wrists and folds hands, back, wrists and dorsal feet. The hands and fin-
beneath the buttocks (infragluteal folds). Why the most gers are frequently involved, probably as a result of con-
flexural sites of the body, i.e. inguinal folds and apex stant irritant exposure, which may result in oedema
of the axillae, are infrequently involved is unclear. and fissures overlying the finger joints (Fig. 15.6) and
Eczematous inflammation at these sites may be more scaling on the palms adjoining the fingers (apron sign).
likely to be a marker of seborrhoeic dermatitis of infancy Adults may only have persisting hand or facial eczema
ATOPIC DERMATITIS
or early‐onset psoriasis. Two points are worthy of note
with regards to flexural involvement; the first is that AD
SECTION 3:
Fig. 15.4 Thickened lichenified atopic dermatitis on the lower leg and Fig. 15.6 Chronic hand eczema with loss of cuticles, nail dystrophy,
dorsal foot in darkly pigmented skin. Source: Courtesy of Professor Hywel fissuring and scaling. Source: © Diepgen TL, Yihune G et al. Dermatology
C. Williams. Online Atlas (www.dermis.net). Reprinted with permission.
(a) (b)
Fig. 15.5 (a and b) Flexural subacute atopic dermatitis involving the antecubital and popliteal fossae with erythema and excoriations. Source: Courtesy of
Professor Hywel C. Williams.
and skin that is sensitive to irritant exposure, or they may

have persistent chronic AD.
Specific sites that are frequently involved by AD are as
follows: lips with cheilitis in childhood (Fig. 15.7), which
can lead to secondary ‘lip‐lick cheilitis’ or exfoliating
cheilitis with perlèche (single or multiple fissures and
cracks at the labial commissures) and involvement of the
vermillion border in adult AD. The infra‐auricular,
supra‐auricular and retroauricular region is frequently
affected by fissures (rhagades) in children (Fig. 15.8)
while eyelids and periorbital skin are frequently
involved in adolescents and adults, resulting in promi-
nent infraorbital creases from skin oedema and postin-
ATOPIC DERMATITIS
Fig. 15.7 Acute cheilitis in a child with atopic dermatitis with erythema flammatory pigmentation resulting in the affected
and swelling of the vermillion border and perioral region and fissuring of individual appearing fatigued. Some sites of predilec-
SECTION 3:
the commissures. Source: © Diepgen TL, Yihune G et al. Dermatology tion of AD such as around the eyes, mouth or nose
Online Atlas (www.dermis.net). Reprinted with permission. (Fig. 15.9) or under the ear also occur probably as a result
of influences other than skin‐to‐skin contact such as air-
borne allergens and irritants, or irritant contact dermati-
tis around the mouth from saliva and wet foods in early
age. Nipple eczema is frequently seen from puberty
onwards, but is also seen in infants and can present with
nipple swelling (Fig. 15.10a and b).
Fig. 15.8 Fissures of the infra‐auricular region in childhood atopic Fig. 15.9 Subacute eczema with fissuring and oedema. Source: ©
dermatitis. Source: © Diepgen TL, Yihune G et al. Dermatology Online Diepgen TL, Yihune G et al. Dermatology Online Atlas (www.dermis.net).
Atlas (www.dermis.net). Reprinted with permission. Reprinted with permission.
(a) (b)
Fig. 15.10 (a) Acute nipple eczema with erythema, erosions, oozing and secondary impetiginization. Source: © Diepgen TL, Yihune G et al. Dermatology
Online Atlas (www.dermis.net). Reprinted with permission. (b) Chronic nipple eczema with lichenification and swelling. Source: Courtesy of Dr Diana Purvis.
ATOPIC DERMATITIS
SECTION 3:
(a) (b)
(c)
Fig. 15.11 (a) Acute, (b) subacute and (c) chronic eczema. Source: Courtesy of Professor Hywel C. Williams.
Morphology
The morphology of AD can be variable and depends on
the stage of the lesion. Acute lesions are characterized by
ill‐defined erythema, papules, papulovesicles, erosions,
oedema and weeping (Fig. 15.11a). Subacute lesions are
erythematous scaly excoriated plaques and papules
(Fig. 15.11b) while thickened purple/grey lichenified
plaques and fibrotic papules (prurigo) are seen in chronic
lesions (Fig. 15.11c). During infancy, AD tends to be acute
and exudative with chronic forms of AD developing later
in childhood. In longstanding AD, individuals may mani-
fest all three stages of AD concurrently or at different
times depending on the level of disease activity, reflecting
the relapsing and remitting nature of eczema.
Fig. 15.12 Symmetrical infraorbital Morgan–Dennie folds. Source:
© Diepgen TL, Yihune G et al. Dermatology Online Atlas (www.dermis.net).
Associated physical signs Reprinted with permission.
A number of clinical signs frequently accompany AD and
these may be clues to the diagnosis when the distribu-
tion and morphology are not classical, although they 50–60% of cases of AD. However, this sign appears to
may not be pathognomonic of AD. A number of these will vary depending on ethnicity, being more common in
be briefly discussed here. darkly pigmented ethnic groups regardless of AD, and
shows significant variability even within individuals [4]
Periocular and ocular signs (Fig. 15.12). Periorbital pigmentation, ‘atopic shiners’,
Infraorbital folds (Dennie–Morgan lines) are frequently describes a periorbital brown to grey discolouration [5].
seen in AD, with most studies reporting their presence in As previously discussed, thinning or absence of the outer
(blanching of the skin at the site of stroking with a blunt

instrument rather than developing a partial or full triple
response of Lewis with reflex erythema), are frequently
described in AD and are thought to represent abnormal
vascular responses (Fig. 15.15).
Dry skin (xerosis) is seen in all age groups with AD and
is considered a hallmark of AD (Fig. 15.16). Atopic xerosis
ATOPIC DERMATITIS
Fig. 15.13 Thinning of the outer eyebrows (Hertoghe’s sign) with extensive
scaling and lichenification of the forehead. Source: © Diepgen TL, Yihune G
SECTION 3:
et al. Dermatology Online Atlas (www.dermis.net). Reprinted with permission.
eyebrows (Hertoghe’s sign), a sign originally described in

hypothyroidism, may also be seen although its preva-
lence has not been extensively studied (Fig. 15.13). Specific
ocular signs such as keratoconjunctivitis, keratoconus
and anterior subcapsular cataracts may be associated with
AD, although their population‐based frequency is diffi-
cult to identify from the literature. A population‐based
survey from Korea reported a 50% increased odds of cata-
ract in individuals with AD [6], while an Israeli study
reported no increased risk of keratoconus with AD,
although associations were observed for other atopic
diseases [7]. A population‐based study of ocular infec-
tious diseases from Hawaii suggested that individuals Fig. 15.15 White dermographism with blanching of the skin at the site of
with AD had a five‐fold increased risk of ocular herpes stroking with a blunt instrument rather than developing a partial or full triple
simplex virus and a two‐fold increased risk of herpes response of Lewis with reflex erythema. Source: © Diepgen TL, Yihune G et al.
zoster ophthalmicus [8]. Dermatology Online Atlas (www.dermis.net). Reprinted with permission.
Other cutaneous ‘minor’ signs

Two features are described in the neck region, namely the
anterior neck folds and atopic ‘dirty neck’ (Fig. 15.14).
The ‘dirty neck’ refers to rippled hyperpigmentation of
the anterior and lateral neck, which clinically resembles
macular amyloid. Facial pallor and white dermographism
Fig. 15.14 Rippled hyperpigmentation of the lateral neck (atopic ‘dirty

neck’). Source: © Diepgen TL, Yihune G et al. Dermatology Online Atlas Fig. 15.16 Xerosis in infantile atopic dermatitis. Source: Courtesy of
(www.dermis.net). Reprinted with permission. Dr Paula E. Beattie.
ATOPIC DERMATITIS
SECTION 3:
(a)
Fig. 15.17 Hyperlinear palms with exaggerated wrinkling of the palms.

Source: Courtesy of Professor Alan Irvine.
may be generalized and is frequently most noticeable on

the shins. Xerosis is characterized by fine scaling without
associated inflammation and roughness on palpation. Dry
skin may be associated with ichthyosis vulgaris, an autoso-
mal dominant condition seen in 8% of individuals with AD
[9,10]. However, studies show that dry skin is also inde-
pendently associated with AD in the absence of ichthyosis
vulgaris [11]. Hyperlinear palms are a frequent finding in
AD (Fig. 15.17). More recently, studies have shown that
palmar hyperlinearity is more frequently seen in AD com-
pared to ‘atopiform’ dermatitis (AD without raised IgE lev- (b)
els) and that this sign is strongly associated with filaggrin Fig. 15.18 (a and b) Pityriasis alba with poorly defined slightly scaly
null mutations and ichthyosis vulgaris [12,13]. hypopigmented patches on the face. (a) Source: Courtesy of Professor
Pityriasis alba describes a condition frequently asso- Nanette Silverberg. (b) Source: Courtesy of Dr Diana Purvis.
ciated with AD characterized by poorly defined slightly
scaly hypopigmented patches on the cheeks and upper
arms (Fig. 15.18). This clinical sign is more obvious in
Nummular or discoid atopic dermatitis
dark skin and can be mistaken for tinea corporis.
This type of AD presents with sharply demarcated c ircular
Atopic dermatitis in racially pigmented lesions (Fig. 15.20) often located on the trunk and distal
skin types extensor limbs including dorsal hands, lower legs and
The diagnosis of eczema in dark skin is complicated by the forearms. The individual lesions are frequently dry and
lack of visible erythema. The diagnosis is made based on infiltrated plaques. This pattern of AD is reported to
the presence of a typical history accompanied by lesions worsen in winter time. It is often misdiagnosed as ring-
demonstrating a distribution and morphology consistent worm by general practitioners and is almost always asso-
with AD. Other features classically seen in pigmented skin ciated with concurrent or past flexural AD in children.
are enhanced follicular lichenification with a papular Nummular AD often requires stronger and longer treat-
appearance and postinflammatory hypo‐ and hyperpig- ment with potent topical corticosteroids. In adults, num-
mentation (Fig. 15.19). mular eczema may be independent of atopy.
Clinical features of specific subtypes Diffuse ‘dry type’ AD

of atopic dermatitis This type of AD was first described in Japan and refers to
Specific subtypes of childhood AD deserve a mention as a diffuse dry type AD, sometimes called patchy pityriasi-
their morphology and distribution have not been previously form lichenoid eczema, which is slightly irritating and
discussed in this chapter. clinically consists of confluent scaly nonhyperkeratotic
ATOPIC DERMATITIS
SECTION 3:
Fig. 15.20 Nummular atopic dermatitis affecting the torso in a young

child. Source: Courtesy of Professor Hywel C. Williams.
Fig. 15.19 Postinflammatory hypo‐ and hyperpigmentation in darkly IgE levels) eczema with palmar hyperlinearity and ker-
pigmented skin. Source: Courtesy of Professor Hywel C. Williams.
atosis pilaris [13,17]; however, filaggrin null mutations
are absent in >50% of individuals with eczema [18–22].
Population‐based studies from Denmark and Sweden
skin‐coloured papules or ‘chicken‐skin spots’, mainly on have reported associations between the presence of
the trunk region [14]. Seasonal variations are described, filaggrin mutations and persistent hand dermatitis in
with worsening in winter. adults, with a further Danish study suggesting addi-
tional associations with self‐reported foot dermatitis
Eczema subtypes/phenotypes [22,23].
There is increasing evidence supporting the existence of AD with eczema herpeticum is another proposed
discrete clinical phenotypes of eczema. This encom- clinical phenotype, reported to be associated with a
passes heterogeneity in the clinical disease course, asso- greater risk of atopic diseases and associated bacterial
ciations with specific infections, disease distribution infections [24].
and responses to treatment. Usual phenotypic group-
ings are based on disease trajectories, atopy status and Complications
associated comorbidities with different groupings in Bacterial infections
published papers. For example Leung et al. describe Staph. aureus colonization can be demonstrated in 90% of
eight categories: onset in infancy and (1) transient or (2) eczema lesions and its density is associated with disease
persistent; onset in adolescence and (3) mild to moder- severity [25]. Clinically infected AD is characterized by
ate or (4) persistent and severe; (5) associated with high honey‐coloured crusted impetigo, folliculitis and pyo-
IgE level and sensitization; (6) non‐IgE associated; (7) derma or as worsening of AD with increased erythema,
associated with Staphylococcus aureus infections; and (8) oozing and pain (Fig. 15.21). Infections are usually caused
associated with disseminated viral infections [15]. by Staph. aureus but β‐haemolytic streptococci may also
Garmhausen et al. report the existence of five pheno- be isolated from infected AD. There is increasing research
typic groups based on disease trajectories and associa- into the mechanisms of increased cutaneous infection
tions with IgE. Most studies concur that persistent AD risk in individuals with AD. This research has focused on
is frequently associated with early‐onset eczema with the roles of the defective skin barrier (genetic and
associated rhinitis and childhood hand eczema [16]. acquired) and staphylococcal colonization, and the role
Recent advances in our understanding of the genetic of staphylococcal superantigens acting in concert with
basis for AD are likely to lead to other subtypes of AD. defects in adaptive and innate immunity, the latter high-
Specific emerging subtypes include eczema associated lighted by the reduced capacity to upregulate cutaneous
with null filaggrin mutations. These mutations appear to antimicrobial peptides including cathelicidin and
be associated with severe early‐onset extrinsic (elevated defensins [26].
ATOPIC DERMATITIS
SECTION 3:
Fig. 15.23 Molluscum contagiosum presenting as infraorbital umbilicated
and crusted papules. Source: © Diepgen TL, Yihune G et al. Dermatology
Online Atlas (www.dermis.net). Reprinted with permission.
Fig. 15.21 Clinically infected infantile atopic dermatitis affecting the
extensor aspects of the limbs and trunk. Source: Courtesy of Professor
Hywel C. Williams
mutations [27]. A clinically similar eruption (eczema
vaccinatum) can be seen following smallpox vaccina-
tion in susceptible individuals, hence AD or house-
hold AD contacts is a contraindication for smallpox
vaccination.
Molluscum contagiosum (MC) is a common childhood
cutaneous poxvirus infection that presents with single or
grouped skin‐coloured papules and is frequently seen in
children with AD (Fig. 15.23). Studies have reported an
increased incidence of MC with AD, with a recent cross‐
sectional study showing that 24% of children with MC
from a tertiary centre had AD [28].
Genetic variants involved in regulation of the immune
response in combination with genetic and acquired skin
barrier defects may increase the risk of viral infections;
staphylococcal toxins may also play a role in the dissemi-
nation of viral infections in AD [26].
Fig. 15.22 Perioral eczema herpeticum displaying grouped punched‐out
erosions with secondary impetiginization. Source: Courtesy of Professor Exfoliative dermatitis
Hywel C. Williams. Exfoliative dermatitis is a life‐threatening dermatosis that
rarely develops in AD (<1% of cases). In this condition,
intense erythema and peeling of more than 90% of the
Viral infections skin surface is accompanied by fever, systemic malaise
Infections with herpes simplex virus (HSV) are more and lymphadenopathy. This usually develops secondary
common in individuals with AD and can result in to either a bacterial infection (e.g. Staph. aureus) or eczema
eczema herpeticum (also known as Kaposi varicelliform herpeticum.
eruption). This is a serious but infrequent complication
occurring in 3% of AD patients. It is characterized by Differential diagnosis
disseminated HSV infection and associated with sig- Although AD is one of the most common causes of an
nificant morbidity, including multiorgan involvement, itchy rash in childhood, and in the vast majority of indi-
and rarely mortality. Clinically this presents with viduals the diagnosis is straightforward, it is important
grouped or widespread umbilicated vesicopustules and to consider other differential diagnoses. Table 15.1 lists
eroded vesicles (Fig. 15.22). This complication is usu- diagnoses that can present in a similar manner to AD.
ally secondary to HSV‐1 infection and recent studies A specific situation in which other differential diagnoses
suggest that there may be an association with filaggrin should be considered is when infants present with a
Table 15.1 Differential diagnosis of atopic dermatitis (AD)
Other forms of dermatitis

Seborrhoeic dermatitis Red, shiny, relatively well‐demarcated eruption typically involving napkin (diaper) area in first 4 months of life. Lower abdomen,
of infancy neck and armpits may also be involved, along with scalp scaling (cradle cap). Non‐itchy – child happy but parents are not.
Good prognosis – clears within a few months
Adult‐type seborrhoeic Poorly defined erythema due to overgrowth/sensitivity to Pityrosporum yeasts in seborrhoeic areas, i.e. sides of nose, eyebrows,
dermatitis external ear canal, scalp, front of chest, axillae and groin creases
Discoid (nummular) Circular ‘cracked’ areas of erythema, 1–5 cm in diameter, on limbs initially, often with secondary infection (Fig. 15.20). In
eczema children, most commonly associated with AD and often confused with tinea (ringworm). In adults may be associated with
Staphylococcus infection and excessive skin dryness
Irritant contact Cumulative damage to the skin barrier from irritants such as soaps and detergents. Clinical appearance of dermatitis can be
dermatitis (ICD) identical to AD, but location at sites of maximal exposure, e.g. fingers, may be helpful. Some degree of ICD is common in AD
sufferers, e.g. around mouth in babies due to constant saliva and wet food, and in napkin area due to urine
ATOPIC DERMATITIS
Allergic contact A hypersensitivity reaction to specific substances to which individuals have been sensitized, such as nickel (jewellery), rubber
dermatitis (gloves) or glues (some shoes). Linear cut‐off and distribution may suggest diagnosis, but patch tests are needed to establish
SECTION 3:
diagnosis. May coexist with AD

Frictional lichenoid Shiny papules occurring in sites of repeated frictional trauma such as outer forearms in children. Probably quite common
dermatitis
Hyper‐IgE syndrome Features of AD within a few weeks of birth accompanied by staphylococcal infections of the skin, sinuses and lungs,
characteristic facies and abnormal dentition. Laboratory findings include high IgE and eosinophils
Wiskott–Aldrich The rash of Wiskott–Aldrich is identical to AD. It occurs usually in male infants in the first month of life and is accompanied by
syndrome petechiae, purpura and bloody diarrhoea
Other immunological A range of other immunological disorders may have eczematous features, including severe combined immunodeficiency,
disorders OMENN and IPEX syndromes
Inherited ichthyosis Inherited ichthyotic disorders may be associated with eczema and dry skin, including ichthyosis vulgaris, Netherton syndrome,
autosomal recessive congenital ichthyosis and X‐linked ichthyosis
Other inflammatory and Diverse inflammatory and bullous skin diseases including psoriasis, dermatitis herpetiformis, graft‐versus‐host disease, urticaria
bullous dermatoses pigmentosa and pityriasis alba may display features that might mimic eczema and the last may be associated with eczema
Other exogenous skin conditions
Scabies May produce nonspecific eczematous changes on the entire body. Burrows and pustules on palms, soles, genitalia and between
fingers help to establish diagnosis
Onchocercarial dermatitis In its chronic phase, may produce a widespread lichenification of the skin similar to that seen in chronic AD
Insect bites May often develop secondary eczematization and be confused with AD, especially on the limbs of children in tropical countries
Nutritional deficiencies A range of nutritional deficiencies can be associated with eczematous features, including zinc, pyridoxine, biotin, niacin,
phenylketonuria, lipid storage disease and cystic fibrosis
Tinea corporis May resemble eczema, particularly in acute florid phase where vesicles are present. Usually asymmetrical
severe eczematous rash with failure to thrive, recurrent 8 Borkar DS, Gonzales JA, Tham VM et al. Association between atopy
and herpetic eye disease: results from the pacific ocular inflammation
infections or petechiae [29]. In this scenario, it is impor-
study. JAMA Ophthalmol 2014;132:326–31.
tant to exclude immunodeficiency states. For example, 9 Wells R. Ichthyosis. Br Med J 1966;2:1504–6.
Omenn, IPEX (immune dysregulation, polyendo- 10 Smith F, Irvine A, Terron‐Kwiatkowski A et al. Loss‐of‐function
crinopathy, enteropathy, X‐linked), Wiskott–Aldrich and mutations in the gene encoding filaggrin cause ichthyosis vulgaris.
Nat Genet 2006;38:337–42.
Job syndromes are associated with eczema. In children 11 Fartasch M, Diepgen T, Hornstein O. Atopic dermatitis – ichthyosis
from the Caribbean and Africa, severe infected AD may vulgaris – hyperlinear palms – an ultrastructural study. Dermatologica
be a manifestation of human T‐lymphotropic virus‐1 1989;178:202–5.
(HTLV1) infection [30–32]. 12 Brenninkmeijer E, Spuls P, Legierse C et al. Clinical differences
between atopic and atopiform dermatitis. J Am Acad Dermatol
2008;58:407–14.
13 Brown SJ, Relton CL, Liao H et al. Filaggrin haploinsufficiency is
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28 Dohil M, Lin P, Lee J et al. The epidemiology of molluscum contagio- have evidence of allergen‐specific circulating IgE anti-
sum in children. J Am Acad Dermatol 2006;54:47–54. bodies as demonstrated by high serum levels and/or
29 Hochreutener H, Wüthrich B, Huwyler T et al. Variant of hyper‐IgE
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30 La Grenade L, Manns A, Fletcher V et al. Clinical, pathologic, and (ISAAC) Phase Two – the largest sample of AD cases,
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31 Purvis D. Guidelines for the diagnosis and assessment of eczema. world – suggests that around 50% of AD cases in devel-
DermNet NZ 2014. http://www.dermnetnz.org/topics/guidelines‐ oped countries are in fact not atopic, and an even greater
for‐the‐diagnosis‐and‐assessment‐of‐eczema/ (accessed 20 October proportion in developing countries are not atopic [2]. The
2018).
study concluded that any association between atopy and
32 Eichenfield LF, Tom WL, Chamlin SL et al. Guidelines of care for
the management of atopic dermatitis: section 1. Diagnosis and examined flexural eczema is weak and more variable than
assessment of atopic dermatitis. J Am Acad Dermatol 2014; previously suggested, and that the strength of this asso-
70:338–51. ciation is positively linked to gross national income. Some
researchers have suggested that there are two types of
AD – atopic (or extrinsic) and nonatopic (intrinsic or
Diagnostic criteria for atopic atopiform) [3,4] – but this division may have arisen in
dermatitis part by the fact that atopy is more common in people with
more severe disease, who typically make up the hospital‐
Although disease definition may sound a potentially
based populations featured in studies trying to separate
boring topic, it is a fundamental aspect of all compara-
atopic from nonatopic eczema. Indeed, some have even
tive knowledge that was summarized perfectly by
argued that raised IgE could be an epiphenomenon of
Kendell [1]:
disease severity [5]. It is not surprising therefore that
those who have mainly studied individuals with severe
It is probably more exciting for an architect to design para- disease have a firm belief that AD is atopic, whereas the
bolic canopies or baroque façades than it is to calculate the
reality is that nonatopic eczema can sometimes form the
size and shape of the concrete slab on which his building will
rest. But theories of causation and therapeutic claims have no
majority of cases in population surveys. It is also worth
more chance of surviving than buildings if they are not built on pointing out that nonatopic and atopic dermatitis are still
secure foundations. Developing reliable diagnostic criteria not clearly distinguishable without recourse to skinprick
may be as tedious as filling in muddy holes with concrete but tests or estimation of circulating IgE antibodies to com-
both provide the foundation on which all else depends. mon and relevant environmental allergens.
Kendell 1975 [1]. Reproduced with In order to overcome confusion about the correct use
permission of John Wiley & Sons of the term ‘atopy’ and different synonyms for AD, the
World Allergy Organization (WAO) nomenclature com-
Much of the evidence discussed in this section has mittee recommended that the term ‘eczema’ be used to
arisen from work that one of the authors (HW) led, that denote what we typically refer to as the phenotype of AD,
culminated in the UK refinement of Hanifin and Rajka’s and that the prefix atopy only be used when defining a
diagnostic criteria [2–4]. Because other criteria for AD subset that is truly atopic as indicated in Fig. 15.24 [1]. The
have also been proposed, more emphasis has been term eczema in the WAO scheme is quite specific to the
placed in this chapter on an independent and thorough AD phenotype, and clearly separated from other types of
Dermatitis communication. The author uses the term ‘eczema’ in his

own publications and clinics as it is based on the most
scientific rationale to date, whereas he is comfortable
using the term ‘atopic dermatitis’ or ‘atopic eczema’ when
Other forms Contact talking to US or other European audiences respectively, as
Eczema
of dermatitis dermatitis
in this chapter. The author is not aware of any evidence
of harm caused by using these terms synonymously.
In future, better classification of dermatitis into various
subtypes may result in a scientific advancement beyond
the WAO classification. Trying to force the whole world to
adopt the term ‘atopic dermatitis’ (which may be neither
atopic nor dermatitis) is unlikely to help and may hinder
Atopic Nonatopic Allergic Nonallergic
harmonious international scientific endeavour to improve
ATOPIC DERMATITIS
eczema eczema CD CD
outcomes for patients with AD.
Fig. 15.24 World Allergy Organization revised classification for atopic Just for consistency with the rest of this chapter, we will
SECTION 3:
dermatitis showing that the term eczema is now the agreed term to use the term atopic dermatitis (AD) to refer to the clinical
replace the transitional term atopic eczema/dermatitis syndrome (AEDS). phenotype without implying that such people are truly
Atopic eczema is eczema in a person of the atopic constitution. Source:
atopic as per the more scientific rationale developed by
Johansson et al. 2004 [1]. Reproduced with permission of Elsevier.
the WAO.
dermatitis such as seborrhoeic, asteatotic, venous, num- References

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of dermatitis’) and the two forms of contact dermatitis as allergy for global use. Report of the Nomenclature Review Committee
in Fig. 15.24. The WAO proposition makes good sense of the World Allergy Organization, October 2003. J Allergy Clin
Immunol 2004;113:832–6.
and it obviates the need for yet more sets of diagnostic 2 Flohr C, Weiland SK, Weinmayr G et al.: the ISAAC Phase Two
criteria such as the millennium criteria [6], which look Study Group. The role of atopic sensitization in flexural eczema:
very similar to the original Hanifin and Rajka criteria [7] findings from the International Study of Asthma and Allergies in
Childhood Phase Two. J Allergy Clin Immunol 2008;121:141–7.
with IgE reactivity added as a necessary criterion.
3 Eedy DJ, Graham‐Brown RA. Atopiform dermatitis: what’s in a name?
Geographical variations in the use of names for AD Br J Dermatol 2002;147:415–17.
occur. ‘Atopic dermatitis’ is the most frequently used 4 Tokura Y. Extrinsic and intrinsic types of atopic dermatitis. J Dermatol
term used by clinicians in the USA, yet the term ‘eczema’ Sci 2010;58:1–7.
5 Flohr C, Johansson SGO, Wahlgren CF, Williams H. How ‘atopic’ is
is used by the National Eczema Association (https:// atopic dermatitis? J Allergy Clin Immunol 2004;114:150–8.
nationaleczema.org/eczema/) and in large population‐ 6 Bos JD, Van Leent EJ, Sillevis Smitt JH. The millennium criteria for
based surveys in the USA [8]. AD is also the most widely the diagnosis of atopic dermatitis. Exp Dermatol 1998;7:132–8.
used term in Japan and other Far Eastern countries such 7 Hanifin JM, Rajka G. Diagnostic features of atopic eczema. Acta
Dermatol Venereol (Stockh) 1980;92:44–7.
as Korea and Taiwan, whereas the phrase ‘atopic eczema’ 8 Kathuria P, Silverberg JI. Association of pollution and climate with
is used more commonly in Europe and just ‘eczema’ in atopic eczema in US children. Pediatr Allergy Immunol 2016;27:478–85.
the UK to denote AD. A review of AD nomenclature by 9 Kantor R, Thyssen JP, Paller AS, Silverberg JI. Atopic dermatitis, atopic
eczema, or eczema? A systematic review, meta‐analysis, and recommen-
Kantor et al. found that of 33 060 relevant publications, dation for uniform use of ’atopic dermatitis’. Allergy 2016;71:1480–5.
64.4% used the term ‘atopic dermatitis’ and 46.9% used
the term ‘eczema’, with many papers using both terms
[9]. The authors (all of whom lived in countries where the Relative importance of sensitive versus
standard term was AD) strongly concluded that the term specific criteria in different study types
AD should be used in future studies. They claimed that It is easy to dive into the topic of diagnostic criteria for AD
the term eczema is a nonspecific one that denotes several in the belief that there may be a universal ‘one size fits all’
forms of skin inflammation, but this statement is simply definition, yet it is critical to think about the purpose of
not the case when the term eczema is used scientifically as the criteria before choosing which set of criteria or which
per the WAO classification in Fig. 15.24. It is worth point- version of the criteria to use. The need for a disease defini-
ing out that the purpose of a name is to increase commu- tion usually arises in the context of research or clinical
nication and understanding – whether this is with patients audit when groups of people need to be described and
and the public or in scientific communications. Insisting compared. In a population survey, for example, where the
that the phrase ‘atopic dermatitis’ should be used hence- main purpose is to estimate the true prevalence of AD,
forth in the UK (for example) for what is widely under- some individuals with AD will always be misclassified as
stood by the public as ‘eczema’ is likely to result in more not having AD and vice versa. Whatever criteria are used,
misunderstanding and possible harm, especially as the no single set of criteria can be perfect with 100% sensitivity
UK public’s understanding of the term ‘dermatitis’ has and specificity. When undertaking a prevalence survey
connotations of occupationally acquired hand eczema. therefore, the ideal criteria represent a trade‐off between
Much scientific energy has been wasted debating whether sensitivity (the proportion with true disease that is cor-
the term eczema or dermatitis should be used. The key rectly classified) and specificity (the proportion without
is to use the term that is most likely to result in clear AD that is correctly identified). Some misclassification is
Systematic
y
T or
ey e
r ic
Screening for
T t ic
r v nc
review of all
ho s t
RC nat
RC m a
c o gno
s u ale
Case-control possible
Pr t
a
possible
ag
ev
pl
o
study inclusion in study
Ex
Pr
Pr
studies of AD
Fig. 15.25 Schematic illustration of the different

requirements of the trade‐off between sensitivity
and specificity of diagnostic criteria for atopic
dermatitis in relation to different study designs.
AD, atopic dermatitis; RCT, randomized More specific More sensitive
controlled trial.
ATOPIC DERMATITIS
tolerable at a group level for the purpose of the study. The the positive predictive values (proportion of those who
SECTION 3:
requirements are different in a case‐control study that test positive who really have the disease) for the UK diag-
wishes to explore possible disease causes, because only nostic criteria vary according to underlying true disease
cases and a proportion of controls are needed. Here, spec- prevalence assuming a sensitivity of 80% and specificity
ificity of the criteria is critically important: criteria with of 97%. Even though the values for sensitivity and speci-
low sensitivity that may miss some true cases are toler- ficity sound quite good, the positive predictive value of
ated if the benefit is more certainty that those included 21% is very low when the true prevalence of disease is
cases and controls are accurately classified. Similarly, for only 1%. Yet it is much higher (90%) when the true popu-
clinical trials or genetic studies, it is also important that all lation prevalence is 25%, even though the sensitivity and
cases are ‘true cases’. In such circumstances, a two‐stage specificity parameters have remained constant. Guidance
process may be employed: cases might be defined first by on the effects of disease misclassification and which ver-
a clinician (in order to identify only ‘true cases’), followed sion of diagnostic criteria to use for different study
by a further filter of widely used criteria in order to char- designs is to be found elsewhere [1].
acterize the phenotype for comparison with other studies.
Cohort studies that follow up cases of AD to evaluate Including a measure of disease severity
prognosis must also be relatively specific in order not to When estimating disease prevalence, it is often important
overestimate disease clearance due to contamination with to include a measure of disease severity in order to deter-
non‐cases, but still have reasonable sensitivity so that mine disease burden and likely use of healthcare resources.
they are representative of most cases rather than a subset For example, Saeki et al. conducted a validation survey of
with more severe disease. The trade‐off between sensitiv- 2137 adults in Hokkaido and Osaka and found that of the
ity and specificity in relation to different study design 6.9% that were deemed to have AD on examination,
requirements is depicted in Fig. 15.25. 76.7%, 18.5%, 3.4% and 1.4% of those affected had mild,
moderate, severe and very severe disease respectively [2].
Effects of low disease prevalence The ISAAC global prevalence surveys of over 1 million
Another important point to consider if using diagnostic children used current eczema that was associated with
criteria to estimate disease prevalence is whether the sleep disturbance of one or more nights per week as a
disease is fairly common or rare. Table 15.2 shows how surrogate method of measuring more severe eczema [3].
Table 15.2 The effect of prevalence of atopic eczema (AE) on predictive values of the UK Diagnostic Criteria for Atopic Dermatitis, assuming a sensitivity
of 80% and specificity of 97%
True prevalence of AE Prevalence of AE by criteria Positive predictive value Negative predictive value
25% 22.2% 90.1 93.6

20% 18.4% 87.0 95.1
15% 14.5% 82.8 96.5
12% 12.2% 78.7 97.3
10% 10.7% 74.8 97.8
9% 9.9% 72.7 98.0
8% 9.2% 69.6 98.2
7% 8.4% 66.7 98.5
6% 7.6% 63.2 98.7
5% 6.8% 58.8 98.9
4% 6.1% 52.5 99.1
3% 5.3% 45.3 99.4
2% 4.5% 35.6 99.6
1% 3.8% 21.1 99.8
Applying diagnostic criteria in the clinic insensibly into normality [1], but many clinicians and
There is a dilemma to be met when diagnostic criteria are researchers still have difficulties in viewing diseases as
applied to individuals in a clinical setting as these criteria continuous processes. Yet in a population setting, even for
were not developed for this purpose. It is important that diseases like scalp ringworm, which might at first appear
those who use the criteria in a clinical setting as a diag- to conform well to a dichotomous disease definition of
nostic aid realize that the criteria refer to probability of diseased or not diseased, one sees a gradation of sickness
disease, and that they should be used as a guide and not ranging from those who are apparently healthy (many of
a rigid rule. Thus it is possible to quote exceptional indi- whom are carriers of the responsible fungus or have sub-
viduals such as a child who has an itchy skin condition clinical infection) to those who have isolated patches of
that began at 3 years of age, who also has a history of hair loss and some who are quite ill with severe inflam-
flexural involvement and visible flexural dermatitis, but matory reactions affecting the entire scalp. Perhaps the
no history of dry skin or other atopic disease, who, most appropriate question therefore is not ‘Has he/she
although not fulfilling the UK diagnostic criteria or some got this disease: yes/no?’ but rather ‘How much of this
ATOPIC DERMATITIS
other criteria, might well have true AD. However, when disease does he/she have?’. Measuring the total amount
applied to a population of children where AD affects 12% of disease in a population on a quantitative scale may
SECTION 3:
of children, the probability that a child does not have AD if sound attractive in that it provides information on all of
he/she does not fulfil the criteria is over 97%. the individuals in that population, but it also presents
some serious difficulties in interpretation. It is important
Defining new cases to return to the main purpose of disease definition, i.e. to
Definition of an incident case is also a tricky area, because aid communication and increase our predictive abilities.
many definitions of AD incorporate having a chronically Whereas a log odds score of AD of 4.321 might mean
relapsing course as a component [4]. A systematic review something to a researcher trying to predict the degree to
of 102 prevention studies found that no definition of an which a hairdressing apprentice is likely to be incapaci-
incident case was given in 27 studies, and that the Hanifin tated by irritant hand dermatitis [2], such a score might
and Rajka criteria (which include disease chronicity as a have little utility to clinicians who wish to describe the
major criterion) had been used in 75 studies [5]. With the disease pattern in their population. Continuous scoring
advent of more birth cohort studies [6] and randomized methods for assessing the degree of AD are probably non-
controlled trials of disease prevention starting at birth [7], linear, i.e. double the score does not mean twice as much
there is a clear need for a uniform definition for an inci- AD, like doubling height and weight. In addition, the
dent case of AD that provides a good trade‐off between weights applied to individual disease features derived
not including all transient irritant eczematous eruptions from regression models are highly dependent upon the
in infancy and not excluding more transient forms of true population that was selected to derive the criteria, and 10
AD [8]. Such a definition has been proposed in a system- different studies could produce 10 different sets of weight-
atic review on this topic [5]. ing, leading to international disputes on which weighting
was ‘correct’. Others have expressed enthusiasm for
References revisiting quantitative methods for assessing AD [3].
1 Williams HC, Flohr C. So How Do I Define Atopic Eczema? A Practical Dichotomous or categorical disease definitions, on the
Manual for Researchers Wishing to Define Atopic Eczema. University other hand, require a line to be drawn between disease
of Nottingham, 1995 (https://www.nottingham.ac.uk/research/groups/
cebd/resources/uk‐diagnostic‐criteria‐for‐atopic‐dermatitis.aspx).
and non‐disease. Indeed the word ‘diagnosis’, which is
2 Saeki H, Oiso N, Honma M et al. Prevalence of atopic dermatitis in derived from the Greek words διá (the number two) and
Japanese adults and community validation of the U.K. diagnostic cri- γιγνώσκειν (to perceive), implies a dichotomous outcome.
teria. J Dermatol Sci 2009;55:140–1. Such dichotomous definitions are far more widely used
3 Odhiambo JA, Williams HC, Clayton TO et al.; ISAAC Phase Three Study
Group. Global variations in prevalence of eczema symptoms in children and easily understood in public health settings, and are
from ISAAC Phase Three. J Allergy Clin Immunol 2009;124:1251–8. therefore logical choices for promoting international com-
4 Hanifin JM, Rajka G. Diagnostic features of atopic eczema. Acta munication. Their main drawback is that the imposition
Dermatol Venereol (Stockh) 1980;92:44–7.
5 Simpson EL, Keck LE, Chalmers JR, Williams HC. How should an inci-
of boundaries between those who are sick and those who
dent case of atopic dermatitis be defined? A systematic review of primary are apparently healthy almost always results in the mis-
prevention studies. J Allergy Clin Immunol 2012;130:137–44. classification of some people. Unless the disease in ques-
6 Yang YW, Tsai CL, Lu CY. Exclusive breastfeeding and incident atopic tion has an abrupt natural cut‐off between normal and
dermatitis in childhood: a systematic review and meta‐analysis of pro-
spective cohort studies. Br J Dermatol 2009;161:373–83. abnormal, the imposition of an arbitrary dividing line
7 Simpson EL, Chalmers JR, Hanifin JM et al. Emollient enhancement of will always be subject to a trade‐off between sensitivity
the skin barrier from birth offers effective atopic dermatitis prevention. and specificity. On balance, a clinical approach of sum-
8 Yates VM, Kerr RE, MacKie RM. Early diagnosis of infantile sebor-
marizing a constellation of symptoms and signs seems to
rhoeic dermatitis and atopic dermatitis – clinical features. Br J Dermatol be the most clinically relevant to the study of AD, as other
1983;108:633–8. groups have concluded [4].
Approaches to disease definition Progressive nosology

Binary versus continuous definitions It is worth noting that new discoveries about disease
Pickering et al. suggested as long ago as 1960 that essen- aetiology can lead to changes in disease classification.
tial hypertension was a graded characteristic that shaded The aetiology of AD is not yet fully understood, and
because the pursuit of an objective test has been fruitless Table 15.3 Between‐observer agreement for 18 signs in atopic dermatitis
to date, a clinical syndrome based on a constellation of from a specially designed repeatability study of UK consultant dermatologists
symptoms and signs remains the most appropriate start-
Substantial (kappa Truncal dermatitis
ing point currently. This statement does not imply that
>0.61)
this clinical syndrome could not be redefined in genetic
Moderate Flexural dermatitis, hand/foot dermatitis, facial
or aetiological terms in the future consistent with the
(kappa 0.41–0.60) dermatitis, hypopigmented patches, orbital fold,
concept of progressive nosology, such as the division of periorbital dermatitis, ear fissure, hyperlinear
‘pemphigus’, which formerly referred to several diseases palms
in which blistering was a feature, into pemphigoid, pem- Fair (kappa Follicular accentuation, periaural dermatitis,
phigus and linear IgA disease on the basis of immuno- 0.21–0.40) cheilitis
logical discoveries. Changes of this sort are not a problem Slight (kappa Keratosis pilaris, fine hair, periorbital pigmentation,
0.01–0.20) dry skin, extensor dermatitis (visible dermatitis)
providing they are explicit, and that they confer benefits
to patients. By analogy, what is recognized as a clinical
ATOPIC DERMATITIS
syndrome of AD today may in time be shown to be com-
posed of three or four different diseases such as a diffuse Repeatability
SECTION 3:
dry type of AD associated with filaggrin gene defects, a Between‐observer and within‐observer variation in
nummular form associated with defective Staph. aureus recording the diagnostic criteria should be kept to a mini-
handling, an early‐onset more severe form and an eczema/ mum. Agreement over dichotomous features, such as the
respiratory form, based on genetic, immunological or presence or absence of periorbital pigmentation, is usu-
aetiological discoveries [5,6]. This does not imply that the ally expressed in terms of a chance corrected measure
original older criteria were ‘wrong’ at the time, provided known as the kappa statistic, which usually varies from 0
they measured something useful or were instrumental (no better than chance) to 1 (perfect agreement), with val-
in stimulating further research into the aetiology of that ues of 0.6 or more indicating substantial agreement. As
syndrome. can be seen from the data on signs of AD recorded by UK
dermatologists in Table 15.3, even experienced physicians
References may exhibit poor agreement over classical features of a
1 Oldham PD, Pickering G, Fraser Roberts JA, Sowry GSC. The nature of skin disease [1]. Many minor signs, such as infraorbital
essential hypertension. Lancet 1960;i:1085–93. crease, can vary according to a number of factors, such
2 Fartasch M, Diepgen TL. Atopic diathesis and occupational derma-
toses. J Invest Dermatol 1994;102:620–1.
as the time of day (Fig. 15.26) or ethnic group [2].
3 Andersen RM, Thyssen JP, Maibach HI. Qualitative vs. quantitative Repeatability can be improved by keeping the number of
atopic dermatitis criteria – in historical and present perspectives. J Eur criteria small, and by clear instructions and training of
Acad Dermatol Venereol 2016;30:604–18. field workers. Although it is true that good validity usu-
4 Darsow U, Wollenberg A, Simon D et al. for the European Task Force
on Atopic Dermatitis/EADV Eczema Task Force. ETFAD/EADV ally implies good repeatability, the converse is not always
Eczema Task Force 2009 position paper on diagnosis and treatment of true; for example, two clocks that are both 10 minutes
atopic dermatitis. J Eur Acad Dermatol Venereol 2010;24:317–28. slow may well agree with each other, but neither is telling
5 Rodríguez E, Baurecht H, Herberich E et al. Meta‐analysis of filaggrin
the correct time.
polymorphisms in eczema and asthma: robust risk factors in atopic
disease. J Allergy Clin Immunol 2009;123:1361–70.
6 Mortz CG, Andersen KE, Dellgren C et al. Atopic dermatitis from Acceptability to the population
adolescence to adulthood in the TOACS cohort: prevalence, persistence
Although it may be possible and appropriate for phy-
and comorbidities. Allergy 2015;70:836–45.
sicians to perform quite invasive tests on patients in a
hospital setting, even relatively noninvasive procedures
Key requirements of a disease definition such as examining the skin in covered areas or taking
for atopic dermatitis nail clippings may result in a low response rate when
Validity attempted in a population setting. The criteria should
Validity refers to the ability of a diagnostic test or set of also be easy and rapid to apply. Complicated and time‐
criteria to measure what it purports to measure. Validity, consuming procedures will lead to observer fatigue,
in the context of defining a case with a skin disease, has errors and lower response rates if conducted as part of a
two components: large study.
• sensitivity, i.e. the definition should catch as many
cases as possible Coherence with prevailing clinical concepts
• specificity, i.e. the definition should exclude as many Criteria should demonstrate a degree of face validity, i.e.
non‐cases as possible. they should contain features that clinicians identify as
Sensitivity and specificity are measured in relation to a key elements for the disease syndrome. It is here that the
reference or ‘gold’ standard. Choosing a gold standard is seminal work of Hanifin and Rajka excels [3]. They sug-
relatively easy for some skin diseases such as malignant gested a list of major features and a long list of minor
melanoma where histology is used, but for many skin features that characterize the clinical syndrome of AD
diseases (including AD) no such objective test is available. based on clinical experience. Although the long list is too
In these circumstances, diagnosis by dermatologist may cumbersome and imprecisely defined to be used as a
serve as a clinical gold standard, providing dermatologists research instrument, the features listed have formed a
can be shown to agree on what constitutes a typical case [1]. good basis for subsequent scientific refinements such as
ATOPIC DERMATITIS
SECTION 3:
Fig. 15.26 Images of the same atopic person

taken 12 hours apart. Although signs such as
infraorbital crease (defined as one or more
prominent creases that extend beyond the midline
when the pupil gazes forward) may sound
straightforward to ascertain, these images show
how unreliable such a sign can be.
the UK Working Party’s minimum list of reliable criteria [4]. scientifically. Many groups have suggested diagnostic
It is also worth pointing out that diagnostic criteria for criteria based on a hunch or consensus but the validity of
AD should also reflect some degree of morbidity; for many diagnostic criteria remains untested. It is also worth
example, it may be possible to develop criteria that noting that instead of focusing on the really important
measure very minor degrees of eczematous inflamma- questions about the diagnostic criteria for AD, i.e. which
tion, but if those identified by such criteria are not itchy criteria are the best discriminators and which can be lost
or bothered by those features, then it is questionable in order to make a minimum list of reliable ones, lots of
whether such a disease is worth studying. This is the studies have focused on the long list of minor features
main reason for making ‘an itchy skin condition’ a neces- and whether or not they apply to a particular study popu-
sary criterion for the UK diagnostic criteria. lation [1–3]. Although these studies are helpful in show-
ing some possible variation in the minor phenotypic
Comprehensiveness features that may be more or less prevalent in some coun-
Criteria need to be applicable to a wide range of groups tries and ethnic groups, they add little to the main quest
such as children and adults, those with dark skins (where for a minimum list of reliable and valid major criteria that
erythema may be less obvious) and different ethnic permit international comparisons.
groups who may have a different cultural understanding At least 10 different sets of diagnostic criteria for
of terms like ‘itching’, especially when compounded by AD had been proposed by 2007 [4–13], prompting
difficulties in translation [5]. Brenninkmeijer and colleagues to undertake a system-
atic review of the validity of such studies [14]. Following
References an extensive search of three databases and citations from
1 Williams HC, Burney PGJ, Strachan D, Hay RJ. The UK Working retrieved papers, they identified 27 validation studies
Party’s diagnostic criteria for atopic dermatitis II: Observer variation
of clinical diagnosis and signs of atopic dermatitis. Br J Dermatol
that were then quality‐assessed by two independent
1994;131:397–405. data extractors using the Quality Assessment of
2 Williams HC, Forsdyke H, Pembroke AC. Infraorbital crease, ethnic Diagnostic Accuracy (QUADAS) tool, which assesses
group and atopic dermatitis. Arch Dermatol 1996;132:51–4. the risk of bias by means of 14 different items [15]. The
3 Hanifin JM, Rajka G. Diagnostic features of atopic eczema. Acta
Dermatol Venereol (Stockh) 1980;92:44–7. authors also compared sensitivity and specificity param-
4 Williams HC, Burney PGJ, Pembroke AC, Hay RJ. The UK working eters and optimum cut‐offs for different criteria using
party’s diagnostic criteria for atopic dermatitis III: Independent receiver‐operator curves. They found that some of the
hospital validation. Br J Dermatol 1994;131:406–16.
proposed diagnostic criteria such as those of the Japanese
5 Chalmers DA, Todd G, Saxe N et al. Validation of the U.K. Working
Party diagnostic criteria for atopic eczema in a Xhosa‐speaking African Dermatological Association, the Danish Allergy Research
population. Br J Dermatol 2007;156:111–16. Centre criteria and the Lillehammer criteria had not
undergone any form of validation at all. The original
A systematic review of diagnostic criteria Hanifin and Rajka criteria had only been validated in
for AD two hospital studies, those of Schultz Larsen in two
The last section highlighted the need for a short list of studies, those of Diepgen et al. and those of Kang and
reliable and valid criteria that can be used widely. Very Tian in one study each, and the UK refinement of Hanifin
few studies have developed and tested diagnostic criteria and Rajka’s criteria in 19 studies.
Overall, sensitivity and specificity of the various criteria

Box 15.1 Attributes of a good validation study for diagnostic
ranged from 10% to 95% and from 77.6% to 100%, respec-
criteria
tively, in hospital‐based studies, and from 42.8% to 100%
and from 44.7% to 96.6%, respectively, in population 1. Use the criteria questions and examination protocol exactly as
studies. The two hospital‐based studies that evaluated recommended.
the Hanifin and Rajka criteria showed a sensitivity of 2. Ensure that translation follows a strict format.
87.9% and 96.0% respectively, and specificity of 77.6% and 3. Test the criteria in the setting in which they are intended to be used.
93.8%. The eight hospital‐based studies validating the UK 4. Ensure that those acting as assessors or as the clinical criterion
refinement of the Hanifin and Rajka criteria showed a standard are blinded to the criteria being tested.
sensitivity ranging from 10% to 95.5% and specificity 5. Ensure that the clinician who is the clinical criterion standard is
from 90.4% to 98.3%. The 13 population‐based validation comparable to other clinicians through interobserver repeatability
studies showed a sensitivity ranging from 42.8% to 100% testing.
and specificity from 89.3% to 99.1%. No meta‐analytic
ATOPIC DERMATITIS
Source: Williams 1999 [22]. Reproduced with permission of the American
summary estimates could be given due to the major Medical Association.
differences between studies in terms of participants,
SECTION 3:
setting and study design. Validity was particularly poor
in one community validation study of the UK criteria that References
had been translated into the Xhosa language [16], 1 Mevorah B, Frenk E, Wietlisbach V et al. Minor clinical features
of atopic dermatitis. Evaluation of their diagnostic significance.
although other studies of translated versions in China, Dermatologica 1988;177:360–4.
Italy and Romania seemed to show good results [17–19], 2 Nagaraja, Kanwar AJ, Dhar S et al. Frequency and significance of
suggesting that cultural factors rather than just translation minor clinical features in various age‐related subgroups of atopic
dermatitis in children. Pediatr Dermatol 1996;13:10–13.
issues are important. One study from Ethiopia showed
3 Hiletework M. Evaluation of Hanifin and Rajka atopic eczema
that the questionnaire used in the ISAAC showed a posi- diagnostic guidelines for reduced minor criteria. Ethiop Med J

tive predictive value of 48.8% and a negative predictive 2009;47:39–47.
value of 91.1% [20]. 4 Asher MI, Keil U, Anderson HR et al. International Study of Asthma
and Allergies in Childhood (ISAAC): rationale and methods. Eur
The methodological quality of the validation studies Respir J 1995;8:483–91.
varied considerably, making comparisons difficult. 5 Bos JD, Van Leent EJ, Sillevis Smitt JH. The millennium criteria for the
Common methodological problems included an inap- diagnosis of atopic dermatitis. Exp Dermatol 1998;7:132–8.
propriate reference standard, lack of blinding of those 6 Diepgen TL, Sauerbrei W, Fartasch M. Development and validation of
diagnostic scores for atopic dermatitis incorporating criteria of data
determining the index test results from the reference test quality and practical usefulness. J Clin Epidemiol 1996;49:1031–8.
results, lack of reporting of intermediate or uninterpreta- 7 Hanifin JM, Rajka G. Diagnostic features of atopic dermatitis. Acta
ble results, and failure to provide details on participant Derm Venereol Suppl (Stockh) 1980;92:44–7.
8 Johnke H, Vach W, Norberg LA et al. A comparison between criteria for
withdrawals. The authors of the systematic review also diagnosing atopic eczema in infants. Br J Dermatol 2005;153:352–8.
point to problems such as the reference standard of 9 Schultz Larsen F, Hanifin JM. Secular change in the occurrence of
clinical diagnosis residing with just one clinician whose atopic dermatitis. Acta Derm Venereol Suppl (Stockh) 1992;176:7–12.
perception of what constitutes AD might be very different 10 Schultz Larsen F, Diepgen T, Svensson A. Clinical criteria in diagnos-
ing atopic dermatitis: the Lillehammer criteria 1994. Acta Derm
from others [21,22]. Another problem when validating Venereol Suppl (Stockh) 1996;96:115–19.
criteria that refer to symptoms over the course of a year 11 Williams HC, Burney PG, Hay RJ et al. The U.K. Working Party’s
(to overcome seasonal variations when making compar- Diagnostic Criteria for Atopic Dermatitis. I. Derivation of a mini-
mum set of discriminators for atopic dermatitis. Br J Dermatol
isons) was that they were often validated by clinical
1994;131:383–96.
examination at just one point in time, a procedure that 12 Kang KF, Tian RM. Criteria for atopic dermatitis in a Chinese popula-
will always underestimate genuine cases that are not tion. Acta Derm Venereol Suppl (Stockh) 1989;144:26–7.
active at the time of examination. The authors concluded 13 Tagami H. Japanese Dermatology Association criteria for the diagno-
sis of atopic dermatitis. J Dermatol 1995;22:966–7.
that the UK diagnostic criteria are the most extensively 14 Brenninkmeijer EEA, Schram M, Leeflang MMG et al. Diagnostic
validated in hospital and community settings, and that criteria for atopic dermatitis: a systematic review. Br J Dermatol
this set of criteria for AD should be recommended in 2008;158:754–65.
future intervention studies. They pointed out that the 15 Whiting P, Rutjes AW, Reitsma JB et al. The development of QUADAS:
a tool for the quality assessment of studies of diagnostic accuracy
ideal set of diagnostic criteria still has to be established, included in systematic reviews. BMC Med Res Methodol 2003;3:25.
and there is considerable scope for improvement of meth- 16 Chalmers DA, Todd G, Saxe N et al. Validation of the U.K. Working
odological design for validation studies. Party diagnostic criteria for atopic eczema in a Xhosa‐speaking
African population. Br J Dermatol 2007;156:111–16.
Guidance on how to design a good validation study for 17 Gu H, Chen XS, Chen K et al. Evaluation of diagnostic criteria for
diagnostic criteria for AD is summarized in Box 15.1 [22] atopic dermatitis: validity of the criteria of Williams et al. in a hospital‐
although it has rarely been followed. Guidance on what based setting. Br J Dermatol 2001;145:428–33.
makes a good prevalence study has been suggested by 18 Girolomoni G, Abeni D, Masini C et al. The epidemiology of atopic
dermatitis in Italian schoolchildren. Allergy 2003;58:420–5.
Radalescu et al. [23]. An interactive website is available in 19 Popescu CM, Popescu R, Williams H et al. Community validation of
the public domain for those interested in finding out more the United Kingdom diagnostic criteria for atopic dermatitis in
about using the UK Working Party’s diagnostic refine- Romanian school children. Br J Dermatol 1998;138:436–42.
20 Haileamlak A, Lewis SA, Britton J et al. Validation of the International
ment of the Hanifin and Rajka criteria, including transla- Study of Asthma and Allergies in Children (ISAAC) and U.K. criteria
tions, detailed field instructions, training images and a for atopic eczema in Ethiopian children. Br J Dermatol 2005;
quality control test [24]. 152:735–41.
21 Firooz A, Davoudi SM, Farahmand AN et al. Validation of the diag- however, that the original instructions on the use of the
nostic criteria for atopic dermatitis. Arch Dermatol 1999;135:514–16.
UK diagnostic criteria in adults in the online manual
22 Williams HC. Defining atopic dermatitis – where do we go from
here? Arch Dermatol 1999;135:583–6. clearly state ‘Recall of onset of eczema under the age of 2
23 Radalescu M, Diepgen T, Williams H. What makes a good prevalence is likely to be inaccurate in adults’, and should be replaced
survey? In: Williams HC, Bigby M, Diepgen T et al. (eds) Evidence‐ by ‘Did your eczema start when you were a child?’ as few
Based Dermatology, 2nd edn. Oxford: Blackwell Publishing and BMJ
Publishing Group, 2008:61–7.
adults will know what happened in the first 2 years of
24 Williams HC, Flohr C. So How Do I Define Atopic Eczema? A Practical their life [5]. Another study of 518 children in Spain found
Manual for Researchers Wishing to Define Atopic Eczema. University of that the UK criteria administered in a telephone interview
Nottingham, 1995 (https://www.nottingham.ac.uk/research/groups/ agreed with physician diagnosis in 75.3% of cases [6].
cebd/resources/uk‐diagnostic‐criteria‐for‐atopic‐dermatitis.aspx).
Within Phase Two of the ISAAC, 30 358 schoolchildren
aged 8–12 years from 18 countries were examined for
Other studies that have emerged since flexural eczema and their parents completed the ISAAC
the systematic review eczema symptom questionnaire [7]. As might be expected,
ATOPIC DERMATITIS
A few other relevant validation studies have emerged the point prevalence for flexural eczema based on a single
since the systematic review by Brenninkmeijer et al. [1]. examination was lower than the questionnaire‐based 12‐
SECTION 3:
The first is a study of validation of the UK diagnostic cri- month period prevalence (mean centre prevalence 3.9%
teria in adults in Japan [2] – a useful study as nearly all vs. 9.4%), yet both were highly correlated (r = 0.77,
work to date has involved children. Saeki et al. compared P <0.001). When analysed at an individual level, ques-
the validity of the UK criteria with clinical examination tionnaire‐derived symptoms of ‘persistent flexural
[2]. Such a comparison will always underestimate the true eczema in the past 12 months’ missed less than 10% of
validity of the criteria because a 1‐year period prevalence cases of flexural eczema detected on physical examina-
is being compared against point prevalence. In other tion, although between 33% and 100% of questionnaire‐
words, many of those who were ‘positive’ for the UK based symptoms of ‘persistent flexural eczema in the past
criteria in the last year may not have had active eczema at 12 months’ were not confirmed on examination. The
the time of examination. Nevertheless, the study found authors concluded that prevalences derived using the
that the UK criteria showed a sensitivity of 68.8% (88/128) ISAAC questionnaires were sufficiently robust for com-
and specificity of 93.5% (1863/1992) in an adult Japanese paring disease prevalence between populations. They
population attending college and university. In an earlier went on to say that when diagnostic precision at the indi-
study of community validation of diagnostic criteria for vidual level is important, questionnaires should always
AD in schoolchildren, Saeki and colleagues illustrated be validated first, or a standardized skin examination
how validity of the UK criteria can appear to improve if protocol should be used such as that used by the UK
the time period for assessing symptoms is restricted to the working party (see Fig. 13.1) [8].
last week to make them more like a point prevalence One study has tried to see whether there are differences
measure, which could then be more realistically com- in diagnostic features in children with AD (i.e. truly atopic
pared with a clinical examination at one point in time [3]. with IgE antibodies) versus those who look similar but
They found in 2002 that when the UK diagnostic criteria who do not have evidence of IgE reactivity (called ‘atopi-
were used as a 1‐year prevalence measure, sensitivity and form’ by some). The authors found that the atopiform
specificity were 71.8% and 89.3%, respectively, with a children had later disease onset, an absence of other atopic
positive predictive value of 44.7%. When used as a point diseases, fewer Dennie–Morgan creases, less hand/foot
prevalence estimate in 2004/5 in a different sample, eczema and a variety of other features, yet some of these
sensitivity had dropped slightly to 58.9% but specificity differences could be due to the fact that the atopiform
had increased to 95.4%, which led to an increase in the cases were milder, an important confounder that was not
positive predictive value to 59.9% [3]. taken into account in the selection of cases or analysis [9].
A further validation study concerning adults was Schram and colleagues in 2011 revisited the millennium
conducted on 1131 nursing staff in a Taiwanese teaching criteria for AD for which allergen‐specific IgE is a manda-
hospital; this achieved a good 93% response rate [4]. The tory criterion, accompanied by three additional criteria,
Taiwanese study compared the validity of the UK criteria two of which need to be positive [10]. They removed the
and the ISAAC criteria in the last year against a derma- requirement for allergen‐specific IgE and derived a set of
tologist’s opinion of whether the person had AD in the clinical predictors for AD based on a sample of 210 clinic
last year (using guidance that broadly followed the patients with a clinical diagnosis of AD. They then applied
Hanifin and Rajka list). They found that sensitivity and these criteria to the same patients from which they were
specificity of the UK criteria were 42.2% and 99.6%, derived and reintroduced specific IgE testing to further
respectively, and for the ISAAC criteria they calculated a subdivide them into truly atopic dermatitis and those
sensitivity and specificity of 36.7% and 92.9%, respec- who had the AD phenotype but who were not atopic
tively. Further analysis by means of receiver‐operator (which they called atopiform dermatitis). They found that
curves indicated that dropping the criterion of ‘onset the refined millennium criteria (without IgE requirement)
under the age of 2 years’ resulted in better discrimination had a sensitivity and specificity of 81.8% and 98.8% respec-
for the UK criteria (sensitivity and specificity of 82.2% tively, compared with corresponding values of 97.7% and
and 94.2%, respectively). It should be pointed out, 72.9% for the UK refinement of the Hanifin and Rajka
criteria, and 100% and 48.8% for the original Hanifin and References
1 Brenninkmeijer EEA, Schram M, Leeflang MMG et al. Diagnostic
Rajka criteria. Relative value (sensitivity plus specificity
criteria for atopic dermatitis: a systematic review. Br J Dermatol
minus 100) was 0.7 for the revised millennium criteria, 2008;158:754–65.
0.72 for the UK criteria and 0.51 for the Hanifin and 2 Saeki H, Oiso N, Honma M et al. Prevalence of atopic dermatitis in
Rajka criteria for phenotypic AD. The study was well Japanese adults and community validation of the U.K. diagnostic
criteria. J Dermatol Sci 2009;55:140–1.
reported, yet it tested the criteria on the same popula- 3 Saeki H, Iizuka H, Mori Y et al. Community validation of the UK
tion from which they were derived, a procedure that diagnostic criteria for atopic dermatitis in Japanese elementary
may overestimate test performance. Further independent schoolchildren. J Dermatol Sci 2007;47:227–31.
studies are awaited. 4 Lan CC, Lee CH, Lu YW et al. Prevalence of adult atopic dermatitis
among nursing staff in a Taiwanese medical center: a pilot study
Silverberg and colleagues in a US study in 2015 found on validation of diagnostic questionnaires. J Am Acad Dermatol
that self‐ and caregiver‐reported diagnosis of eczema in a 2009;61:806–12.
hospital clinic setting was good when compared with 5 Williams HC, Flohr C. So How Do I Define Atopic Eczema? A Practical
Manual for Researchers Wishing to Define Atopic Eczema. University
physician diagnosis of AD, with positive predictive val-
ATOPIC DERMATITIS
of Nottingham, 1995 (https://www.nottingham.ac.uk/research/groups/
ues of 0.87 and 0.76 for caregiver 1‐year reported history cebd/resources/uk‐diagnostic‐criteria‐for‐atopic‐dermatitis.aspx);
of childhood eczema and self‐report of eczema in the last Section 5‐3.
SECTION 3:
year by adults, respectively [11]. The report is well‐written 6 García‐Díez A, Puig L, Ortiz J, Blanco A. [Validity of a telephone
survey for determining the prevalence of atopic dermatitis and its
but their use of the term ‘eczema’ is at odds with a call seasonal variation in Spain]. Actas Dermosifiliogr 2009;100:298–306.
from the same group not to use such a term [12]. 7 Flohr C, Weinmayr G, Weiland SK et al. and the ISAAC Phase Two
Yet another set of criteria has been suggested by the Study Group. How well do questionnaires perform compared with
physical examination in detecting flexural eczema? Findings from
Korean Atopic Dermatitis Association’s atopic dermati-
the International Study of Asthma and Allergies in Childhood
tis diagnostic criteria group. This set is composed of 11 (ISAAC) Phase Two. Br J Dermatol 2009;161:846–53.
questions (two major and nine minor), many of which 8 Williams HC, Forsdyke H, Boodoo G et al. A protocol for recording
are remarkably similar to those used in the UK criteria the sign of visible flexural dermatitis. Br J Dermatol 1995;133:941–9.
9 Brenninkmeijer EE, Spuls PI, Legierse CM et al. Clinical differences
[13]. They derived their criteria from a training sample between atopic and atopiform dermatitis. J Am Acad Dermatol 2008;
(n = 1129) and tested them on an independent commu- 58:407–14.
nity sample of children (n = 1191) and found a sensitivity 10 Schram ME, Leeflang MM, DEN Ottolander JP et al. Validation
and specificity of 75.2% and 96.1% respectively when and refinement of the Millennium Criteria for atopic dermatitis.
J Dermatol 2011;38:850–8.
compared with dermatologist examination performed 11 Silverberg JI, Patel N, Immaneni S, Rusniak B et al. Assessment of
twice over the course of a year. These values were better atopic dermatitis using self‐report and caregiver report: a multicentre
than corresponding values for the simple questions used validation study. Br J Dermatol 2015;173:1400–4.
12 Kantor R, Thyssen JP, Paller AS, Silverberg JI. Atopic dermatitis,
in the ISAAC (sensitivity of 68.8 and specificity of atopic eczema, or eczema? A systematic review, meta‐analysis, and
92.9%), although it is unclear if these values were statis- recommendation for uniform use of ’atopic dermatitis’. Allergy
tically different. The Korean criteria were not compared 2016;71:1480–5.
against the UK or millennium or Hanifin and Rajka cri- 13 Lee SC, Bae JM, Lee HJ et al.; Korean Atopic Dermatitis Association’s
Atopic Dermatitis Criteria Group. Introduction of the reliable estimation
teria in this study and further independent studies are of atopic dermatitis in childhood: novel, diagnostic criteria for childhood
awaited. atopic dermatitis. Allergy Asthma Immunol Res 2016;8:230–8.
212
CHA PTER 1 6
Severity Scoring and Quality of Life Assessment

in Atopic Dermatitis
Christian Apfelbacher1, Cecilia A.C. (Sanna) Prinsen2, Daniel Heinl1 & Hywel C. Williams3
1
Medical Sociology, Institute of Epidemiology and Preventive Medicine, University of Regensburg, Regensburg, Germany
2
VU University Medical Center, Department of Epidemiology and Biostatistics, Amsterdam Public Health Research Institute, Amsterdam, The Netherlands
3
The Centre of Evidence Based Dermatology, University of Nottingham, Nottingham, UK
ATOPIC DERMATITIS
Introduction, 212 Global measurement instruments of atopic Evaluation of quality‐of‐life instruments

SECTION 3:
How has disease severity and quality of life dermatitis severity, 218 for children with atopic dermatitis, 222
been measured in clinical trials in atopic Other ways of measuring severity of atopic Towards standardization of outcome
dermatitis?, 213 dermatitis, 218 reporting for quality of life in atopic
Choosing adequate measurement Evidence‐based recommendation for the dermatitis, 224
instruments, 213 measurement of subjective severity of atopic Instruments to measure family impact of
Evidence‐based recommendations for dermatitis (symptoms) in clinical trials, 219 atopic dermatitis, 224
the measurement of atopic dermatitis Measuring quality of life in children with Conclusion, 225
severity in clinical trials, 215 atopic dermatitis, 219
Abstract the Patient‐Oriented Eczema Measure (POEM) for symptoms

are the preferred instruments to be measured in all clinical trials
In the absence of a reliable biomarker, instruments to measure in AD. There is no well‐validated way to measure AD disease
AD disease severity are questionnaires, which are completed by severity by a global assessment. The Childhood Atopic Dermatitis
patients, significant others or physicians. There is substantial Impact Scale (CADIS) is a promising proxy instrument to meas-
heterogeneity in the way in which objective disease severity ure quality of life in infants and their family with one s ingle
(i.e. clinical signs), subjective disease severity (i.e. symptoms) instrument. Valid and feasible ways of measuring disease severity
and quality of life are measured. The Harmonising Outcome and quality of life in clinical practice are unclear; guidance
Measures for Eczema (HOME) initiative has reached the consen- should be sought from the recommendations for clinical trials
sus that the Eczema Area and Severity Index (EASI) for signs and for the time being.
Key points trials. The SCORing Atopic Dermatitis (SCORAD) index also has
satisfactory measurement properties.
°° For the symptoms domain, the Patient‐Oriented Eczema
• There is substantial heterogeneity in the way in which objective
Measure (POEM) is the preferred instrument to be used in AD
disease severity (clinical signs), subjective disease severity
trials.
(symptoms) and quality of life are measured in AD.
°° For quality of life, the Childhood Atopic Dermatitis Impact Scale
• The Harmonising Outcome Measures for Eczema (HOME)
(CADIS) and the Dermatitis Family Impact (DFI) questionnaire can
initiative has reached international consensus that the core
be used.
outcome set for clinical trials in AD includes clinical signs,
• There is no international consensus regarding the measurement
symptoms, long‐term control and quality of life:
of disease severity and quality of life in clinical practice.
°° For the clinical signs domain, the Eczema Area and Severity
Index (EASI) is the preferred instrument to be used in AD
questionnaires) [2]. The latter are also referred to as

Introduction patient‐reported outcome measures (PROMs). Measuring
In the absence of an accepted, reliable biomarker for disease severity by physician assessment of visible clini-
measuring atopic dermatitis (AD or atopic eczema, or cal signs is often referred to as ‘objective’ whereas patient
eczema) severity [1], consistent and replicable assessment self‐assessment of symptoms or quality of life is referred
of AD disease severity remains a clinical activity that to as ‘subjective’. However, it should be realized that even
requires questionnaires. These are completed either by though the word ‘objective’ implies an accurate measure-
physicians, nurses or relatives (interviewer‐administered ment of an outcome on a numeric scale, all such objective
questionnaires) or by patients themselves (self‐administered measures require subjective judgement by observers, e.g.
Chapter 16 Severity Scoring and Quality of Life Assessment in Atopic Dermatitis 213
grading the intensity of erythema as mild, moderate or the SCORing of Atopic Dermatitis (SCORAD) index [8]
severe, or guessing the amount of surface area involved. and the Simple Scoring System (SSS) [9]. It illustrates the
Therefore, the notion that there is a very clear difference variation in the way the construct ‘disease severity’ is
in objectivity between so‐called objective clinician‐ interpreted in disease severity assessments. Of note, some
assessed and subjective patient‐assessed measures is a instruments include symptoms in their conceptual model
fallacy. Conceptually, it is better to think about who is and some do not. Four further systematic reviews
making the assessment and how it is being done. [4,5,10,11] have been conducted following the cited origi-
nal review by Charman et al. [3], all of which corrobo-
rated the findings of the original systematic review that
there is wide variation in the way in which disease sever-
How has disease severity and quality
ity and quality of life have been measured.
of life been measured in clinical trials
Concerning subjective disease severity, another system-
in atopic dermatitis?
atic review investigated how symptoms were measured
ATOPIC DERMATITIS
A systematic review investigated the use of outcome in RCTs performed in AD between 2000 and 2014 and
measurement instruments used in trials of therapeutic likewise found substantial variation [12]. Seventeen dif-
SECTION 3:
interventions for AD conducted between 1994 and 2001 ferent symptoms (most frequently itch and sleep loss)
[3]. It was found that 85 of the included 93 studies used an were reported in 78% of the investigated 378 trials, with
objective measurement of clinical signs, but only 23 used only 37% of the trials reporting stand‐alone symptom
a published severity scale. Overall, 56 different scales measurements. The remainder used composite measure-
were identified and there was no consensus on which fea- ment instruments such as SCORAD. SCORAD was also
tures should be assessed: 31 different descriptions of the most frequently used instrument, but only 23% of
clinical signs were used across all scales. Erythema, RCTs reported the part C symptom score separately.
lichenification and excoriation were most frequently Overall, 30 different instruments were identified.
assessed. Table 16.1 shows the contents of the most fre- Similar observations concerning the significant varia-
quently used AD disease severity measurement instru- tion in measurement instruments used can be made with
ments: the Eczema Area and Severity Index (EASI) [6], the respect to quality of life (QoL). A 2016 systematic review
Six Area, Six Sign Atopic Dermatitis (SASSAD) score [7], examined how QoL was captured in RCTs performed in
AD between 2000 and 2014 [13]. Only 63 of 303 included
studies assessed QoL, using 22 different QoL measure-
Table 16.1 Content comparison of selected, frequently used measurement instruments. This finding is also in accordance with
ment instruments of atopic dermatitis (AD) disease severity an earlier review looking at the time period of 1985–2010,
which found that 14 different QoL instruments were used
AD disease severity measurement in AD trials [10].
instrument The variation identified in the measurement of clinical
signs, symptoms and QoL means that the comparison and
EASI SASSAD SCORAD SSS meta‐analysis of efficacy studies within systematic
reviews and meta‐analyses is hampered at best and
Clinical signs
impossible at worst. Consequently, it is difficult to iden-
Erythema X X X X
Oedema/induration/ X X X tify the most efficacious therapies [14], which in turn
papulation means that recommendations from clinical research for
Oozing/crusting X X X clinical practice are difficult to make and evidence‐based
Excoriation X X X X healthcare for people with AD cannot be implemented. In
Lichenification X X X X other words, the failure to identify and agree what to
Dryness X X
measure and how to measure AD severity ultimately
Scaling X
Cracking/fissuring X
results in poor patient information and care.
Vesicles X
(De)pigmentation X
Affected body regions Choosing adequate measurement
Extent of affected skin X X instruments
areas (in %)
Inspection of defined x X In order to make an evidence‐based decision on the choice
body areas (e.g. arms) for a specific measurement instrument of AD disease
Symptoms severity or QoL, it is important to compare the quality of
Pruritus x X existing instruments. The measurements generated by
Sleep x X AD severity measurement instruments should, as indeed
should any measurement, be robust and the scores gener-
EASI, Eczema Area and Severity Index; SASSAD, Six Area, Six Sign Atopic
ated will be the more trustworthy the higher the quality
Dermatitis; SCORAD, SCORing Atopic Dermatitis; SSS, Simple Scoring
System.
of the instrument used.
Source: adapted from Deckert et al. 2015 [2], Schmitt, Langan and Williams Generally, systematic reviews of measurement instru-
2007 [4], Schmitt et al. 2013 [5]. Reproduced with permission of Elsevier. ments are important tools that can be used to select the
best instrument available. In such reviews, the content intensity of these signs and not of another combination of
and the measurement properties of all instruments signs. Reliability relates to the precision of measurements.
available are being critically appraised and compared. If two different dermatologists using the same AD sever-
Systematic reviews of measurement instruments focus on ity measurement instrument in a standardized way gen-
two different quality aspects: (i) the methodological qual- erate different scores, inter‐rater reliability will be low.
ity of the included studies on measurement properties, Also if one dermatologist rated a patient with the same
and (ii) the quality of the instrument (i.e. its measurement level of disease severity at two different points in time
properties) itself. How to evaluate the methodological and generated different scores there would be low intra‐
quality of studies on measurement properties is beyond rater reliability. Lastly, responsiveness is defined as the
the scope of this chapter and we refer to the methodology ability of a measurement instrument to detect change
that has been developed by the COnsensus‐based over time in the construct to be measured. If an instru-
Standards for the selection of health Measurement ment is used to evaluate patients’ disease severity over
INstruments (COSMIN) initiative, see: www.cosmin.nl. time, the instrument at issue should be able to pick up
ATOPIC DERMATITIS
In the evaluation of the quality of the instruments three changes over time.
dimensions can be distinguished: reliability, validity and The relevant measurement properties and aspects of
SECTION 3:
responsiveness [15]. Validity means that the instrument measurement properties that are summarized in Table 16.2
measures what it purports to measure. If, for instance, were adapted from the consensus‐based taxonomy that
disease severity is thought to be something that should be was developed by COSMIN [16].
defined by intensity of erythema, lichenification and exco- For the assessment of a measurement instrument, it is
riation, then the selected instrument should be measuring the also important to assess aspects of feasibility. Feasibility
Table 16.2 Taxonomy and definitions of measurement domains, measurement properties and aspects of measurement properties
Domain Measurement Aspect of a Definition

property measurement
property
Reliability The degree to which the measurement is free from measurement error
Reliability The extent to which scores for patients who have not changed are the same for repeated
(extended measurement under several conditions: for example, using different sets of items from the same
definition) HR‐PROs (internal consistency), over time (test–retest) by different persons on the same occasion
(inter‐rater) or by the same persons (i.e. raters or responders) on different occasions (intra‐rater)
Internal The degree of interrelatedness among the items
consistency
Reliability The proportion of total variance in the measurements which is because of ‘true’a differences
among patients
Measurement The systematic and random error of a patient’s score that is not attributed to true change of
error the construct to be measured
Validity The degree to which an HR‐PRO instrument measures the construct(s) it purports to measure
Content validity The degree to which the content of an HR‐PRO instrument is an adequate reflection of the
construct to be measured
Face validity The degree to which (the items of) an HR‐PRO instrument looks as though it is an adequate
reflection of the construct to be measured
Construct validity The degree to which the scores of an HR‐PRO instrument are consistent with hypotheses (for
instance with regard to internal relationships, relationships to scores of other instruments, or
differences between relevant groups) based on the assumption that the HR‐PRO instrument
validly measures the construct to be measured
Structural validity The degree to which the scores of an HR‐PRO instrument are an adequate reflection of the
dimensionality of the construct to be measured
Hypothesis testing See Construct validity
Cross‐cultural The degree to which the performance of the items on a translated or culturally adapted HR‐
validity PRO instrument are an adequate reflection of the performance of the items of the original
version of the HR‐PRO instrument
Criterion validity The degree to which the scores of an HR‐PRO instrument are an adequate reflection of a ‘gold
standard’
Responsiveness The ability of an HR‐PRO instrument to detect change over time in the construct to be measured
Responsiveness See Responsiveness
Interpretability The degree to which one can assign qualitative meaning – that is, clinical or commonly
understood connotations – to an instrument’s quantitative scores or changes in scores
a
The word ‘true’ must be seen in the context of classical test theory (CCT) which states that any observation has two components – a true score and error
associated with the observation.
HR‐PRO, health‐related patient‐reported outcome.
Source: Mokkink et al. 2010 [16]. Reproduced with permission of Elsevier.
refers to the ease of application of the instrument in its Detailed information on the measurement properties
intended setting, given constraints such as time or and their quality criteria is beyond the scope of this chap-
money [17]. The COSMIN initiative together with ter. We refer to textbooks (e.g. the book by De Vet et al.
the Core Outcomes Measures in Effectiveness Trials [15]) and additional medical literature on consensus‐
(COMET) (http://www.comet‐initiative.org/) con- based quality criteria of measurement properties [20] for
ducted a Delphi study in which consensus was reached further information.
that important aspects of feasibility are [16]: patient’s
comprehensibility, interpretability, ease of administra-
tion, length of measurement instrument, completion
Evidence‐based recommendations
time, patient’s mental ability level, ease of standardiza-
for the measurement of atopic
tion, clinician’s comprehensibility, type of instrument,
dermatitis severity in clinical trials
cost of instrument, required equipment, type of admin- The mission of the international, multiprofessional
istration, availability in different settings, copyright, Harmonising Outcome Measures for Eczema (HOME)
ATOPIC DERMATITIS
patient’s physical ability level, regulatory agency’s initiative (www.homeforeczema.org) is to develop a core
requirement for approval, ease of score calculation. set of outcomes and corresponding outcome measure-
SECTION 3:
Interpretability denotes the degree to which one can ment instruments to be measured as a minimum in all
assign qualitative meaning to the quantitative scores or future eczema trials [21]. Based on an e‐Delphi and face‐
changes in scores generated by a particular instrument to‐face consensus voting, four outcome domains (aspects
[16]. For commonly used instruments, such as a ther- of disease that should be measured) were consented as
mometer that measures body temperature in degrees core: clinical signs, symptoms, quality of life and long‐
Celsius or Fahrenheit, interpretability usually causes no term control of flares. Once the core set of outcome
problems once familiarity with the numbers (‘a body tem- domains has been agreed, it is then important to identify
perature of 40 degrees centigrade feels hot’) is established. appropriate measurement instruments for the different
For scores of multi‐item instruments, the interpretation domains, according to step 3 of the HOME roadmap [22]
might be challenging as the meaning of such a score is not (Fig. 16.1).
immediately straightforward (e.g. what does a change in Instruments that objectively assess disease severity in
EASI score from 60 to 52 mean?). Aspects of interpretabil- AD were predominantly created between 1989 and 2009
ity of scores include the distribution of the (total) scores, [4,5]. A systematic review investigated instruments that
floor and ceiling effects, and information on the minimal assess the clinical signs of AD, synthesizing quality grad-
important change (i.e. the smallest change in score which ing of measurement properties and methodological
patients perceive as important [15,18]). study quality to generate recommendations [5]. Sixteen
As an example of feasibility and interpretability issues, such instruments were identified. The Severity Scoring of
a feasibility study was performed for the Eczema Area Atopic Dermatitis (SCORAD) Index [8] was found to
and Severity Index (EASI) [19]. It was shown that it was have adequate validity, responsiveness and interpretabil-
acceptable concerning ease of use with a completion time ity. Although interobserver reliability was adequate,
by trained investigators of approximately 6 minutes. intraobserver reliability was unclear. Internal consist-
Further, bands were suggested guiding the interpretabil- ency of the objective SCORAD, i.e. the part of the
ity of obtained scores, with scores of 0 denoting clear, SCORAD in which clinical signs are assessed, was ade-
0.1–1.0 almost clear, 1.1–7.0 mild, 7.1–21.0 moderate, 21.1– quate. The Eczema Area and Severity Index (EASI) [6]
50.0 severe and 50.1–72.0 very severe disease. was found to have adequate intraobserver reliability,
Just as taking a car driving test without passing is unac- intermediate interobserver reliability, internal consist-
ceptable, it is not sufficient for the measurement proper- ency, validity and responsiveness. However, interpreta-
ties (validity, reliability, responsiveness to change) of an bility and feasibility were unclear. The Three Item
instrument to be simply estimated – they also need to Severity Score (TIS) [23] and the SASSAD [7] met only
meet certain standards. The COSMIN initiative proposed some criteria and in particular were only given an ‘inter-
quality criteria to judge the measurement properties of mediate’ rating for content validity. The remaining
health status measurement instruments [20]. For instance, 12 scales had either (almost) not been validated or per-
according to these, a measurement instrument has ade- formed inadequately. Among the measures with unclear
quate content validity when all items are considered to be measurement properties are the patient‐assessed ver-
relevant for the construct to be measured (disease sever- sions of SCORAD and EASI, the patient‐oriented
ity), for the target population (people with AD), and for SCORAD [24] and the self‐administered EASI [25].
the purpose of the measurement and when the question- However, SCORAD and EASI in their original forms
naire is considered to be comprehensive (from the per- were identified as the two candidate instruments to
spective of both physicians and patients). Involving assess clinical signs.
patients (e.g. by means of focus group discussions) is The European Task Force on Atopic Dermatitis (ETFAD)
essential, but often neglected. developed the SCORAD (Severity Scoring of Atopic
A further example is internal consistency, which is Dermatitis) [8] instrument which combines objective crite-
assumed to be adequate if there is at least evidence for ria with subjective symptoms. The intensity of six clinical
unidimensionality or positive structural validity and signs (erythema, oedema/papulation, oozing/crusts,
Cronbach’s alpha(s) is ≥0.70 and ≤0.95 [18]. excoriation, lichenification, dryness) is assessed on a scale
The Home roadmap to develop core sets of outcome measurements
Step 1: Define scope and applicability

Population (condition)
Intervention
Setting(e.g. trial,registry, clinical practice)
Geographical/regional scope*
Stakeholders
Step 2: Develop core set of outcome domains

ATOPIC DERMATITIS
Consensus study involving representatives of relevant

stakeholders.
SECTION 3:
Step 3: Develop core set of outcome measurements

Identification and recommendation of adequate measurement instrument(s)
for each core outcome domain by a 5 stage process
Stage 1 Stage 2 Stage 3 Stage 4 Stage 5

Identify all Establish the Determine which instruments are good enough quality meet the requirements of Carry out validation Finalise core
Task
instruments extent and the OMERACT filter and be shortlisted for further consideration. studies on shortlisted outcome(s) for
previously used quality of testing scales. domain.
to measure the of the identified
domain. instruments.
Systematic review of Systematic review Apply OMERACT filter: truth, discrimination, and feasibility: Consensus Re-apply the
outcome of validation studies discussion and voting OMERACT filter with
instruments used. of the long-list of Truth Discrimination Feasibility to determine what
the results of the
identified “Is the measure truthful, “Does the measure “Can the measure be validation studies will
instruments be conducted on completed validation
Methodology
does it measure what it discriminate between applied easily in its

short-listed studies.
intends to measure? Is the situation that are of intended setting, given
Highlight any gaps instruments. Gaps in
result unbiased and interest?” constraints of time,
in validation. testing were
relevant?” money and Consensus
highlighted in stage 2
interpretability?” discussion and voting
(systematic review).
on core outcome to
Consensus discussion and Consensus discussion Appropriate methods
Consensus discussion and voting on discrimination: and voting on feasibility: be recommended
used to fill the gaps in
voting on truth: validation.
1.Reliability 1.Time take
1.Face validity 2.Sensitivity to change 2.Cost
2.Content validity 3.Interpretability
3.Construct validity
4.Criterion validity
Long-list of all Summary of which Short-list of potential instruments that meet the requirements of the OMERACT Short-list of fully Recommended core
instruments instruments have filter. tested instruments.
Output
outcome instrument
previously used been tested and
for the domain.
to measure the the quality, extent
domain. and results of any
testing.
Step 4: Disseminate, prepare guidance

material, review, and possibly revise core set
of outcome measurements
*for trials the scope should generally be global

Fig. 16.1 HOME Roadmap. Source: Schmitt et al. 2015 [22]. Reproduced with permission of Elsevier.
from 0 (absence) to 3 (severe) for a representative body site. in less than 10 minutes [29,30]. Training is available freely
The resulting score is combined with a score for the extent on the SCORAD website (http://adserver.sante.univ‐
of the involved body area and an assessment of sleep loss nantes.fr/). There is also specific software designed to
and pruritus on a visual analogue scale, to yield an overall facilitate the assessment of AD, the ScoradCard © 2.0 [31].
SCORAD score with a maximum of 103 points. Based on The EASI was developed in 1998 based on the
the objective SCORAD (intensity of signs plus extent), it Psoriasis Area and Severity Index scoring system [6].
has been suggested that <15 points represents mild, 15–40 The intensity of four clinical signs (erythema, induration/
represents moderate and >40 points represents severe dis- papulation, excoriations, lichenification) is assessed at
ease [26–28]. After training, the SCORAD can be performed each of four defined body sites (Figs 16.2 and 16.3).
Eczema Area and Severity Index (EASI) case report form – age <8 years
Area of Involvement: Each body region has potentially 100% involvement. Score 0 to 6 based on the following table:
% involvement 0 1–9% 10–29% 30–49% 50–69% 70–89% 90–100%

Region score 0 1 2 3 4 5 6
Severity of Signs: Grade the severity of each sign on a scale of 0 to 3:
0 None
1 Mild Take an average of the severity across the
involved area.
2 Moderate
Half points may be used e.g. 2.5.
3 Severe
ATOPIC DERMATITIS
Scoring table:
SECTION 3:
Erythema Edema/ Excoriation Lichenification Region score Multiplier Score per body
(0–3) Papulation (0–3) (0–3) (0–6) region
Body region (0–3)
Head/neck ( + + + ) X X 0.2
Trunk ( + + + ) X X 0.3
Upper extremities ( + + + ) X X 0.2
Lower extremities ( + + + ) X X 0.3
The final EASI score is the sum of the 4 region scores: ____________
(0–72)
Fig. 16.2 EASI (<8 years). Source: Reproduced with kind permission from the HOME group at the Centre of Evidence Based Dermatology at Nottingham, UK.
Eczema Area and Severity Index (EASI) case report form – age ≥8 years
Area of Involvement: Each body region has potentially100% involvement. Score 0 to 6 based on the following table:
% involvement 0 1–9% 10–29% 30–49% 50–69% 70–89% 90–100%
Region score 0 1 2 3 4 5 6
Severity of Signs: Grade the severity of each sign on a scale of 0 to 3:

0 None
1 Mild Take an average of the severity across the
involved area.
2 Moderate
Half points may be used e.g. 2.5.
3 Severe
Scoring table:
Erythema Edema/ Excoriation Lichenification Region score Multiplier Score per body
(0–3) Papulation (0–3) (0–3) (0–6) region
Body region (0–3)
Head/neck ( + + + ) X X 0.1
Trunk ( + + + ) X X 0.3
Upper extremities ( + + + ) X X 0.2
Lower extremities ( + + + ) X X 0.4
The final EASI score is the sum of the 4 region scores: ____________
(0–72)
Fig. 16.3 EASI (≥8 years). Source: Reproduced with kind permission from the HOME group at the Centre of Evidence Based Dermatology at Nottingham, UK.
Additionally, d isease extent is assessed for these sites. (without reference to another time point), some used
Multiplying severity by area by a constant weighted dynamic scales (with reference to a time point, e.g.
value yields a total score for each body region. Summing 50% improved compared to baseline). The number of
these scores yields the total EASI score with a maxi- categories varied between 4 and 7, with 6‐point scales
mum score of 72. As mentioned previously, feasibility, being the most frequently used. The most striking
including interpretability of the EASI, has been finding was the huge variation in the way in which the
assessed. The EASI is a unidimensional measure, mean- disease severity was defined. Only 24% of the trials
ing that it only assesses clinical signs and does not using an IGA provided instructions on how to imple-
incorporate symptoms. Unlike SCORAD, it measures ment the scales. All global assessment scales for which
the intensity of lesions at multiple body parts and does instructions were available included erythema and
not rely on a representative lesion. A user guide, a papulation/oedema with many adding oozing/weep-
training video, an EASI calculator and an EASI calcula- ing and crusting and only some considering excoria-
tor App for smartphone devices are all available tion, scaling and lichenification. Of note, only three of
ATOPIC DERMATITIS
through the website of the HOME initiative (www. the IGA measures included excoriation, which is the
homeforeczema.org). sign that shows the strongest correlation with patients’
SECTION 3:
At the third international HOME meeting (2013), assessments of disease severity [36]. For many scales
broad consensus was achieved that the preferred AD used, no instructions were reported or referenced at
clinical signs measurement instrument should capture all. These scales probably rely on a gestalt approach to
both intensity and extent of AD signs and that intensity assessing global severity, taking into account different
should be assessed for lichenification, oedema/papula- facets of the disease such as symptoms and QoL in
tion, excoriation and erythema [32]. Only the objective addition to clinical signs. Given their widespread use,
SCORAD and the EASI included those four essential primary validation research is urgently needed for
signs, and at the same time, these two instruments had IGA measures of AD disease severity, with the aim to
been identified as candidate instruments in the afore- enhance standardization. Until such research is done,
mentioned systematic review. In the final consensus recommendations cannot be made as to which global
voting, broad consensus was achieved that the EASI measurement instrument is most appropriate.
should be the core outcome measurement instrument Although a global measure of disease severity is not
to assess clinical signs in AD clinical trials [32,33]. included in the Core Outcome Set for AD [37,38], its
Perceived advantages of the EASI over the objective use is recommended by the US Food and Drug
SCORAD were that EASI only includes the four essen- Administration [39] for reasons that are unclear.
tial signs, that signs are assessed not at a single repre-
sentative site but at multiple body sites and that extent
of lesions is given sufficient weighting (50% of total
Other ways of measuring severity
score as opposed to 24% of total score in the objective
of atopic dermatitis
SCORAD).
The quest for objective serum markers to measure AD
severity reliably has had mixed fortunes, and is still far
from clear. A systematic review that included a meta‐
Global measurement instruments analysis of 108 articles suggested that serum thymus
of atopic dermatitis severity activation‐regulated chemokine (TARC) showed the
Although clinical scoring systems such as the EASI best correlation with clinical disease severity in a range
provide a comprehensive way of assessing disease of study designs [40]. A range of other biomarkers
severity as measured by an array of relevant clinical requiring more research such as serum cutaneous T‐
signs, global measures of disease severity are often felt cell attracting chemokine (CTACK) were also identi-
to be more readily accessible for patients and physi- fied. Other objective ways of measuring AD severity
cians as they can be applied in an easy and rapid way. such as measuring scratching at night by wearing
In these scales, disease severity is often rated on a accelerometers have not proven to be very useful to
nominal scale, for instance from 0 to 5 (clear, almost date because of the lack of correlation with other meas-
clear, mild, moderate, severe, very severe [34]. ures of disease severity and QoL, and incomplete
However, such a holistic judgement is subject to inter- and complex data that are difficult to interpret [41].
pretation and may be less precise compared to a sever- Approaches such as infrared monitoring and video
ity measurement instrument with many items. A recording of nocturnal scratching are not practical for
systematic review investigated the use of Investigator most studies. Other indirect measures of AD severity
Global Assessments in randomized controlled trials such as topical corticosteroid and emollient use as
(RCTs) conducted in AD between 2000 and 2014 [35] rescue therapy [42] have been recorded in clinical

and found that about one third of the investigated 317 studies, but mainly as a potential confounder rather
trials used an IGA as outcome measure. There was than a surrogate of disease severity per se because
wide variation in the ways in which global severity many factors contribute to the decision for a patient to
was conceptualized. Some studies used static scales use and report treatment usage.
Evidence‐based recommendation the patient [53]. Examples of PROs include illness

for the measurement of subjective erceptions, satisfaction with care, and health‐related
p
severity of atopic dermatitis quality of life (further referred to as quality of life, QoL).
(symptoms) in clinical trials PROs are most commonly assessed by means of self‐
administered questionnaires, and are often termed as
Just as for the clinical signs domain, a systematic review PRO instruments or patient‐reported outcome measures
was also conducted to evaluate the measurement proper- (PROMs). One of the most commonly used PROs in
ties of existing AD symptom measurement instruments healthcare research and clinical practice is QoL [54].
[43]. Eighteen instruments were identified, five of which Following the definition of the World Health
were supported by sufficient evidence to consider them Organization, the construct QoL entails at least three
as candidate instruments to measure AD symptoms: the domains and reflects patients’ evaluation of the impact of
Patient‐Oriented Eczema Measure (POEM) [44,45], the disease and treatment on their physical, psychological and
paediatric Itch Severity Scale (ISS) [46], Patient‐Oriented social functioning and well‐being [55]. As it is well known
ATOPIC DERMATITIS
SCOring Atopic Dermatitis (PO‐SCORAD) [24,47], Self‐ that chronic skin diseases, such as AD, negatively affect the
Administered Eczema Area and Severity Index (SA‐EASI) lives of children [56,57], QoL has become an essential out-
SECTION 3:
[25] and adapted SA‐EASI [48]. come in clinical trials, clinical practice and healthcare man-
These and other instruments were discussed at the agement [58]. This is also reflected by the fact that the
HOME IV meeting and it was considered that irritated HOME initiative has identified QoL as a core outcome to be
skin, redness/inflamed skin, dryness, sleep loss and itch assessed in all AD clinical trials [40]. A previous study of
were all essential aspects of AD symptoms [49]. ISS was the National Eczema Association for Science and Education
not further considered because it only assesses itch. PO‐ surveyed 429 patients with AD or their parents and 303
SCORAD, SA‐EASI and POEM were voted on and POEM physicians about the effect of AD on QoL [59]. Results
was voted as the preferred core outcome measurement showed that children’s QoL is significantly affected by
instrument for AD symptoms. It is now recommended as their skin disease, particularly children with moderate to
a measure for all clinical trials in AD [50]. PO‐SCORAD severe AD, causing impairment of daily activities, school
and SA‐EASI were not favoured based on the argument performance, social and leisure activities and sleep. The
that these instruments largely represent a self‐assessment authors concluded that QoL issues are a key consideration
of clinical signs rather than true symptom measurement in management of AD. Another study reported on the
instruments. impact of skin disease on different aspects of adolescents’
POEM (Fig. 16.4) has seven items, assessing frequency QoL. The results of this study showed that adolescents’
of pruritus, sleep disturbance, bleeding, weeping or ooz- QoL is impacted by their skin diseases on several issues
ing, cracking, flaking, and dryness or roughness. It must that are specific to adolescents, such as psychological
be noted that the agreed essential symptom of redness is impact (91% of patients), physical impact (81%) and social
not included in POEM. It was deliberately excluded in the impact (81%). This also highlights the need for QoL assess-
development process because redness is difficult to detect ment [60]. Although the measurement of QoL has its ori-
in darker skin [44]. POEM is freely available in a range gins in the clinical trials setting, the use of QoL assessment
of languages (www.nottingham.ac.uk/research/groups/ in clinical dermatology practice is a more recent develop-
cebd/resources/poem.aspx) and takes less than 2 minutes ment and far from established. However, different efforts
for patients and/or carers to complete [43]. Its score ranges have been undertaken to highlight the relevance of meas-
from 0 to 28. A banding study has been conducted, linking uring QoL in clinical practice. An expert‐based opinion
categories to score ranges [45]: 0–2 denotes almost clear, statement of the Task Force on Quality of Life of the
3–7 mild, 8–16 moderate, 17–24 severe and 25–28 very European Academy of Dermatology and Venereology
severe disease. The responsiveness of the POEM has been (EADV) identified five broad categories in which using
investigated in young children [51]. It was found that the QoL information in practice is seen as useful [61]: aware-
minimal clinically important difference in relation to ness of skin disease burden, clinical service administration,
change recalled on a Parent Global Assessment (PGA) was informing consultation, clinician–patient communication,
around 3. Some validation gaps remain regarding struc- and informing clinical decisions. Another paper reported
tural and cross‐cultural validity which will be addressed on why QoL assessment in clinical practice is important, to
in the future by the HOME symptoms working group [50]. whom QoL assessment is particularly relevant and how
QoL can be assessed. The authors indicated that QoL data
can be used in clinical practice for five different purposes:
Measuring quality of life in children
(i) to increase patients’ self‐awareness and empowerment,
with atopic dermatitis
(ii) to increase patient‐centredness in healthcare, (iii) to
The importance of using patient‐reported outcomes make an optimal choice for treatment, (iv) to monitor treat-
(PROs) in research, clinical practice and healthcare man- ment over time and determine treatment effectiveness, and
agement is increasingly being recognized [52]. A PRO is (v) to improve treatment outcome [62].
a measurement of any aspect of a patient’s health status The relationship between QoL and disease severity is not
that is directly assessed by the patient without the inter- straightforward. A Dutch study administered the Infants’
pretation of the patient’s response by anyone other than Dermatitis Quality of Life Index (IDQOL) and SCORAD as
well as the TIS as measures of disease severity to 66 children routine healthcare, measuring QoL in infants, children
at a mean age of 31 months [63]. Weak and moderate‐ and adolescents enables dermatologists to understand the
to‐strong correlations between IDQOL and disease sever- impact of the skin disease in an individual, and it high-
ity were found when investigators and parents assessed lights specific aspects of QoL that are affected the most. A
disease severity, respectively. When used in research, QoL position paper of the EADV provides a comprehensive
measurement instruments should thus be seen as comple- overview of the QoL measurement instruments that have
mentary to established disease severity instruments. In been developed, validated and used in AD [64].
ATOPIC DERMATITIS
SECTION 3:
POEM for proxy completion (e.g by parent)
Patient Details: _______________________

______________________________________
______________________________________
______________________________________
Date:_________________________________
Please circle one response for each of the seven questions below about your child’s eczema. If your child is
old enough to understand the questions then please fill in the questionnaire together. Please leave blank
any questions you feel unable to answer.
1. Over the last week, on how many days has your child’s skin been itchy because of their eczema?
No days 1-2 days 3-4 days 5-6 days Every day
2. Over the last week, on how many nights has your child’s sleep been disturbed because of their eczema?
3. Over the last week, on how many days has your child’s skin been bleeding because of their eczema?
4. Over the last week, on how many days has your child’s skin been weeping or oozing clear fluid because of
their eczema?
5. Over the last week, on how many days has your child’s skin been cracked because of their eczema?
6. Over the last week, on how many days has your child’s skin been flaking off because of their eczema?
7. Over the last week, on how many days has your child’s skin felt dry or rough because of their eczema?
Total POEM Score (Maximum 28):_________________
© The University of Nottingham
Fig. 16.4 POEM.Source: The University of Nottingham, UK.

POEM for proxy completion (e.g by parent)
How is the scoring done? What does a poem score mean?
Each of the seven questions carries equal weight To help patients and clinicians to understand their
and is scored from 0 to 4 as follows: POEM scores, the following bandings have been
established (see references below):
ATOPIC DERMATITIS
No days =0
SECTION 3:
1-2 days =1 • 0 to 2 = Clear or almost clear
3-4 days =2 • 3 to 7 = Mild eczema
5-6 days =3 • 8 to 16 = Moderate eczema
• 17 to 24 = Severe eczema
Every day =4
• 25 to 28 = Very severe eczema
Note:
Do I need permission to use the scale?
• If one question is left unanswered this is scored 0 Whilst the POEM scale is protected by copyright, it
and the scores are summed and expressed as usual is freely available for use and can be downloaded
out of a maximum of 28 from: www.nottingham.ac.uk/dermatology
We do however ask that you register your use of
• If two or more questions are left unanswered the
the POEM by e-mailing cebd@nottingham.ac.uk
questionnaire is not scored
with details of how you would like to use the scale,
• If two or more response options are selected, the and which countries the scale will be used in.
response option with the highest score should be
recorded
References
Charman CR, Venn AJ, Williams HC. The Patient-Oriented Eczema Measure: Development and Initial Validation of
a New Tool for Measuring Atopic Eczema Severity From the Patients' Perspective.
Arch Dermatol. 2004;140:1513-1519
Charman CR, Venn AJ, Ravenscroft JC, Williams HC. Translating Patient-Oriented Eczema Measure (POEM) scores into clinical
practice by suggesting severity strata derived using anchor-based methods.
Br J Dermatol. Dec 2013; 169(6): 1326–1332.
© The University of Nottingham. The Patient Oriented Eczema Measure (POEM) scale is free to use. Permission is
granted to reproduce and/or redistribute this material in its entirety without modification. Any use which falls outside this
remit requires the express consent of the copyright owner.
Fig. 16.4 (Continued)
Types of instruments available Generic instruments

for measuring QoL Generic QoL instruments can be used for the measure-
A simple way of measuring QoL in children is asking ment of QoL in all kinds of diseases as well as in the gen-
patients or their proxy ‘How does your atopic dermatitis eral population. In theory, the use of generic instruments
affect your daily life/the life of your child?’. A single‐ such as the EuroQoL (EQ) – 5D [65] allows comparison of
item question, however, is often less reliable. In order to data across diseases in any specialty, making them par-
collect QoL data in a more comprehensive and system- ticularly useful for health economists to estimate and
atic way, reliable and valid multiple‐item QoL instru- compare the cost‐effectiveness of a treatment for one dis-
ments may be required. In general, QoL instruments can ease against another. Generic instruments, however, may
be distinguished into generic and specific QoL instru- not have been designed with reference to dermatology
ments that are self‐reported or proxy‐reported. and therefore may not capture all aspects that are important
to patients with skin diseases. Multiple generic instru- diseases, such as cystic fibrosis, asthma, diabetes or
ments exist in paediatrics [66], however, data on their use epilepsy, although sample sizes were small [72]. The
in dermatology or AD are sparse. One German study results of this study also showed a reasonably good agree-
examined generic QoL in a population‐based sample of ment between the child’s and parents’ scores on the CLQI
6518 11‐ to 17‐year‐old children/adolescents [67], using a and the dermatology‐specific Children’s Dermatology
revised version of the KINDL (Kindliche Lebensqualität, Life Quality Index (CDLQI [73], see next section).
paediatric quality of life) questionnaire [68]. KINDL‐R
has 24 items and assesses QoL in six dimensions: physical
well‐being, emotional well‐being, self‐worth, well‐being
Evaluation of quality‐of‐life
in the family, well‐being related to friends/peers, and
instruments for children with
school‐related well‐being. A significant impact of AD in
atopic dermatitis
the past 4 weeks remained even when a number of covari- A systematic review of QoL measurement instruments
ates including atopic comorbidity and mental health were for infants, children and adolescents with AD reported
ATOPIC DERMATITIS
controlled for. on the results of 17 studies that evaluated the measure-

ment properties of different QoL instruments for chil-
SECTION 3:
Specific instruments dren with AD [74]. The aim of this systematic review
Specific instruments include dermatology‐specific was to identify the single best currently available instru-
and disease‐specific instruments. Dermatology‐specific ment to assess QoL in infants, the single best currently
instruments were designed for all kinds of skin diseases. available instrument to assess QoL in children, and the
They are generic to dermatology and, in theory, allow for single best currently available instrument to assess QoL
comparison across skin diseases. Disease‐specific instru- in adolescents with AD. Studies that were eligible for
ments were developed for, and at the same time limited inclusion were instrument development and validation
to, a specific skin disease. Disease‐specific instruments studies of dermatology‐ and disease‐specific (i.e. AD‐
may be most informative in clinical research as these specific) QoL instruments in which at least 50% of the
instruments are more sensitive to the patients’ health sta- patients were AD patients younger than 16 years of age,
tus under study. Disease‐specific instruments may also or subgroup analysis was done for AD patients. The
provide relevant and detailed information that can be review authors assessed the measurement properties of
used to inform patient management. five QoL instruments that fulfilled the strict eligibility
criteria: Childhood Atopic Dermatitis Impact Scale
Proxy‐reported instruments (CADIS) [1,75], Children’s Dermatology Life Quality
Proxy‐reported instruments (i.e. instruments that are com- Index (CDLQI) [73], Childhood Impact of Atopic
pleted by someone other than the child) are frequently Dermatitis (CIAD) [76], DISABKIDS Atopic Dermatitis
used as substitutes for the child’s rating when children are Module (DISABKIDS‐ADM) [77], and Infants’ Dermatitis
not able to complete the instrument by themselves or have Quality of Life Index (IDQoL) [56].
difficulty understanding the questions. The opinions of
parents, family members or caregivers may not adequately Dermatology‐specific instruments
reflect the impact of disease on patients’ QoL. There is no to measure QoL in children with atopic
clear consensus about the validity of using a proxy in the dermatitis [78]
assessment of childhood QoL. In the literature, differences The Children’s Dermatology Life Quality Index
between the responses of the child and parent(s) have (CDLQI)
been reported [69,70]. A previous systematic review deter- The CDLQI has been developed for children with skin
mined the relationship between ratings of children’s QoL diseases aged between 4 and 16 years. It is a self‐reported
made by parents and children [71]. Of the included stud- instrument, consisting of 10 items covering six domains.
ies, three studies assessed whether parents perceived the Answers can be given on a 4‐point Likert scale and sum
illness to have a greater impact on their child’s QoL than scores are calculated (range: 0–30), with higher scores
did the child, but no clear conclusions could be drawn having greater impact on QoL. It takes less than 2 minutes
[71]. The level of agreement between the parent’s rating for the child to complete and a cartoon version is availa-
and the child’s ratings may vary depending on the QoL ble [79]. The recall period is 1 week [73]. There are no
aspect assessed; in general, there was greater agreement charges for nonfunded studies. The CDLQI is available in
for observable constructs, such as physical functioning or translation in more than 50 language versions and differ-
symptoms, than with nonobservable constructs, such as ent language cartoon versions (available from: http://
emotional or social functioning [71]. sites.cardiff.ac.uk/dermatology/quality‐of‐life/
An example of a generic proxy‐reported instrument is childrens‐dermatology‐life‐quality‐index‐cdlqi/). The
the Children’s Life Quality Index (CLQI) [72]. The CLQI CDLQI is the most widely used dermatology‐specific
has been developed for school‐aged children. It consists instrument in AD clinical trials involving children [13].
of 12 questions that relate to the child’s health over the Olsen et al. (2016) presented the results of a meta‐
previous 3 months. The CLQI is available in an English analysis of CDLQI data for different childhood skin
language version. diseases, including children with AD [80]. A total of 67
A cross‐sectional study using the CLQI demonstrated studies were included in the review, involving 7798
that AD has a greater impact on QoL than other chronic children with 20 different skin diseases. The authors

concluded that most skin diseases in children have a consisting of 10 items covering eight domains. Answers
‘small’ mean effect on QoL. However, the range of CDLQI can be given on a 4‐point Likert scale and sum scores
scores was wide, which means that a considerable num- are calculated (range: 0–30). The recall period is 1 week
ber of children may experience major impact on their QoL [56,82]. There is no charge for use in nonfunded studies
because of their skin disease. and routine clinical practice. For pharmaceutical com-
panies, $11.50 per patient is charged. The IDQoL is
available in translation in more than 20 language
Disease‐specific instruments to measure versions (available from: http://sites.cardiff.ac.uk/
QoL in children with atopic dermatitis dermatology/quality‐of‐life/the‐infants‐dermatitis‐
The Childhood Atopic Dermatitis Impact
quality‐of‐life‐index‐idqol/). The IDQoL is the most
Scale (CADIS)
widely used disease‐specific instrument in AD clinical
The CADIS has been developed for children with AD aged
trials involving infants [13].
between 0 and 6 years (and their parents). It assesses both
ATOPIC DERMATITIS
the QoL of the infant or child and the QoL of their parents.
It is a proxy‐reported instrument, consisting of 45/41/33 Quality of the included QoL instruments
SECTION 3:
items (i.e. 45 items in the original version, 41 items in the The results of the aforementioned systematic review
long Italian version, and 33 items in the short Italian ver- showed that of all instruments reviewed, only the US ver-
sion) covering five domains: child symptoms, child activity sion of the CADIS [75] has the potential to be recom-
limitation and behaviour, family and social function, par- mended to measure QoL in children, depending on the
ent sleep, parent emotions. The conceptual model under- results of further validation studies. The internal consist-
pinning the CADIS was developed based on published ency of the CADIS was found to be adequate (Cronbach’s
literature and interviews with both parents and expert cli- alpha values ranged from 0.76 to 0.93 for its domains). It is
nicians. Of note, with 17 of 45 items, the domain ‘parent a reliable instrument with adequate construct validity. The
emotions’ represents an important part of the CADIS. completion time of the 45‐item instrument was also found
Answers can be given on a 5‐point Likert scale. Domain to be acceptable. Measurement error and structural valid-
scores are calculated by summing up item scores of all ity of the CADIS have not yet been investigated. Future
items in one domain. A total score is calculated by sum- validation work should focus on content validity, struc-
ming up the scores of all items. The recall period is 4 weeks tural validity, cross‐cultural validity, measurement error,
[1,75]. There are no administration costs. The CADIS is responsiveness and interpretability of the CADIS [81].
available in US English, Italian and Japanese [74]. Use of the other instruments cannot be recommended
until additional validation studies are conducted [81]. It is of
Childhood Impact of Atopic Dermatitis (CIAD) concern that nearly all existing QoL instruments for infants,
CIAD has been developed for children with AD. It is a children and adolescents with AD are lacking validation
proxy‐reported instrument, consisting of 9/7 items (i.e. data. A major reason for this is that most studies of the meas-
9 items in the Dutch, English (UK), French and German urement properties were of poor methodological quality
versions; 7 items in the English (US) version). The num- (76%). The design and/or statistical methods that were used
ber of domains is not described. The response options to evaluate the instruments (i.e. its measurement properties)
are dichotomous (true/not true). The scoring algorithm were found to be inadequate, meaning that the results of the
is not described and a recall period is not applicable as quality of the instruments (i.e. its measurement properties)
questions are referring to ‘at the moment’. It has not cannot be trusted. In addition, data on the interpretability of
been described if administration costs are charged [76]. the included instruments is lacking [81].
CIAD is available in Dutch, English (UK), English (US), Proxy‐reported instruments, including the CADIS, may
French and German [81]. be particularly useful in infants and younger children;
however they are less suitable for older children and ado-
The DISABKIDS Atopic Dermatitis Module lescents. For these age groups, a self‐reported instrument
(DISABKIDS‐ADM) is recommended. However, the self‐reported instruments
The DISABKIDS‐ADM has been developed for children and that were included in the review (i.e. the CDLQI and the
adolescents with AD. It is a self‐ or proxy‐reported instru- DISABKIDS‐ADM) do not have the potential to be recom-
ment, consisting of 12 items covering two domains. Answers mended as they lack validation data. Further, these instru-
can be given on a 5‐point Likert scale (and ‘not applicable’). ments are intended for use in adolescents and not in
For each domain, a mean standardized score can be calcu- children. The review authors stated that factors influenc-
lated (range: 0–100). The recall period is not described. It is ing adolescents’ QoL are fundamentally different from
not clear if administration costs are charged [77]. The those observed in children [81].
DISABKIDS‐ADM is available in Brazilian, Portuguese and
other languages that were not further specified [81]. Conclusions of the systematic review
of QoL measurement instruments
The Infants’ Dermatitis Quality of Life Index for infants, children and adolescents
(IDQoL) with atopic dermatitis
The IDQoL has been developed for infants with AD The authors of the systematic review of QoL measure-
aged under 4 years. It is a proxy‐reported instrument, ment instruments for infants, children and adolescents
with AD reported on the quality of the measurement first measurement instrument to assess the impact of AD
instruments. They concluded that at present there is no on family QoL [86] and the instrument most frequently
self‐reported QoL instrument for children with AD that used in clinical trials in AD [13]. It is a 10‐item AD‐specific
can confidently be recommended for use in AD clinical QoL questionnaire which was developed based on
trials without further research. The review authors sug- ethnographic focus groups and interviews that revealed
gested using the proxy‐reported CADIS for infants and the areas impacted by AD. Items cover the impact of
younger children with AD for the time being, depending helping with treatment on the main caregiver’s life, rela-
on the results of future validation studies. They recom- tionships, emotional distress, shopping, expenditure,
mended that future validation studies should focus on leisure activity, tiredness, sleep, housework and food
the CADIS, and that an evidence base for the validity and preparation. The total score of the DFI ranges from 0 to
interpretability of self‐reported instruments should be 30 with a higher score indicating greater impairment. A
established [81]. systematic review showed that there is evidence for the
construct validity, internal consistency and test–retest
ATOPIC DERMATITIS
reliability as well as responsiveness to change of the DFI,

Towards standardization of outcome but that evidence is missing regarding structural valid-
SECTION 3:
reporting for quality of life in atopic ity and interpretability [87]. In 2007, the Family
dermatitis Dermatology Life Quality Index (FDLQI) became avail-
The results of the meta‐analysis by Olsen et al. indicated able as a dermatology‐specific measurement instrument
that the CDLQI was the most frequently used instrument of the family impact of skin disease [88]. Evidence for its
to measure QoL in children with AD [80]. It seems to be validity is much more rigorous compared to the DFI
reliable, valid and responsive to change in skin diseases [89]. A small study demonstrated evidence for a correla-
[83]. Although the CDLQI is most commonly used, the tion between the FDLQI and the DFI of moderate
results of the systematic review by Heinl et al. suggested strength [90].
that the CDLQI cannot currently be recommended as an There are other instruments available to assess the
instrument of choice as it is lacking validation data in family impact of AD. The Childhood Atopic Dermatitis
children with AD. Impact Scale (CADIS) [75,78] has already been described.
HOME is currently working towards selecting the It puts more emphasis on emotional impact compared to
most appropriate instrument to measure QoL in children the IDLQI, CDLQI and DFI and is the only instrument
with AD in clinical trials. A future research agenda has that assesses the multidimensional effect of AD on both
been set to perform additional validation studies on parents and children. The development of the Parents’
instruments that have the potential to be included in the Index of Quality of Life in Atopic Dermatitis (PI‐QoL)
core outcome set. By using the single best QoL instru- [91,92] conceptually started from a needs‐based model,
ment in all clinical trials in children with AD, standardi- meaning that the instrument assesses how AD interferes
zation in QoL outcome measurement will be enhanced. with the fulfilment of needs rather than measuring
This allows for comparisons and pooling results in sys- impairments (symptoms) and disability (functioning). It
tematic reviews and meta‐analyses, which will lead to thus provides complementary information to existing
an improvement of evidence‐based healthcare decisions instruments. The PI‐QoL is unidimensional and has 28
in the treatment of children with AD. Further validation items. One advantage is that it has been developed and
studies should be undertaken when using instruments validated in several countries simultaneously (UK,
in other countries or ethnic groups differing from the Netherlands, Italy, Germany, France, US and Spain). The
original study group. When translating questionnaires Quality of Life in Primary Caregivers of Children with
into other languages, it is important to obtain at least AD (QPCAD) instrument was developed in Japan [93].
two backward and forward translations to avoid errors The rationale for its development was that instruments
of misunderstanding. such as the DFI and the PI‐QoL only include negative
items and lack positive items (such as pleasure in life)
and that the inclusion of positive items may help to
Instruments to measure family impact
assess QoL more accurately [94]. It has 19 items and
of atopic dermatitis
assesses health‐related QoL in the domains ‘worry about
The field of paediatric health‐related QoL is changing atopic dermatitis’, ‘achievement’, ‘family cooperation’
rapidly and can add much to our knowledge of the and ‘exhaustion’. Another questionnaire has been devel-
impact that skin disease has on children and their fami- oped and validated in Germany [95]. It is a 26‐item
lies. The impact of illness on family/carers is multifac- instrument that assesses health‐related QoL in five
eted, encompassing social activities, leisure time, domains: psychosomatic well‐being, impact on social
education and work, as well as financial, emotional and life, satisfaction with medical care, emotional coping
family relationships, with some of these themes such as with illness, and acceptance of illness. It is currently
social, financial and emotional impact being intercon- unclear which of these instruments best captures the
nected [84]. In dermatology, other family members impact of AD on primary caregivers. A systematic review
affected by a skin disease of one family member have is underway to compare the quality of these instruments
been referred to as the ‘greater patient’ [85]. The (www.crd.york.ac.uk/PROSPERO/display_record.
Dermatitis Family Impact (DFI) questionnaire was the asp?ID=CRD42015027481).
Conclusion 3 Charman C, Chambers C, Williams H. Measuring atopic dermatitis

severity in randomized controlled clinical trials: what exactly are we
Capturing disease severity by clinical signs, patient measuring? J Invest Dermatol 2003;120:932–41.
4 Schmitt J, Langan S, Williams HC. What are the best outcome meas-
reports of symptoms and patient reports of QoL all pro- urements for atopic eczema? A systematic review. J Allergy Clin
vide important information on distinct aspects of AD. Immunol 2007;120:1389–98.
This is reflected by the fact that the HOME initiative has 5 Schmitt J, Langan S, Deckert S et al. Assessment of clinical signs of
reached consensus that these – and long‐term control of atopic dermatitis: a systematic review and recommendation.
flares – be part of the Core Outcome Set (COS) for AD 6 Hanifin JM, Thurston M, Omoto M et al. The eczema area and sever-
clinical trials, meaning that these domains should be ity index (EASI): assessment of reliability in atopic dermatitis. EASI
assessed as a minimum in all future AD clinical trials. Evaluator Group. Exp Dermatol 2001;10:11–18.
7 Berth‐Jones J. Six area, six sign atopic dermatitis (SASSAD) severity
However, substantial variation remains in the way dis- score: a simple system for monitoring disease activity in atopic der-
ease severity – both clinical signs and symptoms – and matitis. Br J Dermatol 1996;135(Suppl 48):25–30.
QoL are actually measured. Systematic reviews of meas- 8 Severity scoring of atopic dermatitis: the SCORAD index. Consensus
ATOPIC DERMATITIS
urement properties and consensus methodology are Report of the European Task Force on Atopic Dermatitis. Dermatology
1993;186:23–31.
suitable to identify appropriate measurement instru- 9 Costa C, Rilliet A, Nicolet M, Saurat JH. Scoring atopic dermatitis: the
SECTION 3:
ments. It is required that these instruments meet quality simpler the better? Acta Derm Venereol 1989;69:41–5.
standards based on validation studies of high methodo- 10 Rehal B, Armstrong AW. Health outcome measures in atopic dermati-
tis: a systematic review of trends in disease severity and quality‐of‐
logical quality. For measuring clinical signs in trials, the
life instruments 1985‐2010. PLoS One 2011;6:e17520.
HOME initiative has determined that the EASI is the 11 Hill MK, Kheirandish Pishkenari A et al. Recent trends in disease
best available instrument. The SCORAD index has also severity and quality of life instruments for patients with atopic
been extensively validated and is widely used. For dermatitis: A systematic review. J Am Acad Dermatol 2016;
75:906–17.
measuring symptoms in AD clinical trials, HOME 12 Gerbens LA, Chalmers JR, Rogers NK et al. Reporting of symptoms in
has identified POEM as the best available instrument, randomized controlled trials of atopic eczema treatments: a system-
although some measurement properties remain to be atic review. Br J Dermatol 2016;175:67886.
investigated. For quality of life, a variety of instruments 13 Heinl D, Chalmers J, Nankervis H, Apfelbacher CJ. Eczema trials:
quality of life instruments used and their relation to patient‐
exist with systematic reviews suggesting the CADIS as reported outcomes. A systematic review. Acta Derm Venereol 2016;
a promising proxy instrument to assess QoL in children 96:596–601.
with AD. Concerning the impact of children’s AD on the 14 Roekevisch E, Spuls PI, Kuester D et al. Efficacy and safety of systemic
treatments for moderate‐to‐severe atopic dermatitis: a systematic
QoL of their family, it is still unclear which instrument review. J Allergy Clin Immunol 2014;133:429–38.
should be used to measure this outcome. However, the 15 De Vet HC, Terwee CB, Mokkink LB, Knol DL. Measurement in
DFI questionnaire is the most widely used instrument. Medicine: A Practical Guide. Cambridge University Press, 2011.
It may be useful to include several different health‐ 16 Mokkink LB, Terwee CB, Patrick DL et al. The COSMIN study reached
international consensus on taxonomy, terminology, and definitions of
related QoL scales in order to capture the maximum measurement properties for health‐related patient‐reported out-
number of data for certain types of studies. Ideally, par- comes. J Clin Epidemiol 2010;63:737–45.
allel proxy and child data should be collected and, in 17 Boers M, Kirwan JR, Tugwell P et al. The OMERACT Handbook 2016.
Available at: https://omeract.org/resources (accessed 14 January
future, different scales should be devised for use in 2019).
infants, young children, preteens and teenagers. 18 Prinsen CA, Vohra S, Rose MR et al. How to select outcome measure-
As the recommendations made by the HOME initia- ment instruments for outcomes included in a “Core Outcome Set” – a
tive focus on clinical trials, they are particularly useful for practical guideline. Trials 2016;17:449.
19 Leshem YA, Hajar T, Hanifin JM, Simpson EL. What the Eczema
researchers. Even though the recommended measurement Area and Severity Index score tells us about the severity of atopic
instruments can also be used in clinical practice, dermatitis: an interpretability study. Br J Dermatol 2015; 172:1353–7.
clinicians may prefer shorter and simpler instruments as 20 Terwee CB, Bot SD, de Boer MR et al. Quality criteria were proposed
for measurement properties of health status questionnaires. J Clin
feasibility aspects play a much more important role in
Epidemiol 2007;60:34–42.
routine clinical care than in clinical trials. Clear recom- 21 Schmitt J, Williams H. Harmonising Outcome Measures for Eczema
mendations for the measurement of disease severity and (HOME). Report from the First International Consensus Meeting
QoL in clinical practice are currently lacking. For the (HOME 1), 24 July 2010, Munich, Germany. Br J Dermatol 2010;
163:1166–8.
time being, we recommend that clinicians who seek to 22 Schmitt J, Apfelbacher C, Spuls PI et al. The Harmonizing Outcome
implement a measurement instrument for disease Measures for Eczema (HOME) roadmap: a methodological frame-
severity, symptoms or QoL in clinical practice use the work to develop core sets of outcome measurements in dermatol-
recommendations of the HOME initiative as guidance. ogy. J Invest Dermatol 2015;135:24–30.
23 Wolkerstorfer A, de Waard van der Spek FB, Glazenburg EJ et al.
Nevertheless, other instruments may be used when Scoring the severity of atopic dermatitis: three item severity score as a
feasibility aspects are an obstacle to the use of the recom- rough system for daily practice and as a pre‐screening tool for studies.
mended instruments. Acta Derm Venereol 1999;79:356–9.
24 Vourc’h‐Jourdain M, Barbarot S, Taieb A et al. Patient‐oriented
SCORAD: a self‐assessment score in atopic dermatitis. A preliminary
feasibility study. Dermatology 2009;218:246–51.
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228
CHA PTER 1 7
Atopic Dermatitis and Related Disorders:

Special Types of Presentation
Nawaf Almutairi
Department of Medicine, Faculty of Medicine, Kuwait University, Kuwait
Pityriasis alba, 228 Infantile seborrhoeic dermatitis, 237 Prurigo pigmentosa, 244
ATOPIC DERMATITIS
Pompholyx, 231 Lichen simplex chronicus, 240

Nummular dermatitis, 235 Prurigo nodularis, 242
SECTION 3:
Abstract may be followed by scaling and lichenification of the skin. Num-

mular eczema is characterized by formation of pruritic discoid
plaques commonly affecting the extensor surfaces of the limbs.
There are several dermatoses that are thought to be related to
Another type of dermatitis is seborrhoeic dermatitis that presents
atopic dermatitis. These include pityriasis alba, seborrhoeic der-
in areas of the skin that are rich in sebaceous glands. Lesions are
matitis, nummular eczema, pompholyx and prurigo. Pityriasis alba
erythematous, scaly plaques or take the form of cradle cap. Lichen
is characterized by hypopigmented patches that are covered with
simplex chronicus and prurigo are highly pruritic lesions that occur
fine scales mainly localized on the face. It could be considered as a
as a result of excessive itching of the skin. Corticosteroids in addi-
minor criterion for diagnosis of atopic dermatitis. Pompholyx usu-
tion to calcineurin inhibitors are the main treatment.
ally appears as deep‐seated vesicles or bullae, located mainly or
commonly on the edges of the fingers, toes, palms and soles. It
Key points • The incidence of pityriasis alba is significantly higher in those

with a history of AD.
• Pompholyx may be responsible for up to 20% of cases of hand
• Up to 10% of infants suffer from one or other form of eczema.
eczema seen in adults. However, it is less common in children.
• Atopic dermatitis (AD) is the most common chronic skin disorder
• Nummular dermatitis is characterized by coin‐shaped lesions
seen in children.
and is more commonly seen in adult males.
• AD is the most common form of eczema seen in children.
• Nummular lesions are the most common nontypical
• AD is not curable, but half of the children affected improve
morphological variants of AD.
between the ages of 5 and 15.
• Lichen simplex chronicus in children is more likely to occur in boys.
• About one quarter of children with AD may have associated
• Prurigo nodularis may be a primary cutaneous disease or a
food allergies.
secondary reaction to pruritus and scratching provoked by a
• Infantile seborrhoeic dermatitis usually clears on its own within
separate cause.
weeks to a few months.
Pityriasis alba
Definition. Pityriasis alba (PA) is a chronic, benign, Epidemiology. PA is reported from all around the world,
inflammatory dermatosis resulting in disordered pig affecting about 1% of the general population. It most
mentation characterized by hypopigmented patches, and frequently affects children aged from 3 to 16 years [7,8].
thin plaques with fine scale [1,2]. It is usually localized on The incidence of PA in children ranges from 1.9% to
the face, trunk and extensor surfaces of arms and legs in 9.9%, but is higher in populations with darker skin pho
children. PA is strongly associated with atopy [3]. It is totypes [9–11]. The role of sex in its incidence has not
considered a minor criterion for diagnosing atopic been established [9,12]. Seasonal variation does occur,
dermatitis (AD) [4]. In the literature, PA is referred to as with the lesions becoming more conspicuous in summer
pityriasis streptogenes, pityriasis simplex faciei, pseudo months when the affected areas do not tan like the sur
leucoderma atopicum, erythema streptogenes, impetigo rounding skin [1,2]. The incidence of PA in patients with
furfuracea, impetigo pityroides, impetigo sicca and pityriasis a history of AD is significantly higher than in the general
maculata [5,6]. population [13].
Chapter 17 Atopic Dermatitis and Related Disorders: Special Types of Presentation 229
microscopic examination of the lesions has revealed

Pathogenesis. The exact aetiology of PA is not known.
degenerative changes in some melanocytes, and a reduced
However, various factors have been implicated. Atopic
number of melanosomes in the keratinocytes [27]. Due to
diathesis has commonly been described as a pathogenic
the similarity of hypopigmentation in PA to postinflam
factor in PA [14], and some authors believe that PA is a
matory hypopigmentation, some have considered PA to
healing AD, where there is regression of the inflamma
be a residual postinflammatory manifestation of AD.
tion, thus leading to hypomelanosis [15]. A hypothesis
Carneiro et al., in their study on dermal dendrocytes of
has been raised that PA and AD are different clinical forms
PA, rolled out this suggestion because, if this were the
within the spectrum of atopy, wherein a patient with a
case, a minimal amount of dendritic cells similar to the
history of atopic disease could develop either towards the
number found in normal skin would be present [16].
AD pole (more inflammatory) or the PA pole (less inflam
matory) [16].
Clinical features. PA is a long‐term, multistage
Microorganisms such as Pityrosporum, Streptococcus,
condition. The early lesions take the form of mildly
ATOPIC DERMATITIS
Aspergillus and Staphylococcus in addition to parasitic fac
erythematous, slightly scaly thin plaques with ill‐defined
tors (Ascaris) have been suggested as causal factors, but
margins; there are usually one to several lesions. PA
SECTION 3:
no relationship has been confirmed [17]. Other contribu
lesions typically last for several weeks [3]. During the
tory factors, such as temperature variations, relative air
following stage, erythema subsides, leaving behind
humidity and altitude, have also been implicated. Also,
smooth scales. Clearly defined areas of hypopigmenta
because of the location of lesions – typically in the areas
tion and scaling off at the edges are observed at this
exposed to sunlight – it has repeatedly been associated
stage [1,2,5]. The face, particularly the cheeks, is the
with overexposure to light [18,19].
most commonly involved site in children [1], although
In addition, a positive correlation between some per
the lateral arms, shoulders, neck and anterior thighs
sonal hygiene habits and PA has been recorded. Long and
may also be affected [1–3]. The lesions of PA are typically
frequent baths, mechanical exfoliation and other similar
asymptomatic, although pruritus may accompany the
treatments may contribute to the development of lesions;
condition [2,28] (Figs 17.1 and 17.2). Generalized PA,
this is attributed to the reduction in the level of defensins
with widespread lesions, is usually seen in young adults,
and skin‐protecting factors [1,20]. In contrast, Inanir et al.
and has been reported by Zaynoun et al. [25].
reported an increased incidence of PA in schoolchildren
Previously, other defined clinical variants of PA included
with low parental income that is associated with poor
the extensive and the pigmenting types [25]. The exten
housing conditions and poor hygiene including frequent
sive type is a less common disease variant. It affects
intestinal parasites [10].
teenagers and young adults, more often females, and con
Some nutritional deficiencies are thought to be con
sists of single, symmetrical lesions that are larger than
nected to the disease. Low levels of serum copper may
those seen in the classical variants. It is not limited to the
account for PA because copper is important in activation
face but involves the neck, trunk and shoulders [25,29].
of tyrosinase in melanocytes, which is critical to melanin
The lesions of pigmenting PA are bluish and are sur
production [21]. Azelaic acid, oxalic acid and other metab
rounded by a halo of depigmented skin. There are usually
olites of Malassezia furfur yeasts that normally colonize
numerous lesions, located on the forehead and cheeks
healthy skin may also cause tyrosinase inhibition [19].
[23,30–32].
Pathology. Skin affected by PA shows a nonspecific pic Course and prognosis. If left untreated, PA tends to be a
ture consisting of spongiosis with exocytosis, hyperkera relatively chronic condition with frequent relapses and a
tosis and dermal perivascular lymphocytic infiltration variable course. The lesions usually persist for several
[3,20,22]. However, these findings may not be helpful in months to a few years [5,8], become more obvious in sum
the diagnosis of PA. It is known that the main findings are mer due to tanning of surrounding skin, and tend to
in the pilar apparatus. The early stages usually show become dry, scaly and inflamed in winter months [3].
follicular plugging, follicular spongiosis and atrophic Although the disease most often resolves spontaneously
sebaceous glands [23], whereas late stages may show prior to adulthood, repigmentation is a slow process that
regression of keratotic aggregates in hair follicles, mild may take months to years to complete. Although PA is
acanthosis, slight spongiosis and sebaceous gland atro chronic and often a cosmetic burden, it is not associated
phy; in some cases the glands are almost completely with any complications or permanent disfigurement [2,3].
absent. The inflammatory infiltrate is predominantly
lymphohistiocytic [24].
Regarding the number of melanocytes in the lesions of Differential diagnosis. The diagnosis of PA is made clinically,
PA, some authors reported them to be fewer in number although certain laboratory tests (e.g. potassium hydroxide
than in the adjoining normal skin, and have suggested preparation) may be used to help differentiate it from
that this might be the possible cause of hypopigmentation other conditions. Biopsy is seldom indicated. Vitiligo
seen in PA [22,25]. On the other hand, some authors have lesions are more sharply demarcated than the lesions of
indicated the number of melanocytes to be normal [26] or PA and completely lack scale and pigment [5]. White
variable [22]. Melanophages have been rarely recorded, patches are accentuated by Wood’s lamp examination
most typically in the papillary dermis [22]. Electron due to complete depigmentation [8,33,34].
ATOPIC DERMATITIS
Fig. 17.1 Pityriasis alba in a 9‐year‐old child characterized by facial annular hypopigmentation and scaling.
SECTION 3:
That is the reason why tacrolimus is effective when

applied to hypopigmented areas of PA [37].
Pimecrolimus, another calcineurin inhibitor, has a
comparable effect. Topical application of 1% cream

significantly reduces itching, peeling, and extension of
hypopigmented areas [2]. Pimecrolimus therapy is pre
ferred because of a rarely reported burning sensation
with tacrolimus application. However, both products are
safe and should be preferred over glucocorticoids, par
ticularly in the case of longlasting lesions on the face.
Although there is no clear relationship between these
drugs and the occurrence of skin infections, a few cases of
molluscum contagiosum and herpes have been reported
during treatment (especially with tacrolimus) [38].
Calcitriol therapy also provides promising results. Its
efficacy is comparable to that of tacrolimus [28]. In addition
Fig. 17.2 Severe form of pityriasis alba on the face of an infant. to its regulatory effect on cell proliferation [39], topical
calcitriol is able to restore epidermal permeability and
the antimicrobial barrier by increasing epidermal and
antimicrobial peptides [40]. These features could account
Pityriasis versicolor can be differentiated from PA using
for its effect in treating PA lesions. Profound improve
potassium hydroxide preparation, which reveals spores
ment of PA was also observed after 308‐nm excimer laser
and hyphae of mycelium. Wood’s lamp examination may
phototherapy [41].
also be helpful, and it shows yellow fluorescence. Disease
differentiation between psoriasis and PA is based on References
patient history and the presence of the typical scaly 1 Weber BM, Sponchiado de Avila LG, Albaneze R et al. Pityriasis
plaques manifested in psoriasis [33,35]. Naevus depig alba: a study of pathogenic factors. J Eur Acad Dermatol Venereol
2002; 16:463–8.
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often present at birth and usually becomes more visible at evaluate the efficacy of pimecrolimus cream 1 % for the treatment of
the age of 3 years. It may affect the whole body, and often pityriasis alba. Int J Dermatol 2007;46:700–5.
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of pityriasis alba. Indian J Dermatol Venereol Leprol 2002;68:338–40.
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PA using diascopy [24]. Derm Venereol Suppl (Stockh) 1980;92:44–7.
The differential diagnosis should also include leprosy, 5 Lin RL, Janniger CK. Pityriasis alba. Cutis 2005;76:21–4.
6 O’Farrell NM. Pityriasis alba. Cutis 1996;61:11–13.
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course of inflammatory skin conditions [8,33] and myco Derm Venereol 1992;872:360.
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an enigmatic disorder of childhood. Cutis 2011;87:66–72.
9 Elfaituri SS. Pediatric dermatoses in Benghazi, Libya. Indian J Pediatr
Treatment. Many treatments for PA have been suggested. Dermatol 2015;16:64–71.
If inflammation is present, mild to potent topical corti 10 Inanir I, Sahin MT, Geundeuz K et al. Prevalence of skin conditions in
costeroids may be used [8]. Other authors suggest topical primary school children in Turkey: differences based on socioeco
nomic factors. Pediatr Dermatol 2002;19:307–11.
tacrolimus 0.1%, a calcineurin inhibitor, to be effective. As well
11 Fung WK, Lo KK. Prevalence of skin disease among school children
as its anti‐inflammatory properties, it has an activating effect and adolescents in a student health service center in Hong Kong.
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12 Dogra S, Kumar B. Epidemiology of skin disease among school chil

dren: a study from northern India. Pediatr Dermatol 2003;20:470–3.
Pompholyx
13 Brenninkmeijer EE, Spuls PI, Legierse CM et al. Clinical differ-
ences between atopic and atopiform dermatitis. J Am Acad Dermatol Definition. Pompholyx, or dyshidrotic eczema, is a
2008; 58:407–14. chronic relapsing form of dermatitis characterized by the
14 Johnke H, Vach W, Norberg LA et al. A comparison between criteria for
diagnosing atopic eczema in infants. Br J Dermatol 2005;153:352–8.
formation of pruritic, small, deep‐seated, clear ‘sagolike’
15 Schmid‐Grendelmeier P, Simon D, Simon HU et al. Epidemiology, clini fluid‐filled vesicles or bullae that appear most commonly
cal features, and immunology of the “intrinsic” (non‐IgE‐mediated) type on the edges of the fingers, toes, palms and soles [1]. Later
of atopic dermatitis (constitutional dermatitis). Allergy 2001;56:841–9. on, scaling, fissures and sometimes lichenification of the
16 Carneiro F, Mendes M, Amaral G, Quaresma J. Tissue immunostain
ing for factor XIIIa in dermal dendrocytes of pityriasis alba skin skin may occur [2,3]. It is also known as dyshidrosis or
lesions. An Bras Dermatol 2014;89:245–8. vesicular eczema of palms and soles. If pompholyx occurs
17 Zaki S, El Mansy M, El Shazly M. Bacteriological studies of pityriasis mainly on the palmar surface of the palms, the term chei
alba. Int J Infect Dis 2010;14:S32–3.
18 Blessmann Weber M, Sponchiado de Avila LG, Albaneze R et al.
ropompholyx may be applied, and if it occurs on the soles
and sides of the toes it is called podopompholyx. Some
ATOPIC DERMATITIS
Pityriasis alba: a study of pathogenetic factors. J Eur Acad Dermatol
Venereol 2002;16:463–8. authors believe that the terms pompholyx and dyshidro
19 Burkhart CG, Burkhart CN. Pityriasis alba: a condition with possible sis are obsolete and favour a new term such as ‘acute and
SECTION 3:
multiple etiologies. Open Dermatol J 2009;3:7–8.
20 In SI, Yi SW, Kang HY et al. Clinical and histopathological
recurrent vesicular hand dermatitis’ [4].
characteristics of pityriasis alba. Clin Exp Dermatol 2009;34:591–7.
21 Galadari E, Helmy M, Ahmed M. Trace elements in serum of pity
Epidemiology. Pompholyx occurs in 5–20% of patients
riasis alba patients. Int J Dermatol 1992;31:525–6.
22 Vargas‐Ocampo F. Pityriasis alba: a histologic study. Int J Dermatol with hand eczema [5]. It accounted for less than 1% of
1993;32:870–3. initial consultations in a 1‐year Swedish study [6] whereas
23 Landeck L, Visser M, Kezic S, John SM. Genotype‐phenotype associa Magina et al. found it to be the third most common type
tions in filaggrin loss‐of‐function mutation carriers. Contact
Dermatitis 2013;68:149–55.
of hand dermatitis (20.3%) in Portugal [7]. Dyshidrotic
24 Miazek N, Michalek I, Pawlowska‐Kisiel M et al. Pityriasis alba— eczema affects individuals aged 4–76 years; the mean age
common disease, enigmatic entity: up‐to‐date review of the litera- is 38 years. The peak incidence of the condition is in
ture. Pediatr Dermatol 2015;32:786–91. patients aged 20–40 years. After middle age, the frequency
25 Zaynoun ST, Aftimos BG, Tenekjian KK et al. Extensive pityriasis
alba: a histological histochemical and ultrastructural study. Br J of dyshidrotic eczema episodes tends to decrease [8,9]. It
Dermatol 1983;108:83–90. is equally common in male and female individuals.
26 Weedon D. Disorders of Pigmentation, 2nd edn. London: Churchill Pompholyx can be affected by seasonal changes, hot and
Livingstone, 2002:321–41.
27 In S, Yi S, Kang H et al. Clinical and histopathological characteris-
cold temperatures, and is usually worse in the spring and
tics of pityriasis alba. Clin Exp Dermatol 2008;34:591–7. summer months (seasonal or summer pompholyx) [1].
28 Moreno‐Cruz B, Torres‐Álvarez B, Hernández‐Blanco D et al. Double‐
blind, placebo‐controlled, randomized study comparing 0.0003 % cal
Pathogenesis. The exact cause of pompholyx is not yet
citriol with 0.1 % tacrolimus ointments for the treatment of endemic
pityriasis alba. Dermatol Res Pract 2012;2012:303275. identified. Various factors have been implicated in its
29 Di Lernia V, Ricci C. Progressive and extensive hypomelanosis and causation and/or aggravation [9,10]. The hypothesis of
extensive pityriasis alba: same disease, different names? J Eur Acad sweat gland dysfunction has been disputed because ves
30 Hacker SM. Common disorders of pigmentation: when are more than icles have not been shown to be associated with sweat
cosmetic cover ups required? Postgrad Med 1996;99:177–86. ducts [11]. Thus, the term ‘dyshidrotic eczema’ is consid
31 du Toit MJ, Jordaan HF. Pigmenting pityriasis alba. Pediatr Dermatol ered a misnomer. Dyshidrotic eczema may be associated
1993;10:1–5.
with atopy and familial atopy. Of all the patients with
32 Dhar S, Kanwar AJ, Dawn G. Pigmenting pityriasis alba. Pediatr
Dermatol 1995;12:197–8. dyshidrosis, 50% are found to have AD. The serum
33 Dıaz Uribe LH. Pitiriase alba: aspectos epidemiologicos, clinicos e immunoglobulin E (IgE) level frequently is increased,
terapeuticos. An Bras Dermatol 2000;75:359–67. even in patients who do not report a personal or familial
3 4 Khalifa ES, Adil AN, Haitham MS. Pityriasis alba versus viti
ligo. J Saudi Soc Dermatol Dermatol Surg 2013;17:51–4.
history of atopy. Occasionally, dyshidrotic eczema is the
35 Aljabre SH, Alzayir AA, Abdulghani M et al. Pigmentary changes of first manifestation of an atopic diathesis [5].
tinea versicolor in dark‐skinned patients. Int J Dermatol 2001;40: Current knowledge suggests the role of a genetic factor
273–5. in pathogenesis of pompholyx. Monozygotic twins have
36 Kang HY, Choi YM. FK506 increases pigmentation and migration of
human melanocytes. Br J Dermatol 2006;155:1037–40. been found to be simultaneously affected. The pompho
37 Rigopoulos D, Gregoriou S, Charissi C et al. Tacrolimus ointment lyx gene has been mapped to band 18q22.1–18q22.3 in the
0.1% in pityriasis alba: an open‐label, randomized, placebo‐con autosomal dominant form of familial pompholyx [12].
trolled study. Br J Dermatol 2006;155:152–5.
38 Goksugur N, Ozbostanci B, Goksugur S. Molluscum contagiosum
Mutations on the filaggrin gene with loss of filaggrin
infection associated with pimecrolimus use in pityriasis alba. Pediatr leads to dyskeratinization, increased transepidermal
Dermatol 2007;24:E63–5. water loss and an increase in transepidermal antigen
39 Körver J, Vissers W, Van Rens D et al. A double‐blind, randomized transfer [13]. Aquaporins, in particular aquaglyceropor
quantitative comparison of calcitriol ointment and calcipotriol oint
ment on epidermal cell populations, proliferation and differentiation. ins, are expressed in patients with AD and may be related
Br J Dermatol 2007;156:130–7. to exacerbation and chronicity of pompholyx through
40 Hong SP, Oh Y, Jung M et al. Topical calcitriol restores the impairment increasing transepidermal water loss [14].
of epidermal permeability and antimicrobial barriers induced by
Emotional stress [15] is a possible factor in dyshidrotic
corticosteroids. Br J Dermatol 2010;162:1251–60.
41 Al‐Mutairi N, Hadad AA. Efficacy of 308‐nm xenon chloride excimer eczema. Many patients report recurrences of pompholyx
laser in pityriasis alba. Dermatol Surg 2012;38:604–9. during stressful periods. Environmental factors (e.g. seasonal
changes, hot or cold temperatures, humidity) have been frequent cause of pompholyx than that of nickel. However,
reported to exacerbate pompholyx. Pompholyx caused by simultaneous occurrence of both allergies is more
ultraviolet (UV)A exposure may possibly be considered a common [22].
variation of seasonal (summer) pompholyx [16]. Nalluri Other factors including aspirin ingestion, oral contra
and Rhodes suggested the term photoaggravated pom ceptives and cigarette smoking have been reported as pos
pholyx in 2016 [17]. sible causes of inducing or aggravating pompholyx [24].
Sometimes, a distant fungal or candidal infection can
cause palmar pompholyx as an id reaction. Pompholyx
Pathology. In acute lesions, the main features are spongi
occasionally resolves when tinea pedis infection is treated,
osis and intraepidermal vesiculation. There is a mild
then relapses when the fungal infection recurs, support
superficial perivascular lymphohistiocytic infiltrate with
ing the existence of this reaction pattern [18]. Bacterial
exocytosis of lymphocytes into spongiotic zones. However,
and viral infections, especially human immunodeficiency
eosinophils can also be present. The compact, thickened
virus (HIV), can also provoke pompholyx. Pompholyx
ATOPIC DERMATITIS
stratum corneum remains intact, and with normal epider

has also been described as a manifestation of sympto
mal thickness. As lesions progress to chronicity, signs of
matic HIV infection. Some patients do not respond to
SECTION 3:
active inflammation and spongiosis start to diminish,

topical and systemic treatments for pompholyx, and their
acanthosis and parakeratosis predominate, and serum
condition improves only with antiretroviral therapy [19].
may be identified within the stratum corneum [25].
Pompholyx‐like eczematous eruptions with the use of
Features of lichen simplex chronicus may be the hallmark
intravenous immunoglobulin (IVIG) infusions have been
of chronic lesions. A periodic acid–Schiff (PAS) stain
reported, and pompholyx is now identified as one of the
should be performed on vesicular lesions of the palms and
most important cutaneous adverse effects of IVIG, being
soles, because fungal infection may mimic pompholyx his
present in 62.5% of the patients reported, with most of
tologically. The intraepidermal part of the eccrine sweat
them developing the lesions after their first IVIG treat
duct (acrosyringium) is not altered even by spongiosis,
ment [20,21].
although histological study of pompholyx showed that
Exogenous factors (e.g. contact dermatitis to nickel, bal
sweat ducts were often pushed aside by the tense vesicles
sam, cobalt; sensitivity to ingested metals) may trigger
or passed between them [26].
episodes. These antigens may act as haptens with a spe
cific affinity for palmoplantar proteins of the stratum luci
dum of the epidermis. The binding of these haptens to Clinical features. There is a sudden onset of symmetrical
tissue receptor sites may cause systemic allergic dermati crops of vesicles and/or bullae (filled with clear fluid) on
tis and pompholyx [22,23]. Nickel allergy has been con the palms and lateral aspects of the fingers. The feet, the
nected to pompholyx. Increased nickel excretion in the soles and the lateral aspects of toes also may be affected.
urine has been reported during exacerbations of pompho Burning pain or pruritus occasionally may be experienced
lyx. Low‐nickel diets have reportedly decreased the before vesicles appear. Palms and soles may be red and
frequency and severity of pompholyx flares. A high palmo wet with perspiration. Vesicles are deep‐seated and have
plantar perspiration rate has been suggested to result in a a tapioca pudding‐like appearance, without surrounding
local concentration of metal salts that may provoke erythema (Figs 17.3 and 17.4). The vesicles usually persist
the vesicular reaction. The oral ingestion of cobalt is a less for 3–4 weeks. They may become large, form bullae and
Fig. 17.3 Pompholyx affecting the palms of a young boy presenting with crops of tense clear vesicles.
ATOPIC DERMATITIS
SECTION 3:
Fig. 17.4 Pompholyx affecting the distal parts of the fingers in a young boy.
The index was found to be a simple standardized method

for assessing the condition and can be used to assess disease
severity and treatment effectiveness [28].
Prognosis. The lesions appear abruptly and generally

persist for 2–3 weeks. Vesicle outbreaks may occur in
waves [29]. Episodes vary in frequency from once per
month to once per year. Each episode usually lasts for few
days to a few weeks, and subsides spontaneously even
without treatment. Secondary bacterial infection of vesi
cles or bullae can rarely result in cellulitis, lymphangitis
and septicaemia. Dystrophic nail changes may develop,
characterized by transverse ridging, thickening, discol
ouration and pitting. Pompholyx has no associated mor
tality, although some severe cases can cause disability by
Fig. 17.5 Severe form of pompholyx presenting with dense bullae on the compromising the function of the hands due to extensive
palms of a young atopic child. bullae (e.g. in schoolchildren). Hsu et al. in their study
determined that dyshidrosis is a risk factor in the devel
opment of herpes zoster. Because of the strong association
become confluent (Fig. 17.5). Vesicles typically resolve between the two conditions, the authors have suggested
without rupturing, followed by desquamation. Patients that patients should be warned about the risk [30].
with pompholyx may report a variety of factors that pos
sibly are related to eruptions such as emotional stress and Differential diagnosis. Palmoplantar pustulosis (PPP) is
hot weather, and more than 50% of individuals with the a chronic and intensely inflammatory skin disease with
pompholyx type of presentation had an atopic diathesis. pustules, erythema and scaling localized to the palms and
With longstanding disease, fingernails may reveal dys soles. Both PPP and pompholyx share similar clinical as
trophic changes (e.g. irregular, transverse ridging; pitting; well as histological features [2]. Therefore, the differential
thickening; discolouration). Interdigital maceration and diagnosis of these two diseases can be quite frustrating.
desquamation of the interdigital spaces often are present, Several histological features can differentiate between
despite the possible absence of a dermatophyte infection. PPP and pompholyx. The presence of confluent parakera
Secondary infection may lead to pustular or haemor tosis, psoriasiform epidermal hyperplasia, clubbing and
rhagic fluid or crusts associated with the blistering. There anastomosing of the rete ridges, loss of the granular layer,
may be surrounding erythema of the hands with associated tortuous capillaries in the papillary dermis touching
pain rather than the more characteristic itch associated the undersurface of the epidermis and extravasated
with the acute blisters. Cellulitis and lymphangitis may erythrocytes in PPP patients could serve as useful ‘clues’
develop [1,27]. for differentiation [31].
The Dyshidrotic Eczema Area and Severity Index (DASI) Keratolysis exfoliativa is characterized clinically by
was developed based on severity grades for the number of intermittent air‐filled blisters with centrifugal collarette of
vesicles per square centimetre (V), erythema (E), desquama the palms and soles. It is histopathologically characterized
tion (S), itch (I), and the extent of affected areas (A) with by cleavage within the stratum corneum and partial degra
defined score points (p) as: DASI = (pV + pE = pS + pI) × pA. dation of corneodesmosomes in the mid stratum corneum;
normal expression of corneodesmosomal components is phosphodiesterase‐4 (PDE4) inhibitors, alitretinoin and

reported by immunofluorescence [32]. Dyshidrosiform phototherapy with high‐dose UVA‐1 and UV‐free photo
pemphigoid may have vesicles (vesicular pemphigoid) or therapy have been introduced [3].
be evident as erythema and swelling with bullae on the
palmoplantar areas [33]. Histopathology and immunofluo References
rescence findings are of help in making the diagnosis. 1 Wollina U. Pompholyx: a review of clinical features, differential
diagnosis, and management. Am J Clin Dermatol 2010;11: 305–14.
Pompholyx may be differentiated from blistering fungus
2 Veien NK. Acute and recurrent vesicular hand dermatitis. Dermatol
infection by scraping of the skin surface scale to identify Clin 2009;3:337–53.
the causative organism under the microscope or by culture 3 Wollina U. Pompholyx: what’s new? Expert Opin Investig Drugs
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ATOPIC DERMATITIS
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30 Hsu CY, Wang YC, Kao CH. Dyshidrosis is a risk factor for herpes increased susceptibility to allergic contact dermatitis to
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32 Chang YY, van der Velden J, van der Wier G et al. Keratolysis exfolia particular staphylococcal allergens, released from a focus
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33 Yasuda M, Miyachi Y, Utani A. Two cases of dyshidrosiform pemphi allergic sensitization and activate the plaques [6]. Elevated
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34 Mazereeuw‐Hautier J. [Infantile acropustulosis]. Presse Med 2004; demonstrated in patients with nummular dermatitis [7].
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35 Kluger N, Moguelet P, Khosrotehrani K et al. Idiopathic recurrent pal The relationship of nummular dermatitis to atopy has
moplantar hidradenitis: a case with late onset and long‐lasting been debated [8]. There are differing views on the possi
course. Clin Exp Dermatol 2007;32:217–18. ble role of atopy in subjects with nummular dermatitis
36 Menne T, Kaaber K. Treatment of pompholyx due to nickel allergy
but recent studies have indicated that nummular lesions
ATOPIC DERMATITIS
with chelating agents. Contact Dermatitis 1978;4:289–90.
37 Schurmeyer‐Horst F, Luger TA, Bohm M. Long‐term efficacy of
are the most common nontypical morphological variants
occlusive therapy with topical pimecrolimus in severe dyshidrosi of AD in both children and adults [9]. In children, a vari
SECTION 3:
form hand and foot eczema. Dermatology 2007;214:99–100. ant of AD may manifest as disseminated nummular
38 Scerri L. Azathioprine in dermatological practice. An overview with
special emphasis on its use in non‐bullous inflammatory dermatoses. lesions. Nummular dermatitis may or may not be associ
Adv Exp Med Biol 1999;455:343–8. ated with high total IgE levels, suggesting no common
39 Egan CA, Ralis TM, Meadows KP et al. Low‐dose oral methotrexate role for IgE in both conditions [10].
treatment for recalcitrant palmoplantar pompholyx. J Am Acad
Contact dermatitis, either irritant or allergic, has been
Dermatol 1999;40:612–14.
40 Pickenacker A, Luger TA, Schwatz T. Dyshidrotic eczema treated with connected to nummular dermatitis. Irritant contact der
mycophenolate mofetil. Arch Dermatol 1998;134:378–9. matitis may present with nummular lesions. Nummular
41 Petersen CS, Menne T. Cyclosporin A responsive chronic severe vesic lesions have been described in case reports of hypersensi
ular hand eczema. Acta Derm Venereol 1992;72:436–7.
42 Ogden S, Clayton TH, Goodfield MJ. Recalcitrant hand pompholyx:
tivity to ethylenediamine [11] and nickel [12].
variable response to etanercept. Clin Exp Dermatol 2006;31:145–6.
43 Petering H, Breuer C, Herbst R et al. Comparison of localized high‐dose Pathology. Histopathological changes of subacute
UVA1 irradiation versus topical cream psoralen‐UVA for treatment spongiotic dermatitis are seen. There is mild to moderate
of chronic vesicular dyshidrotic eczema. J Am Acad Dermatol
2004;50:68–72. spongiosis, usually without vesiculation, together with
44 Polderman MC, Govaert JC, le Cessie S et al. A double‐blind placebo‐ irregular acanthosis with some exocytosis of inflamma
controlled trial of UVA‐1 in the treatment of dyshidrotic eczema. Clin tory cells. There is a superficial perivascular infiltrate,
Exp Dermatol 2003;28:584–7.
45 Odia S, Vocks E, Rakoski J, Ring J. Successful treatment of dyshidrotic
predominantly of lymphocytes with some eosinophils
hand eczema using tap water iontophoresis with pulsed direct cur and occasional neutrophils. Chronic lesions demonstrate
rent. Acta Derm Venereol 1996;76:472–4. epidermal hyperplasia, hyperkeratosis and a pronounced
granular cell layer [13].
Nummular dermatitis Clinical features. Nummular dermatitis is characterized

by coin‐shaped or discoid plaques of eczema that arise
Definition. Nummular (meaning round or ‘coin‐shaped’; quite rapidly from the confluence of tiny papules and
synonym: discoid) dermatitis or eczema is an inflammatory papulo‐vesicles measuring 1–3 cm, only occasionally
skin condition characterized by the presence of pruritic being larger. In the acute phase, the lesions are red, weep
coin‐shaped plaques commonly situated on the extensor ing, crusted and highly irritable. They then progress to a
surfaces of the limbs. Other names used in the literature less vesicular and scalier stage, often with central clear
have included discoid eczema and orbicular eczema. It was ing and peripheral extension, forming ring‐shaped or
first described by Devergie in 1857 [1]. Since then, it has annular lesions. The surface is usually weeping or
been reported in all age groups and in all body areas. crusted and the margins are flat. As they fade, they leave
dry and hyperpigmented areas that gradually lighten.
Epidemiology. Nummular lesions of eczema are not However, pigment may never completely fade, particu
uncommon. The prevalence of nummular dermatitis larly when located below the knee. The itch is often
ranges from 0.1% to 9.1%. Males are affected slightly more severe with excoriations and lichenification secondary to
often and at a later age than females. It is less common in scratching [14]. Sites of predilection include the dorsum
children [2] and has no racial predilection. of the hands, the extensor surface of the forearms, the
lower part of the legs, the outer aspect of the thighs, and
Pathogenesis. The exact pathogenesis of nummular der the posterior aspect of the trunk [15] (Fig. 17.6). Face and
matitis is still obscure. It may represent a reaction pattern, scalp are usually spared [16]. Nummular dermatitis usu
which can be induced and perpetuated by a variety of fac ally takes a very chronic course with remissions and
tors [3]. Nummular dermatitis is frequently accompanied exacerbations. Autoeczematization (i.e. lesional spread
by xerosis. Dryness of the skin results in dysfunction of from the initial focal site) may account for the presence of
the epidermal lipid barrier that allows environmental multiple plaques. A particularly therapy‐resistant variety
allergens to penetrate the skin and induce dermatitis [4]. has been termed ‘oid‐oid disease’ (Sulzberger–Garbe
Impairment of the cutaneous barrier may also result in syndrome) [17].
ATOPIC DERMATITIS
SECTION 3:
Fig. 17.6 Nummular eczema affecting different

parts of the body.
inflammation and treat any associated infection. Lukewarm

Prognosis. Nummular dermatitis has usually a chronic
or cool baths can help in rehydration of the skin, and thus
relapsing course, and may persist for many months and
reduce itching. Application of the medicine to damp skin
require long‐term therapy. It often waxes and wanes with
allows more effective penetration and faster healing. Skin
the season, increasing in winter or in a cold and dry cli
moisturizers should be then applied to wet skin, some
mate. It may improve with sun exposure or humidity or
times under occlusion.
with moisturizer use [18].
Medium‐ to high‐potency topical corticosteroid oint
ments and topical immune modulators (tacrolimus and
Differential diagnosis. Nummular dermatitis should be pimecrolimus) [21] represent the mainstay treatment
differentiated from tinea corporis. Tinea corporis may be options to reduce inflammation. Tar preparations have
excluded by scraping and microscopically analysing a also been used successfully. Systemic steroids may be
potassium hydroxide preparation of a lesion. Differentiating required in cases of severe, generalized eruptions.
between discoid eczema and childhood psoriasis on clini Phototherapy may be of help in generalized and pro
cal grounds can be difficult. Often in discoid eczema, vesic longed eruptions [22]. Broadband or narrowband UVB is
ular lesions with less well‐defined margins to the plaques most commonly used. Immune suppressive medications
and a more severe degree of pruritus are found. Histological such as methotrexate have been found to be efficacious in
examination of skin biopsy may be needed. severely affected patients [23]. Oral antihistamines or
Nummular dermatitis must be distinguished from sedatives may help reduce itching and improve sleep.
nummular lesions of AD. A history of atopy, IgE and Topical antibiotics may help to avoid impetiginization but
radio‐allergosorbent test (RAST) determination and skin oral antibiotics should be used in cases of secondary
test may be diagnostically helpful [19]. Many studies have infection.
recommended patch testing in patients with nummular
dermatitis refractory to treatment to differentiate contact References
and nummular dermatitis [20]. Other conditions to be con 1 Devergie MGA. Traité Pratique des Maladies de la Peau. Paris: Librairie
de Victor Masson, 1857;2:238.
sidered in differential diagnosis are fixed drug eruption, 2 Ozkaya E. Adult‐onset atopic dermatitis. J Am Acad Dermatol

lichen simplex chronicus, pityriasis rosea, seborrhoeic der 2005;52:579–82.
matitis, Bowen disease and mycosis fungoides 3 Khurana S, Jain V, Aggarwal K et al. Patch testing in discoid eczema.
J Dermatol 2002;29:763–7.
4 Aoyama H, Tanaka M, Hara M et al. Nummular eczema: An addition
Treatment. The aim of treatment is to rehydrate the of senile xerosis and unique cutaneous reactivities to environmental
skin with repair of the epidermal lipid barrier, reduce aeroallergens. Dermatology 1999;199:135–9.
5 Bonamonte D, Foti C, Vestita M et al. Nummular eczema and contact

allergy: a retrospective study. Dermatitis 2012;23:153–7. Pathogenesis. The aetiology of SD is not completely
6 Kim W, Ko H, Kim M et al. Features of Staphylococcus aureus coloni understood. Its presence has been associated with over
zation in patients with nummular eczema. Br J Dermatol 2013;
growth of yeast species such as Malassezia (previously
168:656–82.
7 Hellgren L, Mobacken H. Nummular eczema – clinical and statistical Pityrosporum) that normally inhabit sebaceous skin [8].
data. Acta Dermatol Venereol (Stockh) 1969;49:189–96. Various studies have been performed on the role of
8 Taieb A. Atopic dermatitis: definition, epidemiology, natural history, Malassezia and SD in infants and adults [9,10]. The genus
severity and scores. Ann Dermatol Venereol 2005;132:S35–43.
9 Pugliarello S, Cozzi A, Gisondi P et al. Phenotypes of atopic dermatitis.
Malassezia, initially thought to consist of only one species,
J Dtsch Dermatol Ges 2011;9:12–20. M. furfur, is now known to comprise seven species [11].
10 Kreuger GG, Kahn G, Weston WL et al. IgE levels in nummular Six different species of Malassezia were recovered from
eczema and ichthyosis. Arch Dermatol 1973;107:56–8. different dermatosis cases and different anatomical sites
11 Caraffini S, Lisi P. Nummular dermatitis‐like eruption from ethylen
ediamine hydrochloride in two children. Contact Dermatitis [12]. They are normal resident skin flora [12,13]. Under
1987;17:313–14. certain circumstances, M. furfur may behave as an oppor
ATOPIC DERMATITIS
12 Patrizi A, Rizzoli L, Vincenzi C et al. Sensitization to thimerosal in tunistic pathogen or cause or aggravate a spectrum of
atopic children. Contact Dermatitis 1999;40:94–7.
13 Wu H, Schapiro B, Harrist T. Noninfectious vesiculobullous and
skin diseases such as psoriasis, atopic dermatitis, tinea
SECTION 3:
vesiculopustular diseases. In: David E, Rosalie J, Bernett L (eds) versicolor or pityrosporum folliculitis [14].
Lever’s Histopathology of the Skin, 9th edn. Philadelphia: Several lines of evidence suggest a pathogenic role for
Lippincott Williams & Wilkins, 2005:244. yeasts of the genus Malassezia in SD [14–16]. Among the
14 Jiamton S, Tangjaturonrusamee C, Kulthanan K. Clinical features
and aggravating factors in nummular eczema in Thais. Asian Pac J multiple chemical entities that are effective in treating
Allergy Immunol 2013;31:36–42. seborrhoeic dermatitis, such as azoles, hydroxypyridones,
15 Weedon D. Disorders of Pigmentation, 2nd edn. London: Churchill allylamines, selenium and zinc, the sole common mecha
Livingstone, 2002:321–41.
nism of action is antifungal activity [17,18]. Moreover, the
16 Krogh HK. Nummular eczema. Acta Derm Venereol 1960;40:114–26.
17 Sulzberger MB, Garbe W. Nine cases of distinctive exudative discoid number of yeast colonizations of skin was found to be
and lichenoid dermatosis. Arch Dermatol Venereol 1985;65:164–7. decreased with the use of antifungals and to rise again
18 Kulthanan K, Samutrapong P, Tuchina P. Adult‐onset atopic dermati when relapse occurred. Malassezia was shown to have
tis: a cross‐sectional study of natural history and clinical manifesta
tion. Asian Pac J Allergy Immunol 2007;25:207–14.
lipase activity, which hydrolyses human sebum triglycer
19 Agarwal U, Besarwal R, Gupta R et al. Hand eczema. Indian J ides and releases unsaturated fatty acids such as oleic and
Dermatol 2014;59:213–24. arachidonic acid [19,20]. These metabolites cause disrup
20 Bonamonte D, Foti C, Vestita M et al. Nummular eczema and con- tion of epidermal barrier function and induce keratino
tact allergy: a retrospective study. Dermatitis 2012;23:153–7.
21 Bukhari IA. Successful treatment of chronic persistent vesicular cytes to produce pro‐inflammatory cytokines such as
hand dermatitis with topical pimecrolimus. Saudi Med J 2005; interleukin (IL)‐1α, IL‐6, IL‐8 and tumour necrosis factor
26:1989–91. (TNF)‐α, thus initiating an inflammatory response.
22 Gambichler T. Management of atopic dermatitis using photo (chemo)
therapy. Arch Dermatol Res 2009;301:197–203.
Furthermore, arachidonic acid can be a source of prosta
23 Roberts H, Orchard D. Methotrexate is a safe and effective treatment glandins, which are pro‐inflammatory mediators that can
for paediatric discoid (nummular) eczema: a case series of 25 children. cause inflammation via neutrophil recruitment and vaso
Australas J Dermatol 2010;51:128–30. dilation [21,22]. On the other hand, there is no simple rela
tionship between yeast number and severity of SD, and
healthy skin may have a similar organism load to that of
Infantile seborrhoeic dermatitis SD. Moreover, SD lesions that occur in HIV‐infected
patients do not harbour a higher Malassezia load than
Definition. Seborrhoeic dermatitis (SD) is a chronic, recur HIV‐infected patients without SD [23]. It seems that indi
rent, inflammatory papulosquamous skin disorder that vidual predispositions and host interactions with
typically affects areas of the skin that are well supplied with Malassezia, rather than the mere presence of Malassezia,
sebaceous glands (face, scalp, chest, etc.). Its occurrence in contribute to the pathogenesis of SD.
early infancy may be related to hormone‐dependent sebum SD occurs predominantly in areas of the skin with
production, which decreases in childhood and increases active sebaceous glands, and is often associated with
again in adolescence and adulthood [1,2] (see Chapter 21). sebum overproduction. It also has a strong time correla
tion with sebaceous gland activity and higher sebum
Epidemiology. The prevalence rate of SD is 3–5% of the secretion, with cradle cap after birth, increased incidence
total population. Dandruff, which is the mildest form throughout the teens, then a decrease between the third
of this dermatitis, is probably more common, affecting and sixth decades [24]. However, SD patients may have
15–20% of the population [3]. SD has two peaks of normal sebum production, and people with excessive
occurrence, commonly appearing in both infancy (cradle sebum production are sometimes free from SD [25]. These
cap) and after puberty (dandruff) [4]. In a survey on findings suggest that although sebaceous gland activity
Australian children, the highest prevalence of SD was in strongly correlates with SD, the amount of sebum pro
the first 3 months of life, decreasing rapidly by the age of duced per se does not appear to be the decisive risk
1 year [5]. Because of this onset and resolution, it has been factor.
suggested that transplacental hormones (the levels of Abnormalities of lipid composition may also play a role
which are elevated in infancy and decrease by the first in the development of SD. Triglycerides and squalene
year of life) may be a causative factor [6,7]. were found to be reduced in SD patients compared to
healthy individuals. In addition, free fatty acids and cho

lesterol were found to be elevated in sebum of SD patients
[16]. Triglyceride degradation by Malassezia’s lipase leads
to the inflammatory reaction [26]. A major constituent of
the resident microbial skin flora, P. acnes, has been found
to be greatly reduced in SD [27]. SD may thus be linked to
an imbalance of the microbial flora.
SD is usually associated with immune suppression,
particularly in HIV/AIDS patients. Because no clear dif
ferences in Malassezia levels were found between indi
viduals with and without SD, it is likely that an immune
or inflammatory reaction, not the yeast load, is the pre
disposing cause [28]. Total serum IgA and IgG antibod
ATOPIC DERMATITIS
ies were found to be elevated in SD patients [29].

However, no increase in the titres of antibodies against
SECTION 3:
Malassezia was detected [29,30], indicating a change in

cellular immune response instead of humoral response Fig. 17.7 Cradle cap on the scalp of an infant.
[31]. The specific role of lymphocyte activity remains
controversial [32].
The role of genetic factors in SD was underappreciated
until recently, when inherited dominant and recessive
forms of SD were identified, suggesting a role of genetic
factors in the pathogenesis [33]. Various medications have
been reported to flare or induce SD including chlorprom
azine, cimetidine, ethionamide, fluorouracil, gold, griseof
ulvin, interferon alfa, lithium, methoxsalen, methyldopa,
phenothiazines and psoralens [34].
Pathology. Histologically, the development of SD can be

divided into two stages. In the acute and subacute stages,
SD displays spongiosis with a superficial perivascular
and perifollicular lymphocytic infiltrate. Parakeratosis
around follicular openings (‘shoulder parakeratosis’) can
also be seen. Neutrophils can be found in the margins of
follicular ostia, but Munro microabscesses are absent. On
the other hand, marked psoriasiform hyperplasia and Fig. 17.8 Infantile seborrhoeic dermatitis affecting the groin area.
parakeratosis are the characteristics of chronic lesions.
Dilation of the venules of surface plexus, which resembles
SD may also be a cutaneous sign of the immune reconsti
psoriasis, can also be present [24,35].
tution inflammatory syndrome in patients taking highly
active antiretroviral therapy (HAART) [38]. Therefore,
Clinical features. The infantile form usually begins about infants with generalized SD should be evaluated for more
1 week after birth and may persist for several months. serious disease.
Cradle cap is characterized by nonpruritic, thick, greasy
scales (white, off‐white or yellow) on the vertex and ante Differential diagnosis. The diagnosis of SD is usually
rior fontanelle regions (Fig. 17.7). Disseminated lesions, made on clinical grounds. The main differential diagnosis
usually of lesser intensity, can affect the centre of the face, is psoriasis. There is a common type of psoriasis known as
ears and forehead. seborrhoeic psoriasis. The areas affected and morphology
Lesions of the axillae and inguinal folds are acutely of lesions are almost identical to those typical of SD.
inflamed, oozing, sharply demarcated and surrounded by However, typical lesions in psoriasis are thicker and pre
satellite lesions; occasionally they appear earlier than sent as sharply limited plaques with silvery white scales
those of the head and trunk (Fig. 17.8). Pruritus is not an [39]. Atopic dermatitis usually does not appear until after
obligatory feature, but it is often present, mainly in scalp 3 months of age, in contrast to SD which usually appears
involvement [36]. The main complication is secondary at an earlier age and rarely affects extensor areas. Tinea
bacterial infection, which increases the redness and exudate capitis typically shows scaly patches with scalp hair loss,
and local irritation [37]. Candidal overgrowth infantile ‘nap which is not a feature of SD [40]. Mycological examina
kin dermatitis’ may occur. Generalized seborrhoeic eryth tion and fungal culture can be done to rule out tinea
roderma rarely occurs. Generalized SD (i.e. SD appearing capitis. Finally, skin lesions in systemic lupus erythema
on the flexural folds) is uncommon in healthy children and tosus often follow a clear photodistribution, such as acute
is usually associated with immunodeficiencies (Fig. 17.9). flares of bilateral malar rash, and may be associated with
ATOPIC DERMATITIS
SECTION 3:
(a) (b)
Fig. 17.9 Severe form of infantile seborrhoeic dermatitis affecting the face and napkin area.
extracutaneous abnormalities such as arthritis, mouth antifungal properties against Malassezia and can be used
ulcers, glomerulonephritis or cardiomyopathy [41]; SD as a shampoo [47].
does not have a photodistribution pattern, and does not Topical corticosteroids may hasten recurrences, may
affect organ systems other than the skin. foster dependence because of a rebound effect, and are
Other less common conditions that may resemble SD discouraged except for short‐term use. Short courses of
and should be considered in differential diagnosis are low‐potency topical corticosteroids can aid in resolution
pityriasis rosea, napkin dermatitis and cutaneous of erythema and itching. Topical calcineurin inhibitors
Langerhans cell histiocytosis [42]. The majority of these such as tacrolimus and pimecrolimus have been proposed
conditions can be differentiated by clinical presentation, as a steroid‐sparing therapy for SD. Antibiotics should be
although laboratory confirmation may at times be given in secondarily infected lesions.
required. Additionally, some drugs (griseofulvin, ethion
amide, buspirone, haloperidol, chlorpromazine, IL‐2,
interferon alfa, methyldopa, psoralens) and nutritional References
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have proved to be effective in LSC for patients

Clinical features. LSC is characterized by the presence
unresponsive to topical corticosteroid or those with
of one or more erythematous, scaly, lichenified plaques
lesions on thin skin [18,19].
with varying degrees of overlying excoriation from
Other topical medications reported to decrease pruritus
habitual scratching and rubbing of the skin. In cases of
include doxepin cream [20] and capsaicin cream [21]. Oral
longstanding duration, areas of hyperpigmentation
antianxiety medications and sedation may be consid
may also be present. Each plaque may have three
ered in certain patients according to individual need. For
zones: a wide peripheral thickened zone, a middle
infected lesions, a topical or oral antibiotic can be
zone with prurigo papules that may be excoriated, and
considered.
a central zone that has the greatest thickening and pig
mentary alteration. There is a predilection for the
occipital, vulval and nuchal areas in women and the
perineum and scrotum in men. It is uncommon in chil References
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Unfortunately, even with highly effective therapy, the Aetiology and management. Br J Obstet Gynaecol 1995;102:773–9.
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Geraldez MC, Carreon‐Gavino M, Hoppe G, Costales A.
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Topical steroids are the current treatment of choice lichen simplex chronicus. Int J Dermatol 1989;28:603–4.
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Potent topical glucocorticoid creams or ointments are simplex chronicus: A prospective non‐controlled case series.
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Prurigo nodularis Psychosocial disorders are also significantly associated

with PN as a primary association or sometimes second
Definition. Prurigo nodularis (PN; chronic circumscribed ary to the severe itch in PN [11]. Change in the density of
nodular lichenification, Picker’s nodules), is a chronic dermal nerve fibres and the interaction between nerve
inflammatory dermatosis characterized by the presence of fibres and neuropeptides/neurotrophins [12] may also
symmetrically distributed multiple, highly pruritic, hyper have a role in the pathogenesis of PN. Inflammation
keratotic, erosive or crusted nodules and papules usually caused by T lymphocytes, eosinophilic granulocytes
surrounded by an irregular hyperpigmented ring. PN is a and mast cells is involved in the development and
long‐term reaction to the chronic scratching of patients with chronification of PN. Pruritus can be caused by the
chronic pruritus. The extensor area of the limbs, face and release of mast cell products such as histamine, tryptase
trunk are usually affected by the lesions. It can occur at all and prostaglandins [13].
ages [1,2]. Hardaway was the first to describe PN as ‘multi
ple tumors of the skin accompanied by intensive itching’ in Pathology. The histological characteristics of PN include
ATOPIC DERMATITIS
1880, and later it was called lichen obtusus corneus by Brocq thick, compact epidermal orthohyperkeratosis with acan
[3]. Hyde, in 1909, defined the term PN clinically and distin thosis and parakeratosis or superficial epithelial necrosis.
SECTION 3:
guished it from the general term prurigo [4]. Rete ridges are elongated and irregular; there is fibrosis of
the papillary dermis with vertically arranged collagen
Epidemiology. PN can occur at any age, even in children, but fibres, and there are an increased number of fibroblasts
it most often occurs in middle‐aged and elderly people [5,6]. and capillaries with a dense dermal infiltrate consisting of
It can affect both sexes, with special predilection for women neutrophils, eosinophils, histiocytes and monocytes [14].
[7]. It may occur in conjunction with atopy; in that case, it has Also notable in the dermis are thickened nerve fibres and
an earlier age of onset and may be accompanied by cutane fibrosis with thickened collagen bundles [15,16]. Schwann
ous hypersensitivity to various environmental allergens [8]. cells show vacuolization and degeneration with no detect
There is no known racial predilection for PN [9]. able mitochondria. Axons and Schwann cells both show
hyperproliferation [17]. There are increased numbers of
Pathogenesis. The cause of PN is still unknown. Repeated Merkel cells in the epidermis of PN nodules [18]. In addi
mechanical trauma is the main factor. The vicious cycle of tion, mast cells are increased in number and show charac
repeated itching and scratching leads to thickening with teristic morphological changes such as an enlarged cell
plaques or nodular lichenification of the skin. An under body size and a dendritic shape compared with the round
lying disease can be associated with PN in most of the or elongated shape seen in normal skin [19].
patients; atopic diathesis is the most common association.
An associated atopic diathesis may be responsible for ear Clinical features. Clinically, PN is characterized by firm,
lier age of onset (median age 19 years) compared to non pruritic, 0.5–3‐cm diameter, hyperpigmented or purpuric
atopic patients (median age 48 years) [9]. Other diseases nodules with a hyperkeratotic or excoriated surface,
that may be associated with PN include obstructive bil numbering from a few to hundreds (Fig. 17.10). The
iary diseases, mastocytosis, diabetes mellitus, drug reac lesions tend to be symmetrically distributed, with a predilection
tion, chronic renal failure, hepatitis B and C infection, and for the extensor area of the limbs, face and trunk. Palms are
some neoplasms such as Hodgkin lymphoma [10]. seldom affected. Postinflammatory hyper/hypopigmentation
Fig. 17.10 Prurigo nodularis in an adolescent

boy.
with or without scarring may occur [19]. The skin between References
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Cryotherapy is a useful therapeutic modality for nodularis. Arch Dermatol 2000;136:807–8.
the treatment of PN [28]. It helps reduce pruritus and 26 Gencoglan G, Inanir I, Gunduz K. Therapeutic hotline: Treatment of
flattens lesions through destruction of sensory nerves prurigo nodularis and lichen simplex chronicus with gabapentin.
Dermatol Ther 2010;23:194–8.
and impairment of nerve regeneration [29]. UV light 27 Dereli T, Karaca N, Inanir I, Ozturk G. Gabapentin for the treatment of
exposure has been shown to lessen the pruritus, and recalcitrant chronic prurigo nodularis. Eur J Dermatol 2008;18:85–6.
can be beneficial in the treatment of PN; UVB or UVA 28 Waldinger TP, Wong RC, Taylor WB, Voorhees JJ. Cryotherapy

improves prurigo nodularis. Arch Dermatol 1984;120:1598–600.
plus psoralen may be used. The combination of UVB
29 Thai KE, Sinclair RD. Cryosurgery of benign skin lesions. Australas J
308‐nm excimer light and bath PUVA therapy may be Dermatol 1999;40:175–86.
effective in the treatment of PN [30]. UVA‐1 has also 30 Hammes S, Hermann J, Roos S, Ockenfels HM. UVB 308‐nm excimer light
been reported to benefit lichen simplex chronicus and and bath PUVA: combination therapy is very effective in the treatment of
prurigo nodularis. J Eur Acad Dermatol Venereol 2011;25:799–803.
PN. Pulsed dye laser therapy may also be of help 31 Rombold S, Lobisch K, Katzer K et al. Efficacy of UVA1 phototherapy
through reduction of the vascularity of individual in 230 patients with various skin diseases. Photodermatol Photoi
lesions [31]. mmunol Photomed 2008;24:19–23.
Prurigo pigmentosa Although the individual lesions resolve quickly over

1 week, residual netlike hyperpigmentation remains. The
Prurigo pigmentosa (PP) is a rare cutaneous disorder of disease course is punctuated by frequent recurrences
unknown aetiology, first described by Nagashima et al. in followed by remissions lasting weeks to years [3,10,11].
1971. It is diagnosed most commonly in the Japanese pop
ulation [1,2]. It presents with recurrent, pruritic erythe Differential diagnosis. Diseases to be considered in the
matous macules, papules and papulovesicles on the differential diagnosis clinically at an early stage of the
trunk, back, neck and chest that resolve, leaving behind a process are early manifestations of dermatitis herpetiformis,
netlike pigmentation. The disease is seen most commonly linear IgA dermatosis, pigmented contact dermatitis and
in young women, although it has been reported in adoles acute lupus erythematosus. At a resolving stage of the
cence [3,4]. process, PP may be confused with reticular pigmented
papules of confluent and reticulated papillomatosis of
Pathogenesis. The exact aetiology and pathogenesis of Gougerot and Carteaud but, in contrast to those lesions,
ATOPIC DERMATITIS
PP are still unknown. Due to its occurrence mainly in the pigmented macules of PP are not keratotic.
Japan, PP was thought to have a genetic background.
SECTION 3:
However, there are no reports of familial cases, and the Treatment. Several medications are available. Antihis
number of PP cases discovered all over the world is tamines and topical or systemic corticosteroids are usu
increasing. Various mechanisms have been suggested to ally ineffective in the treatment of PP. Oral minocycline
cause PP, such as friction, contact allergy, sensitivity to (200 mg) taken daily is usually considered as the first‐line
sunlight, endocrinological alterations such as diabetes therapy for PP [12,13]. Doxycycline, dapsone, potassium
mellitus and metabolic disorders such as ketosis [5,6], but iodide and macrolide antibiotics have also been reported
none of them has proved to be consistently identifiable. to be effective [14–16]. A favourable response of PP to
As the lesions are mainly restricted to covered areas of the isotretinoin has been reported [16]. Although the medica
body, the occurrence of PP has been considered to be trig tions are quite effective in stopping the inflammatory
gered by rubbing. Clothing friction acting as a mechanical component, treatment of the postinflammatory hyperpig
stimulus has also been suspected as a possible triggering mentation remains problematic.
factor [7].
References
Pathology. Early reports of histological findings in PP 1 Nagashima M, Ohshiro A, Shimizu N. A peculiar pruriginous der-
were nonspecific and not diagnostic. However, Böer et al. matosis with gross reticular pigmentation. Jpn J Dermatol 1971;
81:38–9.
[8] proposed that the histopathological changes of PP 2 Nagashima M. Prurigo pigmentosa–clinical observations of our

may be specific. Early lesions of PP show spongiosis, bal 14 cases. J Dermatol 1978;5:61–7.
looning and necrotic keratocytes in the epidermis, and a 3 Böer A, Asgari M. Prurigo pigmentosa: an underdiagnosed disease?
perivascular neutrophilic infiltrate. Lymphocytes are Indian J Dermatol Venereol Leprol 2006;72:405–9.
4 Corley S, Mauro P. Erythematous papules evolving into reticulated
sprinkled along the dermoepidermal junction. In a fully hyperpigmentation on the trunk: A case of prurigo pigmentosa. JAAD
developed lesion, the infiltrate assumes a patchy lichenoid Case Rep 2015;1:60–2.
pattern, and there are more numerous lymphocytes in the 5 Kwon HJ, Kim MY, Kim HO, Park YM. Two cases of prurigo

pigmentosa in atopic patients. J Dermatol 2006;33:579–82.
dermis. In the epidermis ballooning is more prominent
6 Kubota Y, Koga T, Nakayama J. Bullous prurigo pigmentosa and
than spongiosis, and lymphocytes are increased in num diabetes. Eur J Dermatol 1998;8:439–41.
ber in the lower part of the epidermis. In a resolving 7 Kim MH, Choi YW, Choi HY, Myung KB. Prurigo pigmentosa from
lesion, a sparse infiltrate of lymphocytes is present in the contact allergy to chrome in detergent. Contact Dermatitis 2001;44:
289–92.
upper part of the reticular dermis and the papillary der 8 Böer A, Ackerman AB. Prurigo pigmentosa is distinctive histo-
mis. Necrotic keratinocytes may be found in the basal pathologically. Int J Dermatol 2003;42:417–18.
layer. Immunofluorescence is negative [9]. 9 Kokol R, Miljković J, El Shabrawi‐Caelen L, Prurigo pigmentosa.
J Dtsch Dermatol Ges 2011;9:867–8.
10 Asgari M, Daneshpazhooh M, Chams Davatchi C, Boer A. Prurigo
Clinical features. The eruption of PP is distributed sym pigmentosa: An underdiagnosed disease in patients of Iranian
metrically on the trunk, with predilection for the upper descent? J Am Acad Dermatol 2006;55:131–6.
part of the back, the sacrum, abdomen and chest. 11 Oh YJ, Lee MH. Prurigo pigmentosa: A clinicopathologic study of
16 cases. J Eur Acad Dermatol Venereol 2012;26:1149–53.
Intermammary and submammary zones are involved 12 Matsumoto C, Kinoshita M, Baba S et al. Vesicular prurigo pigmentosa
more commonly. Rarely, the forehead, the arms or the cured by minocycline. J Eur Acad Dermatol Venereol 2001;15:354–6.
abdomen are affected. Individual lesions are symmetri 13 Aso M, Miyamoto T, Morimura T, Shimao S. Prurigo pigmentosa
successfully treated with minocycline. Br J Dermatol 1989;120:705–8.
cally distributed pruritic urticarial papules at the begin 14 Degavre B, Guilhou JJ, Guillot B. [Prurigo pigmentosa]. Ann Dermatol
ning of an eruption, evolving to short‐lived red papules Venereol 1994;121:46–9.
and papulovesicles, and coalescing into plaques. 15 Yazawa N, Ihn H, Yamane K et al. The successful treatment of prurigo
Resolving lesions are crusted and scaly red papules and pigmentosa with macrolide antibiotics. Dermatology 2001;202:67–9.
16 Requena Caballero C, Nagore E, Sanmartin O et al. Vesiculous pru
smooth‐surfaced pigmented macules. Often, secondary rigo pigmentosa in a 13‐year‐old girl: Good response to isotretinoin.
changes of excoriation, scaling or crusting are observed. J Eur Acad Dermatol Venereol 2005;19:474–6.
245
C HA PTER 18
Atopic Dermatitis: Complications

Kevin B. Yarbrough1 & Eric L. Simpson2
Department of Pediatric Dermatology, Phoenix Children’s Hospital, Phoenix, AZ, USA
1
Department of Dermatology, Oregon Health and Science University, Portland, OR, USA
2
Bacterial infections, 245 Sleep disturbance, 248 Mental health disorders, 250
Viral infections, 247 Psychosocial complications, 249 Ocular complications, 251
ATOPIC DERMATITIS
Abstract
SECTION 3:
in children with AD. Extracutaneous complications of AD include
not only the classic atopic comorbidities like asthma and hay fever,
but also extend to ocular problems, sleep disturbance and mental
Complications of atopic dermatitis (AD) include both cutaneous and
health conditions. Recognizing the array of potential comorbid con-
extracutaneous conditions. Acute cutaneous complications include
ditions enables the clinician to work with consultants to treat the
both bacterial and viral infections that have unique presentations
whole patient.
Key points • Medical visits should include a discussion with the family regarding
a child’s sleep, mood, social functioning and school performance
• Caring for a child with atopic dermatitis (AD), especially one to help identify signs of mental health disorders such as anxiety,
with moderate‐to‐severe disease, encompasses much more than depression and attention‐deficit hyperactivity disorder.
treatment of the skin inflammation. • Recognizing the multidimensional impact AD may have on a
• Clinicians should identify Staphylococcus aureus infections of child aids the clinician in providing a comprehensive approach to
the skin and remain alert to the varied presentations of eczema the patient with the hopes of improving a child’s overall health
herpeticum. status.
Bacterial infections Few studies address the rate of true infection (as com-
pared to colonization) in AD, possibly due to the difficulty
Epidemiology. Cutaneous infections with Staphylococcus in clinically differentiating infection from colonization.
aureus commonly complicate the course of atopic derma- One population‐based study from Japan found an almost
titis (AD), especially in patients with severe disease, and two‐fold increase of impetigo in children with a history of
are due to high Staph. aureus colonization rates. Lesional AD [7]. The risk of invasive Staph. aureus infections is also
colonization rates reported in the literature range between not well‐quantified in AD, but cases of endocarditis,
28% and 99%, with the first such study dating back to the osteomyelitis and septicaemia have all been reported in
1970s by Leyden et al. [1]. Totté et al., in a 2016 systematic this population [8–10].
review, identified 95 observational studies attempting to
quantify Staph. aureus colonization in AD [2]. Pooled esti-
mates for Staph. aureus carriage in AD were 70% on Pathogenesis. Microbiome studies confirm that AD
lesional skin, 39% on nonlesional skin and 62% in the flares are associated with heavy Staph. aureus growth and
nose. Studies showed significant variability in coloniza- correlate with a reduction in bacterial diversity on the
tion rates, probably due to differences in the ages of the skin [11]. Basic and translational research identifies sev-
patients and their underlying disease severity. This pro- eral potential pathogenic mechanisms underlying the
pensity for Staph. aureus colonization also leads to higher observed susceptibility to Staph. aureus colonization
colonization rates among family members [3]. Studies and infection. The elevated skin pH found in AD p romotes
conflict on whether patients with AD represent a signifi- Staph. aureus growth, as does a barrier disrupted by
cant reservoir of meticillin‐resistant Staph. aureus (MRSA) spongiosis and excoriation. Inflamed AD skin displays

colonization, with some studies showing increased colo- increased expression of fibronectin and fibrinogen‐binding
nization rates compared to the general population [4,5] sites for Staph. aureus [12]. AD skin also exhibits an
and other studies failing to confirm these findings [6]. impaired ability to produce certain antimicrobial peptides
(AMPs) that protect against Staph. aureus [13]. Underlying Hextall et al. found no evidence that oral or topical
T‐helper type 2 (Th2) inflammation also probably plays antibiotics improved AD outcomes in clinically unin-
an important role in Staph. aureus susceptibility. Th2 fected patients [26]. An oral or topical antimicrobial can
cytokines inhibit AMP production by keratinocytes [14] be used depending on infection severity; there are no
and augment the destruction of keratinocytes by Staph. studies comparing various antimicrobial regimens in this
aureus alpha toxins [15]. AD patients colonized with Staph. population. Patients are at risk for developing antimicro-
aureus also display peripheral blood biomarkers consist- bial resistance with repeated or long‐term antibiotic
ent with Th2 skewing, such as elevated IgE levels and courses. Dicloxacillin or first‐generation cephalosporins
peripheral eosinophils [16]. The role of FLG mutations on are most commonly used as first‐line therapy. Antibiotics
Staph. aureus colonization/infection risk remains unclear such as clindamycin or trimethoprim–sulfamethoxazole
with some studies finding associations [17]. A study by may be needed in cases of MRSA. Dilute bleach baths
Lopes et al. suggests that different loss‐of‐function muta- have been shown to improve disease severity, and it was
tions in the FLG gene may have different effects on coloni- initially thought the effects were due to a reduction in
ATOPIC DERMATITIS
zation risk [18]. Staph. aureus colonization [27]. Wong et al. measured a
Whereas several host factors allow Staph. aureus the reduction in Staph. aureus density with bleach bath use
SECTION 3:
opportunity to colonize, several Staph. aureus factors con- [28] but a recent trial found no additional benefit of bleach
tribute to AD severity, and in one study nasal colonization baths to standard topical corticosteroid treatment with
was found to actually precede AD onset in children [19]. respect to microbiome diversification [29]. Dilute bleach
Staph. aureus strains from AD patients, more so than from has, however, been shown to reduce inflammation by
normal controls, create exotoxins (e.g. toxic shock syndrome inhibiting expression of NF‐κB‐dependent genes [30].
toxin 1 and Staphylococcus enterotoxins) that act as superan- Further studies on the effects of bleach baths on Staph.
tigens leading to nonspecific activation of T cells and Th2 aureus colonization and infection rates are needed in AD.
cytokine production [20]. High levels of alpha toxin lead to
keratinocyte necrosis, whereas low levels promote inflam- References
mation [21]. Serine protease activity, both endogenous and 1 Leyden JJ, Marples RR, Kligman AM. Staphylococcus aureus in the
lesions of atopic dermatitis. Br J Dermatol 1974;90:525–30.
exogenous from Staph. aureus, probably adds to the deleteri- 2 Totté JE, van der Feltz WT, Hennekam M et al. Prevalence and odds
ous effects of Staph. aureus on the skin by degrading the skin of Staphylococcus aureus carriage in atopic dermatitis: a systematic
barrier and promoting inflammation [22,23]. review and meta‐analysis. Br J Dermatol 2016;175:687–95.
3 Bonness S, Szekat C, Novak N, Bierbaum G. Pulsed‐field gel electro-
phoresis of Staphylococcus aureus isolates from atopic patients
Clinical findings. Classic clinical findings of cutaneous revealing presence of similar strains in isolates from children and
Staph. aureus infection in children with AD include pus- their parents. J Clin Microbiol 2008;46:456–61.
tules and honey‐coloured crusts with erosion (Fig. 18.1). 4 Klein PA, Greene WH, Fuhrer J, Clark RA. Prevalence of methicillin‐
resistant Staphylococcus aureus in outpatients with psoriasis, atopic
Differentiating crusting and weeping found in acute AD dermatitis, or HIV infection. Arch Dermatol 1997;133:1463–5.
from Staph. aureus infection can be near impossible; how- 5 Chung HJ, Jeon HS, Sung H et al. Epidemiological characteristics of
ever, pain, erosion and pustulation are more frequently methicillin‐resistant Staphylococcus aureus isolates from children
found in infection. Overall AD severity and skin barrier with eczematous atopic dermatitis lesions. J Clin Microbiol 2008;
46:991–5.
function strongly associate with Staph. aureus coloniza- 6 Matiz C, Tom WL, Eichenfield LF et al. Children with atopic dermati-
tion [24,25]. tis appear less likely to be infected with community acquired methi-
cillin‐resistant Staphylococcus aureus: the San Diego experience.
Treatment and prevention. The use of antimicrobial 7 Hayashida S, Furusho N, Uchi H et al. Are lifetime prevalence of
treatment in AD should be reserved for clinically appar- impetigo, molluscum and herpes infection really increased in chil-
ent infection. A systemic review of 26 studies by Bath‐ dren having atopic dermatitis? J Dermatol Sci 2010;60:173–8.
8 Benenson S, Zimhony O, Dahan D et al. Atopic dermatitis—a risk fac-
tor for invasive Staphylococcus aureus infections: two cases and
review. Am J Med 2005;118:1048–51. Review.
9 Hoeger PH, Ganschow R, Finger G. Staphylococcal septicemia in chil-
dren with atopic dermatitis. Pediatr Dermatol 2000;17:111–14.
10 Onoda K, Mizutan H, Komada T et al. Atopic dermatitis as a risk factor
for acute native valve endocarditis. J Heart Valve Dis 2000;9:469–71.
11 Kong HH, Oh J, Deming C et al; NISC Comparative Sequence
Program, Murray PR, Turner ML, Segre JA. Temporal shifts in the
skin microbiome associated with disease flares and treatment in
children with atopic dermatitis. Genome Res 2012;22:850–9.
12 Cho SH, Strickland I, Boguniewicz M, Leung DY. Fibronectin and
fibrinogen contribute to the enhanced binding of Staphylococcus
aureus to atopic skin. J Allergy Clin Immunol 2001;108:269–74.
13 Ong PY, Ohtake T, Brandt C et al. Endogenous antimicrobial pep-
tides and skin infections in atopic dermatitis. N Engl J Med
2002;347:1151–60.
14 Howell MD, Boguniewicz M, Pastore S et al. Mechanism of HBD‐3
deficiency in atopic dermatitis. Clin Immunol 2006;121:332–8.
15 Brauweiler AM, Goleva E, Leung DY. Th2 cytokines increase

Staphylococcus aureus alpha toxin‐induced keratinocyte death
Fig. 18.1 Eroded plaques on the neck. Culture showed Staph. aureus and through the signal transducer and activator of transcription 6 (STAT6).
Group A Streptococcus. J Invest Dermatol 2014;134:2114–21.
Chapter 18 Atopic Dermatitis: Complications 247
16 Warner JA, McGirt LY, Beck LA. Biomarkers of Th2 polarity are pre- EH is much more common than EV and affects approxi-
dictive of staphylococcal colonization in subjects with atopic dermati-
mately 3% of AD patients [4]. Patients with more severe
tis. Br J Dermatol 2009;160:183–5.
17 Cai SC, Chen H, Koh WP et al. Filaggrin mutations are associated skin disease and a history of other viral and bacterial
with recurrent skin infection in Singaporean Chinese patients with infections appear at greatest risk [5].
atopic dermatitis. Br J Dermatol 2012;166:200–3.
18 Lopes C, Rocha L, Sokhatska O et al. Filaggrin polymorphism

Pro478Ser is associated with the severity of atopic dermatitis and Pathogenesis. The tendency towards exaggerated cuta-
colonization by Staphylococcal aureus. J Investig Allergol Clin neous viral infections observed in AD may be explained
Immunol 2016;26:70–2. by both underlying skin barrier and immune defects. FLG
19 Lebon A, Labout JA, Verbrugh HA et al. Role of Staphylococcus
gene mutations confer a risk of EH in both European and
aureus nasal colonization in atopic dermatitis in infants: the
Generation R Study. Arch Pediatr Adolesc Med 2009;163:745–9. African populations [6], however it is unclear if the viral
Erratum in: Arch Pediatr Adolesc Med 2010;164:334. susceptibility is due to the barrier defect or the subse-
20 Akdis M, Simon HU, Weigl L et al. Skin homing (cutaneous lympho- quent immune alterations that occur downstream of a
cyte‐associated antigen‐positive) CD8+ T cells respond to superanti-
disrupted barrier. Observed immune defects include
ATOPIC DERMATITIS
gen and contribute to eosinophilia and IgE production in atopic
dermatitis. J Immunol 1999;163:466–75. peripheral blood Th2 skewing, expanded peripheral skin‐
21 Bantel H, Sinha B, Domschke W et al. alpha‐Toxin is a mediator of homing T‐regulatory cells at the onset of the infection,
SECTION 3:
Staphylococcus aureus‐induced cell death and activates caspases via and reduced expression of interferon(IFN)‐γ and IFN‐γ
the intrinsic death pathway independently of death receptor signal-
ing. J Cell Biol 2001;155:637–48. receptor in peripheral blood mononuclear cells [5,7,8].
22 Williams MR, Nakatsuji T, Sanford JA et al. Staphylococcus aureus Gao et al. found loss‐of‐function variants in the IFN‐γ
induces increased serine protease activity in keratinocytes. J Invest receptor to be a predisposing factor for EH [9], partially
Dermatol 2017;137:377–84.
23 Hirasawa Y, Takai T, Nakamura T et al. Staphylococcus aureus extra-
explaining some of the immune abnormalities observed.
cellular protease causes epidermal barrier dysfunction. J Invest
Dermatol 2010;130:614–17. Clinical features. EH can start as a simple herpes labialis
24 Hon KL, Tsang YC, Pong NH et al. Clinical features and Staphylococcus infection with subsequent spreading to the head and neck
aureus colonization/infection in childhood atopic dermatitis. J
Dermatolog Treat 2016;27:235–40. or it may occur de novo in any area of the body. It is most
25 Simpson EL, Babineau D, Villarreal M et al. S. aureus colonization is often characterized by vesicles spreading beyond the
associated with impaired skin barrier function and greater Th2 activa- original focus of infection accompanied by fever and lym-
tion in adult subjects with AD. J Invest Dermatol 2016;136:S56.
26 Bath‐Hextall FJ, Birnie AJ, Ravenscroft JC, Williams HC. Interventions
phadenopathy. Often vesicles are not witnessed and the
to reduce Staphylococcus aureus in the management of atopic eczema: condition can be recognized by the presence of multiple
an updated Cochrane review. Br J Dermatol 2010;163:12–26. 2–3‐mm monomorphous punched‐out erosions (Fig. 18.2).
27 Huang JT, Abrams M, Tlougan B et al. Treatment of Staphylococcus A scalloped border created from coalesced erosions is
aureus colonization in atopic dermatitis decreases disease severity.
Pediatrics 2009;123:e808–14.
28 Wong SM, Ng TG, Baba R. Efficacy and safety of sodium hypochlorite
(bleach) baths in patients with moderate to severe atopic dermatitis in
Malaysia. J Dermatol 2013;40:874–80.
29 Gonzalez ME, Schaffer JV, Orlow SJ et al. Cutaneous microbiome
effects of fluticasone propionate cream and adjunctive bleach baths in
childhood atopic dermatitis. J Am Acad Dermatol 2016;75:481–93.e8.
30 Leung TH, Zhang LF, Wang J et al. Topical hypochlorite ameliorates
NF‐kB‐mediated skin diseases in mice. J Clinc Invest 2013;123:
5361–70.
Viral infections
Epidemiology. It is not clear whether patients with AD are
more susceptible to routine cutaneous viral infections such
as warts or molluscum. Studies are sparse and conflicting.
The tendency for patients with AD to develop exaggerated
viral infections such as to molluscum, vaccinia or cox-
sackie exposures, however, has been well documented.
Two exaggerated infections that are particularly
important to recognize in the AD patient are eczema vac-
cinatum (EV) and eczema herpeticum (EH), as these con-
ditions can cause acute and severe morbidity and
possibly death. EV is exceedingly rare and mainly occurs
when military recruits receiving the smallpox vaccine
inadvertently expose susceptible family members with
AD at home. Having AD or someone in the household
with AD is a strict contraindication to receiving the
smallpox vaccine. The ability of vaccinees to report these
contraindications is poor, however, and new cases of EV Fig. 18.2 Grouped crusted erosions consistent with eczema herpeticum in
are emerging [1–3]. a young adult.
Treatment. Antiviral therapy should be initiated imme-

diately for EH, either oral or intravenously depending
on disease severity. Age less than 1 year, male sex, fever
and systemic symptoms were all important factors lead-
ing to admission in one large retrospective study of EH
paediatric patients [11]. Treatment of EV includes vac-
cinia immune globulin, cidofovir or tecovirimat – an
antiviral with anti‐orthopox activity [12]. Treatment
options for widespread warts or molluscum mirror
those in children without AD. Topical steroids do not
appear to complicate viral infections of the skin and may
be used. Topical calcineurin inhibitors are contraindi-
ATOPIC DERMATITIS
cated in active infection, although there are no rigorous

data regarding their role in predisposing to infection or
SECTION 3:
in disease exacerbation.
References
1 Naleway AL, Belongia EA, Greenlee RT et al. Eczematous skin disease
and recall of past diagnoses: implications for smallpox vaccination.
Ann Intern Med 2003;139:1–7.
2 Moses AE, Cohen‐Poradosu R. Images in clinical medicine. Eczema
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3 Vora S, Damon I, Fulginiti V et al. Severe eczema vaccinatum in a
household contact of a smallpox vaccinee. Clin Infect Dis 2008;46:
1555–61.
Fig. 18.3 Verrucae vulgaris in a child with atopic dermatitis. 4 Tay YK, Khoo BP, Goh CL. The epidemiology of atopic dermatitis at a
tertiary referral skin center in Singapore. Asian Pac J Allergy Immunol
1999;17:137–41.
5 Beck LA, Boguniewicz M, Hata T et al. Phenotype of atopic derma-
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presentations often occur and can include pustules, haem- Immunol 2009;124:260–9, 9.e1–7.
6 Gao PS, Rafaels NM, Hand T et al. Filaggrin mutations that confer
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additional clues that EH should be considered. Herpes J Allergy Clin Immunol 2009;124:507–13, 513.e1–7.
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nation may occur leading to death. ties in IFN‐γ response. J Allergy Clin Immunol 2011;127:965–73.
Other viral infections of note in children with AD e1–5. Erratum in: J Allergy Clin Immunol 2011;128:833.
include widespread wart or molluscum infections 8 Takahashi R, Sato Y, Kurata M et al. Pathological role of regulatory T
(Fig. 18.3). Recently, a particularly virulent strain of cox- cells in the initiation and maintenance of eczema herpeticum lesions.
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that may mimic EH, termed eczema coxsackium [10]. The rare loss‐of‐function variants in IFNGR1 for risk of atopic dermatitis
exanthem affects hands and feet like a typical coxsackie complicated by eczema herpeticum. J Allergy Clin Immunol 2015;
136:1591–600.
infection, but commonly affects perioral areas and trunk
10 Mathes EF, Oza V, Frieden IJ et al. “Eczema coxsackium” and unusual
with accentuation in areas of AD lesions. cutaneous findings in an enterovirus outbreak. Pediatrics 2013;132:
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Laboratory testing. Samples of blister fluid should be 11 Luca NJ, Lara‐Corrales I, Pope E. Eczema herpeticum in children:
clinical features and factors predictive of hospitalization. J Pediatr
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confirming the presence of HSV. Serological testing has
no value as many children have been exposed to HSV‐1
and will test positive. If EV is suspected, local health
Sleep disturbance
authorities and, in the USA, the Centers for Disease
Control should be contacted for immune globulin ther- Sleep disturbance is a common issue faced by patients
apy consideration. with AD as well as their families. It affects up to 60% of
Coxsackie virus testing can be performed using culture children with AD, with closer to 80% experiencing
or PCR from blister fluid, oropharynx or stool sample, but sleep disturbance during flares [1]. Patients with AD
the diagnosis is most often made on clinical grounds. have difficulty falling asleep as well as staying asleep,
Testing of the stool or a swab from the rectal area may leading to difficulty awakening, daytime tiredness and
provide greater sensitivity (and perhaps less specificity) irritability [1–5]. Nocturnal pruritus and scratching
for detection since shedding of the virus in the gastroin- lead to difficulty falling asleep, as well as frequent
testinal tract may continue even after clinical disease is no movements during sleep and prolonged awakenings.
longer evident. Some sleep changes are even seen when the AD is in
clinical remission [3]. Interestingly, while prolonged 8 Chamlin SL, Mattson CL, Frieden IJ et al. The price of pruritus: Sleep
disturbance and cosleeping in atopic dermatitis. Arch Pediatr Adolesc
nighttime arousals are common in patients with AD,
Med 2005;159:745–50.
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be similar to healthy children [1,3,6,7], perhaps point- attention‐deficit/hyperactivity disorder and atopic eczema modified
ing to compensatory mechanisms whereby children by sleep disturbance in a large population‐based sample. J Epidemiol
Community Health 2010;64:269–73.
modify their bed and rise times [1]. Parents also suffer 10 Stewart AC, Thomas SE. Hypnotherapy as a treatment for atopic der-
from fragmented, disrupted sleep as they care for their matitis in adults and children. Br J Dermatol 1995;132:778–83.
children with AD. This familial sleep disruption can 11 Klein PA, Clark RF. An evidence‐based review of the efficacy of anti-
negatively impact the reported happiness of parents histamines in relieving pruritus in atopic dermatitis. Arch Dermatol
1999;135:1522–5.
and children struggling with AD [8]. Similar to children 12 Sidbury R, Tom WL, Bergman JN et al. Guidelines of care for the man-
without AD, sleep disturbance has also been linked to agement of atopic dermatitis: Section 4. Prevention of disease flares
impaired neurocognitive functioning and behavioural and use of adjunctive therapies and approaches. J Am Acad Dermatol
2014;71:1218–33.
issues [5]. Lack of sleep may be one component contrib-
ATOPIC DERMATITIS
13 Endo K, Sano H, Fukuzumi T et al. Objective scratch monitor evalua-
uting to the association of AD with attention deficit tion of the effect of an antihistamine on nocturnal scratching in atopic
hyperactivity disorder (ADHD) and other mental dermatitis. J Dermatol Sci 1999;22:54–61.
SECTION 3:
health disorders [9] (see Mental health disorders). 14 Schad CA, Skoner DP. Antihistamines in the pediatric population:
Achieving optimal outcomes when treating seasonal allergic rhinitis
and chronic urticaria. Allergy Asthma Proc 2008;29:7–13.
Treatment. Few studies have evaluated specific treat- 15 Chang Y‐S, Lin M‐H, Lee J‐H et al. Melatonin supplementation for
children with atopic dermatitis and sleep disturbance: a randomized
ments for improving sleep in patients with AD. One clinical trial. JAMA Pediatr 2016;170:35.
study showed improvement in sleep with hypnother- 16 Sowden JM, Allen BR, Berth‐Jones J et al. Double‐blind, controlled,
apy as reported by parents using a 10‐point visual ana- crossover study of cyclosporin in adults with severe refractory atopic
logue scale [10]. Antihistamines have long been used in dermatitis. The Lancet 1991;338:137–40.
17 Leo HL, Bender BG, Leung SB et al. Effect of pimecrolimus cream 1%
the treatment of AD for their soporific effects, with a on skin condition and sleep disturbance in children with atopic der-
goal of decreasing sleep latency as well as nighttime matitis. J Allergy Clin Immunol 2004;114:691–3.
scratching and awakenings; however, most of the evi- 18 Bieber T, Vick K, Fölster‐Holst R et al. Efficacy and safety of methyl-
prednisolone aceponate ointment 0.1% compared to tacrolimus 0.03%
dence for this is anecdotal [11]. Short‐term intermittent in children and adolescents with an acute flare of severe atopic der-
use of sedating antihistamines may be helpful in com- matitis. Allergy 2007;62:184–9.
bating sleep disturbance, but more research in this area
is needed [12,13]. The sedative effect of these drugs may
help with sleep but care is needed in prescribing to chil- Psychosocial complications
dren because sedating antihistamines have been shown
to affect school performance [14]. Melatonin supple- AD imposes a tremendous financial, social, emotional and
mentation has also been investigated, and in one rand- personal toll on patients and their families. These burdens
omized controlled trial of 48 children it decreased are not always immediately evident but nonetheless
sleep‐onset latency and led to an improvement in dis- important to consider when treating children with AD
ease severity. No significant difference was seen, how- and in interacting with caregivers. The interplay between
ever, in patient self‐reported sleep parameters [15]. children’s psychosocial environment and their skin dis-
Sleep can also improve with management of the under- ease is complex and multidirectional. Increased personal
lying AD. Studies evaluating the changes in sleep dur- stress and family tension can increase the severity of AD
ing treatment of AD, with both topical and systemic [1], while worsening AD can lead to increased stress.
treatments, have shown some improvement in sleep Chronic AD can also lead to high rates of psychological
parameters [1,16–18]. disturbance in children, causing behavioural difficulties
and an impaired capacity to cope with stress [2,3].
References AD most often begins in early infancy or childhood,
1 Camfferman D, Kennedy JD, Gold M et al. Eczema and sleep and its coinciding with crucial periods of psychosocial develop-
relationship to daytime functioning in children. Sleep Med Rev ment. Children with AD have behavioural difficulties,
2010;14:359–69.
increased dependency, fearfulness and clinginess [4].
2 Dahl RE, Bernhisel‐Broadbent J, Scanlon‐Holdford S et al. Sleep dis-
turbances in children with atopic dermatitis. Arch Pediatr Adolesc Noticeable skin disease can lead to difficulties in social
Med 1995;149:856–60. development with poor self‐esteem, teasing and isolation
3 Reuveni H, Chapnick G, Tal A, Tarasiuk A. Sleep fragmentation in from peers. Other children and adults may avoid contact
children with atopic dermatitis. Arch Pediatr Adolesc Med 1999;153:
249–53.
with children with AD, due to fear of a communicable
4 Bender BG, Leung SB, Leung DY. Actigraphy assessment of sleep dis- condition [5]. This can lead to poor self‐image and low
turbance in patients with atopic dermatitis: an objective life quality self‐esteem. In school‐age children academic performance
measure. J Allergy Clin Immunol 2003;111:598–602. may be negatively affected by missed days, as well as
5 Camfferman D, Kennedy JD, Gold M et al. Sleep and neurocognitive
functioning in children with eczema. Int J Psychophysiol 2013;89: poor attention related to lack of sleep and possibly ADHD
265–72. (see Mental health disorders).
6 Stores G, Burrows A, Crawford C. Physiological sleep disturbance in The psychosocial burden is felt by caregivers as well. As
children with atopic dermatitis: a case control study. Pediatr Dermatol
1998;15:264–8.
with most chronic childhood illness, AD has been shown to
7 Monti JM, Vignale R, Monti D. Sleep and nighttime pruritus in chil- lead to increased family stress. The lack of sleep and paren-
dren with atopic dermatitis. Sleep 1989;12:309–14. tal anxiety can lead to higher levels of depression. Parents
can feel tremendous amounts of guilt related to their child’s 7 Fivenson D. The effect of atopic dermatitis on total burden of illness
and quality of life on adults and children in a large managed care
AD. Mothers caring for children with AD report feelings of
organization. J Manag Care Pharm 2002;8:333–42.
social isolation due to their child’s illness and they are less 8 Ersser SJ, Cowdell F, Latter S et al. Psychological and educational
likely to be employed outside the home [4]. Strangers and interventions for atopic eczema in childrenCochrane Database Syst
family members may offer conflicting advice as well as Rev 2014;CD004054.
9 Staab D. Age related, structured educational programmes for the
judgement regarding care of the child’s AD. This can be dif- management of atopic dermatitis in children and adolescents: mul-
ficult to manage as a parent or primary caregiver [5]. ticentre, randomised controlled trial. BMJ 2006;332:933–8.
Management of AD can be equally demanding of parents’ 10 Chida Y, Steptoe A, Hirakawa N et al. The effects of psychological inter-
economic resources, with missed days of work, frequent vention on atopic dermatitis. Int Arch Allergy Immunol 2007;144:1–9.
specialist visits and prescription and non‐prescription
treatments. This is especially true in our modern health- Mental health disorders
care system with increasing patient financial responsibil-
ity. Costs can be divided into direct and indirect costs. Since the early 1900s, a link between one’s mental state
ATOPIC DERMATITIS
Direct costs include funds used to provide care for AD, and AD has been recognized, leading to the term ‘neuro-
including physician visits and medications. Indirect costs dermatitis’ [1]. Psychological disturbances affect children
SECTION 3:
include loss of productivity resulting from missed work/ with AD more so than their peers, with the severity of
school, as well as poor work performance and changes in disturbance related to the severity of the skin disease
quality of life. Annual direct costs in the USA have been [2–4]. Parents of children with AD experience higher lev-
estimated at US$1–4 billion [6]. Indirect costs are more els of stress and difficulty with child discipline [5].
difficult to quantify but one study found loss of work to Several population‐based studies revealed that children
account for at least 50% of the total economic burden [7]. with AD, especially those with severe disease or with
sleep disturbance, often carry a diagnosis of ADHD [6].
Treatment. AD has many effects on children’s lives More detailed study of this population is needed to
beyond the skin. Correspondingly, our treatment determine whether these children have true ADHD
should aim to address the psychological and emotional upon careful diagnostic scrutiny, or whether they have
needs of our patients and their families. Psychosocial been misclassified based on the symptoms of severe AD.
interventions can be primarily educational or more Other neuropsychiatric disorders have been reported to
structured psychological therapy, depending on need. be increased in children with AD including anxiety,
Educational programmes have been studied in a variety depression and autism [7–10]. These studies have been
of settings including multidisciplinary teams, nurse‐led cross‐sectional in nature and higher levels of evidence
groups, educational videos and parent‐ or patient‐ are needed to confirm these associations and establish
directed education [8]. The largest study of this kind causal relationships.
evaluated the effectiveness of age‐specific education
for 992 families. After 6 weeks of weekly sessions, sig- Pathogenesis. The causal relationships between AD and
nificant reductions in disease severity as well as mental disorders are not understood. Chronic sleep dis-
improvement in quality of life measures were seen [9]. turbance from pruritus may be an important causal link.
Psychological treatments can include cognitive behav- It is well‐known that disrupted sleep patterns negatively
ioural therapy, hypnotherapy, individual and family affect the mental state of normal children, affecting behav-
therapy and stress management. These interventions iour, mood and school functioning [11–13]. Disrupted sleep
probably have significant benefit but are less well stud- patterns are features of childhood depression, anxiety,
ied. The need for additional high‐quality studies in this ADHD and autism [14,15]. Inflammatory mediators may
area was highlighted by a Cochrane review as well as a also play a role. Pro‐inflammatory cytokines may not
meta‐analysis [8,10]. only affect skin, but could affect the developing brain
[16]. Pro‐inflammatory cytokines have been found in
References patients with depression, autism and ADHD [17–19].
1 King RM, Wilson GV. Use of a diary technique to investigate psychoso-
matic relations in atopic dermatitis. J Psychosom Res 1991;35:697–706.
2 Absolon CM, Cottrell D, Eldridge SM, Glover MT. Psychological dis- Treatment. A good medical history and exploration of a
turbance in atopic eczema: the extent of the problem in school‐aged child’s mood, behaviour, social life and school perfor-
children. Br J Dermatol 1997;137:241–5. mance with the family helps identify concerning pat-
3 Saunes M, Smidesang I, Holmen TL, Johnsen R. Atopic dermatitis in
adolescent boys is associated with greater psychological morbidity
terns. Referral to a childhood psychologist or other
compared with girls of the same age: the Young‐HUNT study. Br J mental health professional can yield significant benefits
Dermatol 2007;156:283–8. for both child and family and potentially improve skin
4 Daud LR, Garralda ME, David TJ. Psychosocial adjustment in pre- outcomes.
school children with atopic eczema. Arch Dis Child 1993;69:670–6.
5 Chamlin SL, Frieden IJ, Williams ML, Chren M‐M. Effects of atopic
dermatitis on young American children and their families. Pediatrics References
2004;114:607–11. 1 Brunsting LA. Atopic dermatitis (disseminated neurodermatitis) of
6 Mancini AJ, Kaulback K, Chamlin SL. The socioeconomic impact of young adults: analysis of precipitating factors in one hundred and
atopic dermatitis in the United States: a systematic review. Pediatr one cases and report of ten cases with associated juvenile cataract.
Dermatol 2008;25:1–6. Arch Derm Syphilol 1936;34:935–57.
2 Faulstich ME, Williamson DA, Duchmann EG et al. Psychophysiological reveal giant cobblestone‐like papillae of the upper tarsal
analysis of atopic dermatitis. Jo Psychosom Res 1985;29:415–17.
conjunctiva or at the limbus. Although vernal keratocon-
3 Absolon CM, Cottrell D, Eldridge SM, Glover MT. Psychological dis-
turbance in atopic eczema: the extent of the problem in school‐aged junctivitis has a favourable prognosis, with resolution in
children. Br J Dermatol 1997;137:241–5. the majority of patients around puberty, it can be associ-
4 Chamlin SL. The psychosocial burden of childhood atopic dermati- ated with permanent reduction in visual acuity due to cor-
tis. Dermatol Ther 2006;19:104–7.
5 Daud LR, Garralda ME, David TJ. Psychosocial adjustment in pre-
neal damage in about 6% of patients [5]. Atopic
school children with atopic eczema. Arch Dis Child 1993;69:670–6. keratoconjunctivitis is bilateral and symmetrical, usually
6 Schmitt J, Buske‐Kirschbaum A, Roessner V. Is atopic disease a risk with associated eyelid swelling, erythema and scaling
factor for attention‐deficit/hyperactivity disorder? A systematic (atopic blepharoconjunctivitis) and is more prone to scar-
review. Allergy 2010;65:1506–24.
7 Yaghmaie P, Koudelka CW, Simpson EL. Psychiatric comorbidity in ring than vernal keratoconjunctivitis. Symptoms of itch-
pediatric eczema. J Invest Dermatol 2011;131(suppl 1):S41. Abstract #246. ing, discharge and conjunctival injection are similar to
8 Magalhaes ES, Pinto‐Mariz F, Bastos‐Pinto S et al. Immune allergic vernal keratoconjunctivitis [2]. Patients with AD are also
response in Asperger syndrome. J Neuroimmunol 2009;216(1‐2):108–12.
prone to developing both irritant and allergic contact der-
ATOPIC DERMATITIS
9 Mostofa GA, Hamza RT, El‐Shahawi HH. Allergic manifestations in
autistic children: Relation to disease severity. J Pediatr Neurol 2008; matitis and blepharitis affecting the eyelids [4].
6:115–23. Other ocular complications including cataracts, kerato-
SECTION 3:
10 Sacco R, Curatolo P, Manzi B et al. Principal pathogenetic components conus and retinal detachment are uncommon in patients
and biological endophenotypes in autism spectrum disorders. Autism
Res 2010;3:237–52. with AD but can result in severe impairment [3,6,7]. Both
11 Yokomaku A, Misao K, Omoto F et al. A study of the association posterior and anterior subcapsular cataracts have been
between sleep habits and problematic behaviors in preschool chil- described in AD [4,6]. Anterior subcapsular cataracts are
dren. Chronobiol Int 2008;25:549–64.
less commonly seen but are more specific for AD, as they
12 Hiscock H, Canterford L, Ukoumunne OC, Wake M. Adverse associa-
tions of sleep problems in Australian preschoolers: national popula- are not seen frequently in patients without AD [6]. The
tion study. Pediatrics 2007;119:86–93. aetiology of cataracts in patients with AD is not com-
13 Gregory AM, Van der Ende J, Willis TA, Verhulst FC. Parent‐reported pletely understood. It does not seem to correlate with
sleep problems during development and self‐reported anxiety/
depression, attention problems, and aggressive behavior later in life.
severity of AD, or corticosteroid therapy [4,6,8–10]. Some
Arch Pediatr Adolesc Med 2008;162:330–5. studies have implicated oxidative stress to the lens result-
14 Owens JA, Maxim R, Nobile C et al. Parental and self‐report of sleep ing from chronic inflammation [6,8].
in children with attention‐deficit/hyperactivity disorder. Arch Keratoconus is a noninflammatory progressive ectasia
Pediatr Adolesc Med 2000;154:549–55.
15 Ivanenko A, Johnson K. Sleep disturbances in children with psychiat- of the cornea. It is characterized by thinning and protru-
ric disorders. Semin Pediatr Neurol 2008;15:70–8. sion of the central cornea [11,12]. Classically it presents at
16 Buehler MR. A proposed mechanism for autism: an aberrant neuroim- puberty and progresses until the third or fourth decade
mune response manifested as a psychiatric disorder. Med Hypotheses
2011;76:863–70.
[13]. Evidence suggests that keratoconus is related more
17 Kiecolt‐Glaser JK, Belury MA, Andridge R et al. Omega‐3 supplemen- to the chronic rubbing of the eyelid commonly seen in
tation lowers inflammation and anxiety in medical students: a rand- patients with AD, than to the presence of AD alone [12].
omized controlled trial. Brain Behav Immun 2011;25:1725–34. Retinal detachment is a rare ocular complication of AD
18 Pollak Y, Yirmiya R. Cytokine‐induced changes in mood and behav-
iour: implications for ’depression due to a general medical condi- that is primarily seen in Japanese patients with facial
tion’, immunotherapy and antidepressive treatment. Int J involvement [14–16]. The aetiology seems to be related to
Neuropsychopharmacol 2002;5:389–99. trauma caused by either rubbing or tapping the eyes or
19 Zimmerman AW, Jyonouchi H, Comi AM et al. Cerebrospinal fluid
eyelids but it can also occur as a complication following
and serum markers of inflammation in autism. Pediatr Neurol
2005;33:195–201. surgical correction of cataracts [14,16,17].
These ocular complications require prompt treatment
and evaluation, usually with the help of an ophthalmolo-
Ocular complications gist. Periodic ocular examination and questioning regard-
ing ocular symptoms should be a part of routine
Atopic eye disease encompasses similar but distinguisha- dermatological care for a patient with AD.
ble conditions including seasonal allergic conjunctivitis,
vernal keratoconjunctivitis, atopic keratoconjunctivitis
References
and atopic blepharoconjunctivitis. Atopic keratoconjunc- 1 Chen JJ, Applebaum DS, Sun GS, Pflugfelder SC. Atopic kerato-
tivitis is a chronic condition characterized by noninfec- conjunctivitis: A review. J Am Acad Dermatol 2014;70:569–75.
tious inflammation and is one of the most severe and 2 Guglielmetti S, Dart JK, Calder V. Atopic keratoconjunctivitis and
atopic dermatitis. Curr Opin Allergy Clin Immunol 2010;10:478–85.
potentially damaging ocular complications of AD [1]. 3 Carmi E, Defossez‐Tribout C, Ganry O et al. Ocular complications
Atopic keratoconjunctivitis is most often seen in adults of atopic dermatitis in children. Acta Derm Venereol 2006;86:515–17.
with onset ranging from 20 to 50 years of age but it has 4 Rich LF, Hanifin JM. Ocular complications of atopic dermatitis and
been reported in children as young as 7 years old [1], other eczemas. Int Ophthalmol Clin 1985;25:61–76.
5 Bonini S, Bonini S, Lambiase A et al. Vernal keratoconjunctivitis
while vernal keratoconjunctivitis is more common in chil- revisited: A case series of 195 patients with long‐term followup.
dren, typically appearing between 5 and 15 years of age Ophthalmology 2000;107:1157–63.
[2–4]. Vernal keratoconjunctivitis is seen more often in 6 Bair B, Dodd J, Heidelberg K, Krach K. Cataracts in atopic dermati-
tis: A case presentation and review of the literature. Arch Dermatol
boys and is characterized by intense itching, mucous dis- 2011;147:585–8.
charge, conjunctival injection and photophobia that is not 7 Hirano S, Katoh N, Kishimoto S et al. Cataract in atopic dermatitis
always bilateral [2,5]. Ophthalmological examination can with facial involvement. J Dermatol Sci 1993;6:94.
8 Niwa Y, Iizawa O. Abnormalities in serum lipids and leukocyte 14 Hida T, Tano Y, Okinami S et al. Multicenter retrospective study of
superoxide dismutase and associated cataract formation in patients retinal detachment associated with atopic dermatitis. Jpn J
with atopic dermatitis. Arch Dermatol 1994;130:1387–92. Ophthalmol 2000;44:407–18.
9 Garrity JA, Liesegang TJ. Ocular complications of atopic dermatitis. 15 Yoneda K, Okamoto H, Wada Y et al. Atopic retinal detachment.
Can J Ophthalmol 1984;19:21–4. Report of four cases and a review of the literature. Br J Dermatol
10 Tm B, Ja B, Jm S. Atopic dermatitis: a case report and current clinical 1995;133:586–91.
review of systemic and ocular manifestations. Optom St Louis Mo 16 Taniguchi H, Ohki O, Yokozeki H et al. Cataract and retinal detach-
2001;72:94–102. ment in patients with severe atopic dermatitis who were with-
11 Krachmer JH, Feder RS, Belin MW. Keratoconus and related nonin- drawn from the use of topical corticosteroid. J Dermatol 1999;26:
flammatory corneal thinning disorders. Surv Ophthalmol 1984;28: 658–65.
293–322. 17 Oka C, Ideta H, Nagasaki H et al. Retinal detachment with atopic der-
12 Bawazeer AM, Hodge WG, Lorimer B. Atopy and keratoconus: a matitis similar to traumatic retinal detachment. Ophthalmology 1994;
multivariate analysis. Br J Ophthalmol 2000;84:834–6. 101:1050–4.
13 Rabinowitz YS. Keratoconus. Surv Ophthalmol 1998;42:297–319.
ATOPIC DERMATITIS
SECTION 3:
253
C HA PTER 19
Management of Atopic Dermatitis

Lea Solman & Mary Glover
Department of Paediatric Dermatology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK
Introduction, 253 Systemic therapy, 257 Psychological impact of atopic

Education and general advice, 253 Biologics in atopic dermatitis, 259 dermatitis, 261
Initial therapy, 254 Allergy in atopic dermatitis, 260 Conclusion, 261
ATOPIC DERMATITIS
Unresponsive disease, 256 Prevention of atopic dermatitis, 261
SECTION 3:
Abstract of emollients to improve the integrity of the skin barrier, topical
application of corticosteroids and calcineurin inhibitors, avoidance
Atopic dermatitis is a chronic inflammatory disease, affecting more of apparent exacerbating factors, and multidisciplinary patient
than 20% of children in some developed countries. The main aims education. In patients with severe atopic dermatitis that is nonre-
of treatment are to control symptoms, prevent exacerbations and sponsive to topical treatment, phototherapy or systemic therapy
minimize therapeutic risk. Initial therapy consists of the application may be required.
Key points • Systemic immunomodulating medications are indicated for

the management of severe atopic dermatitis that has failed
to respond to appropriate topical treatment and attention to
• The management of atopic dermatitis is complex and will
aggravating factors.
depend on the age of the child, the extent, severity, location
• There is relatively little experience with biological response
and chronicity of the condition; it must take into consideration
modifiers in the management of childhood atopic dermatitis,
social and environmental factors.
but they can be expected to play an increasing role.
• Education, emollients and topical corticosteroids are the
mainstay in the treatment of childhood atopic dermatitis.
Introduction so need the opportunity to understand when and why a

particular treatment or intervention is needed.
The management of atopic dermatitis (AD) is complex, and Attention to education of families of children with
will depend on the age of the child and the extent, severity, atopic dermatitis (AD) has been shown to reduce disease
location and chronicity of the condition (Fig. 19.1); it must severity and improve quality of life over a period of at
take into consideration social and environmental factors. least 1 year [1]. Discussion time with families is important
Although prevention remains the ideal, early effective to dispel misconceptions, bring clarity to areas of confu
treatment offers the best hope of reducing the likelihood sion, limit exposure of the child to irritants, and prevent
of progression to chronic disease and the risk of develop inappropriate or harmful treatments and unnecessary
ment of allergen sensitization. dietary intervention. It is particularly important to dis
Families of children with AD are often subjected to cuss the role of factors that may impair the epidermal
conflicting advice, particularly in relation to the safety of barrier, including low‐humidity environments and expo
topical corticosteroids and the role of diet, leading to sure to soaps and detergents. Parents should be reminded
confusion, anxiety, adoption of unhelpful interventions that AD may worsen during common childhood illnesses
and failure to use effective treatment. Effective, safe and teething. Family members should be discouraged
management depends on listening to and addressing from smoking in the house.
concerns, full explanation of the rationale for specific Many parents have been led to believe that food
treatments and discussion of risk and benefit. allergies are the primary driving force of AD, leading
to children being on exclusion diets despite lack of evi
dence of a clinically relevant allergy, or of benefit from
Education and general advice
the exclusion.
The management of AD is complicated, time‐consuming, Although swimming pool water can lead to drying of
messy and often resisted by the children concerned. the skin, because swimming is a vitally important life skill
Parents are frequently subjected to conflicting advice and and an enjoyable family activity, patients with AD should
Biologic therapy
T Systemic therapy
r
Phototherapy
e
a
Calcineurin inhibitors Calcineurin inhibitors
t
m
Mild-potency TCS Moderate-potency TCS Potent TCS
e
n
Emollient Emollient Emollient
t
ATOPIC DERMATITIS
Mild eczema Moderate eczema Severe eczema

SECTION 3:
Fig. 19.1 Treatment options in atopic dermatitis.

Eczema severity
TCS, topical corticosteroids.
not be excluded from swimming lesions but should be of symptoms [5]. Emollients should be applied at least
encouraged to shower and moisturize thoroughly after twice a day and immediately after bathing and hand
swimming. washing. It can be useful to allow patients to try a range
Parents should be advised that live vaccines should be of emollients. To reduce the risk of folliculitis, emollients
avoided in children on systemic immunosuppressive should be applied in the direction of hair growth. In warm
medication, but the vaccination schedule should be conditions, less greasy emollients will be required. It is
followed as normal in other children with AD. important to prescribe sufficient quantities of emollients
(250–500 g weekly).
Initial therapy
Topical corticosteroids
Bathing TCS have been the mainstay of therapy for AD since they
Parents frequently receive conflicting advice regarding were first introduced in 1952. The anti‐inflammatory
the benefits of bathing, probably because hard water, action is thought to arise mainly from regulation of gene
detergents and soaps can aggravate AD. However, bath transcription through the ligand‐activated glucocorti
ing with moisturizing cleansers hydrates the skin and coid receptor and posttranslational regulation of gene
the majority of patients find it soothing. The skin must expression [6].
be cleansed gently, but thoroughly, to remove skin scales, Age, anatomical site and vehicle, as well as severity
crusts and exudate. Nonirritant, moisturizing soap and type of AD, should be taken into consideration when
substitutes with or without antiseptics should be used. prescribing TCS treatment. TCS are available in a variety
The addition of bath oil provides the skin with a thin of potencies and preparations. The European classifi
lipid layer. Caution needs to be taken when adding oils cation uses four potency groups from mild (group I) to
to the bath, as the bathtub can become very slippery. super‐potent (group IV). The American classification uses
Bath time should be kept to around 7–10 minutes. The seven groups, with group 1 being the most potent and
water temperature should be just warm enough for group 7 the least potent.
the child to be comfortable, but not hot. The skin should For dry skin, application of TCS in ointment base is
be patted dry rather than rubbed, and an emollient most effective, providing better lubrication and occlu
applied while the skin is still slightly damp. sion than a cream base, though the greasy quality of
ointments can be unappealing, particularly in warm
Emollients conditions, and may result in poor compliance. Creams
Poor skin barrier function is a key risk factor for develop are more cosmetically acceptable but contain preserva
ment of AD [2,3]. Skin barrier dysfunction enables aller tives, which can cause stinging, irritation and contact
gen penetration into the skin, leading to irritation and dermatitis. Gels and lotions are the least greasy and so
inflammation. Application of emollients improves the are convenient to use on the scalp.
integrity of the skin barrier. In a randomized controlled Absorption of TCS has been demonstrated to vary
trial (RCT) of infants with AD requiring moderate‐ or not only between individuals but also with anatomical
high‐potency topical corticosteroids (TCS), infants treated location [7]. Anatomical regions with thinner epidermis
with emollients had significantly decreased requirements are significantly more permeable than areas with thicker
for TCS compared with a control group of infants who skin. While absorption on the forearm is relatively low
were not treated with emollients [4]. A more recent RCT (1%), the scalp absorbs around 4% and the scrotum up to
demonstrated that the regular use of emollients alone in 35% of applied TCS [7]. Penetration varies between eyelid
children with mild‐to‐moderate AD reduces the severity and plantar skin about 300‐fold [7]. Corticosteroids are
Chapter 19 Management of Atopic Dermatitis 255
better absorbed through areas of inflammation and Wet wraps

desquamation than normal skin, and more readily Wet wraps can be useful for severe AD, especially in
through the thin stratum corneum of infants [8]. Hydration young children. A widely used technique involves the
promotes steroid penetration, for example, after a bath or application to the torso and limbs of tubular bandage
shower. To limit the risk of adverse effects, eyelid and soaked in diluted TCS cream, changed twice a day, for
genital AD should be treated with low‐potency topical 3–5 days. Another approach is to apply TCS directly to
steroid. Low‐ to medium‐strength preparations should the areas of inflammation, followed by dampened tubular
be considered when large areas are treated, to limit sys bandage, then a dry layer of tubular bandage. Wet wraps
temic absorption, but medium‐ to high‐potency TCS serve as an occlusive dressing to prevent itching and
may be considered for limited areas of severe nonfacial/ improve retention of the TCS on the skin. Wet wraps can
nonintertriginous AD. be administered in hospital, but may be used at home if
Most studies on TCS use in AD have involved twice‐ the parents are educated and closely supervised by a
daily application, but it has been suggested that once‐ specialist nurse. Emollient‐only wet wraps are less effec
ATOPIC DERMATITIS
daily application may not result in loss of efficacy and tive than wet wraps using diluted TCS [13], but can be
could lead to fewer local side‐effects. Application of TCS soothing and may help to reduce nocturnal pruritus.
SECTION 3:
just once a day may be more convenient for patients and
may save costs if established preparations are used [9]. Silk therapeutic clothing
Application of TCS of appropriate potency in sufficient Preliminary results of an RCT to evaluate the effective
quantities early after the onset of AD, and promptly to ness of silk therapeutic clothing when used in addition
flares, offers the best chance of bringing the inflamma to usual care over a period of 6 months in children aged
tory process under rapid control, allowing restoration of 1–15 years with AD suggest that that there is unlikely to
skin barrier function and so keeping TCS requirement to be additional benefit [14].
a minimum. The TCS must be sufficiently potent and
applied in sufficient quantities to induce remission over Topical calcineurin inhibitors
a matter of days, so that control can then be maintained Topical calcineurin inhibitors (TCI) are macrolactam deriv
primarily with emollients and avoidance of aggravating atives with immune‐modulating and anti‐inflammatory
factors. properties. Their anti‐inflammatory effects result from
In order to reassure parents about TCS, clear informa inhibition of pro‐inflammatory cytokine production from
tion must be provided and sufficient time allocated to T cells, whereas their antipruritic effects are attributed to
listen and respond fully to their concerns. Education of an inhibition of mast cell degranulation [15]. Pimecrolimus
parents, carers and patients is an essential aspect of TCS cream and tacrolimus ointment have been licensed for the
prescription, with particular attention to the significance treatment of AD in the UK since 2001, subject to National
of different potencies, and how much, for how long, and Institute for Health and Care Excellence (NICE) guidance.
to what site each TCS should be applied. Demonstration Both topical pimecrolimus and tacrolimus (0.03%) are
of exactly how to apply the preparation, which areas second‐line treatments for children in whom AD is not
should be covered and how thick the layer of ointment or adequately controlled with TCS, or when prolonged
cream should be is extremely helpful. Although the fin use of TCS is not advisable. They can be used in non‐
gertip unit has been used widely as a simple guide to how immunocompromised patients as steroid‐sparing agents
much TCS should be applied to a particular area [10], this for the treatment of mild‐to‐moderate AD involving the
method can lead to dabbing of inadequate amounts of the face, including the eyelids, neck and skin folds. Three
TCS, resulting in undertreatment. studies on pimecrolimus noted greater improvement on
Anxiety among both the general public and some fam the face and neck compared to other body sites [16–18].
ily doctors about potential adverse effects of TCS has led TCI can be used as a proactive, intermittent treatment two
to widespread inadequate treatment [11]. A survey of 200 or three times a week to prevent relapses [19]. TCS may be
dermatology outpatients with AD found that 72.5% were required initially, to induce remission.
worried about use of TCS on their own or their child’s TCI applied once or twice a day have been shown to be
skin, with 24% admitting noncompliance with therapy as significantly more effective than vehicle in decreasing
a result of these concerns [11]. signs of inflammation [20]. A systematic review compar
In practice, clinically significant adverse effects of TCS ing TCI and TCS has shown similar rates of improvement
are rarely encountered. Excessive application of the more of AD and treatment success [21]. TCI were associated
potent TCS may lead to atrophy, telangiectases, purpura, with higher costs and more adverse events, such as burn
striae, focal hypertrichosis and acneiform eruptions. ing and pruritus [21]. A meta‐analysis of 25 RCTs found
Cutaneous atrophy is most likely to occur with extended tacrolimus 0.1% to be as effective as the mid‐potency TCS
application to thin skin, such as the flexures, and use of hydrocortisone butyrate 0.1%, while tacrolimus 0.03% is
higher‐potency steroids, particularly under occlusion. If a less effective than hydrocortisone butyrate 0.1% but
potent or super‐potent steroid is used, sites of treatment more effective than the low‐potency TCS hydrocortisone
should be closely monitored and the skin regularly acetate 1% [22].
reviewed for signs of atrophy. Because young children The most frequently observed adverse effect is transient
have a higher surface‐to‐weight ratio than adults, systemic burning at the application site during the first few days
absorption represents a proportionately greater risk [12]. [23], usually from about 5 minutes after application and
lasting up to 1 hour. The intensity and duration of the family and encourage a positive approach to treatment,
sensation typically decrease within 7 days if twice‐daily and to re‐explore the role of aggravating factors.
application is continued [24]. This should be explained to
patients and parents before the start of treatment, to avoid Management of infection
premature discontinuation. A few days of treatment with Skin infections are very common in patients with AD,
TCS before switching to TCI may reduce the burning arising as a result of a disrupted skin barrier and abnor
sensation, and an overlap period of 1 week may be advis malities in both innate and adaptive immune responses.
able [25]. Generalized viral infections, such as eczema Staphylococcus aureus is a frequent skin colonizer in
herpeticum [26] and widespread molluscum contagio patients with AD. It has an important role in disease
sum [27], have been reported in patients treated with TCI, pathogenesis as it can trigger recurrent flares by stimu
and although a number of studies have failed to replicate lating the release of the highly pruritogenic cytokine,
these findings [15], it is advised that TCI should not be IL‐3. Staph. aureus can also directly disrupt the skin
applied in the context of cutaneous infection. barrier through production of bacterial proteases, which
ATOPIC DERMATITIS
Rare cases of malignancy (skin cancer and lymphoma) break down epidermal proteins such as filaggrin [35].
have been reported in patients treated with TCI, although Staph. aureus can be isolated from skin lesions in 76–100%
SECTION 3:
a causal relationship has not been confirmed. Long‐term of patients with AD compared to 2–25% of unaffected
studies have not shown increased risk of malignancy with individuals [36]. Clinical signs of infection include
TCI in a paediatric population [28]. However, parents and weeping, honey‐coloured crusts, worsening of AD and
patients should be informed of the concern about a theo poor response to treatment. Nasal and skin swabs should
retical increased risk of skin malignancy, based on data be taken from patients with recurrent infection that fails
from long‐term oral calcineurin inhibitor therapy in trans to respond to treatment. For patients with localized skin
plant patients, and from animal studies using exposures infection, short‐term use of topical antibiotics may be
25 to nearly 50‐fold the maximum recommended human beneficial. In patients with more extensive infection, oral
dose [29]. antibiotics are recommended.
Patients with recurrent infection may benefit from anti
Phosphodiesterase 4 inhibitors septic baths, although the evidence is limited [37,38].
Phosphodiesterase 4 (PDE4) is involved in the regulation Eczema herpeticum is a serious complication of AD
of pro‐inflammatory cytokines and is increased in the associated with high morbidity. Affected children are often
inflammatory cells of patients with AD. Targeting PDE4 unwell and in pain, with widespread vesicles, erosions
reduces the production of these pro‐inflammatory media and crusted punched‐out ulcers. Secondary complications
tors in AD. Both topical and oral PDE4 inhibitors have a such as meningitis, keratoconjunctivitis and encephalitis
favourable safety profile. Crisaborole 2% ointment, a can occur. Immediate treatment with aciclovir is required,
topical PDE4, is now US Food and Drug Administration‐ which must be given intravenously in severe cases.
approved for children older than 2 years for the treatment Eczema coxsackium is a newer entity caused by
of AD. Crisaborole 2% ointment shows early and sus coxsackievirus A6. In children with AD, lesions tend to
tained improvement in disease severity and pruritus and concentrate in areas previously or currently affected by
other AD symptoms, with burning and/or stinging upon the AD, similar to eczema herpeticum [39]. Treatment of
application as the only related adverse event. Other PDE4 eczema coxsackium is supportive and affected children
inhibitors are currently in trials with promising efficacy recover fully without permanent scarring.
and safety [30,31].
Contact allergy
Janus kinase (JAK) inhibitors Contact allergy should be suspected when compliance
Janus kinases (JAKs) are required for several inflamma has been good, no infection is evident and the AD is
tory cytokine signalling pathways and have been impli failing to respond. The most common allergens are nickel,
cated in the pathogenesis of AD [32]. Although the study cobalt, thimerosal and fragrance [40]. A retrospective
of JAK inhibitors for AD is still in its early stage, evidence study of 2614 children showed similar rates of positive
has identified topical JAK inhibitors as a potential new patch test reactions in children with and without AD, but
treatment for AD [33]. Large safety and efficacy trials are children with AD were more likely to have positive patch
needed before widespread use of JAK inhibitors can be test reactions to potassium dichromate, Compositae mix
advocated for AD [34]. and disperse blue [41]. Patients with isolated hand and/
or foot eczema should always have patch testing.
Unresponsive disease Phototherapy
Failure to respond to initial treatment should not auto Narrowband UVB is the preferred form of phototherapy
matically lead to provision of more potent TCS. The most for AD in children. The mechanism of action in AD is still
common causes of failure to respond to treatment are not fully understood, although narrowband UVB is known
inadequate application and persistence of aggravating to induce T‐cell apoptosis and anti‐inflammatory and
factors. Clinicians should enquire about the quantities of immunosuppressive cytokines [42] and has been shown
emollients and TCS used between visits. The follow‐up to reduce levels of cutaneous Staph. aureus and suppress
appointment is an excellent opportunity to educate the production of superantigen in children with AD [43].
Older children and adolescents with severe AD gener Systemic therapy

ally tolerate narrowband UVB phototherapy well, but it
is time consuming and the frequency of hospital visits Systemic immunomodulating medications are indicated
for treatment can be disruptive of schooling. Adverse for the management of severe AD that has failed to
effects may include transient erythema, blistering, herpes respond to appropriate topical treatment and attention to
simplex reactivation and anxiety [44]. aggravating factors (Table 19.1).
Data on the efficacy of narrowband UVB in paediatric
patients with AD are limited. In a study of 77 patients Systemic corticosteroids
aged from 4 to 16 years with psoriasis or AD treated Although systemic corticosteroids can offer short‐term
with narrowband UVB phototherapy, 17 of the 25 relief of symptoms, severe rebound of AD occurs when
patients with AD had minimal residual disease after a attempts are made to withdraw treatment. Long‐term
median of 24 treatments [44]. A retrospective study of treatment with systemic corticosteroids is not recom
paediatric patients with severe AD who completed mended for AD, owing to the likelihood of significant
ATOPIC DERMATITIS
more than 10 narrowband UVB treatments showed adverse effects including weight gain, adrenal suppres
complete clearance or good improvement in 30 of the sion, decreased linear growth, hypertension, glucose
SECTION 3:
50 patients [45]. A cohort study comparing patients aged intolerance and decreased bone density [48]. Occasionally
3–16 years who received narrowband UVB phototherapy systemic steroids may be considered for relatively short‐
with unexposed children reported a 61% reduction in term use while another slower‐acting systemic treatment
mean six‐area, six‐sign atopic dermatitis (SASSAD) is being initiated.
score in the phototherapy cohort at 12 weeks of treat
ment compared with an increase of 6% in the unexposed Methotrexate
cohort [46]. Methotrexate inhibits DNA synthesis by substrate compe
There are no studies evaluating the risk of cancer in tition with dihydrofolate reductase. It is also thought to
children with AD treated with phototherapy. A systematic negatively affect T‐cell function. Gastrointestinal distur
review of four studies assessing the risk of skin cancer bance, anorexia, fatigue, stomatitis and alopecia are the
among adults and children with psoriasis treated with most common adverse effects. Hepatotoxicity and bone
narrowband UVB did not find an increased risk of skin marrow suppression are the most serious adverse effects.
cancer [47]. An RCT of 40 patients aged 8–14 showed very similar
Table 19.1 Systemic treatments for AD
Systemic Starting dose Baseline testing Monitoring Adverse effects

agent
Methotrexate 10–15 mg/m2 weekly FBC, U&E, LFT, VZV status FBC, U&E, LFT every 1–2 weeks Hepatotoxicity, bone marrow
Consider HIV, TB, hepatitis for the first month, then suppression, GI disturbance, nausea,
screen and pregnancy test monthly for the first 3 fatigue, headache
months, then every 3 months
Ciclosporin 2.5–5 mg/kg/day Blood pressure measurement Blood pressure measurement, Nephrotoxicity, hypertension, nausea,
FBC, U&E, LFT FBC and U&E every 2 weeks paraesthesia, hypertrichosis,
VZV status for the first 1–2 months, then swollen gums, headache, rhinitis,
Consider HIV, TB, hepatitis 4–6‐weekly upper respiratory tract infection,
screen abdominal pain, folliculitis and
hyperuricaemia
Azathioprine Dependent on TPMT TPMT activity, FBC, U&E, LFT, FBC and LFT weeks 1, 3, 7, then Viral cutaneous infections, nausea,
activity VZV status every 3 months headaches, bone marrow
TMPT normal: Consider HIV, TB, hepatitis suppression, malignancy,
2–3 mg/kg/day screen and pregnancy test hepatotoxicity
TPMT reduced:
1–1.5 mg/kg/day
TPMT absent – do not

give azathioprine
Mycophenolate 40–50 mg/kg/day FBC, U&E, LFT FBC and LFT every 1–2 weeks Nausea, vomiting, diarrhoea, bone
mofetil young children VZV status for the first month then every marrow suppression, hypertension,
30–40 mg/kg/day Consider HIV, TB, hepatitis 3 months nephrotoxicity
adolescents screen and pregnancy test
FBC, full blood count; GI, gastrointestinal; HIV, human immunodeficiency virus; LFT, liver function tests; TB, tuberculosis; TPMT, thiopurine methyl‐transferase;
U&E, urea and electrolytes; VZV, varicella zoster virus.
efficacy between methotrexate and ciclosporin, with a recurrent neutropenia (1), persistently raised alanine
mean SCORing Atopic Dermatitis (SCORAD) reduction aminotransferase (1), headaches (1), recurrent chest infec
of 45% in both groups [49]. Time to response was margin tions (1), and recurrent herpes labialis (1) [55].
ally longer for patients in the methotrexate arm, but better Malignancy has been reported in patients treated with
sustained on discontinuation of treatment. Adverse azathioprine for inflammatory bowel disease, and
effects of methotrexate reported in this study included although malignancy has not been reported in children
anaemia (30%), fatigue (30%), abnormal liver function on azathioprine for AD, it is advisable to explain these
(25%), nausea and vomiting (20%) and glossitis with oral reports to parents and to limit treatment to no more than
ulceration (20%). No patient had significant liver toxicity 2 years’ duration if possible.
or other adverse effects that required stopping or adjust Parents and patients should be advised that azathioprine
ment in treatment. Another multicentre retrospective has a slow onset of action, with clinical improvement
study reviewing the medical records of 26 paediatric sometimes not evident until 8–12 weeks after starting.
patients with AD confirmed that methotrexate is a toler The dose of azathioprine required depends on the
ATOPIC DERMATITIS
able and effective agent for treating refractory childhood activity of the enzyme thiopurine methyl‐transferase
AD [50]. Multiple studies in paediatric patients with (TPMT). Patients with reduced or absent TPMT activity
SECTION 3:
psoriasis have shown methotrexate to be a safe and (10% and 0.3%) are at risk of profound immunosuppres
well‐tolerated treatment [51]. sion. If TPMT activity is within the normal range the start
Baseline blood tests should include full blood count ing dose should be 2–3 mg/kg/day. If TPMT activity
(FBC), urea and electrolytes (U&E), liver function tests is reduced, the starting dose should be no more than
(LFT) and varicella zoster immune status. In selected 1–1.5 mg/kg/day. In patients with absent TPMT activity,
cases tuberculosis (TB), human immunodeficiency virus azathioprine should not be administered. Children with
(HIV), hepatitis B and C serology, and pregnancy testing higher TPMT levels may respond less well to treatment
should be considered. If the child is not varicella immune, but may have a greater risk of hepatotoxicity [56]. In addi
vaccination should be considered before starting treat tion to TPMT, baseline blood tests should include FBC,
ment. Dosing for the paediatric population is 10–15 mg/m2 U&E, LFT and varicella immune status. In selected cases
once a week. Dividing the dosing results in fewer gastro HIV, TB, hepatitis B and C serology and pregnancy testing
intestinal adverse effects [49]. Treatment with methotrexate should be considered. Monitoring of FBC and LFT should
must be supplemented with folic acid (1 mg/day). be done at weeks 1, 3, and 7 after starting treatment, and
Recommendations for monitoring vary. A commonly three 3‐monthly thereafter, if there is no breach in blood
used schedule consists of FBC, U&E and LFT every parameters [55]. Photoprotection should be advised.
1–2 weeks for the first month, then monthly for 3 months, Live vaccines are contraindicated during treatment
and then every 3 months thereafter if the dose is stable with azathioprine and should be given at least 2 weeks
and results have been normal. Amino terminal type III (preferably 4 weeks) prior to starting treatment with
procollagen peptide (P3NP) measurement is not useful as azathioprine and at least 3 months after stopping. Varicella
an indicator of liver fibrosis in children as levels are influ vaccine should be considered in children without
enced by linear growth rate. immunity.
Live vaccines must not be given 2 weeks (preferably
4 weeks) before starting the treatment with methotrexate Ciclosporin
and at least 3 months after stopping. Inactivated vaccines Ciclosporin (cyclosporine) is an effective medication that
can be given, however methotrexate may lower the level is useful when a rapid response is required; however,
of immunity achieved. Varicella vaccination should be patients can experience similarly rapid relapse after
considered in children without immunity before starting discontinuation.
the treatment. A multicentre study involving 27 children with AD
found 22 patients to have marked improvement or com
Azathioprine plete clearing at 6 weeks of treatment [57]. Most of the
Azathioprine is converted into 6‐mercaptopurine in the patients relapsed within weeks of stopping treatment, but
body where it blocks purine metabolism and DNA three were in remission 6 months after ceasing. Headache
synthesis. It selectively inhibits lymphocytes, especially and abdominal pain were the most commonly reported
T lymphocytes [52]. Three retrospective studies, including adverse effects. A trial of 40 children aged 2–16 years
17, 28 and 82 patients respectively, and one prospective with severe AD comparing ciclosporin 5 mg/kg per day
study including 12 patients, showed that azathioprine is for multiple periods of 3 months or continuously for
an effective and well‐tolerated medium‐term treatment 12 months showed no difference between the two groups
for paediatric AD [52–55]. In the largest study, clinical in overall disease improvement at 1 year [58]. There is
adverse effects were seen in 16 of 82 patients (20%). Most limited evidence that a lower dose of ciclosporin for
common were cutaneous viral infections (molluscum longer periods may be associated with prolonged remis
contagiosum and viral warts) in 12%, with single cases sion after discontinuation [59].
of nausea, lethargy, indigestion, asthma exacerbation, Adverse effects of ciclosporin include nephrotoxicity,
unconfirmed possible myopathy, headache, and recurrent hypertension, hypertrichosis, tremor, infection, headache,
chest infections [55]. In total, five patients (6%) had to gingival hyperplasia and increased risk of skin cancer
stop azathioprine because of adverse effects including and lymphoma. Nephrotoxicity and hypertension are the
most concerning but no evidence of these adverse effects It inhibits downstream signalling of IL‐4 and IL‐13,
was seen at 1‐year follow‐up in a study of 40 patients [58]. cytokines of Th2 lymphocytes that are believed to play a
Long‐term safety studies in children are lacking. key role in atopic diseases. A series of four RCTs were
In paediatric patients the recommended dose is recently published in which dupilumab was evaluated in
2.5–5 mg/kg/day, divided into two doses. Treatment can 207 adult patients with moderate‐to‐severe AD [62].
be started at 2.5 mg/kg/day and gradually increased or Dupilumab treatment in adults with moderate‐to‐
at 5 mg/kg/day and tapered. FBC, U&E, LFT, varicella severe AD resulted in marked reductions in signs,
serology and blood pressure should be checked before symptoms and associated biomarker levels in two
starting. In selected cases HIV, TB, hepatitis B and C serology 4‐week monotherapy trials, one 12‐week monotherapy
should be considered. Monitoring should include blood trial and a 4‐week combination study with topical
pressure measurement, FBC, urea and creatinine every glucocorticoids [62].
2 weeks for the first 1–2 months, then 4‐ to 6‐weekly. If Two double‐blinded, randomized phase III trials
creatinine increases more than 30% from baseline, ciclo (SOLO 1 and SOLO 2) enrolled adults with moderate‐to‐
ATOPIC DERMATITIS
sporin should be discontinued. severe AD whose disease was inadequately controlled by
Live vaccines are contraindicated during treatment topical treatment [63]. Patients were randomly assigned
SECTION 3:
with ciclosporin and should be given at least 2 weeks to receive, for 16 weeks, subcutaneous dupilumab
(preferably 4 weeks) before starting the treatment, including (300 mg) or placebo weekly or the same dose of dupilumab
varicella vaccine in children without immunity and at every other week alternating with placebo. A total of 1379
least 3 months after stopping the treatment. patients were enrolled in both studies. In SOLO1, 38% of
the patients who received dupilumab every other week
Mycophenolate mofetil and 37% who received dupilumab weekly reached
Mycophenolate mofetil (MMF) blocks the purine biosyn primary outcome (investigator’s global assessment clear
thesis pathway via the inhibition of inosine monophos or almost clear) as compared with 10% of patients who
phate dehydrogenase [48]. It selectively affects B cells and received placebo. The results were very similar in the
T cells, as other cells have compensatory purine scaven SOLO 2 study. Off‐label use of dupilumab in children has
ger mechanisms [48]. A paediatric case series involving 14 shown it to be effective and well tolerated [64]. There are
patients with AD treated with mycophenolate mofetil currently studies under way in the use of dupilumab in
showed a very good response with minimal adverse children [65].
effects [60]. A case series [53] of 12 patients with severe The significant impact on disease severity achieved
AD reported significant improvement in eight patients with dupilumab probably reflects the role of IL‐4 and
who had failed to improve with azathioprine [48]. IL‐13 in the Th2 pathway. Pruritus was not previously
Adverse effects include nausea, vomiting, diarrhoea, thought to be related to these mediators, although the
leucopenia, hypertension and nephrotoxicity. extent of improvement with dupilumab suggests a rela
The suggested dose of MMF in children is 600–1200 mg/ tionship [66].
m2 [48] equating to 40–50 mg/kg/day in young children
and 30–40 mg/kg/day in adolescents [48]. FBC, U&E, Rituximab
LFT and varicella serology should be checked before Rituximab is a chimeric monoclonal antibody against
starting treatment. Pregnancy test, tuberculosis testing, CD20 leading to circulating B‐cell depletion and inter
HIV, hepatitis B and C serology should be considered ference with antigen presentation. A study of six adult
before starting the treatment. FBC and LFT should be patients showed rituximab to be very effective in clear
checked every 1–2 weeks for the first month of treatment, ing recalcitrant AD [67]. This finding was not repeated
and every 3 months thereafter. in two other patients [68]. There are no reports of pae
Live vaccines are contraindicated during treatment diatric patients treated for AD with rituximab in the
with MMF and at least 2 weeks (preferably 4 weeks) literature.
before starting and at least 3 months after stopping the
treatment. Varicella vaccine should be considered in chil Omalizumab
dren without varicella immunity. Omalizumab is a humanized monoclonal antibody selec
tively directed against circulating IgE, although the
extent to which IgE plays a role in the pathogenesis of
Biologics in atopic dermatitis
AD is unclear [69]. A randomized, double‐blind, placebo‐
There is relatively little experience with biological response controlled study of eight patients between the ages of
modifiers in the management of childhood AD, but they 4 and 22 with severe AD treated with omalizumab every
can be expected to play an increasing role [61]. 2–4 weeks for a total of 24 weeks [70] showed a signifi
cantly greater decrease in serum IgE levels and in several
Dupilumab cytokines involved in Th2 polarization in the omalizumab
Dupilumab has recently been approved by the US Food group compared to the placebo group [70]. This was not
and Drug Administration (FDA) and licensed in the UK reflected in clinical benefit based on SCORAD. No severe
as the first biologic treatment for adults with moderate adverse events were reported. The ADAPT clinical study,
and severe eczema. Dupilumab is a human monoclonal comparing omalizumab with placebo in paediatric
antibody that binds to the alpha subunit of the IL‐4 receptor. patients with AD, will provide valuable data [71].
Ustekinumab of EASI [81]. Two patients stopped the treatment early

Ustekinumab is a human monoclonal antibody against due to worsening of the disease.
IL‐12 and IL‐23. Although high IL‐17 and IL‐23 levels
have been observed in children with AD, their role in the Mepolizumab
AD inflammatory process remains poorly understood. Mepolizumab is a monoclonal antibody against IL‐5,
Improvement has been reported in an adolescent with which is essential for eosinophil growth, differentiation
refractory AD after 4 months of treatment with usteki and migration [82]. In an RCT involving 18 adults with
numab [72]. Another adolescent experienced initial moderate‐to‐severe AD [82], no significant clinical improve
improvement, but the benefit diminished with continued ment was noted in the group receiving mepolizumab
treatment [73]. compared with placebo, despite a significant decrease of
eosinophil count in peripheral blood.
Infliximab and etanercept
Infliximab is a chimeric monoclonal tumour necrosis Allergy in atopic dermatitis
ATOPIC DERMATITIS
factor (TNF)‐α inhibitor. Nine adult patients are reported

to have experienced initial improvement of severe AD, Food allergy
SECTION 3:
but responses were not sustained through the mainte There is increasing evidence that sensitization to food
nance phase [74]. There are no reports to date of using antigens arises through environmental exposure early in
infliximab for AD in children. infancy through eczematous skin [83], and that early oral
Etanercept is a recombinant dimeric fusion protein of intake may help produce immune tolerance [84].
the human 75 kDa TNF‐α receptor (TNFR) with the Fc The European Academy of Allergy and Clinical Immu
fragment of human immunoglobulin IgG1 [75]. Etanercept nology’s (EAACI) Taskforce on Prevention of Food Allergy
has been reported to be unhelpful in two children with Guidance advises all mothers to have a normal diet
recalcitrant AD [76]. without restrictions during pregnancy and lactation [85].
For all infants, exclusive breastfeeding is recommended
Tralokinumab and lebrikizumab for at least the first 4–6 months of life. If breastfeeding is
Tralokinumab and lebrikizumab are humanized IgG4 insufficient or not possible, infants at high risk can be rec
monoclonal anti‐IL‐13 antibodies. Because IL‐13 is ommended a hypoallergenic formula. There is no evidence
responsible for many of the pathogenic Th2 effects in AD, of benefit from delaying the introduction of complemen
tralokinumab and lebrikizumab may hold promise for tary foods beyond 4 months, or from withholding or
AD treatment [77]. Lebrikizumab has been evaluated in a encouraging exposure to potentially allergenic foods after
phase II RCT (TREBLE) in adults with moderate‐to‐severe 4 months once weaning has commenced, irrespective of
AD, showing significant improvement when combined atopic heredity. There is no evidence to support the use of
with the use of topical steroids [78]. prebiotics or probiotics for food allergy prevention [85].
For infants and children with AD who already have
symptoms suggestive of food allergy, diagnosis and
Nemolizumab
management should follow evidence‐based recommen
Nemolizumab is IL‐31 targeting agent, currently in phase
dations [85]. In unselected patients with AD there does
II clinical trials. IL‐31 is a Th2 cytokine, also known as the
not appear to be any benefit in cow’s milk avoidance, or
‘pruritus cytokine’ that has been shown to compromise
in the use of elemental or few foods diets [86].
epidermal terminal differentiation and inhibit lipid
synthesis, perpetuating the ‘itch–scratch’ cycle of AD [35].
Airborne allergens and pollution
Many children experience exacerbation of AD on expo
Tocilizumab sure to airborne allergens, pollens, house dust mite and
Tocilizumab is a monoclonal IL‐6 receptor antibody. animal dander being the most commonly cited. Avoidance
Treatment of three adult patients with AD with tocilizumab is problematic and of variable benefit. There is limited
resulted in improvement in Eczema Area and Severity understanding of how and when airborne allergies
Index (EASI) score by more than 50% after 3 months, com develop, with some evidence that very early exposure
pared to baseline. During treatment one patient developed may be relevant to prevention [87].
uncomplicated conjunctivitis and another developed Neonatal domestic dog exposure has been shown to be
streptococcal bursitis of the heel [79]. associated with a strongly reduced risk of AD in two
independent birth cohorts and in a dose‐dependent man
Alefacept ner. While the mechanisms involved are unclear, the find
Alefacept is a fusion protein that binds to CD2. It inhibits ings raise the question whether in utero exposures may
T‐cell activation, and selectively reduces memory T cells. affect the risk of AD [88]. Specific immunotherapy, mainly
One uncontrolled pilot study of ten adult patients with to house dust mite and pollens, has been reported to
moderate‐to‐severe AD, treated for 12 weeks, reported a improve symptoms in a small number of controlled stud
78% reduction in AD severity [80]. In a study of nine adult ies, but the evidence is limited [89].
patients, two had at least a 50% reduction of EASI score There is limited evidence that traffic‐related air pollu
after 18 weeks of treatment, four had a less than 50% tion is associated with AD. Better long‐term studies are
reduction of baseline EASI score, and one had worsening needed [90].
Management of pruritus A recent systematic review [101] of 37 RCTs did not find
Pruritus is an integral part of AD and it is the most intense a significant difference in risk of developing AD between
and distressing symptom, to the extent that AD has been infants fed hydrolysed formula and those fed standard
called the ‘itch that rashes’. Scratching can worsen AD, as cow’s milk formula, leading to the need to revise previous
it causes breaching of the skin, increasing the risk of infec guidelines recommending the use of hydrolysed milk
tion. As patients become more pruritic, they scratch more, formula to prevent allergic disease in high‐risk patients
which then worsens their dermatitis and leads to more who cannot be exclusively breastfed [102,103].
itch [91]. Nocturnal itching and scratching are very com
mon, frequently leading to sleep disturbance. AD‐related Psychological impact of atopic
pruritus is the most common cause of chronic sleep loss in dermatitis
young people [92]. The stress and sleep disturbance
derived from the itch–scratch cycle profoundly disrupt Management of AD should include attention to the
the well‐being of children and the overall quality of their impact of the disease on education, social life and emo
ATOPIC DERMATITIS
adolescent development [93]. The whole family can be tional well‐being of the child and family.
adversely affected by the child’s scratching. Children with AD rate itching and sleep loss as the most
SECTION 3:
The only really effective way to control pruritus is to important aspects of their disease [104]. Sleep disturbance
adequately treat the AD that is causing the pruritus. In the due to the itching leads to tiredness, mood changes and
short term pruritus may be relieved temporarily by the impaired psychosocial functioning of the child and the par
application of emollients and wet dressings. Although his ents. Pharmacological treatments of pruritus, usually in the
tamine has been recognized as an important mediator of form of sedating antihistamines, are of limited benefit and
pruritus in certain conditions, it does not seem to have a may leave the child tired and unable to concentrate.
major role in AD, accounting for the limited efficacy of The ability to play or do sports, particularly swimming,
oral antihistamines in controlling the pruritus of AD. may be limited because of embarrassment, discomfort and
Sedating antihistamines may have a role as a result of their exacerbation of disease [104]. Embarrassment, unkind
soporific effect [94]. Nonsedating antihistamines such as comments, teasing and bullying frequently cause social
cetirizine or loratadine may occasionally be useful when isolation and may lead to depression or school avoidance
there is a concurrent urticarial element, food allergic reac [105]. In older age groups, when physical appearance
tions or allergic rhinoconjunctivitis. Distraction techniques becomes increasingly important, chronically inflamed skin
focusing on manual or mental activities such as games, is seen as unattractive and can cause anxiety and depres
storytelling and music may be helpful in some cases. sion. Rates of psychological disturbance have been shown
The severity of pruritus can be limited by avoidance of to be twice as high in children with moderate‐to‐severe AD
aggravating factors such as overheating and sweating as in children without AD [106]. Rapid improvement in
[95]. At night, bedroom temperatures should be kept AD has been observed following management of the dys
below 20 °C. Bedding and night clothes should be light functional parent–child relationships that have been found
and made of cotton. Contact with wool should be avoided. to occur in many cases of intractable childhood AD [107].
Cognitive behavioural therapy, as an adjunct to phar
macological treatment, is effective in reducing disease
Prevention of atopic dermatitis severity and psychological sequelae in patients with
Skin barrier enhancement AD [108]. Interventions such as multidisciplinary group
There is evidence from two RCTs that daily emollient patient education and relaxation methods have been
application could reduce the incidence of AD in infants shown to lead to improvements in AD severity and
with a family history of atopy, with relative risk reduc quality of life for both children and families [109].
tion of 50% [96] and 26% [97]. Whether eczema can
be prevented by daily application of emollient for
Conclusion
12 months in newborns with a family history of AD is
being assessed in The Barrier Enhancement for Eczema Although there have been advances in the understanding
Prevention (BEEP) study, currently running (www. of aetiopathogenesis, AD, particularly if severe, remains a
isrctn.com/ISRCTN21528841). condition that can be very difficult to manage.
To improve management we require better understand
Probiotics and nutritional intervention ing of many issues, including whether restoration of
A systematic review of 21 studies showed that supple barrier function and/or increase in filaggrin expression
mentation with probiotics in infants and pregnant moth early in the course of AD can prevent disease progression
ers can prevent development and reduce severity of AD and the atopic march, the role of genetic factors other than
[98]. A meta‐analysis of 16 randomized trials including filaggrin, and whether specific genetic factors could be
approximately 3500 participants found that probiotics used as a guide towards particular treatments [110].
given in the prenatal and postnatal period reduced the Currently success depends on detailed assessment of
risk of AD in the first years of life in both children at high the clinical features, an understanding of the percep
risk of AD and in those from the general population [99]. tions and needs of the child and the family, thorough
However, subsequent RCTs have not provided evidence explanation of the rationale for, and risks and benefits of,
that probiotics either prevent AD or reduce its severity [100]. each intervention, and ongoing support.
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ATOPIC DERMATITIS
SECTION 3:
265
C HA PTER 20
Napkin Dermatitis
Arnold P. Oranje1, Ernesto Bonifazi2, Paul J. Honig3,4 & Albert C. Yan4,5,6
Kinderhuid.nl, Rotterdam, Hair Clinic, Breda and Dermicis Skin Clinic, Alkmaar, The Netherlands
1
Dermatologia Pediatrica Association Bari, Italy

2
Division of Dermatology, Denver Children’s Hospital, Denver, CO, USA

3
Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
4
Section of Dermatology, Children’s Hospital of Philadelphia, Philadelphia, PA, USA

5
Department of Dermatology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
6
Introduction, 265 Granuloma gluteale infantum, 271 Neoplastic napkin conditions, 276
Aetiology, 266 Infectious napkin dermatitis, 271 Metabolic napkin conditions, 277
Clinical and differential diagnosis, 268 Primary and secondary inflammatory Other important napkin conditions, 278
SECTION 4: OTHER TYPES

Contact napkin dermatitis, 269 conditions, 274
Simple intertrigo, 270
OF DERMATITIS
Abstract apkin dermatitis. Allergic forms of contact dermatitis in the
n
napkin area may be difficult to distinguish from irritant napkin
dermatitis, although clinically allergic contact dermatitis is often
Napkin dermatitis refers to a collection of common disorders
pruritic rather than sore, and unusual patterns corresponding
affecting the napkin area. Napkin dermatitis includes a range of
to specific components of the napkin may indicate an aetiology.
conditions including irritant dermatitis, Candida napkin dermati-
Napkin psoriasis may be the presenting sign of psoriasis during
tis, erosive napkin dermatitis and allergic contact dermatitis. Nap-
infancy, and in older children is often the initial manifestation of
kin area involvement may also be the presenting sign for napkin
Kawasaki disease.
psoriasis or Kawasaki disease, and may rarely be an indicator of
This chapter focuses on a description of the clinical features,
child abuse.
aetiology and treatment of napkin dermatitis.
Primary irritant napkin or diaper dermatitis may over time
evolve into secondary Candida napkin dermatitis or erosive
Key points • Treatment of napkin dermatitis if persisting longer than 1

week should include anticandidal and antibacterial creams or
ointments.
• Napkin dermatitis is only present in the napkin area when a child
• Napkin psoriasis is sometimes the initial presenting sign of
or adult uses napkins.
psoriasis.
• Candida albicans as secondary invader plays a moderate role.
• Napkin dermatitis and napkin psoriasis in an ill infant may be an
• Primary candidiasis is relatively rare, except in the early neonatal
early characteristic feature of Kawasaki disease.
period.
• Unexplained severe napkin dermatitis may be a part of child abuse.
Introduction and urine as a secondary factor. Most cases of napkin der-

matitis are mild and it is estimated that only 5% of cases
Definition. Primary irritant napkin dermatitis (nappy are severe [2].
rash, diaper dermatitis) is a dermatitis typically localized,
at least initially, to the area covered by napkins. It is only History. At the beginning of the twentieth century,
observed when napkins are used. It is also observed in investigators assumed that ammonia released from the
adults using large napkins because of urinary and faecal urine was the primary irritant in napkin dermatitis [2,3].
incontinence. In 1921, Cooke claimed that Bacterium ammoniagenes was
responsible for napkin dermatitis, resulting in the term
Aetiology and clinical presentation. The aetiology of ammoniacal dermatitis [4]. This theory was widely
napkin dermatitis involves multiple factors [1] (Fig. 20.1). accepted for decades. Subsequent studies showed, how-
Irritant napkin dermatitis can be considered as a toxic ever, the same incidence of urea‐splitting bacteria in the
contact dermatitis that occurs in the napkin area because napkins of babies with and without rash. In 1977, Leyden
of prolonged contact with faeces as the primary factor et al. demonstrated that ammonia did not cause skin
266 Section 4 Other Types of Dermatitis
Intact skin forms are now infrequently observed. Variants of napkin

dermatitis characterized by severe erythema, large pustules
Activating factors Caregiver intervention
and ulcers have become rare.
• skin hydration • increased napkin
• mixing faeces change Napkins or diapers
and urine • medical treatment The role played by napkins is supported by all causative
Induction
considerations. The decreased frequency and severity of
Compromised skin Napkin dermatitis napkin dermatitis in developed countries can be attrib-
Napkin dermatitis uted to the improvement of napkin materials. The intro-
• Irritation, friction duction of disposable napkins and, more importantly,
• enzyme activity
• microbial infection
newer disposable napkins with superabsorbent gels that
are able to absorb 50 times their own weight of water, has
Fig. 20.1 The aetiology of napkin dermatitis, in a model according to Berg
probably been responsible for significant improvement in
and Buckingham, adapted from Oranje and de Waard‐van der Spekk 1995
and Oranje 1995.
the prevalence of napkin dermatitis. Despite the term
napkin dermatitis, napkins are not themselves frequent
causes of the rash. In fact, allergic or irritant contact der-
irritation when patch tested on the skin of adults and chil- matitis caused by napkins has been reported but remains
dren [5]. They observed no irritation even when the con- an uncommon cause of napkin rashes in children [1].
OF DERMATITIS
centrations of ammonia were much higher than those Modern disposable napkins mainly consist of an inner
attributed to ‘ammoniacal diapers’. Investigations in the filtering layer, an intermediate layer able to absorb liq-
1980s and 1990s showed that the aetiology of napkin der- uids, and an outer layer that is waterproof. The water-
matitis was more complex and different from that thought proof layer prevents perspiration and therefore increases
previously [6,7]. the temperature and humidity of the environment. This
Activated faecal lipases and proteases primarily dam- layer plays a fundamental role in maintaining the imper-
age the skin. These enzymes are activated in alkaline and meability of the napkin. From this point of view, the mod-
hydrated conditions. Therefore, the key approach to pre- ern disposable napkin is much better than the traditional
venting napkin dermatitis is to keep the skin in the nap- cotton napkin. The latter is characterized by significantly
kin area protected from faeces and urine. lower absorbency and thus is associated with higher
The specific role of Candida albicans in the pathogenesis humidity in the napkin area. In addition, cotton napkins
of napkin dermatitis remains debated though its presence must always be worn together with outer plastic water-
is well established, especially in prolonged napkin der- proof pants. Compared with the traditional cotton nap-
matitis [8]. kins, modern disposable napkins reduce the contact time
of the skin with urine. Tight elastic around the waist and
References legs of disposable napkins is useful, especially in nurser-
1 Atherton D. Maintaining healthy skin in infancy using prevention of ies and daycare centres, to prevent the spread of gastroin-
irritant napkin dermatitis as a model. Community Pract
2005;78:255–7.
testinal infection. Allergic contact dermatitis has been
2 Jordan WE, Lawson KD, Berg RW et al. Diaper dermatitis: frequency occasionally reported and attributed to dyes used in older
and severity among a general infant population. Pediatr Dermatol napkin products as well as to fragrances that are common
1986;3:198–207. to many napkin brands. Most modern products now use
3 Zahorsky J. The ammoniacal diaper in infants and young children. Am
J Dis Child 1915;10:437–44. newer plant‐based pigments that are less likely to trigger
4 Cooke JV. The etiology and treatment of ammonia dermatitis of the contact dermatitis.
gluteal region of infants. Am J Dis Child 1921;22:481–92. The ideal napkin should be able to contain water
5 Leyden JL, Katz S, Stewart R et al. Urinary ammonia and ammonia
without preventing air flow. As such, the ideal napkin
producing microorganism in infants with and without diaper dermati-
tis. Arch Dermatol 1977;113:1678–80. does not yet exist, although significant improvements
6 Berg RW, Miligan MC, Sarbaugh FC. Association of skin wetness and in technology now allow for rapid absorption of waste
pH with diaper dermatitis. Pediatr Dermatol 1994;11:18–20. products and can inform caregivers with colour indica-
7 Buckingham KW, Berg RW. Etiologic factors in diaper dermatitis: the
role of feces. Pediatr Dermatol 1986;3:107–12.
tors when the baby urinates.
8 Stamatas GN, Tierney NK. Diaper dermatitis. Pediatr Dermatol
2014;31:1–7. Faeces
Prolonged contact with faeces is the most irritant toxic
factor on the skin. Even babies who have never suffered
Aetiology
from napkin dermatitis will develop it when they have
Prolonged contact with urine, faeces, friction, hydration, diarrhoea, especially that due to infections [2,3].
temperature, chemical irritants and the napkin itself are Diarrhoea results in prolonged contact of faeces with
considered among the causative factors for napkin der- the skin and excessive hydration of the skin. Napkin
matitis [1]. Napkin dermatitis only occurs in countries or dermatitis improves immediately after diarrhoea stops.
settings where conventional napkins are used. In the Many factors have been suggested to be responsible for
1990s, the frequency and severity of napkin dermatitis the irritant capacity of faeces, ranging from acid stools
significantly decreased in westernized countries com- burning the skin to alkaline stools [3]. Berg et al. [4] and
pared with previous rates. Above all, the most severe Buckingham and Berg [5] suggested that faecal enzymes,
Chapter 20 Napkin Dermatitis 267
including proteases and lipases, could be responsible Chemical irritants

for the irritant potential of faeces. However, Yamamoto Chemical compounds have a direct toxic effect on the
[6] was not able to show increased levels of proteases in skin. Among these chemical irritants are deodorants, pre-
children with napkin dermatitis. Kuwayama et al. [7,8] servatives, creams and oils, in particular when used fre-
showed that faecal proteases and lipases play a minor quently throughout the day. Many antimycotics are not
role in the pathogenesis of napkin dermatitis. No sig- well tolerated [14].
nificant relationship between faecal enzyme activity
and severity of napkin dermatitis could be found. Microorganisms
Moreover, lipase and protease activities were destroyed Candida albicans is now considered the most important
by heating faeces at 100 °C for 5 min without a signifi- causative microorganism contributing to napkin dermati-
cant decrease in the irritation potential of the faeces. tis. Previously, Bacterium ammoniagenes was seen as
Kuwayama et al. concluded that other faecal factors responsible for urea splitting and free ammonia release,
are responsible for such toxic activities. The toxic leading to the term ‘ammoniacal dermatitis’ [14,15].
substances are probably present in the fraction of
Besides C. albicans and B. ammoniagenes, other microor-
substances of the water‐soluble extract that exceed
ganisms have been implicated, such as Proteus,
5000 kDa. The interaction between faeces and other Pseudomonas, Escherichia coli, Streptococcus, Staphylococcus

factors is complex. However, the occurrence of napkin and Enterococcus [15]. Often, Staph. aureus and C. albicans
dermatitis around the normal, healthy anus shows that were isolated simultaneously. The role played by anaero-
OF DERMATITIS
faeces alone can induce napkin dermatitis [5,9]. bic bacteria has been emphasized [5].
The frequency with which C. albicans occurs in the
Urine various clinical forms of napkin dermatitis is not signifi-
Urine may contribute to the pathogenesis of napkin cantly different [14]. However, the severity and duration
dermatitis through skin hydration [10,11]. Urine and
of napkin dermatitis are more important in determining
ammonia as single factors fail to induce erythema. The colonization by C. albicans than the type of napkin derma-
interaction of ammonia, bacteria, faeces, friction and titis [16–18]. Three infantile disorders are definitively asso-
other factors contributes to the development of dermatitis ciated with C. albicans: oral thrush, chronic mucocutaneous
[12]. However, urine, especially after incubation at 37 °C candidiasis and congenital candidiasis [17]. An association
(body temperature), may contain as yet unidentified between oral thrush and napkin dermatitis has not been
factors that could be responsible for irritation after
clearly demonstrated [17–19]. Meneghini and Bonifazi [20]
prolonged exposure [13]. prospectively studied 112 healthy children aged 5–15
months. They studied the clinical aspects of the napkin
area, and combined their data with bacterial and fungal
Friction
cultures. The mycological examination proved positive for
Rubbing of the napkin on the skin or skin‐to‐skin contact
C. albicans in 19 of 1001 cases, not a particularly low pro-
(friction) due to movement of the infant can be responsi-
portion considering that the authors studied healthy chil-
ble for chafing dermatitis [13]. The causative role of fric-
dren. Conversely, the study of a healthy population
tion is stressed by the predilection of napkin dermatitis
allowed the observation of the initial lesions of napkin
for the convex surfaces of the genitalia, the buttocks and
dermatitis. These investigations were repeated consecu-
the waistline. This type of napkin dermatitis spares the
tively for many weeks, thus establishing that C. albicans
depth of the folds. The latter variant is also called W‐
can be isolated from the most intensely erythematous
shaped napkin dermatitis in female infants [13].
lesions independent of the site involved and the type of
lesions. C. albicans was rarely isolated before the appear-
Hydration ance of napkin dermatitis. In this study, oral thrush was
Excessive hydration of the skin in the napkin area can be never associated with a positive culture for C. albicans
caused by napkins that prevent evaporation of moisture from the napkin area. These findings seem to suggest that
from the skin [13]. Napkins may facilitate hydration C. albicans is a secondary invader of skin that is already
induced by fever and sweating (causing miliaria). Urea damaged. Most authors favour this hypothesis [17–23].
also facilitates hydration of the skin. Excessive hydration is However, other authors believe that C. albicans can be a
responsible for maceration of the skin, leading to compro- primary factor in the pathogenesis of napkin dermatitis
mised barrier properties of the epidermis and providing [17,23]. The quantity of organisms might be more impor-
an ideal environment for the proliferation of microorgan- tant than the simple presence of C. albicans in establishing
isms [12]. Excessive hydration also makes the skin more its aetiological role. According to some authors [17], under
susceptible to frictional trauma [12,13]. occlusive conditions, 10 000 organisms of C. albicans per
square centimetre could induce primary skin infection.
Temperature
Increased temperature in the napkin area is caused by Allergy
napkins that prevent perspiration, reducing heat loss. The term napkin dermatitis is often interpreted as a contact
Napkins may also aggravate the effect of fevers. The allergy to the napkin. This misunderstanding leads some
increased temperature is responsible for vasodilation and caregivers to choose cotton in preference to disposable nap-
promotion of inflammation. kins, with consequent worsening of the napkin dermatitis.
Allergic contact dermatitis in the n

apkin area is a possibility, 13 Leyden JL, Katz S, Stewart R et al. Urinary ammonia and ammonia
producing microorganisms in infants with and without diaper der-
with possible sensitizers including rubber, detergents, lano-
matitis. Arch Dermatol 1977;113:1678–80.
lin, preservatives, fragrances, neomycin and mercurial 14 Dixon PN, Warin RP, English MP. Role of Candida albicans infec-
compounds [22,23]. In addition, disperse dye has recently tion in napkin rashes. Br Med J 1969;5:23–7.
been implicated as a potential contact sensitizer in some 15 Weston WL, Lane AT, Weston JA. Diaper dermatitis: current concepts.
Pediatrics 1980;66:532–6.
children with napkin dermatitis, as confirmed by epicuta- 16 Meneghini CL, Barile F, Bonifazi E. Ruolo della Candida albicans nella
neous patch testing [23]. However, allergic contact dermati- dermatite da pannolino. Arch Argent Dermat 1988;38:287–9.
tis is uncommon, especially in the first year [21]. Some 17 Caputo RV. Fungal infections in children. Dermatol Clin 1986;4:
authors consider napkin dermatitis as contact hypersensi- 137–49.
18 Jacobs AH. Eruptions in the diaper area. Pediatr Clin N Am 1978;25:
tivity to products associated with the presence of C. albicans 209–24.
[20]. However, no evidence of acquired hypersensitivity to 19 Katz R. Treatment of diaper dermatitis. Postgrad Med 1972; Nov:153–6.
C. albicans could be demonstrated in subjects with multiple 20 Meneghini CL, Bonifazi E. Diaper rash. Pediatr Dermatol News
1982;1:69–75.
consecutive infections of C. albicans [21]. 21 Koblenzer PJ. Diaper dermatitis – an overview emphasis on rational ther-
apy based on etiology and pathodynamics. Clin Pediatr 1973;12:386–92.
22 Roul S, Ducombs G, Leaute‐Labreze C et al. Lucky Luke contact
References dermatitis due to rubber components of diapers. Contact Dermatitis
1 Oranje AP, de Waard‐van der Spek FB. Comparison of cloth and 1998;38:363–4.
superabsorbent paper diapers for preventing diaper dermatitis. Eur 23 Alberta L, Sweeney SM, Wiss K. Diaper dye dermatitis. Pediatrics
J Pediatr Dermatol 1991;1:225–32. 2005;116:e450–2.
2 Austin AP, Miligan MC, Pennington K et al. A survey of factors associ-
OF DERMATITIS
ated with diaper dermatitis in 36 pediatric practices. J Pediatr Health

Care 1988;2:295–9.
3 Jordan WE, Lawson KD, Berg RW et al. Diaper dermatitis: frequency Clinical and differential diagnosis
and severity among a general infant population. Pediatr Dermatol
1986;3:198–207. Napkin dermatitis represents a descriptive phenotype for
4 Berg RW, Miligan MC, Sarbaugh FC. Association of skin wetness and multiple dermatoses that may affect the anogenital skin
pH with diaper dermatitis. Pediatr Dermatol 1994;11:18–20. of napkin‐wearing infants. These range from common
5 Buckingham KW, Berg RW. Etiologic factors in diaper dermatitis: the
role of feces. Pediatr Dermatol 1986;3:107–12. problems such as a primary irritant dermatitis directly
6 Yamamoto K. Hygienic care of the diaper area in childhood. Pediatr caused by occlusion and friction, to rare diseases such as
Dermatol News 1987;6:239–41. Langerhans cell histiocytosis, unrelated to the wearing of
7 Kuwayama M, Kon Y, Yamamoto K. New etiologic factors in diaper
dermatitis: skin irritability and focal irritancy as major causes of dia-
a napkin. Thus, napkin dermatitis should be viewed not
per dermatitis. J Pediatr Dermatol 1992;11:93–102. as a specific diagnostic entity but rather as a regional
8 Kuwayama M, Kon Y, Yamamoto K. New etiologic factors in diaper diagnosis, like hand dermatitis, that encompasses various
dermatitis: the confirmation of irritant in feces. J Pediatr Dermatol skin diseases of multifactorial aetiology.
1992;11:103–11.
9 Bonifazi E. Diaper rash in practical pediatric dermatology. Eur J There can be significant overlap in the clinical presenta-
Pediatr Dermatol 1993;3:57–62. tion of the conditions that cause napkin dermatitis, and
10 Leyden JJ. Diaper dermatitis. Dermatol Clin 1986;4:23–8. specific diagnosis may be difficult. Although history and
11 Cooke JV. The etiology and treatment of ammonia dermatitis of the
correlating physical signs are often helpful, the differen-
gluteal region of infants. Am J Dis Child 1921;22:481–92.
12 Brook J. Microbiology of secondarily infected dermatitis. Int J tial diagnosis is based primarily on the morphology and
Dermatol 1992;31:700–2. location of the rash (Table 20.1, Box 20.1).
Table 20.1 Common types of napkin rash
Morphology Location History Diagnostic

tests
Primary Glazed, confluent erythema or wrinkled Convex surfaces (buttocks, thighs, Rash may wax and wane; recent None
irritant parchment‐like skin, scale, papules abdomen, mons pubis, labia majora, diarrhoea; infrequent napkin
scrotum) changes; use of plastic pants
Candidal Bright‐red, scaly plaques; sharply Skinfolds Antibiotic therapy; diarrhoea; rule KOH
marginated satellite papules and out oral thrush
pustules; papulosquamous id (rare)
Atopic Same as primary irritant, excoriations, Convex surfaces; eczema at other sites Family history of atopy; pruritus; None
lichenification, crusting (e.g. cheeks, antecubital and popliteal chronicity
fossae)
Seborrhoeic Salmon‐coloured, scaly plaques; sharply Skinfolds with subsequent spread over Asymptomatic; presents early in None
marginated, greasy, yellow scale convex surfaces; involvement of scalp, infancy; good response to
postauricular folds, axilla, neck treatment
Intertrigo Sharply demarcated erythema; skin Skinfolds Often seen in overweight infants None
maceration; little scale; no satellite lesions
Bullous Flaccid bullae; honey‐coloured crust Usually convex surfaces (thighs, buttocks, Common in newborns Gram stain;
impetigo lower abdomen); may spread rapidly to (Staphylococcus colonization of bacterial
other areas of the body umbilicus) culture
KOH, potassium hydroxide.

Box 20.1 Differential diagnosis of napkin rash*
Eczematous/papulosquamous
• Primary irritant contact dermatitis

• Allergic contact dermatitis
• Candidiasis
• Intertrigo
• Seborrhoeic dermatitis
• Atopic dermatitis
• Psoriasis
• Kawasaki disease
• Langerhans cell histiocytosis (Letterer–Siwe)
• Perianal streptococcal disease
Nodular

• Granuloma gluteale infantum
• Extrafacial periorificial granulomatous dermatitis
• Metastatic Crohn disease
OF DERMATITIS
Vesiculobullous/erosive Fig. 20.2 Irritant contact napkin dermatitis. Erythema primarily involves
• Acrodermatitis enteropathica convexities of the napkin area.
• Biotin‐responsive multiple carboxylase deficiency
• Cystic fibrosis compromised skin [3]. In some cases, irritant contact
• Bullous impetigo ermatitis may arise from topically applied medicaments
d
• Miliaria designed to protect the napkin area.
• Scabies Clinically, irritant contact napkin dermatitis is charac-
• Other vesiculobullous disease (varicella, herpes simplex, hand, foot terized by a glazed, confluent erythema, sometimes
and mouth disease, chronic bullous disease of childhood, bullous resembling a burn. There may be erythematous papules,
mastocytosis, incontinentia pigmenti, epidermolysis bullosa) oedema and scaling of the involved skin (Fig. 20.2). When
• Child abuse (burns) the eruption begins to resolve, a wrinkled parchment‐like
• Laxative‐induced dermatitis
appearance may be noted. The rash, however, may wax
• Human immunodeficiency virus
and wane. This form of napkin rash primarily involves
the skin where contact with the napkin is greatest, i.e. the
Verrucous
convexities of the buttocks, medial thighs, mons pubis
• Congenital syphilis (condylomata lata) and scrotum or labia majora. The intertriginous areas are
• Perianal pseudoverrucous papules and nodules generally spared. An early manifestation of this type of
napkin dermatitis, especially in infants less than 4 months
* There is significant overlap with regard to the morphological grouping of age, is mild perianal erythema [4].
of these dermatoses. This list is intended to provide general guidelines. There are two less common morphological subtypes of
irritant contact napkin dermatitis. One is the so‐called
‘tide water’ mark dermatitis in which an erythematous
macular eruption is band‐like and confined to the mar-
Contact napkin dermatitis gins of the napkin area on the thighs (Fig. 20.3) or abdo-
Primary irritant contact napkin dermatitis men. This characteristic rash results from the exaggerated
Irritant contact dermatitis is by far the most prevalent chafing that may occur at the edges of the napkin. Skin
form of napkin dermatitis. In fact, this ‘chafing’ napkin integrity is compromised by the frequent cycles of wet-
rash is probably the most common skin problem of ting and drying [5] combined with the traumatic friction
infancy. It is precipitated by the constant moisture, due to the plastic border of a disposable napkin. There is
occlusion and frictional forces that occur under a napkin also a severe form of irritant contact napkin dermatitis
and which compromise skin integrity. With maceration known as Jacquet dermatitis or erosive napkin dermatitis.
of the stratum corneum, the skin barrier function is This presents with papuloerosive lesions that have a
impaired, predisposing it to secondary irritants. These punched‐out or crater‐like appearance (Fig. 20.4). These
secondary factors include urinary ammonia, increased ulcers have also been referred to as ‘ammoniacal ulcers’.
urine pH (due to urea‐splitting bacteria), faecal proteases This eruption, when it occurs, tends to affect older
and lipases, C. albicans, bacterial overgrowth and frequent napkin‐wearing children. In male infants, ulceration
washing, especially with detergent soaps [1,2]. Urinary involving the glans penis and urinary meatus may cause
ammonia was for many years mistakenly believed to be discomfort or difficulty urinating.
the primary instigator of irritant napkin dermatitis. It is The differential diagnosis in atypical cases (wherein
now thought to increase inflammation only in already an antecedent history of napkin dermatitis is absent)
Fig. 20.3 Irritant contact napkin dermatitis: the ‘tide water’ mark.
OF DERMATITIS
Fig. 20.5 Toxic napkin dermatitis (induced by bleaching solution). Source:

Courtesy of Professor Arnold Oranje.
Fig. 20.4 Jacquet erosive napkin dermatitis.
would include herpes simplex virus infection, which Fig. 20.6 Allergic contact dermatitis secondary to rubber components in
the napkin: the ‘holster sign’. Source: Courtesy of Dr. Neil Prose.
may be associated with a history of abuse or vertical
transmission.
an eczematous eruption. The vesicular phase may not be
Allergic contact napkin dermatitis apparent after the first few days of the rash. Allergic con-
A true allergic contact dermatitis may complicate another tact napkin rash typically complicates a primary irritant
type of napkin rash or present de novo. This is an uncom- napkin rash and therefore follows the same distribution,
mon occurrence, particularly in children under 2 years of i.e. the convex surfaces of the skin under occlusion. There
age. Allergic contact dermatitis should be considered, may, however, be prominent flexural involvement, par-
however, if a child does not respond appropriately to ticularly if the sensitivity is to a topical preparation that
treatment. It should also be suspected if the application of concentrates within the skinfolds. The characteristic pat-
a potential allergen causes the napkin rash to become tern of contact dermatitis to rubber components around
more intense or to spread. Contact allergy may develop to the proximal thighs and the waistline associated with dis-
certain medicaments applied to the skin such as those posable napkins has been dubbed the ‘holster sign’ [8,9]
containing paraben, lanolin or neomycin. Allergic sensi- (Fig. 20.6).
tivity may also occur to chemicals contained within dis-
posable napkins or to napkin covers (as with disperse
Simple intertrigo
dyes used to colour older napkins) [6] or fragrances, or an
irritant reaction may develop to laundry detergents used Intertrigo is an inflammatory process that occurs in areas
with cloth napkins (Fig. 20.5) [7]. where skin rubs against skin, as in the folds of the groin,
Morphologically, allergic contact dermatitis begins posterior thighs and intergluteal cleft. Heat, moisture and
with erythema and small vesicles that rupture, leading to sweat retention, coupled with friction, cause maceration,
inflammation and sometimes skin erosion. Intertrigo may factor, but Candida is frequently cultured from common
present with sharply demarcated moist erythema con- irritant napkin rash and the development of granuloma
fined to the skinfolds. In contrast to a candidal napkin gluteale infantum in these patients is rare. Finally, fluori-
rash, there is little associated scale and no satellite lesions. nated topical steroids have also been implicated in the
As intertrigo is essentially due to friction and retained development of these nodules because, in most reported
moisture, it may be considered a subtype of irritant con- cases, relatively potent topical steroids were used [11].
tact dermatitis. The tropical climate of the napkin area The role of topical corticosteroids is supported by the lack
makes the napkin‐wearing child susceptible to the devel- of cases of granuloma gluteale infantum prior to the intro-
opment of simple intertrigo; however, it is most often duction of corticosteroids. Its lower prevalence today
seen in overweight infants. might be attributable to parental corticosteroid phobia.
In cases of intertrigo, there may be secondary infection
with C. albicans or bacteria. Also, the clinical presentation References
of intertrigo may be indistinguishable from other disor- 1 Berg RW. Etiology and pathophysiology of diaper dermatitis. Adv
Dermatol 1988;3:75–98.
ders in which the role of C. albicans is controversial, such
2 Weston WL, Lane AT, Weston JA. Diaper dermatitis: current concepts.
as infantile seborrhoeic dermatitis or inverse napkin pso- Pediatrics 1980;66:532–6.
riasis. This overlap in clinical features may make defini- 3 Leyden JJ, Katz S, Stewart R et al. Urinary ammonia and ammonia

tive diagnosis difficult. producing microorganisms in infants with and without diaper der-
matitis. Arch Dermatol 1977;113:1678–80.
4 Rasmussen JE. Diaper dermatitis. Pediatr Rev 1984;6:77–82.
OF DERMATITIS
Granuloma gluteale infantum 5 Koblenzer PJ. Diaper dermatitis: an overview. Clin Pediatr
1973;12:386–92.
Granuloma gluteale infantum is a rare nodular eruption 6 Alberta L, Sweeney SM, Wiss K. Diaper dye dermatitis. Pediatrics
2005;116:e450–2.
that may arise within an area of pre‐existing irritant 7 Jacobs AH. Eruptions in the diaper area. Pediatr Clin North Am
napkin dermatitis. It is characterized by firm, painless, 1978;25:209–24.
reddish‐brown to purple nodules varying in size from 0.5 8 Larralde M, Raspa ML, Silvia H et al. Diaper dermatitis: a new clinical
feature. Pediatr Dermatol 2001;18:167–8.
to 4 cm (Fig. 20.7). These nodules usually appear on the 9 Roul S, Ducombs G, Leaute‐Labreze C et al. ‘Lucky Luke’ contact der-
buttocks and inner thighs and occasionally on the lower matitis to the rubber components of diapers. Contact Dermatitis
abdomen. Lesions have also been reported outside the 1998;38:363–4.
napkin area involving the folds of the axilla and neck. 10 Sweiden NA, Salman SM, Kibbi AG et al. Skin nodules over the
diaper area: granuloma gluteale infantum. Arch Dermatol 1989;
These angioma‐like swellings can be ominous in appear- 125:1706–7.
ance, resembling lesions of Kaposi sarcoma or lymphoma. 11 Uyeda K, Nakayasu K, Takaisski Y et al. Kaposi sarcoma‐like granu-
The nodules may persist for weeks to months but they loma on diaper dermatitis. Arch Dermatol 1973;107:605–7.
eventually regress spontaneously. When the lesions
resolve, atrophic scars may remain.
Infectious napkin dermatitis
The aetiology of granuloma gluteale infantum is
unclear. Several factors, however, have been suspected. Candidal (monilial) napkin dermatitis
Because this condition invariably arises in an area of pre‐ Provided there is sufficient warmth and moisture, as
existing napkin dermatitis, it may represent a localized occurs under an occlusive napkin, C. albicans can prolifer-
cutaneous response to longstanding inflammation. There ate on the skin surface and penetrate the stratum cor-
is no correlation, however, between the severity of the neum. It can then activate complement via the alternative
napkin rash and the incidence of this nodular eruption pathway and induce inflammation [1].
[10]. Lesions may appear even when the napkin rash is Morphologically, candidal napkin dermatitis is perhaps
resolving. C. albicans has been considered an aetiological the most characteristic of the napkin rashes. It presents
with sharply marginated, intensely red, scaly plaques
with satellite papules and pustules (Fig. 20.8). These satel-
lite lesions may have peripheral scale. In some severe
cases of candidiasis, there may be widespread skin ero-
sion. When candidiasis involves the genitalia, there is
usually confluent erythema involving the entire scrotum
or labia. This is unlike psoriasis, in which genital involve-
ment is usually more localized and in which the lesions
are more sharply demarcated.
The diagnosis of candidal napkin rash is primarily
based on its characteristic morphology. Potassium
hydroxide (KOH) scrapings may reveal pseudohyphae
and help to confirm the diagnosis. Scrapings may be neg-
ative, however, if they are taken from inflamed areas or in
longstanding cases in which the inflammatory response
has led to the death of the Candida organism. Yield on
KOH is greatest from scrapings of the periphery of the
Fig. 20.7 Granuloma gluteale infantum. rash or a fresh papular or pustular lesion.
trunk, usually sparing the extremities. This eruption may

last for days to weeks. Generally, C. albicans cannot be
cultured from these plaques. However, active candidiasis
of skinfolds in the neck and axilla, in addition to the
inguinal area, may be seen. The pathogenesis of this
allergic skin eruption is not well understood; it is pre-
sumed to be a response to an antigenic stimulus.
Although it was once thought that this reaction sug-
gested an underlying psoriatic or atopic diathesis, most
affected infants do not go on to develop psoriasis or
atopic dermatitis [2]. Confusion exists over the entity
‘napkin psoriasis’ [3]. Balasubramanian et al. [3] recently
described napkin psoriasis as diaper dermatitis with pso-
riasiform id eruptions and stressed that it is nowadays
rare. Psoriasis‐like eruptions were described in patients
with Kawasaki disease by Haddock et al. [4]; the overall
Fig. 20.8 Candida napkin dermatitis with satellite lesions. clinical and histopathological findings were identical to
conventional psoriasis. The last two reports illustrate
OF DERMATITIS
that a psoriatic clinical presentation includes an aspecific

id reaction and does not predict psoriasis in later life.
The rare congenital onset of candidal napkin dermatitis
may represent a manifestation of congenital cutaneous
candidiasis. Neonates with congenital cutaneous candidi-
asis may present with characteristic macerated areas of
erythema in the anogenital region; however, infected
infants may also present with papulopustules, widespread
erosions or a burn‐like dermatitis [5]. In term infants,
congenital cutaneous candidiasis is typically a benign,
self‐limited eruption attributed to vertical transmission
from the colonized mother. The condition responds to
topical antifungal agents. However, preterm neonates,
especially those manifesting signs of respiratory distress,
are at risk for associated systemic candidiasis, which war-
rants systemic antifungal therapy.
Perianal streptococcal disease

and streptococcal intertrigo
Perianal streptococcal disease is an often unsuspected
condition, the signs of which may be quite subtle. It may
be mistaken for an irritant napkin dermatitis, a perianal
candidiasis, psoriasis or pinworm infestation. When
blood‐streaked stools are present, inflammatory bowel
disease may also be a consideration. Perianal cellulitis is
Fig. 20.9 Psoriasiform skin reaction to Candida napkin dermatitis. caused by group A β‐haemolytic Streptococcus. Despite its
name, it is not a true cellulitis but rather a superficial skin
infection.
Children presenting with candidal napkin dermatitis This entity typically presents as sharply demarcated,
frequently have a recent history of treatment with broad‐ bright erythema in the perianal area. There may be peri-
spectrum antibiotics. Diarrhoea also makes an infant rectal fissuring. Other intertriginous areas, such as the
more susceptible to candidiasis. The oral cavity should be neck, axillae and inguinal folds, may also become affected.
examined to rule out concomitant thrush. When the rash The condition is usually associated with itching and pain.
is chronic or recurrent, seeding from the gastrointestinal The pain occurs particularly during defaecation and can
tract or from a maternal candidal vaginitis should be con- lead to faecal hoarding. Often, there is a history of
sidered. Other potential sources include maternal masti- repeated streptococcal pharyngitis in family members.
tis, if the mother is breastfeeding, or a contaminated Diagnosis can be made by cotton swab bacterial culture of
dummy (pacifier) or nipple. the affected perianal skin.
On rare occasions, a psoriasiform skin reaction Streptococcal intertrigo involves bacterial infection of
(Fig. 20.9) may occur as a complication of severe candidal the inguinal creases (Fig. 20.10) and other intertriginous
napkin rash. Shortly after therapy is initiated, scaly pso- areas, including the axillae, popliteal spaces and neck
riasiform papules and plaques rapidly develop on the folds of infants [6]. Coexistent perianal disease may or
and lower abdomen [7]. Rapid spread to other areas of the

body also occurs.
This infection is caused by coagulase‐positive, usually
phage type II, Staph. aureus. This organism produces an
epidermolytic toxin that separates the upper layers of the
epidermis. Diagnosis can be confirmed with a Gram stain
and bacterial culture.
Nonbullous (encrusted) impetigo due to other types of
Staph. aureus and streptococci may occur in the napkin
area. Nonbullous impetigo is characterized by vesicles
and pustules that develop quickly into scabs with thick,
often honey‐coloured crusts.
Scabies
Scabies should be considered in the differential diagnosis
of napkin rash when pruritic papules, vesicles and vesic-

Fig. 20.10 Streptococcal intertrigo. Intertriginous, foul‐smelling, ulopustules are seen. Typically, these primary lesions
macerated erythema is a typical presentation. are intermingled with eczematization, excoriation and
OF DERMATITIS
crusting. Linear burrows are pathognomonic of scabies.
However, because burrows are extremely difficult to visu-
alize, this clinical sign is not of great clinical value. Sites of
predilection for scabies are the finger webs, wrists, ante-
cubital fossae, axilla, areolae and areas around the umbili-
cus, lower abdomen, genitals and buttocks. In infants and
young children, the palms, soles, head, neck and face may
also be affected. A high percentage of children with
scabies may develop nodular lesions. These persistent,
reddish‐brown, infiltrated nodules are more likely to
occur in covered parts of the body, such as the groin, but-
tocks and genitalia. The nodules often persist for months,
despite therapy, and may be mistaken for mastocytosis,
histiocytosis or cutaneous lymphoma.
In addition to the presence of lesions in a characteristic
distribution, the diagnosis of scabies is aided by a history
Fig. 20.11 Impetigo bullosa. Source: Courtesy of Professor Arnold Oranje. of intense itching and pruritus in family members or car-
egivers. Definitive diagnosis is made by microscopic
may not be present. The infection is characterized by a examination of scrapings of suspicious lesions with the
foul‐smelling, macerated erythema of intertriginous finding of the mite, ova or faecal matter. In many cases of
areas. Occasionally, mixed infections with Staphylococcus scabies infestation a scabies scraping may be negative,
aureus, Pseudomonas or Proteus species have been observed. and therapy may be prescribed empirically.
Frequently misdiagnosed as candidal intertrigo, cases of
streptococcal intertrigo are often resistant to topical anti- Congenital syphilis
fungal medications. Therapy with oral penicillin deriva- Until the early years of the twentieth century, syphilis was
tives for streptococcal intertrigo or appropriate coverage believed to be the major cause of napkin rash [8]. Although
for mixed infections is curative. Topical anti‐inflamma- we are now more enlightened as to the causes of napkin
tory medications, such as topical corticosteroids, may dermatitis, because of the recent increase in the incidence
assist in reducing associated inflammation more quickly of syphilis, congenital syphilis remains within the differ-
to provide more rapid symptomatic relief. ential diagnosis.
Clinical signs of early congenital syphilis may present
Bullous impetigo at birth or develop within the first 3 months of life. In the
The constant moisture and warmth of the napkin environ- anogenital region raised, moist, wart‐like lesions (condy-
ment are predisposing factors to the development of bul- lomata lata) may be seen in addition to moist eroded
lous impetigo, which is relatively common in the napkin areas. There may be a generalized erythematous papulos-
area. It is especially common in newborns as a result of quamous eruption similar to that seen in secondary syph-
colonization of the umbilicus with Staphylococcus aureus. ilis. Erythema, oedema, vesiculobullous lesions, fissuring
Bullous impetigo is characterized by the formation of and desquamation may occur on the palms and soles, and
large flaccid bullae arising from apparently normal skin. pale, slightly raised mucous membrane patches may be
The bullae rupture easily, leaving red, moist, denuded found in the mouth and on the lips. Other clinical features
areas and honey‐coloured crusts (Fig. 20.11). There are include anaemia, fever, wasting, hepatosplenomegaly,
usually multiple lesions involving the thighs, buttocks rhinitis (‘snuffles’), osteochondritis or periostitis, and
pseudoparalysis. Dark‐field examination of moist skin

lesions, especially the condylomata lata, should reveal
spirochaetes, and serological testing for syphilis will con-
firm the diagnosis.
Human immunodeficiency virus (HIV)

Severe napkin dermatitis can be a manifestation of paedi-
atric HIV infection. Leibovitz et al. [9], in a study of
Romanian children with HIV, noted napkin dermatitis, in
some cases very severe, in eight out of 23 infants. Unusual
erosive napkin dermatitis with deep gluteal cleft ulcera-
tion has been reported as a presenting sign of HIV infec-
tion [10]. In addition, ulcerative eruptions in the anogenital
area of HIV‐infected infants can be caused by, or compli-
cated by, infection with herpes simplex, cytomegalovirus
[11] and other opportunistic agents. Therefore, HIV infec-
tion should be considered in infants with unusually

severe or erosive napkin dermatitis.
OF DERMATITIS
References
1 Leyden JJ. Diaper dermatitis. Dermatol Clin 1986;4:23–8.
2 Singalavanija S, Frieden IJ. Diaper dermatitis. Pediatr Rev
1995;16:142–7.
Fig. 20.12 Infantile seborrhoeic dermatitis with involvement of the
3 Balasubramanian P, Jagadeesan S, Thomas J et al. Diaper dermatitis
with psoriasiform id eruptions. Indian J Dermatol 2015;81:435–7. inguinal folds.
4 Haddock ES, Calame A, Shimizu C et al. Psoriasiform eruptions dur-
ing Kawasaki disease (KD): a distinct phenotype. J Am Acad Dermatol
2016;75:69–76.e2.
5 Darmstadt GL, Dinulos JG, Miller Z. Congenital cutaneous can- spread to involve the forehead or the entire face. Other
didiasis, clinical presentation, pathogenesis, and management typical areas of skin involvement, primarily flexural
guidelines. Pediatrics 2000;105:438–44.
areas, include the axilla, neck, postauricular folds and
6 Honig PJ, Frieden IJ, Kim HJ et al. Streptococcal intertrigo: an under-
recognized disease. Pediatrics 2003;112(6):1427–9. umbilicus.
7 Rasmussen JE. Diaper dermatitis. Pediatr Rev 1984;6:77–82. The lesions of infantile seborrhoeic dermatitis are gen-
8 Leyden JJ, Kligman AM. The role of microorganisms in diaper derma- erally asymptomatic; affected children appear to be com-
titis. Arch Dermatol 1978;114:56–9.
9 Leibovitz E, Orlow S, Lawrence R et al. Children of Romania: the
fortable and do not exhibit signs of significant pruritus.
AIDS legacy. Children’s Hosp Q 1991;3:99–108. Infantile seborrhoeic dermatitis typically presents early in
10 Sweiden NA, Salman SM, Kibbi AG et al. Skin nodules over the infancy, generally within the first 3 months of life, most
diaper area: granuloma gluteale infantum. Arch Dermatol 1989; commonly at 3–6 weeks of age. The prognosis is good
125:1706–7.
11 Thiboutot DM, Beckford A, Mart CR et al. Cytomegalovirus diaper and, in most cases, the condition resolves spontaneously
dermatitis. Arch Dermatol 1991;127:396–8. by 3–6 months of age.
Atopic dermatitis
Primary and secondary inflammatory Atopic dermatitis usually spares the napkin area. This is
conditions somewhat surprising given that atopic individuals are
Infantile seborrhoeic dermatitis more susceptible to irritant reactions and do poorly with
Infantile seborrhoeic dermatitis is an inflammatory skin frequent exposure of the skin to water. Nevertheless,
disease which can commonly affect the napkin area of when atopic dermatitis presents in the napkin area, its
infants. It is characterized by salmon‐coloured, scaly appearance is similar to that of primary irritant napkin
plaques that involve the inguinal folds (Fig. 20.12). In dermatitis. The rash, however, tends to be more chronic
severe cases, there can be spread of the eruption from the and refractory to treatment. There may be oozing or crust-
skinfolds to convex skin surfaces of the napkin area. ing due to secondary infection with Staph. aureus. There
Typically, the lesions are sharply demarcated. The scales may also be lichenification and excoriations. In most cases
of infantile seborrhoeic dermatitis tend to be greasy and of atopic napkin dermatitis there are more typical eczem-
yellowish in colour. There may be associated fissuring, atous lesions elsewhere on the body, involving particu-
crusting and weeping. Unlike candidiasis, which also larly the cheeks and antecubital and popliteal fossae.
involves the skinfolds of the napkin area, there are no sat- Pruritus is a cardinal feature of this disease, and the atopic
ellite lesions. infant may be irritable and uncomfortable, constantly
A major clue to the diagnosis of this type of napkin rash rubbing or scratching the affected areas. One must bear in
is the presence of the eruption in characteristic areas away mind, however, that the signs of pruritus usually do not
from the anogenital region. Infantile seborrhoeic dermati- occur until the child is 2 months of age and is able to rub
tis often begins with diffuse erythema and thick, adher- or scratch. A family history of atopy is often obtained and
ent, greasy scales involving the scalp. The eruption may may also lend support to the diagnosis.
cases of simple intertrigo or seborrhoeic dermatitis

because of the primary flexural involvement.
There is also a risk for secondary bacterial infection
of these types of napkin dermatitis. This is particularly
important in cases of atopic dermatitis. If crusting
or blistering occurs, Staph. aureus infection should be
considered.
Psoriasis can be precipitated by pre‐existing napkin
dermatitis such as an irritant contact dermatitis or sebor-
rhoeic dermatitis, but a psoriasis id reaction pattern is
also possible. This is due to the isomorphic response to
skin injury known as the Koebner phenomenon. Thus,
because psoriasis may appear secondarily, it may present
with a distribution more characteristic of the primary
condition. Diagnosis may be suggested by the relatively
rapid response of the primary condition to specific

therapy and the recalcitrance of the secondary psoriatic
eruption.
OF DERMATITIS
Fig. 20.13 Psoriasis napkin change. Note sharply marginated border of
plaque. Source: Courtesy of Professor Arnold Oranje. Miliaria
Miliaria (prickly heat) is commonly concentrated in the
napkin area because of the tropical conditions under
Psoriasis
the napkin. Other typical areas of involvement include
Psoriasis is rare in infancy. When it does occur in the first
the face, neck and axilla. Miliaria may be precipitated
year of life, it is likely to appear in the napkin area because
by fever, high ambient temperature or use of an occlu-
of the Koebner phenomenon caused by more common
sive ointment or plastic napkin pants [2]. Increased
types of napkin rash. It typically presents as sharply
heat and humidity cause blockage of the eccrine sweat
demarcated, erythematous plaques of variable size, with
glands. Different clinical forms of miliaria result based
involvement of the convex surfaces of the buttocks as well
on the level at which the eccrine duct is obstructed.
as the inguinal folds (Fig. 20.13). Unlike psoriatic plaques
Miliaria crystallina is more commonly seen in the new-
elsewhere on the body, there may be little or no scale
born and appears as clear, small, superficial vesicles with-
due to the constant hydration under the napkin. Diagnosis
out associated erythema. The eccrine duct obstruction in
may be difficult and become clear only after long‐term
this form of miliaria occurs within the stratum corneum.
observation. Psoriasis‐like eruptions were described in
In older infants, miliaria rubra (or pustulosa) is more
patients with Kawasaki disease by Haddock et al. [1]. As
common. This form occurs when the sweat duct is
opposed to irritant contact napkin dermatitis, or sebor-
obstructed within the deeper layers of the epidermis.
rhoeic dermatitis, psoriasis in the napkin area tends to be
Miliaria rubra is characterized by small, uniform erythe-
chronic and more resistant to treatment with low‐potency
matous grouped papules and pustules which are nonfol-
topical steroids. Topical corticosteroids that are slightly
licular. The pustules are sterile, and Gram stain will reveal
more potent than 1% hydrocortisone, such as desonide
polymorphonuclear leucocytes but no bacteria or yeast.
0.05% or alclometasone dipropionate 0.05%, may be nec-
In cases of miliaria pustulosa, it is important to rule out a
essary. A positive family history of psoriasis may be elic-
staphylococcal pustulosis.
ited. Often, when psoriasis involves the groin, it is also
present in other flexural areas such as the axillae and
neck. Certainly, the development of more classic psoriatic ‘Perianal pseudoverrucous papules
lesions with silvery micaceous (mica‐like) scale elsewhere and nodules’ entity
on the body and the presence of nail pitting can help in ‘Perianal pseudoverrucous papules and nodules’ entity is
making the diagnosis. a rare condition that was first described in patients with
urostomies [3]. It was attributed to chronic irritation from
Mixed napkin dermatitis leakage of urine. This eruption has more recently been
Sometimes several of the previously described types of reported also to occur in the perianal area of children in
napkin dermatitis occur together, making diagnosis very association with chronic faecal soiling. In the reported
difficult. Irritant contact napkin dermatitis is commonly cases, stool leakage was due to severe constipation with
secondarily infected with C. albicans, and this may alter secondary encopresis or followed surgical colonic re‐
the appearance of the rash. If the rash is severe or present anastomosis in patients with Hirschsprung disease [4].
for more than 2–3 days, anticandidal agents such as nys- This entity is characterized by 2–8 mm, red, moist, flat‐
tatin, clotrimazole, econazole, ketoconazole or mupirocin topped round papules and papulonodules (Fig. 20.14). It
should be used in addition to low‐potency topical ster- is believed that the pathogenesis of this entity is similar to
oids, barrier creams and frequent napkin changes. that of Jacquet dermatitis in that it is a local response to
Additionally, it is often difficult to rule out candidiasis in chronic irritation. Pseudoverrucous papules and nodules
Fig. 20.14 Perianal pseudoverrucous papules and nodules. Source:

Courtesy of Dr Neil Prose.
may be mistaken for cutaneous Crohn disease, granu-

loma gluteale infantum, condylomata acuminata or
OF DERMATITIS
Langerhans cell histiocytosis.
Perioral dermatitis with extrafacial

genital manifestations and metastatic
Crohn disease
Perioral dermatitis classically presents with noncome- Fig. 20.15 Metastatic Crohn disease of the vulvar area.
donal, acneiform papules in a perioral and periocular dis-
tribution. Histologically, these lesions resemble the first week of the onset of symptoms. The rash was charac-
granulomatous lesions of adult rosacea. The condition terized by confluent, sometimes tender, macular to
appears to be associated in some cases with a history of plaque‐type erythema involving part or all of the perineal
topical steroid use. Similar granulomatous lesions may region. The erythema was followed shortly by desquama-
appear on the genital surfaces [5]+. Patients with such tion. In fact, the authors found that this rash appeared
findings should also be screened for the possibility of more frequently than ‘strawberry’ tongue or reddened
inflammatory bowel disease because granulomatous oropharyngeal mucosa. They concluded that this perineal
lesions in the perioral, oral and genital areas, which may eruption, which may be mistaken for napkin rash, was a
be associated with labial or genital swelling, may r epresent valuable early clinical finding of Kawasaki disease, facili-
metastatic areas of Crohn disease (Fig. 20.15) [6]. tating more rapid diagnosis and treatment.
Kawasaki disease References

An erythematous, desquamating perineal eruption has 1 Haddock ES, Calame A, Shimizu C et al. Psoriasiform eruptions dur-
ing Kawasaki disease (KD): a distinct phenotype. J Am Acad
been noted as an early sign of Kawasaki disease, but a pso-
Dermatol 2016;75:69–76.e2.
riasis id reaction pattern is also possible [1]. This disease, 2 Uyeda K, Nakayasu K, Takaisski Y et al. Kaposi sarcoma‐like granu-
also known as mucocutaneous lymph node syndrome, is loma on diaper dermatitis. Arch Dermatol 1973;107:605–7.
an acute multisystemic illness of unknown aetiology that 3 Borglund E, Nordstrom G, Nyman CR. Classification of peristomal
skin changes in patients with urostomy. J Am Acad Dermatol
affects infants and young children. The principal clinical 1988;19:623–8.
signs include: (i) fever for more than 5 days; (ii) nonsup- 4 Goldberg NS, Esterly NB, Rothman KF et al. Perianal pseudoverru-
purative cervical lymphadenopathy; (iii) conjunctival cous papules and nodules in children. Arch Dermatol 1992;128:240–2.
infection; (iv) reddened, cracked lips, ‘strawberry’ tongue 5 Urbatsch AJ, Frieden I, Williams ML et al. Extrafacial and
generalized granulomatous periorificial dermatitis. Arch Dermatol
and erythema of the oropharyngeal mucosa; (v) oedema, 2002;138:1354–8.
erythema and desquamation of the hands and feet; and 6 Schrodt BJ, Callen JP. Metastatic Crohn’s disease presenting as chronic
(vi) a polymorphous exanthem. Although usually a self‐ perivulvar and perirectal ulcerations in an adolescent patient.
Pediatrics 1999;103:500–2.
limiting illness, cardiovascular abnormalities, particularly 7 Friter BS, Lucky AW. The perineal eruption of Kawasaki syndrome.
coronary artery aneurysm, may occur. This may lead to Arch Dermatol 1988;124:1805–10.
coronary thrombosis, stenosis and ultimately myocardial
infarction. Early treatment with intravenous gamma glob-
ulin and high‐dose aspirin may prevent these potentially
Neoplastic napkin conditions
fatal cardiovascular complications. Thus, early diagnosis Langerhans cell histiocytosis (formerly
of Kawasaki disease is crucial. Letterer–Siwe disease)
Friter and Lucky [7] studied 58 patients with Kawasaki This acute disseminative, potentially fatal form of
disease and found that 39 (67%) presented with a distinc- Langerhans cell histiocytosis (LCH) can present with
tive perineal eruption that usually occurred within the skin findings in the napkin area. Although this is a rare
which appears to be mediated in some affected patients

by SLC39A4 (ZIP4), an intestinal zinc/iron transporter
protein [2], or there may be a defective zinc transporter,
SLC30A2 (ZnT2) family, that affects the movement of zinc
into breast milk in affected mothers. [3]. Manifestations of
the disease typically present when the affected infant is
weaned from breastfeeding; breast milk is felt to be pro-
tective because it contains a zinc ligand‐binding protein
[4]. The transient acquired form is due to nutritional zinc
deficiency. It is seen in infants with severe malabsorption,
in premature infants who receive prolonged parenteral
alimentation [5] and in breastfed infants when the zinc
level in the mother’s milk is abnormally low [4].
Acrodermatitis enteropathica is characterized by a
periorificial and acral vesiculobullous eczematoid erup-
tion. Scaly, sharply demarcated, crusted plaques are

seen in the folds of the napkin area, around the mouth,
nose and eyes and on the distal extremities. In chronic,
OF DERMATITIS
untreated cases, the lesions become lichenified and psori-
asiform in appearance. Secondary infection with bacteria
and C. albicans is frequent. Other clinical characteristics
include failure to thrive, photophobia, diarrhoea, alope-
cia, paronychia, nail dystrophy, irritability or listlessness.
Diagnosis is confirmed by a plasma zinc level lower than
Fig. 20.16 Langerhans cell histiocytosis. Note haemorrhagic satellite 50 μg/mL (normal values: 70–110 μg/mL). The alkaline
papules and intertriginous dermatitis. phosphatase, a zinc‐dependent metalloenzyme, is also
low in prolonged cases of acrodermatitis enteropathica.
The disease responds rapidly and quite dramatically to
treatment with zinc supplementation. The irritability or
disease, it should be considered in cases of intractable apathy usually disappears within 24 h after initiating
napkin dermatitis. This infantile form of LCH usually therapy.
occurs during the first year of life but may occur in chil- Biotin‐responsive multiple carboxylase deficiency is a
dren up to the age of 3 years. It often starts with an rare, recessively inherited, metabolic disorder that can
inguinal rash resembling seborrhoeic dermatitis. The present in infancy with a periorificial eruption similar to
inguinal eruption of infantile LCH, however, is often that of acrodermatitis enteropathica. Likewise, superin-
more erosive (Fig. 20.16) and fails to respond to local fection with C. albicans is common. Other manifestations
therapy. The infant then develops postauricular erosions of biotin deficiency include alopecia, seizures, ataxia and
and a scaly rash of the scalp and trunk. This eruption intermittent metabolic acidosis.
consists of yellowish to reddish‐brown infiltrated pap- Cystic fibrosis is yet another disease to keep in mind
ules, often with a purpuric component. Lesions may when one sees acrodermatitis enteropathica‐like skin
show haemorrhagic crusting. Petechiae and epidermal lesions. The main clinical features of cystic fibrosis are
atrophy may also be seen. The development of purpuric chronic lung disease, exocrine pancreatic insufficiency
nodules of the palms and soles is associated with a poor with malabsorption, retarded growth and hepatic dis-
prognosis. ease. In this condition, secreted mucus has an increased
Systemic manifestations of the disease include fever, viscosity and there is an abnormally high sodium concen-
anaemia, diarrhoea, thrombocytopenia, hepatospleno- tration in the sweat. The periorificial eruption is consid-
megaly, lymphadenopathy and skeletal tumours. A skin ered to be a manifestation of essential fatty acid and zinc
biopsy should be performed in order to confirm the diag- deficiency which is due to gastrointestinal malabsorption.
nosis in suspected cases. Other metabolic disorders associated with acrodermatitis
enteropathica‐like presentations include ornithine tran-
scarbamylase deficiency [6], nonketotic hyperglycinae-
Metabolic napkin conditions
mia [7], methylmalonic acidaemia [8] and maple syrup
Acrodermatitis enteropathica urine disease [9], as well as other organic acidurias. In
Acrodermatitis enteropathica is another rare disease that these cases, low‐protein diets to minimize excess patho-
should be considered in cases of atypical or persistent logical organic acids may result in secondary zinc defi-
napkin rash. This entity is caused by zinc deficiency. ciency and acrodermatitis enteropathica‐like eruptions.
There is an inherited form of the disease as well as an However, in some patients with maple syrup urine dis-
acquired, transient form. In the autosomal recessive ease and acrodermatitis enteropathica, zinc levels are nor-
inherited form of acrodermatitis enteropathica, there is an mal and the clinical course of the skin eruption appears to
inborn defect in the gastrointestinal absorption of zinc [1] be correlated with serum isoleucine levels [9].
References
1 Van Wouwe JP. Clinical and laboratory diagnosis of acrodermatitis
enteropathica. Eur J Pediatr 1989;149:2–8.
2 Kury S, Dreno B, Bezieau S et al. Identification of SLC39A4, a gene
involved in acrodermatitis enteropathica. Nat Genet 2002;31:239–40.
3 Michalczyk A, Varigos G, Catto‐Smith A et al. Analysis of zinc trans-
porter hZnT4(Slc30a4), gene expression in a mammary gland disor-
der leading to reduced zinc secretion into milk. Hum Genet 2003;
113:202–10.
4 Zimmerman AW, Hambridge M, Lepow ML et al. Acrodermatitis in
breast‐fed premature infants, evidence for a defect of mammary zinc
secretion. Pediatrics 1982;69:176–83.
5 Arlette JP. Zinc and the skin. Pediatr Clin North Am 1983;30:583–96.
6 Lee JY, Chang SE, Suh CW et al. A case of acrodermatitis enteropathica
like dermatosis caused by ornithine transcarbamylase deficiency. J Am
Acad Dermatol 2002;46:965–7.
7 Samady JA, Schwartz RA, Shih LY. Acrodermatitis enteropathica‐like
eruption in an infant with nonketotic hyperglycinemia. J Dermatol
2000;27:604–8.
8 Howard R, Frieden IJ, Crawford D et al. Methylmalonic acidemia,
cobalamin C type, presenting with cutaneous manifestations. Arch
Dermatol 1997;133:1563–6.
9 Giacoia GP, Berry GT. Acrodermatitis enteropathica‐like syndrome sec-
OF DERMATITIS
ondary to isoleucine deficiency during treatment of maple syrup urine

disease. Am J Dis Child 1993;147:954–6.
Other important napkin conditions Fig. 20.17 Herpes simplex virus infection. Source: Courtesy of Professor
Arnold Oranje.
Other vesiculobullous disorders
The maculopapular and vesicular lesions of varicella can
sometimes be more florid in areas of pre‐existing skin feet are affected, then child abuse by lowering a child into
inflammation. Thus, patients with a napkin dermatitis scalding hot water must be seriously considered. The
have a predilection for the development of varicella burned skin is usually sharply demarcated and involves
lesions in the napkin area. the convexities of the buttocks with sparing of the peria-
Uncommon systemic blistering diseases may present nal area. A thorough history should exclude the inciden-
with lesions in the anogenital region of napkin‐wearing tal ingestion of caustic laxatives by children, which may
children. These include neonatal herpes simplex present with findings suggestive of abusive immersion
(Fig. 20.17), hand, foot and mouth disease, chronic bul- injury because of the perianal erosive erythema that can
lous dermatosis of childhood, bullous mastocytosis, result [2,3].
incontinentia pigmenti, epidermolytic hyperkeratosis
and epidermolysis bullosa. Diagnosis is based on the References
1 Schanzer MC, Wilkin JK. Diaper dermatitis. Am Fam Physician
morphology of the lesions, their distribution outside the 1982;25:127–32.
napkin area and other diagnostic criteria. 2 Giacoia GP, Berry GT. Acrodermatitis enteropathica‐like syndrome
secondary to isoleucine deficiency during treatment of maple syrup
urine disease. Am J Dis Child 1993;147:954–6.
Child abuse 3 Leventhal JM, Griffin D, Duncan KO et al. Laxative‐induced
If the skin of the buttocks is red and blistered in a ‘dunk- dermatitis of the buttocks incorrectly suspected to be abusive burns.
ing’ pattern [1], and especially if the lateral aspects of the Pediatrics 2001;107:178–9.
279
C HA PTER 21
Adolescent Seborrhoeic Dermatitis

Roselyn Kellen & Nanette Silverberg
Icahn School of Medicine at Mount Sinai, New York, NY, USA
Abstract probably a combination of individual predisposition, the presence

of Malassezia yeast on the skin and inflammatory response to the
yeast species. Physical examination reveals mildly erythematous
While seborrhoeic dermatitis is a common inflammatory skin
patches with yellowish‐white, greasy scales, typically affecting
disorder often observed in infants 0–3 months of age, it is also
areas of the skin with increased sebum production such as the
seen in adolescents with onset at the age of puberty. Occasion-
scalp, eyebrows and nasolabial folds. The prognosis is favourable
ally, the condition is found in toddlers and school‐aged children
and treatment options include medications with antifungal, anti‐
as well. Although the exact pathophysiology is unknown, it is

inflammatory and keratolytic properties.
OF DERMATITIS
Key points • The scalp, ears, eyebrows and nasolabial folds are most
commonly involved and l show erythematous patches with
yellowish‐white greasy scales.
• Paediatric seborrhoeic dermatitis is a biphasic illness with clinical
• Treatment can involve the use of agents with antifungal, anti‐
peaks in infancy and adolescence.
inflammatory and keratolytic properties.
• There is strong evidence for the involvement of Malassezia
• The prognosis is favourable; however, inflammatory
yeast.
symptoms may be chronic and require intermittent or ongoing
• There also appears to be individual predisposition towards an
intervention.
inflammatory response.
M. restricta [18–21] although there may be geographical

Introduction/history. Seborrhoeic dermatitis (SD)
variation [22].
(verna
cular: dandruff or cradle cap) is a chronic
It is important to note the detrimental effects of SD on
inflammatory skin disease caused by Malassezia yeasts,
quality of life. In infancy, SD can be generalized and asso-
which are commensal eukaryotic organisms found in
ciated pruritus can interfere with sleep and daily activi-
the normal skin flora of the superficial sebaceous folli-
ties if severe. Children and adolescents can suffer from
cle [1]. Knowledge of the association of yeast with skin
social stigma and feelings of low self‐esteem. In turn, all
diseases goes back as far as the nineteenth century
these factors also place a tremendous amount of stress on
when yeast cells and filaments were found in the scales
their caregivers. As there is no cure for dermatitis, it is
of patients with pityriasis versicolor (tinea versicolor)
essential to establish a management plan to keep the dis-
[2] and M. furfur was identified as the organism associ-
ease under control and address flares in a timely manner.
ated with dandruff [3,4].
In the early 1900s, Sabouraud separated Malassezia
furfur, which forms filaments, and Pityrosporum malassezii, Epidemiology. SD is a relatively common skin disorder,
which does not form filaments and is found in dandruff estimated to have a prevalence of approximately 11.6%
and scales from patients with SD, into separate genera [5]. in the general population (with males more commonly
Pityrosporum malassezii was then re‐named Pityrosporum affected than females) and 3–5% in the USA [23,24].
ovale [6], which was then confirmed to be identical to Disease activity peaks at two time points during child-
Pityrosporum orbiculare [7]. The common denominator of hood: the first 3 months of life (when it is known as infan-
successful treatments for SD was antifungal activity, and tile SD or cradle cap) and during puberty, time periods of
in 1984 it was shown that P. ovale was the causative agent increased sebaceous gland activity [1].
of SD [8,9]. The genus Malassezia includes 14 species, of In contrast to infantile SD, which is self‐limiting and
which the majority are lipophilic [1]. The species most resolves by 1 year of age [25], adolescent SD tends to be
commonly associated with SD are M. globosa [10–17] and more chronic [26]. In an Australian study of over 1000
children ≤5 years of age, the prevalence was 10.4% in boys be of benefit [36,45]. Interestingly, M. furfur appears to
and 9.5% in girls [27]. Prevalence was highest during the produce pityriacitrin, which acts as a UV filter [46].
first 3 months of life and rapidly decreased after age 1 Nutrients in sweat such as amino acids might also play a
[27]. Of those with disease, 72% had minimal to mild role as one study showed that the addition of glycine
severity [27]. Berk and Scheinfeld reported that up to 70% stimulated the growth of M. furfur [47]. The virulence fac-
of infants have SD in the first 3 months of life [23]. tor might be production of phospholipases, a known vir-
Aside from the two peaks during childhood, SD is also ulence factor of Candida albicans [48], which results in
noted in school‐aged children and later jumps in fre- disruption of epidermal lipids and therefore the barrier
quency among adults in their third and fourth decades in protection of the epidermis [1]. Other contributors could
whom sebum production is decreased [1,28–30]. SD is also be emotional stress, sleep deprivation and nutritional
more common in those with Parkinson disease, cranial deficiencies [33]. DeAngelis et al. suggested that fungal
nerve palsies [31] and drug‐induced parkinsonism [32], metabolites such as free fatty acids released by sebaceous
and in patients taking haloperidol decanoate, lithium, triglycerides trigger the clinical findings of dandruff [41].
buspirone and chlorpromazine [23], calling into question They found that a Malassezia metabolite called oleic acid
neurogenic factors [33]. SD is one of the most common was able to induce scaling similar to that of dandruff but
dermatological disorders in patients with human immu- only in patients known to have dandruff [41]. The authors
nodeficiency virus (HIV), with incidence rates as high as attributed this to underlying defects in the permeability
85% [31], and is often severe, especially in patients with barrier function, which brings into play the idea of indi-
OF DERMATITIS
low CD4 counts [34]. SD is also associated with depres- vidual susceptibility to developing disease [41]. Further
sion, acute traumatic spinal cord injuries [35,36], familial research can help us understand why certain species are
amyloidotic polyneuropathy [37] and children with pathogenic or virulent, what the virulence factors are, and
Down syndrome [38] and Leiner’s phenotype [39]. clarify the mechanism behind the inflammatory process
generated in the skin [1].
Pathogenesis. The role of Malassezia in SD has been
c ontroversial; as reviewed by Gupta et al., there are con- Clinical features. The name of this skin condition is
flicting data on the number of yeasts in affected versus actually a misnomer because seborrhoea, or increased

nonaffected skin [36]. Yet the efficacy of antifungal treat- sebum production from sebaceous glands, is not a feature
ments is strong proof that these yeasts play a central role of seborrhoeic dermatitis [49]. Rather, a more appropriate
in triggering inflammation at the centre of disease patho- name would be ‘dermatitis of the sebaceous areas’ [49].
genesis [40]. That being said, these are commensal yeasts Since most species of Malassezia depend on lipids for
found in normal flora [31], so why do only certain people growth [50], they have a preference for seborrhoeic
develop disease? There are probably multiple compo- regions with increased sebum production [1,36].
nents involved in SD: the presence of Malassezia yeast, The classic presentation consists of symmetrical,
the role of sebum production and inflammation, and an poorly‐demarcated erythematous patches with white to
individual predisposition, the latter mechanisms not yellow greasy scales [23], but there is considerable varia-
being mutually exclusive [41]. tion in the degree of erythema and scaling [36]. Dandruff
The clinical manifestations of SD are probably the result is probably a mild form of SD characterized by dry flakes
of an inflammatory reaction to the yeast [1]. As reviewed (Fig. 21.1) confined to the scalp with minimal to no
by Gaitanis et al., Malassezia yeast cells interact with
keratinocytes [42] and immune cells including dendritic
cells, macrophages, eosinophils and neutrophils, with
various effects on levels of cytokines, chemokines and
adhesion molecules [1]. The presence or absence of the
lipid capsule of Malassezia spp. is associated with an
increase or decrease in the production of interleukins
(IL)‐1α, IL‐6, IL‐8 and IL‐10 [43]. Skin biopsies from
patients with SD showed higher levels of markers for
CD4, human leucocyte antigen (HLA)‐DR, natural killer
(NK)1, CD16 and CD54 (ICAM‐1) cells compared to
healthy volunteers [8]. The same was true for markers for
C1q, IL‐1α, IL‐1β, TNF‐α, IFN‐γ, IL‐2, IL‐4, IL‐6, IL‐10,
IL‐12 and IL‐4 [8]. Moreover, the various Malassezia spp.
can stimulate different profiles of these inflammatory
cytokines, which might explain the numerous clinical
presentations of Malassezia‐associated skin conditions
[1,42]. In addition, certain species might be preferentially
found in specific body regions [44].
Although sebum production on the face is lower in
autumn compared to summer, flares are often seen dur- Fig. 21.1 Teenage female with seborrhoeic dermatitis of the scalp in
ing the autumn and winter, suggesting that sunlight may association with androgenic alopecia and polycystic ovaries.
Chapter 21 Adolescent Seborrhoeic Dermatitis 281
Differential diagnosis. Patients with simultaneous fea-

tures of seborrhoeic dermatitis and psoriasis, known as
sebopsoriasis, can be difficult to diagnose [1]. The same is
true for severe SD that presents as erythematous plaques
with thicker scale [31]. Clinicians should look for extracu-
taneous signs of psoriasis, such as nail pitting or other
nail involvement as well as joint disease. Yellow, greasy
scales are also more suggestive of SD, whereas sharply
demarcated erythematous plaques with a silvery scale
are more consistent with psoriasis. The distribution of
lesions can also be helpful given that psoriasis tends to
favour the extensor surfaces.
Atopic dermatitis can be difficult to discern from SD,
particularly in infancy; the two conditions often coexist
and might be associated [53–55]. Reports document infants
with infantile seborrhoeic dermatitis (ISD) who go on to

develop atopic dermatitis 4 months later [55]. This overlap
Fig. 21.2 African‐American male with nummular hypopigmented
can be seen in adolescents and adults as well on occasion.
OF DERMATITIS
seborrhoeic dermatitis, sometimes termed petaloid seborrhoeic dermatitis
due to the flower‐like shape in some cases. Treatment is similar in all cases, The distinction between the two is primarily clinical: one
but pigmentation can take months to return. can consider the age of the patient, the presence or absence
of pruritus, oozing and weeping, response to topical medi-
cations, family history and distribution of the lesions [55].
In atopic dermatitis, skin lesions are pruritic and diffuse
inflammation [1]. Adolescents with SD may report mild and involve the face, trunk and extensor surfaces in
pruritus [26] and paediatric cases have been associated infants, and flexural surfaces in children [53]. On the other
with posterior neck adenopathy, although the latter is not hand, involvement of the axilla and anterior neck is more
specific for SD and should prompt screening for active suggestive of ISD [55]. Chronic atopic dermatitis can lead
infections of the head and neck such as tinea capitis and/or to lichenified skin with associated pigment changes [53].
upper respiratory infections [28]. Patients with atopic dermatitis usually have a parent or
In adolescents, the most commonly affected areas are sibling with atopic disorders including asthma and aller-
the scalp, external ears, eyelids, eyebrows, moustache gic rhinitis [53,55]. They may also have high levels of
and beard areas, nasolabial folds, and retroauricular immunoglobulin E (IgE) and eosinophils [53]. Interestingly,
folds, and occasionally nuchal and neck with patches and Malassezia might also play a role in atopic dermatitis, espe-
plaques that are thinner than their adult counterparts [26]. cially of the head and neck; such patients are more likely
Occasionally, the upper/mid chest and back are involved, to have Malassezia‐specific IgE compared to patients with
and less commonly the axillae and inframammary and atopy but no head and neck dermatitis [56,57].
perineal folds are affected [26]. Patients who are dark‐ Williams et al. conducted a cross‐sectional study of 300
skinned, especially African Americans, may manifest children to determine the most common causes of scalp
with petaloid seborrhoeic dermatitis which is hypopig- scaling [28]. Overall, the most common aetiologies were
mented and can be concentrated on the cheeks and fore- seborrhoeic dermatitis (54.5%), undetermined (30.3%) and
head areas. This may mimic pityriasis alba, vitiligo and atopic dermatitis (24.2%). The most common diagnoses
mycosis fungoides, but is typically located in seborrhoeic in children <2 years of age were seborrhoeic dermatitis
areas and has typical histology (Fig. 21.2). and atopic dermatitis. For children between the ages of 2
There are several conditions that can present alongside and 10, the most common causes were unknown aetiol-
SD that clinicians should be aware of. Malassezia folliculi- ogy, seborrhoeic dermatitis and atopic dermatitis/eczema.
tis is characterized by erythematous papules or (less com- Tinea capitis is also a common concern in the differential
monly) pustules on the back, chest and upper arms, which diagnosis although the incidence of tinea capitis begins to
can be pruritic or asymptomatic [51,52]. Biopsy results wane during adolescence. Potassium hydroxide (KOH)
would illustrate the presence of abundant yeast growth in preparation of skin scrapings from these patients would
hair follicles but there is also an accompanying inflamma- reveal hyphae (whereas pseudohyphae would be indica-
tory infiltrate composed of lymphocytes, histiocytes and tive of candidiasis) [23,58,59]. A retrospective chart review
neutrophils [51]. Similar to SD, Malassezia folliculitis is to determine the causes of scalp hyperkeratosis and/or
treated with topical antifungals, with systemic therapy alopecia in inner‐city children [58] identified the records of
reserved for severe, refractory cases [51,52]. Aside from 164 children aged 0–17, of whom 75 were black and 56
folliculitis, patients may have blepharitis leading to mei- were Hispanic/Latino. Of the children with scalp hyper-
bomian gland blockage and abscess, otitis externa and keratosis, 60% had tinea capitis. Of the children with
simultaneous acne vulgaris [33]. Patients should also be hyperkeratosis and alopecia, 82.1% had tinea capitis.
examined for signs of secondary infection, most com- Interestingly, another cross‐sectional study also found that
monly due to Staphylococcus aureus. only 10.5% of children who had scalp scaling combined
with head and neck adenopathy had tinea capitis in their

Treatment and prevention. As shown in Box 21.1, there
population, which was mostly Caucasian [28]. Three per-
are many treatment options for adolescents and adults
cent of patients had cultures positive for a dermatophyte;
with seborrhoeic dermatitis, ranging from topical to sys-
all these cultures grew Trichophyton tonsurans and all were
temic agents, which can be divided into four groups: anti-
from black patients.
fungals (azoles, selenium sulfide), anti‐inflammatory
In one retrospective chart review where treatment out-
agents (topical corticosteroids, topical calcineurin inhibi-
comes for paediatric patients with skin of colour were
tors), keratolytics (salicylic acid, urea, ammonium lactate)
evaluated, 60.6% of patients were African‐American and
and others (tar, tea tree oil) [23,40]. Table 21.1 lists the
28.2% were Hispanic [59]. Eighty patients (of 84 identified
therapies that are approved by the US Food and Drug
cases of tinea capitis) were started on griseofulvin sus-
Administration (FDA) for use in the paediatric popula-
pension and/or crushed tablets and 61 had complete
tion [26]. As many therapies are used off‐label in children,
responses. Of the 19 griseofulvin failures, 15 were treated
both sets of agents are herein reviewed.
and cleared in response to fluconazole suspension, terbi-
Several agents work through more than one mechanism,
nafine sprinkles or oral itraconazole.
which makes them especially useful for compliance in
Erythema of the central face can be misdiagnosed as
adolescents. Ketoconazole has antibacterial, anti‐
rosacea, systemic lupus erythematosus or discoid lupus
inflammatory, sebostatic and antiproliferative effects [61].
[23]. The differential also includes drug eruptions, contact

Tar is anti‐inflammatory and keratolytic and is available
dermatitis, erythrasma and, less commonly, dermatomy-
as a shampoo or in precombined topical preparation [62].
OF DERMATITIS
ositis, cutaneous lymphoma, Langerhans cell histiocyto-

Sulphur is antifungal, antibacterial and keratolytic, and
sis and vitamin B or zinc deficiency [23,33].
can be combined with sodium sulfacetamide or salicylic
Hypopigmented seborrhoeic dermatitis can mimic
acid [63].
mycosis fungoides, pityriasis alba and vitiligo.
The most commonly used agents for SD are antifungal
Children can present with a generalized eczematous
agents, available in both topical and systemic form,
eruption of SD similar to that found in Wiskott–Aldrich
which come in two classes: imidazoles (e.g. ketoconazole,
syndrome, however purpura and petechiae, as well as
other systemic symptoms, will be absent [23]. Individuals
with rapid onset of widespread lesions in adulthood
should be tested for HIV [23]. Box 21.1 Different classes of medications used for the
treatment of adolescent and adult seborrhoeic dermatitis
Histological findings. SD is characterized by changes in Antifungal Anti‐ Keratolytic Other
the stratum corneum that can be seen throughout the inflammatory
scalp, even in areas without flaking [60]. Findings include
parakeratosis, the presence of lipids within corneocytes, Azoles Corticosteroids Salicylic acid Tea tree oil
fewer desmosomes and excess of disorganized lipids in Terbinafine Tacrolimus Coal tar Crude honey
the cells [60]. Ciclopirox Pimecrolimus Urea Hormonal
therapies that
Biopsy is rarely performed unless there is suspicion for
block
a disease such as Langerhans cell histiocytosis, but find- androgens
ings include neutrophils in the scale crust near the follicu- Zinc Nonsteroidal Ammonium Borage oil
lar ostia [33]. Individuals with acquired immune pyrithione creams (e.g. lactate
deficiency syndrome (AIDS)‐induced SD can have par- Promiseb®)
akeratosis, necrotic keratinocytes, and plasma cells visible Selenium More
sulfide frequent
in the dermis [33]. Special stains can be used to identify
washing
the yeast cells associated with keratinocytes [33]. Hyphae Sulfacetamide
are an indicator of dermatomycosis whereas short hyphae
and spores, so‐called ‘meatballs and spaghetti’, are con- Source: Adapted from Poindexter et al. 2009 [26].
sistent with tinea versicolor [33].
Table 21.1 FDA‐approved therapies for paediatric seborrhoeic dermatitis
Therapy Brand name Frequency of use Age group
Ciclopirox 0.77% gel Loprox® Twice a day for 4 weeks ≥16 years of age
Ciclopirox 1% shampoo Twice a week for 4 weeks ≥16 years of age
Ketoconazole 2% foam Exina® Twice a day for 4 weeks ≥12 years of age
Ketoconazole 2% gel Xelogel® Daily for 2 weeks ≥12 years of age
Selenium sulfide 1% or 2.5% shampoo Selsun Twice a week for 2 weeks ≥2 years of age
Sulfacetamide 10% lotion, cream, gel, wash, foam Carmol Scalp Treatment®, Klaron®, Ovace® Daily for 8–10 days ≥12 years of age
Sulfacetamide/sulphur 10%/5% wash, cream, or gel Plexion®, Rosac®, Rosula® Daily or twice daily ≥12 years of age
econazole, clotrimazole, miconazole) and triazoles (flu- adverse effect, irritative dermatitis, was thought to be
conazole) [40]. Azoles inhibit the fungal P450 enzyme, treatment related [77]. In 1996, Zeharia et al. reported the
thereby blocking the formation of ergosterol from lanos- results of evaluating the use of bifonazole shampoo for
terol, which is required for cell membrane synthesis [40]. scalp seborrhoeic dermatitis in 36 patients between the
The end result is a decrease in growth yet many antifun- ages of 1 month and 10 years [73]. Ninety seven percent of
gals have also been shown to have anti‐inflammatory the patients improved with 70.6% showing complete
properties [24,40]. One of the best studied, and most fre- response. Although two patients reported burning of the
quently used agents, is ketoconazole. Currently, there is a eyes when using the shampoo and one patient had a tem-
2% ketoconazole gel approved for children ≥12 years of porary generalized rash (that resolved after a few hours),
age with seborrhoeic dermatitis [64]. The double‐blind there were no major side‐effects. Van Esso et al. found that
trial enlisted 459 patients over the age of 12 with moderate 2% sertaconazole cream was well tolerated in 16 children
to severe seborrhoeic dermatitis who applied the gel once (aged 2–16) being treated for cutaneous mycoses with no
a day for 14 days [64]. The proportion of patients that were local or systemic adverse effects observed [78].
effectively treated was 25.3% in the group that received Anti‐inflammatory agents include topical corticosteroids
the gel compared to 13.9% in the placebo group [64]. and nonsteroidal creams. Corticosteroids are available
Collectively, in the three trials that were carried out, 7% of in numerous strengths and vehicles, such as ointments,

patients reported at least one adverse event with the most creams, lotions, solutions, shampoos, gels and foam
common being burning upon application (4%) [64]. [26,33]. Although off‐label, the topical calcineurin inhibi-
OF DERMATITIS
A large, double‐blind, placebo‐controlled study com- tors tacrolimus [79] and pimecrolimus have been used for
pared the use of 2% ketoconazole shampoo to placebo in SD in adults, especially for facial SD [33], and are espe-
575 adult patients with SD [65]. Results showed that topi- cially helpful for patients of colour with petaloid sebor-
cal application of 2% ketoconazole shampoo was more rhoeic dermatitis of the mid‐face. Side‐effects include
effective in clearing scalp SD and dandruff and was well local pruritus and burning [79,80]. Off‐label usage should
tolerated. Furthermore, the 312 patients who responded be weighed against the FDA‐issued black‐box warning for
were instructed to use the shampoo as prophylaxis for topical calcineurin inhibitors concerning a risk of increased
6 months and fewer of these patients suffered relapses malignancies and age restriction to 2 years and over [81].
(19%) compared to the placebo group (47%) [65]. Safety A nonsteroidal anti‐inflammatory cream known as
data in the paediatric population are more limited and Promiseb® was extremely well tolerated in one double‐
often extrapolated from use in other paediatric disorders. blind, placebo‐controlled study of 42 paediatric patients
The use of 2% ketoconazole shampoo for tinea capitis was with cradle cap, with no adverse events related to either
evaluated in 16 black children (ages 3–6), and no patient treatment group [69].
or parent reported adverse effects [66]. No major safety Keratolytic agents can help remove scale to improve
concerns were noted in a retrospective analysis evaluat- absorption of other topical medications such as topical
ing 2% ketoconazole shampoo prophylaxis for children corticosteroids [26]. Salicylic acid, the agent most com-
(aged 1–21) at high risk for tinea capitis [67]. Wannanukul monly used, can be found as a shampoo or as part of a
et al. compared the efficacy of 2% ketoconazole cream topical mixture [26]. A combination of keratolytics and
and 1% hydrocortisone cream for infants with sebor- corticosteroids has been found to be very effective for
rhoeic dermatitis [68]. Both therapies were comparable, treatment of SD [36]. The efficacy of tar had been noted as
and again, no major safety concerns were noted with early as the nineteenth century [82] and it is available in
ketoconazole. Of note, keratolytic shampoos (e.g. zinc many preparations, either alone or mixed with other topi-
pyrithione, salicylic acid) are not recommended in infants cal compounds [31]. However, its use is limited by con-
because of the potential for systemic absorption [69]. cerns regarding its safety, notably a possible association
Other topical therapies that have been used in adults with squamous cell carcinoma [83] and side‐effects such
include flutrimazole gel [70], topical clotrimazole, topical as irritation to the skin [23]. However, these agents are
miconazole [71], 2% sertaconazole cream [72], bifonazole typically reserved for severe cases and adolescent or adult
shampoo [73], ciclopirox olamine shampoo [74], zinc patients with thick scale.
pyrithione (which also has keratolytic activity) [33] and The last category comprises other agents that do not fall
selenium sulfide. Unfortunately, scant safety data are into the above three mechanisms. These include MAS04D
available in children and infants to support these thera- (Sebclair®), a steroid‐free herbal cream found to be effec-
pies. A randomized, double‐blinded study evaluated the tive for mild to moderate SD of the face [84], crude honey
use of 1% selenium sulfide shampoo and 1% ciclopirox [85], 5% tea tree (Melaleuca) oil shampoo for dandruff [86],
shampoo, in combination with griseofulvin, for children borage oil containing 24% gamma linolenic acid [87], lith-
(aged 1–11) with tinea capitis [75]. No major safety con- ium gluconate ointment [88], and conflicting evidence
cerns were noted and no doses were missed because of regarding the efficacy of topical metronidazole [89,90].
adverse effects. A randomized trial comparing 1% and However, none of these therapies has been studied exten-
2.5% selenium sulfide in children with tinea capitis (aged sively in the paediatric population. One agent that was
1–15) did not report major safety concerns [76]. A small studied in 48 children with ISD was borage oil, on the
phase II study in 21 patients (aged 3 months to 9 years) basis that ISD is associated with impaired function of an
found that ciclopirox cream 1% was effective for der- enzyme that desaturates linoleic acid into a product that
matomycosis but also had a good safety profile: only one is found in borage oil [87]. All the children were treated
successfully with twice‐daily applications of the oil for 9 Shuster S. The aetiology of dandruff and the mode of action of
therapeutic agents. Br J Dermatol 1984;111:235–42.
10–12 days. They were maintained on a prophylactic regi-
10 Gupta AK, Kohli Y, Summerbell RC, Faergemann J. Quantitative
men of oil application 2–3 times/week for 6–7 months, culture of Malassezia species from different body sites of individuals
after which no child suffered relapses. Most importantly, with or without dermatoses. Med Mycol 2001;39:243–51.
no side‐effects occurred. There are limited in vitro data 11 Nakabayashi A, Sei Y, Guillot J. Identification of Malassezia species
isolated from patients with seborrhoeic dermatitis, atopic dermatitis,
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Interestingly, although topical oils (such as olive oil) may 12 Tajima M, Sugita T, Nishikawa A, Tsuboi R. Molecular analysis of
not be physically harmful, Siegfried and Glenn point out Malassezia microflora in seborrheic dermatitis patients: comparison
that the use of oils is not advisable in children because with other diseases and healthy subjects. J Invest Dermatol 2008;
128:345–51.
saturated fatty acids might precipitate Malassezia over- 13 Gaitanis G, Velegraki A, Alexopoulos EC et al. Distribution of
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inflammation and scaling [92]. in Greece. Typing of the major pityriasis versicolor isolate M. globosa.
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such as 1% or 2% ketoconazole (≥12 years of age), ciclopirox based study on patients with Parkinson’s disease and seborrheic der-
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287
C HA PTER 22
Irritant Contact Dermatitis

David Luk1,2
United Christian Hospital, Hong Kong
1
The Chinese University of Hong Kong, The University of Hong Kong, Hong Kong
2
Abstract and include biological agents, household products, medical agents,

skin care products, hobby‐ and recreation‐related equipment,
food, physical irritants and even personal electronic devices. Both
Irritant contact dermatitis (ICD) is common but is under‐researched
genetic and environmental factors may contribute to the develop-
in children. It is a nonspecific local inflammatory dermatosis caused
ment of ICD.
by single or repeated skin contact with irritants. The exposure to
ICD is mainly a diagnosis of exclusion based on a thorough
irritants is specific to the developmental stages of children and

history, negative or irrelevant patch tests, proven exposure to

can occur from neonates to adolescents. The clinical presentation
irritants and a typical course of disease. There may be many clinical
of ICD is highly variable and can be classified into acute, delayed
differential diagnoses for ICD and the clinical distinction between
OF DERMATITIS
acute and slowly developing forms. Most ICDs are cumulative ICD,
ICD and allergic contact dermatitis can be vexing. Stopping and
in which exposure to one or more chemical irritants occurs over
avoiding further contact with irritants is the mainstay of manage-
weeks to months and face, hands, feet and perineum are com-
ment of ICD. Short‐period application of topical steroid is generally
monly affected sites. Irritants reported to cause ICD are numerous
helpful, and monitoring for complications may be necessary.
Key points • The irritants cause direct damage to the skin resulting in a
nonspecific inflammatory reaction.
• ICD occurs on the area of skin exposed to the irritant and is a
• Irritant contact dermatitis (ICD) is common in children.
clinical diagnosis supported by a negative patch test.
• ICD can occur in any child when the irritant is strong enough and
• Avoidance of irritants and skin protection remain the mainstay
the exposure is long enough.
of management.
• The exposure to irritants is related to the age and the
developmental environment of the child.
and bubble baths [1,6]. However, while there is no lack of

Background. Contact dermatitis is common in children
research on adult ICD, large‐scale studies on paediatric
and is an under‐recognized burdensome paediatric
ICD have been rare.
disease that leads to significant health and economic
adversities [1]. It is usually divided into irritant and
allergic forms [2]. Irritant contact dermatitis (ICD) is Definition. ICD is a nonspecific local inflammatory
more common and has less serious potential conse- dermatosis caused by single or repeated skin contact

quences than allergic reactions such as allergic contact with chemical, physical or biological agents (the irritants)
dermatitis (ACD) and allergic contact urticaria [34]. in the environment p roducing a direct toxic insult to
The circumstances leading to ICD in children are cutaneous cells [2,7–9]. There is no specific antigen‐primed
different from those in adult ICD. ICD in adults is often immune response [1] and the nonimmunological reaction
occupational or related to housework [5]. On the other develops after sufficient contact with the substance.
hand, paediatric ICD has been reported from extremely Everyone exposed to the same irritating agent is poten-
premature neonates in neonatal intensive care units to tially capable of responding in a stereotyped manner,
adolescents with various hobbies, behaviours and topical although factors such as the presence of ongoing dermati-
medications. Thus, some contact irritants are specific tis (atopic dermatitis), environmental factors or physical
to developmental stage. For example, the most common traumas may facilitate onset [2].
form of ICD in early infancy is nappy rash, which becomes ICD is distinct from ACD, in which the inflammatory
less common after children have established continence [2]. skin disease is initiated by specific cell‐mediated (type IV)
Other common causes of ICD in the paediatric age group hypersensitivity reactions to a hapten and requires an
include drooling (toddlers, cerebral palsy), o verbathing initial sensitization phase followed by the elicitation
phase that causes the skin lesions in predisposed subjects reaction [7,12,22,23]. In this process, keratinocytes have
[2]. It is also distinct from photodermatitis, in which light a major role, and they release cytokines on the disruption
exposure is required to cause skin inflammation. of the skin barrier, upregulate their major histocompati-
bility class II antigens, and upregulate cell adhesion mole-
Epidemiology cules [24]. The pro‐inflammatory cytokines interleukin‐1α,
Age interleukin‐1β and TNF‐α are upregulated [25]. The
Contact dermatitis is an extremely common occurrence in chemokine CCL21, produced by dermal lymphatic
the paediatric age group. It accounts for a large number of endothelial cells, is also upregulated [26]. These mediators
paediatric cases of dermatitis [1], representing approxi- facilitate the migration of naive T lymphocytes, resulting in
mately 20% of all dermatitis seen in childhood [6]. a skin inflammatory response [23]. Interestingly, many of
Although the exact incidence is unknown, ICD is the most the same cytokines that are found in ACD are also detected
common form of contact dermatitis, comprising approxi- in ICD [12]. Indeed, Smith and colleagues reported that
mately 80% of cases [1,2,10]. Susceptibility to ICD is ICD may promote or enhance ACD because some of these
inversely proportional to age [11,12] and the threshold for mediators play a role in both ICD and ACD [27,28].
skin irritation is lower in younger children [7]. Children
under 8 years old are more vulnerable to irritation Clinical features. The clinical presentation of ICD is
whereas skin reactivity becomes normal above this age highly variable and depends on multiple factors includ-
[11]. ICD may develop in newborns and infants as the ing the nature and intrinsic properties of the irritant and
OF DERMATITIS
percutaneous absorption of substances is greater with specific individual‐ and environment‐related variables
their thinner skin and higher skin surface area to body- [7]. Ten clinical types of ICD have been recognized and
weight ratio [2], and their high microcirculatory efficiency can be categorized into acute, delayed acute, and slowly
also facilitates inflammatory cell recruitment to the site of developing forms [21,29].
inflammation [7,11]. Whereas ICD may develop from
birth, ACD generally starts to develop at the age of Clinical types of ICD
2–3 years (sometimes even as early as 6 months) because Acute ICD
of progressive exposure to sensitizing agents and the Acute ICD results from skin exposure to a potent irritant
immaturity of the cell‐mediated immune system during or caustic chemical such as acids or alkaline solutions [21]
the first two years of life [2]. and the onset of symptoms is within minutes to hours of
exposure [7,18]. There could be immediate burning, itch-
Gender ing or stinging [21]. It usually occurs in a private environ-
Researches on gender differences in ICD have not been ment, for example, when disinfection solutions were used
conclusive [11,13]. There have been conflicting data on incorrectly [5]. It is difficult to differentiate very severe
whether males or females have a greater tendency irritant contact dermatitis from a chemical burn when
towards ICD [11,14]. erythema, oedema and vesicles may rapidly progress to
necrosis and ulceration [30] [Table 22.1].
Race
There have been few studies on racial differences of skin Delayed acute ICD
irritation responsiveness in adults [15,16] and an increased A delayed acute ICD may be initiated 8–24 hours follow-
reactivity was noted for Asians versus Caucasians [14]. ing acute exposure to chemicals such as anthralin
(dithranol), benzalkonium chloride and hydrofluoric acid
Genetic factors [31]. Contact dermatitis related to surgical exposures is
Genetic factors certainly have a role in chronic ICD [7,17]. also typified by delayed onset of symptoms and signs
Atopic dermatitis has been shown to predispose to ICD [32]. Otherwise, the symptoms and signs of delayed acute
[18] and skin atopy at least doubles the risk of developing ICD are similar to those of acute ICD [21].
ICD in adults [19]. Loss‐of‐function polymorphisms in
Cumulative ICD
the filaggrin gene were also found to be associated with
Most ICDs are cumulative ICD, in which exposure to one
increased susceptibility to chronic ICD [17]. A nonatopic
or more chemical irritants [7,23,33] occurs over weeks
genetic marker for irritant susceptibility, TNF‐α polymor-
to months [21] (arbitrarily defined as 6 weeks [34]) after
phism in normal individuals, has also been reported [20].
multiple subthreshold skin insults from milder irritants [18].
In cumulative ICD, the skin barrier function does not
Pathogenesis. As ICD does not elicit an antigen‐specific
immune response to irritants, the pathogenesis of ICD was Table 22.1 Clinical severity of ICD
thought to be nonimmunological in the past. It is now
known that pro‐inflammatory cytokines and the innate Grade Severity Signs
immune system play a key role in its pathogenesis [21].
Grade 1 Mild Erythema
In ICD, chemical or physical insults lead to a cascade of
Grade 2 Moderate Erythema, oedema, small vesicles
innate immune responses: (i) skin barrier disruption; Grade 3 Severe Blisters, bullae
(ii) direct cytotoxic effects on keratinocytes; (iii) induction Grade 4 Most severe Epidermo‐dermal necrosis, ulceration
of cytokine cascades; and (iv) a clinical inflammatory
Chapter 22 Irritant Contact Dermatitis 289
have time to heal properly, resulting in the associated

itch, pain, dryness, erythema and sharply demarcated
lesions [21]. The chronic exposure leads to lichenification
while vesiculation may be less apparent or absent [6].
In addition to the above three major forms, other forms

reported include irritant reactions, subjective irritations,
nonerythematous (suberythematous) irritations, traumit-
erative dermatitis, traumatic irritant dermatitis, pustular
and acneiform dermatitis [21].
Patient characteristics
Age
Age is an important factor for ICD in children as different
types of ICD tend to occur at various stages of develop-
ment of childhood with different exposure to irritants.

The most common form of ICD in early infancy is nappy
Fig. 22.2 Irritant contact dermatitis due to thumb sucking in an infant.
rash [2], and this topic is covered in Chapter 20. In the first
OF DERMATITIS
few years of life, perioral dermatitis and irritant cheilitis
caused by contact with a pacifier, habitual lip biting or as to increased transepidermal water loss on the chin and
a result of excessive saliva production during erupting nasolabial areas in younger people [40,41]. Perioral
dentition are common [2,35]. Irritation from oral secre- ICD may be aggravated by the use of tooth whiteners/
tions (saliva or food) is frequently noted in toddlers [6]. fluoride with clinical signs accentuated at the commissure
The repeated wet and dry cycles from saliva disrupt the of the lips [36]. In addition to the face, intertriginous
epithelial barrier and cause perioral fissuring [10,36] and thigh areas are also vulnerable areas for ICD [22].
(Fig. 22.1). The common habit of thumb and finger suck- ICD of hands in children may be related to inappropri-
ing in young children can result in ICD on their fingers ate use of cleansers, exposure to harsh soaps, sanitizing
[37] (Fig. 22.2). Lip licker dermatitis is more often found solutions [1], hair care products, hobbies, activities
in older children who lick their lips frequently to soothe that involve contact with water (e.g. washing clothes,
lips irritated by cold dry weather [6]. Children who play cookery) and even prolonged wearing of protective
outdoors may develop phytodermatitis by means of a gloves [42]. On the feet, chemicals used in shoe manu-
traumatic, chemical or toxic mechanism (airborne or the facturing have been reported to cause severe acute ICD
result of direct contact), which may also be favoured or and ACD in adults and contact urticaria in children
worsened by exposure to the sun (contact phytophoto- [43]. Barefoot individuals in India have been reported
dermatitis) [2]. Adolescents may have ICD due to irrita- to develop ICD with continuous exposure to water and
tion by topical acne treatment, cosmetics [23], henna detergents [44].
tattooing and hair highlighting [38]. In this age group, Perineal ICD can occur at any age [6]. Poor hygiene,
hobbies and regular activities may result in ICD by repeti- such as inadequate wiping after urinating, wiping poste-
tive contact with the equipment. riorly to anteriorly, or where a young child showers with-
out adult supervision, may result in perineal ICD [45].
Body sites The use of perfumed creams or powders and feminine
There is regional variation in ICD on the body. The face hygiene sprays can lead to either an irritant reaction from
is a common site for ICD by virtue of its permeability the propellant or an allergic contact reaction from per-
[39] due to a relatively thin epidermis and a tendency fumes in the spray. Bubble bath is a common cause of
ICD in children and can cause contact dermatitis in the
vulvar area [6].
Coexisting medical conditions

Children with coexisting medical conditions may have
additional causes of ICD [22]. Licking of the lips is found
frequently among developmentally delayed patients. The
tongues of such patients are commonly enlarged, and
salivation is often excessive. The habit involves sweeping
the tongue about the perioral region, keeping the part wet
with saliva, which may result in perioral ICD [37].
Obsessive compulsive behaviours involving handwash-
ing may result in ICD of the hands [46,47]. In the intensive
care unit, the barrier function of the skin of critically ill
children is compromised by its hypoperfusion with a
Fig. 22.1 Perioral dermatitis with perioral fissuring in an infant. resultant increased susceptibility to ICD [22].
History
Children are exposed to irritants in the environment
where they live, learn and play, which can be both indoor
or outdoor [8]. Details including plants that they have
plucked or touched [48], hygiene products, clothing, foot-
wear, jewellery, cosmetics, recent travel, new products,
medicaments, herbal supplements, hobbies, extracurricu-
lar activities and environments may be helpful. As ICD
may occur after only brief exposures or intermittent expo-
sures over a prolonged period of time [48], a thorough
history is important. Sometimes the offending substance
may not be apparent, but it is also possible that multiple Fig. 22.4 Sharp ‘cut‐off’ borders of irritant contact dermatitis skin lesions.
irritants are acting at the same time [2]. In addition, clari-

fying the details of exposure including time, duration, provide diagnostic information regarding the aetiology of
concentration, chemical ingredients, environmental fac- the reaction [6].
tors, protection employed and subsequent treatment Although the clinical presentation of ICD is usually
received would be very helpful. It is often useful to ask confined to sites of direct contact, fomites can secondarily
also about parents’ or siblings’ products because of the transfer irritants from sites of primary contact to other
locations on the body. There have been reports of a leather
OF DERMATITIS
potential for indirect or even direct exposure from their

products [10,49]. Furthermore, one must also consider the watchband serving as a fomite, causing cutaneous irrita-
time course necessary for an ICD reaction which can tion for up to 3 months after initial contact with spurge
range from minutes to hours for acute ICD and weeks to latex [52]. The secondary eruptions that occur by fomite
months for cumulative ICD [30]. transfer can manifest themselves anywhere but frequently
Family, drug or atopy history including atopic derma- present on sensitive areas such as the axilla, eyes, but-
titis, a history of previous contact dermatitis and coex- tocks and genitalia [27]. A general examination of the skin
isting medical problems may be helpful [50]. Patients is also helpful to identify autoeczematization of ICD [19],
with ICD usually do not have fever or other systemic concomitant dermatoses such as atopic dermatitis and
symptoms [50]. xerosis and other differential diagnoses of ICD.
Apart from examining the patient, the examination of
Physical examination the suspected irritants and understanding the environ-
ICD is generally characterized by erythema and vesicula- ment by reviewing relevant photos is also helpful.
tion in the acute phase, and by xerosis, fissuring and
lichenification in the chronic phase [51]. Eczematous, ery- Irritants
themato‐desquamative lesions [2], pruriginous pustular A substance is an irritant when it has the potential to irri-
lesions, pustule remnants and thin scales over an ery- tate skin [5] and virtually every agent can function as an
thema have all been described [50]. More severe cases irritant when there is excessive exposure, including even
with bullae or necrosis accompanied by intense pain may paper and water [5–7,33]. The irritation potential of the
suggest a severe ICD reaction [29,48] (Fig. 22.3). agent is affected by its concentration, pH [53,54], molec-
Rashes localized to one area (e.g. hands) or those that ular size, ionization state and fat solubility which deter-
have discrete shapes and sharp ‘cut‐off’ borders raise a mine its skin penetration [7,22,23,55]. The nature of the
suspicion for contact dermatitis [6] (Fig. 22.4). The distri- contact such as the time duration [7,55], the frequency of
bution of lesions corresponding to the contact areas may contact [5], the amount [7] and the solvent [7] may also
affect the degree of ICD. Occlusion (e.g. by gloves and
clothing) may increase the signs of skin inflammation
by altering the pH, transepidermal water loss, stratum
corneum hydration, skin surface temperature and skin
permeability [12].
Environmental temperature and humidity are exoge-
nous factors contributing to the development of ICD
[12,23]. Cold temperatures increase transepidermal water
loss and susceptibility to irritants [56] but warm ambient
temperatures are also damaging [57]. A low environmental
humidity may enhance irritability of skin [23]. The pres-
ence of sweat and friction [58] may further aggravate ICD
as mechanical irritation supports chemical irritation [5].
Irritants reported to cause ICD are numerous and can
be grouped into eight categories: (i) biological agents; (ii)
household products; (iii) medical‐related agents; (iv) skin
care products; (v) hobbies and recreations; (vi) food; (vii)
Fig. 22.3 Severe irritant contact dermatitis with blisters. physical irritants; and (viii) others.
Biological agents greenhouse‐cultivated plants, would cause ICD [61]. In

Body fluids. Children’s own body fluids are an important North America, the bright red foliage of E. pulcherrima
source of irritants. Saliva (toddlers, cerebral palsy), urine, and child‐accessible placement in households resulted in
faeces, and the body fluid leaking around a stoma are the majority of exposures in children, especially for those
some of the common causes of ICD in children [1]. younger than 2 years [62]. On the other hand, blisters
developing after children played in the fields were also
Plants. Phytodermatitis can be classified into ICD, ACD, reported [48].
photoallergic contact dermatitis and phototoxic reaction
(phytophotodermatitis) [59]. ICD accounts for the major- Insects. Paederus dermatitis is a self‐limiting form of acute
ity of plant dermatoses [27] (Fig. 22.5). Potential irritant ICD caused by pederin released by rove beetles when
plants are ubiquitous in our environment: home, garden, accidentally brushed or crushed on the skin [63,64]. Itch,
workplace and recreational settings [27]. Calcium oxalate, stinging or burning sensation on exposed parts of the
protoanemonin, isothiocyanates, bromelain, diterpene body may be accompanied by vesicles and pustules on an
esters, alkaloids and naphthoquinone are some of the erythematous base in a linear configuration [63]. In severe
known plant chemicals causing ICD [27]. The clinical cases, pederin can cause skin necrosis [65] and constitu-
presentation may range from mild chronic eczematous tional symptoms [66]. Seasonal outbreaks have been

dermatitis due to mechanical irritation by hairs on some reported worldwide including Africa, South America,
plants to severe acute toxic reactions with necrosis due to Australia, the Middle East and Asia [63,64,66–69] and the
OF DERMATITIS
potent alkaloids from plant sap [27]. Juglone, the active signs of periorbital dermatitis and linear lesions may hint
ingredient of green shells of walnuts, is a strong irritant at the diagnosis [63,64].
and circumscribed hyperpigmented and combustiform Topical envenomation from caterpillars is another
skin lesions have been reported to appear suddenly after insect‐associated ICD [1]. Caterpillars can cause reactions
two children played in a garden with green walnut husks through mechanical, chemical and allergic means [70].
[60]. The spurge (Euphorbiaceae family) is also ubiqui- The barbed hairs adhere to the skin and mucous mem-
tous and toxic, and is a significant cause of ICD world- branes, causing clinical symptoms due to mechanical
wide [41]. Children often unwittingly encounter the plant irritation and the presence of a foreign body [71].
through play [41]. The active irritants in the spurge sap Envenomation by caterpillars with thaumetopoein elicits
are diterpene esters, which are also present in the plant’s a toxic response by direct non‐IgE‐mediated mediator
stem, petals, roots and leaves and can cause both ICD release [71]. Type 1 hypersensitivity reactions have also
and ACD [41]. It has been suggested that wild, but not been reported after contact with caterpillars [71,72].
Household products
Common household items, such as soap and detergents,
can be a cause of ICD in children. Detergents may con-
tain highly irritating compounds such as quaternary
ammonium compounds, phenol and formaldehyde [53].
When detergent is left on a toilet seat, bilateral symmetri-
cally distributed ICD on the posterior thighs and but-
tocks can result [1] and toilet‐seat dermatitis continues to
be a common condition in children around the world [53]
(Fig. 22.6). Residues of detergents or fabric softeners in
laundered clothes can also cause ICD.
Medical‐related agents
Medications, antiseptics and medical devices have been
reported to result in ICD in both hospital and non‐hospi-
tal settings.
Medications. In the paediatric age group, topical acne

drugs are notorious for irritation because of their intrinsic
mechanisms of action [73]. Benzoyl peroxide is known to
be a strong irritant [74], resulting mainly in ICD rather
than ACD [73,74]. Formulations of less than 5% cause less
irritation, and cream and lotion vehicles are better toler-
ated than gel preparations [73]. In the topical retinoid
group, tretinoin 0.05–0.1% (all‐trans retinoic acid) and
tazarotene 0.05–0.1% are most irritating whereas isotreti-
noin 0.05% has a lower irritating potential [73]. Adapalene,
a third‐generation retinoid, at 0.1%, is less irritating [73].
Fig. 22.5 Configuration of lesion providing important clinical clues. Ultraviolet light protection is recommended to reduce
Fig. 22.6 Toilet‐seat dermatitis.

irritation due to topical retinoids [73]. In addition, s alicylic

OF DERMATITIS
acid 2% is commonly associated with scaling and burning

[73], and azelaic acid is commonly associated with itching, Fig. 22.7 Irritant contact dermatitis due to topical acne drugs.
burning and dysaesthesia. Although topical antibiotics
(tetracyclines, erythromycin, clindamycin) in the treatment as medical adhesives [89], pulse oximetry [90], immobili-
of acne have low irritating potential, their prolonged zation boards [90] and casts [91], orthotics [90], silicone
application may induce antibiotic resistance [73] (Fig. 22.7). gel sheets [92], ear prostheses [93], dental materials [94]
Topical medications for other common dermatoses are and continuous positive airway pressure devices [90], all
also reported to cause ICD. Topical calcipotriol [75], of which have the potential to induce mechanical or
dithranol [76] and tar [77] for the treatment of psoriasis chemical ICD. Surgery‐related ICD [32] and peristomal
can cause both ICD and ACD [75]. Scabies medications ICD can be caused by the use of dressings, adhesive tapes,
known to be irritating include lindane, 1% gamma ben- antiseptics, medicaments, ostomy pouch systems, sutures,
zene hexachloride [78], benzyl benzoate and precipitated barrier films and adhesive paste and removers [90,95,96].
sulphur. Applying the same preparation to the whole
family may result in ICD in young children without par- Skin care products
ents being affected. It is common for skin care products to cause ICD [97] and
Topical analgesic creams (lidocaine and prilocaine there is a long list of potential irritants in these products
cream under occlusion) have been reported to cause both (Tables 22.2 and 22.3). Modern cleansers are primarily
ICD and ACD [79–81]. The methylphenidate transdermal made up of surfactants that act by decreasing the surface
system used in children with attention deficit hyperactiv- tension between water and oil. Surfactants create lather
ity disorder also commonly causes ICD [4]. and allow fat‐soluble impurities to be removed from the
skin surface [98]. However, surfactants are also irritants
Antiseptics. Chlorhexidine is a widely used broad‐ as they weaken the skin barrier and increase transepi-
spectrum topical antiseptic agent, and chlorhexidine dermal water loss [98]. Aqueous creams or emollients
baths are among the methods employed to reduce containing sodium lauryl sulphate (a detergent and sur-
meticillin‐resistant Staphylococcus aureus (MRSA) infection factant) should not be used as emollients or as leave‐on
[82]. Although ICD due to chlorhexidine is rare [22,83], skin products due to their irritating properties [108].
infants and young children are the most susceptible age Bath oil has also been reported to cause ICD whether
groups [22]. The Centers for Disease Control and with inadequate dilution [109], prolonged contact [101]
Prevention recommend its use as a skin cleanser prior to or even with appropriate use [102] (Fig. 22.8). Active
insertion of central venous catheters in children but not ingredients of sunscreens may be allergens or irritants.
in infants less than 2 months of age [84]. Premature Dexpanthenol is widely used in topical medical products
infants, immunosuppressed or critically ill patients are and cosmetics [50] due to its moisturizing and skin‐
particularly vulnerable and cases of severe ICD to softening properties, but ICD after accidental use of a
chlorhexidine have been reported [85,86]. Although
parental moisturizer on a child’s skin has been reported
povidone–iodine has low toxicity, its postoperative use [50]. Bandages, hair dye, deodorants and antiperspirants
on skin for 8 hours has also resulted in ICD [87]. are also reported to contain irritants [32].
Antiseptics containing cetrimide are also widely used as
disinfectants and sanitizers but improper (undiluted) Hobbies and recreations
application of the antiseptic liquids has led to ICD [88]. As children become actively involved in various recrea-
tions and hobbies, the use of equipment may result in
Medical devices. Children requiring long‐term medical ICD. Face paints mixed with dishwashing liquid were
support are exposed to a variety of medical devices such reported to cause severe ICD in children in 1980 [110].
Table 22.2 Irritancy potential of common surfactants In sports activities, children have been reported to have
ICD secondary to soccer shin guards [57,111], kendo prac-
Relative irritancy Surfactant tice [112] and baseball pitching [113]. Accidental contact
with jellyfish during swims has also resulted in ICD [114].
High Benzalkonium chloride
In a recent survey of instrument‐related skin disorders in
Bromide
Dodecyl trimethyl ammonium
musicians, various patterns of ICD were found [115]. Lip
Linear alkyl benzene sulphate ICD caused by a saxophone causing and fiddler’s neck due
Sodium lauryl sulphate to ICD or ACD have been reported in children [116–118].
Sodium dodecyl sulphate
Sodium alkyl sulphate Food
Sodium or potassium cocoate Irritants in food usually result in cumulative chronic ICD
Sodium or potassium tallowate
affecting the hands. The erythematous scaly eruptions can
Sodium palmitate
Sodium or potassium stearate be limited to the finger tips but other distributions are also
Sodium olefin sulphonate possible: scattered, generalized, arms and even face [119].
Triethanolamine laurate ICD is more common among food handlers and children
Moderate Sodium ethoxylates with atopic dermatitis [120]. Non‐occupational exposure

Sodium laureth sulphate to food in children is usually sporadic and may occur at
Ammonium laureth sulphate
home or at school [120]. Occupational hand dermatitis
Low Sodium cocoyl isethionate
OF DERMATITIS
Sodium alkyl glycerol ether sulphonate
in food industry apprentices has been reported [121].
Sodium cocoyl sulphosuccinate Much of the food we eat is capable of causing one or
Disodium stearyl sulphosuccinate more types of dermatitis [122]. For example, garlic causes
ACD and ICD as well as photoallergic contact dermatitis
Source: Kuller [98]. Reproduced with permission of Wolters Kluwer [122]. In the Cross‐Sectional Analysis of North American
Health, Inc. Contact Dermatitis Group Data, 2001–2004, ICD is com-
monly due to general food products, bakery products,
Table 22.3 Skin care products with potential to cause ICD fruits, nuts, vegetables, meat and poultry [119] while spices,
garlic, onion, citrus fruits, corn, radish, mustard, potato,
Skin care products Irritants pineapple and carrot are also common [120,122]. Pineapple
contains bromelin, a proteolytic enzyme that can cause a
Cleansers and See Table 22.2 [98,99]
separation in the epidermis along with an increase in capil-
soaps [98]
Shampoo [100] Sodium lauryl sulphate, benzalkonium chloride
lary permeability [122,123]. Capsicum peppers such as cay-
Emollients Sodium lauryl sulphate enne and jalapeno contain the oleoresin capsaicin which
Bath additives Benzalkonium chloride can irritate the mucous membranes of the eyes, nose and
[101,102] mouth in addition to causing ICD to skin.
Sunscreen [103] PABA, benzophenones, benzotriazole derivatives Food additives are also a source of irritants which
Dressing [32,104] Rubber products, adhesives (methacrylate, include acetic acid, ascorbinic acid, calcium acetate, cal-
epoxy diacrylate)
cium sulphate, lactic acid, potassium bicarbonate, potas-
Cosmetics [50,100] Dexpanthenol
Hair dye [105] Hydrogen peroxide, persulphates sium iodide, potassium bromate and yeast [122].
Deodorant [106] Aluminium sulphate
Antiperspirant [107] Aluminium chloride Physical irritants
Apart from chemical irritants, ICD can also be caused by
physical irritants but this area is relatively under‐
researched [33]. Physical irritants include friction [12],
pressure [12], vibration [12], heat [12] and sweat [12,57]
and these can result in ICD via mechanical trauma or
microtrauma [27].
Mechanical ICD caused by labels from clothing
may lead to ‘label dermatitis’ over the upper back [124].
Although textile contact dermatitis is more often an
immune‐mediated reaction, rough‐textured clothing,
woollen clothing and clothes contaminated by fibreglass
can lead to mechanical ICD [125]. Fibreglass with fibres of
diameter 5.3 μm or more may cause mechanical irritation,
and a fibreglass‐reinforced plastic chair has been reported
to cause ICD at school [126].
There can be overlap between chemical ICD and
mechanical ICD. For example, in plant‐induced ICD
caused by Narcissus bulbs, the physical microtrauma from
handling the bulbs may enhance the cutaneous penetra-
Fig. 22.8 Irritant contact dermatitis due to bath additives. tion and effects of chemical irritant calcium oxalate
Fig. 22.9 Irritant contact dermatitis due to traditional remedies for joint
pain.
Fig. 22.10 Skin lesion localized to the contact area – bandage.
crystals [27,127]. Physical irritation by friction on skin has

also been shown to potentiate the chemical irritation on the duration and concentration of the exposure)
caused by sodium lauryl sulphate [128].
OF DERMATITIS
and a monomorphic rather than polymorphic clinical

In the wake of the use of personal electronic devices in picture [149]. All potential exposures to irritants should
the modern era, new groups of cutaneous pathologies be explored [1]. Careful physical examination should be
have been reported. Games console/cellphone thumb performed to identify features of ICD and the possible
due to friction was first described in 2004 [129] and started differential diagnoses [51]. Typically, ICD remains local-
as a new epidemic in teenagers. Physical ICD can cause ized to the area of skin contact (Fig. 22.10). This is unlike
blisters on the exact site of fingers under recurrent pres- ACD, which can spread to distant parts of the body [19].
sure and friction with the controller of a games console
[130]. Chemical ICD may result from exposure to certain Differential diagnoses
chemicals in keyboards, mice and wrist pads [131] but There is a long list of differential diagnoses for contact
ACD from nickel is also possible from the use of laptop dermatitis, and diagnosis depends on the clinical appear-
computers and pads [131–133]. With repeated and pro- ance of individual lesions. ICD should be differentiated
longed use of laptop computers, erythema ab igne may be from ACD, photodermatitis and contact urticaria [122].
found on the thighs of children [131,134,135]. This was Xerosis [88], infections (e.g. tinea [88], herpes zoster, her-
first described in 2004 and was due to long‐term exposure pes simplex [63], impetigo), inflammatory dermatoses
to mild heat in the range 43– 47 °C [131,136,137]. This is (e.g. periorificial dermatitis), structural skin lesions (e.g.
now an emerging condition among adolescents [138] with lymphangioma circumscriptum [150]) and infiltrative
the youngest reported child being 9 years old [135]. skin diseases (e.g. histiocytosis [6]) have been included as
differential diagnoses in appropriate clinical settings.
Others Cases of contact dermatitis mimicking child abuse have
The list of irritants causing ICD is long but studies on also been reported [151,152] with a 12‐year‐old girl hav-
local products, e.g. traditional remedies [139–141] and ing skin lesions due to contact dermatitis which were ini-
traditional medicines [48,142–144], may be lacking tially suspected to be caused by nonaccidental injury or
(Fig. 22.9). Airborne ICD is mainly an occupational haz- self‐harm, thus causing great distress and concern to the
ard in adults and is rarely reported in children. Airborne family [153].
irritants implicated include phosphates, metal dusts, ACD should be differentiated from ICD because treat-
cleaning products, animal dander, epoxy resin, isothia- ment and prognosis are different. On clinical features
zolinones, ammonia, anhydrous calcium sulphate and alone, ICD and ACD may be very similar and difficult to
formaldehyde [145,146]. Fibre‐related ICD has been distinguish. Like ICD, ACD can present in many different
reported in an apprentice fitter in an aircraft factory (car- forms, the most common of which is an erythematous
bon‐fibre composite wing components) [147] and an out- oedematous eruption at sites of allergen contact [27].
break has been reported in an intensive care unit due to Acute ICD tends to develop on the day of contact with the
fibres from an air‐conditioning filter [148]. In airborne irritant [27]. ACD generally intensifies between 24 and 48
ICD, the skin lesions are usually localized to uncovered hours after exposure, but persons who have been previ-
areas of skin initially. ously sensitized to an allergen may develop symptoms
more rapidly [27]. Pruritus is also not a distinguishing
Diagnosis feature as both types of reactions have been documented
Diagnosis to be extremely pruritic [27].
ICD is an exclusion diagnosis based on a thorough his- In fact, many chemical agents are capable of producing
tory, negative or irrelevant patch tests, proven exposure more than one pathological effect on contacting skin. For
to irritants, typical course of disease (healing and new example, colourants used in cosmetics, foods and feeds
outbreak within a short time of one another, depending may cause ICD, ACD and phototoxic reactions [154].
Chemicals such as benzoyl peroxide [74], formaldehyde Ultimately, removing the suspected offending agent is
[1], benzalkonium chloride [155], dexpanthenol [50,156], a test that can also provide treatment if there is symptom
henna tattoo [157] and dimethyl sulphate [158] are known relief [1]. In case of outbreaks of ICD, multidisciplinary
to cause both ICD and ACD. In addition, contact dermati- investigations including field evaluation may also be
tis may have concurrent allergic and irritant components needed to identify and remediate the causes.
[159] and it is not uncommon for more than one condition
to be present in the same patient [119]. In fact, ICD is a risk Management. Stopping and avoiding further contact
factor for the development of ACD [5] and skin irritation with irritants is the mainstay of management of ICD.
predisposes the skin to develop sensitization so that a
clinical exacerbation of ICD may reflect development of
ACD. The clinical distinction between the two types of Acute care
contact dermatitis can be vexing and may not be always In acute ICD, cool compresses of water or physiological
possible [6]. In the cross‐sectional analyses of North saline not only provide symptomatic relief but can also
American Contact Dermatitis Group Data, 1994–2004, have a profound effect on the healing of experimentally‐
one third of patients with hand ACD had identifiable rel- induced ICD [165]. Water has a known hygroscopic effect
evant irritants [159]. that may increase the capacity for intracellular moisture
retention [166]. Saline’s osmotic properties may allow

Phytophotodermatitis is a phototoxic reaction resulting
from the interaction of plant psoralens with ultraviolet fluid to be drawn from the oedematous lesions in some
patients [166]. Finally, cool compresses may decrease both
OF DERMATITIS
radiation and can result from exposure to plant fruit rind,
juices (most commonly limes), leaves (figs) or, less com- the inflammation and surface temperature associated
monly, stems. An example might be a child at the beach with the ICD [21].
under the sun in contact with plant psoralens from his Rarely, when the acute ICD is very severe with
parents’ drinks such as lemon, lime, celery, dill, parsnip intense pain, bullae and necrosis, hospitalization may
and carrot juices [6]. Severe phytophotodermatitis in a 10‐ be needed [30].
year‐old child has been reported to be caused by contact
with giant hogweed [160]. Phytophotodermatitis is dis- Minimizing contact with irritants
cussed in more detail in Chapter 80. Preferably, contact with irritants should be completely
removed. For example, prevention of ‘label dermatitis’
Investigations from clothes requires the complete removal of labels
There is a lack of confirmatory diagnostic tests for ICD including the threads [124]. If use of the irritant is
[18] and abnormal results on blood tests such as complete essential, replacement with a less irritating agent may
blood count, routine biochemistry including hepatic and help. ICD due to chlorhexidine‐impregnated dressings
renal function testing, thyroid function tests and erythro- may improve on changing to povidone–iodine dressings
cyte sedimentation rate are not expected [50]. Laboratory [22,55]. In situations when the irritant cannot be removed,
studies may be helpful to rule out some of the differential a reduction in exposure may also be helpful [5]. Lip ICD
diagnoses. caused by a saxophone in a 12‐year‐old boy improved
The use of patch testing to differentiate ICD from ACD with less frequent playing [116]. Clear instructions may
is important [23] and is indicated when there is a clinical help reduce irritation of topical acne drugs by specifying
suspicion of contact dermatitis or when a child fails to the quantity, frequency and duration of application
benefit from the recommended treatment for a dermato- of the drugs. Topical acne drugs applied on the face
logical disease such as atopic dermatitis. In addition, it is should be limited to 0.6 g each time, usually used once
helpful for dermatitis on areas at risk of contact dermati- daily, and be rinsed off after 8–12 hours. The use of
tis: face, eyelids, genitals, hands and feet [2]. Although lower concentration preparations may also be helpful.
patch testing in children using reagents at the same con- Conversely, cleansers and masks containing salicylic
centrations as those used for adults has generally been acid, benzoyl peroxide, sulphur or sodium sulphaceta-
recommended [2], a reduction of allergen concentration mide should be rinsed off after few minutes. Alternating
has been suggested for children below 8 years old [161]. the site of application may improve ICD in chil-
Some patch tests may show irritant reactions at 48 hours, dren requiring regular transdermal methylphenidate
especially when using higher adult concentrations, but treatment [4].
these have often resolved by the 96‐hour reading whereas When irritants such as urine, saliva and wound dis-
allergic contact reactions are often more manifest at this charges are unavoidable, using exogenous barrier pro-
later time. The details of patch testing as well as repeated tectants becomes important [1]. Barrier creams may
open application tests are discussed in Chapter 23. inhibit and delay cutaneous penetration of irritants
Histology is generally thought to be unhelpful in estab- [167]. Zinc paste, petrolatum or special dressings are
lishing the diagnosis but may be required in atypical pres- helpful and emollients may provide additional barrier
entations when alternative dermatological diagnoses are protection [10,104]. Protective gloves, clothing, dress-
suspected [23,50]. Newer technologies such as confocal ings and equipment reducing contact with irritants are
microscopy [162,163] and high‐definition optical coher- also important. However, protective equipment may
ence tomography [164] may have a role in facilitating the also be a cause of ICD so care must also be taken when
differentiation of acute ACD and ICD. wearing it [5,168].
Skin care to enhance recovery Phototherapy

Moisturizing creams Phototherapy is mainly reserved for patients with refrac-
Humectants in moisturizers increase skin hydration and tory ACD and chronic ICD that is unresponsive to topical
their lipid components act as emulsifiers to accelerate or oral corticosteroids or for patients who cannot avoid all
skin barrier recovery [168] so applying moisturizers gen- provoking factors in their daily environment. Ultraviolet
erously and frequently may be helpful [23]. However, the light has intrinsic immunosuppressive properties [51]
effect of moisturizers on transepidermal water loss and and both PUVA and UVB light therapy have been used to
susceptibility to irritants depends on the composition of treat chronic ICD in adults [176,177]. However, research
the moisturizer [169]; care must be taken to choose an on the role of phototherapy in children is lacking.
appropriate one [170]. It is prudent to recommend using
moisturizers which have been used on the child previ- Monitoring for complications
ously without problems. ICD has also been reported to have short‐term complica-
tions such as superimposed infection [6,22] and long‐term
Avoiding factors that exacerbate irritation complications such as residual hypopigmentation [157],
Exogenous factors aggravating ICD should be minimized. scar [23] and keloid formation [114].
Mechanical friction on the skin should be avoided and
washing clothes with fabric softeners may be beneficial Prevention of recurrences

[168,171]. The risk of ICD to topical acne drugs is increased Healing in ICD is described as a decrescendo phenomenon,
OF DERMATITIS
if there is repeated daily washing or rubbing by sponges implying that this process starts immediately after removal
of the face [73]. Skin should be washed with mild cleanser of the offending agent, in contrast to ACD when there is a
in cool or tepid rather than hot water, and baths and transient worsening before healing occurs (crescendo phe-
showers should be limited to 5–10 minutes [23]. Adhesive nomenon) [23]. The prognosis for ICD is usually good if
tape on skin should be avoided [104] and oil‐based prod- contact with irritants can be aborted. Complete healing
ucts (e.g. petroleum jelly or bland oils) can be used to after removal of the irritants may take up to 4 weeks.
loosen any residual adhesive instead of nonmedical Although lesions of acute ICD may resolve within a
removers or acetone‐based products. week with appropriate management [48], it may take
more than 4 months for barrier function to normalize in
Specific medical treatment adults [23,178]. Therefore, protection measures need to be
Topical corticosteroids [50,172] continued after the skin lesion heals and regular moistur-
ICD is generally treated with topical corticosteroids [172] izing [23] is useful. Continuation of avoidance of irritants
due to their anti‐inflammatory effects and inhibitory is important as the symptoms of ICD may not reappear
effects on T‐cell activation and leucocyte migration [51]. until 1–2 weeks after re‐exposure.
Theoretically, their antiproliferative properties may pre- For ICD related to medical procedures and devices,
vent proper healing of the stratum corneum barrier [21] planning to reduce the risk of ICD is helpful [89]. To moti-
but short‐term use of a low‐ or mid‐potency topical corti- vate and educate patients for self‐care to prevent recur-
costeroid is usually helpful. Stronger halogenated topical rence of ICD, training programmes and even behavioural
corticosteroids such as fluocinonide or mometasone furo- modification [168,179] may be effective. Career counsel-
ate can be used to treat contact dermatitis reactions for a ling may be relevant to atopic adolescents or those already
short period (<2 weeks) in areas other than the face, axil- exhibiting features of contact dermatitis who are contem-
lae and groin. Occasionally, severe contact dermatitis plating high‐risk occupations for ICD [19,149].
requires systemic corticosteroid therapy for 10–14 days as
early discontinuation may lead to recurrence of the erup-
Summary. In summary, ICD in children is common and
tion [6]. However, studies on the effects of corticosteroids
the clinical problem and its management are age specific.
on ICD are far from unanimous [51] and their role still
The diagnosis of ICD requires a thorough history, detailed
warrants further studies [51].
clinical examination and a negative patch test. Avoidance
Topical immunomodulators of irritants and skin protection are the mainstay of treat-
Calcineurin inhibitors block signal transduction path- ment. More large‐scale studies are required to understand
ways of T cells and inhibit inflammatory cytokine pro- the full scope of ICD in children.
duction [51]. Both topical tacrolimus and pimecrolimus
References
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300
CHA PTER 2 3
Allergic Contact Dermatitis

Sharon E. Jacob1, Hannah Hill2 & Alina Goldenberg3
1
Loma Linda University, Loma Linda, CA, USA
2
Department of Dermatology, Mayo Clinic, Scottsdale, AZ, USA
3
Department of Dermatology, University of California, San Diego, CA, USA
Abstract (AD), even more so when they are concurrent. Furthermore, the
barrier disruption inherent to AD appears to increase the risk for
developing ACD.
In the last decade, allergic contact dermatitis (ACD) has become
The gold standard diagnostic tool for ACD is the epicutaneous
an increasingly recognized diagnosis in children presenting with
patch test. Confirmation of clinically relevant contact allergens is
eczematous skin. Although the immunological pathway of a

critical in order to direct avoidance and appropriately manage the
delayed hypersensitivity reaction is specifically distinct, it can be

disease. This chapter discusses the epidemiology, pathophysiology
phenotypically difficult to distinguish from the clinical presentations
and clinical features of ACD in the context of the available evidence
OF DERMATITIS
of chronic irritant contact dermatitis (ICD) and atopic dermatitis

in the literature.
Key points • The most common allergens in children share some overlap with
those seen in adults and include: metals (such as nickel, cobalt),
antibiotics (neomycin, bacitracin), fragrances and other plant‐
• Allergic contact dermatitis is increasingly being recognized as a
related exposures, preservatives, surfactants and emulsifiers, lano-
common problem among children presenting with eczematous
lin, rubber‐ and leather‐related agents, corticosteroids and dyes.
skin.
• In some cases, systemic exposure to contact allergens can also
• Comprehensive epicutaneous patch testing, while not approved
result in widespread dermatitis, as can be seen with nickel and
for children by the US Food and Drug Administration (FDA), can
propylene glycol.
be performed on children by experienced clinicians. However,
• Once allergens are identified, patient education to help provide
the selection of allergens for testing and the concentrations of
guidance for prevention of re‐exposures to allergens is especially
some allergens may need to be titrated for use in children.
important.
Epidemiology. In 1931, Straus found that neonates have Norwegian schoolchildren aged 7–12 years screened with
the potential for developing contact sensitization to 20 contact allergens found that 23% had at least one PPTR,
Rhus – and thus proved that even immature skin has the most frequently to nickel, and in one third of cases,
capacity to develop delayed‐type hypersensitivity sensitization to nickel was associated with contact

reactions [1]. In 1986, Weston et al. patch‐tested 314 well dermatitis [5].
children, of whom 20% experienced at least one positive A review of more recent patch test studies (interna
patch test reaction. With this same study, the authors con tional and national) shows prevalence rates of at least one
cluded the safety and efficacy of the commercially avail positive patch test between 25.1% and 95.6% in children
able American Academy of Dermatology (AAD) patch referred for suspected ACD (Table 23.1). Extrapolating
test kit in infants, children and adolescents [2]. To date, from both the domestic and international prevalence rates
this is the only general paediatric population‐based study in both well and afflicted children, the conservative
to enroll more than 100 children for patch testing in the estimate is that between 1.5% and 5.4% of the general
USA. That said, comparative analysis suggests that aller population has ACD. Applying these rates to the current
gens causing significant morbidities and cost burden are US population of children of 72 million, it is estimated
similar in American, Canadian and European children, that there are at least one million incident cases of ACD in
where investigators have examined the frequencies of children each year [16].
contact allergy in unselected populations [3]. For exam The prevalence of ACD represents a considerable cost
ple, a Danish cross‐sectional analysis of 1501 Odense burden, both in direct and indirect patient morbidity and
schoolchildren aged 12–16 years demonstrated that 15% to the general healthcare system. An estimated 250 000 US
had at least one positive patch test reaction (PPTR) (8% to children are affected by nickel contact dermatitis each
nickel and 2% to fragrance mix) and 7% had associated year, which represents one quarter of at least one million
past or present ACD [4]. Likewise, a similar survey of 424 children affected with ACD each year. Denmark reported
Chapter 23 Allergic Contact Dermatitis 301
Table 23.1 Review of 2010–2015 paediatric patch test studies
Author/date/ Study n Patient population/series tested Findings

country period
Milingou et al. 1994–2007 255 Children <15 years old • 60% displayed 1+ PPT
Greece 2010 Modified European basic standard series • Most frequent allergens nickel, thiomersal (thimerosal),
[6] (Trolab, Hermal, Germany), and with cobalt, potassium dichromate
additional series as indicated
Fortina et al. 2002–2008 321 Children <3 years old • 62.3% displayed 1+ PPT
2010 Italy [7] Paediatric standard series of 30 allergens • Most frequent allergens nickel, potassium dichromate,
CAPB, cobalt, neomycin, MCI/MI
• Rates of contact sensitization similar between children
with and without AD
Sarma et al. 2005–2008 70 Children 5–15 years old • 80% displayed 1+ PPT
2010 Indian standard battery • Top allergens parabens, potassium dichromate,
India [8] fragrance mix, cobalt, PPD, neomycin
Jacob et al. 2004–2006 45 Children 6 months to 18 years old • 95.6% displayed 1+ PPT

2010 Custom‐tailored patch test series • 76.7% of children in this study had history of AD
USA [9] • Those tested with history of AD were more likely to
react to CAPB and disperse dyes
OF DERMATITIS
Toledo et al. 2005–2008 111 Children 15 years and younger • 46.8% displayed 1+ PPT
2011 Spanish baseline series • Top allergens nickel sulphate, MCI/MI, fragrance mix,
Spain [10] balsam of Peru
Kuljanac et al. 1994–2009 412 Children <18 ears old • 26% displayed 1+ PPT
2011 Standard series of allergens manufactured • Most frequent allergens nickel, thiomersal, cobalt,
Croatia [11] in Croatia fragrance, white mercury, formaldehyde
Jacob et al. 2008–2009 102 Children 6–18 years • 76.2% PPT
2011 T.R.U.E. test ® • Most frequent allergens nickel, p‐tert‐butylphenol
USA [12] formaldehyde resin, wool alcohols, fragrance and cobalt
• Demonstrated T.R.U.E. test® is safe and efficacious in
paediatric population
Schena et al. 2004–2011 349 Children 0–15 years old • 69.3% PPT
2012 Standard series of allergens of the SIDAPA • Younger children showed higher sensitization rates
Italy [13] • Most frequent allergens nickel, cobalt, MCI/MI,
potassium dichromate, fragrance, neomycin
• Patients with AD had more widespread dermatitis than
those without AD
Silny et al. 2008–2011 155 Children 1–20 years old (104 with AD, 15 • 45.2% of patients with AD had PPT
2013 with seborrhoeic dermatitis, 36 healthy) • 13.9% of healthy patients had PPT
Poland [14] 1–5 years: paediatric set (established in our • Highest frequency of PPT was in youngest age group
department) consisting of 12 haptens 1–5 years old
6–20 years old: European standard series • Highest‐frequency allergens were nickel, cobalt and
chromium
Zug et al. 2005–2012 883 Children 18 years and younger suspected • 62.3% 1+ PPT
2014 of ACD • Most frequent allergens nickel, cobalt, neomycin,
USA, Canada [15] Tested with variants of screening series from balsam of Peru and lanolin alcohol 50% petrolatum
NACDG and/or supplemental allergens
ACD, allergic contact dermatitis; AD, atopic dermatitis; CAPB, cocamidopropyl betaine; MCI/MI, methylchloroisothiazolinone/methylisothiazolinone;
NACDG, North American Contact Dermatitis Group; PPD, para‐phenylenediamine; PPT, positive patch test; SIDAPA, Società Italiana di Dermatologia
Allergologica Professionale e Ambientale; T.R.U.E., thin‐layer rapid use epicutaneous.
cost savings of $2 billion over the past 20‐year period occurs when patients are incorrectly assigned into ACD
since adoption of legislation that limited the level of ‘affected’ and ‘unaffected’ groups. In particular, in the
nickel that could be released from items intended for sus context of AD, many study participants have been reflex
tained contact with the skin [17]. As the US population ively classified into a presumed AD‐affected category
(318 881 992) is 56 times that of Denmark (5 627 235), US without full diagnostic work‐up and exclusion of other
adoption of a similar nickel directive has been estimated diagnoses, such as ACD. This ultimately leads to null‐
to project savings of $5.7 billion per year, ultimately favouring results and further complicates final diagnosis.
reaching $113 billion in savings over the next 20‐year Finally, of considerable note, unlike the global evaluation
period [16]. of comorbidities prevalent to the study of psoriasis, the
When it comes to correctly reporting the epidemiology incidence of contact allergy and ACD in relation to envi
of ACD and identifying associated risk factors, the litera ronmental exposures, concomitant prevalence of AD and
ture may be studded with misclassification bias which risk factors for sensitization are yet to be elucidated.
eterinarians and athletes [22]. Persons with underlying

v
Pathogenesis. There are two phases in the mechanism of
atopy‐related skin diseases or other chronic skin barrier
ACD: sensitization/induction and elicitation. Both phases defects or inflammation are also at higher risk. In particu
require a complex interaction to occur between the cells lar, children with AD have a greater likelihood of having
typically residing in the skin and cells of the immune a relative positive patch test than those without AD
system that are recruited to the epidermis in contact with [23,24]. Furthermore, the standard treatment for AD
the allergen. For ‘sensitization’ to occur, lipophilic hap requires application of multiple topical preparations
tens (low‐molecular‐weight chemicals) must penetrate potentially containing sensitizing chemicals to dermatitic
the skin. Although this process is not dependent on the skin. Exposure of the skin to entrapped haptens under
epidermal barrier being impaired, it occurs more readily occlusion or in moist environments is also believed to
if this is the case. Once the hapten has penetrated the increase the risk of developing contact allergy to a chemi
epidermis, it combines with endogenous protein, forming cal [25–28]. An example of this is development of allergy
the hapten–protein complex. When a dendritic cell to textile dyes from clothing or cosmetics that are in
encounters the hapten–protein complex, it releases inter prolonged contact with skin. In a similar manner, irritant
leukin (IL)‐1β, resulting in nearby mast cell, keratinocyte contact dermatitis has been associated with the develop
and endothelial cell release of tumour necrosis factor ment of ACD, because the epidermal barrier is disrupted
(TNF)‐α, IL‐1 and IL‐18. Eosinophils and IL‐5 have also
as a result of irritation. One reason hairdressers have a

been shown to play a modulator role in this induction higher rate of developing ACD is their increased expo
phase [18]. Ultimately, these interleukins and cytokines
OF DERMATITIS
sure to skin irritants such as water and detergents.

stimulate the migration of the dendritic cell to the local In the past it was questioned whether or not the
lymph node where antigen presentation takes place. developing immune system of very young children had
Specifically, antigen presentation involves interaction the capability of producing the delayed‐type hypersensi
between the hapten–protein complex and a naive, CD4+ tivity response seen in ACD. It has since been shown that
or CD8+ T cell, via the major histocompatibility complex the immature dermal–epidermal barrier of children in
(MHC), type II or I respectively. IL‐12 and IL‐1β, impor their first few years of life, with its thinner epidermis,
tant chemokines in the antigen presentation process in the lower lipid content and thus lower quantity of natural
lymph node, play a role in T‐cell maturation and subse moisturizing components, and higher pH may actually
quent formation of a memory T‐cell population [19,20]. increase the ability of haptens to penetrate and encounter
The sensitization phase is considered complete when cells of the immune system [29–31]. This confirms that
memory T cells are released into circulation. prevention, when possible, and recognition of the correct
Elicitation occurs when the skin is re‐exposed to the diagnosis and treatment of ACD in even the youngest
same hapten. Immunologically, the hapten–protein paediatric patients, is critical.
complex gets presented once again to the immune system There are also genetic factors that are known to predis
via an antigen‐presenting cell. A number of cells are capa pose individuals to developing ACD. Loss‐of‐function
ble of acting as antigen presenters, most importantly mutations in the filaggrin gene, commonly associated
Langerhans cells but also keratinocytes, mast cells, with AD and other forms of atopy, have been associated
endothelial cells, and macrophages [18]. Current data with predisposition to ACD [32,33]. One specific German
suggest that both Th1 and Th2 subtypes are involved in study connected deficits in filaggrin to higher incidence
the response to re‐challenge [18,19]. The release of of contact allergy to nickel, particularly in fashion jewel
numerous chemical mediators, including IFN‐γ, leads to lery, which explains the stronger association that was
neutrophil recruitment to the site of hapten exposure and noted in women [34]. Two small case‐control studies have
the maturation of T cells (specifically under the influence investigated the relationship between hand eczema and
of IL‐1), resulting in the secondary inflammatory response filaggrin mutations, the first noting that loss‐of‐function
and the clinical signs of contact allergy [19,21]. In most mutations may be implicated in hand eczema when in
individuals repeated exposure to a chemical is required to conjunction with AD, and the second showing significant
incite an immune response and subsequent clinical ACD. association between chronic irritant hand dermatitis and
It is important also to note that the majority of people in filaggrin mutations [35,36]. More evidence to associate
regular contact with known sensitizers may not develop filaggrin deficiency to hand dermatitis is necessary,
allergy. That said, there are certain known strong sensitiz although filaggrin may play less of a role in the thick‐
ers, including paraphenylenediamine (PPD) and formal skinned palmar area than in areas of thinner skin, such as
dehyde, which have been top allergens for over 70 years, flexural areas. Patients with diffuse exposure to certain
that play a significant clinical role in both adult and chemicals have developed contact dermatitis only in the
paediatric contact dermatitis. flexural areas, suggesting that the thinner epidermis and
Any alteration of an intact skin barrier can disrupt the lower level of protective function may increase the sus
protective role the epidermis plays against transepider ceptibility of flexural surfaces to developing ACD, and
mal water loss, infectious agents and other chemicals, the potential for misdiagnosis as AD [28].
thus allowing a higher degree of contact between causa The development of chronic allergic dermatitis has also
tive haptens and cells of the immune system. Particular been linked to deficiency of cathelicidin LL‐37, an antimi
populations are at higher risk of developing ACD, for crobial peptide (AMP) that is located in the skin’s cornified
example certain occupations such as hairdressers, envelope and functions as part of the skin’s innate
immune system, with antiviral, antibacterial and Table 23.2 Regional dermatitis more prevalent in children
antifungal properties. Cathelicidin LL‐37 also plays an
anti‐inflammatory role, having been found to have a sup Eyelids Shampoos, cleansers – cocamidopropyl betaine;
pressive function on dendritic cell activation via inhibition metals, e.g. nickel from hand to face – toys, coins, keys
of toll‐like receptor 4. One study showed that the addition

Face Cell phones – nickel and chromate; connubial – PPD,
of exogenous cathelicidin was able to inhibit ACD in vivo fragrance
[37]. Polymorphisms in the IL‐16 gene and the gene region Perioral Musical instruments – nickel; flavoured lip balms;
encoding N‐acetyltransferase, the enzyme responsible for chewing gum – flavourings; pacifiers – rubber
metabolism of the strong sensitizer PPD, have also been Neck Cell phones – nickel; atomizer sign – fragrance
associated with development of ACD [38,39]. Ears Costume jewellery, wireless headsets – nickel
Although the most well‐known exposure to chemicals Diaper Baby wipes – preservatives;
diapers – mercaptobenzothiazole, PTBFR
leading to the development of allergy is through the
Thighs Toilet seat – wood, plastic, cleaners (irritant);
integument, it is also recognized that oral, inhalation and chairs – nickel bolts
intravenous exposure to haptens all have the potential to Extremities Shin guards, splints – urea formaldehyde resin/PTBFR,
lead to dermatitis [18,40]. In the context of ‘oral exposure’, thioureas
chemicals used as food additives (e.g. propylene glycol Scalp Car seats

and propolis), pesticides and flavouring agents found in Trunk Nickel clothing snaps on infant clothing, breast and
both natural and artificial products have been indicated nipple dermatitis from PTBFR in padded training bras
Feet Shoes – PTBFR, rubber accelerants in children’s shoes,
OF DERMATITIS
as causative agents [41]. Once absorbed from the gastroin
e.g. Crocs™, potassium dichromate (leather sandals
testinal tract, these haptens can distribute through the and shoes)
blood and initiate a widespread inflammatory reaction
[42]. Of interest, oral exposure has been linked to cutane Source: Brod et al. 2015 [46]. Reproduced with permission of Elsevier.
ous tolerance of certain haptens in some individuals, PPD, para‐phenylenediamine; PTBFR, para‐tertiary butylphenol‐
including nickel and chromate, especially if the oral expo formaldehyde resin.
sure predates the cutaneous one. For example, it has been
shown among Danish schoolchildren that exposure to
nickel from orthodontic braces through the mucocutane allergen and may cause difficulty in establishing r elevance
ous surfaces resulted in a 93% reduction in the risk of and connecting the culprit allergen, especially if consider
sensitization to nickel [43]. Another study comparing
able time has passed since the prior exposure [47,48].
populations of Russian and Norwegian women with the Systemic or idiopathic reactions are also possible, pre
same rates of ear piercing credited the lower rates of senting as nonspecific dermatitis in locations not in direct
nickel sensitization in the Russian population to higher contact with the allergen [47]. Because of the varied pres
levels of nickel in the Russian cohort’s drinking water entation of ACD, an indication for patch testing children
[44]. In a similar way, it is postulated that the common is uncontrollable or worsening chronic dermatitis that has
practice of consuming chrysanthemum (a plant in the been present for 2 or more months, or failure to improve
Compositae plant family) tea in Singapore led to the following the standard protocols [47,49].
lower rates of ACD to Compositae in that area [40,45]. Dermatitis located in the flexural surfaces, including
the skin crease area in the neck, antecubital and popliteal
Clinical features fossae and the anterior ankle, may not necessarily confer
Everyone knows how eczema looks like, yet no one the diagnosis of AD [25,50]. Due to the specific combina
knows what eczema is. tion of moisture, warmth and friction in the flexural areas,
Heinrich Adolf Gottron they are a common place to experience skin barrier dis
ruption and potentially increased percutaneous chemical
The variable clinical features of ACD in children are akin absorption, predisposing to the development of ACD
to the clinical presentations seen in adult populations, [26,28]. Other factors contributing to this disruption may
and include acute eczematous reactions, (localized, be particular types of microorganisms and antimicrobial
idiopathic and systematized), oedema and/or erythema, peptides that reside preferentially in the flexural areas as
lichenoid, granulomatous and microvesicular or bullous‐ opposed to the environment of the skin in other parts of
type reactions. Phenotype association is related both to the body [25]. It should be noted that patients presenting
the nature of the allergen, regional distribution of the con with flexural eczema should have a complete work‐up
tact and duration of the hypersensitivity (with chronicity referring to stringent diagnostic criteria for AD prior to
conferring greater lichenification), in addition to the associating the skin findings to atopy, and should be con
inherent barrier function of the individual [22]. In its most sidered for patch testing if the diagnosis is uncertain. Of
commonly recognized form, eczematous ACD is known note, a recent study review examined 1142 patch test cases
to occur in the location specifically exposed to the aller of children younger than 18 years and found that patients
gen, with a propensity to extend beyond the direct expo with AD had different reaction profiles than those with
sure site. See Table 23.2 for location‐based ACD, adapted out AD, specifically increased frequency of reactions to
from Brod et al. [46]. cocamidopropyl betaine, wool alcohol and lanolin, and
‘Recall reactions’ are possible; these result in the devel lower frequency of reactions to methylisothiazolinone,
opment of dermatitis at a site of previous exposure to the cobalt and potassium dichromate [51].
As with adults, patch testing is the gold standard method

Patch testing in children. A multicentre retrospective study
for confirming a clinically relevant contact allergy in chil
reviewed the results of paediatric patch testing in North
dren. Guidelines established by the International Contact
America [52]. The study reported patch testing results from
Dermatitis Research Group (ICDRG) have standardized
456 affected children who were tested over an average of
patch test procedures, allergen concentrations and screen
5.3 years, indicating that an average of only 86 children in
ing panels in the evaluation of adults that have provided
total were being tested and reported on per year [52]. A
an opportunity to draw comparisons across international
limitation of the study was that the majority of the data
databases. The US Food and Drug Administration (FDA)
were being reported by large tertiary care centres, which
has granted a paediatric indication for patch testing with
confer a risk of referral bias and may not be generalizable to
the thin‐layer rapid use epicutaneous test (T.R.U.E. Test®,
the paediatric population as a whole. In 2014, the Loma
Smartpractice, Phoenix, AZ). That said, contact dermatitis
Linda University Pediatric Registry Initiative administered
experts advocate for comprehensive patch testing in chil
a cross‐sectional electronic demographic survey to provid
dren with strong clinical indication. The general consen
ers patch testing children across the USA [53]. In the first
sus is that children 12 years of age and over may be patch
year of enrollment, over 250 providers confirmed that they
tested equivalently to adults. This is supported by global
patch test children across all 50 states, as well as Washington,
paediatric patch test studies that have demonstrated
DC. The data reported a range of 1700–4700 afflicted
safety and efficacy utilizing the adult patch test allergen

children patch tested per year, as determined by provider‐
concentrations, with no increased rates of false‐positive
stated ranges for testing (1–10, 11–25, 26–50, 51–99, and over
OF DERMATITIS
reactions [52]. Some authorities extend these parameters

100 cases per year). Within one year of data collection 1142
down to include 6‐ to 12‐year‐olds, while other experts
cases from 34 US states, entered by 84 providers, were ana
such as the German Patch Test Research Group and
lysed. The study found that 65% of paediatric cases had one
authors of the North American Pediatric Standard
or more positive patch test (PPT), and 48% of cases had one
advocate a separate limited patch test series for children
or more relevant positive patch test (RPPT). The most com
6–12 years of age, with some allergens specifically not
mon PPT allergens were nickel (22%), fragrance mix I (11%),
tested without indication (e.g. paraphenylenediamine,
cobalt (9.1%), balsam of Peru (8.4%), neomycin (7.2%), pro
epoxy, gold); see Table 23.3 for recommendations for pae
pylene glycol (6.8%), cocamidopropyl betaine (6.4%),
diatric screening series, adapted from Admani and Jacob.
bacitracin (6.2%), formaldehyde (5.7%) and gold (5.7%) [54].
Table 23.3 Recommendations for paediatric screening series
Allergen Concentration
1 Bacitracin 20% pet.

2 Budesonide 0.1% pet.
3 Carba mix 3% pet.
4 Cobalt chloride 1% pet.
5 Cocamidopropyl betaine 1% aq.
6 Colophonium (colophony) 20% pet.
7 Compositae mix/dandelion extract 6% pet/2.5% pet.
8 Disperse blue 124/106a 1% pet./1% pet.
9 Formaldehyde 1% aq.
10 Fragrance mix I 8% pet.
11 Fragrance mix II (Lyral) 14% pet. (5% pet.)
12 Lanolin alcohol 50% pet.
13 Methylchloroisothiazolinone/methylisothiazolinone (MCI/MI)b (3 : 1) 0.01% aq.
14 Myroxylon pereirae (balsam of Peru) 25% pet.
15 Neomycin sulfate 20% pet.
16 Nickel sulphate 2.5% pet.
17 Potassium dichromate 0.25% pet.
18 Propylene glycol 30% aq.
19 Quaternium 15 2% pet.
20 Tixocortol‐21‐pivalate 1% pet.
Source: Adapted from Admani and Jacob [47]. Reproduced with permission of Springer Nature.
pet., petrolatum; aq, aqueous.
a
Mix two components in equal amounts.
b
MI can be tested alone as well.
Additional allergens to consider screening (if indicated by associated history): Amerchol L‐10125 (exposure to emollients, lotions), black rubber mix
(tyres, playground, toys), clobetasol 17‐propionate (topical steroid, chronic dermatitis patient), mixed dialkyl thioureas (rubber‐containing sportswear, bras,
footwear), mercaptobenzothiazole (rubber cements, gardening hose, rubber in sports equipment, toys), methylisothiazolinone (preservative), para‐
phenylenediamine (hair dye, black henna tattoo), para‐tertiary butylphenol‐formaldehyde resin (rubber‐containing bras, footwear, sports gear), sorbitan
sesquioleate (emulsifier, emollients, lotions), thiuram (rubber‐containing footwear, athletic gear, bras, toys).
[47]. It has been suggested that for this younger age group coatings attached to the back as a single polyester film
(6–12) allergens could be applied initially for only with paper tape. With the limited number of allergens
24 hours and readings be performed at 48 and 72 hours that can be tested with the commercially available series,
[55], though the standard 48‐hour initial application cycle there is a higher likelihood that the diagnosis of ACD
has been shown to be both safe and efficacious in this would be missed than when custom‐tailored comprehen
same age group [12,15]. There are also recommendations sive testing is utilized (especially in children). A recent
by the German Contact Dermatitis group that children systematic review of the latest paediatric patch‐test results
under 6 only be patch tested when there is a high degree published in US‐based medical journals identified the
of clinical suspicion for allergen exposure [55]. most common allergens in the paediatric population [29].
Several of these top allergens, including propylene glycol
Patch procedural considerations and cocamidopropyl betaine (CAPB), do not appear on
Several different types of chambers can be used to apply the T.R.U.E. test®, neither do other allergens coming
allergens to be tested to the skin, from small circular discs under increasing scrutiny in the paediatric population,
made of aluminium (commonly Finn® chambers) to plas such as benzoates [56]. Notably, the T.R.U.E. Test® was
tic chambers. Aluminium chambers should not be used to shown to be safe and efficacious for use in children over
test patients with known or suspected metal allergy, or 6 years of age in the PREA‐1 study [12], with the original

those being tested for suspected allergy to vaccine compo set of 28 allergens in 2011. In 2017, the FDA approved the
nents. Finn® chambers (SmartPractice, Canada) are also T.R.U.E test® for individuals 6 years of age and older [57].
OF DERMATITIS
available with a polypropylene coating, which should be Special considerations and limitations for patch testing
used in cases of suspected aluminium allergy or when children include their small back size, limiting the number
testing mercury solutions. Plastic options include aller of allergens that can be tested, particularly in very small
gEAZE® and allergEAZEclear® (SmartPractice, Canada) children. The limited space for testing further underlines
made of polyethylene terephthalate, additive‐free poly the need for detailed history taking of potential allergen
ethylene chambers from IQ UltraTM (Chemotechnique exposures, utilizing this information to guide choosing
Diagnostics, Vellinge, Sweden), and polypropylene cham allergens, and testing patients to their own personal care
bers from van der Bend (van der Bend, Brielle, the products, which may carry a particularly high yield. Other
Netherlands). Curatest® and Curatest® F (Lohmann and important pieces of the patient’s history to gather include
Raucher, Rengsdorf, Germany) provide disc frames with personal history of eczema or atopy, family history of
a polyester film (Table 23.4). Loadable chambers allow for atopy, known allergies, hobbies, leisure and after‐school
customization of the allergen series to be tested, and or work activities, topical and systemic medications used,
smaller chambers can be used when space is limited, and use of or exposure to cosmetics and skin care products
though this leads to volume variances, and therefore [58]. A thorough history should also include information
differences in the amount of allergen applied. The com on all caregivers and those coming into contact with the
mercially available limited screening panel (T.R.U.E. patient. The age of the child should also be taken into con
[thin‐layer rapid use epicutaneous] Test®, Smartpractice, sideration when suggesting more likely allergens.
Phoenix, AZ) may be utilized in instances where compre There are certain allergens that have been recom
hensive testing is not available. mended to be tested in lower concentration in very young
The current T.R.U.E. test® contains 35 allergens/mixes children (less than 6 years old), including nickel, formal
and a negative control in the form of uniform dried gel dehyde, and rubber additives, such as carbamates [49,59],
Table 23.4 Available patch test chambers
Type of chamber Material composing Contents Notes

chamber
Aluminium Finn® chambers Aluminium Flexible sizing of aluminium Epitest Ltd, Oy, Tuusula, Finlandare
Polypropylene‐coated Aluminium chambers (8, 12 and 18 mm) Use polypropylene‐coated when
Finn® chamber without pre‐fixed filter paper suspected aluminium allergy or
when testing mercury solutions
Plastic allergEAZE® Polyethylene terephthalate 40 μL with pre‐fixed filter paper SmartPractice, Canada
allergEAZEclear® Polyethylene terephthalate and raised edges for occlusion
IQ Ultra™ Additive‐free polyethylene 65 μL with pre‐fixed filter paper Chemotechnique Diagnostics, Vellinge,
Sweden
Van der Bend Polypropylene 40 μL with pre‐fixed filter paper van der Bend, Brielle, the Netherlands
Curatest® Polyester film disc frame Pre‐fixed filter paper Lohmann and Raucher, Rengsdorf,
Curatest® F Polyester film disc frame Germany
Commercially T.R.U.E. Test® Single polyester film Pre‐measured hydrophilic gels Limited to 35 allergens/mixes and a
available limited (dried to film) on negative control; higher likelihood
screening panel impermeable backing for that the diagnosis of allergic contact
maximum contact and dermatitis would be missed
penetration
which presents another limitation of the commercially Later visits can and should also be planned for, to confirm
available screening tool. When patch tests are not that the dermatitis has cleared upon avoidance of the
customizable, testing with nonspecific preloaded aller indicated allergen.
gens may lead to children being tested for chemicals that Clinical relevance is then designated as definite, prob
they have not previously been routinely exposed to and able, possible, past or unlikely by the practitioner at the
unnecessary exposures, for example epoxy and paraphe follow‐up visit, once avoidance has been initiated to the
nylenediamine. Furthermore, utilizing the preconstructed allergen associated with the positive patch test reaction
panel also means potential exposure to chemicals that are (PPT). Definite relevance is determined only if the derma
no longer routinely tested (unless there is specific titis is improved with avoidance of the inciting allergen,
indication) at patch test centres nationwide due to their and then re‐occurs after re‐exposure to the responsible
clinical irrelevance, such as the mercuric derivative allergen.
preservative thiomersal (thimerosal) and gold. If the diagnosis is uncertain due to highly suspicious
As with adults, activity should be limited during patch allergens yielding negative results on patch testing, or the
testing to prevent movement of the patches. Adhesive relevance of a positive test is in question, further tests can
tape can be used to more firmly secure the patch test to be confirmed to guarantee a more certain diagnosis of
the child’s skin. Whenever possible, patch tests should be allergy, such as repeated open application tests (ROAT).
applied to unaffected skin on the upper back or inner In a ROAT, the allergic substance is applied to the flexor
arms, noting that in children with AD even seemingly aspect of the forearm twice daily for 10–14 days, unless
OF DERMATITIS
unaffected skin can be more reactive or prone to irritant dermatitis appears earlier. A positive test is the develop
reactions [60]. In addition, because approximately 90% of ment of clinical dermatitis [58].
patients with AD are colonized with Staphylococcus aureus
[61], the environment created by patch testing has the Allergens of particular importance in children. It has
potential to result in bacterial overgrowth and secondary been demonstrated that although there are similar rates of
infection because of the inherent occlusive nature of the contact sensitization, there are some variances in allergen
patch testing procedure. This can further complicate the frequency between children and adults [15]. For example,
reading of patch tests. For this reason, particularly in children are less likely to suffer from ACD due to occupa
patients with AD, it is important to note carefully areas of tional exposures (e.g. to adhesives, epoxy resin and
baseline dermatitis prior to patch testing. acrylates), but are more likely to become sensitized to
It has been recommended that patients with a history of personal care products and cosmetics [65]. A review of
bacterial superinfection be evaluated for, and if necessary many of the top paediatric allergens by location can be
treated for, nasal carriage of Staph. aureus, or perform found in Table 23.2.
bleach baths for 10 minutes, three times a day, for 1 week
prior to patch testing, stopping 4 days prior to patch Nickel
testing. Furthermore, it is paramount in this population to Nickel is the number one cutaneous allergen detected in
perform delayed reads (day 5–7) in order to record irritant US children through patch testing [15,66,67]. It is esti
reactions as false positives [62]. Topical steroids should mated that nickel allergy affects 250 000 children each year,
not be used in the area of the patch test application for and the rates of nickel sensitization in the US paediatric
1 week prior to testing, and oral corticosteroids should population have been on the rise [16,47,68]. Sensitization
also be avoided in the week surrounding testing, if to nickel is not uncommon in asymptomatic children, as
possible. Topical corticosteroids can, however, be used in the first test proving the safety of patch testing children in
other areas of dermatitis on the body during the patch test 1986 found that 7.6% of 314 healthy, asymptomatic chil
process in order to suppress further flares that could dren were already sensitized to nickel [2]. Sensitization is
occur during the testing process. Administration of oral caused by exposure to metal objects that release a signifi
antihistamines to control pruritus during the testing cant amount of nickel, for example as a result of ear pierc
process is also appropriate. In extreme cases, it may be ing, which is believed to be the reason why sensitization to
necessary to maintain a minimal level of systemic nickel is more common in girls [43,69]. Ear piercing is
immunosuppressant therapy during patch testing [63,64]. highly associated with sensitization due to the disruption
Allergens are typically applied on day 1 and then kept of the skin barrier through piercing of the skin. Although
on for 24–48 hours. Between application and the first read no study has identified a specific point of highest likeli
the patients are required to keep their back dry and to not hood of developing nickel sensitization by comparing
rub the area to disrupt the position of the allergens. At the early or late ear‐piercing practices, it stands to reason that
first read (day 3), the patches are removed and sites are the earlier the piercing, the greater the time for cumulative
evaluated. On day 5–7, the second read is performed. The direct skin‐piercing exposure. One study demonstrated
second reading is critical because it allows for the differ that women who had ear piercing performed before the
entiation of irritant reactions, which are delineated by a age of 20 were more likely to become sensitized to nickel
more intense reaction on the first read than on the second. compared to those who had ear piercing after the age of 20
Usually, a true allergic reaction tends to increase in inten [70]. This may be related to a greater tendency in youths to
sity between the first and second reads, whereas irritant wear cheaper metal jewellery [71]. Of interest, a study
reactions dissipate. Certain reactions require a third read found that adolescent girls pierced after wearing dental
(day 7 or later) because of a particularly delayed response. braces had a decreased risk of nickel sensitization
c ompared to girls who had ears pierced without previously rates of sensitization in Danish children, from 24.8% in
wearing dental braces. It is believed that the mucosal 1992 to 9.2% in 1998 [79,80]. The European Union (EU)
exposure to nickel‐releasing metals led to development of emulated this in 1994 by passing similar legislation, called
immunological tolerance prior to the opportunity for cuta the EU Nickel Directive. Not only have sensitization rates
neous sensitization [43]. decreased in countries belonging to the EU, but Denmark
Nickel is inexpensive and is used in many industries, reported an estimated savings of 2 billion US dollars over
making avoidance difficult for those suffering from nickel the 20‐year period since the enactment of related legisla
allergy. More important than the amount of nickel in an tion [17]. The cost‐savings potential seen in Denmark
item is the rate at which nickel is released from it. For when projected to the much larger US population is
example, although stainless steel is a metal alloy that striking [16]. Nevertheless, such regulation is not cur
often contains nickel, contact with stainless steel rarely rently present in the USA, however the alarming rise in
incites dermatitis in allergic patients because the rate of sensitization rates has gained the attention of national
nickel release is low. Certain items made of alloys includ groups such as the American Academy of Dermatology.
ing nickel may initially release a low amount of nickel,
but over time, as the outer layer receives more wear, more Cobalt and gold
nickel may be released. One alloy known to do this is Cobalt results in many positive patch test reactions in

nitinol, a nickel–titanium alloy with shape memory used children, often second only to nickel, yet its clinical rele
for eyeglass frames, underwired bras, medical devices vance can be difficult to determine. To explain this, cobalt
OF DERMATITIS
and novelty items [16,72]. Nickel often incites dermatitis sensitization is a well‐known ‘co‐reactor’ to nickel, due to
in classic locations, including the ear lobes from jewellery simultaneous exposures to both metals in metal alloys.
(most often costume jewellery), at the umbilicus from but Gold is another metal that should probably not be
tons or belt buckles containing nickel, and on the waist tested on children unless their history warrants it. The
line from nickel‐containing studs on clothing. Idiopathic North American Contact Dermatitis Group data have
reactions have also been reported from nickel, including a determined that there is very little clinical relevance to
paediatric case resulting from electronic tablet use [73,74]. sensitization to gold in children under 12, and for this rea
Other sources of nickel exposure in children include eye son it has been removed from their standard patch test
glass frames, zips, clothing snaps, orthodontic braces, screening tray [52]. Gold currently remains an allergen on
school chairs, mobile phones and toys [13]. the T.R.U.E. test®.
Systemic contact dermatitis to nickel, or dermatitis
following systemic exposure to a previously sensitized Neomycin and other topical antibiotics (e.g. bacitracin)
allergen (e.g. by inhalation, ingestion or implantation), Neomycin, a topical aminoglycoside antibiotic, has a long
has been reported [75]. A meta‐analysis of 17 studies on history of being one of the most prevalent contact
oral nickel exposure noted that 1% of nickel‐sensitized allergens in adults in the USA – over three decades [81]. It
patients suffered adverse systemic symptoms when is believed that a week or more of consistent use of neo
exposed to significant nickel in their diet [76]. Certain mycin has greater potential to cause sensitization than
foods are known to be consistently higher in nickel, occasional application to small cuts or wounds [81,82].
including wholegrain flour, oats, soybeans, shellfish, Bacitracin is commonly seen in combination topical
nuts and legumes [77], and a dose–response relationship antibiotic preparations, often with neomycin and/or pol
has been noted between nickel‐rich foods and dermatitis ymyxin B sulfate. Due to their popularity, the use of these
flares [78]. The real‐life effectiveness of prescribing a over‐the‐counter combination medicaments can result in
low‐nickel diet for nickel‐sensitive patients has been co‐sensitization or simultaneous sensitization to both of
controversial, particularly because compliance with a these allergens, leading to polysensitization of patients
low‐nickel diet can be difficult, as avoidance and elimi [9]. Of note, more than 25 cases of anaphylaxis have
nation of nickel from the diet can seem impossible with resulted from application of topical bacitracin to skin
nickel levels in foods varying with the level of nickel in abrasions, indicating the potential for type I hypersensi
soil and water, potentially even from season to season. tivity reaction to the compound as well as delayed type
Despite this, a trial of a low‐nickel diet is a potential [83]. Similar to what is seen with corticosteroids, atopic
treatment option to consider in patients highly sensi patients may suffer from higher rates of sensitization to
tized to nickel, as evidence suggests the potential for topical antibiotics such as neomycin because of their
clinical improvement in symptoms in some cases [75]. A increased rate of use to treat superficial bacterial infec
points‐based system utilizing mean concentration of tions imposed on atopic skin [84].
nickel in foods (as reported by the FDA), limiting nickel
consumption for the most nickel‐sensitized patients to Fragrance (including fragrance mixes I and II, cinnamic
less than 150 μg per day (aka 15 points) [77] can be uti aldehyde, cinnamic alcohol, propolis, Compositae/
lized to improve compliance. dandelion colophony, balsam of Peru)
In response to a rising trend of nickel sensitization in Many allergens are clumped into the ‘fragrance’ category,
Denmark, legislation was passed in 1992 that limited the including balsam of Peru, fragrance mixes I and II,
amount of nickel that can be released from products benzoates, cinnamic aldehyde and cinnamic alcohol,

coming into prolonged contact with skin (limited to
propolis (beeswax), Compositae/dandelion and colophony.
0.5 μg/cm2 per week), resulting in significantly lower Fragrance mix includes geraniol, cinnamaldehyde,
hydroxycitronellal, cinnamyl alcohol, eugenol, isoeugenol, sesquiolate is used in screening trays to test for fragrance‐
α‐amylcinnamaldehyde and oak moss. Although cases of related allergy, as it is an emulsifier and is found in many
systemic dermatitis have been connected to fragrance fragrance cosmetics.
allergy, typical sites of dermatitis resulting from fragrance
allergy are the face, neck and axilla, where the greatest Potassium dichromate
contact with the chemicals occurs [85]. Apart from the Tanned leather products such as shoes and belts are the
obvious sources such as perfumes, fragrances are used in most common sources of positive patch tests to the
many products such as cosmetics, sunscreens, cleaning allergen potassium dichromate. In fact, potassium dichro
products and other hygiene products. In children, fra mate is a known allergen responsible for inducing foot
grance is commonly the cause of ‘connubial’ dermatitis, or dermatitis in children [13,96,97]. Several studies have
facial eczema in a child being carried or cheek‐to‐cheek demonstrated a higher rate of sensitization to potassium
with an adult wearing cosmetics or other fragrances. dichromate in children with AD than those without,
Fragrance, consistently one of the top allergens in both which has been explained by atopic children having a
adult and paediatric populations, is used even in products higher incidence of juvenile plantar dermatosis, suggest
marked ‘unscented’ if the fragrance is used to mask ing that the impaired epidermal barrier may enable pen
another fragrance. For this reason, patients with fragrance etration of haptens across the skin of the foot [98]. An
allergy are encouraged to seek products that are marked alternative for affected children is footwear made from
specifically ‘fragrance‐free’. Fragrances have also been vegetable‐tanned leather. Vitamins, paints and anti‐rust
OF DERMATITIS
used in products marked ‘hypoallergenic’ if their purpose products, and matches are other important sources of
in the products is for preservative properties instead of exposure to potassium dichromate [99].
fragrance properties [86,87]. Clinical significance of fra
grance allergy is extremely high, with over 90% of positive Lanolin and other wool alcohols (including Amerchol
patch tests reported in adults with definite, probable or L‐101™)
possible relevance [88]. Lanolin is a product of alcohol extraction of sebum from
Balsam of Peru, an extract from a tree known as wool, and consists of long‐chain waxy esters. Utilized for
Myroxylon pereirae, is a mixture of many fragrant chemi its emulsifying and hydrating properties, lanolin is com
cals and is related to fragrances such as benzoates, monly incorporated into cosmetic and hygiene products
cinnamic aldehyde and alcohol. It is tested in screening (including shaving cream, soap and shampoos) and heal
trays as a general marker of fragrance allergy, along with ing salves. Rates of contact sensitization to lanolin in the
the fragrance mixes, and is used in many products, paediatric population have been reported as recently
including toothpaste, mouthwash, topical medications increasing [100,101]. However, patch testing patients to
and healing salves [89,90]. Related chemicals are used as lanolin has been notoriously difficult. In part this is due to
artificial flavouring in soft drinks and other food items, the ‘lanolin paradox’: essentially that contact sensitization
including flavours such as vanilla, curry, cloves and cin to the allergen is less likely to be apparent on intact skin
namon. Because of the known potential for oral exposure than expression on disrupted skin. Variability in lanolin
to related chemicals, there is some evidence that dietary composition can result in low yield from testing patients
intervention and avoidance of related flavours may if just one lanolin‐containing agent or single concentra
benefit patients with particularly difficult‐to‐treat fra
tion is tested [102]. Amerchol L‐101™ (50%) has been rec
grance allergy [91,92]. By testing both to balsam of Peru ommended as the testing substrate and is now currently
and fragrance mix, it is estimated that more than 80% of included in the American Contact Dermatitis Society core
fragrance allergy can be detected [93,94]. allergen series because in at least one study it was shown
Compositae, also known as Asteraceae, is a plant fam to be a better determinant of allergy to wool alcohol than
ily representing 10% of the world’s flowering plants, the standard lanolin 30% [103]. Also, due to potential var
including chamomile, dandelion and ragweed. Both iability of lanolin used in products, patients should be
localized and diffuse‐airborne patterns of ACD to these tested with their own lanolin‐containing personal items if
compounds have been reported, at times mimicking pho allergy is suspected.
todermatoses. Use and exposure to these allergens in teas,
herbal supplements and personal care products leads to Carba mix/carbamates (and other rubber materials:
sensitization. The sesquiterpene lactones are the chemi thiuram mix, thioureas, mercaptobenzothiazole,
cals responsible for most of the Compositae plant family’s mercapto mix)
allergenicity [48,95]. Colophonium, balsam of Peru and Carbamates, thiuram, mercaptobenzothiazole and mer
propolis have all been known to cross‐react in individuals capto mix are included in all standard patch test series.
allergic to this family of plants [92]. Children may become These chemicals are rubber accelerators, used in rubber
exposed to colophony, a member of the Pinaceae family, production to catalyse transformation from a liquid to
in preparations used for treating verrucae, soaps, glues, solid state. The mercapto compounds are primarily found
varnishes, violinist’s rosin and gripping powder used by in heavier rubber items, such as the soles of shoes, while
gymnasts. Propolis (beeswax) is advertised and widely thiurams and carbamates are a significant component of
used for its immune‐stimulating, antioxidant and wound‐ gloves. Exposure and resulting allergy in children can be
healing properties, resulting in strong association with traced to gloves and shoes, elastic waistbands in pants and
self‐medication with ‘natural’ substances [13]. Sorbitan elastic in socks, sports gear, bras, swimwear, pacifiers and
other toys [99]. Napkin dermatitis has been historically Tixocortol‐21‐pivalate and budesonide are the corticos
associated with mercaptobenzothiazole allergy, as it is teroids on the recommended paediatric screening tray.
used in the elastic waistband [104]. In addition, the Identification of this allergy is particularly important for
environment in which a person is exposed to mercapto paediatric atopic patients or others with chronic inflam
compounds is believed to affect sensitization. For exam matory skin diseases who require frequent application of
ple, the warm, moist environment in shoes and gloves topical medicaments as part of their treatment regimen.
may increase the rate of release of rubber additives from There is an increased risk that these patients develop sen
these compounds, leading to sensitization [105]. sitization to the medicament ingredients because of their
disrupted skin barrier. A newer classification of steroids
Cocamidopropyl betaine (CAPB) and related allergens was suggested by Baeck et al. in 2011, which differenti
(3‐dimethylaminopropylamine, amidoamine) ated steroids based on their allergic potential: ‘Group 1’
Cocamidopropyl betaine is used as a surfactant, foaming representing non‐methylated molecules (traditional clas
and thickening agent in many soaps, shampoos, body sification Group A, D2 and budesonide) which carry the
washes and toothpastes. It was initially seen in Johnson & most allergic potential, ‘Group 2’ being the halogenated
Johnson’s ‘No More Tears’ shampoo in the 1950s, as it is C16/17 cis‐ketal/diol structure and Group B steroids,
less irritating to eyes than alternative surfactants due to and ‘Group 3’ (Group C and D1) carrying the least aller

its zwitterion chemical structure, with both positively and gic potential [113].
negatively charged elements [106,107]. While increas As for ingredients, propylene glycol has been identi
OF DERMATITIS
ingly recognized as causing ACD, particularly in paediat fied as the top allergen found in many topical steroids
ric populations, CAPB is not an allergen included in the [114,115]. The vehicle used for patch testing patients to
commercially available patch test. Positive patch tests to corticosteroids may also affect the sensitivity of the test,
3‐dimethylaminopropylamine (DMAPA) and amidoam relating to the penetration of the allergen into the skin.
ine (AA), chemical byproducts/impurities generated in Patients not responding as expected to treatment for
the manufacturing of CAPB, have been reported, some chronic dermatitis in particular should be patch tested
investigators even suggesting that these chemicals may for allergy to both steroids and individual components of
be the true sensitizers leading to CAPB allergy [107]. steroids, in addition to the patient’s current personal top
ical formulation. These patients may also benefit from
Formaldehyde and formaldehyde releasers (p‐tert‐ use of the ‘Group 3’ steroids with the least allergenic
butyl‐phenol formaldehyde resin, diazolidinyl urea, potential. Examples of steroids in this group include
imidazolidinyl urea, quaternium‐15, DMDM alclometasone dipropionate, betamethasone valerate,
hydantoin, bronopol, etc.) mometasone furoate, desoximetasone and clobetasol
Formaldehyde and related chemicals have been tested as propionate (listed in increasing order of potency). If a
part of standard screening series since the first screening reaction to a topical steroid is observed, it is important to
series was recommended in 1939 [108]. These products determine the range of hypersensitivity by patch testing
are ubiquitous, as they are used in personal hygiene prod with other steroids as well.
ucts and cosmetics as antimicrobial preservatives to
maintain shelf‐life and to maintain wrinkle‐free fabrics, to Para‐phenylenediamine
name a few. The FDA notes that formaldehyde‐releasing Para‐phenylenediamine (PPD) is a common hair dye
preservatives are found in an estimated 20% of personal chemical that is related to printer ink and photography
hygiene products [109]. Cases of persistent dermatitis products and is used to enhance and darken the colour of
have been traced to systemic exposure to formaldehyde henna tattoos (black henna). The permitted concentration
in cigarette smoke inhalation and products in foods that of PPD in permanent hair dyes is 6%, but the concentra
metabolize into formaldehyde (e.g. aspartame, smoked tion in black henna tattoos has been found to be up to
meats and maple syrup), suggesting that there may be 15.7% [116]. Reactions to PPD in temporary and black
benefit from dietary avoidance in patients with difficult‐ henna tattoos have caused permanent scarring and hypo
to‐treat formaldehyde allergy [110,111]. P‐tert‐butyl‐phe pigmentation as a result of severe hypersensitivity reac
nol formaldehyde resin (PTBFR), a compound chemically tions. Known as one of the five allergens recognized as
related to formaldehyde, is found in adhesives used to ‘strong sensitizers’, PPD has been responsible for leading
make shoes, watch straps or sports gear such as shin to extreme, even life‐threatening reactions in children and
guards. One study with 102 patients found a surprising adolescents [117–119]. Testing is warranted only if a rele
number of children with positive patch tests to PTBFR vant history is elicited, due to the potential harm from
associated with sneakers and sports equipment, where possibly sensitizing children to this allergen or eliciting a
the moist environment due to sweat combined with hypersensitivity reaction. Almost 25% of those sensitized
mechanical irritation probably increases the chance of to PPD may also demonstrate allergy to related semi‐
sensitization [12,112]. permanent dyes in dark synthetic clothing [120,121].
Corticosteroids Thiomersal (thimerosal)

ACD from topical corticosteroids is not rare, yet can be Sensitization commonly occurs during routine vaccina
complex to detect because allergy can be to both the active tion, where thiomersal serves as a preservative [122].
steroid components and the ingredients of the vehicle. Other less common sources of exposure and sensitization
include contact lens solution and other ophthalmic or otic of sensitization to propylene glycol [114,115]. Historically,
preparations, which have resulted in periorbital d ermatitis propylene glycol has created difficulty in identifying
[123]. Although positive patch test reactions to thiomersal allergy through patch testing, as it has been known to
are common, relevance is often not established and may cause irritant reactions that may be difficult to distinguish
only represent prior sensitization from past exposure. from mild allergic reactions [137].
Routine patch testing for this chemical is more recently
considered unnecessary, and one study suggested that Benzalkonium chloride
rates of sensitization decrease with age [124]. Thiomersal Benzalkonium chloride is another preservative utilized in
has been removed from all US vaccines routinely recom topical medications, cleaning products and personal care
mended for children, with the exception of inactivated products. A significant amount of sensitization and expo
influenza vaccine, tetanus toxoid vaccine and diphtheria, sure is believed to occur from its use in disinfectants and
tetanus and activated pertussis, but is still used in vac sanitizers as an alternative to alcohol‐based products
cines given in European countries [125]. [138]. Known recently as a contact allergen from its use in
household cleaning wipes, it has been known for longer
Methylchloroisothiazolinone/methylisothiazolinone as a skin irritant, thus necessitating the exclusion of irri
(MCI/MI) tant reactions when testing for contact allergy to this
The combination preservative methylchloroisothiazol chemical.

inone/methylisothiazolinone, or MCI/MI (also known
OF DERMATITIS
as Kathon CG and Euxyl K100), is found in many p ersonal Disperse dyes

care products specifically for use in children, including Disperse dyes are used in polyester‐blended textiles, as
wipes, body washes, bubble baths and moisturizers. It seen in children’s gym clothes and school uniforms [139].
also has the potential of causing airborne (systematized) Allergy to disperse dyes has also been attributed to dyes
ACD from freshly painted sources (since these agents are used in napkin materials [140]. Although disperse blue is
frequently used as preservative agents in common house the most common colour of dye allergen, the colour of
paints), body mist [126], air fresheners [127] and cleaning fabric or material causing allergy may not be blue, as it
supplies [128–130]. In 2013, Aerts et al. reported the first should be considered that multiple colours are often com
case of a 4‐year‐old girl who was sensitized specifically to bined to create colour blends. While disperse dyes are
MI in her baby wipes, but subsequently had airborne included in many paediatric screening series, it is also an
(partly systemic) contact dermatitis (presumably by option to apply a suspect garment directly to the skin to
inhalation of vapour from house paint), which notably test for development of hypersensitivity reaction [99].
mimicked atopic dermatitis [131].
MCI/MI allergy has been increasingly reported [132], Rhus tree (Toxicodendron)
leading to such great concern in the EU that MCI/MI is There are a number of Toxicodendron species, and the most
now prohibited from use in ‘leave‐on’ products [114,115]. common ones to cause dermatological problems are poi
The particular concern for this chemical being used in son ivy (Toxicodendron radicans) and poison oak
paediatric personal care products is due to its significant (Toxicodendron diversilobum), as they contain a potent aller
sensitization rates [133]. Most standard screening panels gen present in the oleoresin. Rhus dermatitis occurs
test for allergy to MCI/MI mix (3 : 1) 0.01% aqueous solu particularly in the USA. The acute dermatitis develops
tion, yet it is estimated that testing with the mix alone after direct contact with the plant but may occur from
may miss approximately 40% of allergy [134]. Instead, MI indirect exposure such as from burning plant material.
(0.2% aqueous solution) can be tested alone in addition to The eruption is characteristically a papular/vesicobul
the mix. MI alone is also not currently included in the lous event with a streaky distribution. Cross‐reactions
T.R.U.E. test®, which makes testing for sensitization to may occur with the oleoresins of other plants including
this common allergen less accessible. mango, cashew and the Japanese lacquer tree. In other
circumstances, phototoxic reactions to plant materials

Propylene glycol such as rue may result in a similar rash.
Propylene glycol has been implicated as the causative
agent in several reported cases of generalized dermatitis Primary interventions – prevention, avoidance, educa-
[7,66,135]. Ingestion of propylene glycol, used as an addi tion, regulation. Once patch testing is completed and an
tive in food as a solvent for flavouring agents and dyes, allergen has been identified, relevance can be assigned to
has been shown to carry the potential to flare propylene guide avoidance strategy. Patients can be directed in their
glycol dermatitis, suggesting that patients with dermati avoidance of pertinent allergens and seeking alternative
tis related to cutaneous allergy to propylene glycol may products through provider‐registered electronic manage
also benefit from an avoidance diet [136]. The most likely ment databases such as the Contact Allergen Management
sources of exposure of paediatric patients to propylene database (CAMP) and Contact Allergen Replacement
glycol include personal care products such as leave‐on Database (CARD), which is now known as ‘Skin Safe’. The
moisturizers, deodorants and cosmetics, while it is also Dermatitis Academy offers free open‐access, online, patient‐
used in varnishes, lacquers, lubricants and cutting fluids, centred resources including a ‘Simple and Free’ guideline
serving as an excellent solvent, vehicle, emulsifier or highlighting products devoid of the top 10 paediatric aller
humectant. Topical steroids are another common source gens. It is important that sufficient post‐patch test patient
education be performed to assure understanding of the At the same time, not all eczema is associated with a
need for avoidance of the identified allergens, such as where filaggrin mutation, and not all with the mutation develop
the allergen is found, what are the most likely exposures, AD [146]. It is possible that filaggrin and other epidermal
and alternative practices, strategies or products for its defects may contribute to enhanced penetration of
avoidance. Patients should be encouraged to bring to the allergens through the damaged epidermis, leading to a
visit their routinely used personal products for review with polarized immune response that is more Th2 heavy [147].
the patch test education coordinator to eliminate source The Th2‐dominant immune response common to atopics
products containing the contact allergen. may also interact differently with epidermal proteins, and
For easy identification of items releasing significant while not completely understood, this immune dysregu
amount of nickel, available to both patients and provid lation may affect both the integrity of the epidermal bar
ers, the dimethylglyoxime/ammonia (DMG‐A) nickel rier and the response of the innate immune system [148].
release spot test allows for detection of the level of nickel The Th2‐polarized response (high in IL‐4 and IL‐13), com
release sufficient to cause sensitization. Upon rubbing a mon in atopics, along with the reduction of antimicrobial
white cotton swab coated with DMG on a metal item, for peptides (e.g. cathelicidin LL‐37 and HBD‐3) and dimin
mation of a pink precipitate indicates a concentration of ished recruitment of cells such as neutrophils, also prob
0.44 μg/cm2 nickel release (0.05 μg/cm2 has been shown to ably leads to the high incidence of colonization of atopic

elicit nickel sensitization) [141,142]. A colour scale can be patients by Staph. aureus [148]. Downstream changes in
utilized to determine the level of nickel being released inflammatory and regulatory innate immune system
OF DERMATITIS
from an item [143]. Patients should re‐test their items over responses, and a decreased response of the innate immune
time as the top layer of items may contain less nickel than system, could explain the prevalence of growth of the
the alloys underneath that will be exposed for further bacteria in these patients [145,148].
wear and time. Investigation into the realm of possibilities for treating
Strict avoidance regimens may need to be adhered to for ACD with biologic agents, comparable to the likes of what
2–3 months in more extensive cases of dermatitis [49], we have for psoriasis, has lately been under way and
requiring diligence and patience on the part of the patient, sheds light on the immune mechanisms at play in the
patient’s family and providers. For the many patients development of ACD. Phosphodiesterase inhibitors
without access to patch testing, the concept of ‘virtual (particularly PDE‐4), in the form of topical agents, have
patch testing’ has arisen, utilizing trends from national been known to inhibit TNF‐α, an important inflammatory
patch test data sets to estimate which allergens are proba cytokine in the development of ACD, and have been
bly causing the majority of ACD, which patients can pre‐ investigated for the treatment of ACD [149,150]. They
emptively avoid and observe if their symptoms abate represent an additional nonsteroidal option to topical tac
[144]. A review of the largest five studies published by US‐ rolimus and pimecrolimus. Other anti‐TNF‐α medica
based medical journals reporting results of patch testing tions, such as etanercept and infliximab, have been
children after the year 2000 indicated a high frequency of suggested as holding potential roles in the treatment of
known sensitizers appearing in paediatric personal care contact dermatitis, although this is not as well documented
products. By utilizing products devoid of these a llergens, as their role in treating other inflammatory diseases such
pre‐emptive avoidance strategy (PEAS), a significant as psoriasis. Additionally, there is evidence that topical
number of children could potentially improve their calcineurin inhibitors could aid in the repair of barrier
dermatitis. Likewise, a similar PEAS has been suggested defects common to atopic dermatitis, and that antibiotics
for children with chronic dermatitis, recommending such as gentamicin may be able to influence production of
avoidance of highly prevalent high‐frequency sensitizing filaggrin chains by impacting the interaction between resi
allergens found in paediatric‐marked personal care prod dent skin flora and the innate immune system [151].
ucts. The authors suggested that it may be possible to Further evaluation of the role of racial differences in the
improve approximately one third of paediatric ACD with development of ACD is necessary. Despite their signifi
strategies pre‐patch test avoidance utilizing personal care cant populations in the USA, both Hispanics and blacks
products devoid of these allergens [29]. have been historically underrepresented in the dermato
logical literature. Data from the Pediatric Contact
Emerging concepts. From its pivotal discovery by Dermatitis Registry showed that black children were
Jadassohn in 1895, the immunology of contact sensitiza noted to experience dermatitis 1.2 years longer than
tion and subsequent allergic presentation has intrigued whites and 1.6 years longer than Hispanics [152].
dermatologists and allergists alike. The complex inter Additionally, patch‐tested patients designated as Asian or
play between ACD and atopic skin disease is poorly African American were more likely to have concurrent
understood, confounded by conflicting evidence in the atopic dermatitis (odds ratio [OR], 1.92; 95% confidence
literature. An estimated 20–40% of atopic infants are interval [CI], 1.20–3.10; P = .008; and OR, 4.09; 95% CI,
known to have an innate genetic filaggrin mutation 2.70–6.20; P <
.001, respectively). Because minorities
resulting in an impaired skin barrier and increased tran account for a growing proportion of the American
sepidermal water loss. Also related to filaggrin mutations population, the need for more data to better understand
are an increased pH and alteration of inherent antimicro disease manifestation in skin of colour is imperative.
bial peptides, all which could potentially contribute to an Understanding the intrinsic and extrinsic co‐morbidi
increased risk for allergen sensitization [145]. ties that put patients at risk for developing ACD is an area
in need of further research, especially given the reported 7 Fortina AB, Romano I, Peserico A, Eichenfield LE. Contact sensitiza
tion in very young children. J Am Acad Dermatol 2010;65:772–8.
rising rates in the paediatric population. Rates of both AD
8 Sarma N, Ghosh S. Clinico‐allergological pattern of allergic contact
and ACD in the USA are notably higher than that of dermatitis among 70 Indian children. Indian J Dermatol Venereol
developing nations. Interestingly, vitamin D deficiency Leprol 2010;76:38–44.
has been connected to the development of allergic 9 Jacob SE, Yang A, Herro E, Zhang C. Contact allergens in a pediatric
population: association with atopic dermatitis and comparison with
illnesses, and furthermore vitamin D may play an impor other North American referral centers. J Clin Aesthet Dermatol
tant role in regulating antimicrobial peptides in 2010;3:29.
keratinocytes [153,154]. Other environmental factors have 10 Toledo F, García‐Bravo B, Fernández‐Redondo V et al. Patch testing in
been postulated to play roles, including the abundant use children with hand eczema. A 5‐year multicentre study in Spain.
Contact Dermatitis 2011;65:213–19.
of cleansing antibacterial products aimed at removing 11 Kuljanac I, Kneževic ́ E, Cvitanovic ́ H. Epicutaneous patch test results in
bacteria from the skin, including the protective normal children and adults with allergic contact dermatitis in Karlovac county:
skin flora such as Staphylococcus epidermidis. These resi a retrospective survey. Acta Dermatovenerol Croat 2011;19:91–7.
12 Jacob SE, Herro EM, Sullivan K, Matiz C et al. Safety and efficacy
dent flora have been shown to perform many ‘mutualis evaluation of TRUE Test Panels 1.1, 2.1, 3.1, in children and adoles
tic’ functions contributing to effective skin barrier cents. Dermatitis 2011;22:204–10.
function, including producing antibacterial peptides that 13 Schena D, Papagrigoraki A, Tessari G et al. Allergic contact dermatitis
aid the skin’s innate immune system and assist in main in children with and without atopic dermatitis. Dermatitis
2012;23:275–80.
taining the skin’s barrier function through enhancing 14 Silny W, Bartoszak L, Jenerowicz D et al. Prevalence of contact allergy
tight junction expression and decreasing pro‐inflamma in children suffering from atopic dermatitis, seborrhoeic dermatitis
OF DERMATITIS
tory cytokines [145,155,156]. Colonization of the skin by and in healthy controls. Ann Agric Environ Med 2013;20:55–60.
15 Zug KA, Pha AK, Belsito DV et al. Patch testing in children from 2005
Staph. epidermidis is also known to impair the establish
to 2012: Results from the North American Contact Dermatitis Group.
ment of colonization with Staph. aureus, an organism often Dermatitis 2014;25:345–55.
responsible for superimposed infection on atopic or other 16 Jacob S, Goldenberg A, Pelletier J et al. Nickel allergy and our
chronically inflamed skin [145]. Researchers recently children’s health: a review of indexed cases and a view of future
prevention. Pediatric Dermatology. 2015;32(6):779–85.
found increased Staph. aureus infections in atopic patients 17 Thyssen J, Hald M, Avenstorp C, et al. Characteristics of nickel‐
with nickel allergy in comparison to atopic patients and allergic dermatitis patients seen in private dermatology clinics in
healthy volunteers without nickel allergy. Furthermore, Denmark: a questionnaire study. Acta Derm Venereol 2009;89:384–8.
elevated secretion of IL‐2 under nickel sulphate stimula 18 Elsaie M, Olasz E, Jacob S. Cytokines and Langerhans cells in allergic
contact dermatitis. G Ital Dermatol Venereol 2008;143:195–205.
tion in vitro was found exclusively in atopic patients with 19 Fuhlbridge R, Kieffer J, Amerding D, Kupper T. Cutaneous lympho
nickel allergy infected by Staph. aureus, suggesting a link cyte antigen is specialized form of PSGL‐1 expressed on skin‐homing
between nickel allergy and staphylococcal infection in T cells. Nature 1997;389:978–81.
20 Friedmann P. Contact sensitization and allergic contact dermatitis:
AD [157]. immunobiological mechanisms. Toxicol Lett 2006;162:49–54.
As ACD in children continues to be better recognized, 21 Rietschel R, Fowler JJ. The pathogenesis of allergic contact hypersen
further investigation is needed. Collaboration between sitivity. In: Fisher’s Contact Dermatitis, 5th edn. Philadelphia:
patients, medical practitioners, industry and policy Lippincott Williams and Wilkins.
22 So J, Hamstra A, Calame A et al. Another great imitator: allergic
makers is necessary to promote safety directives that
contact dermatitis: differential diagnosis, clues to diagnosis, histopa
appropriately regulate known chemical sensitizers result thology, and treatment. Curr Treat Options Allergy 2015;2:333–48.
ing in preventable sensitizations and a reduction of the 23 Czarnobilska E, Obtulowicz K, Dyga W et al. The most important
contact sensitizers in Polish children and adolescents with atopy and
burden of ACD.
chronic recurrent eczema as detected with the extended European
Baseline Series. Pediatr Allergy Immunol 2011;22:252–6.
24 Goldenberg A, Jacob S. Pediatric Patch Test Registry: Abstract
Disclosure Presentation. Paper presented at the ACDS Annual Conference, 2016,
Washington, DC.
Sharon E. Jacob is the Founder and Chief Executive 25 Jacob S, Goldenberg A, Nedorost S,et al. Flexural eczema versus
Officer of the Dermatitis Academy, a free online resource atopic dermatitis. Dermatitis. 2015;26:109–15.
on contact dermatitis. 26 Winnicki M, Shear N. A systematic approach to systematic contact
dermatitis and symmetric drug‐related intertriginous and flexural
exanthema (SDRIFE): a closer look at these conditions and an
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117 United States Consumer Product Safety Commission (CPSC). Immunology, Houston, 2015.
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Immunol 2008;121:533–4.

OF DERMATITIS
316
CHA PTER 2 4
Hypereosinophilic Disorders
Eirini E. Merika & Nerys Roberts
Chelsea & Westminster Hospital, London, UK
Introduction, 316 Hypereosinophilic syndrome, 324 Eosinophilic panniculitis, 333

Eosinophilic pustular folliculitis in infancy Eosinophilic cellulitis (Wells syndrome), 328
and childhood (syn. Ofuji disease), 318 Eosinophilic fasciitis, 331
Abstract utlines the clinical features, investigation and treatment of those

o
hypereosinophilic disorders where the eosinophil is thought to be
central to the pathogenesis (i.e. eosinophilic cellulitis, panniculitis,

Eosinophils are well established as inflammatory cells and are now
fasciitis and pustular folliculitis and hypereosinophilic syndrome).
recognized to have an important role in host protection, immune
OF DERMATITIS
Childhood rashes where eosinophils are present (such as atopic

regulation and inflammation. This chapter discusses the common-
dermatitis, drug rashes and immunobullous disorders) are not
est context in which peripheral blood eosinophilia is a ssociated
discussed as they are covered elsewhere.
with a skin rash in neonates, infants and older children and
Key points with high mortality in view of potential cardiac complications.

Symptomatic patients are usually steroid responsive.
• Eosinophilic cellulitis is a rare but important diagnosis.
• Eosinophils are multifunctional cells that contribute to both
Infection, drug reaction, trauma, connective tissue disease or
innate and adaptive immunity. They are involved in the
haematological malignancy may underlie it. It is characterized
initiation, propagation and resolution of immune responses,
by abrupt onset of tender lesions that rapidly spread in a well
including tissue repair.
child. Flame figures on histology are the most common feature.
• Eosinophilic pustular folliculitis of infancy most frequently
If treatment is required, it should be anti‐inflammatory rather
appears in the first months of life and resolves by the age of 3.
than antibiotic treatment.
All patients have scalp lesions, tissue eosinophilia and recurrent
• Eosinophilic fasciitis is characterized by eosinophil‐rich, symmetrical
outbreaks. Blood eosinophilia is present during flares but may
sclerodermatous skin changes in the extremities. It is associated with
normalize in between. It is usually benign and self‐limiting.
connective tissue disorders, underlying malignancy, haematological
• A hypereosinophilic syndrome (HES) diagnosis requires blood
disease and drug reactions. Peripheral blood eosinophilia is seen in
eosinophilia and tissue damage due to eosinophil accumulation.
70% of cases. It is usually steroid responsive.
Persistent eosinophilia is a feature. End‐organ damage must be
• Eosinophilic panniculitis presents with subcutaneous nodular
present for the diagnosis to be made. Patients should be investigated
swelling. It is associated with underlying disease. It is a lobular
for an underlying haematopoietic neoplasm. Reactive causes must
and septal eosinophil‐rich panniculitis without vasculitis and is
be excluded for a diagnosis of idiopathic HES. HES is associated
usually steroid responsive.
Introduction
also dependent on transcription factors – GATA‐binding
Eosinophils have been easily recognizable in tissues for protein 1, enhancer binding protein alpha, box binding
over a century because of the characteristic staining of protein and interferon consensus sequence binding pro-
their granules with eosin on haematoxylin, yet their pre- tein. Surface immunoglobulin‐like transcripts 2 and 5
cise role in health and disease is only gradually being receptors are also emerging as important controllers of
elucidated. development and apoptosis.
Eosinophils are multifunctional cells that contribute to Eosinophils are involved in the initiation, propagation
both innate and adaptive immunity. They are bone mar- and resolution of immune responses, including tissue
row derived and develop from progenitor cells when repair. Eosinophils are able to sense pathogens and pro-
stimulated by interleukin (IL)‐3, granulocyte‐macrophage mote innate immune responses via expression of comple-
colony‐stimulating factor and IL‐5, the last being the ment receptors, Fc receptors and pattern recognition
major regulator of eosinophil accumulation in tissues, receptors including multiple toll‐like receptors.
which can modulate eosinophil behaviour at every stage Once activated, eosinophils promote host protection
from maturation to survival. Eosinophil development is via direct effects on pathogens, immune responses by
Chapter 24 Hypereosinophilic Disorders 317
modulation of lymphocyte and dendritic cell function Familial or hereditary eosinophilia has been described,
and inflammation via tissue damage, remodelling and with multiple family members showing eosinophilia, and
mast cell activation. an autosomal dominant inheritance was proposed. Initial
Eosinophils release soluble mediators such as reports, however, were not followed by other familial
cytokines, chemokines, growth factors and bioactive cases so it is difficult to be certain if this is a distinct entity
lipids. Their cytokines can induce both T‐helper 1 and [10,11]. Furthermore, Ota et al. reported three siblings
T‐helper 2 type inflammation as well as fibrosis (trans- with features of familial eosinophilia but who clinically
forming growth factor beta). IL‐4 production by eosino- had lung disease – two had a Churg–Strauss syndrome
phils is thought to be important not only in regulating (eosinophilic granulomatosis with polyangiitis [EGPA])
immune, but also metabolic, processes including beige phenotype and the third had eosinophilic pruritus. Thus
fat development. In addition, eosinophils produce cyto- there seems to be an overlap with hypereosinophilic syn-
toxic proteins: major basic protein, eosinophil peroxi- drome (HES) [12].
dase, eosinophil cationic protein and eosinophil‐derived In Down syndrome, eosinophil numbers are often nor-
neurotoxin. mal but there is a higher percentage of eosinophils with
Eosinophil transit time in the blood is short (about multilobed nuclei in the bone marrow. Clonal eosino-
1 day) but they accumulate in tissues for several days. philia in Down syndrome has recently been shown to be

Extravasation is chemokine receptor 3 dependent. Thymic linked to the N‐terminal truncating mutation of GATA‐1
stromal lymphopoietin and IL‐33 are important recruiting (which has also been linked to transient leukaemia in
OF DERMATITIS
factors. Down syndrome neonates) [13].
Eosinophils undergo apoptosis in the absence of the A number of genetic syndromes may have eosinophilia
proper cytokine milieu but when activated induce as a feature, including Netherton syndrome, incontinentia
increased vascular permeability, recruit leucocytes (espe- pigmenti, Dorfman–Chanarin syndrome, trichothiodys-
cially T‐helper T cells but also prime B cells to produce trophy, hyper‐IgE syndrome, Omenn syndrome, IPEX
immunoglobulin [Ig]M) to sites of inflammation, interact (immune dysregulation, polyendocrinopathy, enteropathy,
with dendritic cells (activation, maturation and migration X‐linked) syndrome and peeling skin syndrome; also
to lymph nodes) and IgA and IgE antibodies and produce hypereosinophilic syndrome in a child mosaic for a congen-
or store mediators which are pro‐inflammatory, profibro- ital triplication of the short arm of chromosome 8 has been
genic, proangiogenic and cytotoxic (some are bacterio- described. Congenital Langerhans histiocytosis, congenital
static). In addition, neurotoxin release may account for Wells syndrome, congenital Ofuji and congenital toxoplas-
the intense itch (and sometimes pain) associated with mosis also may be associated with hypereosinophilia.
eosinophilic dermatoses. Recent studies suggest that
eosinophils may also have a role in antitumoural immune Neonatal eosinophilia
surveillance and have tumouricidal potential [1–3]. In neonates, tissue eosinophilia is seen in erythema toxi-
Furthermore eosinophils are now thought to be key par- cum neonatorum, infantile acropustulosis and transient
ticipants in innate immunity and tissue remodelling neonatal pustular melanosis.
events [4] given their ability to both store and synthesize Peripheral blood eosinophilia may be a feature of
a range of immunomodulatory factors that can be rapidly incontinentia pigmenti, but marked peripheral blood
released upon activation [5]. eosinophilia in a baby with erythroderma should arouse
In the clinical setting, in developed countries, a circulat- suspicion of an immunodeficiency, namely Omenn
ing eosinophilia most often signals an atopic condition syndrome.
(eczema, asthma, hay fever) or other allergic state (e.g. In a sick neonate, sepsis should be considered, as eosin-
drug reaction); in the East or Africa, an underlying inter- ophilia in this age group may be an indicator of sepsis
nal parasitosis is the cause until proven otherwise. and thus infection should be in the differential diagnosis
International air travel can thus spring occasional clinical of a sick neonate with eosinophilia >700/mm3.
surprises. Transient hypereosinophilia has been described in the
infant of a mother with HES.
Congenital eosinophilia
In the newborn, the blood eosinophil count is usually Infantile eosinophilia
<0.7 × 109/L, although counts of 1–2 × 109/L are seen occa- Eosinophilia is most common in food allergy and atopic
sionally in otherwise normal infants [6,7]. Cord blood dermatitis, in which tissue eosinophilia is characteristic.
contains more eosinophils and precursor cells than adult Tissue eosinophilia may also be a feature of Langerhans
peripheral blood. cell histiocytosis and annular erythema of infancy. A high
Congenital eosinophilia following intrauterine and to moderate eosinophilia is a feature of eosinophilic pus-
exchange blood transfusions is not uncommon and tular folliculitis.
occurred in 60% of neonates in one series [8]. This is Very marked peripheral blood eosinophilia in infants
thought to be the result of a hypersensitivity reaction as it must be taken seriously, as it may herald either idiopathic
can be associated with a rash, thrombocytopenia and HES or leukaemia. WT1 reverse transcription polymerase
lymphopenia. A case has recently been reported of con- chain reaction (RT‐PCR) is a useful diagnostic tool to
genital blaschkoid angiolymphoid hyperplasia with distinguish these as WT1 gene expression is increased in
eosinophilia of the anogenital region [9]. virtually all patients with acute leukaemias [14,15].
Eosinophilia in older children 17 Salomon J, Białynicki‐Birula R, Woźniak Z, Baran E. Pachydermatous

eosinophilic dermatitis. Acta Dermatovenerol Croat 2011;19:31–5.
Marked eosinophilia is seen in idiopathic HES, Kimura 18 Dierksmeier U, Frosch PJ, Czarnetzki BM. Eosinophil chemotactic
disease/angiolymphoid hyperplasia with eosinophilia factor (ECF) in blister fluid of dermatological diseases. Br J Dermatol
and hyper‐IgE syndrome (the last two are described in 1980;102:43–8.
Chapter 113).
Moderate peripheral blood eosinophilia is a feature of
Wells syndrome, eosinophilic fasciitis and Ofuji syn-
Eosinophilic pustular folliculitis
drome. The few cases of pachydermatous eosinophilic
in infancy and childhood (syn.
dermatitis are characterized by peripheral blood eosino-
Ofuji disease)
philia and pruritic papular lesions on a pachydermatous
base [16,17]. Clearly, the possibility of infestations and Brief introduction/history. Eosinophilic pustular folliculitis is
infections such as scabies and coccidioidomycosis must an uncommon disorder first described in adults by Ise and
be considered. Ofuji in 1965 [1], although the term eosinophilic pustular
Tissue eosinophilia is a feature of numerous derma- folliculitis was ascribed by Ofuji et al. in 1970 [2]. There
toses discussed elsewhere. A low‐molecular‐weight have been fewer than 70 reports of this entity in children.
chemotactic factor for eosinophils has been found in the Broadly, there are three variants: (i) classic, (ii) immu-
nosuppression‐associated, which is subdivided into
skin of patients with bullous pemphigoid, atopic dermati-

tis/eczema, drug reaction and contact sensitivity [18]. human immunodeficiency virus (HIV) and non‐HIV
associated, and (iii) infancy‐associated.
OF DERMATITIS
Other dermatoses include urticaria (Chapter 63), mycosis

fungoides (Chapter 88), graft‐versus‐host disease The classic adult disease is a rare inflammatory disease
(Chapter 157), mastocytosis (Chapter 92), vasculitides of unknown aetiology characterized by recurrent plaques
including polyarteritis nodosa and EGPA (Chapter 148), with clusters of sterile follicular pustules and papules
systemic sclerosis (Chapter 100), dermatitis herpetiformis affecting the face, trunk and limbs, mainly in Japanese
(Chapter 75), pemphigus (Chapter 8) and Langerhans cell patients. The use of the term ‘folliculitis’ has been chal-
histiocytosis (Chapter 90). lenged because hair follicles are not seen on the palms or
the soles, which may be affected.
References
There is a variation of the classic type that has been
1 Neves JS, Weller PF. Functional extracellular eosinophil granules: reported as ‘episodic eosinophilic dermatosis of the face’
novel implications in eosinophil immunobiology. Curr Opin which affects seborrhoeic areas of the face but lacks typi-
Immunol 2009;21:694–9. cal features of classic EPF such as pustule formation and
2 Minai‐Fleminger Y, Levi‐Schaffer F. Mast cells and eosinophils: the
two key effector cells in allergic inflammation. Inflamm Res peripheral extension of the lesions; it responds well to
2009;58:631–8. indometacin.
3 Blanchard C, Rothenberg ME. Biology of the eosinophil. Adv In 1984, Lucky et al. described a variant in infants that
Immunol 2009;101:81–121.
4 ShamriR, Xenakis JJ, Spencer LA. Eosinophils in innate immunity:
had its own set of characteristics, which distinguish it
an evolving story. Cell Tissue Res 2011;343:57–83. from the adult and childhood forms [3]. There is debate
5 Davoine F, Lacy P. Eosinophil cytokines, chemokines, and growth over whether the infantile form is truly a variant of the
factors: emerging roles in immunity. Front Immunol 2014;5:570. adult form or a completely separate disorder [3–15], and
6 Lawrence R Jr, Church JA, Richards W,Lipsey AI. Eosinophilia in
the hospitalized neonate. Ann Allergy 1980;44:349–52. the name eosinophilic pustulosis of the scalp has been
7 Kien CL, Chusid MJ. Eosinophilia in children receiving parenteral proposed for infants in whom the scalp is primarily
nutrition support. JPEN J Parenter Enteral Nutr 1979;3:468–9. affected [16] and there is no true follicular involvement
8 Chudwin DS, Ammann AJ, Wara DW et al. Posttransfusion syndrome.
[17,18]. In adult patients, an association with HIV infec-
Rash, eosinophilia, and thrombocytopenia following intrauterine and
exchange transfusions. Am J Dis Child 1982;136:612–14. tion and haematological malignancy or its treatment is
9 Su HH, Shan SJ, Elston DM et al. Congenital blaschkoid angiolym- well established [19–22]. There has been a single case
phoid hyperplasia with eosinophilia of the anogenital region. Am J report of HIV‐associated eosinophilic pustular folliculitis
Dermatopathol 2016;38:305–6.
10 Rioux JD, Stone VA, Daly MJ et al. Familial eosinophilia maps to
in an infant [23]. In children, the condition has not been
the cytokine gene cluster on human chromosomal region 5q31‐q33. associated with any underlying disease before or after its
Am J Hum Genet 1998;63:1086–94. diagnosis.
11 Klion AD Law MA, Riemenschneider W et al. Familial eosino-
philia: a benign disorder? Blood 2004;103:4050–5.
12 Ota M, Takenaka K, Takahashi M, Nagasaka K. Eosinophilia with Epidemiology and pathogenesis. Both the classic and
organ involvement in 3 siblings. Nihon Rinsho Meneki Gakkai Kaishi infantile forms exhibit a strong male predilection
2012;35:533–8.
13 Maroz, A, Stachorski L, Emmrich S et al. GATA1s induces hyperpro- (male : female ratio 4 : 1); however, in the 4‐ to 9‐year age
liferation of eosinophil precursors in Down syndrome transient group, which represents by far the smallest cohort, more
leukemia. Leukemia 2014;28:1259–70. cases have been reported in girls. The disease tends to
14 Menssen HD, Renkl HJ, Rieder H et al. Distinction of eosinophilic leu-
present before 14 months of life and spontaneously
kaemia from idiopathic hypereosinophilic syndrome by analysis of
Wilms’ tumour gene expression. Br J Haematol 1998;101:325–34. resolves by 3 years of age in 80% of cases. Presence at
15 Cilloni D, Messa F, Martinelli G et al. WT1 transcript amount discrimi- birth has been recorded [24]. It has a higher incidence in
nates secondary or reactive eosinophilia from idiopathic hypereo- Caucasians and is rare in Japan. Although there does not
sinophilic syndrome or chronic eosinophilic leukemia. Leukemia
2007;21:1442–50.
seem to be a familial predisposition, eosinophilic pustular
16 Jacyk WK, Simson IW, Slater DN, Leiferman KM. Pachydermatous folliculitis has been reported in two brothers, born at differ-
eosinophilic dermatitis. Br J Dermatol 1996;134:469–74. ent times, both with onset in the neonatal period [25].
The origin of this dermatosis is unknown. Currently, The study of indometacin, a potent cyclo‐oxygenase
many theories exist, particularly for the classic adult inhibitor, has provided valuable insight and potential
form, none of which has been validated. Most theories into the pathogenesis and treatment of the disease
evoke immunological mechanisms in the initiation of respectively (Fig. 24.1). It acts as a potent agonist of
lesions, particularly because of the association with atopy, CRTH2 (chemoattractant receptor‐homologous mole-
diabetes, infection (HIV, hepatitis C and Giardia), stem cell cule expressed on Th2 cells), which is a receptor for
transplantation and drugs (minocycline, allopurinol, PGD2 (prostaglandin D2). PGD2 mediates its biological
anticonvulsant therapy, timepidium bromide and activities through CTH2 receptors, including eosinophil
indeloxazine hydrochloride). Resolution of the lesions of chemokinesis and chemotaxis and degranulation
eosinophilic pustular folliculitis in a patient with (Fig. 24.1). Indometacin is thought to both desensitize
Gorlin syndrome when her jaw cyst was excised was the CRTH2 receptor and downmodulate cell surface
thought to reflect the removal of an immune dysregula- expression of both CRTH2 and CCR3 (eotaxin receptor
tory stimulus [26]. on eosinophils) and therefore reduce eosinophil responses
The presence of an eosinophilic infiltrate around to PGD2. Importantly, Th2 cells and basophils are also
and into the dermal hair follicles is hypothesized to known to express CRTH2 [29] and a basophilic infiltrate
suggest involvement of a Th2‐type response in the has also been reported in skin lesions of eosinophilic

pathogenetic mechanism and resultant IL‐4 and IL‐13 pustular folliculitis [30]. Reduction of eosinophil CRTH2
mediated eotaxin synthesis and thus eosinophil expression in association with improvement of skin
OF DERMATITIS
induction and migration. Eotaxin‐1, a highly specific lesions and reduction in blood eosinophilia has been
chemokine, is also thought to play a crucial role in observed in the context of oral indometacin treatment,
eosinophil recruitment, inflammation and tissue dam- further supporting the hypothesis of PGD2–CRTH2
age, and its autocrine production has been postulated interaction in the pathogenesis [30,31].
to account for the chronicity seen in eosinophilic pus- The presence of PGD2‐producing enzyme in hair
tular folliculitis [27,28]. follicle epithelium, dermal eccrine glands, eccrine ostia in
PPAR-γ
PGD2 Sebocyte
CRTH2
in hair
PGD2
follicle
Th2
L-PDGS
Th0
INDOM
IL-4
CCL26
IL-5
TGF-β Eotaxin-3
Dendritic IL-4
cell
TLR INDOM
PRR
Produces
HPGDS PGD2
Fc
Basophil PGD2
is
ax
ot
R
R
CRTH2 activation em
Ca2+mobilisation Ch
cell migration
CCR3
TSLP degranulation
IFN-γ Eotaxin
IL-12 CD11b
INDOM
Th1
Proinflammation
Host
protection Immunoregulation
Fig. 24.1 Eosinophil function. CCL, chemokine (C‐C motif) ligand; CRTH, chemoattractant receptor‐homologous molecule; HPGDS,
haematopoietic prostaglandin D synthase; IFN, interferon; IL, interleukin; INDOM, indometacin; L‐PDGS, lipocalin‐type prostaglandin D2
synthase protein; PGHDE, prostaglandin; PPAR, peroxisome proliferator‐activated receptor; PRR, pattern recognition receptor; TGF,
transforming growth factor; Th, T helper; TLR, toll‐like receptor; TSLP, thymic stromal lymphopoietin.
stratum corneum and epidermal keratinocytes but also face, trunk and extremities. There is a tendency for central
the acrosyringium [32] (where hair follicles are lacking) healing with peripheral extension. Scalp involvement is
around eosinophilic pustules is suggestive of local syn- present in only 6% of adult patients [38]. This classic form
thesis of PGD2 and accumulation of CRTH2‐expressing has rarely been reported in older children and adolescents
cells in the disease pathogenesis [31]. [5,36,38–48].
PGD2 also stimulates sebocyte production of eotaxin‐3 Eosinophilic pustular folliculitis in infancy appears to
(CCL26) leading to accumulation of eosinophils in seba- be a variant of this disorder and principally involves the
ceous hair follicles [33]. It is postulated that upstream scalp [3–15,25,49]. The lesions, similar to those in the
PGD2 signalling as well as downstream CCR3 signalling adult form, occur as grouped, pruritic firm papules
is implicated in the underlying accumulation of eosino- (occasionally vesicles), which evolve into follicular
phils, and indometacin mediates its effects through pustules, measuring pinpoint to 3 mm, on an erythema-
desensitization of the CRTH2 signals in eosinophils as tous base. The lesions can present as a solitary plaque or
well as through inhibition of PGD2 synthesis locally [31]. as scattered pustules throughout the scalp [23]. Unlike
An exaggerated response to skin saprophytes or der- the adult and childhood forms, annular or serpiginous
matophytes, or autoantibodies directed against the inter- plaques are not observed in infants and small children.
cellular substance of the lower epidermis [34] or the They resolve spontaneously without scarring after
cytoplasm of basal cells of the epidermis and the outer evolving through a yellow, crusted phase in approximately
sheath of hair follicles [35], has also been proposed. In 5–10 days, often leaving a 3–4 mm hyperpigmented
OF DERMATITIS
adult eosinophilic pustular folliculitis, autoimmunity macule. New crops of lesions appear approximately
against sebaceous glands has been postulated as an aetio- every 2–8 weeks. In addition to the scalp, the majority of
logical factor, especially for the classic and HIV‐related infants have involvement of the extremities, hands, feet
forms [19]; however, it is presumed that this is probably and trunk. The face [5,16,40], groin [6] and genitals [5]
not the case for the paediatric variants. may be affected. Mucosal involvement was noted in one
A case series of 15 paediatric cases published in 2013 7‐year‐old child [43]. In the infantile variant, onset is
identified a possible association with atopy [18]. Boone most likely in the first 6 months of life, with approxi-
et al. [36] described three children, two with childhood mately one quarter presenting at or just after birth [9,15].
onset and one with onset in infancy, who tested positive Spontaneous resolution occurs mostly after a total dura-
with specific immunoglobulin E (sIgE) radio‐allergosorbent tion of 3 months to 5 years. It appears that the earlier the
testing to the dust mite Dermatophagoides pteronyssinus disorder appears, the less chronic it becomes. The clini-
(DPT), suggesting a hypersensitivity reaction in the cal characteristics of eosinophilic pustular folliculitis in
pathogenesis of eosinophilic pustular folliculitis. Two of the 4‐ to 9‐year age group fall between the other groups
the three patients had neither personal nor family history in that scalp involvement is unusual, seborrhoeic areas
of atopy. are less involved than in the classic form and there are
Nitric oxide has been implicated in the pathogenesis of fewer annular and more diffuse lesions as seen in the
eosinophilic pustular folliculitis. Nitric oxide is a simple infantile form [38].
inorganic molecule that can regulate vascular tone, plate- The term necrotizing eosinophilic folliculitis has been
let aggregation and leucocyte adhesion and is implicated coined for a variant of eosinophilic folliculitis presenting
in neurotransmission, immunomodulation and with ulcerating nodules. Magro and Crowson [50]
inflammation. Neuronal nitric oxide synthase (nNOS) is described 10 patients, one of whom was an 11‐year‐old
expressed by neurons but was also found in the eosino- girl, who had in common a history of atopy and evidence
phils that infiltrate the dermis and hair follicles of patients of follicular and dermal necrosis with an eosinophilic
with eosinophilic pustular folliculitis. Similar immuno- vasculitis on biopsy of their ulcerated nodules.
histochemical findings have been described in other
eosinophilic dermatoses such as Kimura disease, leading
the authors to speculate that eosinophil‐derived nitric Differential diagnosis. The differential diagnosis for
oxide may be pathogenic in this inflammatory condition. eosinophilic pustular folliculitis in infancy should
It is postulated that nNOS can catalyse the formation of include most pustular eruptions in infancy, in particular
ONOO–, which leads to cellular and tissue injury. scalp pyoderma or infectious folliculitis caused by
Furthermore, nitric oxide and its other isoforms have Staphylococcus aureus, dermatophyte infections, sca-
been shown to reduce eosinophil locomotion and prolong bies, erythema toxicum neonatorum, transient neonatal
eosinophil survival, hence aiding their accumulation [37]. pustular melanosis, herpes simplex infection, infantile
Eosinophilic pustular folliculitis shares some histo- acropustulosis, Langerhans cell histiocytosis, incontinen-
pathological characteristics with erythema toxicum neo- tia pigmenti, hypereosinophilic syndrome and drug
natorum and some hypothesize that it may represent a eruptions. The generalized form of eosinophilic pustular
more persistent form [16]. folliculitis in adults tends to be drug induced, most often
in association with allopurinol, but carbamazepine and
Clinical features. Eosinophilic pustular folliculitis (Fig. 24.2) minocycline have also been implicated, whereas there
is characterized by recurrent crops of intensely pruritic have been no such reports in children.
annular or polycyclic plaques, composed of coalescing, When eosinophilic pustular folliculitis presents in older
sterile papulopustules on the seborrhoeic areas of the children, the differential diagnosis should include fungal,
(a) (b)

OF DERMATITIS
(c)
(d)
Fig. 24.2 Eosinophilic pustular folliculitis on the (a) scalp, (b) face, (c) trunk and (d) limbs. Note the sparing of the skin creases.
parasitic and herpetic infections, eosinophilic cellulitis, mid dermis, composed predominantly of eosinophils
insect bites, eczema, impetigo, lymphoma and drug together with neutrophils and mononuclear cells
eruptions. (Fig. 24.3). Mast cells of the tryptase‐positive chymase‐
negative subtype are moderately increased [39]. The infil-
Laboratory findings. In all age groups there is mild to trate may extend to the deep dermis [25,39,40] and
moderate leucocytosis and in 50–83% of cases eosino- subcutaneous fat [5,16]. Most cases demonstrate intersti-
philia; this is usually associated with exacerbations and tial eosinophilic flame figures between collagen bundles,
an absence of systemic symptoms [18,51]. IgE is usually representing degranulated eosinophils [5,52]. Eosinophil,
normal or marginally elevated. neutrophil and mononuclear cell exocytosis into the
A Wright’s‐stained smear of pustular contents demon- pilosebaceous unit, with spongiosis, subsequent abscess
strating abundant eosinophils may be helpful in making formation and ultimate destruction of the hair follicle, is
the diagnosis. The diagnosis is based on the clinical pres- frequently demonstrated in the adult and older paediatric
entation, associated haematological abnormalities and cases [49,53], whereas most, but not all, of the infantile
histological evidence of eosinophilic folliculitis. cases present with simply perifollicular mixed, but pre-
dominantly eosinophilic, inflammation [21]. Sebaceous
Histopathology. Histopathology of the infantile scalp glands may be infiltrated and, with follicular involve-
lesion displays a moderate to dense perifollicular and ment, the infundibulum is most affected [40]. The epidermis
periappendiceal inflammatory infiltrate in the upper and may also exhibit exocytosis, spongiosis and occasionally
(a) (b)
Fig. 24.3 Histopathology of skin biopsy taken from the child illustrated in Fig. 24.2. Source: Courtesy of Dr Nick Francis.
OF DERMATITIS
eosinophilic subcorneal pustules, parakeratosis or crust Responses to oral antibiotics (penicillin G, erythromycin,
[5,9]. The scalp is the preferred biopsy site in infants, as it cephalexin) have been variable [3,13,16,40].
is invariably affected in this age group and consistently In adults, it has been suggested that nonsteroidal
yields a specific histological picture [16,40]. Follicular anti‐inflammatory drugs such as indometacin and nap-
mucinosis, mycosis fungoides and other cutaneous T‐cell roxen are the agents of choice [16,57]. Both topical and
lymphomas are important to consider in the histopatho- oral (0.4 mg/kg) indometacin have been successfully
logical differential diagnosis. used for refractory infantile cases [58,59]. It is not advisa-
ble to use indometacin in children; it is unlicensed in the
Treatment. Because of the rarity of eosinophilic pustular UK, has a high incidence of side‐effects including head-
folliculitis, there have been no controlled clinical trials for ache, dizziness, and gastrointestinal disturbances, and
its treatment in adults or children. In addition, its recur- children may be more sensitive to serious liver problems.
rent and self‐limited features, especially in infants, make In patients with HIV‐associated disease, there is generally
evaluation of anecdotal treatments difficult. a good response to antiretroviral therapy, but eosinophilic
Antihistamines are indicated for associated pruritus, pustular folliculitis can occur with immune reconsti-
and there may be a role for the eosinophil antimigration tution. Other treatment options include topical and
drugs such as cetirizine dihydrochloride [6,54] and systemic steroids, isotretinoin, dimethyl diphenyl
ketotifen. Dose‐dependent response to hydroxyzine has sulfone, sulfamethoxazole, oxyphenbutazone, minocycline,
also been reported [24], but concerns regarding prolon- doxycycline, metronidazole, itraconazole, cyprohepta-
gation of the QT interval with this sedating antihista- dine, colchicine, glycyrrhizin, interferon‐α2b, interferon‐γ
mine should be heeded in infants and young children. and ciclosporin. Topical permethrin 5% cream, transdermal
The H2 antagonist cimetidine was used with success in a nicotine patches and, for the acquired immunodefi-
9‐month‐old girl [55]. ciency syndrome (AIDS)‐associated variety, phototherapy
A large comprehensive analysis of therapeutic (PUVA [psoralens and ultraviolet A] and narrow‐band)
responses by Nomura et al. [56] reported on 115 regimens may be successful [40,60]. Radiation was helpful in a
used in infantile eosinophilic pustular folliculitis. The recalcitrant case [61].
review showed that topical steroids were highly effica- Monitoring of children with infantile eosinophilic
cious in the majority of cases (n = 50, efficacy 82%). pustular folliculitis is advised as it may rarely be the
Tacrolimus was associated with the highest clearance rate presenting complaint of hyper‐IgE syndrome. Some
in a small number of children. Carbon light and topical children went on to develop hyper‐IgE syndrome an
tacalcitol have also been tried without reports on efficacy. average of 18 months later [62,63], but these children had
Combination therapies, such as antihistamines with topi- associated systemic features.
cal indometacin or topical steroids, or systemic antimicro-
bials with topical steroids, have also been used in infants.
Dapsone, at a dose of 2 mg/kg per day, was effective in References
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folliculitis: report of the first British case. Eur J Dermatol 1997;7:385–7. tular folliculitis. Report of two cases with a review of the Japanese
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Hypereosinophilic syndrome [5–7] and lungs [8]. The muscles [9], gastrointestinal
tract [10–13], eyes, nasopharynx [14], bone marrow and
Brief introduction. The normal eosinophil count in the central nervous system [15–18] may be involved.
peripheral blood ranges from 50 to 500 × 109/L. Rarely, the kidneys [19] and bladder [20] are involved.
Eosinophilia can be divided into mild eosinophilia (up to 3 Exclusion of known primary and secondary causes of
1500 × 109/L) and marked eosinophilia (>1500 × 109/L). eosinophilia.
Recent advances in cytogenetics, immunology and
molecular biology have led to the re‐classification of Epidemiology and pathogenesis. Although HES is rare
hypereosinophilia (HE) as follows [1–3]: in childhood (mean age of onset 37 years), in the series
1 Familial (hereditary); reported by Alfaham 16 of the 18 children had cardiac
2 Of undetermined significance (unexplained, persistent, involvement; untreated, this carries a high mortality [21].
asymptomatic eosinophilia) (in lieu of the previous term There is a male to female ratio of 1.47.
idiopathic hypereosinophilia); HES is an important syndrome to recognize because
3 Primary (clonal/neoplastic, where eosinophils are con- eosinophilic infiltration of the cardiac tissue induces
sidered neoplastic); and endomyocardial thrombosis and fibrosis and resultant
4 Secondary (reactive, to an underlying condition with restrictive cardiomyopathy, valvular dysfunction and
cytokine‐driven eosinophilia, such as parasitic or viral increased thrombotic tendency as well as aneurysmal
infections, allergic diseases, drug‐ or chemical‐induced disease [22–24].
OF DERMATITIS
eosinophilia, hypocortisolism and neoplasms). It is still not clear whether eosinophils themselves or
‘Hypereosinophilic syndrome’ (HES) is a term reserved for their precursors are abnormal in HES, or whether there is
any variant with blood eosinophilia and clear evidence of a problem in the regulatory mechanism of eosinophil
end‐organ damage and is a multisystem disease with a high production.
mortality rate. It is usually considered a provisional diagno- The Splendore–Hoeppli phenomenon (presence of
sis until a primary or secondary cause for eosinophilia is asteroid bodies) may occur in HES. This phenomenon is
identified. An absolute eosinophil count of >1500/mm3 well recognized as a pathological response to infection
must be present on two occasions 1 month apart and some and has been described with fungi (including sporotri-
authorities suggest that the eosinophilia should persist for chosis, Pityrosporum folliculitis, zygomycosis, candidiasis,
at least 6 months before this diagnosis is established. aspergillosis and blastomycosis), bacteria (botryomyco-
Similar to HE, HES is classified as follows: sis, nocardiosis and actinomycosis) and parasites (includ-
1 Idiopathic HES, a diagnosis of exclusion, where there is ing orbital pythiosis, strongyloidiasis, schistosomiasis
end‐organ damage attributable to HE but no underly- and cutaneous larva migrans). It can also occur around
ing cause for HE, including a reactive or neoplastic biologically inert substances (in HES and allergic conjunc-
condition. tival granulomas).
2 Primary (neoplastic), where there is an underlying stem It is thought to represent the in vivo formation of
cell, myeloid or eosinophilic neoplasm classified intensely eosinophilic material which produces radiating,
according to WHO guidelines and end‐organ damage star‐like, asteroid or club‐shaped configurations (around
attributable to HE. In this case eosinophils are consid- microorganisms or inert material). The Splendore–
ered neoplastic. Hoeppli reaction material is made up of antigen–antibody
3 Secondary (reactive), where there is an underlying non‐ complexes, tissue debris and fibrin and is thought to be a
neoplastic or paraneoplastic condition responsible for localized immunological response to an antigen–antibody
the production of nonclonal eosinophils. Eosinophils in precipitate related to fungi, parasites, bacteria or inert
this group are usually cytokine (most often IL‐5) driven materials. It is thought that this reaction prevents phago-
and end‐organ damage is attributable to HE. The lym- cytosis and intracellular killing of the insulting agent,
phoid variant (L‐HES) is a form of reactive HES, but the leading to chronicity of infection [25].
lymphocytes show an aberrant phenotype (CD3‐CD4+),
and sometimes associated with monoclonality of T cells. Clinical features. Presentation may be with an asympto-
Therefore, if there is no end‐organ damage and no under- matic eosinophilia in as many as 10% of cases, but angi-
lying cause is identified, ‘eosinophilia of undetermined oedema or muscle pains was the presenting feature in 14%
significance’ is the preferred diagnosis. If there is end‐ of the National Institutes of Health (NIH) series, whereas
organ damage, ‘idiopathic hyper‐eosinophilic syndrome’ a rash or fever was the main problem in another 12% [26].
is a diagnosis of exclusion. Tiredness, excessive sweating, cough, breathlessness and
The most recent diagnostic criteria for idiopathic HES retinal lesions are other common presentations.
are as follows [4]: The most common cutaneous features are urticarial and
1 Peripheral blood eosinophilia more than 1.5 × 109/L on include erythematous, pruritic maculopapules and
at least two occasions 1 month apart, and/or tissue nodules [27], angioedema [28,29] or urticarial plaques
hypereosinophilia. (Fig. 24.4). Immediate‐pressure urticaria has been observed
2 Organ damage and/or dysfunction attributable to tis- in some patients. Dermographism may be marked but is
sue hypereosinophilia. Symptoms and signs of end‐ not correlated with other features of the disease.
organ involvement with eosinophil tissue infiltration/ Eczematous changes and erythroderma can be seen,
injury of the skin and principally the heart (40–70%) but there are no features distinguishing them from other
(a) (b)

Fig. 24.4 Idiopathic hypereosinophilic syndrome extensive papular eruption with perifollicular accentuation affecting the torso and arms with postinflam-
matory hyperpigmentation.
OF DERMATITIS
(a) (b)
Fig. 24.5 Haematoxylin–eosin low and high power. Nonspecific chronic dermatitis with tissue eosinophilia and pigmentary incontinence. Source: Merika
et al. [22]. Reproduced with permission of John Wiley & Sons.
types of eczema. However, some case reports have indi- youngest child was 5, and three other patients were aged
cated that eosinophilic cellulitis [20,30], cutaneous 18 or under.
necrotizing eosinophilic vasculitis [31], Raynaud phe-
nomenon [31,32], superficial thrombophlebitis, cutaneous Differential diagnosis. Eosinophilia may be due to parasitic
ulceration as a result of dermal arteriole thrombosis [33], infection, tumours and hypersensitivity. These some-
and digital gangrene [34,35] may also occur as cutaneous times only become apparent at a later date.
features of HES. A recent case report suggested that juve- Investigations to exclude clonality and lymphoprolif-
nile temporal arteritis of unknown cause may also be a erative disorders are also required as HES is a diagno-
manifestation of HES. Juvenile temporal arteritis is char- sis of exclusion.
acterized by an asymptomatic nodule in the temporal A child with an eosinophilia of >1500/mm3 on at least
artery area in young adults. Histologically, the lesion is two occasions 1 month apart and/or persisting for
characterized by a significant intimal thickening with 6 months and/or with tissue eosinophilia should be
moderate eosinophilic infiltrates, constriction or occlu- investigated (Fig. 24.6).
sion of the vascular lumen and absence of giant cells [32]
(Fig. 24.5). Secondary (reactive causes)
In a review of the lymphoid variant of HES in the These patients have an underlying inflammatory, neo-
French population [36], 81% had skin manifestations, plastic or other condition causing hypereosinophilia.
with associated lymphadenopathy (62%), rheumatologi- Nevertheless an underlying haematopoietic neoplasm
cal (29%), gastrointestinal (24%), pulmonary (19%), neu- producing clonal eosinophils must be excluded by histo-
rological (10%) and cardiovascular (5%) involvement. The pathological, cytogenetic and molecular analysis.
Screen for reactive causes

Atopic or allergic disease Neoplasia
Total and specific lgEs Immunoglobulins
as appropriate Protein electrophoresis
Blood film
Other infections
Syphilis serology Parasitosis
TB Elispot/mantoux Stool OCP
Borrelia serology Strongyloides
EBV Medications
EBV lgG/lgM and PCR
If negative
Screen for: Screen for:

FIP1L1-PDGFRA by FISH or RT-PCR Abnormal T-cell immunophenotype
OF DERMATITIS
Bone marrow aspirate and biopsy with and/or in vitro Th2 cytokine production Fig. 24.6 Algorithm for investigating a child with
cytogenetic analysis (lymphocyte variant) hypereosinophilia of >1500/mm3 on at least two
Reciprocal translocations Other clonal or molecular abnormality, occasions 1 month apart. EBV, Epstein–Barr virus;
clonal eosinophils and,or increased FISH, fluorescence in situ hybridization; Ig,
4q12(PDGFRA), 5q31-q33 (PDGFRB)
marrow blasts (0.5–20%) in chronic immunoglobulin; OCP, ova, cysts and parasites;
or 8p11-12 (FGFR1) in myeloid and
eo leukaemia or WHO defined myeloid PCR, polymerase chain reaction; RT‐PCR, reverse
lymphoid neoplasms
neoplasm with associated eosinophilia transcription polymerase chain reaction; TB,
tuberculosis.
Reactive causes include: lymphomyeloproliferative disease. One study has identi-

• Common atopic allergic diseases. fied immunoglobulin heavy chain rearrangement as a fre-
• Parasites/helminth infections. quent molecular feature of paediatric HES and an
• Epstein–Barr virus (EBV) infection: EBV has recently association with B‐cell clonal expansion and subsequent
been implicated as a cause of lymphocyte‐mediated HE B‐cell malignancies in children [38].
(see Section 8).
• Drug‐induced eosinophilia (allergic or toxic).
• Other infectious agents: syphilis, tuberculosis, coccidi- Primary (clonal) eosinophilia (HES‐N)
oidomycosis, Borrelia burgdorferi, allergic bronchopul- Haematopoietic neoplasms producing HE are usually,
monary aspergillosis and even neuroborreliosis [37]. but not always, associated with a molecular or cytoge-
• Chronic graft‐versus‐host disease. netic marker (as proof of clonality).
• Indolent systemic mastocytosis. • Myeloid, lymphoid and haematopoietic stem cell
• Chronic inflammatory disorders such as irritable bowel neoplasms:
disease. • PDGFRA‐rearranged neoplasms (4q12 translocation)
• Autoimmune diseases. • PDGFRB‐rearranged neoplasms (5q31–q33 translocation)
• Hypocortisolism – salivary cortisol is a useful measure • FGFR1 (8p11–12 translocation)
but clues may be present with hyperkalaemia, • Others: JAK2 fusion gene, FLT3 fusion gene
hyponatraemia, hypoglycaemia, hypercalcaemia and a without chromosomal or gene defect
leucocytosis (due to eosinophilia, lymphocytosis and with a nonspecific chromosomal/gene defect.
sometimes accompanied by neutropenia). In some • Eosinophilic leukaemia
cases hypothyroidism and hyperprolactinaemia may • WHO‐defined myeloid neoplasm with HE:
occur. BCR/ABL1+ chronic myeloid leukaemia
• Neoplasia: JAK2 V617F+ myeloproliferative neoplasms
Hodgkin disease KIT D816V+ systemic mastocytosis
B‐ or T‐cell lymphoma/leukaemia CBFB fusion gene‐related acute myeloid leukaemia
solid tumours/malignancy Myelodysplastic syndrome with HE
Langerhans cell histiocytosis. Other WHO‐defined myeloid neoplasms with HE.
In certain haematopoietic neoplasms, such as Hodgkin All patients in whom a neoplastic HES is being consid-
lymphoma, T‐cell lymphoma and B‐lymphoblastic leu- ered should receive histopathological, cytogenetic and
kaemia/lymphoma (with certain molecular defects, such molecular analysis by fluorescence in situ hybridization
as the translocation t(5;14)(q31;q32) that induces hypere- (FISH) or reverse transcription polymerase chain reaction
osinophilia), HE may be reactive. (RT‐PCR), bone marrow aspirate and biopsy with cytoge-
Early identification of HES in the paediatric population netic analysis and evaluation for reciprocal translocations
is of paramount importance as it may evolve towards a or other gene defects.
If the above investigations are negative, proceed to When treatment is necessary, then glucocorticosteroids
screening for the lymphoid variant of HES (L‐HES). This are the first‐line treatment [41] although the skin manifes-
includes abnormal T‐cell immunophenotype and/or in tations may be responsive to montelukast and ketotifen.
vitro Th2 cytokine production. This results in IL‐5 over- The response to corticosteroids is variable, but a rapid
production, which is key in eosinophil activation. The response to prednisolone, especially with a rapid reduc-
expansion of the abnormal T‐cell subset is usually asymp- tion in peripheral blood eosinophilia, is a good prognostic
tomatic but a few cases evolve to a T‐cell lymphoma. indicator, along with a high IgE level and a history of
Importantly, Lefevre et al. observed that nearly half of the angioedema. In adults, the usual starting dose is 1 mg/kg
patients were atopic before CD3‐CD4+ L‐HES diagnosis prednisolone with tapering to the lowest dose maintain-
[36]; their report highlights the fact that L‐HES should be ing remission. For isolated cutaneous involvement lower
considered in atopic patients who have HE. Changes in starting doses can be used (e.g. 0.5 mg/kg).
skin lesions, appearance of new symptoms (i.e. gastroin- Although in general patients with HES do not respond
testinal, rheumatological, pulmonary symptoms) and/or to the tyrosine kinase (TK) inhibitor imatinib mesylate at
appearance of marked HE in atopic patients should lead doses used in chronic eosinophilic leukaemia (CEL), there
to consideration of HES, and notably L‐HES. The majority have been almost 50 adult case reports of its successful
of these patients have a persistent CD3‐CD4+ T‐cell sub- use in FIP1L1–PDGFR α‐negative HES. Adults have also

set on blood T‐cell phenotype. Seventy six percent had a been treated with other TK inhibitors, and dasatinib, nilo-
clonal TCRγδ gene rearrangement [36]. Two other immu- tinib, sorafenib and etoposide proved helpful when other
OF DERMATITIS
nophenotypes are more frequent: CD3+CD4+CD7‐ and treatments, including imatinib, had failed.
CD3+CD4+CD8‐TCRαβ+. It is, however, notable that imatinib mesylate has been
Progression to T‐cell lymphoma is rare but L‐HES may associated with a variety of adverse cutaneous reactions,
evolve to: including urticaria, maculopapular exanthem, acute gen-
• Hodgkin lymphoma. eralized exanthematous pustulosis (AGEP), exfoliative
• Cutaneous T‐cell lymphoma. dermatitis and Stevens–Johnson syndrome.
• Angioimmunoblastic T‐cell lymphoma. In patients with steroid resistance, or if a steroid‐sparing
• Mediastinal T‐cell anaplastic lymphoma kinase (ALK) agent is required (e.g. if requiring more than 8 mg predni-
negative systemic anaplastic large‐cell lymphoma has solone/day maintenance), options include hydroxycarba-
been reported in a 2.5‐year‐old boy with HES [39]. mide [42–45], ciclosporin [36,46,47], interferon‐α [42] and
• B‐lymphoblastic lymphoma. Overproduction of IL‐3 mepolizumab [48], dapsone, sodium cromoglicate,
may also be an important factor in the induction of suplatast tosilate [49], cyclophosphamide, vincristine
eosinophilia. Bomken et al, describe a child with eosin- [50–53], L‐asparaginase [52] and 6‐mercaptopurine [51].
ophilia and Loeffler endocarditis who subsequently Infliximab or the humanized monoclonal antibodies to
developed a B‐lymphoblastic lymphoma and was IL‐5 and CD52 (alemtuzumab, reslizumab) have recently
found to have an IL3/IgH@ fusion in the cutaneous lym- shown efficacy as steroid‐sparing agents in HES
phoma cells [40]. [36,54–56].
Immunoglobulin heavy chain (IGH) clonality can In newly diagnosed symptomatic children with evi-
precede a B‐cell lymphoma in children with eosino- dence of acute life‐threatening complications involving
philia. Rapanotti et al. reported five children who vital organs, corticosteroids are the recommended first‐
showed IGH clonality at presentation: of these, two line option followed by vincristine [57]. In adults with
developed a B‐cell non‐Hodgkin lymphoma and a severe disease or refractory to all other treatments, both
B‐lineage acute lymphocytic leukaemia at 6 and bone marrow transplantation and stem cell transplanta-
12 months respectively, two spontaneously reverted tion have been successful.
to a polyclonal IGH profile during the follow‐up,
and the last one persisted with HES without B‐clonal References
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ing as cutaneous necrotizing eosinophilic vasculitis and Raynaud’s
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Eosinophilic cellulitis (Wells syndrome)
32 Ito K, Hara H, Okada T, Terui T. Hypereosinophilic syndrome with
various skin lesions and juvenile temporal arteritis. Clin Exp Dermatol Brief history/introduction. This syndrome was first
2009;34:e192–5. described by Wells [1] in 1971 as ‘a changing symptom
33 Oppliger R, Gay‐Crosier F, Dayer E, Hauser C. Digital necrosis in a
patient with hypereosinophilic syndrome in the absence of cutaneous
complex with a phase of the disease characterized by
eosinophilic vasculitis. Br J Dermatol 2001;144:1087–90. episodes of acute eosinophilic cellulitis followed by granu-
34 Funahashi S, Masaki I, Furuyama T. Hypereosinophilic syndrome lomatous dermatitis with its distinctive histopathology’.
accompanying gangrene of the toes with peripheral arterial occlu-
sion—a case report. Angiology 2006;57:231–4.
Epidemiology and pathogenesis. This is a rare condition,
35 Hamada T, Kimura Y, Hayashi S et al. Hypereosinophilic syndrome
with peripheral circulatory insufficiency and cutaneous micro- with some 100 cases reported in the literature, and fewer
thrombi. Arch Dermatol 2007;143:812–13. than 50 paediatric cases [2–9]. Both sexes are equally
affected. Two cases of congenital eosinophilic cellulitis

have been documented [10,11] and familial eosinophilic
cellulitis associated with short stature and mental retar-
dation has been recorded [12].
It is postulated that different triggers, such as insect
[6,8,13] and spider [13] bites, viral infections (particularly
mumps, molluscum contagiosum and varicella) [14], bac-
terial, fungal and parasitic (onchocerciasis) infection,
rheumatoid arthritis and Raynaud disease, as well as
drug eruptions (in particular antibiotics [2], cholesterol‐
lowering drugs, local anaesthetics) and vaccinations
[15,16], surgery and cryosurgery [17] may induce a hyper-
sensitivity reaction with eosinophil‐induced cytotoxicity
of collagen and histiocytic phagocytosis as a response to
the damage. A recent study reported high prevalence of Fig. 24.7 A child with Wells syndrome. Note the urticaria‐like plaques
atopy in affected children serving as a predisposing envi- resembling cellulitis with some blistering.

ronment for an eosinophil‐rich inflammatory response to
these triggers [18]. In adults, there is a recognized associa-
OF DERMATITIS
tion with haematological malignancy, and there have Milder cases have multiple annular or circinate erythe-
been three case reports of eosinophilic cellulitis associated matous plaques with infiltrated borders persisting and
with non‐haematological malignancy: a 42‐year‐old recurring over a few years. Erythematous papulonodular
patient with a squamous cell carcinoma, a 79‐year‐old lesions with a faint punctate erythema at another skin site
woman with a squamous cell carcinoma of the bronchus, were noted in one patient and, in another, scaling (mycol-
a 58‐year‐old with renal cell carcinoma and a 17‐year‐old ogy negative) of the feet was associated with scaly, itchy
girl with nasopharyngeal carcinoma [19,20]. Histological annular lesions resembling granuloma annulare, which
features of Wells syndrome within a mastocytoma have showed the histology of eosinophilic cellulitis.
been reported [21].
IL‐5 and eosinophil cationic protein (ECP) have been Differential diagnosis. Annular erythema of infancy is a
implicated in the pathogenesis. Levels of IL‐5 and ECP rare entity first described by Peterson and Jarratt in 1981
are elevated in blister fluid and the elevation in the blood [24]. Kunz et al. [25] demonstrated a predominantly
and marrow of patients with eosinophilic cellulitis corre- perivascular eosinophilic infiltrate but no peripheral
lates with disease activity [12,22]. Furthermore, Plotz eosinophilia. Clinically the lesions start as nonpruritic
et al. [23] reported evidence of spontaneous overproduc- erythematous papules and progress within weeks to
tion of IL‐5 by lymphocytes (predominantly of the gyrate and annular erythematous, often urticated, lesions.
CD3+CD4+ T‐cell phenotype) in a patient with eosino- The condition shows a relapsing course and may remit for
philic cellulitis. several months. Spontaneous resolution occurs; response
to systemic steroids, antimalarial therapy [26], dapsone,
Clinical features. Patients are generally well but may be nicotinamide, indometacin and UVB [27] has been
febrile, and occasionally there is general malaise and reported.
arthralgia. Presentation can be abrupt, especially in Peripheral blood eosinophilia is a feature of eosino-
severe cases with single or multiple lesions that itch or philic cellulitis, but is not usually sufficiently severe or
cause a tender burning sensation. Lesions spread rap- persistent to cause confusion with HES. Furthermore, the
idly and evolve over a few weeks, and often recur over lack of multisystemic involvement and the presence of
many months. Lesions begin as red plaques or, less flame figures (which are not seen in the cutaneous lesions
commonly, nodules that clinically resemble urticaria of HES, although perivascular eosinophil and monocyte
and cellulitis, often with some blistering, and are haem- infiltration can be marked) help to differentiate these
orrhagic in some cases (Fig. 24.7). As the lesions extend conditions.
rapidly, they often demonstrate blue central discoloura- Serological tests for Toxocara should be carried out to
tion and a peripheral red rim, and are sometimes pain- exclude this infection. Heiner and Kevy [28] described a
ful at the outset. The skin is not generally hot to the child with itchy papular erythema due to Toxocara canis
touch. Lesions undergo gradual resolution over about larva migrans infection and the biopsy showed dermal
4–8 weeks and often develop a greenish hue and firm infiltration of eosinophils and histiocytes with areas of
induration before resolving. Generally there is no scar- ‘fibrinoid degeneration of collagen’. Rook and Staughton
ring, although postinflammatory hyperpigmentation is [29] similarly observed perivascular and fat infiltration by
common, but atrophic alopecia was observed following eosinophils and histiocytes in an adult patient with
scalp involvement in an 11‐year‐old boy [3]. Any site toxocariasis and infiltrated skin lesions. The resolving
can be involved. Mucosal involvement with tongue lesions may resemble morphoea. EGPA is differentiated
swelling and throat swelling was a feature in Wells’ clinically by the systemic onset, the less favourable out-
original cases. Lesions following Blaschko’s lines have come and histologically by the presence of a true vasculi-
been described. tis. Clinically, the lesions tend to be purpuric, with tender
(a) (b)
OF DERMATITIS
(c)
Fig. 24.8 Histology of Wells syndrome.
subcutaneous nodules and cutaneous infarcts rather than In cases subjected to direct immunofluorescence (IMF),
urticarial/cellulitic lesions. However progression from perivascular C3, IgM and IgA have been observed.
Wells syndrome to EGPA has been reported in the litera- Dermal fibrin may also stain positively. Electron micros-
ture [20,30]. copy reveals eosinophil granule‐coating collagen fibres in
the flame figures.
Laboratory findings/histopathology. Where there is blis-
tering, it is subepidermal and crowded with eosinophils. Treatment. Often, no treatment is necessary. Cetirizine [33],
There is marked dermal oedema and infiltration with low‐dose corticosteroids [2,7,34], antimalarials [35], dap-
eosinophils and phagocytic histiocytes together with scat- sone [36] or ciclosporin can be helpful if needed for resistant
tered ‘flame figures’ in the mid to deep dermis, which cases. Steroid‐recalcitrant bullous eosinophilic cellulitis in a
consist of a core of collagen and eosinophilic debris sur- child was successfully treated with dapsone [37].
rounded by eosinophils, palisading histiocytes and, in
established lesions, foreign body‐type giant cells
(Fig. 24.8). The collagen appears to be displaced rather References
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32 Peters MS, Schroeter AL, Gleich GJ. Immunofluorescence identifi-
cation of eosinophil granule major basic protein in the flame fig- counter essential amino acids such as L‐tryptophan (and its
ures of Wells’ syndrome. Br J Dermatol 1983;109:141–8. metabolite quinolinic acid).
33 Aroni K, Aivaliotis M, Liossi A, Davaris P. Eosinophilic cellulitis in a child Case reports have emerged of eosinophilic fasciitis
successfully treated with cetirizine. Acta Derm Venereol 1999;79:332.
34 Gilliam AE, Bruckner AL, Howard RM et al. Bullous “cellulitis”
occurring as a rare complication of haemodialysis, radio-
with eosinophilia: case report and review of Wells’ syndrome in therapy, stem cell transplantation and allogeneic bone
childhood. Pediatrics 2005;116:e149–55. marrow transplantation.
Familial cases have emerged [3,4] and a purported role Bone marrow biopsy may reveal plasmocytosis and
for HLA‐A2 suggested. eosinophilia and, rarely, aplastic anaemia and thrombocy-
There is no apparent racial predisposition. There is a topenia occur.
female preponderance in children. Over 100 cases have A deep biopsy including muscle fascia is necessary for
now been reported, the youngest patient being only diagnosis. Magnetic resonance imaging and fluorodeoxy-
1 year old [2,5–16]. glucose positron emission tomography have proved use-
ful both in diagnosis and in monitoring progress of the
Clinical features. Painful swelling of the distal part of the disease [19,20].
limbs, progressing to symmetrical indurated lesions that On histology, there is dermal sclerosis with inflamma-
limit movement although the hands and feet are usually tion and fibrosis of the fat and deep fascia. The fascia
spared, is the usual presentation. Occasionally the face, becomes thickened, with collagen hypertrophy and infil-
abdomen and hands and feet are affected [3]. There may tration by lymphocytes, plasma cells, histiocytes and
be superficial blistering and haemorrhage. Peau d’orange eosinophils. Lack of new collagen deposition in early
surface changes and erythema are seen and the ‘groove’ lesions distinguishes this from scleroderma.
sign with depression of the veins is a useful clue [16]. Immunofluorescence demonstrates IgG and C3 in
Rarely, pitting oedema symmetrically affecting the arms the deep fascia. The serum of these patients contains a
as well as the legs can be the first sign. serum factor that suppresses in vitro myeloid and
Fever, myalgia and weight gain may be a feature. erythrocyte precursors and factors with eosinophil
OF DERMATITIS
Raynaud phenomenon and nailfold capillary defects are chemotactic activity [21]. Serum levels of the tissue
not usually a feature, although Quintero‐Del‐Rio et al. inhibitor of metalloproteinase 1 (TIMP‐1) are elevated
[17] argued that Raynaud phenomenon and hepatosple- and positive staining for TIMP‐1 is observed in the fas-
nomegaly can occur in the spectrum of childhood eosino- cia of affected patients. Furthermore, serum TIMP‐1
philic fasciitis. Myalgia and arthralgia may be experienced levels in patients with eosinophilic fasciitis were sig-
but polyarthritis is rarely associated. Established cases nificantly correlated with serum γ‐globulin and IgG
may have joint contractures [10]. Development of aplastic levels, suggesting that TIMP‐1 is involved in the patho-
anaemia is reported more commonly than by chance and genesis, and that it may be a useful marker for disease
isolated chronic severe neutropenia unresponsive to activity as well as serum γ‐globulin or IgG levels [22].
granulocyte colony‐stimulating factor has occurred. Pro‐inflammatory and fibrogenic cytokine responses
Internal organs are not usually involved although peri- including IL‐5, CD‐40 ligand, transforming growth fac-
carditis, pulmonary fibrosis and reduced pulmonary dif- tor β1 and interferon‐γ are postulated to result in
fusion capacity, primary biliary cirrhosis, oesophageal inflammatory cell infiltration that dysregulates pro-
hypokinesia, eosinophilic colitis and intestinal pseudo‐ duction of extracellular matrix proteins and increases
obstruction, nephritis [13], myositis and haemorrhagic collagen production by fibroblasts which ultimately
stroke with cerebral vasculitis have been reported in asso- leads to progressive fibrosis of affected tissues [23].
ciation with eosinophilic fasciitis.
Treatment. There is no generally accepted effective treat-
Differential diagnosis. Early disease can mimic angi- ment. Many patients will respond to systemic steroids
oedema [3]. The differential diagnosis of more established (prednisolone or pulsed methylprednisolone) [5,10,12,15].
disease includes morphoea profunda, disabling panscle- Spontaneous remission can occur so that more aggressive
rotic morphoea of children, amyotrophic lateral sclerosis, treatments should only be used in recalcitrant cases.
sclerodermatous graft‐versus‐host disease, nephrogenic Individual patients have responded to antihistamines,
systemic fibrosis (nephrogenic fibrosing dermopathy), including cetirizine, ketotifen, hydroxyzine [14], cimeti-
scleromyxoedema, scleroedema, fasciitis panniculitis dine, isotretinoin, chloroquine and hydroxychloroquine,
syndrome, eosinophilia myalgia syndrome and cutane- sulfasalazine, dapsone, d‐penicillamine, cyclophospha-
ous amyloidosis. mide, methotrexate [3,5], ciclosporin, tacrolimus, azathio-
prine, mycophenolate mofetil [24], colchicine, infliximab
Laboratory and histology findings. Peripheral blood [3,6] and rituximab. Phototherapy (bath PUVA and
eosinophilia, up to 30%, is observed in the majority (65– UVA‐1) and extracorporeal photochemotherapy can be
80% of cases) but is transient and thus not necessary for beneficial.
diagnosis. The sedimentation rate is raised and there is In adults, Mendoza et al. [25] concluded that the early
hypergammaglobulinaemia. Serum aldolase may be ele- introduction of antifibrotic treatment offered better out-
vated, but creatinine phosphokinase is normal. comes following a prospective but non‐randomized trial
Cytoplasmic antineutrophil cytoplasmic antibodies of d‐penicillamine in conjunction with corticosteroids.
(c‐ANCA) and anti‐nuclear and thyroid antibodies may Residual fibrosis is more common in childhood‐
be positive. Hypercalcaemia for which no other cause was onset eosinophilic fasciitis, particularly where there
found, but which resolved with treatment of the eosino- are morphoea‐like skin changes and truncal
philic fasciitis, has been reported in one adolescent [18]. involvement [9,26].
References
1 Schulman H, Hertzog L, Zirkin H, Hertzanu Y. Cerebral sinovenous
Eosinophilic panniculitis
thrombosis in the idiopathic hypereosinophilic syndrome in child-
hood. Pediatr Radiol 1999;29:595–7. Brief introduction. There is some controversy as to
2 Doyle JA, Connolly SM, Hoagland HC. Hematologic disease in scle- whether eosinophilic panniculitis is a distinct entity or
roderma syndromes. Acta Derm Venereol 1985;65:521–5.
3 Poliak N, Orange JS, Pawel BR, Weiss PF. Eosinophilic fasciitis mim-
represents a reaction pattern to an underlying systemic
icking angioedema and treatment response to infliximab in a pediat- condition. The original patient reported by Burket and
ric patient. Ann Allergy Asthma Immunol 2011;106:444–5. Burket [1] presented with asymptomatic subcutaneous
4 Sullivan C, Coughlan R. Eosinophilic fasciitis in siblings. J Rheumatol swellings that histologically showed eosinophilic lobular
2013;40:105.
5 Ortega‐Loayza AG, Merritt BG, Groben PA, Morrell DS. Eosinophilic and septal panniculitis with flame figures. The lesions
fasciitis in a female child. J Am Acad Dermatol 2008;58:S72–4. underwent spontaneous resolution within days.
6 Tzaribachev N, Holzer U, Schedel J et al. Infliximab effective in ster- Subsequent cases have had a similar presentation, includ-
oid‐dependent juvenile eosinophilic fasciitis. Rheumatology (Oxford)
ing a 6‐year‐old boy reported by Samlaska et al. [2] in
2008;47:930–2.
7 Antic M, Lautenschlager S, Itin PH. Eosinophilic fasciitis 30 years whom other causes of eosinophils in the skin and subcutis
after ‐ what do we really know? Report of 11 patients and review of were excluded.
the literature. Dermatology 2006;213:93–101.
8 Pillen S, van Engelen B, van den Hoogen F et al. Eosinophilic fasciitis in
a child mimicking a myopathy. Neuromuscul Disord 2006;16:144–8. Epidemiology and pathogenesis. The exact pathogenesis

9 Farrington ML, Haas JE, Nazar‐Stewart V, Mellins ED. Eosinophilic remains unclear but the entity is thought to be associated
fasciitis in children frequently progresses to scleroderma‐like cuta- with the atopic diathesis, heightened allergic reactivity or
OF DERMATITIS
neous fibrosis. J Rheumatol 1993;20:128–32.
infection of the gastrointestinal tract. It has also been
10 Huppke P, Wilken B, Brockmann K et al. Eosinophilic fasciitis leading
to painless contractures. Eur J Pediatr 2002;161:528–30. reported in advanced HIV disease. An antigenic trigger in
11 Huemer M, Seeber A, Huemer C. Scleroderma‐like syndrome in a the setting of underlying immunodeficiency may trigger
child: eosinophilic fasciitis or scleredema adultorum? Eur J Pediatr an altered immune response with excess IL‐4 and IL‐5
2000;159:520–2.
12 Balat A, Akinci A, Turgut M et al. Eosinophilic fasciitis—progression
production and eosinophil drive. It is seen more fre-
to linear scleroderma: a case report. Turk J Pediatr 1999;41:381–5. quently in females (3 : 1) and is more common in the third
13 Kirschstein M, Helmchen U, Jensen R et al. Kidney involvement in a and sixth decade. Two patients aged 6 are thought to be
17‐year‐old boy with eosinophilic fasciitis. Clin Nephrol 1999; the youngest reported cases: a boy with scalp nodules [2],
52:183–7.
14 Uckun A, Sipahi T, Akgün D, Oksai A. Eosinophilic fasciitis success- the other a girl with an insidiously enlarging swelling
fully treated with oral hydroxyzine: a new therapeutic use of an old over the back of the left knee [3].
drug? Eur J Pediatr 2002;161:118–19.
15 Britt WJ, Duray PH, Dahl MV, Goltz RW. Diffuse fasciitis with
eosinophilia: a steroid‐responsive variant of scleroderma. J Pediatr
Clinical features and differential diagnosis. Eosinophilic
1980;97:432–4. panniculitis most often presents as subcutaneous nodules
16 Pinal‐Fernandez I, Callejas‐Moraga EL, Roade‐Tato ML, Simeon‐ on the legs, arms, trunk and face. Urticarial papules, pur-
Aznar CP. Groove sign in eosinophilic fasciitis. Lancet 2014;15:1774. ple plaques or even purpura, pustules and ulcerative
17 Quintero‐Del‐Rio AI, Punaro M, Pascual V. Faces of eosinophilic
fasciitis in childhood. J Clin Rheumatol 2002;8:99–103. lesions have been reported. There will invariably be a
18 Rutter MM, Prahalad S, Passo M, Backeljauw PF. Idiopathic hypercal- nodular subcutaneous component.
cemia and eosinophilic fasciitis: a novel association. J Pediatr There is a wide differential diagnosis, including B‐ and
Endocrinol Metab 2004;17:1251–4.
19 Kirchgesner T, Dallaudière B, Omoumi P et al., Eosinophilic fasciitis:
T‐cell lymphoma, arthropod bites, gnathostomiasis (nod-
typical abnormalities, variants and differential diagnosis of fasciae ular migratory eosinophilic panniculitis due to foodborne
abnormalities using MR imaging. Diagn Interv Imaging 2015; parasitic zoonosis, usually from contaminated raw fish),
96:341–8. zygomycosis (e.g. Basidiobolus ranarum [4]), streptococcal
20 Marie I, Sauvetre G. Fluorodeoxyglucose positron emission tomogra-
phy in eosinophilic fasciitis. Joint Bone Spine 2014;81:541. and other bacterial infections, toxocariasis, Fasciola hepat-
21 Wasserman SI, Seibold JR, Medsger TA Jr, Rodnan GP. Serum eosino- ica infection, leucocytoclastic vasculitis, polyarteritis
philotactic activity in eosinophilic fasciitis. Arthritis Rheum nodosa, erythema nodosum, atopic and contact dermati-
1982;25:1352–6.
22 Jinnin M, Ihn H, Yamane K et al. Serum levels of tissue inhibitor of
tis, eosinophilic cellulitis, angiolymphoid hyperplasia
metalloproteinase‐1 and 2 in patients with eosinophilic fasciitis. Br J with eosinophilia, Ofuji disease, granuloma faciale,
Dermatol 2004;151:407–12. EGPA, Langerhans cell histiocytosis [5], HES, drug erup-
23 Dziadzio M, Chee R, McNamara C et al. EBV‐driven diffuse tions, injection granuloma [6] and refractory anaemia
large B‐cell lymphoma confined to the liver in a patient with a
history of idiopathic CD4 lymphocytopenia. BMJ Case Rep 2013; with blasts.
21:2013.
24 Loupasakis K, Derk CT. Eosinophilic fasciitis in a pediatric patient. Histology findings. The condition is characterized by
J Clin Rheumatol 2010;16:129–31.
prominent eosinophil infiltration of subcutaneous fat
25 Mendoza FA, Bai R, Kebede AG, Jimenez SA. Severe eosinophilic
fasciitis: comparison of treatment with d‐penicillamine plus corti- septa and lobules with occasional fat necrosis and flame
costeroids vs. corticosteroids alone. Scand J Rheumatol 2016; figures but absence of vasculitis. Changes may extend up
45:129–34. to the reticular tissue of fascia. Although eosinophils are
26 Endo Y, Tamura A, Matsushima Y et al. Eosinophilic fasciitis:
report of two cases and a systematic review of the literature deal-
seen in the panniculitis of both lupus and morphoea pro-
ing with clinical variables that predict outcome. Clin Rheumatol funda, they were found in the minority of cases (24% and
2007;26:1445–51. 25% respectively) in the series of Peters and Su [7].
4 Mahamaytakit N, Singalavanija S, Limpongsanurak W. Subcutaneous

Treatment and prevention. Most patients respond to zygomycosis in children: 2 case reports. J Med Assoc Thai 2014;97:
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5 Ahmed H, Rafindadi AH, Pindiga UH, Opara WE. Suppurative granu-
lesions will also resolve spontaneously. Success with dap-
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sone and ciclosporin has also been reported. 709–12.
6 Gomez Rodriguez N, Ortiz‐Rey JA, de la Fuente Buceta A, Ibáñez
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1 Burket JM, Burket BJ. Eosinophilic panniculitis. J Am Acad Dermatol dilemma]. An Med Interna 2001;18:635–7.
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2 Samlaska CP, de Lorimier AJ, Heldman LS. Eosinophilic panniculi- profunda. J Cutan Pathol 1991;18:189–92.
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3 Jain S, Jain P, Jakhar P, Shivkumar VB. Eosinophilic panniculitis in a
female child: An unusual presentation. Indian Dermatol Online J
2015;6:34–6.
OF DERMATITIS
335
C HA PTER 25
Juvenile Plantar Dermatosis

John C. Browning1,2 & Margaret Brown3
1
Baylor College of Medicine, Houston, TX, USA
2
Children’s Hospital of San Antonio, San Antonio, TX, USA
3
Division of Dermatology, The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
Abstract The differential diagnosis of JPD includes atopic dermatitis, a llergic

contact dermatitis, tinea pedis and psoriasis. The diagnosis is
clinical, but patch testing may be helpful in identifying relevant
Juvenile plantar dermatosis (JPD) is a chronic condition affecting
allergens if contact sensitivity is suspected. Biopsy is rarely, if ever,
children and young adolescents and characterized by symmetri-
indicated for diagnosis but often shows characteristic inflammation
cal, shiny erythema, superficial desquamation and fissuring of the

of the acrosyringium or eccrine duct. Treatment and prevention are
weightbearing surfaces of the feet. Moisture, friction and the tran-
aimed at moisture control via the use of absorbent cotton socks and
sition from ‘wet to dry’ probably play a role in its development,
breathable footwear or sandals. Topical barrier creams, emollients,
OF DERMATITIS
but the exact aetiology and pathophysiology remain unknown.
antiperspirants and topical steroids may also be effective.
Key points • The diagnosis of JPD is clinical; the differential diagnosis

includes atopic dermatitis, allergic contact dermatitis, tinea
pedis and psoriasis.
• Juvenile plantar dermatosis (JPD) affects children and young
• Patch testing may be helpful in identifying relevant allergens if
adolescents.
a sensitivity is suspected.
• JPD is characterized by symmetrical, erythematous, shiny skin on
• Biopsy is rarely, if ever, indicated for diagnosis but often shows
the weightbearing surfaces of the feet, especially at the great
characteristic inflammation of the acrosyringium or eccrine duct.
toe and forefoot, sparing the interdigital web spaces.
• Treatment and prevention are aimed at moisture control and
• Moisture, friction and the transition from ‘wet to dry’ probably
include the use of absorbent cotton socks, breathable footwear,
play a role in the development of JPD.
sandals, topical barrier creams, emollients, antiperspirants or
topical steroids for acute flares.
Brief introduction/history. Juvenile plantar dermatosis Epidemiology and pathogenesis. The prevalence of JPD
(JPD) is a chronic condition affecting children and is not known, although it may be quite common [5]. JPD
young adolescents and characterized by symmetrical, occurs in children aged 3–15 and is more common in boys
shiny erythema, superficial desquamation and fissuring aged 4–8 [6]. In one South Indian study of 200 patients
of the weightbearing surfaces of the feet. with various types of lower leg and foot eczemas, juvenile
JPD was first recognized as a distinct entity in 1976 plantar dermatosis was the most common type of lower
when Mackie and Husain described a group of school‐ leg and foot eczema in patients younger than 15 years of
aged children with scaling, fissuring and itching or age. In the same study, JPD was the most common type of
burning of the weightbearing areas of the feet [1]. Prior lower leg and foot eczema in students, presumably due to
to that, ‘atopic winter feet’ had been described by Moller their regular use of shoes and socks [7]. JPD has also been
in 1972 [2] and ‘recurrent juvenile eczema’ was also described in adults [8,9]. In a study of 64 patients, JPD
reported by Schultz and Zachairiae in 1972 [3]. Before was found more commonly in Chinese than Malays or
then, JPD was probably thought to be eczema, contact Indians [8]. It seems that some individuals have a family
dermatitis or tinea pedis. In the medical literature, JPD predisposition to developing JPD, as it has been described
has been described under a variety of names including in twins [10]. A personal or family history of atopy is com-
forefoot eczema, juvenile plantar dermatitis, forefoot mon in affected children, and this may implicate an
dermatitis, dermatitis plantaris sicca, peridigital derma- impaired skin barrier in its development.
titis, wet and dry syndrome, sneaker feet and sweating Occlusive footwear, moisture and friction play an
sock dermatitis [4]. important role in the development of JPD [11]. It has been
hypothesized that transition from ‘wet to dry’ is probably

the culprit in precipitating the condition [12,13]. Occlusion,
especially by shoes with rubber soles or synthetic socks,
can lead to perspiration. Many affected individuals also
complain of plantar hyperhidrosis. It has been posited that
persistent, occluded moisture disrupts the epidermal bar-
rier which leads to maceration and permits the excessive
evaporation of subcutaneous moisture. This results in des-
iccation, shrinkage and separation of corneocytes which is
clinically manifested as fissuring [5]. JPD often becomes
clinically evident during the summer months, which is
thought to be related to perspiration leading to aggrava-
tion of the condition [14]. However, worsening of the con-
Fig. 25.1 Erythematous, shiny skin with superficial peeling on the
dition during the winter months has also been reported, weightbearing surfaces of the forefoot.
perhaps due to the use of warmer shoes and thicker socks,
and one study found no seasonal variation [15,16].
Clinical features and differential diagnosis. JPD is

OF DERMATITIS
c haracterized by symmetrical, erythematous, shiny skin

on the weightbearing surfaces of the feet, especially at
the great toe and forefoot [17] (Figs 25.1 and 25.2). Less
commonly, it may extend to the dorsal foot as well. There
is notable sparing of the interdigital web spaces and
arches. Some children experience discomfort with peeling,
redness and fissuring [15]. Pruritus is less common and is
noted to be a variable associated symptom [4]. JPD is typi-
cally seen in school‐aged children and often recurs over
many years. JPD is self‐limiting and usually resolves by
12–16 years of age [6,12].
The differential diagnosis of JPD includes tinea pedis,
atopic dermatitis, allergic contact dermatitis (ACD) and
psoriasis. Tinea pedis may be considered in the differen-
tial diagnosis but it would be unusual without interdigi-
tal involvement. JPD may be misdiagnosed as atopic
dermatitis of the foot, given its prevalence in children [5].
ACD may also be considered but it is typically character-
ized by more intense pruritus, along with involvement of
the dorsal foot and lichenification in longstanding
cases [18]. Psoriasis may also affect the feet but would
probably be accompanied by thick, silvery scale and Fig. 25.2 Erythema with a glazed appearance on the plantar foot with
fissuring which is accentuated at the great toe.
often involves the non‐weightbearing areas of the plantar
foot.
Interestingly, JPD has not been seen as frequently in the impaired epidermal barrier from JPD. Of note, rubber
paediatric dermatology clinic in recent years, according to components were found to be the principal allergens in
one set of authors who suggest a decreasing frequency of one study of ACD of the feet, followed by chromated
the condition [15]. It may also be that JPD is now more leather and adhesives [20].
commonly recognized by paediatricians and other primary Biopsy is rarely, if ever, indicated but may help guide
care providers and not referred as often to dermatologists. the clinical diagnosis [21]. Histologically, JPD is character-
ized by subacute or chronic spongiotic dermatitis with
Laboratory/histology findings. JPD is a clinical diagno- inflammation at the junctions of the acrosyringium or
sis. Mycological studies and a potassium hydroxide prep- eccrine sweat duct at the epidermis starting edge [16,22].
aration can help rule out tinea pedis if it is clinically Eccrine duct involvement has not been described in other
suspected. Patch testing should be considered to investi- forms of eczema and may be a clue to the diagnosis of
gate an allergic component, particularly in recalcitrant JPD, but its absence does not rule out the diagnosis [22].
cases [19]. In contrast to earlier studies that did not iden-
tify a significant correlation between ACD and JPD, a Treatment and prevention. The use of cotton socks,
2012 study showed a high prevalence of contact allergy in breathable footwear and sandals has been recommended
children with sole dermatoses [1,19]. While this finding to decrease the perspiration and friction which can serve
could represent cases of ACD that are clinically similar to as aggravating factors in JPD. Lubrication with petrola-
JPD, it could also suggest sensitization secondary to an tum or use of dimethicone barrier creams has been
Chapter 25 Juvenile Plantar Dermatosis 337
s uggested for acute flares and maintenance [6]. Mid‐ to 6 Kalia S, Adams SP. Dermacase. Juvenile plantar dermatosis. Can Fam
Physician 2005;51:1203, 1213.
high‐potency topical steroids may also be used in cases
7 Chougule A, Thappa DM. Patterns of lower leg and foot eczema in
where pruritus is a significant factor, but recurrence is south India. Indian J Dermatol Venereol Leprol 2008;74:458–61.
common after discontinuation and their use may pre- 8 Moorthy TT, Rajan VS. Juvenile plantar dermatosis in Singapore. Int J
cipitate secondary tinea pedis [5]. Tacrolimus ointment Dermatol 1984;23:476–9.
9 Czarnecki DB, Cowen PS, Connors TJ. Juvenile plantar dermatosis in
0.1% has been reported to be beneficial, when used in an adult. Br J Dermatol 1981;104:599–600.
conjunction with an emollient [15]. Topical antiperspi- 10 Stankler L. Juvenile plantar dermatosis in identical twins. Br J

rants such as aluminium chloride can be helpful if Dermatol 1978;99:585.
hyperhidrosis is a significant associated symptom. 11 Lachapelle JM, Tennstedt D. Juvenile plantar dermatosis: a report of
80 cases. Am J Ind Med 1985;8:291–5.
Avoidance of topical allergens is advisable. 12 Jones SK, English JS, Forsyth A et al. Juvenile plantar dermatosis: an
8‐year follow up of 102 patients. Clin Exp Dermatol 1987;12:5–7.
Acknowledgements 13 Steck WD. Juvenile plantar dermatosis: the ‘wet and dry foot syn-
drome’. Cleve Clin Q 1983;50:145–9.
The authors would like to acknowledge Dr Alanna Bree 14 Kint A, Hecke EV, Leys G. Dermatitis plantaris sicca. Dermatologica
for her authorship in the Third Edition of this chapter 1982;165:500–1.
(Harper’s Textbook of Pediatric Dermatology, 3rd edition: 15 Shipley DR, Kennedy CTC. Juvenile plantar dermatosis responding
to topical tacrolimus treatment. Clin Exp Dermatol 2006;31:453–4.
Chapter 43, Juvenile Plantar Dermatosis).
16 Ashton RE, Jones RR, Griffiths A. Juvenile plantar dermatosis. A clin-

icopathologic study. Arch Dermatol 1985;121:225–8.
References 17 Neering H, van Dijk E. Juvenile plantar dermatosis. Acta Derm

OF DERMATITIS
1 Mackie RM, Husain SL. Juvenile plantar dermatosis: a new entity? Clin Venereol 1978;58:531–4.
Exp Dermatol 1976;1:253–60. 18 Weston JA, Hawkins K, Weston WL. Foot dermatitis in children.
2 Moller H. Atopic winter feet in children. Acta Derm Venereol
Pediatrics 1983;72:824–7.
1972;52:401–5. 19 Darling MI, Horn HM, McCormack SK et al. Sole dermatitis in chil-
3 Schultz H, Zachairiae H. The trafuril test in recurrent juvenile eczema dren: patch testing revisited. Pediatr Dermatol 2012;29:254–7.
of hand and feet. Acta Derm Venereol 1972;52:398–400. 20 Shackelford KE, Belsito DV. The etiology of allergic‐appearing foot
4 Brar KJ, Shenoi SD, Balachandran C, Mehta VR. Clinical profile of fore- dermatitis: a 5‐year retrospective study. J Am Acad Dermatol
foot eczema: a study of 42 cases. Indian J Dermatol Venereol Leprol 2002;47:715–21.
2005;71:179–81. 21 Zagne V, Fernandes NC, Cuzzi T. Histopathological aspects of juve-
5 Bikowski J. Barrier disease beyond eczema: management of juvenile nile plantar dermatosis. Am J Dermatopathol 2014;36:359–61.
plantar dermatosis. Practical Dermatology for Pediatrics 2010;July/ 22 Van Diggelen MW, van Dijk E, Hausman R. The enigma of juvenile
August:28–31. plantar dermatosis. Am J Dermatopathol 1986;8:336–40.
338
CHA PTER 2 6
Perioral Dermatitis
Marius Rademaker1,2
1
Dermatology Department, Waikato, District Health Board, Hamilton, New Zealand
2
Waikato Clinical Campus, Faculty of Medical and Health Sciences, The University of Auckland, Hamilton, New Zealand
Abstract variant has been described as childhood granulomatous periorificial

dermatitis.
Several factors have been implicated in its pathogenesis, includ-
Perioral, or periorificial, dermatitis is an inflammatory skin disease
ing decreased barrier function, infections (Demodex, Fusobacte-
that affects predominantly older girls and women. In prepubescent
rium), cosmetics and topical glucocorticosteroids.
children, perioral dermatitis affects boys and girls equally. Perioral
It is generally self‐limiting, but responds well to avoidance of
dermatitis is characterized by a papulosquamous inflammatory erup-
topical preparations and/or sub‐antimicrobial doses of systemic

tion around the mouth (generally sparing the vermillion), nose and
tetracyclines/macrolides.
eyes, with an absence of flushing or comedones. A g ranulomatous
OF DERMATITIS
Key points • Several factors have been implicated in its pathogenesis,

including decreased barrier function, infections (Demodex,
Fusobacterium), cosmetics and topical glucocorticosteroids.
• Perioral, or periorificial, dermatitis is an inflammatory skin
• It is generally self‐limiting, but responds well to avoidance of
disease that affects predominantly older girls and women.
topical preparations and/or sub‐antimicrobial doses of systemic
• In prepubescent children, perioral dermatitis affects boys and
tetracyclines/macrolides.
girls equally.
• A granulomatous variant has been described as childhood
• It is characterized by a papulosquamous inflammatory eruption
granulomatous periorificial dermatitis.
around the mouth (generally sparing the vermillion), nose and
eyes, with an absence of flushing or comedones.
History. The term ‘perioral dermatitis’ was first used in Epidemiology and pathogenesis. Childhood perioral
1964 [1], although the dermatosis had been described as dermatitis is relatively uncommon, with no apparent gen-
a ‘light sensitive seborrheid’ in a series of 92 patients, der predominance [11,12]. In a large study of 222 children,
including children from 11 years of age, several years average age of presentation was 6.6 years, 45% were
earlier [2]. boys, 62.2% were Caucasian, and a third reported a past
In 1970, five cases of perioral dermatitis were reported history of atopic dermatitis [12]. In contrast, adult perio-
specifically in children [3]. Several years later an unusual ral dermatitis is more common, affecting predominantly
papular and acneiform facial eruption was reported in 22 young women. The granulomatous variant of perioral
black children aged 9 months to 12 years [4]. In a 12‐year dermatitis occurs mostly in children with skin phototypes
review of perioral dermatitis, 15 out of 173 cases (8.6%) 4 and 5 [4,7,9,13].
were in children [5]. In a series of 14 children aged 9 The aetiology of perioral dermatitis remains unclear; it is
months to 6 years with perioral dermatitis, most, but not probably an idiosyncratic response to a variety of exoge-
all, had been using fluorinated topical corticosteroids to nous factors (Box 26.1). Traditionally, intentional or inad-
treat pre‐existing mild facial dermatoses [6]. vertent application of topical corticosteroids [5–7,11,12,14]
Gianotti and colleagues were the first to characterize a (including inhaled and/or intranasal steroids [15–17]) has
granulomatous variant of perioral dermatitis in children, been implicated in the pathogenesis of perioral dermatitis.
both clinically and histologically [3]. Several subsequent However, in over half of patients there is no history of prior
reports have further delineated childhood granuloma- topical corticosteroid use, thus other factors have been
tous periorificial dermatitis [4,7–9], including some cases reported in association with perioral dermatitis, including
that had been previously diagnosed as sarcoidosis [7,10]. sunscreens, moisturizers, toothpastes, antiseptics, etc.
Chapter 26 Perioral Dermatitis 339
Box 26.1 Triggers of perioral dermatitis in children
Cosmetics
• Skin care ointments and creams

• Sunscreens
• Fluorinated toothpaste
Microbiological factors
• Fusobacterium spp.
• Candida spp.
• Demodex folliculorum
Physical factors
• Ultraviolet light
• Heat

• Wind
OF DERMATITIS
Pharmaceuticals
• Topical corticosteroids (fluorinated and nonfluorinated)

• Inhaled/intranasal prescription steroid sprays/solutions
Skin disease
• Barrier dysfunction/atopic dermatitis

Fig. 26.1 Perioral and periocular dermatitis. Source: Courtesy of Dr
Amanda Oakley, DermNet, New Zealand.
[18–21]. This has led one author to suggest separating
perioral dermatitis into ‘corticosteroid‐induced rosacea‐

like dermatitis’ (CIRD) and perioral dermatitis not
associated with topical corticosteroid use (idiopathic

perioral dermatitis) [22].
Various microbial organisms have also been linked
with perioral dermatitis [23], including Fusobacterium
spp. [24,25] and Candida spp. Demodex folliculorum has
been implicated in the development of perioral dermati-
tis, but whether it plays a primary or secondary role
remains undetermined [26]. Impaired barrier dysfunction
with significantly increased transepidermal water loss
compared to controls has been reported in adults with
perioral dermatitis [20,27]. Topical corticosteroids may
alter the epidermal structure, increase transepidermal
water loss and cause vascular instability in some children
[14]. Abrupt discontinuation of corticosteroids often
results in flaring of perioral dermatitis with intense
erythema and stinging, burning and itching. Fig. 26.2 Perioral dermatitis. Source: Courtesy of Associate Professor
David Orchard, Royal Children’s Hospital, Melbourne, Australia.
Clinical features. The term ‘perioral dermatitis’ is an inac-

curate appellation, as both perinasal and periocular In childhood granulomatous periorificial dermatitis,
lesions (Fig. 26.1) are common, occasionally even without the lesions are often discrete, small, firm, dome‐shaped,
perioral involvement [5,6,12,13,28]. Periorificial dermati- flesh‐coloured papules without perceptible erythema or
tis may be a more appropriate term. In perioral disease, scale. It occurs predominantly in children with skin pho-
the vermillion border of the lip is usually spared totypes 4 and 5, aged 9 months to 13 years of age. Diascopy
(Fig. 26.2). In most cases, small erythematous papules are of individual lesions may reveal an apple‐jelly colour.
present, superimposed on a background of erythema and Extrafacial involvement (e.g. trunk, extremities and geni-
scaling. In severe cases, pinpoint vesiculopustular lesions tals) may be extensive [30,31].
may be evident (Fig. 26.3). Rarely, other sites including
the glabella [12], chest [29], perianal skin and vulva [28] Differential diagnosis. The differential diagnosis of peri-
may be involved. Pruritus is variable and mild, but older oral dermatitis includes contact dermatitis (both irritant
patients may complain of a burning itch [1,2]. and allergic), lip licking, atopic and seborrhoeic dermatitis,
Fig. 26.4 Noncaseating granuloma in a patient with granulomatous

perioral dermatitis.
Fig. 26.3 Severe perioral dermatitis. Note vesiculopustular lesions.
Table 26.1 Key therapeutic steps in treating perioral dermatitis in children

OF DERMATITIS
Demodex folliculitis [26,32] and, very rarely, diverse meta-

Step 1 ‘Zero/null’ treatment. Discontinue any potential triggers
bolic disorders such as acrodermatitis enteropathica and
(moisturizers, sunscreens, topical steroids, toothpastes,
biotin deficiency [33]. There is an overlap between perioral other cosmetic substances)
dermatitis and rosacea. Step 2 Avoid lipophilic agents
A clue to possible allergic contact dermatitis may be Step 3 If the perioral dermatitis is mild, and not responding to
involvement of the vermillion of the lips, such as is steps 1/2: metronidazole gel, twice daily, for 3–4 weeks
described to colophony (rosin) [34]. Step 4 If not controlled by step 3: topical calcineurin inhibitors, or
Taken in isolation, individual lesions of perioral derma- mild topical steroids (class VII, but only if no history of
antecedent use)
titis may be difficult to distinguish from lesions of rosa-
Step 5 Sub‐antimicrobial doses of oral antibiotics (>8 years of
cea; however, perioral dermatitis lacks the associated age: tetracyclines; <8 years: macrolides) for 6–8 weeks
telangiectasia, flushing, periorbital swelling and blephar- Step 6 In more persistent cases, consider low‐dose isotretinoin
itis of rosacea. Steroid‐induced rosacea in prepubertal (5–10 mg /day) for 3–6 months (non‐FDA‐approved)
children is nearly indistinguishable in appearance from
perioral dermatitis [35].
The differential diagnosis of childhood granulomatous inflammatory infiltrate may be mixed lymphohistiocytic.
periorificial dermatitis includes granulomatous rosacea Noncaseating granulomas are found in childhood gran-
(including lupus miliaris disseminatus faciei), acne agmi- ulomatous periorificial dermatitis (Fig. 26.4). The dis-
nata, sarcoidosis, benign cephalic histiocytosis, granulo- tinction between childhood granulomatous periorificial
sis rubra nasi and Demodex folliculitis [7,26,36,37]. dermatitis and sarcoidosis may be difficult [3,4,7].
Demodex folliculitis in particular can have marked clinical Patch testing [42], bacteriology, mycology for Candida,
overlap [26]. It most commonly occurs in patients receiv- and a search for Demodex (e.g. dermoscopy, which can
ing chemotherapy for malignancy and/or in immunode- demonstrate follicular openings containing Demodex
ficiency [32]. ‘tails’ [43]), may be helpful in the investigation of the dif-
There is overlap between childhood granulomatous peri- ferential diagnosis of perioral dermatitis.
orificial dermatitis and granulomatous rosacea. Potential
distinguishing features of rosacea include skin lesions pre- Treatment and prevention. The response to treatment
dominantly involving the cheeks, telangiectases and facial (Table 26.1) depends on the severity, extent and duration
flushing [38]. The coexistence of ocular signs or symptoms of the disease. In severe, longstanding disease, the
of rosacea such as blepharitis can also suggest rosacea, response to therapy is one of slow improvement, with
although these are quite uncommon in children [39]. occasional relapses over many months, whereas mild dis-
ease often clears within a few weeks [11,44–49]. Children
Laboratory/histology findings. The histopathology of whose perioral dermatitis develops from a pre‐existing
perioral dermatitis is essentially indistinguishable from perinasal erythema (Fig. 26.5) tend to have a relapsing/
that of rosacea including both granulomatous and non- remitting course, particularly if moisturizers and/or sun-
granulomatous forms [40,41]. Histologically there may be screens continue to be used. Patients with steroid‐induced
mild epidermal acanthosis, focal spongiosis, hyperkera- perioral dermatitis frequently rebound (often with
tosis with parakeratosis and a mild perivascular and peri- increasing severity) after stopping topical corticosteroids.
adnexal lymphohistiocytic infiltrate centred around hair Childhood granulomatous periorificial dermatitis tends
follicles and in the upper dermis. Focal follicular rupture to resolve over a few months to several years, but may
with microabscess formation is present in some cases. The leave behind milia and pinpoint scarring [31,37].
Chapter 26 Perioral Dermatitis 341
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343
C HA PTER 27
Psoriasis: Epidemiology
Matthias Augustin & Marc Alexander Radtke
Institute for Health Services Research in Dermatology and Nursing (IVDP), University Medical Center Hamburg‐Eppendorf (UKE), Hamburg, Germany
Epidemiology of childhood psoriasis, 343 Epidemiology of different clinical Epidemiology of comorbidity in childhood
Prevalence of childhood psoriasis, 344 presentations, 345 psoriasis, 346
Incidence of childhood psoriasis, 345 Epidemiology of nail psoriasis in
Gender distribution, 345 childhood, 346
Abstract and North America. The reported percentage of children developing

guttate psoriasis ranges from 6.4% to 44%. Although guttate pso
riasis is mostly self‐limiting, resolving within 3–4 months of onset,
Psoriasis vulgaris can occur at any age, and prevalence in child
the long‐term prognosis is unknown. About one third of children
hood ranges between 0.1% and 1.5%, showing a nearly linear
with guttate psoriasis develop classical plaque‐type disease. Nail
increase from birth to the age of 18 years. Early onset is more
involvement is reported in between 2% and 39.3% of children.
frequently associated with a positive family history and heralds
Increasing evidence suggests an association between juvenile
a graver prognosis. The median age at onset of psoriasis was
SECTION 5: PSORIASIS
psoriasis and other morbidities including hyperlipidaemia, obesity,
found to be between 7 and 10 years. Data from the UK suggest
hypertension, diabetes mellitus and rheumatoid arthritis. Disease
a prevalence of 0.55% in the age group 0–9 years and 1.37% in
patterns of the metabolic syndrome may occur independently of
the age group 10–19 years, which is consistent with data from the
patient age and disease duration. A high proportion of children
Netherlands, Germany and the USA. Estimates of the proportion
and adolescents will continue to have psoriatic disease and co
of psoriatic children with a positive family history in any family
morbidity throughout their lives, suggesting the need for careful
member range between 4.5% and 88%. Psoriasis may represent
work‐up and specialized care and information.
4.1% of all dermatological diseases under the age of 16 in Europe
• Disease burden and quality of life impairment can be considerable

Key points and there is marked risk of cumulative life course impairment.
• Clinical pictures show large variations but a higher proportion of
• Psoriasis can occur in all age groups; prevalence increases in an guttate psoriasis in children compared to adults.
almost linear fashion from early childhood to adolescence. • Nail disease is common.
• In most children and adolescents, onset of psoriasis predicts • Children with psoriasis show significantly increased rates of comorbi
lifelong disease. dity, including obesity, cardiovascular disease, arthritis and diabetes.
Epidemiology of childhood psoriasis leading to some uncertainty on the age of onset in child-
hood psoriasis. It is estimated that psoriasis begins in
Childhood psoriasis differs in many ways from adult‐ childhood in almost one third of the cases [1–3]. Although
onset psoriasis. It is crucial that patients and their parents it is well accepted that two incidence peaks may exist, one
understand the natural history of the disease [1] as the in early adolescence and the other in adulthood, there are
stigma associated with visible skin lesions creates a strong few data with regard to the early peak. Thirty percent of
psychological burden affecting different facets of patients’ all psoriasis patients develop first symptoms before the
everyday lives. Difficulties in developing coping strate- age of 15 years, which underlines the epidemiological
gies may lead to cumulative life course impairments, dimension in the paediatric age group [4–6]. Furthermore
especially when disease onset is in early childhood. there is some evidence that early onset is more frequently
Although psoriasis is common in childhood, data on associated with a positive family history and heralds a
epidemiology are sparse despite a growing number of graver prognosis [7]. Familial occurrence is more com-
observational studies during the last decade. Furthermore mon in childhood‐onset than in adult‐onset psoriasis
there is inconsistency in epidemiological research on [8–12]. Estimates of the proportion of psoriatic children
subtype definition (e.g. napkin psoriasis) and a notable with a positive family history in any family member
variation in how psoriasis is ascertained (secondary data, range between 4.5% and 88%. In a literature review by
physician examination, self‐reported, diagnostic codes), Burden‐Teh et al. [13], the proportion of children with a
344 Section 5 Psoriasis
positive history in a first‐degree relative varied from 6.2% prevalence of children with atopic dermatitis/eczema
to 54.7%. In a study by Farber et al. [14], adolescents were decreased from 17.1% at the age of 0–2 years to 7.3% at
most likely to have a positive family history compared to the age of 14–18 years. These data were comparable
other age groups during childhood. Gene–environment with a study by De Jager et al. [2] from the Netherlands
interactions might play a role when trying to explain who found a prevalence of 0.37% in the age group from
major differences between latitudes and countries. 0 to 10 years and a prevalence of 1.09% in the age group
from 11 to 19 years old. Gelfand et al. [18] reported a
prevalence of 0.55% in the age group 0–9 years and 1.37%
Prevalence of childhood psoriasis in the age group 10–19 years in the UK. A study of 2194
Population‐based German statutory health insurance children in Egypt postulated that the prevalence of pso-
data from 1.3 million persons, including 33 981 patients riasis among people 18 years of age and younger was
with psoriasis, revealed a total prevalence rate of 0.71% in 0.05% [19] (Table 27.1). However, there are few studies
children younger than 18 years [15,16]. The prevalence and those that do exist reveal variations between almost
rates increased linearly from 0.2% at the age of 1 year to absence of juvenile psoriasis in Taiwan, China, and 2.15%
1.2% at the age of 18 years (Fig. 27.1). Another data set lifetime prevalence in children in Italy [26–28].
from Germany comprised 1.64 million persons nation- Psoriasis both in children and adults is supposed to
wide, including 293 181 children and young adults aged affect 2.0–3.5% of the global population [8]. Depending on
up to 18 years (Fig. 27.1). Approximately 1313 children the study population the prevalence ranges up to 8.5%
(0.45%) carried the diagnosis of psoriasis. The data con- [9]. Psoriasis may represent 4.1% of all dermatological
firmed that the prevalence in children correlates linearly diseases under the age of 16 in Europe and North America
with age and increases from 0.13% at the age of 0–2 years [10]. Taking all available data together, the average age of
to 0.67% at the age of 14–18 years [17]. In contrast, the onset varies from 2.1 months to 10.6 years [13].
1.40
1.22 1.24
1.20 1.17
1.12
1.04
1.00
Prevalence (in %)
1.00
0.88
0.79
0.80
0.72
0.60 0.56 0.55 0.56
0.40 0.41
0.40
0.30
0.22 0.24 0.20
0.20
0.12
0.00
<1 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18
Age (in years)
Fig. 27.1 Prevalence of juvenile psoriasis according to age group (n = 306 020 persons). Physician‐recorded ICD‐10 codes were computed from a database
comprising 1.3 million persons. Persons identified as psoriasis patients <18 years (n = 2549) were studied. There is an almost linear increase in prevalence
rates with age.
Table 27.1 Summary of studies on the prevalence of psoriasis in children
Country Years of study Sample size (n) Estimate Female Male Age
China, Taiwan [3] 2004 4067 0.00% 6–11

China, Taiwan [20] 2005 3273 0.00% 6–11
Egypt [19] 2008–2009 2194 0.05% <18
Germany [15] 2005 306 020 0.71% 0.76% 0.66% <18
Germany [21] 2009 293 181 0.45% <18
Germany [22] 2008 16 500 1.37% 0–17
Italy [23] 2006 145 233 0.09% 0–14
Italy [23] 2012 145 233 0.20% 0–14
Sweden [24] 1975–1976 8298 0.30% 0.50% 0.10% 12–17
Source: Adapted from WHO 2016 [25]. Reproduced with permission of the World Health Organization.
Chapter 27 Psoriasis: Epidemiology 345
Among children (0–18 years), the median age at onset Morris et al. [6] reported no difference in gender distribu-
of psoriasis was found to be between 7 and 10 years tion whereas Fan et al. reported that 46.9% of the patients
[18,29–31]. It has been estimated that in 10% of psoriasis were male and 53.1% female [28]. Accordingly, in the
patients disease onset is before the age of 10 years and in larger studies, Matusiewicz et al. [21] and Augustin et al.
2% before 2 years [32], although data regarding onset [15] concluded that the prevalence of psoriasis in child-
vary among investigators. In a study on 5600 patients hood was lower in boys than in girls: the ratio was 0.35%
with psoriasis, Farber and Carlsen stated an onset before versus 0.45% in the paper by Matusiewicz and 0.42% ver-
the age of 20 years in 35% of cases [11], whereas sus 0.48% in the study by Augustin et al. The latter
Raychaudhuri and Gross [1] reported an onset before the revealed a relative ratio of 47.7% boys versus 52.3% girls
age of 20 years in 46.3%. Furthermore, different studies in the psoriasis population. The sex difference is most
demonstrated that 2–12% of adult patients had psoriasis obvious in children under the age of 10 years where the
before the age of 10 years [10,33]. manifestation of psoriasis is more common in girls than in
boys. In contrast, when considering all epidemiological
studies focusing on gender and age (including adults),
Incidence of childhood psoriasis the vast majority indicate a male predominance [42].
Few studies elaborated on the incidence of psoriasis in Looking at the lifetime course independent of age, psoriasis
childhood. Tollefson et al. [34] assembled a population‐ is considered almost equally prevalent in both sexes [43].
based incidence cohort of children aged <18 years first
diagnosed with psoriasis between 1970 and 1999. The
overall age‐ and sex‐adjusted annual incidence of Epidemiology of different clinical
paediatric psoriasis was 40.8 per 100 000. When psoria- presentations
sis diagnosis was restricted to cases confirmed by a The clinical presentation of psoriasis in childhood can
dermatologist, the incidence was 32.2 per 100 000 with be very heterogeneous with guttate lesions, napkin
a significant increase over time from 29.6 per 100 000 in (diaper) distribution and facial involvement being more
1970 to 1974 to 62.7 per 100 000 in 1995–1997 [35]. Seyhan typical in children. In children, lesions are commonly
et al. [29] revealed an incidence of psoriasis among a triggered by upper respiratory infections, tonsillitis,
group of dermatological patients in childhood and skin injury (Koebner phenomenon) and emotional stress.
adolescence of 3.8%. The development of plaque psoriasis in children is often
There is some evidence that the incidence and preva- preceded by guttate psoriasis [37,44]. Guttate psoriasis
lence of psoriasis in general have increased over the last (with papules less than 1 cm in diameter presenting in a
decades. Data from the USA derived from the National rash‐like distribution mainly on the trunk) is one of the
Health and Nutrition Examination Survey in 2004 indi- main manifestations in childhood. It typically presents
cated an increase in prevalence from 1.62% in 2004 to following infections caused by β‐haemolytic streptococci
3.10% in 2010 although limitations in the methodology such as tonsillitis or pharyngitis, but also subsequent to
of this study do not allow for a precise conclusion [35,36]. viral infections [45]. The reported percentage of children
In China the prevalence of psoriasis was estimated to be developing guttate psoriasis ranges from 6.4% to 44%
0.17% in 1984, whereas 25 years later another study [46]. Although guttate psoriasis is mostly self‐limiting,
found it to be 0.59% [37,38]. The prevalence in Spain in resolving within 3–4 months of onset, the long‐term
1998 was 1.43%, whereas 15 years later it was reported prognosis is unknown. There is evidence that about one
as 2.31% [39,40]. A study in Norway (Tromsø) analysed third of children with guttate psoriasis develop classical
the trend between 1979 and 2008 and revealed an plaque‐type disease [44]. Horton et al. [47] reported gut-
increased self‐reported lifetime prevalence from 4.8% to tate psoriasis to be the most common variant in 18.9% of
11.4% [41]. Tollefson et al. identified an increase in the the cases. Fan et al. [28] revealed a proportion of 28.9%
overall annual incidence when the incidence cohort was displaying guttate psoriasis and 68.9% of the patients
restricted to dermatologist‐confirmed subjects from 25.6 displaying plaque‐type psoriasis. Kumar et al. [30]
per 100 000 (1970–1974) to 49.4 per 100 000 (1995–1999) found classical plaque‐type psoriasis to be the most fre-
[34]. Taken together, the published studies indicate an quent type of psoriasis at the time of presentation
increase in psoriasis incidence in the past decades. (60.6%), followed by plantar psoriasis (12.8%). Data
However, due to methodological limitations, the data from China and India have revealed that in juvenile pso-
need further confirmation. riasis 28.9% of the patients exhibited guttate psoriasis
[28]. Kwon et al. [48] analysed the clinical data of 358
patients under 18 years of age referred to a tertiary refer-
Gender distribution ral psoriasis clinic. The most prevalent phenotype was
Different studies on the gender distribution revealed plaque‐type psoriasis (67.3%) and the most frequently
inconsistent results, some of them reporting that female affected body part was the trunk (69.5%), followed by
patients are primarily affected by childhood psoriasis the legs (65.3%).
[1,28,31], while others claim similar prevalences for male Studies on the clinical presentation of childhood psori-
and female patients. Seyhan et al. [29] reported a gender asis collectively showed that the most commonly affected
distribution of 37.7% boys and 62.3% girls for 61 derma- body sites are the scalp (17.9–64.8%), limbs (9.5–90%), and
tological patients in childhood and adolescent groups. trunk (7.8–93.3%) respectively [13]. The face is involved
Table 27.2 Mean age at onset and clinical distribution at onset
Country Sample size (n) Ages (years) Mean age at onset (years) Clinical distribution at onset
Turkey [29] 61 <18 Girls: 9.2 Scalp (60.7%), face (18.0%), trunk (73.8%), extremities (78.7%),
Boys: 6.8 nail (21.3%)
• Plaque psoriasis: 54.1%
• Guttate psoriasis: 35.9%
• Inverse psoriasis: 6.6%
• Palmoplantar: 1.6%
• Pustular psoriasis: 13.1%
• Erythrodermic psoriasis: 3.3%
Korea [48] 358 ≤18 Childhood: 7.1 Scalp (57.8 %), face (46.3%), trunk (69.5%), arms (47.5%), legs
(0–12 years) (65.3%)
Adolescence: 12.4 • Plaque psoriasis: 52.0% (childhood); 76.0% (adolescence)
(13–18 years) • Guttate psoriasis: 27.6% (childhood); 13.5% (adolescence)
• Erythrodermic psoriasis: 1.6% (childhood); 0.9% (adolescence)
Malaysia 315 <16 7.7 Scalp (64.8%), face (19.7%), trunk (30.8%), extensor limbs
[50] (37.1%), palms and soles (5.1%), nails (7.6%)
• Palmoplantar pustulosis: 1.0%
China [28] 277 <16 Median age at onset: 10 Scalp (46.5%), face (19.7%), trunk (42.9%), arms (51.4%), legs
(65.5%), knees (23.9%), palms and soles (39.2%), nail (4.4%)
• Erythrodermic psoriasis: 1.4%
India [30] 419 <14 Girls: 9.3 Scalp (20.7%), face (4.7%), trunk (7.8%), arms (10%), legs
Boys: 8.1 (25%), palms (3.1%), nails (31%)
• Palmoplantar psoriasis: 5.7%
Kuwait [31] 305 ≤12 5.7 Scalp (30%), face (3.6%), trunk (10%), legs (22%), arms (9.5%),
soles (12%)
• Palmoplantar pustulosis: 0.3%
in 3.5–56.7 % of all cases, being a more common sign in

Epidemiology of comorbidity
children compared to adults [49] (Table 27.2).
in childhood psoriasis
Large‐scale studies show that the overall rate of comor-
Epidemiology of nail psoriasis bidity in juvenile psoriatic patients has markedly
in childhood increased. Augustin et al. revealed that the overall rate of
Nail involvement is reported in between 2% and 39.3% of comorbidity in psoriatic patients younger than 20 years
children suffering from psoriasis. De Jager et al. [2] was two‐fold compared with persons without psoriasis
reported nail deformities in 5.3–7.4% of juvenile psoriasis (14.4% vs. 7.2%) (Table 27.3). After adjusting for age and
patients whereas Kumar et al. [30] found nail involve- sex, patients with psoriasis have a significantly higher
ment in 31% of cases. All types of nail changes were seen risk of developing metabolic disease. Juvenile psoriasis
in these patients, pitting being the most frequent one was associated with increased rates of hyperlipidaemia,
followed by ridging and discolouration. In a survey obesity, hypertension, diabetes mellitus, rheumatoid
reported from Kuwait, nail involvement was observed in arthritis and Crohn disease [15].
36% of children, with pitting being the most common fea- In a consecutive analysis of German claims data on
ture (87%) [51]. Mercy et al. [52] found that nail psoriasis 293 181 children, prevalence data were derived from the
was more frequent in boys compared to girls whereas database of a German statutory health insurance com-
scalp psoriasis was more frequent in girls than in boys. pany (Gmünder Ersatzkasse) according to ICD‐10 codes
They explained this with the Koebner phenomenon but L40 for psoriasis and L20 for atopic eczema. Data extrac-
there are insufficient data to confirm this observation, tion involved all data sets of persons younger than
especially in children. 18 years insured in 2009. In addition, prevalence rates of
Table 27.3 Prevalence of comorbidities (%) in persons in the age range 0–20 years with psoriasis (n = 2549) and without psoriasis (n = 331 758 persons)
Diagnosis ICD‐10 code(s) % without psoriasis % with psoriasis Prevalence rate

(95% confidence interval)
Crohn disease K50 0.14 0.51 3.69 (2.15–6.35)

Hyperlipidaemia E78 0.99 2.12 2.15 (1.65–2.80)
Diabetes mellitus E11, E13, E14 0.43 0.86 2.01 (1.32–3.04)
Arterial hypertension I10– I13 0.83 1.65 1.89 (1.47–2.67)
Rheumatoid arthritis M05 4.90 8.40 5.21 (1.40–19.44)
Obesity E66 4.90 8.40 1.70 (1.49–1.93)
Ischaemic heart disease I20– I25 0.49 0.75 1.52 (0.97–2.38)
Ulcerative colitis K51 0.10 0.12 1.13 (0.38–3.33)
All comorbidities (at least one) 7.20 14.40 2.00 (1.82–2.20)
comorbidity were evaluated by ICD‐10 diagnoses (1313 psoriasis [53–57]. Although children with psoriasis display
diagnosed with psoriasis and 30 354 diagnosed with a higher risk of developing diseases such as diabetes
atopic eczema). Obesity, hyperlipidaemia, arterial hyper- and hypertension, clinical studies are so far lacking to
tension and diabetes were more often diagnosed in further characterize the causal association of psoriasis
children with psoriasis in comparison to children without with comorbidity.
psoriasis and those with atopic eczema (Table 27.4) [17]. The study conducted by Augustin et al. [17] confirmed
However, these studies do not prove a causal relation- previous descriptions of specific comorbidity patterns in
ship. Nevertheless, they suggest that disease patterns of juvenile psoriasis and atopic eczema [15,58]. Comorbidities
chronic inflammation associated with metabolic syndrome known to be associated with adult psoriasis are also seen
may start independently of patient age and disease dura- in children, indicating the need for screening and inter-
tion. Rheumatoid arthritis, ulcerative colitis and Crohn disciplinary management.
disease have also been suggested as being caused by Hazard ratios for psychiatric disorders have signifi-
underlying inflammatory immune mechanisms similar to cantly increased [59]. Kimball et al. compared incidences
Table 27.4 Prevalence of comorbidity (%) in persons in the age range 0–18 years with psoriasis (n = 1313), without psoriasis (n = 291 868 persons),
with atopic eczema (n = 30 354) and without atopic eczema (n = 262 827)
Diagnosis Children Children with Prevalence of Prevalence of Children with Prevalence of Prevalence of
(n) psoriasis and diagnoses in diagnoses of atopic eczema diagnoses in diagnoses of children
diagnosis psoriasis (%) children without and diagnosis atopic without atopic
of (n) psoriasis (%) of (n) eczema (%) eczema (%)
Hyperlipidaemia 1883 15 1.14 0.64 216 0.71 0.55

Obesity 10 630 93 7.08 3.61 1248 4.11 3.10
Arterial hypertension 1289 12 0.91 0.44 120 0.40 0.39
Diabetes mellitus 900 8 0.61 0.31 103 0.34 0.26
Keratitis 953 7 0.53 0.32 101 0.33 0.28
Arthritis 17 2 0.15 0.01 2 0.01 0.005
Crohn disease 213 0 0 0.07 23 0.08 0.06
Ulcerative colitis 151 2 0.15 0.05 21 0.07 0.04
Ischaemic heart 183 1 0.08 0.06 24 0.08 0.05
disease
Depression 2274 17 1.29 0.77 251 0.83 0.67
ADHD 20 950 106 8.07 7.14 2462 8.11 6.10
Vitiligo 328 3 0.23 0.11 80 0.26 0.08
Allergic rhinitis 28 505 199 15.16 9.70 5963 19.64 7.44
Chronic bronchitis 6153 29 2.21 2.10 1178 3.88 1.64
Bronchial asthma 27 484 160 12.19 9.36 5780 19.04 7.16
Contact dermatitis 5097 48 3.66 1.73 1096 3.61 1.32
Herpes infection 6217 36 2.74 2.12 1035 3.41 1.71
Urticaria 5941 30 2.28 2.03 1096 3.61 1.60
Nail disorders 2756 38 2.89 0.93 391 1.29 0.78
Alopecia areata 349 6 0.46 0.12 65 0.21 0.09
Impetigo 4338 44 3.35 1.47 1084 3.57 1.07
Viral warts 21 449 159 12.11 7.29 2963 9.76 6.10
Iridocyclitis 120 5 0.38 0.04 19 0.06 0.03
Atopic eczema 30 354 322 24.52 10.29 30,354 100 0
ADHD, attention deficit hyperactivity disorder.

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350
CHA PTER 2 8
Psoriasis: Aetiology and Pathogenesis

Jonathan Barker
St John’s Institute of Dermatology (King’s College), Guy’s Hospital, London, UK
Introduction, 350 Environmental risk factors, 351 Pathogenetic model of psoriasis, 352
Genetic epidemiology, 350 Pathogenetic mechanisms, 351 Pustular psoriasis, 353
Abstract epidermal barrier and innate immune mechanisms leading to ac-

tivation of adaptive T‐cell immune pathways which in turn lead
There have been very significant advances made over the past 20 years to changes in skin homeostasis and inflammation. Specific signal-
in our understanding of the pathogenesis of psoriasis underpinned ling (e.g. NF‐κB) and T‐cell differentiation pathways (Th IL‐17) have
by a combination of genetic discovery and immunological func- been identified which in turn have led to therapeutic advances.
tional studies. Key to pathogenesis is the interplay between the Pustular forms of the disease have a distinct genetic background.
Key points • Genetic studies reveal multiple loci associated with psoriasis.
However a full genetic map remains to be established.

• The primary genetic determinant for psoriasis is within the
• Genetic and immunological studies indicate that the skin barrier
major histocompatibility complex on chromosome 6.
and innate and adaptive immunity play a key role in psoriasis
• There is evidence that pustular forms of psoriasis have a different
vulgaris pathogenesis.
pathogenetic basis when compared to plaque forms.
• Current evidence strongly supports a pivotal role of Th17 T cells
in psoriasis pathogenesis.
Introduction second‐degree relatives of sufferers than unaffected

Psoriasis vulgaris (PV) is a common, complex chronic c ontrol subjects. Swedish studies support these data and
inflammatory disorder often referred to as an immune‐ reveal the prevalence of psoriasis to be 7.8% in first‐degree
mediated inflammatory disease in common with other relatives compared with a prevalence of 3.14% in matched
organ‐specific immune‐mediated diseases such as rheu- controls and 1.97% in the overall population. Based on
matoid arthritis and inflammatory bowel disease. Disease population data, the risk of psoriasis to a child has been
pathogenesis is multifactorial and in great part involves calculated to be 14% if one parent was affected, 41% if
interplay between genetic mechanisms and environmen- both parents were affected, and 6% if one sibling was
tal agents [1]. Rarer forms of psoriasis including general- affected, compared to 2% when no parent or sibling was
ized pustular psoriasis (GPP) may have a different affected [4]. Henseler and Christophers [5] demonstrated
pathogenetic basis and potentially more closely follow a bimodal peak in disease onset. Thus, type I is hereditary,
Mendelian patterns of inheritance. Furthermore, their strongly HLA associated (particularly HLA‐C:06:02),
onset at a very early age makes them important in paedi- early onset and more likely to be severe. Type II is spo-
atric dermatological practice. radic, HLA unrelated, of late onset and usually mild.
Thus when disease onset is in childhood it tends to be
more severe and a family history is more likely, as is asso-
Genetic epidemiology ciation with HLA‐C:06:02. Interestingly, the development
There is overwhelming evidence that psoriasis has an and severity of psoriasis may be influenced by the sex of
important genetic component (reviewed in [2, 3]). In the contributing parent. Thus several studies have noted
Lomholt’s classic epidemiological study of psoriasis in evidence for a preferential paternal effect, while one
the Faroe Islands (1963), in which he examined more than Scottish study further showed earlier age of onset when
10 000 inhabitants, he made the key observation that the the disease was inherited from the father, consistent with
incidence of psoriasis was much greater among first‐ and ‘genetic anticipation’ [6].
Chapter 28 Psoriasis: Aetiology and Pathogenesis 351
Support for these population studies comes from Historically, psoriasis was classified as a disorder of
a nalysis of various family pedigrees in which psoriasis keratinization but a combination of serendipitous obser-
appears throughout multiple generations. Perhaps the vations and science has revealed a primary role for
most robust data supporting a genetic basis to psoriasis immune mechanisms in disease pathogenesis (reviewed
come from studies examining concordance for the disease in [3]). There is considerable evidence that T lymphocytes
in twins (reviewed in [2]). Examination of individuals play an important role in the development of plaques of
from the Danish Twin Registry has shown concordance psoriasis. This evidence includes:
for psoriasis in 64% of monozygotic (identical) twins • early influx of T cells into expanding lesions
compared to 15% for dizygotic twins, corresponding to • strong association with the major histocompatibility
an estimated heritability of 91%. Very similar figures complex (MHC), particularly HLA‐C:06:02
(73% and 20% respectively) were found in a retrospective • ablative effect of anti‐T‐cell therapy
study in the USA, although in an Australian study lower • anecdotal evidence of development of psoriasis after
concordance rates were observed: 35% in monozygotic syngeneic bone marrow transplant
twins compared to 12% in dizygotic twins. Of interest, • induction of lesional phenotype in nonlesional psori-
when monozygotic twins are concordant for psoriasis, atic skin transplanted on to severe combined immuno-
the age of onset, distribution of the disease and severity deficient mice after injection of autologous T cells.
are very similar, suggesting that genetic factors play a More recently it has emerged that the innate immune
role in these parameters. However, concordance rates do system, which provides an early response against harm
not reach 100%, even when older twins are examined, to the host, is dysregulated in psoriasis. Further, in
indicating that other factors including the environment psoriatic stratum corneum, there is an abundance of

play a key role in disease expression. Variable extent, antimicrobial peptides such as defensins and cathelici-
clinical features and pattern of inheritance suggest that dins, which have the capacity to activate innate immune
significant disease heterogeneity exists. Thus rare fami- responses. These in turn lead to antigen‐driven T‐cell
lies exist in which changes in a single gene may be suffi- expansion and activation. The key question remains the
cient to cause the disease while in more common forms it nature of the antigen involved. To date this is unresolved
is likely that changes in multiple genes, interacting both but evidence of an antigen‐specific response includes:
with each other and the environment, are required for (i) limited clonality of infiltrating T cells; (ii) persistence
disease expression. of T‐cell clones in plaques over several years; and
Little is known of the genetic epidemiology of other (iii) identical T‐cell clones in tonsils and skin of patients
forms. Guttate psoriasis, which frequently has onset in with Streptococcus‐associated psoriasis [8].
childhood, is almost invariably HLA‐C:06:02 associated A primary role for Th1‐type responses has previously
[7] and thought to be closely linked pathogenetically to been postulated in disease pathogenesis but more recent
Type I plaque psoriasis. GPP, although usually manifest- observations strongly suggest that Th17 cells are likely to
ing in middle age, has been reported in infants and in be the primary pathogenic subset. Evidence includes
childhood. Families with parental consanguinity and genetic association, with IL‐23 a key cytokine in genera-
multiple affected individuals have been observed, tion of Th17 cells, abundance of IL‐23 in psoriatic tissue
suggesting autosomal recessive inheritance, at least in and induction of a psoriatic phenotype by IL‐23 in animal
some pedigrees. models. Other cytokines downstream of IL‐23 in Th17
pathways, including IL‐17 and IL‐22, have similar func-
tional effects [9].
Environmental risk factors
Present evidence indicates that interactions between Molecular genetics
genes and the environment are important in disease cau- Very significant progress (reviewed in [10]) has been
sation. Many environmental factors have been linked to made in understanding the genetic architecture of psoria-
psoriasis and have been implicated in, for example, initia- sis, aided in great part by technological advances made
tion of the disease process and exacerbation of pre‐exist- possible by the human genome mapping project and
ing disease. However, robust evidence validating these subsequent large‐scale molecular genetic projects. With
factors is often lacking. They include: respect to PV, genome‐wide association studies (GWAS)
• trauma (Koebner phenomenon) have revealed significant new knowledge. Pustular forms
• infection, especially Streptococcus have benefited from methods allowing rapid cost‐
• drugs, especially lithium, β‐blockers, antimalarials effective sequencing (next‐generation sequencing) such
• sunlight as whole exome sequencing.
• psychogenic factors. In PV, studies clearly indicate that the primary genetic
susceptibility locus is on chromosome 6p21.3. Most
evidence indicates that the causative gene involved is
Pathogenetic mechanisms HLA‐C:06:02 although extensive linkage disequilibrium
The cardinal features of lesional psoriatic skin are: at this locus makes it difficult to be categorical.
• epidermal hyperproliferation with loss of differentiation HLA‐C:06:02 positive individuals have a five‐fold
• dilatation and proliferation of dermal blood vessels increased risk of developing psoriasis. The heritability
• cutaneous inflammation. due to HLA‐C:06:02 is greater than for all other identified
Gene/
Chr Function P value OR (95% CI)
locus
5q15 ERAP1 Antigen processing 2.56 × 10–11 1.27
6p21 HLA-C Ag presentation 4.06 × 10–214 4.66
1p31 IL23R IL-23 signalling 7.13 × 10–07 1.49
5q33 IL12B IL-23 signalling 4.93 × 10–11 1.39
12q13 IL23A IL-23 signalling 2.49 × 10–07 1.49
6q21 TRAF3IP2 IL-17/NF-κB signalling 5.29 × 10–20 1.36
19p13 TYK2 IL-23/NF-κB signalling 4.04 × 10–11 1.34
2p16 REL NF-κB signalling 3.59 × 10–9 1.23
5q33 TNIP1 NF-κB signalling 3.92 × 10–05 1.27
6q23 TNFAIP3 NF-κB signalling 6.54 × 10–07 1.22

14q13 NFKBIA NF-κB signalling 1.52 × 10–11 1.19

Fig. 28.1 Genetic loci with strongest association to
psoriasis vulgaris as revealed by genome‐wide association
1q21 LCE3D Skin barrier 3.32 × 10–10 1.29
studies. Colour coding groups together overlapping
functions to demonstrate that such genetic studies
1p36 IL28RA IFN signalling 6.89 × 10–8 1.22 highlight specific biological pathways that associate with
psoriasis vulgaris. Chr, chromosomal localization; Gene,
2q24 IFIH1 IFN signalling 1.06 × 10–13 1.38 top candidate gene at each locus; Function, putative
function of candidate gene; P value, statistical validation of
20q13 ZNF313 IFN signalling 1.65 × 10–06 1.20 association; OR, odds ratio or size of effect; Ag, antigen;
IFN, interferon; IL, interleukin; NF, nuclear factor.
loci combined. Approximately 50% of patients with homeostasis and altered growth pattern in genetically
severe psoriasis in UK tertiary practice are HLA‐C:06:02 predisposed individuals [9]. The initiation phase involves
positive (Jonathan Barker, personal communication). a close interplay between external factors and the
HLA‐C is involved in antigen presentation to CD8 and epidermal barrier. Triggers include physical injury (which
NK T cells, implicating them in disease pathogenesis. causes Koebner phenomenon), infections and medica-
GWAS have so far identified 46 genetic loci that associ- tions, although in most cases they are never identified.
ate with PV (Fig. 28.1), explaining about 30% of the Such triggers lead to activation of innate immunity, pos-
genetic contribution to the disease [11]. Currently the sibly through the release of the antimicrobial peptide
‘missingness’ remains unexplained but multiple genetic LL37 (cathelicidin) by keratinocytes. LL37 binds with
explanations exist. Each identified locus has a low impact pathogen‐derived DNA or self‐DNA that has been
on heritability, with odds ratios (OR) of effect size released by stressed or dying cells and forms complexes
between 1 and 2. Nevertheless they provide major that activate toll‐like receptor (TLR) 9 on plasmacytoid
insights into disease biology and give specificity to dendritic cells [12]. Imiquimod has been shown to induce
immunological models of disease pathogenesis, clearly psoriasiform skin inflammation in mouse m odels, indi-
identifying disease‐specific biological pathways. This cating that TLR‐7 and TLR‐8 may also be involved in pso-
knowledge has been used to important clinical benefit, riasis pathogenesis. TLR activation promotes type I
for example by identifying new drug targets including interferon (IFN) release, which, along with tumour necro-
those targeted by the biologic therapies. sis factor (TNF)‐α, IL‐6 and IL‐1β, activates local myeloid
dendritic cells, consequently inducing T‐cell‐mediated
(adaptive) inflammation. Genetic data would suggest
Pathogenetic model of psoriasis that nuclear factor (NF)‐κB mechanisms are important in
Combining immunological and genetic knowledge allows these processes [10]. Myeloid dendritic cells migrate into
the building of a pathogenetic model of psoriasis draining lymph nodes and release cytokines including
(Fig. 28.2) in which dynamic interactions between multi- TNF‐α, IL‐23 and IL‐12 that activate allogeneic T cells.
ple cell types and numerous cytokines in response to trig- GWAS studies suggest that endoplasmic reticulum amin-
gers culminate in the disruption of skin immune opeptidase (ERAP)‐1 plays a role in antigen processing
Chapter 28 Psoriasis: Aetiology and Pathogenesis 353
activate keratinocytes, resulting in the release of cytokines

Pathogens and chemokines that continue to recruit and activate
inflammatory cells and induce altered growth in keratino-
cytes and the dermal vasculature (transforming growth
factor [TGF]‐β and vascular endothelial growth factor
Tissue
[VEGF] respectively have been implicated in these
(skin)
LCE3D
specific processes).
events
Pustular psoriasis
IL28RA
Interferon While most attention has been paid to PV, the common
signalling IFIH1 form of the disease, recent genetic studies supported by
ZNF313
functional genomic experiments have provided major
insights into pathogenetic mechanisms in pustular forms
REL of psoriasis. With respect to onset in childhood, perhaps
Innate the most important example is GPP. Indeed, in von
TNIP1
immunity: Zumbusch’s original description of the disease, one case
TNFAIP3 NF-κB/TNF
pathways IL23R
had onset in very early childhood. Two studies, one using
NFKBIA classic linkage analysis [14] and a second using next‐
IL12B generation sequencing [15], identified mutations in the
Immune IL23A gene for IL36RN, a receptor antagonist and member of
signalling the IL‐1 superfamily. As a consequence, signalling
TRAF3IP2
through the IL‐36 receptor is not regulated and an autoin-
Adaptive TYK2 flammatory syndrome results. Many studies from around
immunity: the world have since confirmed these findings.
ERAP1
Ag processing
& presentation References
HLA-C
1 Mahil SK, Capon F, Barker JN. Update on psoriasis immunopatho-
Differentiation genesis and targeted immunotherapy. Semin Immunopathol 2016;
IL-17
38:11–27.
2 Barker J. Psoriasis heritability: 125 years and counting. Br J Dermatol
2014;171:3–5.
3 Elder JT, Nair RP, Guo SW et al. The genetics of psoriasis. Arch
Dermatol 1994;130:216–24.
4 Andressen C, Henseler T. [Inheritance of psoriasis. Analysis of 2035
family histories]. Hautarzt 1982;33:214–7.
5 Henseler T, Christophers E. Psoriasis of early and late onset: charac-
terization of two types of psoriasis vulgaris. J Am Acad Dermatol
1985;13:450–6.
6 Burden AD, Javed S, Bailey M et al. Genetics of psoriasis: paternal
inheritance and a locus on chromosome 6p. J Invest Dermatol
1998;110:958–60.
7 Mallon E, Bunce M, Savoie H et al. HLA‐C and guttate psoriasis. Br J
Fig. 28.2 Schematic representation of immunopathogenesis model of Dermatol 2000;143:1177–82.
psoriasis (see text for more detail). Tissue‐specific events lead through 8 Diluvio L, Vollmer S, Besgen P et al. Identical TCR beta‐chain rear-
interferon signalling to activation of innate immune pathways. In turn this rangements in streptococcal angina and skin lesions of patients with
leads to activation of adaptive T‐cell pathways involving specific differen- psoriasis vulgaris. J Immunol 2006;176:7104–11.
tiation pathways. Characters in columns on left and right reference 9 Nestle FO, Kaplan DH, Barker J. Psoriasis. N Engl J Med
candidate genes listed in Fig. 28.1 to demonstrate overlap between 2009;361:496–509.
10 Mahil SK, Capon F, Barker JN. Genetics of psoriasis. Dermatol Clin
immunological pathways and identified genetic loci. Ag, antigen; IFN,
2015;33:1–11.
interferon; IL, interleukin; NF, nuclear factor; TNF, tumour necrosis factor.
11 Capon F, Burden AD, Trembath RC, Barker JN. Psoriasis and other
complex trait dermatoses: from loci to functional pathways. J Invest
Dermatol 2012;132:915–22.
and HLA‐C in antigen presentation [13]. Once activated, 12 Lande R, Botti E, Jandus C et al. The antimicrobial peptide LL37 is a
T‐cell autoantigen in psoriasis. Nat Commun 2014;5:5621.
T cells enter the circulation and move towards inflamed 13 Genetic Analysis of Psoriasis Consortium & the Wellcome Trust Case
skin through interactions with adhesion molecules Control Consortium 2, Strange A, Capon F, Spencer CC et al.
(including P‐selectin and E‐selectin) on the endothelial A genome‐wide association study identifies new psoriasis suscepti-
cells of blood vessels. Functional immunology and genet- bility loci and an interaction between HLA‐C and ERAP1. Nat Genet
2010;42:985–90.
ics clearly indicates that the primary T cell involved in 14 Marrakchi S, Guigue P, Renshaw BR et al. Interleukin‐36‐receptor
psoriasis pathogenesis is differentiated along the IL‐17 antagonist deficiency and generalized pustular psoriasis. N Engl J
pathway. This is supported by clinical studies showing Med 2011;365:620–8.
15 Onoufriadis A, Simpson MA, Pink AE et al. Mutations in IL36RN/
dramatic clinical benefit from therapeutic monoclonal
IL1F5 are associated with the severe episodic inflammatory skin dis-
antibodies that inhibit IL‐23 and IL‐17. The effector mol- ease known as generalized pustular psoriasis. Am J Hum Genet
ecules secreted by T cells including IL‐17 and IL‐22 then 2011;89:432–7.
354
CHA PTER 2 9
Psoriasis: Clinical Features and Comorbidities

Derek H. Chu1 & Kelly M. Cordoro2
1
Stanford University School of Medicine, Palo Alto, CA, USA
2
University of California San Francisco, San Francisco, CA, USA
Clinical features, 354 Disease comorbidities, 359
Abstract Major categories include plaque, guttate, inverse, nail, pustu-

lar and erythrodermic psoriasis. In addition to arthritis, children
with psoriasis are at increased risk for other comorbidities such as
Paediatric psoriasis is a common and often chronic inflammatory
metabolic and cardiovascular disease, psychiatric disorders, social
disorder of the skin. Clinical subtypes of psoriasis are based pri-
stigma and reduced quality of life.
marily on the site of involvement and predominant morphology.
Key points receptor antagonist (IL36RN) and caspase recruitment family

member 14 (CARD14).
• A diagnosis of juvenile psoriatic arthritis can be made in the

• Plaque psoriasis is the most prevalent form of psoriasis in the
presence of arthritis and psoriasis, or arthritis coupled with a
paediatric population and commonly features facial and anogenital
family history of psoriasis in a first‐degree relative, nail pitting
involvement, annular morphology and prominent pruritus.
or onycholysis, and/or dactylitis.
• Guttate psoriasis has been reported in up to 44% of children
• Emerging data suggest that children with psoriasis are at
with psoriasis and is frequently preceded by streptococcal
increased risk for metabolic and cardiovascular comorbidities,
pharyngitis or perianal infection. A subset of patients may go on
including obesity, hyperlipidaemia, diabetes and hypertension.
to develop chronic plaque psoriasis.
Age‐related screening should be performed to facilitate early
• Psoriatic napkin dermatitis is common in children under the age
intervention.
of 2 years, and can acutely progress to widespread disease, the
• Psoriasis can have detrimental psychosocial effects on paediatric
so‐called psoriatic napkin rash with dissemination.
patients regardless of the extent of disease, leading to social
• A subset of patients with early onset and severe generalized
stigma, poor quality of life, depression and anxiety.
pustular psoriasis carry genetic mutations in interleukin 36
Clinical features Fortunately, many children have limited disease amenable

to topical treatment, although a subset of patients present
Psoriasis is a common inflammatory disorder that affects with severe and recalcitrant psoriasis requiring photo-
the skin, nails and joints. One third of cases present therapy and/or systemic medications.
in childhood [1]. Although the classic description of pso- There are multiple recognized clinical subtypes of pso-
riasis is a well‐demarcated erythematous plaque with riasis, the classification of which encompasses both pri-
silvery‐white scale, there can be significant age‐related mary morphology and site of involvement. Major
variations in the morphology, distribution and severity. subtypes include plaque, guttate, pustular and erythro-
Compared to adults, young children tend to have more dermic. Subtypes with special features based on site
facial and anogenital involvement. Individual lesions include inverse or flexural psoriasis, napkin (anogenital)
may be smaller and thinner and commonly feature annu- psoriasis and nail psoriasis (Box 29.1) [4].
lar morphology. Pruritus is a frequent symptom in chil-
dren [2]. Psoriasis may be triggered or exacerbated by Plaque psoriasis
trauma (Koebner phenomenon), infection, stress and Plaque psoriasis is the most common form of psoriasis in
medications [3]. Paediatric psoriasis may be mild and the paediatric population, with a reported prevalence of
localized or diffuse, severe and debilitating. In most cases, 34–84% [5,6]. Classically, patients develop well‐demarcated
psoriasis is a chronic condition that follows a relapsing erythematous papules and plaques with overlying silvery
and remitting course. The unpredictable natural history, scale (Fig. 29.1), often distributed symmetrically over the
typified by periods of exacerbation and spontaneous extensor extremities, scalp and face. The removal of scale
remission, makes management rather challenging. results in pinpoint bleeding, known as the Auspitz sign.
Chapter 29 Psoriasis: Clinical Features and Comorbidities 355
Box 29.1 Clinical variants of childhood psoriasis
Plaque
Facial
Scalp
Palmoplantar
Annular
Eczema–psoriasis overlap
Linear
Guttate Fig. 29.2 Facial psoriasis – 6‐year‐old boy with psoriasis over the eyelids
Follicular/micropapular and periorbital skin.
Inverse (intertriginous)
Napkin (diaper)/anogenital
Nail
Pustular
Erythrodermic
Source: Cordoro [4]. Reproduced with permission of Elsevier.
Fig. 29.3 Scalp psoriasis – 4‐year‐old girl with plaque psoriasis involving
the postauricular and occipital scalp.
it can be difficult to differentiate facial psoriasis from

eczema, unlike eczema, lesions of psoriasis on the face
tend to be more sharply marginated, more plaque‐like,
may be annular and are less pruritic [8]. Periorbital
involvement is common (Fig. 29.2). Facial psoriasis may
be accompanied by not only severe symptoms such as
itch and discomfort, but also social stigmatization.
Fig. 29.1 Plaque psoriasis – 9‐year‐old boy with multiple discrete, sharply Scalp
marginated, erythematous papules and plaques with overlying silvery‐ The scalp is the most frequent site of involvement of
white scale.
plaque psoriasis in children (Fig. 29.3). It is the initial site
of presentation of psoriasis in about 40–60% of children
and adolescents [9]. Like facial psoriasis, scalp disease can
Plaque psoriasis can be subcategorized based on location, also occur exclusively for many years. Scalp psoriasis
such as facial, scalp and palmoplantar, as well as by may present as diffuse scaling or discrete plaques, regu-
morphology, including annular, eczema–psoriasis overlap larly involving the postauricular and occipital scalp
and linear variants. although it can occur anywhere on the scalp as well as
on, and within, the ears. The scale may become very
Facial thick and lead to matting of the hair, known as pityriasis
The face is a common site for psoriasis in children as amiantacea [10]. When severe and prolonged, this pres-
opposed to adults [7]. Facial psoriasis may arise in isola- entation can result in focal nonscarring alopecia. The alo-
tion or as part of a more disseminated eruption. In a large pecia is generally reversible with adequate treatment [3].
case series of 1262 children with psoriasis in Sydney, Perhaps the most debilitating aspect of scalp psoriasis
Australia, 38% of patients had facial involvement [8]. is the propensity for intense pruritus. Scalp psoriasis
About 4% of cases had isolated facial plaques. Facial may be difficult to differentiate from, and may occur
involvement is a characteristic feature of psoriatic napkin simultaneously with, seborrhoeic and atopic dermatitis.
rash with dissemination (see Inverse psoriasis). Although Tinea capitis should be ruled out with a fungal culture.
Fig. 29.5 Annular psoriasis – 11‐year‐old boy with numerous annular

plaques on the back.
Fig. 29.4 Plantar psoriasis – 12‐year‐old boy with severe hyperkeratotic

coalescent plaques on the plantar feet.
Palmoplantar
This is an uncommon variant of psoriasis in the paediatric
population, the prevalence of which was only 4% in a
large series of 1262 cases of childhood psoriasis [8]. The
palms and soles can either have a ‘glazed’ appearance with
erythema and fissuring, or more typical thick coalescent
plaques with silvery scale (Fig. 29.4). Both presentations
typically have a sharp demarcation at the medial and lat-
eral borders of the palms and soles.
Annular
In contrast to adults with psoriasis, children more often
present with annular and serpiginous plaques on the face,
trunk and extremities (Fig. 29.5). The annular plaques
may be studded with peripheral pustules and these chil-
dren are at risk of generalized pustular psoriasis. Annular
presentations of psoriasis may be confused clinically with Fig. 29.6 Eczematous psoriasis – 9‐year‐old boy with overlapping features
tinea corporis and nummular dermatitis. of psoriasis and eczema consisting of diffuse xerosis, follicular accentuation
and discrete scaly pink patches.
Eczema–psoriasis overlap
A small subset of patients present with overlapping fea- Linear
tures of both eczema and psoriasis. Variably referred to as This is a rare form of childhood psoriasis. Only one case
eczematous psoriasis or psoriasiform eczema, these patients was identified in a child >2 years of age in the case series
present with either an admixture of eczematous and pso- by Morris et al [8]. Patients manifest with psoriasiform
riatic lesions, or have individual lesions with an interme- plaques following the lines of Blaschko. Histopathological
diate morphology (Fig. 29.6). These children typically evaluation may be necessary to differentiate this subtype
have an atopic background, or have a family history of from inflammatory linear verrucous epidermal naevus
atopy and psoriasis. (ILVEN).
Fig. 29.7 Guttate psoriasis – 12‐year‐old boy with numerous ‘drop‐like’ Fig. 29.8 Napkin (diaper) psoriasis – 19‐month‐old girl with well‐defined
scaly papules on the trunk. shiny red plaque with minimal scale involving the perineum. There is early
dissemination of disease with formation of erythematous plaques on the
abdomen.
Guttate psoriasis
Guttate psoriasis is the second most common variant of
psoriasis in children and adolescents, with a reported fre- have more typical plaques elsewhere on the body. Infants
quency of 6.4–44% [5]. Patients present with an abrupt in particular will manifest with a napkin dermatitis or
onset of small <1 cm ‘drop‐like’ scaly papules primarily anogenital disease.
on the trunk, proximal extremities and face (Fig. 29.7).
Group A β‐haemolytic streptococcal pharyngitis or peria- Napkin/anogenital psoriasis
nal infection 1–2 weeks prior to onset of the eruption is Psoriatic napkin dermatitis, or ‘napkin psoriasis’, is a
frequently noted [11]. Recent data suggest that guttate common presentation in children under the age of 2
psoriasis in children may have a variable prognosis years. In fact, 45% of psoriasis patients in this age group
depending on the presence or absence of streptococcal will manifest with napkin rash [8]. In patients present-
infection as a trigger. Ko et al. found that preceding strep- ing with other variants of psoriasis, more than 20% have
tococcal pharyngitis predicted guttate morphology and a history of psoriatic napkin rash [8]. Well‐defined,
eventual resolution of the psoriasis [12], while Mercy glazed‐appearing red plaques in the napkin area, often
et al. found that preceding streptococcal pharyngitis pre- with attenuated scale or devoid of scale altogether and
dicted guttate morphology but not disease severity. In the involving the creases, characterize this subtype of pso-
latter study, initial guttate morphology in the absence of riasis (Fig. 29.8). The distribution and morphology of the
streptococcal infection predicted progression to severe eruption can help to distinguish psoriasis from other
psoriasis [13]. Therefore, although guttate psoriasis may napkin eruptions including irritant and candidal derma-
spontaneously resolve after 3–4 months, a subset of titis and acrodermatitis enteropathica. As these condi-
patients will go on to develop classic, and possibly severe, tions can overlap, the most helpful distinguishing
plaque psoriasis. A very small subset of patients with gut- feature is finding more typical psoriasis elsewhere on
tate psoriasis may present with 1–3 mm micropapular, the body. A subset of patients with napkin psoriasis
follicular‐based lesions alone or in the presence of more acutely progress from localized to widespread disease,
typical guttate morphology. Guttate psoriasis is often so‐called psoriatic napkin rash with dissemination.
confused with pityriasis rosea, a viral exanthem that fol- Reports suggest that those with psoriatic napkin rash
lows Langer’s lines on the trunk to create a ‘Christmas with dissemination are at higher risk of developing
tree’ pattern. A biopsy, if necessary, will differentiate classic psoriasis later in life [15].
between the two conditions.
Nail psoriasis
Inverse psoriasis Nail psoriasis has been reported to occur in up to 40% of
Inverse or flexural psoriasis, in contrast to chronic children and adolescents [13]. Nail changes may arise in
plaque psoriasis, has a distinct morphology with bright isolation or can precede, coincide with, or develop after
red or shiny erythema, frequent maceration and mini- the onset of cutaneous disease [14]. Pitting of the nails
mal scale [14]. Common sites of involvement include is most frequently observed (Fig. 29.9). Additional
the neck, groin and axillae. In addition, patients may features include onycholysis, oil spots, subungual

Fig. 29.11 Pustular psoriasis – 8‐year‐old boy with generalized pustular

psoriasis of von Zumbusch.
Fig. 29.9 Nail psoriasis – 11‐year‐old girl with pitting, oil spots and distal
onycholysis of the fingernails.
A proportion of patients with generalized pustular

psoriasis harbour autosomal recessive mutations in the

interleukin (IL)‐36 receptor antagonist (IL36RN). This
recently described monogenic autoinflammatory syn-
drome is referred to by the acronym DITRA, (deficiency
of interleukin‐36 receptor antagonist) [17]. Aberrant
IL‐36RN structure and function leads to unregulated
secretion of inflammatory cytokines, generalized pustulo-
sis and unopposed activation of inflammatory pathways
[18]. This variant of generalized pustular psoriasis typi-
cally occurs in the absence of concomitant plaque psoria-
sis. More recently, gain‐of‐function mutations have been
discovered in caspase recruitment family member 14
Fig. 29.10 Pustular psoriasis – 14‐year‐old boy with discrete pustules at
(CARD14), a mediator of NF‐κB signalling that predis-
the periphery of bright red annular plaques on the arm. poses patients to earlier onset disease and severe gener-
alized pustular psoriasis refractory to treatment [19]. Of
note, CARD14 mutations have also been identified in
hyperkeratosis, splinter haemorrhages, onychodys- overlap presentations of psoriasis and pityriasis rubra
trophy and trachyonychia. The presence of nail disease pilaris [20].
has been associated with psoriatic arthropathy (see Deficiency of IL‐1 receptor antagonist (DIRA) is another
Disease comorbidities). rare, autosomal recessive, neonatal onset, life‐threatening
autoinflammatory disease that may be confused with early
Pustular psoriasis onset pustular psoriasis. Patients present with dissemi-
Pustular psoriasis is rare, but does occur, in children of all nated pustules soon after birth, along with periostitis,
ages [14]. Pustular psoriasis in the paediatric age group sterile multifocal osteomyelitis and elevated inflammatory
may be localized or generalized and often follows a markers [21]. IL‐1 antagonists are life‐saving therapies for
relapsing and remitting course. Discrete and coalescent these patients.
sterile superficial pustules arise on an erythematous base
and may form annular plaques (Fig. 29.10). Another vari- Erythrodermic psoriasis
ant common in children is the development of pustules at This is an extremely rare form of psoriasis in paediatric
the periphery of pre‐existing psoriatic plaques [16]. patients and may arise de novo or in a child with pre‐
Generalized forms of pustular psoriasis, including the existing plaque psoriasis (Fig. 29.12). Psoriasis should be
von Zumbusch variant, are sometimes associated with considered in the differential diagnosis of an erythroder-
systemic symptoms such as fever, malaise, arthralgias mic infant or child. Characterized by diffuse erythema
and elevated inflammatory markers (Fig. 29.11). Localized and scaling involving >90% of the body surface area in
forms, including acrodermatitis continua of Hallopeau severe cases, erythrodermic psoriasis can be compli-
and palmoplantar pustulosis, are characterized by severe cated by temperature dysregulation, hypernatraemic
involvement of the digits and nail unit and palms and dehydration, hypoalbuminaemia, infection and cardiac
soles, respectively. failure [22].
c ommon presentation. The presence of dactylitis favours

a diagnosis of psoriasis over other arthritides. A relatively
milder form of disease commonly associated with spon-
dyloarthritis and HLA‐B27 positivity tends to affect ado-
lescent males, while a more severe and recalcitrant form
peaks at 2 years of age and is frequently characterized by
a positive anti‐nuclear antibody (ANA) and female pre-
disposition [25]. Rheumatoid factor is typically negative.
One study suggests that there is a significantly increased
risk of joint involvement in patients of all ages with eryth-
rodermic, generalized pustular, inverse and nail psoriasis
[26]. Of note, asymmetrical anterior uveitis has been
reported in up to 17% of children with psoriatic arthritis,
underscoring the importance of ophthalmic evaluation in
the setting of psoriatic arthritis [27].
Metabolic and cardiovascular
Obesity
Paediatric patients with psoriasis appear to have a higher
Fig. 29.12 Erythrodermic psoriasis – 10‐year‐old boy with erythroderma in prevalence of excess adiposity and obesity when com-
context of prior plaque psoriasis. pared with children without psoriasis [28]. In a large mul-
ticentre international cross‐sectional study of 614 children
aged 5–17 years with a 6‐month or more history of psoria-
Disease comorbidities sis, the odds ratio (OR) of obesity (body mass index [BMI]
≥95th percentile) and excess adiposity (BMI ≥85th percen-
Sufficient evidence exists to underscore the importance
tile) when compared with controls was 4.29 and 2.65,
of carefully evaluating and monitoring paediatric psori-
respectively [29]. Moreover, those with severe psoriasis,
asis patients for potential extracutaneous comorbidities.
based on physician global assessment and an affected
Psoriatic arthritis is the most widely recognized. Patients
body surface area of greater than 10%, had an overall
are also at higher risk for components of the metabolic
higher risk for obesity than those with mild psoriasis (OR
syndrome, especially obesity, as well as dyslipidaemia,
4.92 vs. 3.6). Waist circumference, a surrogate marker for
diabetes and hypertension. Of equal importance is the
central adiposity, was also greater in psoriatic patients. A
potentially detrimental effect of psoriasis on a child’s
>90th percentile waist circumference was found in 21.2%
quality of life. Children with psoriasis may suffer from
of patients with severe psoriasis compared to only 14%
poor self‐esteem, depression and anxiety. Historically,
with mild psoriasis and 9.3% of controls [29]. Some
the rate of counselling and screening for paediatric pso-
authors postulate that obesity may predispose suscepti-
riasis comorbidities has been low [23]. In order to inter-
ble individuals to the development of psoriasis, perhaps
vene early and potentially mitigate any long‐term health
related to a systemic pro‐inflammatory state mediated by
consequences, it is critical to actively screen patients
excess adipose tissue. In fact, one study demonstrated
and identify risk factors for these potential disease
that being overweight and obese preceded psoriasis by at
comorbidities.
least 2 years in 93% of children with psoriasis [30]. It is,
however, still unclear whether weight loss can help to
Psoriatic arthritis
reduce psoriasis severity.
The exact prevalence of psoriatic arthritis in children is
not known as historically there has been a lack of uni-
versally accepted diagnostic criteria. Prevalence esti- Dyslipidaemia
mates vary widely and range from 5% to 40% [10]. In Emerging data suggest that dyslipidaemia is associated
recent years, the International League of Associations for with psoriasis not only in adults, but also in children. In a
Rheumatology (ILAR) criteria have become the diagnos- cross‐sectional study of 710 949 patients aged 2–19 years
tic standard for juvenile psoriatic arthritis. A diagnosis enrolled in Kaiser Permanente Southern California health
can be made in the presence of arthritis and psoriasis, or plan, including 1350 patients diagnosed with psoriasis,
arthritis coupled with a family history of psoriasis in a the mean total cholesterol, low‐density lipoprotein cho-
first‐degree relative, nail pitting or onycholysis, and/or lesterol, triglycerides and alanine aminotransferase were
dactylitis [24]. significantly higher in children with psoriasis compared
Cutaneous disease often precedes the onset of joint dis- to children without psoriasis after adjusting for BMI [31].
ease, although arthritis may be the initial manifestation in There is a lower high‐density lipoprotein level in paediat-
up to 15% of patients [3]. The peak onset of disease is ric patients with psoriasis compared to controls [32].
between the ages of 9 and 12 years [14]. Psoriatic arthritis Additionally, there is an association between psoriasis
is clinically heterogeneous, with asymmetrical oligoar- and higher apolipoprotein B concentrations, decreased
ticular arthritis of the hands and feet being the most large high‐density lipoprotein particles, and reduced
cholesterol efflux capacity [33]. These compositional and Table 29.1 Paediatric psoriasis comorbidity screening recommendations
functional abnormalities in lipoproteins reveal a tendency
towards atherogenesis even early in the course of disease. Psoriasis Screening recommendations
comorbidity
Diabetes
Arthritis Periodic history and physical examination to assess
The literature supports psoriasis as an independent risk for: (i) joint pain/swelling; (ii) joint stiffness after
factor for diabetes in adults. Further studies are needed to rest; (iii) dactylitis; and (iv) limp
determine whether this is also true in the paediatric popu- Overweight/obesitya Annual BMI starting at age 2 years
lation. In a small study of 20 children aged 9–17 years with Dyslipidaemia Universal lipid screen starting at age 9–11 and
moderate to severe psoriasis and 20 age‐ and sex‐matched 17–21 years
controls, patients with psoriasis had a statistically signifi- Additional/repeat testing if patient has other
personal or familial cardiovascular risk factors
cant higher mean fasting blood glucose of 91.1 mg/dL
Diabetes Overweight and ≥10 years old:
compared to 82.9 mg/dL [34]. However, no subject met the Fasting glucose every 2 years if patient has risk
fasting blood glucose requirement for diabetes. In a large factors for insulin resistance
cross‐sectional survey of 1.3 million patients aged 0–20 Obese and ≥10 years old:
years registered in a German health insurance organiza- Fasting glucose every 2 years
tion, of whom 33 981 carried a diagnosis of psoriasis, the Hypertension Annual blood pressure starting at age 3 years
Nonalcoholic fatty Overweight and ≥10 years old:
prevalence ratio of diabetes in those with psoriasis versus
liver disease AST/ALT every 2 years if patient has risk factors for
those without psoriasis was 2.01 [35]. As such, high‐risk insulin resistance
children should be considered for routine diabetes screen- Overweight and ≥10 years old:
ing (see Screening recommendations). AST/ALT every 2 years
Mood disorders/ Annual screen for mood disorders and substance

Hypertension substance abuse abuse
Elevated blood pressure represents another component of
the metabolic syndrome, and may be associated with Source: [40–42].
a
Overweight, BMI ≥85th and <95th percentile; obese, BMI ≥ 95th
childhood psoriasis. A prevalence ratio for hypertension
percentile.
of 1.89 in paediatric psoriasis patients compared to those ALT, alanine transaminase; AST, aspartate transaminase; BMI, body
without psoriasis has been reported [35]. Further studies mass index.
are needed to confirm whether psoriasis is an independent
risk factor for hypertension in children and adolescents.
Screening recommendations
Nonalcoholic fatty liver disease Routine monitoring of children with psoriasis and
There are multiple adult studies reporting the association screening for potential comorbidities will help identify
between psoriasis and nonalcoholic fatty liver disease problems at an early age when prevention of downstream
(NAFLD). To date, investigations in children are lacking. sequelae may be possible. The data available for comor-
Given the association of obesity and insulin resistance bidities of paediatric psoriasis suggest that age‐related
with NAFLD [36], children with these comorbidities screening as recommended by the American Academy of
should be screened for the development of liver disease. Paediatrics is sufficient, unless signs or symptoms arise
that point to the need for additional evaluation. These
Psychosocial recommendations are summarized in Table 29.1 [40–42].
Psoriasis can have profound psychosocial effects on chil-
dren and adolescents, regardless of the extent of disease. References
Patients commonly report a reduced quality of life as a 1 Raychaudhuri SP, Gross J. A comparative study of pediatric onset
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Pediatr Clin North Am 2014;61:261–77.
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than 18 years of age, and in particular found a 25–30% future. Am J Clin Dermatol 2013;14:195–213.
6 Lewkowicz D, Gottlieb AB. Pediatric psoriasis and psoriatic arthritis.
greater risk of depression and anxiety subsequent to diag- Dermatol Ther 2004;17:364–75.
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clinical review of 1262 cases. Pediatr Dermatol 2001;18:188–98.
arate retrospective cohort study by Kim et al. revealed
9 Howard R, Tsuchiya A. Adult skin disease in the pediatric patient.
that a younger age at diagnosis of psoriasis seemed to be Dermatol Clin 1998;16:593–608.
associated with depression, social discrimination and 10 Bhutani T, Kamangar F, Cordoro KM. Management of pediatric pso-
higher lifetime Dermatology Life Quality Index (LT riasis. Pediatr Ann 2012;41:e1–7.
11 Honig PJ. Guttate psoriasis associated with perianal streptococcal dis-
DLQI) [39]. It is important to note that treatments we use ease. J Pediatr 1988;113:1037–9.
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362
CHA PTER 3 0
Psoriasis: Classification, Scores and Diagnosis

Nirav Patel & Megha Tollefson
Departments of Dermatology and Pediatrics, Mayo Clinic, Rochester, MN, USA
Classification, 362 Scores, 363 Diagnosis, 363
Abstract a clinical scoring tool such as the Psoriasis Area and Severity Index
(PASI) and the Physician Global Assessment (PGA) can be used to
measure disease severity. The PGA has been validated in children
Psoriasis in the paediatric population can be classified into a vari-
and is easiest to use. Diagnosis is largely made on a clinical basis,
ety of morphologies. The plaque subtype is the most common, fol-
but skin biopsy, laboratory work and radiography may be indicat-
lowed by guttate psoriasis. Once a diagnosis has been established,
ed depending on the clinical scenario.
Key points scoring systems for paediatric psoriasis, with the PGA having
validation for use in children.

• Diagnosis of psoriasis is almost always made clinically, but
• Psoriasis can be classified into a number of subtypes with plaque
histology and laboratory investigation can be helpful in
psoriasis being the most common.
confirming a diagnosis and aiding in evaluation of systemic
• Guttate and inverse psoriasis are seen more commonly in the
findings.
paediatric population compared to adults.
• The Psoriasis Area and Severity Index (PASI) and the Physician
Global Assessment (PGA) are the two most commonly used
Classification
Inverse or flexural psoriasis occurs more commonly in
Psoriasis in children may have a variety of morphologies. children than adults. Napkin psoriasis is a variant of this
As with adults, the plaque subtype is the most common and is a common presentation of psoriasis in children
[1–4]. Often the scalp and extremities are most commonly under the age of 2. A family history of psoriasis may be
involved, with finer scaling than is seen in adult plaque present in these patients [3,9–11]. This location poses
psoriasis [3]. challenges with treatment due to urine, stool and friction
Scalp psoriasis is often seen in children, and is more in the area, but often improves after potty training.
common in girls [1-3]. It can be an isolated finding or be Significant nail psoriasis can be seen in children, but
seen in conjunction with plaque psoriasis and may be is less common compared to adults [4,12], and its pres-
extremely symptomatic and challenging to treat but does ence does not correlate with psoriasis severity. Pure
not correlate with psoriasis severity [1]. nail‐only involvement is rare, and pitting is the most
Guttate psoriasis is the second most common form seen common finding followed by ridging and discoloura-
in children and is more commonly seen in the paediatric tion due to subungual hyperkeratosis. The fingernails
population as compared to adults [1–3]. Development of tend to have more involvement than toenails [4]. Nail
guttate psoriasis is often closely linked to a preceding involvement is more common in boys, suggesting koeb-
Streptococcus pyogenes infection causing pharyngitis or nerization as an aetiology, and in those with later onset
perianal dermatitis [2,5–7]; streptococcal infection may disease. An association of nail psoriasis with psoriatic
also reside in the inguinal folds. Guttate psoriasis may arthritis has not been observed in the paediatric popula-
resolve spontaneously or after clearance of infection, but tion [2,13].
some children may progress to plaque psoriasis. In those Pustular psoriasis is a rare variant of psoriasis and is
patients who progress to plaque type psoriasis after an seen even less frequently in the paediatric population
initial guttate presentation, a more severe phenotype may [1,3,4]. When it is seen in children, an annular morphol-
be seen as compared to patients who did not present with ogy is more common. Pustular psoriasis can be associated
a guttate morphology [2,3,8]. with streptococcal infection and may have a more benign
Chapter 30 Psoriasis: Classification, Scores and Diagnosis 363
course than in adults [14–16]. The erythrodermic form of (BSA) and may also underestimate erythema in darker
psoriasis is similarly rare and presents with full‐body skin types. The PASI also does not factor in disease involv-
redness with or without the specific features of psoriasis ing the nails, acral surfaces, genitals or face [20,23,24].
[2,4]. Palmoplantar psoriasis is a form of acral psoriasis PASI scores correlate only moderately with quality of life
that is only occasionally seen in the paediatric population; (QoL) scores in children [22,23].
it is far more common in adults [3,12]. The PGA has multiple variations, but the most com-
Psoriatic arthritis, a rare comorbidity of psoriasis, par- monly used form is a five‐point scoring system assess-
ticularly in the paediatric population, is thought to have a ing plaque thickness, scale and degree of erythema.
bimodal peak of onset at age 2 and in puberty [17]. The PGA is inherently more simple and easier to use
Arthritis has not been linked to severity of skin disease compared to the PASI, and probably better suited for
[2]. Both linear and congenital psoriasis have also been tracking psoriasis outcomes outside the clinical trial
described as very rare variants [18,19]. setting. The PGA has been validated for use in chil-
dren [23,25]. Due to the lack of BSA in the score, a
patient may continue to have an unchanged score,
Scores even with improvement of BSA, if the character of the
Several scoring systems or clinical tools can be used to remaining plaques is unchanged [23]. Similar to the
measure disease burden in patients with psoriasis. The PASI, the PGA correlates only moderately with QoL
Psoriasis Area and Severity Index (PASI; Box 30.1) and the scores in children [21,22].
Physician Global Assessment (PGA) are the two best
studied and most commonly used tools [20]. The PASI is
more detailed than the PGA, is better studied and is Diagnosis
the most commonly used tool in clinical trials. However, The diagnosis of psoriasis is almost always made clinically.
the PASI, although used in studies, is not validated in the Classic psoriasis in children is very similar in appearance
paediatric population [21,22]. to the adult counterpart with well‐defined, erythematous
It is therefore mainly used for older children and plaques with silvery scale. There are many variants and the
adolescents only. It is less sensitive for disease that is mild differential diagnosis of psoriasis is site and morphology
to moderate and involving minimal body surface area dependent (Table 30.1). If the correct diagnosis is in ques-
tion, a biopsy can be performed but may not always be
Box 30.1 The Psoriasis Area and Severity Index diagnostic. Classic histology demonstrates regular acan-
thosis, a diminished granular layer, parakeratosis, dilation
(a) Divide body into four areas: head, arms, trunk to groin, and legs of papillary dermal vessels, Munro microabscesses (collec-
to top of buttocks tions of neutrophils in the stratum corneum) and spongi-
(b) Generate an average score for the erythema, thickness and scale form pustules of Kogoj (neutrophilic pustules in the
for each of the four areas (0 = clear; 1–4 = increasing severity)a epidermis). If there is concern for an inciting factor or for
(c) Sum scores of erythema, thickness and scale for each area
comorbidities, laboratory testing and imaging may be per-
(d) Generate a percentage for skin covered with psoriasis for each area
and convert that to a 0–6 scale (0 = 0%; 1 = <10%; 2 = 10–<30%;
formed (Box 30.2). In patients suspected of having a strep-
3 = 30–<50%; 4 = 50–<70%; 5 = 70–<90%; 6 = 90–100%) tococcal infection, or in patients presenting with the guttate
(e) Multiply score of item (c) above times item (d) above for each form of psoriasis, investigation of antistreptolysin titre and
area and multiply that by 0.1, 0.2, 0.3, and 0.4 for head, arms, a throat, inguinal fold or perianal culture may be appropri-
trunk and legs, respectively ate [7]. Patients with generalized pustular psoriasis should
(f) Add these scores to get the PASI score be evaluated for leucocytosis with neutrophilia, renal or
hepatic impairment, disturbed electrolyte balance and low
a
Erythema, induration and scale are measured on a 0–4 scale (none,
calcium. If psoriatic arthritis is suspected, imaging of the
slight, mild, moderate, severe).
Source: Feldman 2005 [24]. Reproduced with permission from BMJ Pub-
affected joints is appropriate as well as a set of parameters
lishing Group Ltd. to rule out other causes of joint involvement (e.g. infection,
autoimmune diseases) [26].
Table 30.1 Cutaneous psoriasis variants
Type Age Clinical findings Differential diagnosis
Chronic plaque Any Well‐defined erythematous plaques, Nummular eczema

silvery white scale Atopic dermatitis
Auspitz sign Allergic contact dermatitis
Extensor surfaces, trunk, periumbilical Tinea corporis
May be follicular or annular Pityriasis rubra pilaris
Scalp Any Well‐defined erythematous scaly Seborrhoeic dermatitis

plaques Tinea capitis
Tinea amiantacea Atopic dermatitis
Often extends onto forehead
Guttate Children, Small, “drop‐like” <1 cm Pityriasis rosea

adolescents, erythematous scaly papules Tinea corporis
young adults Trunk, extremities, face, scalp Pityriasis rubra pilaris
Nummular eczema
(Continued)
Inverse Younger children Erythematous plaques with little scale, Intertrigo

possible maceration Seborrhoeic dermatitis
Flexural areas and face Erythrasma
Contact dermatitis
Napkin Ages 0–2 Well‐defined bright red plaques in Irritant contact dermatitis
napkin area Allergic contact dermatitis
Little scale, may be macerated Intertrigo
Involves inguinal folds Candidal napkin dermatitis
Acrodermatitis enteropathica
Nail Any age, more Pitting, onycholysis, oil spots, Onychomycosis

common in subungual hyperkeratosis, Pityriasis rubra pilaris
older children trachyonychia Lichen planus
and adults May or may not have skin signs of
psoriasis
(Continued)
Pustular Older children and Superficial sterile pustules on Candida infection

adults erythematous skin Dyshidrotic eczema
May have annular configuration Staphylococcal scalded skin
May be localized to palmoplantar syndrome
areas Blistering dactylitis
Tinea infection
Erythrodermic Any Generalized erythema Minimal scale Staphylococcal scalded skin

Very rare syndrome
Pityriasis rubra pilaris
Cutaneous T‐cell lymphoma
Atopic dermatitis
Congenital At birth Any of the above morphologies Atopic dermatitis

Seborrhoeic dermatitis
Bacterial infection
Candida infection
Dermatophyte infection
Langerhans cell histiocytosis
Erythema toxicum
Transient neonatal pustular
melanosis
Immunodeficiency syndromes
Ichthyosis
Source: Adapted from Tollefson 2014 [11].
Box 30.2 Psoriasis investigation
Physical parameters Radiology
• Height, weight, body mass index, blood pressure in all patients • Ultrasound and/or radiographs of affected joints in those suspected
to have psoriatic arthritis
Laboratory investigations
Histology
• Guttate – culture swab from appropriate location for group A
Streptococcus, ASL • Consider skin biopsy in cases of uncertain diagnosis or atypical presentation
• Pustular, generalized – full blood count, CRP, LFTs
ANA, anti‐nuclear antibodies; ASL, antistreptolysin; CRP, C‐reactive
• Psoriatic arthritis – ESR, CRP, RF, ANA protein; ESR, erythrocyte sedimentation rate; LFTs, liver function tests;
• Concern for metabolic syndrome – fasting blood glucose and lipid RF, rheumatoid factor.
profile, blood pressure measurement
Source: Adapted from Tollefson 2014 [11].
Chapter 30 Psoriasis: Classification, Scores and Diagnosis 367
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erature. Pediatr Dermatol 2003;20:506–10. ment and management. Ann Rheum Dis 2011;70(suppl 1):i77–84.
368
CHA PTER 3 1
Psoriasis: Management
Marieke M.B. Seyger
Department of Dermatology, Radboud University Medical Center, Nijmegen, The Netherlands
Introduction, 368 Systemic therapies, 370

Topical treatments, 368 Summary, 374
Abstract this age group in particular, long‐term safety of treatments is

crucial and one of the most important concerns for dermatologists
The management of paediatric psoriasis is challenging as many treating children and adolescents with psoriasis.
treatments are not approved for use in this age group, and In this chapter, the efficacy and safety of all available treatments
evidence on efficacy and safety of most treatments is limited. In for paediatric psoriasis are presented, including some practical
addition, international evidence‐based guidelines are lacking. Even advice. Based on the available evidence, a treatment algorithm
mild forms of psoriasis may exert a significant burden of morbidity, is proposed that can serve as general guidance for the treating
and therefore adequate and effective treatment is important. In physician.
Key points • Narrow‐band UVB (NB‐UVB) should be used cautiously in the

paediatric population, particularly in young and fair‐skinned
children.
• Topical corticosteroids and/or vitamin D analogues or a
• Methotrexate is the conventional systemic drug of choice
compound formulation are standard therapeutic agents for
for children and adolescents with moderate to severe plaque
topical therapy.
psoriasis.
• If available, dithranol in a daycare setting should be commenced
• The biologics represent a promising therapeutic alternative to
before systemic treatments are considered.
conventional systemic treatment options.
Introduction are influenced by many factors such as age, severity,

location and type of psoriasis, previous treatments, QoL,
In almost one third of cases the onset of psoriasis is before practicality of the regimen, costs, accessibility, benefits
adulthood [1,2]. The management of paediatric psoriasis and risks of individual treatments. However, in this
is challenging, as many treatments are not approved for vulnerable age group, long‐term safety is one of the most
use in this age group, and evidence on efficacy and safety important concerns for all dermatologists treating
of most treatments is limited [3]. In addition, international children with psoriasis [8].
evidence‐based guidelines are lacking [4].
Another challenge in the treatment of paediatric psoria-
sis is adherence, which is especially a problem in adoles-
Topical treatments
cents and even more so when topical agents are used.
Therefore, education of patients and family members The majority of children with psoriasis can be managed
about the chronicity of the disease and the rationale of the with topical treatments. Corticosteroids, vitamin D ana-
treatment is important, as is taking patient preferences logues, calcineurin inhibitors and dithranol are used for
into consideration in selecting a treatment [5]. Timing of the treatment of mild to moderate paediatric psoriasis.
the first return visit may also be a practical tool to enhance Topical corticosteroids are generally considered to be first
patient adherence [6]. choice [9], although others prefer to start with vitamin D
Paediatric psoriasis has a negative impact on the qual- analogues [10]. In order to increase efficacy and decrease
ity of life (QoL), self‐esteem and psychosocial develop- potential side‐effects, it is advised to use treatments inter-
ment of those affected, and treatments can positively mittently, preferably in a combination of treatments (e.g.
influence QoL [7]. Even mild forms of psoriasis may exert topical corticosteroid 4 days per week combined with a
a significant burden of morbidity, and therefore adequate vitamin D analogue 3 days per week). As adjunctive
and effective treatment is important. Treatment choices agents, emollients can be used to reduce scaling, dryness
Chapter 31 Psoriasis: Management 369
and itch. Coal tar preparations are one of the oldest combination with topical corticosteroids is necessary to
treatment modalities for psoriasis, but due to lack of evi- achieve maximal effect. An often used regimen is the ‘week-
dence on effectiveness, unpleasant side‐effects (smell, end scheme’, where corticosteroids are used on weekend
staining of clothes) and concern among some physicians days, and vitamin D analogues the other days [14].
about contamination with polyaromatic compounds are A commercially available compounded formulation con-
now less and less frequently used [10]. The most common taining calcipotriol and betamethasone dipropionate has
topical treatments for paediatric psoriasis, which are been developed. Recently, four studies on the efficacy and
largely not approved for use in children and adolescents, safety of calcipotriol/betamethasone dipropionate oint-
are reviewed here. ment and gel in children and adolescents with psoriasis
were performed [15–18]. The two‐compound formulation
Pretreatment was found to be effective in all four studies, with mild
In order to permit access of active ingredients to inflamed adverse effects. In the two daily clinical practice studies
skin, intense scaling must be addressed first. Emollients with a 48‐week follow‐up, striation of the skin was reported
are used to decrease scaling and dryness and are also in up to 5% of patients. It is, however, questionable whether
used to decrease pruritus. Daily application of an these striae were steroid‐induced, as those patients were
emollient (ointment) is advised. In addition, keratolytics adolescents (pubertal growth) and/or obese [15,16]. In both
(salicylic acid, lactic acid, urea) are helpful in removing phase II, prospective, open‐label, multicentre, single‐arm,
layers of thick scale. Salicylic acid should be avoided in 8‐week studies, no serious adverse events, including clini-
infants and children aged under 2 years because of the cally relevant changes in calcium metabolism, were
risk of percutaneous salicylism, and many restrict usage observed [17,18]. Daily application should be limited to
to children over 6 years of age [6]. 4 weeks, followed by alternation of the compound formula-
tion at weekends with vitamin D analogues on weekdays.
Topical corticosteroids
Topical corticosteroids are the most commonly prescribed Calcineurin inhibitors
medication and are generally first‐line for the treatment of Tacrolimus (0.03% and 0.1% ointment) and pimecrolimus
active plaques in paediatric psoriasis [9]. However, evi- 1% cream are only licensed for use in atopic dermatitis in
dence on the efficacy and safety of topical corticosteroids children. A few studies show beneficial effects of calcineu-
in this specific patient group is limited. In a few small rin inhibitors (especially tacrolimus 0.1%) in the treat-
studies, topical corticosteroids have been shown to be effi- ment of intertriginous and facial psoriasis in paediatric
cacious, with relatively mild side‐effects [4,11]. Potential patients. Apart from pruritus, adverse effects were not
side‐effects include local telangiectasias, a trophy, striae of reported. Generally, it is advised to avoid combining
the skin and, if used extensively, s uppression of the hypo- calcineurin inhibitors with phototherapy or extreme sun
thalamic–pituitary–adrenal axis. Therefore corticosteroids exposure due to a possibly increased risk of ultraviolet
should be used with caution through intermittent and (UV) light‐related skin tumours [4,19].
rotational application [2,6]. High‐potency corticoster-
oids should be avoided in flexural areas, whereas ultra- Dithranol (anthralin, cignolin)
potent steroid ointment should only be used for a short Dithranol treatment for psoriasis has a long history (over
period, preferably restricted to the palms and soles. In 100 years) and is therefore one of the oldest and safest
the majority of cases, however, a modern class III topical topical antipsoriatic treatments [14,20]. Only a few stud-
steroid (e.g. mometasone) is effective and sufficient ies have described the efficacy and safety of dithranol in
for the initial treatment of most cases of paediatric the treatment of paediatric psoriasis [21–23]. In these
psoriasis. studies, dithranol was shown to be very effective with
good or excellent results achieved in most patients. In a
Vitamin D analogues and combination prospective observational study, a reduction in Psoriasis
with corticosteroids Area and Severity Index (PASI) score of 69.3% was found
Calcipotriol (calcipotriene in the USA) and calcitriol are using short‐contact dithranol cream [21]. Short‐contact
vitamin D3 analogues that are effective and reasonably dithranol cream at increasing concentrations (between
well tolerated treatment options for children with plaque‐ 0.01% and 4%) and application periods between 15 and 45
type psoriasis [4]. The most common side‐effects are minutes (until irritation develops) maintains efficacy but
localized skin irritation and pruritus, particularly when diminishes the risk of irritation and staining [2]. It
used on the face and flexural areas. However, calcitriol involves daily treatment with a median duration of
has been found to be less irritating than calcipotriol if 2 months. For adequate instructions and to avoid unnec-
used in intertriginous psoriasis [2]. To prevent the unlikely essary permanent staining of any object, it is preferable to
event of hypercalcaemia, it is important to confine the carry out some of the applications in a daycare setting.
application area to 30% of the body surface, not exceeding Visits to a daycare setting (once a week) can be combined
the maximum recommended dose of 45 g/week per m2 with telemedicine consultations (once a week) without
[12,13]. If larger areas are affected, calcipotriol must losing efficacy or safety [21]. Irritation and transient stain-
be used on alternating areas. Vitamin D analogues can be ing of the skin are the most often mentioned side‐effects.
used as monotherapy in very mild cases with thin A detailed protocol for the use of short‐contact dithranol
patches and plaques. In the majority of patients, however, cream can be downloaded at www.radboudumc.nl/
dithranol. As long‐term safety is important in the treatment

Box 31.1 Indications for systemic treatment in paediatric
of paediatric psoriasis, this valuable alternative topical
psoriasis
treatment should not be disregarded in the treatment
regimen of paediatric psoriasis. If possible, it should be Paediatric ‘Rule of tens’
commenced before systemic treatments are considered [22]. • PASI ≥10
and/or
Phototherapy • BSA ≥10
Due to concerns about potential long‐term side‐effects, and/or
UV therapy in pre‐adolescents should be avoided wher- • CDLQI ≥10
ever possible. In adolescents, UVB is the preferred form of
BSA, body surface area; CDLQI, Children’s Dermatology Life Quality
phototherapy, with narrow‐band UVB (NB‐UVB, 311– Index; PASI, Psoriasis Area and Severity Index.
313 nm) being more effective than broad‐band and less
erythrogenic [24]. The combination of psoralens and UVA
(PUVA) is contraindicated for the treatment of children also gives the opportunity to start a systemic treatment in
and will therefore not be discussed in this chapter [10,20]. a child with less severe psoriasis but severely affected
As potential long‐term carcinogenic effects of NB‐UVB QoL. The CDLQI and the validated cartoon version of the
have not been assessed, it should be used cautiously in CDLQI for younger children are available in a variety of
the paediatric population, particularly in young and languages and can be downloaded from the website
in fair‐skinned children [4,10,20]. It can be considered in of Cardiff University [http://www.cardiff.ac.uk/
adolescents who have failed topical treatment, especially dermatology/quality‐of‐life/childrens‐dermatology‐life‐
in patients who cannot receive systemic therapy for their quality‐index‐cdlqi/cdlqi‐information‐and‐instructions/).
moderate to severe psoriasis [25]. See also Chapters 16 and 30.

The last few years, evidence has accumulated that NB‐
UVB demonstrates potential benefit in the treatment of Methotrexate
plaque and guttate paediatric psoriasis [25]. In several Methotrexate (MTX) has been used to treat (adult) psoriasis
studies, half of the treated patients received more than for decades and also has a long track record of safe use in the
90% improvement of their PASI scores whereas no treatment of juvenile idiopathic arthritis [30]. MTX has the
improvement was found in approximately 10% of advantage over ciclosporin, fumaric acid and retinoids of
patients. Most studies were performed in adolescents, clearing or improving psoriatic arthritis. Despite the fact that
and the majority had Fitzpatrick skin phototype III or IV MTX is probably the most widely prescribed conventional
[25,26]. Short‐term side‐effects of phototherapy include systemic drug for the treatment of paediatric psoriasis, the
erythema, xerosis, pruritus, blistering, photoactivation of evidence on its safety and efficacy in this particular patient
herpes virus and anxiety. Long‐term side‐effects include group is limited. Until recently, all evidence was derived
premature photoageing and carcinogenesis [25]. from retrospectively collected case series [3]. Two studies
presented prospective data on MTX use in paediatric plaque
psoriasis. A single‐group, prospective, observational daily
Systemic therapies clinical practice study showed ≥75% improvement in PASI
Systemic therapies can be divided into conventional (PASI75) in 33.3% of patients at week 24 with a maximum
treatments and the newer ‘biologic’ treatment options. MTX dose between 0.14 and 0.63 mg/kg once weekly [31].
The best known conventional systemic treatments for More or less similar effectiveness data were found in a pro-
paediatric psoriasis are methotrexate, ciclosporin (cyclo- spective, multicentre, randomized, double‐blind trial inves-
sporine), retinoids and fumaric acid esters. To date, the tigating the safety and efficacy of MTX versus two doses of
biologics etanercept, adalimumab and ustekinumab are adalimumab [32]. In this trial PASI75 was achieved in 32.4%
approved for use in children and adolescents with psoria- of patients treated with MTX (0.1–0.4 mg/kg up to 25 mg/
sis by the European Medicines Agency (EMA). Systemic week) at week 16. MTX is usually dosed once weekly at a
therapies should only be used in paediatric patients with dose of 10–15 mg/m2 BSA [20]; less commonly, the dose is
moderate to severe psoriasis that does not respond to top- adapted according to bodyweight (0.2–0.4 mg/kg/week)
ical treatments, including dithranol, if available. The ‘rule (see Box 31.2). Approximately 3 months after therapeutic
of tens’ [27], used in adults to indicate moderate to severe control is achieved, tapering to the minimum effective dose
psoriasis, can also be applied in paediatric psoriasis as an is recommended to minimize possible side‐effects [19]. The
indication for the use of systemic therapy [10] (Box 31.1). most common side‐effects reported in children and
This modified ‘paediatric rule of tens’ would be PASI ≥10 adolescents are nausea, vomiting, transient elevation of liver
and/or body surface area (BSA) ≥10 and/or CDLQI ≥10. enzymes and fatigue. Bone marrow suppression, pulmo-
Because paediatric psoriasis can have a significant impact nary toxicity, infections and hepatotoxicity including liver
on QoL, it is advised that the CDLQI be used in daily fibrosis have only rarely been reported in children.
clinical practice [28]. This commonly used dermatology‐ Laboratory testing on a regular basis is recommended [2].
specific QoL questionnaire is validated for children Addition of folic acid supplementation helps protect against
between 4 and 16 years. It is a simple, self‐administered side‐effects without significant alteration of efficacy [33,34].
10‐item questionnaire [29] which not only provides more It is still a subject of debate whether different folic acid
insight into the QoL of paediatric psoriasis patients but administration regimens (ranging from 1–5 mg daily to
aediatric psoriasis. The majority of this evidence comes

p
Box 31.2 Recommendations for methotrexate (MTX) therapy
from three recently published retrospective studies, in
• Dosage: once weekly 10–15 mg/m2 body surface area or which ciclosporin was reported to be effective and safe
0.2–0.4 mg/kg/week [38–40]. Only one study used PASI as a severity measure
• Folic acid: 1 mg 6 days/week avoiding MTX day, or 5 mg 24 h after and reported achievement of PASI75 in 39.5% of patients
MTX at week 16, whereas 39.5% were non‐responders [39].
• Monitoring: Dosages range between 2 and 5 mg/kg/day in two sepa-
Pretreatment: complete blood count, liver enzymes, serum rate doses, with a gradual tapering after improvement.
creatinine, hepatitis A/B/C, (varicella) Rebounds or relapses after tapering of the dose are occa-
Follow‐up (week 1, 3, 5, 8, 12 and every 3 months): blood sionally seen [19].
count, liver enzymes
Commonly mentioned side‐effects are increase in
• Tapering down is advised: after clearance with steps of 2.5 mg
serum creatinine level, hypertension, hypertrichosis,
every 6–8 weeks
headache, gingival hyperplasia and gastrointestinal dis-
turbances [19,39]. Close monitoring of blood pressure and
5–10 mg once a week, 24 h after MTX administration) can renal function is required. In one retrospective study in
influence the occurrence of side‐effects. Administration of paediatric psoriasis, ciclosporin was stated to be the treat-
1 mg folic acid supplementation 6 days a week, avoiding the ment with the highest rate of severe side‐effects requiring
MTX day, seems favourable over once weekly 5 mg with termination of treatment of all systemic treatments [38].
respect to gastrointestinal side‐effects [35]. Vomiting and In particular, nephrotoxicity, immunosuppression and the
nausea can be controlled by changing the route of adminis- potential risk of developing malignancies are of some
tration (from oral to subcutaneous or intramuscular) and/or concern in children [8].
by adding antiemetics [36]. In most instances, ciclosporin is considered an ideal
drug for the control of unstable disease, because of its
Retinoids rapid onset of action [19]. It seems to be especially effective
In a systematic evidence‐based review on systemic treat- in erythrodermic, pustular and palmoplantar psoriasis
ments in paediatric psoriasis, retinoids were found to be [38,41]. It is recommended that ciclosporin be reserved for
primarily effective in pustular and erythrodermic psoria- use in carefully selected children, and the lowest possible
sis [3]. This was recently confirmed by a retrospective dose and shortest treatment period should be used [6,42].
study in 18 children with pustular psoriasis [37]. However,
a large French retrospective study also showed good Fumaric acid esters
(clearance of >75% of lesions) or partial (clearance of Fumaric acid esters (FAEs) are used in various European
50–75%) response to acitretin in 78 children with plaque countries for the treatment of psoriasis in adults.
psoriasis [38]. Doses of acitretin ranging from 0.5 to 1 mg/ Skilarence is indicated for the treatment of moderate to
kg/day are considered appropriate, but retinoid dose severe plaque psoriasis in adults in need of systemic
should be kept as low as possible to limit side‐effects, medicinal therapy. Data on the efficacy and safety of FAEs
particularly mucocutaneous dryness. Conversely, dose
in children and adolescents are scarce and consist of a few
reduction may lead to inadequate efficacy [8] and hence case reports, retrospective case series and one small pro-
discontinuation of therapy. Frequently reported short‐ spective case series [3,43,44]. In a large retrospective
term side‐effects of acitretin are cheilitis, pruritus, hair German multicentre study in 127 patients, of whom 75.6%
loss and skin fragility [4]. Other reported adverse effects had plaque psoriasis, PASI was available in 59 patients at
are blepharoconjunctivitis, cataracts, myalgias and baseline and improved from 17.3 (mean) at baseline to 9.0
arthralgias. Blood monitoring is necessary to detect eleva- at 3 months and 7.7 at 6 months. In more than 80% of
tion of liver transaminases and triglycerides. Long‐term patients in this study, FAEs were the first systemic treat-
use of retinoids in higher dosages (>1 mg/kg/day) has ment used [44]. In a prospective case series of 14 patients,
been associated with hyperostosis resembling diffuse PASI improved from 10.5 (mean) at baseline to 8.6 at week
idiopathic skeletal hyperostosis, premature epiphyseal
12 and 4.9 at week 24. These patients had recalcitrant
closure, and ligamentous calcification. However, evidence plaque psoriasis, with the majority being treated with
linking radiological skeletal abnormalities to long‐term, other systemic treatments before commencing FAEs [43].
low‐dose acitretin is conflicting, and abnormalities are In general, dosing of FAEs in the paediatric population is
likely to be rare if interval therapy is applied [8]. Retinoids according to the standardized progressive dose regimen
are known to be potent teratogens, with a delayed applied in adult patients, increasing the daily dose (30 mg)
clearance of 3 years. It is advised to reserve retinoids for by one tablet per week. At week 4, an increase of one tab-
short‐term treatment of especially pustular or erythroder- let of 120 mg per week is started, to a maximum daily
mic psoriasis in infants and male adolescents [4]. dose of six tablets (720 mg/day), based on clinical
response and tolerability [45].
Ciclosporin Gastrointestinal complaints, flushing, lymphocytope-
Another alternative for the systemic treatment of psoria- nia, eosinophilia and increased liver enzymes were the
sis in children and adolescents is ciclosporin. In the past most common reported side‐effects of FAEs [43,45].
few years, new evidence has become available on the There is an increased concern about the possibility
efficacy and safety of ciclosporin in the treatment of
of FAE‐induced lymphocytopenia and manifestation of
rogressive multifocal leucoencephalopathy (PML)

p treatments in paediatric psoriasis is warranted. If
which has been described in adults [46,47]. Therefore, it t reatment with biologics of a child with severe psoriasis
is extremely important to closely monitor laboratory is being considered, it is important to discuss the benefits
abnormalities and follow the recommendations from and risks of this treatment in a balanced way with the
the updated European S3‐guideline on FAE‐induced child and its caregivers.
leucocytopenia and/or lymphocytopenia [48].
Etanercept
Biologics Etanercept was approved by the EMA in 2009 for the
The biologics etanercept, adalimumab and ustekinumab treatment of children ≥6 years who are suffering from
are approved for use in paediatric psoriasis by the EMA severe, chronic plaque psoriasis refractory to or intolerant
(Table 31.1). In contrast, the US Food and Drug of other systemic agents or phototherapy [55]. The US
Administration (FDA) has only approved etanercept FDA approved this drug for children ≥4 years in 2016. The
and ustekinumab for use in children and adolescents. dose regimen of this subcutaneously administered drug
They represent a promising therapeutic alternative to is 0.8 mg/kg to a maximum of 50 mg once weekly or
conventional treatment options. Several randomized 0.4 mg/kg twice weekly [56].
controlled trials have been published recently, with high The majority of evidence on the efficacy and safety of
efficacy rates and reassuring short‐term safety profiles. etanercept in the treatment of paediatric psoriasis comes
In addition, biologics offer the convenience of less fre- from a phase III double‐blind randomized controlled trial
quent dosing and laboratory monitoring than the con- comparing etanercept 0.8 mg/kg weekly to placebo in 211
ventional systemic treatments. However, these results patients aged 4–16 years. At week 12, 57% of patients
need to be balanced against the considerable financial treated with etanercept reached PASI75, compared to 11%
costs and, more importantly, the relative lack of long‐ of the placebo‐treated patients. A PASI90 response was
term safety data in this indication [3]. Paradoxical TNF‐ reached in 27% of etanercept‐treated patients, compared
inhibitor‐associated psoriasis has also been reported as a to 7% in the placebo group [56]. In a 5‐year, open‐label
complication of these therapies among both children extension study, efficacy rates were maintained in those
and adults, and may in some cases require substitution who remained in the study for up to 264 weeks [57]. The
of alternative treatment options [49,50]. most common side‐effects included infections such as
An increased risk of lymphoma and other malignan- upper respiratory tract infections, nasopharyngitis and
cies in children and adolescents with arthritis, inflamma- headache. No deaths, malignancies or opportunistic
tory bowel disease or sarcoidosis treated with TNF‐α infections were reported, and in the 5‐year follow‐up no
inhibitors is hypothesized [42,51,52]. However, a clear new safety concerns were observed [57].
causal relationship has not been established because the
contribution of underlying illnesses and concomitant use Adalimumab
of other immunosuppressant agents to the risk of malig- In the EU, subcutaneous adalimumab is indicated for the
nancies is still not fully characterized [53,54]. To date, treatment of severe chronic plaque psoriasis in children
there have not been any reports of malignancies in paedi- and adolescents from 4 years of age who have had an
atric psoriasis patients treated with biologics. In the inadequate response to or are inappropriate candidates
future, as the evidence on the long‐term safety of for topical therapy and phototherapies. In children and
biologics in paediatric psoriasis increases, there might be adolescents, the recommended dosage is 0.8 mg/kg (up
an expanding role for the use of biologic agents in the to a maximum of 40 mg per dose) weekly for the first two
treatment of this population. Until then, more long‐term doses and every other week thereafter [58].
safety data are indispensable and a prospective, interna- Apart from a few case reports, the evidence on efficacy
tional registry on the safety and efficacy of systemic and safety of adalimumab in paediatric psoriasis has only
Table 31.1 EMA‐approved biologics in paediatric psoriasis [55,58,59]
Indication Age Dosage Interval
Etanercept Severe chronic plaque psoriasis refractory to or ≥6 years 0.8 mg/kg Once weekly
intolerant of other systemic agents or phototherapy (max 50 mg/dose)
Adalimumab Patients with severe chronic plaque psoriasis who have ≥4 years 0.8 mg/kg First two doses weekly, then every
had an inadequate response to or are inappropriate (max 40 mg/dose) other week (week 0, 1, 3, 5, etc.)
candidates for topical therapy and phototherapies
Ustekinumab Patients with moderate to severe plaque psoriasis who ≥12 years <60 kg: 0.75 mg/kg Week 0, 4, then every 12 weeks
are inadequately controlled by or intolerant to other ≥60 kg to ≤100 kg: 45 mg
systemic therapies or phototherapies >100 kg: 90 mg
Monitoring of biologics:
• Pre‐treatment: complete blood count, liver enzymes, serum creatinine, C‐reactive protein, hepatitis A/B/C, varicella, PPD and/or IGRA, chest X‐ray, and
updated vaccinations. HIV and pregnancy test only if at risk/childbearing age.
• Follow‐up (week 4, 12, and every 3–6 months): complete blood count, liver enzymes. PPD or IGRA annually.
IGRA, interferon‐gamma release assay; PPD, purified protein derivative.
recently been described in the literature. In a randomized, 21.6 %) or PASI100 response (18.4 vs. 2.7%). The most
double‐blind, multiperiod study, children and adoles- f requently reported adverse events were infections; rates
cents with severe plaque psoriasis were randomly were similar for adalimumab and methotrexate (51.9% vs.
assigned 1 : 1 : 1 to receive adalimumab (0.8 mg/kg up to 54.1%, respectively) [32].
40 mg or 0.4 mg/kg up to 20 mg) at week 0, then every
other week from week 1, or methotrexate weekly (0.1– Ustekinumab
0.4 mg/kg up to 25 mg/week thereafter) for 16 weeks Ustekinumab is approved by both the EMA and the US
[32]. Overall, 114 patients aged 5–18 years were rand- FDA for the treatment of moderate to severe plaque pso-
omized (adalimumab 0.8 mg/kg, n = 38; adalimumab riasis in paediatric patients from the age of 12 years or
0.4 mg/kg, n = 39; methotrexate, n = 37). At week 16, sig- older, who are inadequately controlled by or intolerant to
nificantly more patients receiving adalimumab 0.8 mg/kg other systemic therapies or phototherapies [59]. The rec-
versus methotrexate achieved PASI75 (57.9% vs. 32.4%). ommended dose for adolescents <60 kg is 0.75 mg/kg, for
Of patients receiving adalimumab 0.4 mg/kg, 43.6% those with a weight ≥60 to ≤100 kg the dose is 45 mg, and
achieved PASI75. At 16 weeks, a higher proportion of patients >100 kg should be given 90 mg. Ustekinumab
patients in the adalimumab 0.8 mg/kg group than the should be administered at week 0 and 4, then every
methotrexate group achieved a PASI90 response (28.9 vs. 12 weeks thereafter.
TCS and vit D Consider

Facial/flexural
analogues topical calcineurin
psoriasis?
(or two-compound) inhibitors
Dithranol
Narrow-band
Adolescent Yes
UVB
No Consider retinoids
Pustular or
erythrodermic
or
psoriasis ciclosporin
(rapid action required)
Methotrexate
MTX ineffective or
Fumaric acid
contraindicated
Biologicals
Etanercept Adalimumab Ustekinumab
Fig. 31.1 Treatment algorithm for the management of paediatric psoriasis. MTX, methotrexate; TCS, topical corticosteroids.
In a phase 3, multicentre, double‐blind, placebo‐ conventional systemic treatment options. Because their
controlled study in adolescents (aged 12–17) with moder- dosing and indications in paediatric psoriasis differ, they
ate to severe plaque psoriasis, patients (n = 110) were empower the possibility of patient‐tailored treatment.
randomly assigned to ustekinumab standard dosing (SD;
0.75 mg/kg [≤60 kg], 45 mg [>60–≤100 kg], and 90 mg References
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377
C HA PTER 32
Pityriasis Rubra Pilaris

Department of Dermatology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
Abstract surrounding islands of normal‐appearing skin, and orange‐coloured

palmoplantar keratoderma. On histopathology, alternating paraker-
atosis and orthokeratosis in a checkerboard pattern, hypergran-
Pityriasis rubra pilaris (PRP) is a rare inflammatory papulosqua-
ulosis, broad thickening of the rete ridges, thick suprapapillary
mous disorder of unknown aetiology. PRP occurs equally in men
plates and follicular hyperkeratosis are typical features, although
and women and affects all races. Most cases are sporadic, however
repeated biopsies may be required to demonstrate them. Most cas-
in a minority of cases autosomal dominant inheritance has been
es are self‐limiting but a chronic course with frequent relapses and
described caused by mutations in CARD14. PRP has been classified
recalcitrant disease can rarely occur. Milder cases are best treated
into six types based on age of onset, clinical features and prog-
with topical treatments while systemic therapies are reserved for
nosis. Classical PRP features keratotic follicular papules, salmon‐
more severe and extensive disease.
coloured erythematous plaques covered with fine powdery scales,
Key points The classic juvenile subtype (type III) is characterized by

keratotic follicular papules coalescing into salmon‐coloured
erythematous plaques, surrounded by islands of normal‐
• Although most cases of pityriasis rubra pilaris (PRP) are sporadic,
appearing skin, and palmoplantar keratoderma. The atypical
PAPULOSQUAMOUS DISORDERS
up to 6.5% of all cases are inherited in an autosomal dominant
juvenile subtype (type V) which appears at birth or during
fashion.
infancy is characterized by hyperkeratotic follicular papules,
• Familial PRP results from gain‐of‐function mutations in CARD14,
ichthyosiform features and scleroderma‐like changes on the
encoding caspase recruitment domain family member 14, which
SECTION 6: OTHER
palms and soles. Most familial cases belong to the atypical
is a known activator of NF‐κB signalling. Although most cases of
juvenile type.
sporadic PRP do not carry germline mutations in CARD14, they
• Typical but not pathognomonic histopathological features include
do demonstrate evidence of heightened NF‐κB signalling.
alternating parakeratosis and orthokeratosis, hypergranulosis,
• Six subtypes of PRP have been recognized, three of which affect
broad thickening of the rete ridges, thick suprapapillary plates
children and adolescents.
and follicular hyperkeratosis.
• The circumscribed juvenile PRP subtype (type IV) represents
• Remission usually occurs within 3 years in the classic and
the most common variant before adulthood, and is associated
circumscribed juvenile types. In contrast, the atypical juvenile
with well‐demarcated thick erythematous scaly plaques with
type is characterized by a protracted and often lifelong course.
follicular keratotic papules mostly on the knees and elbows.
Introduction. Pityriasis rubra pilaris (PRP) is a rare History. PRP was first described by Devergie in 1856 and
chronic inflammatory papulosquamous disorder. PRP is named pityriasis pilaris [1,2]. Later on, the appearance of
subdivided into six subtypes based on clinical features, a follicular eruption in association with psoriasis pal
age of onset and prognosis. Types I and II are typically maris, pityriasis capitis and pityriasis rubra as part of the
seen in adults and account for more than half of the cases. same disorder led to this constellation of manifestations
Types III–V are the forms most commonly seen in the being termed PRP in 1889 by Besnier [1]. The familial
paediatric population while type VI includes patients occurrence of PRP was first described by De Beurmann
infected with the human immunodeficiency virus (HIV). and Bith in 1910 [3].
PRP is characterized by the association of diffuse orange‐
coloured palmoplantar keratoderma (PPK), small erythe Epidemiology. PRP occurs worldwide and affects all
matous hyperkeratotic follicular papules which may ethnic groups and both sexes [4]. The prevalence may
coalesce into confluent erythematous scaly plaques vary with ethnicity. PRP is seen in approximately 1 in
(exfoliative erythroderma) surrounding islands of nor 5000 individuals diagnosed with skin disease in the USA
mal skin. There is great variability in presentation and and the UK [5,6], while in India a prevalence of 1 in
disease course. Treatment is challenging due to resist 50 000 has been reported [7]. The disease is characterized
ance to therapy and frequent relapses, although sponta by three peaks of onset: early childhood (0–10 years),
neous regression is common. late childhood (11–19 years) and adulthood (40–60 years)
378 Section 6 Other Papulosquamous Disorders
[3,6,8–16]. Although in adults males and females are mineral, both composed of calcium magnesium carbon
equally affected, in children some studies suggest a ate. PRP has also been suggested to represent a delayed‐
higher prevalence in males [17]. Up to 6.5% of all PRP‐ type hypersensitivity reaction to microbial or chemical
affected individuals report a positive family history agents [62–65]. Environmental factors may also play a
[3,18,19], with onset at birth or within the first years role in the disease pathogenesis. Indeed, photoaggrava
of life [18–23]. tion could be a possible eliciting factor in some cases of
PRP, particularly in type I [1,66,67], since photosensitivity
Pathogenesis. The pathogenesis of PRP remains elusive and worsening with ultraviolet (UV)A and UVB have also
and there is no consistent association between PRP and been reported [68–70].
specific diseases or laboratory findings. A number of the A positive family history exists in up to 6.5% of all PRP
ories have been advanced based on associations with cases (mostly type V PRP) with evidence of autosomal
laboratory abnormalities or preceding events, although dominant inheritance and partial penetrance [18–
most cases occur without any obvious foregoing event 21,23,71–73]. Autosomal recessive inheritance has been
[1,3,9,17,19,24–27]. described [22]. In addition, an occurrence of PRP in
PRP has been postulated to be associated with defective monozygotic twins has been reported [24]. Familial PRP
vitamin A metabolism given the clinical and histological has recently been shown to result from gain‐of‐function
resemblance between PRP and phrynoderma [5]. In addi mutations in CARD14, which encodes the caspase recruit
tion, defective synthesis of retinol‐binding protein (RBP), ment domain family member 14, a known activator of
a specific carrier protein of vitamin A, has been proposed nuclear factor kappa B (NF‐κB) signalling [74–76].
as a biochemical marker for PRP [28,29]. However, the CARD14 is upregulated in the epidermis of familial PRP
serum level of vitamin A and RBP is often normal in PRP patients with concomitant evidence of heightened NF‐κB
patients, and treatment with high doses of vitamin A has signalling activity, increased transcription of NF‐κB target
met with variable success [30–37]. genes and aberrant immunological activation [20]. NF‐κB
A role for infections in aetiology has been proposed promotes keratinocyte viability during differentiation
based on clinical observations showing antecedent bacte [77,78], and mice displaying constitutive activation of
rial or viral infections mostly in juvenile PRP (e.g. upper NF‐κB develop a generalized skin disorder histologically
respiratory tract infection, diarrhoea, acute staphylococ featuring abnormal epidermal differentiation, T‐cell infil
SECTION 6: OTHER
cal or streptococcal infections) [8,9,17,38–40]. This associ tration and the formation of microabscesses. CARD14
ation has been proposed to be due to immune system germline mutations are rarely found in sporadic PRP
dysregulation with an abnormal response to antigenic cases [79–81]. Nevertheless, NF‐κB signalling is activated
triggers [5,8]. PRP has been reported following various in the epidermis of patients with sporadic PRP, even in
viral infections and vaccinations including Epstein–Barr the absence of pathogenic CARD14 mutations [81], sug
virus (EBV), cytomegalovirus (CMV), varicella, rubella, gesting that NF‐κB activation is key to the phenotype,
herpes simplex viruses [8,41–46] and measles–mumps– independent of the underlying cause. Mutations in
rubella (MMR), diphtheria–pertussis–tetanus (DPT) and CARD14 have also been identified in familial psoriasis
oral poliovirus vaccines [47,48]. Moreover, the association indicating that, beyond morphological (clinical and histo
between PRP and HIV infection is well established [49– pathological) differences, psoriasis and PRP may share a
52], and follicular inflammation secondary to infection of common pathophysiology [20,24,82,83].
the hair follicle by HIV has been suggested as a triggering
event [51]. The concomitant appearance of Kawasaki dis Clinical features. PRP often represents a diagnostic chal
ease and PRP has also been reported [53]. lenge and is commonly confused with other papulosqua
Drugs have also been proposed as possible aetiological mous disorders, especially psoriasis. Diagnosis is based
agents. PRP‐like eruption, mostly simulating the classic on clinical features and histopathology.
adult type, has been reported following exposure to sev PRP was originally classified by Griffiths in 1980 into
eral drugs including labetalol, simvastatin, ramipril, five types based on age of onset, clinical course, morpho
imatinib, multikinase inhibitors (ponatinib and sorafenib) logical appearance and prognosis [6] (Table 32.1). A sixth
and antiviral drugs (telaprevir and sofosbuvir) [54–60]. category, HIV‐associated PRP, was designated in 1995 by
The PRP‐like eruption appeared 1–12 weeks after the Miralles et al. to account for the prevalence of PRP in
beginning of treatment. Imatinib is known to interfere HIV‐infected individuals and the atypical clinical find
with regulatory T cells and the T‐cell receptor signalling ings and prognosis seen in those cases compared to the
pathway by reducing the phosphorylation of the leuco classic adult type [50]. Despite its limitations, including
cyte‐specific protein tyrosine kinase. Since enhanced the absence of clear correlation between clinical findings
activity of T‐suppressor cells and impaired T‐helper func and prognosis [40,84,85] and the existence of alternative
tion have been documented in PRP [61], imatinib phar systems such as the classification system proposed by
macological activity may be directly related to the onset Piamphongsant and Akaraphant [86], the Griffiths classi
of the disease [56]. Similarly, sorafenib interferes with fication remains widely used [86,87].
RAF/MEK/ERK signalling, which may underlie altera
tions in keratinocyte proliferation and differentiation [59]. Type I PRP: classic adult
One report described the appearance of PRP following Fifty five percent of PRP cases belong to the classic adult
exposure to dolomite, a sedimentary carbonate rock and a type I. This form of PRP carries the best prognosis, and
Chapter 32 Pityriasis Rubra Pilaris 379
Table 32.1 Classification of pityriasis rubra pilaris in adults and children according to Griffith
Type % Age of Clinical features Prognosis

onset
I Classic adult 55 Adults Follicular hyperkeratotic papules spreading caudally into red‐ 80% remission within 3 years
orange confluent plaques covered with fine powdery scale;
islands of sparing; diffuse red‐orange waxy PPK
II Atypical adult 5 Adults Ichthyosiform scale; sparse scalp hair; eczematous changes; Chronic
coarse PPK
III Classic juvenile 10 5–10 years Same as classic adult type 16% remission within 3 years;
CR may be seen in a year
but long duration possible
IV Circumscribed 25 3–10 years Well‐demarcated thick erythematous plaques with hyperkeratotic 32% remission within 3 years.
juvenile follicular papules over the knees and elbows; PPK Protracted course possible
V Atypical juvenile 5 0–4 years Hyperkeratotic follicular papules; ichthyosiform features; Persistent
scleroderma‐like changes on palms and soles
VI HIV‐associated Rare V Erythematous follicular papules; follicular plugging with the Poor
formation of spicules; associated with acne conglobata,
hidradenitis suppurativa and lichen spinulosus‐like eruption
CR, complete response; HIV, human immunodeficiency virus; PPK, palmoplantar keratoderma; V, variable.
although it is severe and disabling in some cases, more than resembling ichthyosis vulgaris especially on the legs,
80% of patients experience remission within 3 years [6,88]. sparse scalp hair, eczematous changes and coarse
Whereas in juvenile cases lesions usually start on the palmoplantar keratoderma with lamellated scale. This

lower half of the body, in adults PRP typically begins with type is characterized by a long clinical course of 20 years
upper body involvement (mostly scalp and face) and pro or more [6].
gresses gradually in a caudal direction towards the lower
SECTION 6: OTHER
parts of the body in a few weeks or months [6,88]. Primary Type III PRP: classic juvenile
lesions are small erythematous follicular keratotic pap Approximately 10% of PRP patients are affected by the
ules with an erythematous halo, which coalesce into con classical juvenile subtype, which is considered to be the
fluent erythematous to salmon‐coloured scaly plaques juvenile counterpart of PRP type I. Disease course and
surrounding islands of normal skin (‘islands of sparing’, lesion morphology and distribution are similar to type I,
previously termed ‘nappes claires’), which is a character but onset is typically between 5 and 10 years of age. In
istic feature [2,5]. Scales may be fine and powdery (scalp addition, febrile illnesses and trauma have been reported
and face), or coarse, especially on the lower part of the to precede the appearance of type III PRP in several
body. The rash is usually symmetrical and bilateral and cases [3,9,38,41]. The eruption starts on the head, upper
often evolves into an exfoliative erythroderma, the fre trunk or neck as red‐orange macules covered with fine
quency and incidence of which vary among the different bran‐like scales (especially over the scalp and face).
types [5,17,34,86]. PPK usually appears within weeks and Within a few weeks or months, further macules appear
typically features a prominent red‐orange colour and with the formation of perifollicular erythematous papules
waxy appearance associated with painful fissures. with a central keratotic plug. Lesions coalesce and spread
Skin involvement may be associated with itching, espe in a cephalocaudal direction, resulting eventually in exfo
cially in a generalized distribution, and it might be com liative erythroderma with up to 1 cm islands of sparing.
plicated by Kaposi varicelliform eruption [89,90]. While one series reported the development of erythro
Oral mucosa involvement, mostly the buccal mucosa, derma in 17% of cases, this was not observed by others
gingivae and tongue, may include white plaques and [17,87]. Cephalic involvement is characteristic in children
nodules and erythematous lesions covered with white and appears in 40% of cases. It may extend towards the
streaks that may be associated with pain and irritation neck and the upper torso in a cape‐like appearance with
and resemble lichen planus [91–93]. Nail findings consist sharp borders, and large adhesive scales overlying the
of thick nail plates with a rough surface, yellow‐brown typical red‐orange erythema [87]. These features are asso
discolouration, splinter haemorrhages, atrophy, longitu ciated with prominent PPK with a characteristic yellow‐
dinal ridging and subungual hyperkeratosis [6,93,94]. orange hue; when seen on the soles, this is referred to as
Ectropion has been reported in association with erythro ‘keratodermic sandal’. The keratoderma in children is
derma, as have other ocular complications such as periph characterized by oedema (often disabling) with sharply
eral ulcerative keratitis and corneal perforation [95–98]. demarcated borders and extension towards the dorsal
Reactive lymphadenopathy is not uncommon. aspect of the palms and soles. The Achilles tendon is fre
quently involved [87]. Widespread eruptions are often
Type II PRP: atypical adult accompanied by pruritus and a burning sensation. The
Atypical adult type II PRP affects approximately 5% of Koebner phenomenon may be seen in approximately 10%
PRP patients. It is characterized by ichthyosiform scales of children with PRP [87,99].
Nail involvement is relatively common in juvenile PRP spontaneously in 3 years while other series reported a pro
(Fig. 32.1), appearing in 13–33% of cases. The nails may tracted course longer than 3 years [3,6,40]. Partial healing of
become thickened, yellowish and curved. In addition, the lesions may result in transformation into type IV [3],
subungual hyperkeratosis, longitudinal striae, ‘half and and mixed type III and IV cases have been reported [102]. A
half’ nails with terminal hyperaemia and splinter haem case of classic juvenile PRP evolving into a classic adult type
orrhages may also be seen [17,87,100]. Although hair and after a long latency period has also been described [103].
teeth are usually unaffected, mucous membrane involve
ment may be observed with a diffuse whitish appearance Type IV PRP: circumscribed juvenile
of the buccal mucosa [101]. The circumscribed juvenile type represents the most com
Ectropion may be evident in severe cases and was mon juvenile variant, and the second most common vari
reported in up to 13% of juvenile PRP cases in one ant overall, accounting for approximately 25% of all cases,
series [17]. although a few paediatric PRP series have identified PRP
The eruption reaches a peak and often begins to resolve type III as the most common type in children, which prob
spontaneously after several months to a year. Although ably reflects geographical or ethnic differences [17,62].
complete remission may be seen in a year, Griffiths Type IV affects prepubertal children and young adults. It
originally estimated that 16% of type III patients clear
is characterized by well‐demarcated erythematous scaly
plaques with follicular accentuation and plugging on the
knees and elbows and occasionally the anterior shins.
Transient erythematous macules and grouped follicular
papules with keratin plugs may appear on other parts of
the body (e.g. trunk and scalp) and hyperkeratosis may
be found over bony prominences (Fig. 32.2). Palmoplantar
involvement is characteristic but may be absent [104].
Dermoscopy examination of the lesions over the extensor
surfaces, which can help in differentiating the lesions

from psoriasis vulgaris, reveals multiple whitish keratotic
follicular plugs and a yellow peripheral keratotic ring,
SECTION 6: OTHER
surrounded by erythema with some linear vessels [105].

The clinical course of the disease is marked by remissions
and exacerbations even when mild and localized, and the
3‐year remission rate of 32% is substantially less than the
Fig. 32.1 Nail dystrophy in juvenile PRP. Source: Courtesy of Prof. Peter Itin. 81% seen in the classical adult type [3,6]. Gelmetti et al.
(a) (b)
Fig. 32.2 (a) PRP manifests in a young child with circumscribed plaques over the trunk, (b) featuring prominent follicular accentuation. Source: Courtesy of
Prof. Peter Itin.
proposed classification into an acute form that resolves in enteropathy and membranous nephropathy have also
6 months, an intermediate form that disappears after 1 been reported [137,138]. Moreover, both PRP and associ
year, and a chronic form that lasts more than a year and ated arthritis have been found to improve following
may evolve into erythroderma (types I or III) [87]. retinoids and tumour necrosis factor (TNF)‐α blockade
therapy [127,139], although not in every case [126].
Type V: atypical juvenile Dermatomyositis may present as a PRP‐like cutaneous
The atypical juvenile type occurs in up to 5% of PRP eruption, a variant known as Wong dermatomyositis. Skin
patients and is the rarest form of the juvenile types. It lesions with both clinical and histopathological features of
appears at birth or during infancy and manifests as hyper PRP may occur simultaneously with, before, or after the
keratotic follicular papules, widespread erythema and myositis [125,132,140–142]. It has been postulated that in
scales, and scleroderma‐like changes on the palms, soles cases of erector pili muscle myositis, the hair cycle is
and particularly the digits [18,23,106,107]. Most cases of altered by abnormalities of infundibular keratinization
familial PRP belong to this type, although familial type III and subsequent follicular keratotic plugging [143,144].
and type IV have been reported [88,108], in addition to a PRP is also associated with autoimmune hypothyroid
combination of type V and other types within the same ism, and thyroid hormone replacement has been shown
family [18]. Type V usually persists throughout life. to bring about rapid and complete remission of PRP. It
has been suggested that the occurrence of PRP in those
Type VI: HIV‐associated patients is related to the fact that thyroid hormone defi
This subtype of PRP was added to the classification by ciency inhibits the transformation of carotene to vitamin
Miralles et al. in 1995 because HIV patients with PRP pre A which has been suggested to play a role in PRP patho
sent with different clinical features and have a poorer genesis [131,133,145].
prognosis than patients with type I [50]. This type may be PRP can develop in conjunction with immunoglobulin
the presenting symptom of HIV infection although it A deficiency and common hypogammaglobulinaemia.
usually appears in patients with known HIV. It is charac Moreover, enhanced activity of T‐suppressor cells and
terized by erythematous follicular papules and prominent impairment of T‐helper function have been described
follicular plugging with the formation of spicules distrib in PRP, suggesting an underlying immune mechanism
uted symmetrically over the extensor surfaces of the [61,146,147].
SECTION 6: OTHER
body, mainly the face and trunk [49,50]. Its association Although a coincidental finding cannot be ruled out,
with acne conglobata, hidradenitis suppurativa and lichen PRP has been identified in several patients with Down
spinulosus‐like eruption has led to the concept of HIV‐ syndrome and one of these cases was associated with
associated follicular syndrome [109]. In contrast with vitiligo [25–27].
type I, the occurrence of nail involvement and PPK is
variable. PRP type VI is notoriously resistant to treatment. Histopathology and laboratory findings. The histo
Complete remission may be seen with antiretroviral pathological findings in PRP are characteristic but not
therapy although relapses are frequent [110]. specific or pathognomonic, emphasizing the need for
clinicopathological correlation. Early PRP lesions and
Associated diseases. PRP may appear in conjunction cases of erythroderma can be difficult to diagnose histo
with other benign cutaneous disorders including eruptive logically because of subtle pathology [148]. Nevertheless,
seborrhoeic keratosis (mainly in the context of an erythro pathology is important for ruling out other diseases in the
dermic flare of PRP), sebaceous and glandular diseases, differential diagnosis, mainly psoriasis.
hidradenitis suppurativa and dermatitis herpetiformis The epidermis shows acanthosis with a ‘checkerboard’‐
[1,111–114]. like pattern of alternating orthokeratosis and parakera
An association of PRP with several noncutaneous con tosis, focal or confluent hypergranulosis as well as thick
ditions, mostly malignancies and autoimmune diseases, suprapapillary plates with broad thickening of the rete
has been postulated. There are several reports of PRP ridges (Fig. 32.3). Dilated hair follicles with a keratotic plug
associated with various malignancies including renal cell and ‘shoulder parakeratosis’ (parakeratosis on both sides
carcinoma, hepatocellular carcinoma, squamous cell car of the keratin plug) are a characteristic finding [149,150]. A
cinoma, adenocarcinoma, bronchogenic carcinoma, laryn sparse superficial lymphohistiocytic perivascular and peri
geal carcinoma, Merkel cell carcinoma and aggressive follicular infiltrate may be seen in the underlying papillary
cutaneous malignancies (e.g. Kaposi sarcoma, malignant dermis in conjunction with limited vascular dilation. The
melanoma, multiple basal cell carcinoma) [91,115–121]. In infiltrate does not contain neutrophils but eosinophils
some cases, PRP has been considered a paraneoplastic and plasma cells may be seen, possibly supporting the
manifestation [91,116,122,123] as resolution has coincided theory of a delayed‐type hypersensitivity reaction to
with curing the associated neoplasm. antigenic triggers [62–64]. Munro microabscesses, a dimin
PRP has been diagnosed in association with autoim ished granular layer and elongated rete ridges usually seen
mune diseases including myasthenia gravis, coeliac in psoriasis are absent. Although circumscribed juvenile
sprue, lupus erythematosus, dermatomyositis, systemic PRP exhibits more psoriasiform features than classic PRP,
sclerosis, autoimmune thyroiditis and hypothyroidism, it lacks Munro microabscesses [150].
seronegative arthritis and rheumatoid arthritis [124–136]. Other less common histological findings have been
Single cases of PRP in conjunction with protein‐losing reported in PRP. Acantholysis with or without dyskeratosis
Table 32.2 Features differentiating pityriasis rubra pilaris (PRP)

from psoriasis
Features PRP Psoriasis
Clinical
Scalp scaling Diffuse, fine, Well‐demarcated
powdery erythematous plaques with
thick, silvery, adherent scale
Keratoderma Diffuse, red‐orange, Mostly focal, well‐demarcated
waxy erythematous plaques with
thick adherent scale
Follicular Common Not common
accentuation
Islands of Common Not common
sparing
Arthritis Absent May be present
Nail changes No pitting or oil Present
Fig. 32.3 Skin biopsy showing alternating ortho‐ and parakeratosis, stains
epidermal hyperplasia and a mononuclear infiltrate (H&E, ×400).
Source: Courtesy of Prof. Peter Itin. Histopathological
Granular layer Hypergranulosis Hypogranulosis
Rete ridges Short and broad Elongated
has been reported in several case reports and series Suprapapillary Thick Thin
plates
[62–64,90,151]. Magro and Crowson demonstrated acan
Follicular plugging Common Not common
tholysis in 25 of 32 biopsies of PRP, while a more recent Munro Very rare Common
case series found acantholysis in 22% of biopsies microabscesses

obtained from patients with type I [63,151]. In addition, Vascular dilatation Mildly increased Significantly increased
pemphigus‐like acantholysis has been reported in PRP Dermal infiltrate Lymphocytes and Mainly PMNs
SECTION 6: OTHER
[55,152]. Hashimoto and Fedoronko suggested that monocytes.

Eosinophils possible
acantholysis in PRP is induced by proteolytic enzymes
Acantholysis May be present Not common
and urea in eccrine sweat located in the keratin‐plugged
acrosyringia [153], a theory not confirmed by others Electron microscopy
[154]. A lichenoid infiltrate rather than a sparse superfi Tonofilaments in the granular layer Decreased Diminished
cial perivascular infiltrate and lichen nitidus‐like find Keratohyalin granules Normal to increased Diminished
ings have been reported in isolated cases of PRP
[63,64,153,155]. Accordingly, the presence of eosinophils, Treatment
focal acantholysis and lichenoid infiltrate should not Response to UVB Variable Good
exclude a diagnosis of PRP.
Immunoblot analysis demonstrates abnormal keratin Disease course
expression in the epidermis of PRP patients including Prognosis Mostly self‐limited Chronic with exacerbations
KRT6/KRT16 expression, abnormal KRT14 expression,
and expression of a 45 kDa acidic keratin not normally PMN, polymorphonuclear neutrophil; UVB, ultraviolet B.
expressed in epidermis, consistent with abnormal epider
mal differentiation [23]. Moreover, the epidermis of PRP
patients demonstrates a hyperkinetic state with turnover
time between normal and that found in psoriasis longitudinal clinical observation and repeated biopsies
[32,149,156–158], and overexpression of p53 in PRP epi may be necessary.
dermis [159]. The main differential diagnosis in both classic and
Electron microscopy findings include a decreased localized forms of juvenile PRP is psoriasis. A clinical
number of tonofilaments and desmosomes, enlarged course with caudal progression of the lesions, islands
intercellular spaces, parakeratosis with lipid‐like vac of sparing and typical yellow‐orange confluent kerato
uoles, a large number of keratinosomes, splitting of derma, the characteristic histopathological findings
the basal lamina, a reduced number of tonofilaments with lack of Munro microabscesses, poor response to
in the stratum granulosum and parakeratosis with phototherapy, recalcitrance to topical corticosteroid
irregular keratinization, vacuoles and lipoid droplets treatment and a relatively shorter disease duration
[33,149]. all favour a diagnosis of PRP over psoriasis [5]. Key
differences between psoriasis and PRP are given in
Differential diagnosis. Although no specific diagnostic Table 32.2.
features exist for PRP, the diagnosis can be established Additional differential diagnoses include cutaneous T‐cell
with a high degree of certainty in the presence of typical lymphoma, seborrhoeic dermatitis (especially during early
clinical and histopathological features. Not uncommonly, scalp involvement in PRP types I and III), hypersensitivity
Management of juvenile pityriasis rubra pilaris
Mild disease Severe disease
Emollients
Topical treatments Topical corticosteroids
Emollients Topical treatments Vitamin D analogues
Topical corticosteroids Keratolytic agents
Vitamin D analogues Tazarotene*
Keratolytic agents Calcineurin inhibitors*
Tazarotene*
Calcineurin inhibitors*
NB-UVB
Phototherapy Re-PUVA*
UVA1*
(+/– systemic retinoids)
Bath PUVA*
Systemic retinoids - 1st line

Methotrexate - 2nd line
Other oral therapies:
• Azathioprine
Systemic therapies • Cyclosporine A
• Fumaric acid
Biologics:
• Infliximab
• Etanercept
• Adalimumab
• Ustekinumab**
Fig. 32.4 Management of juvenile pityriasis rubra pilaris. *Reported in individual cases; **first‐line in patients with activating mutations in CARD14. NB‐UVB,
SECTION 6: OTHER
narrow‐band UVB; Re‐PUVA, oral retinoids + photochemotherapy.
reactions, subacute cutaneous lupus erythematosus and

Treatment. No treatment has been reported as univer
Wong‐type dermatomyositis. The circumscribed juvenile
sally effective in PRP. The fact that spontaneous remis
type may be confused with pemphigus foliaceus, Grover
sions are not uncommon complicates the interpretation
disease or epidermal naevus [63,104]. Atopic dermatitis
of uncontrolled clinical trials, while controlled trials are
and Netherton syndrome may be confused with PRP
not feasible given the rarity of the disease. In addition,
[19,23,71,160], particularly in children. Moreover, in the
given the generally favourable course, aggressive systemic
paediatric population, in whom PRP may follow an infec
treatment is usually not warranted. The management of
tion, the differential diagnosis also includes scarlet fever,
juvenile PRP is summarized in Fig. 32.4.
staphylococcal scalded skin syndrome and Kawasaki
disease.
The circumscribed form of PRP might be confused Topical treatments
with other dermatoses associated with follicular plugging Topical treatments are the mainstay of therapy in milder
as a main feature including keratosis pilaris, follicular cases of juvenile PRP and include emollients, topical cor
mycosis fungoides, discoid lupus erythematosus, Darier ticosteroids, vitamin D analogues, keratolytic agents (e.g.
disease, lichen planopilaris, lichen spinulosus, phryno formulations containing urea, salicylic acid, lactic acid or
derma and lichen scrofulosorum [3]. In particular, α‐hydroxy acid) and tazarotene alone or in combination,
the atypical juvenile form should be differentiated with variable response.
from autosomal recessive congenital ichthyosis (ARCI), Emollients, including equal parts of white soft paraffin
ichthyosis vulgaris and erythrokeratoderma variabilis and liquid paraffin alone or in a combination with 20%
(EKV). The presence of follicular keratotic papules with propylene glycol and 10% urea for keratoderma, are
keratin plugs and the red‐orange colour of the lesions always beneficial.
distinguish PRP from nonbullous ichthyosiform eryth PRP is generally not steroid‐responsive but corticoster
roderma, and the prominent erythema favours PRP over oids can be helpful in cases of exfoliative erythroderma,
ichthyosis vulgaris. EKV can be associated with a and topical corticosteroids may lead to complete resolu
positive family history and symmetrically‐distributed
tion in juvenile PRP [16,17].
migratory well‐demarcated red‐orange plaques with fine Calcipotriol has been shown to be effective in PRP and
scale in conjunction with more persistent hyperkeratotic resulted in disappearance of the inflammatory infiltrate
plaques and PPK. on histology [161]. However, absorption of vitamin D
The differential diagnoses of erythroderma and kerato analogues is a limiting factor in children with PRP.
derma in the setting of PRP are described in Chapters 10 The use of keratolytics is also limited in children due to
and 127. burning, stinging and systemic absorption.
Although reported only in individual cases, a sustained cases when single therapy has not been shown to be
remission was achieved in a child with juvenile circum e ffective, although it increases the risk of hepatotoxicity
scribed PRP with topical tazarotene [160], pimecrolimus [5,11,179]. Low‐dose MTX may be effective in treating
1% has been shown to be effective in scalp and face PRP‐induced lower eyelid cicatricial ectropion [97].
involvement in PRP [162] and topical capsaicin was effec
tive in a case of severe pruritus resistant to topical corti Other oral treatments
costeroids and antihistamines [163]. Refractory adult and juvenile cases with no response to
Clinicians should be aware that a generalized form of retinoids and MTX might respond to low‐dose short‐term
PRP was described in a few cases following topical treat treatment with ciclosporin (cyclosporine A) [180–182],
ment with imiquimod, a toll‐like receptor agonist and and azathioprine has been used with variable clinical
immune response modifier, used for actinic keratosis and response [173,183]. Fumaric acid treatment in increasing
viral warts [164]. dosages was very effective in a child with type V PRP,
recalcitrant to various treatment modalities. The sug
Phototherapy gested mechanism of action is related to the immune‐
Although PRP can be aggravated by UV exposure [68–70], modulating and inhibitory effects on keratinocyte
phototherapy may be an effective treatment. Successful proliferation and activation of fumaric acid [184].
treatment of PRP with narrow‐band UVB (NB‐UVB) alone
or in combination with retinoids has been reported Biologics. Recently, there has been an increasing number
[102,165,166]. Oral retinoids in combination with photo of reports demonstrating the effectiveness and safety of
chemotherapy (Re‐PUVA) [163] or UVA1 [167] may also biologic therapies in PRP, many of which have been tried
be an effective option, and in a case of UVB‐provoked PRP, given PRP’s similarities to psoriasis [8,24,185,186]. TNF‐α
good results were achieved with bath PUVA [168]. Some blockers were the first biologic therapies investigated in
authors reported improvement with the Goekerman regi PRP. Those agents are known to target the NF‐κB signal
men [17], although this was not confirmed by others [34]. ling pathway and response to these drugs is in part
determined by polymorphisms in genes encoding vari

Systemic therapy ous elements of the NF‐κB pathway, explaining their ben
Systemic therapy should be considered for severe and eficial effect in cases of familial PRP with CARD14
SECTION 6: OTHER
extensive disease. Systemic retinoids seem to be the most mutation [19,187]. Infliximab has been shown to be effec
effective therapy, while other therapies including metho tive mostly in adults with erythrodermic or refractory
trexate (MTX), azathioprine, ciclosporin (cyclosporine) PRP as monotherapy or in combination with adjunctive
and fumaric acid have been reported with variable systemic treatments [188–196]. However, less favourable
response [17]. Systemic corticosteroids are not effective in results were published in two cases [197,198]. A few
PRP, and their discontinuation can result in disease flare reports of protracted type III PRP with significant
[17,169]. improvement of both skin lesions and nail changes have
been reported with infliximab [199,200]. Etanercept
Retinoids administered alone or in combination with other thera
Isotretinoin (13‐cis‐retinoic acid) is given in a daily oral pies in adults with PRP led to favourable responses
dose of 0.75–2 mg/kg while acitretin is given in a single [139,197,201–203]. Successful treatment was reported in
oral daily dose of 0.5–1 mg/kg [17,34,170–172]. A thera two cases of juvenile and familial PRP [19,204]. Similar
peutic trial of retinoids is considered adequate with at promising results were achieved also with the third TNF
least 4–6 months of treatment with careful monitoring of inhibitor, adalimumab, in adults with PRP [205–211]. A
lipid profile, liver function tests and, where appropriate, 17‐year‐old boy unresponsive to etanercept was success
bone disease. A single case of extraspinal hyperostosis has fully treated with adalimumab [212]. In addition, usteki
been reported after 13 years of oral retinoid therapy in a numab has proved to be effective in cases of recalcitrant
child with PRP [173]. Recent reports of individual cases, PRP [72,76,213–217]. As ustekinumab is directed against
one small series in adults and one case of circumscribed the p40 subunit of both interleukin (IL)‐12 and IL‐23
juvenile PRP demonstrated favourable response to treat which are known to activate the NF‐κB pathway induced
ment with alitretinoin (9‐cis‐retinoic acid) [107,174–177]. by CARD14, it may be considered as the first‐line treat
Treatment with systemic retinoids may shorten disease ment option in patients with activating mutations in
course but short‐term treatment, which is safe and well CARD14 [20,60,72].
tolerated, is required given the fact that most cases in chil
dren are self‐limited [170,178]. A clinical response is typi Other treatments
cally seen in 14–16 weeks [34]. Three adult patients, one with type II PRP and two with
erythrodermic PRP not responsive to various therapies,
Methotrexate were successfully treated with extracorporeal photopho
Oral MTX at a dose of 10–15 mg/week can be considered resis (ECP), two of them in combination with either acitre
in refractory cases, but variable responses have been tin or ciclosporin [218,219]. One patient with recalcitrant
reported and a greater benefit has been seen in adults type II PRP was treated with intravenous immunoglo
than in children [6,17,34,173]. The combination of sys bulin (IVIG) at a dosage of 2 g/kg (over 3 days) every 3
temic retinoids and MTX has been reported successful in weeks, and demonstrated a dramatic improvement [220].
Patients with HIV‐associated PRP may benefit from 28 Bergamaschini L, Tucci A, Colombo A et al. Effect of stanozolol in
patients with pityriasis rubra pilaris and retinol‐binding protein
ifferent combinations of antiretroviral treatment alone
d
deficiency. N Engl J Med 1982;306:546–7.
or in combination with other treatments [110,221]. 29 Finzi AF, Altomare G, Bergamaschini L et al. Pityriasis rubra pilaris
Of note, several cases of PRP with an erythema gyratum and and retinol‐binding protein. Br J Dermatol 1981;104:253–6.
repens‐like appearance have been reported following 30 Stoll DM, King LE Jr, Chytil F. Serum levels of retinol binding
protein in patients with pityriasis rubra pilaris. Br J Dermatol

treatment with retinoids or MTX. Currently there is no 1983;108:375.
evidence that those patients have an increased risk of 31 van Voorst Vader PC, van Oostveen F, Houthoff HJ et al. Pityriasis
malignancy, and malignancy evaluation should be age‐ rubra pilaris, vitamin A and retinol‐binding protein: a case study. Acta
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32 Griffiths WA. Vitamin A and pityriasis rubra pilaris. J Am Acad
Surgical management should be considered in cases of Dermatol 1982;7:555.
cicatricial ectropion in PRP [98]. 33 Kanerva L, Lauharanta J, Niemi KM et al. Ultrastructure of pityriasis
rubra pilaris with observations during retinoid (etretinate) treatment.
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390
CHA PTER 3 3
Lichen Planus
Vibhu Mendiratta & Sarita Sanke
Lady Hardinge Medical College and associated hospitals, New Delhi, India
Abstract Classic, hypertrophic, annular and linear LP are the common

childhood variants. LP is multifactorial in origin and is thought
Lichen planus (LP) is a papulosquamous autoimmune T‐cell‐ to be a T‐cell‐mediated injury to the basement membrane which
mediated disease that affects skin, mucous membranes, hair results from infections, drugs and vaccinations. The lesions may
follicles and nails. It affects all age groups including children. last for up to 1–2 years, but the hypertrophic, mucosal, nail and
Childhood LP cases can be sporadic or familial. Classic LP is follicular LP variants may last significantly longer. The nail and
characterized by faintly erythematous, violaceous, flat‐topped, follicular variants can lead to the scarring processes of anonychia
polygonal papules that are characteristically pruritic. White and cicatricial alopecia, respectively. Treatment is multidimensional
crisscrossing lines called Wickham’s striae are seen on the and includes topical corticosteroids and calcineurin inhibitors,
surface. Several clinical variants are recognized according to the as well as systemic medications including nonsteroidal anti‐
configuration of the lesions, their morphological appearance inflammatory agents, systemic steroids, dapsone, methotrexate,
and the site involved. Vacuolar degeneration of the basement ciclosporin (cyclosporine), azathioprine and phototherapy. This
membrane with a band‐like lymphocytic infiltrate at the chapter outlines the clinical profile, aetiopathogenesis, course and
dermoepidermal junction constitutes a histopathological hallmark. treatment options in childhood LP.
Key points • Several morphological variants are described including annular,

linear, actinic, hypertrophic, atrophic, inverse, bullous, lichen
• Lichen planus (LP) is a papulosquamous disease characterized planus pemphigoides and lichen planopilaris.
SECTION 6: OTHER
by itchy, shiny, violaceous, flat‐topped, polygonal papules and • Diagnosis relies on clinical and histological features. Vacuolar
plaques. Lesions often koebnerize. degeneration of the basement membrane with a band‐
• LP can affect skin, mucous membrane, hair follicles and nails. like lymphocytic infiltrate at the dermoepidermal junction
• LP is a multifactorial disease resulting from an interplay of constitutes the histopathological hallmark.
genetic and environmental factors. The condition can be • Choice of treatment depends on the age of the patient and the
sporadic or familial. disease severity. Therapy is aimed at removal of the triggering
• Prevalence is about 0.5–2% with female to male ratio of factor, topical/oral corticosteroids, topical calcineurin inhibitors,
approximately 2 : 1. Childhood LP is relatively rare. dapsone, phototherapy and immunosuppressive agents.
Introduction. Lichen planus (LP) is a papulosquamous 1895 [2]. Darier is credited with ascribing these striae to
disease of unknown aetiology that affects the skin, hypergranulosis [3].
mucous membranes, hair follicles and nails. It is clinically The term ‘lichenoid’ refers to lesions that morphologi-
characterized by itchy, shiny, violaceous, flat‐topped, cally resemble LP (as grouped, shiny, flat‐topped papules)
polygonal papules and plaques. Vacuolar degeneration of and also describes a specific histopathological pattern
the basement membrane with a band‐like lymphocytic characterized by vacuolar degeneration of the basement
infiltrate at dermoepidermal junction constitutes the membrane along with a dense lymphohistiocytic infil-
histopathological hallmark of the disease. trate at the dermoepidermal junction. In contrast to LP,
lichenoid lesions do not show the classic Wickham’s striae
History. Lichen planus is derived from the Greek word on their surface.
leichen meaning to lick and planus denoting ‘flat’‐topped
papules. The word leichen was earlier used to refer to a Aetiology and pathogenesis. LP is a multifactorial dis-
form of symbiotic plant life found on rocks and trees. It ease resulting from an interplay of genetic and environ-
was von Hebra who first used the term ‘leichen ruber’ to mental factors (Box 33.1). Sporadic occurrence is more
refer to LP [1], but it was Erasmus Wilson who coined the common, but occurrence within a family and among
term ‘lichen planus’ in 1869. Wickham later described monozygotic twins points to a genetic linkage [4]. Familial
‘dots and streaks over the lesions’ as Wickham’s striae in LP comprises 1–2% of all childhood cases and has an early
Chapter 33 Lichen Planus 391
The autoimmune mechanism of LP was first proposed

Box 33.1 Aetiological factors in the pathogenesis of lichen
by Black in 1977 based on the coexistence of LP with
planus
disorders such as myasthenia gravis, alopecia areata,

Predisposing factors
vitiligo and ulcerative colitis [12]. Current evidence

supports that LP is a T‐cell‐mediated disease. Several trig-
Genetic association: HLA‐B7, HLA‐3, HLA‐5, HLA‐DR6, HLA‐DRB1 gers have been identified, including viruses, drugs, radia-
Gene polymorphisms tion and contact sensitivity to metals such as mercury
Autoimmunity amalgam, copper, gold, palladium and beryllium, that
alter antigenicity of epidermal keratinocytes and initiate
Infectious agents
T‐cell activation. Active LP shows increased expression of
Viral major histocompatibility complex class (MHC) I antigen,
Hepatitis B CD8+ T cells, activated macrophages and Langerhans
Hepatitis C cells. CD8+ T cells from lesional skin of LP have shown
Human herpesvirus‐7 cytotoxic activity against lesional and normal keratino-
Human papillomavirus cytes [13]. Keratinocyte apoptosis results from damage
caused by cytotoxic T cells [14].
Bacterial
Several reports describe LP following hepatitis B vac-
Staphylococcus
Streptococcus
cination, combined measles–mumps–rubella vaccine and
hepatitis C infection [15–18]. The possible association of
Vaccinations recombinant hepatitis B virus (HBV) vaccines with child-
hood LP or LP‐like eruptions has been scrutinized in only
Hepatitis B biopsy‐proven cases of LP over a period of 3 years, and
Measles–mumps–rubella five patients <16 years of age were reported in whom
Diphtheria–pertussis–tetanus
such an association could be supported by relevant
Polio
data [19]. Cross‐reactivity between hepatitis B antigen
Influenza
and epitopes in the keratinocytes could possibly trigger
autoimmunity. Kanwar and De reported an average inter-
SECTION 6: OTHER
Environmental agents
val of 3 years between hepatitis B vaccination and LP [20].
Trauma LP has also been linked with upper respiratory tract infec-
Radiation exposure tion and viral exanthems by Nanda et al. [21]. However
other studies have failed to identify any precipitating
Drugs (see Box 33.4 for additional detail) factor in childhood LP [20,22,23].
Angiotensin‐converting enzyme inhibitors The association of LP with liver disease (chronic active
Anti‐inflammatory drugs hepatitis, hepatitis B and hepatitis C infection) continues to
Antibiotics be contentious [24] (Box 33.2) Autoimmune mechanisms
Antidiabetic agents can support the association of LP with chronic active
Antifungals hepatitis (CAH) [25]. There appears to be a relationship
Anticonvulsants between LP and hepatitis C virus as a Nigerian study found
Antimalarials higher prevalence rates among affected subjects as
Antimycobacterial agents compared to the control group [26]. A recently conducted
Diuretics meta‐analysis and systematic review of case‐control studies
Lipid‐lowering agents examined the prevalence of anti‐HCV antibodies in the
Metals serum of cases and controls to determine the association
Miscellaneous drugs between hepatitis C virus and oral LP and showed a
statistically significant difference in the proportion of HCV
Others
seropositivity among oral lichen planus patients, compared
Psychological stress with controls. This points towards a link between hepatitis
Graft‐versus‐host disease C virus infection and oral lichen planus [27].
Restorative dental materials
Gold, mercury Epidemiology. The prevalence of lichen planus is about
0.5–2% with the female‐to‐male ratio approximating 2 : 1
[28,29]. LP is common in adults whereas children comprise
less than 2–3% of the total cases [29]. LP is relatively uncom-
onset, a more generalized distribution, a longer relapsing mon in the western hemisphere, but is more commonly
course and a greater propensity for mucosal involvement encountered in Asian countries including the Middle East
[5,6]. Several HLA types show a probable association with and India [20,22,30]. There is a higher prevalence of child-
LP. These include HLA‐3, HLA‐5 and HLAB‐7 [7–9]. An hood LP among those from the Indian subcontinent. In one
association between HLA‐DR1 and HLA‐DR‐10 was particular study utilizing UK census data, the majority of
reported among those of Arabic descent and HLA‐ children included in the census data were white, but 80.8%
DRB*0101 in those of Mexican descent [10,11]. of those with LP were from the Indian subcontinent [31].
The natural course of disease in children and adults

Box 33.2 Various conditions associated with lichen planus
varies. In adults, lesions may persist from a few months to
even years and may be marked by acute flares or exacer-
Infections
bations. There is subsidence of activity in 65–90% of
Hepatitis B patients after 1 year [33]. One study revealed that patients
Hepatitis C with cutaneous lesions were more likely to have a shorter
Chronic active hepatitis course of disease compared to those having mucosal LP.
Epstein–Barr virus infection There was a recurrence of disease in a small percentage of
Helicobacter pylori patients, especially among those with generalized cutane-
ous involvement [34].
Autoimmune
Thymoma Clinical presentation.

Pemphigus LP consists of discrete or grouped, shiny, erythematous
Lupus erythematosus to violaceous, polygonal, flat‐topped, itchy papules with
Alopecia areata a whitish network of Wickham’s striae on the surface.
Hypothyroidism Lesions are distributed over flexor surfaces of the wrists,
Ulcerative colitis forearms, the back and the legs. This constitutes the clas-
Coeliac disease sic variant of LP which is the most common presenta-
Myasthenia gravis tion, representing about 42–76% of LP cases (Fig. 33.1)
Vitiligo
[20–23]. Approximately 6–28% of childhood LP cases
Psoriasis
demonstrate lesions following a linear pattern [20,22,25].
Autoimmune polyendocrinopathy
Extracutaneous sites such as the mucosae (oral and
Dermatitis herpetiformis
genital), scalp and nails can also be involved.

Morphoea
Dermoscopy reveals small pinpoint vessels associated
Others
with whitish striations (projections) with a ‘fern leaf’
aspect on an erythematous background. Papules may
Atopic dermatitis coalesce to form plaques of varied morphologies, such
SECTION 6: OTHER
Dyslipidaemia as annular, hypertrophic, linear and atrophic. Linear and

Psychological stress blaschkoid LP can also be observed in individual
Lichen sclerosus et atrophicus patients. Annular lesions result from convergence of LP
Anxiety/depression
papules which form round, ring‐shaped lesions with
central clearing with a peripheral, raised rim studded
with lichenoid papules. Genitalia and trunk are common
The mean age of onset varies from 7.1 to 8.4 years [20–22]. sites. Annular LP resembles granuloma annulare and
LP is rare in infants: the youngest reported case was a tinea corporis. Lichen planus hypertrophicus is noted as
3‐month‐old infant [32]. An equal sex distribution is noted, itchy, raised, indurated, hypertrophic plaques and
but boys have outnumbered girls in a ratio of 2 : 1 in some nodules over shins and ankles which heal with postin-
studies, possibly due to a reporting bias [23]. LP occurs in a flammatory hyperpigmentation [23]. Actinic LP is seen
sporadic manner; however, familial forms have been over the face and extremities [23]. Greyish‐white plaques
described in 1–2% of all childhood cases [5,20,21]. or patches with superficial atrophy characterize the
Fig. 33.1 Classic variant of lichen planus showing

Wickham’s striae.
atrophic variant of LP. Nail and scalp LP, bullous LP and may affect both the nail bed and nail matrix. NLP may be
mucosal LP are less common in children. Oral LP is limited to one nail (12% of NLP cases) or affect all finger-
characterized by violaceous plaques with a reticulate nails and toenails (10% of NLP cases). Isolated toenail LP
lacy pattern as well as erosions or ulcerative lesions is rare (6% of NLP cases) [36,37]. Characteristic features of
which can result in discomfort when eating spicy food. nail LP include longitudinal striations, ridging, nail thin-
ning and pterygium formation (Fig. 33.2a). Nonspecific
features such as pitting, yellow discolouration, dystrophy,
Clinical variants (Box 33.3)
onycholysis and onychomadesis can also be seen
Nail lichen planus (NLP) (Fig. 33.2b) [38]. A recent report identified two children
The nails are involved in approximately 19% of those with onychomadesis with generalized eruptive LP [39].
affected [20,35]. NLP is more common than mucocutane- Peluso and Tosti et al. identified three patterns of nail
ous LP in children [4]. Underdiagnosis as well as misdiag- LP in children: so‐called typical nail changes of LP, 20‐nail
nosis as onychomycosis is common, possibly due in part dystrophy (trachyonychia) and idiopathic atrophy of
to the reluctance to perform nail biopsies in children. Nail nails [37]. Trachyonychia is seen more commonly in
involvement may be isolated without cutaneous LP. It children than adults and may involve all 20 nails with a
lustreless, roughened and brittle nail plate. The idiopathic
variety of trachyonychia is more common in children and
many of these cases show spontaneous resolution.
Box 33.3 Clinical variants of lichen planus (LP) Trachyonychia is also seen in psoriasis, alopecia areata
and atopic dermatitis. The performance of nail biopsies in
According to morphology children is controversial. In cases where nails show typi-
Classic papulosquamous type
cal plate thinning, longitudinal ridging and fissuring, nail
Hypertrophic LP
biopsies can usually be avoided. When necessary, Kanwar
and De and Goettmann et al. suggest performing several
Atrophic LP
Eruptive LP 3‐mm punch biopsies during one procedure to increase
Linear and zosteriform LP the possibility of finding a typical histopathological image
Annular LP for LP [36,40]. Nakamura et al. analysed the dermoscopic
SECTION 6: OTHER
Actinic LP abnormalities observed in NLP and their diagnostic
Follicular LP relevance [41]. Nail biopsies are typically avoided in

Bullous LP trachyonychia as many childhood cases improve sponta-
LP pemphigoides neously over the years [42].
Miliary/micropapular LP Corticosteroids form the cornerstone of treatment. Oral
LP pigmentosus prednisone or prednisolone at 0.5 mg/kg or intramuscu-
lar triamcinolone acetonide at 0.5–1 mg/kg/month has
According to sites involved been used over a period of 5–7 months. Sixty five percent
Oral LP of patients respond to a 5–7 month course of systemic
Reticular corticosteroids [21]. Dapsone may represent an effective
Plaque steroid‐sparing alternative [43]. Local treatment is often
Erosive not particularly effective. Local treatment options include
Atrophic intralesional injections of triamcinolone acetonide or
Bullous topical corticosteroids. Prevost and English reported a
Genital LP case that responded well to topical therapy with clobet-
Erosive asol gel and tazarotene gel [44]. Pinter et al. described a
Annular good clinical response to topical alitretinoin in NLP [45].
Atrophic Relapses occur in 55% of cases and are usually observed
Hypertrophic in the first year after finishing treatment.
Vulvo‐vaginal‐gingival syndrome
Scalp LP Follicular lichen planus
Lichen planopilaris
Follicular lichen planus or lichen planopilaris (LPP) is
Nail LP
considered rare in children. In a report of 30 cases of LPP
Nail plate thinning
by Chieregato et al., only two patients were under 18
Pterygium
years of age and both had isolated involvement of the ver-
Longitudinal ridging
tex scalp [46]. A retrospective chart review of LPP cases
Onycholysis
Longitudinal melanonychia
over 37 years identified only four cases of LP from 13 to 16
Nail dystrophy
years [47]. Scalp involvement can be patchy or diffuse.
Palms/soles LPP can be symptomatic or involve scalp dysaesthesia
Diffuse keratoderma and pruritus. Follicular papules with perifollicular scales
Yellow/red scaly plaques and violaceous plaques associated with loss of hair con-
Punctate keratosis stitute early signs. Loss of follicular ostia and epidermal
atrophy are seen in the later stages (Fig. 33.3). A hair pull
(a)
SECTION 6: OTHER
Fig. 33.2 (a) Thinning of the nail plate in nail

lichen planus. (b) Nail lichen planus showing
(b) dystrophy of the nails.
psoriasis is known to be a potential cause of lichen plano-

pilaris. Paradoxical LPP was reported to arise de novo in
an 8‐year‐old girl undergoing treatment with adali-
mumab for her arthritis [49]. It has also been reported
after TNF‐α [50]. Trichoscopy reveals multiple irregular
cicatricial alopecic areas with perifollicular whitish‐grey
scaling associated with erythema, arborizing vessels,
absence of follicular openings and follicular plugging.
The impact of cosmetic disfigurement is immense, and it
can impair the quality of life in children.
Oral lichen planus

Oral LP in childhood is exceptionally rare (<2–3% of the
total) [51]. The majority of reported cases are from India
with some from the UK, Italy, Mexico, Africa, the Americas
and Kuwait. The buccal mucosa, tongue, lips, hard palate
and gingivae can be involved. Reticulated papules with a
Fig. 33.3 Lichen planopilaris of the scalp showing cicatricial alopecia and fine, white lacy pattern in the buccal mucosa are the most
hyperpigmentation. common manifestation [52] (Fig. 33.4a). Erosive oral LP
in children is extremely rare (Fig. 33.4b). Occasionally
test is positive in the active stage. Patches of cicatricial ulcerations and, very rarely, white plaque forms of oral LP
alopecia may continue to progress inexorably, and can are present [53]. Patchy brown pigmentation of the oral
lead to a pseudo‐pelade of Brocq or the so‐called appear- mucosa may be the only manifestation of oral LP [54].
ance of ‘white footprints in the snow’ [48]. Etanercept and Squamous cell carcinoma is known to arise particularly
biologic anti‐tumour necrosis factor (TNF) therapy of in erosive and atrophic variants of oral LP, hence early
Fig. 33.4 (a) Reticulate oral lichen planus. (b)

Erosive oral lichen planus in children is extremely
rare. Here it is shown in an adult patient. (a) (b)
diagnosis is important. Periodic oral examination, good in some. Ultraviolet light‐induced alterations of self‐
oral hygiene and avoidance of spicy foods are helpful antigens on keratinocytes may lead to recruitment of
adjuncts. Corticosteroids administered topically, intrale- cytotoxic T cells. Epidermal atrophy on histopathology is
sionally or systemically, depending on the age and condi- a distinguishing feature of ALP. The differential diagno-
tion of the patient and site and severity of the lesions, sis includes discoid lupus erythematosus, polymorphous
represent the mainstay of therapy [51,54]. A recent review light eruption, melasma and lichenoid drug eruption.
SECTION 6: OTHER
and meta‐analysis showed that topical tacrolimus is an Sun avoidance, topical corticosteroids or calcineurin
effective alternative to topical clobetasol and may be con- inhibitors form the cornerstone of management.
sidered as a first‐line therapy in the management of oral LP Antimalarials are typically given for multiple, recurring
[55]. There are, however, no controlled trials in children. lesions. ALP was described in six children including five
Treatment of oral LP with ciclosporin (cyclosporine), boys and one girl. The mean age at diagnosis was 11 years
azathioprine, levamisole, griseofulvin, retinoids, hydroxy- of age. The disease started during the summertime in
chloroquine, dapsone and psoralen/UVA has been reported. five cases. The face and the upper limbs were the most
commonly affected sites, and the annular form was most
Ocular lichen planus common followed by the pigmented melasma‐like form.
There are reports of isolated ocular LP in children. In one Cheilitis was noted in three cases. The d
isease relapsed in
report, an 8‐year‐old girl with severe, filamentous dry one child after treatment interruption [58]. Ramírez et al.
eyes and persistent conjunctival hyperaemia with bilat- reported one case of ALP in a 9‐year‐old Colombian girl
eral progressive conjunctival symblepharon was who had an excellent response to hydroxychloroquine
described. Oral and topical ciclosporin combined with and photoprotection [59].
methotrexate and low‐dose oral steroids led to sustained
disease remission [56]. Hypertrophic lichen planus
The hypertrophic form of LP is relatively common in
Actinic lichen planus (ALP) children. Sharma and Maheshwari reported an inci-
Actinic LP, also known as LP subtropicus, LP tropicus dence of 26% in their series, while others reported a
and lichenoid melanodermatitis, is a photosensitive vari- lower incidence (8–10%) [21–23]. The hypertrophic vari-
ant of LP encountered commonly in young adults and ant presents as intensely pruritic, keratotic, dark brown
children from the Middle East and India. Its reported to grey‐blue, indurated plaques and nodules predomi-
incidence from India ranged from 2% to 11.5% [22,23]. nantly over the shins and the dorsal surface of the feet as
Four childhood cases have been described in Spanish is also seen with classic LP (Fig. 33.5). Lesions are often
children [57]. Lesions burn rather than itch, and are recalcitrant and tend to relapse. Moderately potent corti-
accompanied by a history of summer aggravation and costeroids under occlusion are used for treatment, but
associated photosensitivity. Three clinical variants recog- intermittent and regular patient re‐examinations are
nized are the plaque type, the annular variant and dys- needed to keep vigil for signs of epidermal atrophy.
pigmentation. The annular variant presents as brown to Intralesional steroids are an option for adolescents and
violaceous circular plaques with central hyperpigmenta- adults who may desire a faster response. Squamous cell
tion with a hypopigmented halo, typically appearing carcinoma, cutaneous horns and, recently, epidermal
over the dorsal aspects of hands, arms, neck, lips and inclusion cysts have been reported in association with
face. Melasma‐like pigmentation may be the only finding hypertrophic LP [60–62].
Atrophic lichen planus Linear lichen planus

The atrophic subtype presents clinically as greyish‐white Linear LP is well recognized in children and represents
macules with superficial skin atrophy. This variant may approximately 6.9–9.2% of cases of paediatric LP [22,43].
be seen late in the course of disease when the induration Kabbash et al. described three adolescents with eruptive
subsides or secondary to the application of potent topical linear lesions of the back, abdomen and extremities dis-
corticosteroids. Morphoea closely clinically resembles tributed along the lines of Blaschko. Clinically, one of
atrophic LP. these lesions resembled an epidermal naevus in its mor-
phology and distribution [65]. Linear LP may occur as a
Acute, eruptive lichen planus Koebner phenomenon which results in linear distribution
Eruptive LP is infrequently encountered in children. A of lesions along lines of skin trauma. On the other hand,
study from India reported eruptive LP in 16.5% of patients true linear LP is often more extensive and follows lines of
[43]. A paediatric patient with eruptive LP was reported Blaschko (Fig. 33.6). The histopathology is similar to
by Pedraz et al. [63]. The onset of lesions is acute, and they classic LP. The lines follow a curvilinear S‐shaped pattern
may arise over a span of a few days to weeks with a wide- on the abdomen, V‐shaped lines along the posterior
spread, generalized distribution. This form of LP consists midline, linear patterns on the lower trunk and limbs and
of numerous, tiny, erythematous, skin‐coloured to viola- serpiginous patterns on the scalp and face. Linear LP is
ceous, pruritic papules over trunk, face, extremities, presumed to arise as a result of cutaneous mosaicism. It
palms, soles and oral mucosal surfaces. Lesions may last has been described in association with classic LP in a
for several months before healing with residual hyperpig- 4‐year‐old girl [66].
mentation. Generalized LP in a 7‐year‐old boy who had Other blaschkolinear conditions can be considered in
multiple white‐greyish papules and plaques was treated the differential diagnosis. Lichen striatus, inflammatory
with topical corticosteroid therapy resulting in healing linear verrucous epidermal naevus (ILVEN), linear psori-
within 4 weeks [64]. The differential diagnosis includes a asis and linear Darier–White disease can cause diagnostic
lichenoid drug eruption which can present very similarly. confusion due to their close morphological similarity
with linear LP.
Bullous LP and lichen planus (LP) pemphigoides

SECTION 6: OTHER
Bullous LP is a rare variant of LP and is diagnosed when

vesicular or bullous lesions develop within pre‐existing
lesions of LP. The bullae are formed secondary to
immune‐mediated damage to the basement membrane.
This leads to liquefactive degeneration of the basal layer
and results in the formation of subepidermal bullae in
longstanding LP. Both direct and indirect immunofluores-
cence are negative in bullous LP [67].
LP pemphigoides is a rare immunobullous disease. It
was described first by Kaposi in 1892 who coined the term
‘lichen ruber pemphigoides’ to describe a case of typical
LP complicated by widespread bullous eruption [68]. It is
extremely rare in children. Tense bullae develop over pre-
viously uninvolved skin, typically overlying extremities,
Fig. 33.5 Hypertrophic lichen planus. and may arise either simultaneously with or following
Fig. 33.6 Linear (zosteriform) lichen planus.

development of classic, pruritic lesions of LP. Development folds [83]. Lesions are not itchy, but sometimes patients
of LP pemphigoides over pre‐existing scars on the limbs complain of a burning sensation. Rarely, LP pigmentosus
and buttocks was described in an 8‐year‐old Indian girl has been described in a linear or segmental distribution
[69]. Palmoplantar involvement is seen in about 50% of [84]. Dermoscopy reveals a mixed pattern: blue, grey or
cases. This form of LP may run a protracted course for 1–2 brown dots and brownish structureless areas. Treatment
years. Review of paediatric LP pemphigoides cases is not generally satisfactory and aims at identifying exter-
showed that it occurred on average around 12 years of age nal triggering agents such as dyes, chemicals, oils and
with a male‐to‐female ratio of 3 : 1. The mean time lag drugs. Tacrolimus is used to treat associated pigmenta-
between LP and LP pemphigoides was 7.9 weeks [70]. tion [85]. Oral dapsone and colchicine can be used to treat
Bullous LP will have classic LP lesions clinically, while his- widespread pigmentation.
topathology shows subepidermal bullae, presence of a
lichenoid infiltrate and negative immunofluorescence Inverse lichen planus
studies. In contrast, LP pemphigoides shows subepider- Inverse LP was first described as pruritic, hyperpig-
mal bullae filled with fibrin, eosinophils and neutrophils, mented, slightly scaly papules that were confined to flex-
without a lichenoid infiltrate. Direct immunofluorescence ural and intertriginous areas (axilla, popliteal fossae,
of the peribullous skin shows linear deposits of IgG and inframammary folds, inguinal folds and intergluteal
C3 along the basement membrane zone [71]. IgG autoanti- clefts). Mucosal, scalp, palmoplantar, nail or cuticular
bodies to either one or both of the 180 kDa bullous pem- abnormalities are usually absent. Given the hyperpig-
phigoid antigen (BPAg2, type XVII collagen) and the mentation seen in inverse LP, there may be overlap with
230 kDa pemphigoid antigens (BPAg1) can be demon- LP pigmentosus [86]. Erythroderma secondary to LP has
strated in these cases [72,73]. LP pemphigoides can be trig- also been reported [87].
gered by viral infections (e.g. varicella and hepatitis B
infection), ultraviolet B light exposure and henna tattoo- Lichenoid reactions
ing [74–77]. Medications such as ramipril, cinnarizine, Lichen planus–lupus erythematosus (lupus planus)
simvastatin, captopril, psoralen ultraviolet A therapy and overlap. Some patients show hypertrophic papules and
antitubercular drugs can also cause LP pemphigoides [78]. plaques overlying acral areas which clinically resemble
The concept of ‘epitope spreading’ following an inflam- both LP and discoid lupus erythematosus (DLE).
SECTION 6: OTHER
matory process may cause tissue damage which releases However, histopathology and direct immunofluorescence
or exposes a previously ‘sequestered’ antigen, leading to a (DIF) may favour either LP or DLE. The eruption is
secondary autoimmune response against the newly chronic and can be difficult to manage [88].
released antigen [79]. Systemic agents including oral dap-
sone, oral glucocorticoids and methotrexate are used for
Lichenoid drug eruptions. A number of drugs including
the treatment of LP pemphigoides [80].
oral hypoglycaemic agents, antimalarials, methyldopa,
Bullous pemphigoid resembles LP pemphigoides;
angiotensin‐converting enzyme inhibitors, β‐blockers
however, bullous pemphigoid occurs in the elderly age
and anticonvulsants are commonly implicated (Box 33.4).
group and rarely in children, whereas patients with LP
Histopathology demonstrates parakeratosis, basal cell
pemphigoides are more typically middle‐aged and
vacuolization and eosinophils in the dermis.
several reports have described LP pemphigoides in chil-
dren. In LP pemphigoides, the IgG and C3 are found in
the base of the bullae, as opposed to the roof in bullous Lichenoid or lichen planus‐like graft‐versus‐host
pemphigoid [79]. Reactivity to only 180 kDa antigen is disease. Approximately 100 days or so following haema-
seen in LP pemphigoides, whereas reactivity to both topoietic stem cell or peripheral blood stem cell trans-
180 kDa and 230 kDa antigens is observed in bullous pem- plantation, an eruption comprised of violaceous papules
phigoid. Immune electron microscopy has demonstrated and plaques – which clinically and histologically are
antibody deposits in the lamina lucida of lesions of indistinguishable from those of LP – may develop over
LP pemphigoides, as seen in bullous pemphigoid [80]. LP the dorsal surfaces of hands, feet and trunk. Areas heal
pemphigoides has been reported in association with with hyperpigmentation. Involvement of nails and
benign and malignant neoplasms such as lymphomas, mucous membrane may be observed. Bullous and follicu-
neuroblastoma, reticulosarcoma, chromophobe pituitary lar variants of graft‐versus‐host disease have also been
adenoma, craniopharyngioma and LP pemphigoides‐like described [89]. Sclerodermoid changes, when they occur,
variant of paraneoplastic pemphigus [81]. develop later.
Lichen planus pigmentosus Differential diagnosis. The various differential diagnos-

LP pigmentosus was first described by Bhutani et al. [82]. tic considerations are enumerated according to the clini-
It is encountered among various ethnic groups including cal type of LP in Box 33.5.
those of Arabic, Hispanic and Asian Indian background.
LP pigmentosus is more common in the third to fourth Diagnosis. Diagnosis of LP is based on the collective clin-
decades of life and is uncommon in children. LP pigmen- ical and histopathological features. Dermoscopy can aid
tosus begins as dark‐brown or slate grey macules in the in the diagnosis, especially in children and in nail and
sun‐exposed areas including the face, neck and flexural scalp LP, as it is noninvasive. Dermoscopic features of LP
Box 33.4 Drugs implicated in lichenoid drug eruption
Anti‐inflammatory drugs Antidiabetics
Aspirin Chlorpropamide
Ibuprofen Glipizide
Indometacin Insulin
Leflunomide Tolazamide
Naproxen Tolbutamide
Sulindac
Sulfasalazine ACE inhibitors
Enalapril
Antibiotics
Captopril
Para‐aminosalicylic acid
Sulfamethoxazole Antimalarials
Tetracycline or its derivatives Chloroquine
Hydroxychloroquine
Antimycobacterial
Quinacrine
Dapsone
Ethambutol Diuretics
Isoniazid Chlorothiazide
Rifampicin Furosemide
Streptomycin Spironolactone
Antifungals
Miscellaneous
Amphotericin B
Allopurinol
Griseofulvin
Henna
SECTION 6: OTHER
Ketoconazole
Isotretinoin
Anticonvulsants Levamisole
Lithium
Carbamazepine Paraphenylene‐diamine
Oxcarbazepine Penicillamine
Phenytoin
Valproate sodium Metals
Lipid‐lowering agents Gold

Mercury
Gemfibrozil
Nickel
Pravastatin
Simvastatin
Box 33.5 Differential diagnosis of lichen planus (LP)
Classic papulosquamous LP Annular LP
Pigmented plane warts Granuloma annulare

Lichenoid graft‐versus‐host disease Pityriasis rosea
Lichen nitidus Psoriasis
Secondary syphilis Tinea corporis
Lupus erythematosus Lichen simplex chronicus
Papular acrodermatitis of childhood Discoid or nummular eczema
Pityriasis rosea
LP hypertrophicus
Eruptive LP
Prurigo nodularis
Lichen nitidus Lichenoid amyloidosis
Lichenoid drug reaction Tuberculosis verrucosa cutis
Guttate psoriasis Lichen simplex chronicus hypertrophicus
Pityriasis lichenoides chronica Lichenoid psoriasis
Nekam disease
Box 33.5 Continued
Actinic LP Leucoplakia
Stomatitis migrans
Polymorphic light eruption
Autoimmune bullous diseases
Fixed drug eruption
Behçet disease
Discoid lupus erythematosus
Pachyonychia congenita
Dyskeratosis congenita
Linear LP
White sponge naevus
Lichen striatus Allergy to flavourings
ILVEN
Linear psoriasis Genital LP
Linear Darier disease
Lichen sclerosus et atrophicus
Vulvovaginal blistering diseases
LP pigmentosus
Vulval eczema
Macular amyloidosis Vulval intraepithelial neoplasia
Erythema dyschromicum perstans Cicatricial pemphigoid
Riehl melanosis
Addison disease Nail LP
Psoriasis
Atrophic LP
Alopecia areata
Lupus erythematosus Onychomycosis
Lichen sclerosus et atrophicus Idiopathic trachyonychia
Follicular LP Lichen planopilaris of scalp
Lichen scrofulosorum Discoid lupus erythematosus
SECTION 6: OTHER
Keratosis pilaris Pseudopalade of Brocq
Pityriasis rubra pilaris Morphoea
Lichen spinulosus Secondary syphilis
Oral LP Palmoplantar LP
Candidiasis Psoriasis
Aphthous stomatitis Eczema
Lupus erythematosus Focal palmoplantar keratoderma
Viral infections (herpes simplex, Coxsackie, HIV) Secondary syphilis
include grey‐blue dots, comedos, milium‐like cysts and dermoepidermal junction with pigmentary incontinence
vascular structures (red lines). Trichoscopy shows and abundant melanophages in the dermis. Artefactual
perifollicular scales (black stars), diminished follicular separation of the dermis from the epidermis may create
ostia and white dots (red stars). Blue‐grey dots (yellow small clefts known as Max Joseph spaces. In bullous LP
arrows) around the follicular structures are seen as a the clefts are often large. Histology from lichen planopila-
‘target’ pattern. Dermoscopic findings of perifollicular ris shows compact orthokeratosis, dilated follicular infun-
scale, white dots and reduced follicular ostia have been dibula filled with hyperkeratosis, slight hypergranulosis,
linked to lichen planopilaris. atrophic follicular epithelia with perifollicular fibrosis,
In atypical cases, a 4‐mm punch biopsy specimen can and new collagen formation. A dense lichenoid infiltrate
be obtained, ideally from a representative, active lesion. of lymphocytes and histiocytes at the dermoepidermal
Histopathology shows hyperkeratosis, irregular acantho- junction of the upper portion of the hair follicles, promi-
sis, wedge‐shaped hypergranulosis and sawtoothing of nent vacuolar degeneration and keratinocytic necrosis of
rete ridges (pointed rete ridges). Liquefactive degenera- the basal layer, plasma cells and eosinophils in varying
tion manifesting as vacuolization of the basal layer of the numbers in the infiltrate, and perifollicular fibrosis can be
epidermis results in loss of the usual morphology of the observed. Lichenoid drug eruption shows parakeratosis,
basal cells. This may result in loss of cohesiveness between eosinophils or neutrophils, with both a superficial and
the individual basal cells and between the epidermis and deep infiltrate. DIF studies of LP typically show fibrin at
the dermis. Civatte bodies or necrotic keratinocytes can the dermoepidermal junction and IgM (on the cytoid bod-
be seen in the lower epidermis and papillary dermis ies). Shaggy fibrin deposition at the dermoepidermal
where they appear as homogeneous, eosinophilic, PAS‐ junction is the single best indicator in the diagnosis of LP.
positive and diastase‐resistant bodies. There is presence Staining indicating IgG, IgA, C3 and fibrin can also be
of dense band‐like lymphocytic infiltrates hugging the seen. In lichen planopilaris, DIF may reveal deposition of
Table 33.1 Treatment of lichen planus (LP)
Type of LP Topical Oral Others
Cutaneous LP Potent to mid potent steroids Systemic glucocorticoids Narrow‐band UVB

Tazarotene gel 0.05% Griseofulvin Broad‐band UVB
Hydroxychloroquine PUVA therapy
Azathioprine Intralesional triamcinolone
Mycophenolate mofetil acetonide
Acitretin
Dapsone
Thalidomide
Ciclosporin
Sulfasalazine
Levamisole
Nail LP Tazarotene gel 0.05% Oral corticosteroid mini‐pulse Intramatrix triamcinolone
Mid‐potency topical (betamethasone) acetonide
corticosteroids Acitretin
Oral LP Aloe vera gel Dapsone _
Triamcinolone acetonide in Acitretin
Orabase™
Viscous lidocaine
Diphenhydramine elixir
Ciclosporin rinse
Scalp LP Topical mid‐potency Hydroxychloroquine PUVA
corticosteroids Oral mini pulse
Methylprednisolone
Thiazolidinediones (pioglitazone)
Ciclosporin
Tetracycline or its derivatives
Acitretin
SECTION 6: OTHER
Mycophenolate mofetil
IgM and/or IgA, IgG and uncommonly C3 at the infun- modality can be considered: although short‐term use of
dibulum and isthmus level. Indirect immunofluorescence oral corticosteroids can provide more rapid initial relief,
of the lesional skin may show a specific fluorescence pat- ongoing steroid‐sparing therapy in the form of narrow‐
tern corresponding to the distribution of LP‐specific anti- band ultraviolet light phototherapy (NB‐UVB) or an oral
gen in the stratum spinosum and granulosum. It can be a systemic agent such as oral dapsone or oral acitretin or
useful adjunct for the diagnosis of LP, particularly in isotretinoin may need to be considered. Generalized LP,
atypical cases [90]. eruptive LP, LP pemphigoides, lichen planopilaris with
cicatricial alopecia and nail LP with destruction of nails
are also candidates for systemic corticosteroids.
Treatment. Identification of any possible triggering drugs or
Corticosteroids are administered in different regimens.
other exposures (such as to dyes or chemicals) is important
Some advocate a weekly pulse of betamethasone at
because their elimination can ameliorate the condition. The
0.2 mg/kg on two consecutive days of the week while
choice of treatment modality depends on the age of the
others recommend daily corticosteroid at 0.5 mg/kg
patient as well as the severity and type of LP (Table 33.1).
which is tapered over 4–6 weeks to arrest formation of
A topical corticosteroid (preferably mild to moderately
new lesions. Sulfasalazine, ciclosporin, methotrexate and
potent), along with a second‐generation oral antihistamine
azathioprine have also been used to control highly active
(levocetirizine/fexofenadine/desloratadine), constitutes the
disease as steroid‐sparing agents. Metronidazole, pheny-
mainstay of therapy in children. However, topical tacroli-
toin, thalidomide and mycophenolate mofetil can be tried
mus or pimecrolimus can also be used for cutaneous and
in severe cases unresponsive to conventional agents.
oral LP. These drugs are also particularly useful for main-
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temic glucocorticoids and dapsone. Pediatr Dermatol 2014;31:751–3. 2016;82:89–91.
77 Rosmaninho A, Sanches M, Oliveira A et al. Lichen planus pemphig- 88 Van der Horst JC, Cirkel PKS, Nieboer C. Mixed lichen planus‐lupus
oides induced by a weight reduction drug. Cutan Ocul Toxicol erythematosus disease: a distinct entity? Clinical, histopathological
2011;30:306–8. and immunopathological studies in six patients. Clin Exp Dermatol
78 Chan LS, Vanderlugt CJ, Hashimoto T et al. Epitope spreading:
1983;8:631–40.
Lessons from autoimmune skin diseases. J Invest Dermatol 89 Johnson ML, Farmer ER. Graft‐versus‐host reactions in dermatology.
1998;110:103–9. J Am Acad Dermatol 1998:;38:369–92.
79 Duong B, Marks S, Sami N, Theos A. Lichen planus pemphigoides in 90 Rao R, Shenoi SD. Indirect immunofluorescence to demonstrate

a 2‐year‐old girl: response to treatment with methotrexate. Am Acad lichen planus specific antigen (LPSA) in lichen planus. Indian
Dermatol 2012;67:e154–6. J Dermatol Venereol Leprol 2006;72:350–2.
SECTION 6: OTHER
403
C HA PTER 34
Lichen Nitidus
Jasem M. Alshaiji
Dermatology Department and Pediatric Dermatology Unit, Amiri Hospital, Kuwait
Abstract been rarely reported. Most cases are isolated, but various diseases,
either inherited or acquired, have been reported in association
with LN. The pathogenesis of LN remains unclear. No laboratory
Lichen nitidus (LN) is an acquired inflammatory cutaneous disor-
abnormalities are found. The diagnosis is based largely on clinical
der affecting mostly school‐aged children and young adults. There
features, but the characteristic histological findings are very helpful
is no apparent gender or race predilection. Typically, it manifests
to confirm the diagnosis when needed. LN is usually a self‐limited
with multiple, grouped, glistening, skin‐coloured, dome‐shaped
disease, resolving within a few months to 1 year, but in some cases
or flat‐topped, pinhead‐sized papules. They are mostly seen on
the condition may be persistent, generalized or disfiguring, in which
the extremities, trunk and genitalia, but lesions can arise on any
case therapeutic modalities can be used including topical or systemic
cutaneous surface. Usually asymptomatic, LN can occasionally be
agents and, occasionally, phototherapy with ultraviolet A or B.
mildly pruritic. It is most often localized, but generalized cases have
Key points • LN is most often localized, but can be generalized.

• Other variants include confluent, vesicular, haemorrhagic,
perforating, spinous follicular, linear and actinic.
• Lichen nitidus (LN) is a chronic benign inflammatory skin disorder.
• Mucous membranes, palms and soles and nail involvement are
• LN affects mainly school‐aged children and young adults.
rarely reported.
• The pathogenesis of LN is still unclear.
• No laboratory abnormalities have been consistently reported.
• There is no sex or race predilection.
SECTION 6: OTHER
• LN is diagnosed clinically, but can be confirmed by histology.
• LN manifests as multiple, skin‐coloured, dome‐shaped or
• It is a self‐limited disease, usually resolving within a few months
flat‐topped papules, seen predominantly on the trunk, upper
up to 1 year, although some persistent cases have been reported.
extremities and genitalia.
• LN is usually asymptomatic, but it can be pruritic.
The occurrence of LN during infancy is extremely rare but

Introduction. Lichen nitidus (LN) is a benign chronic
has been reported [3,4].
inflammatory skin disease affecting mainly school‐aged
children and young adults. There is no sex or race predi-
lection. Familial cases have been rarely reported. Its Pathogenesis. The pathogenesis of LN is still unclear.
pathogenesis is still unclear although an immunological There are reports of LN and lichen planus (LP) co‐
basis is suspected. It manifests with multiple, 1–2 mm, occurring in the same patient, which suggests the
glistening skin‐coloured or slightly pinkish or hypopig- controversial possibility that LN might represent a

mented dome‐shaped or flat‐topped papules limited to micropapular variant of LP with similar aetiologies [4].
the extremities, trunk and genitalia. No laboratory abnor- One study observed LN‐like lesions in nearly a third of
malities have been reported. The diagnosis is based patients with LP; however, histopathological and immu-
largely on clinical features, but can be confirmed by the nohistochemical patterns of LN are diagnostic and dis-
characteristic histological findings. LN is usually a self‐ tinctly different from those of LP. Immunohistochemical
limited disease resolving within a few months up to 1 staining of LN reveals an infiltrate of CD4+ and CD8+
year, although some cases can persist for longer. lymphocytes as well as macrophages and Langerhans
cells. Similar studies of LP more typically demonstrate a
History. Felix Pinkus first described lichen nitidus in predominance of CD4+ cells that display HECA‐452 (a
1907 [1]. skin homing receptor), supporting the notion that LN
and LP are distinct entities [4].
Epidemiology. LN affects mostly school‐aged children One aetiological theory proposes that LN is an
and young adults with a median age of 7 years in boys immunological response to an infectious agent or an
and 13 years in girls [2]. There is no sex or race predilection. idiopathic response to nonviable microbial antigens
(viruses/bacteria) that may activate a cell‐mediated

response, initiate lymphocyte accumulation and form
inflammatory papules [5].
Clinical features. LN manifests clinically as multiple,

1–2 mm, discrete, glistening, skin‐coloured or slightly
pinkish or hypopigmented, dome‐shaped or flat‐topped
pinhead‐sized papules (Figs 34.1–34.3). They are usually
arranged in groups and are mainly seen on the upper
extremities, chest, abdomen and genitalia (especially the
glans and shaft of the penis, and prepuce), but lesions can
arise anywhere on the cutaneous surface. Usually asymp-
tomatic, LN can be mildly pruritic and disfiguring. It is
most often localized, but a generalized variant is rarely
seen [3,6–9]. Many associated diseases with generalized
LN have been reported (Box 34.1).
Other clinical variants of LN include confluent, vesicu- Fig. 34.3 Lichen nitidus on the extensor aspect of the lower limb with
lar, haemorrhagic [18], perforating [19,20], spinous follic- Koebner phenomenon. Source: Courtesy of Shehab Al‐Dhafiri, MD.
ular [7,21], linear/blaschkolinear [22–24] and actinic [4,5].
Actinic LN (ALN) is a unique, photodistributed sea-
sonal variant of LN seen mainly in children and young Box 34.1 Diseases associated with lichen nitidus [4,10–17]
adults with Fitzpatrick skin types IV–VI [4,25–27]. A case Crohn disease
Down syndrome
Human immunodeficiency virus infection
Juvenile chronic arthritis

Juvenile myelomonocytic leukaemia
Multiple endocrine neoplasia
SECTION 6: OTHER
Neurofibromatosis, type 1
Niemann–Pick disease
Postpartum thyroiditis
Russell–Silver syndrome
of ALN developing in a young Caucasian male with

Fitzpatrick skin type III has been described more recently
[28]. Bedi first reported this entity in 1978 as summertime
actinic lichenoid eruption (SALE) [29]. Isaacson et al. con-
sidered the lesions as part of the spectrum of actinic LP
(ALP) [30]. Kanwar and Kaur, and Hussain, proposed the
Fig. 34.1 Lichen nitidus on the forehead – actinic variant. Source: term actinic lichen nitidus [31–33].
Courtesy of Shehab Al‐Dhafiri, MD. ALN is clinically and histopathologically different from
actinic LP. There are similarities to a pinpoint papular
variant of polymorphous light eruption (PMLE), so both
PMLE and ALN can be regarded as variants of the same
entity in this author’s opinion [4].
As with LP, the Koebner phenomenon can be observed
and is a hallmark of LN [5,34].
Involvement of the mucous membranes, palms and
soles and nails is rarely reported [5,18,35–40].
When LN is present at this site, the oral cavity shows
minute grey‐white flat papules on the buccal mucosa or
tongue [40–42]. LN of the palms may differ from classic
LN in its clinical appearance: hyperkeratotic fissured and
pitted papules/plaques with central plugs or more rarely
purpuric lesions and lesions resembling pompholyx may
be observed. It tends to occur at an older age with mean
age at onset being 45 years (age range: 37–52), and to be
accompanied by plantar lesions [18,35–38]. Classic LN
Fig. 34.2 Lichen nitidus on the extensor aspect of the upper limb. Source: lesions at other sites usually accompany the palmoplantar
Courtesy of Shehab Al‐Dhafiri, MD. lesions, and nail dystrophy associated with the palmar
Chapter 34 Lichen Nitidus 405
Box 34.2 Cutaneous diseases reported in association Box 34.3 Differential diagnosis of lichen nitidus
with lichen nitidus [5,21,43,44]
Classic form [35,45–49]
Lichen planus
Erythema nodosum Keratosis pilaris
Segmental vitiligo Lichen planus
Lichen spinulosus Follicular eczema
Lichen striatus Contact dermatitis to parthenium or nickel
Psoriasis vulgaris Molluscum contagiosum
Atopic dermatitis Verruca plana
Tattooing Pityriasis rubra pilaris
Phrynoderma
Lichen simplex chronicus
Keratosis follicularis (Darier disease)
lesions has been reported [36]. Nail involvement is rarely Secondary syphilis
reported and can precede the onset of skin lesions. Unlike Id reaction
nail LP, nail LN is more common in children, and is less Lichen scrofulosorum
severe with no pterygium formation or anonychia [39]. Prurigo nodularis
The nail changes when present include thickening, lon- Psoriasis
gitudinal ridging, pitting, distal detachment, rippling, Granuloma annulare (GA)
trachyonychia and median canaliform dystrophy in the Langerhans cell histiocytosis (LCH)
absence of nail bed tumours or a history of trauma [39,40]. Papular mucinosis
Clues to the diagnosis include the presence of subtle
papules on the affected digit and swelling with Perforating lichen nitidus [19]
hyperpigmentation of the nail fold due to nail matrix Primary perforating disorders (such as Kyrle disease, reactive
involvement [39]. perforating collagenoses, elastosis perforans serpiginosa and
Rarely, LN can be associated with various other cutane- perforating folliculitis)
ous diseases as noted in Box 34.2. Secondary perforating dermatoses (such as GA and calcinosis cutis)
SECTION 6: OTHER
The simultaneous occurrence of molluscum contagio-
sum (MC) or condyloma acuminatum and LN has been Actinic lichen nitidus [26,27]
rarely reported and may be coincidental [45]. Actinic lichen planus
Actinic folliculitis
Differential diagnosis. There are many cutaneous disor- Follicular eczema
ders that can clinically mimic the classic and variant Sarcoidosis
forms of LN (Box 34.3). Mucinosis (lichen myxoedematosus)
Laboratory/pathology findings. No laboratory abnor- Palmoplantar lichen nitidus [35,36,38]

malities have been reported.
Arsenical keratosis
The diagnosis is largely based on clinical features, but Darier disease
can be confirmed by histopathological features, which are Naevoid basal cell carcinoma
quite characteristic (Figs 34.4 and 34.5). Porokeratotic eccrine ostial and dermal duct naevus
The histology demonstrates a sharply circumscribed Chronic eczema and pompholyx
inflammatory infiltrate within the dermis that generally Keratodermas
spans approximately four to five dermal papillae. The bor- Palmar lichen planus
ders are marked by extensions of epidermal rete ridges, Pitted keratolysis
giving a so‐called ‘ball‐in‐claw’ appearance. The infiltrate
is composed of lymphocytes and epithelioid histiocytes.
The overlying epidermis is thin and parakeratotic with
basal cell hydropic degeneration and cytoid bodies [50]. cells. The basal cell layer overlying the top of the dilated
The accumulation of S‐100+ CD1a+ Langerhans cells and dermal papilla is poorly refractile, possibly because of the
CD68+ macrophages/histiocytes in the papillary dermis is depletion of melanocytic cells [52]. In cases of palmoplan-
a typical feature of LN [51]. In addition to these immuno- tar LN, if typical LN lesions at other regions are not pre-
histochemical findings, factor XIIIa+ and fascin+ cells in sent, dermoscopy can be a valuable tool for confirming
the dermis have been found in cases of generalized spinous the diagnosis [53]. In plantar LN, linear scales in parallel
follicular LN with perifollicular granuloma [7]. are discontinued by oval, well‐defined depressions sur-
In vivo imaging with confocal laser scanning micros- rounded by ring‐shaped, silvery‐white scales. The long
copy (CLSM) is a useful diagnostic tool that can be uti- axes of the depressed patterns are parallel to the lines of
lized before performing skin biopsy. CLSM reveals round, scales. Fewer and finer scales on the surface of depressed
enlarged, well‐circumscribed dermal papillae that are areas are found. In palmar LN, a similar structure of
heavily laden with individual highly refractive cells, depressions and arrangement of scales is found, but the
consistent with melanophages and possibly mononuclear depressions are flatter and have longer patterns [53].
Treatment. Treatment of LN is often unnecessary given

its asymptomatic nature and tendency for spontaneous
improvement. However, treatment may be required for
persistent and generalized cases and for individual
patient cosmetic concerns.
For symptomatic localized cases, mid‐ to high‐
potency topical corticosteroids or topical calcineurin
inhibitors and antihistamines may be effective.
Successful treatment of penile LN in a 20‐year‐old man
has been reported with topical pimecrolimus 1% cream
applied twice daily for 2 months [54]. Ablative laser
therapy for penile LN should be avoided due to the
potential for scarring [55].
For actinic LN, additional measures including sun-
screen use and sun avoidance may help prevent
development of new lesions. Facial ALN in a 23‐year‐
old female was successfully treated with hydroxy-
chloroquine 200 mg twice daily for 4 weeks and then
a maintenance dose of 200 mg per day for a total of 6
months [27].
For generalized LN, topical corticosteroids and
calcineurin inhibitors may be helpful [47,56]. Successful
treatment of generalized LN in an 8‐year‐old child with
pimecrolimus 1% cream twice daily for 8 weeks has been
reported [47]. Systemic agents that have been reported as

having some success include systemic retinoids (acitretin,
isotretinoin), astemizole, dinitrochlorobenzene/diphe-
SECTION 6: OTHER
Fig. 34.4 Histology of lichen nitidus (×4). Source: Courtesy of Mohammad

Al‐Enezi, MD. nylcyclopropenone immunotherapy, systemic steroids,
ciclosporin (cyclosporine), itraconazole, isoniazid and
enoxaparin [4,15,47,57]. Ultraviolet light phototherapy in
the form of narrow‐band UVB and PUVA has been
reported to have some therapeutic benefit [4,15,47,58].
While these may be reasonable considerations in some
adult patients, many of these modalities may not be
entirely suitable for use in children.
Prognosis. LN is a chronic but self‐limited disease and the

lesions usually resolve spontaneously within several
months to 1 year.
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2012;53:e16–e17. S‐100+ CD1a+ Langerhans cells as a characteristic of lichen nitidus.
27 Bouras M, Benchikhi H, Ouakkadi A, Zamiati S. Facial actinic
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408
CHA PTER 3 5
Lichen Striatus
Franck Boralevi1 & Alain Taïeb2
1
Pediatric Dermatology Unit, Hôpital Pellegrin‐Enfants, Bordeaux, France
2
Department of Dermatology and Paediatric Dermatology, Reference Center for Rare Skin Diseases, Hôpital Saint André, Bordeaux, France
Abstract coloured flat‐topped papules, typically with a lichenoid appearance,

arising along a Blaschko’s line. Multiple lesions may occur simultane-
Lichen striatus is a transient linear eruption that arises along ously. Hypochromic, or more rarely hyperchromic sequelae may occur.
Blaschko’s lines and lasts several months to a few years, eventu- Treatment is usually not needed. Pathological examination typically
ally healing spontaneously. Children are much more often affected shows a mixed spongiotic and lichenoid pattern, with a perivascular
than adults, and females are significantly more frequently affected and periadnexal lymphocytic infiltrate. Lichen striatus and blaschkitis
than males. The lesions consist of erythematous or sometimes skin‐ belong to the same clinical and pathological spectrum.
Key points • Light microscopy shows a mixed spongiotic–lichenoid histological

pattern.
• Lichen striatus is a benign and self‐limited disease. Usually no
• Lichen striatus (LS) is a transient linear eruption that arises along
treatment is required.
Blaschko’s lines.
• Similarly to other linear conditions, LS may be considered a
• LS most frequently occurs in children, with a mean age of 3.5.
superimposed segmental manifestation of polygenic skin disorders.
• Usually, a single linear lesion occurs and exhibits a self‐limited

• To avoid confusion with other lichenoid conditions, the name
course of several months’ duration.
‘blaschkitis’ may also be used.
SECTION 6: OTHER
lichenoides [10], lichen striatus [11,12], lineare neurodermatitis

Introduction. Lichen striatus is a transient but prolonged
[13], dermatosis linearis pruriens [14] and lineären Ekzem [15].
linear eruption more frequently observed in children
The authors’ own review of these original sources suggests
than in adults [1]. Usually a single linear lesion occurs
that some of the patients described may have actually had
along the developmental lines of Blaschko (Fig. 35.1) and
inflammatory linear verrucous epidermal naevus (ILVEN),
exhibits a self‐limited course and a duration varying from
linear lichenification or linear porokeratosis [12,14].
several weeks to 2–3 years. Postinflammatory hypopig-
Later, in the 1960s, Gianotti and Frugis, from a study of
mentation or hyperpigmentation may persist even longer.
nine cases, suggested that viral diseases may trigger
Relapses rarely occur. Several conditions such as atopic
lichen striatus [16]. Jackson, in his review, emphasized the
dermatitis or vitiligo may be associated. Familial cases
distribution along the lines of Blaschko [17,18], and this
have been reported. Characteristically, light microscopy
was revisited by Grosshans [19,20], who proposed the
shows a mixed spongiotic–lichenoid histological pattern,
name blaschkitis or Blaschko dermatitis (blaschkite in
frequently with a lymphocytic infiltrate along eccrine
French) as a more precise name. More recently, in order to
ducts or glands [2]. The pathogenesis of this Blaschko’s
underline the distribution of this disorder and its relation
line disorder remains unclear, with suggestions that a
to a latent developmental abnormality, Taïeb et al. sug-
postzygotic genomic event or that epigenetic mosaicism
gested the name blaschkolinear acquired inflammatory
could be involved, associated with a triggering event,
skin eruption (BLAISE) [1]. The acronym BLAISE has not
possibly a viral infection.
been widely used since the 1990s but its use could be
encouraged as it emphasizes the concept of a spectrum
History. Senear and Caro are credited with the description including LS and blaschkitis [21].
and naming of lichen striatus [3]. In their paper, published
in the middle of the twentieth century, they reviewed the Epidemiology. LS most frequently occurs in children 1–10
literature and compiled the numerous terms that have years of age, with a mean age of 3.5 in the largest series
been used to describe this disorder: éruption lichénoïde [4], (Table 35.1) [1,22–25]. Cases have been reported in infants
naevus linearis [5], trophonévrose lichénoïde en bande linéaire from the first months of life [25,26], but LS may occur at
[6], neurodermite zoniforme [7], linear cutaneous eruption [8], any age from infancy to adulthood in all ethnic groups
systematisierter Lichenifikation [9], dermatosis linearis [20,26]. It is more common in children than in adults and
Chapter 35 Lichen Striatus 409
to a common trigger [39]. Pathological findings suggest

that cytotoxic events eventually eliminate mutant cells
through a cell‐mediated immunological process involv-
ing CD8+ cytotoxic T cells. The late occurrence in many
cases suggests a breakdown of immune tolerance towards
a cell clone that was hitherto quiescent. The time course of
the disease may vary according to the duration of the
scavenging process. The abnormal immune status usually
associated with atopy might contribute to the develop-
ment of LS.
Similarly, other immune or autoimmune disorders
have already been shown to follow the lines of Blaschko
[40,41]. These are considered as superimposed segmental
manifestations of polygenic skin disorders and include
linear psoriasis, fixed drug eruption, atopic dermatitis,
lupus erythematosus, vitiligo, pemphigus vulgaris,
chronic graft‐versus‐host disease, granuloma annulare,
lichen planus, lichen nitidus and lichen planopilaris [39].
The peripheral blood hypereosinophilia described in one
case before the onset of LS might be considered an early
part of the immune response [1].
What might stimulate the sudden loss of tolerance to an
abnormal cutaneous clone in patients with this acquired
disorder? Perhaps an acute event causes the aberrant
clone to express a novel membrane antigen, as has been
hypothesized in autoimmune disease. Several precipitat-
ing factors have been identified in isolated cases, with LS
SECTION 6: OTHER
arising after skin trauma or sunburn [42,43], topical wart
therapy [25], contact dermatitis or an infectious disease
Fig. 35.1 Typical presentation of lichen striatus arising here on the upper
(flu‐like fever, tonsillitis, varicella [44]), or bacillus
limb of a young child, with an erythematous, linear and slightly papular
lesion along a line of Blaschko.
Calmette–Guérin (BCG) or yellow fever vaccination
[2,45–47]. One case arising after a bumblebee sting has
been recently reported [48].
most common in younger children (2–3 years) than in
The simultaneous occurrence of LS in pairs of (even
older ones, as reporting bias may have led to the prepon-
nonrelated) siblings and the seasonal influence men-
derance of older children in the past literature [3]. LS is
tioned in several papers provide some circumstantial evi-
significantly more common in females, with a sex ratio of
dence of an infective trigger associated with intrinsic
1 : 2.1 [3,25,27,28]. There are a few reports of familial cases,
susceptibility [29–31]. Increased quantities of IL‐1β in the
mainly arising in siblings, and more rarely concomitant
lesions [32] could support an in situ inflammasome‐
cases in a child and one of the parents [30–34]. The asso-
driven process triggered by infectious pathogens. Based
ciation with atopic dermatitis has been widely noted in
on histological findings, the primary target of the inflam-
several papers, especially among Italian or Spanish series
matory reaction in LS is the keratinocyte in the basal and
that showed signs of atopy in 48–61% of cases [24,25]. In
suprabasal layers. The occurrence along the lines of
one series, 84% of patients with LS had a positive history
Blaschko also favours the keratinocyte as the target cell
of atopic disorders [27]. A few cases of LS with psoriasis
[1]. Familial occurrence is unlikely via the somatic muta-
have been published [35], and more recently the associa-
tion mechanism because these mutations take place by
tion with vitiligo has been reported, with onset of vitiligo
chance. Epigenetic mosaicism has been suggested to con-
and LS at around the same time in a young girl, suggest-
tribute to skin diseases following the lines of Blaschko
ing a common trigger or a common background [36].
[38]. These skin diseases might be caused by visualization
of the actions of transposable elements that are partly
Pathogenesis. Lichen striatus is characterized by a mixed expressed and partly silenced at an early developmental
lichenoid and spongiotic histological pattern with a dis- stage. Epigenetic rather than genomic mechanisms fit bet-
tribution along the lines of Blaschko. Current embryologi- ter the familial observations of lichen striatus.
cal theory suggests that Blaschko’s lines correspond to the
direction of growth of clones of epidermal and dermal
cells derived from precursor cells [37,38]. The segmental Clinical features. Lichen striatus is not rare, but it may
involvement may be explained by an early postzygotic frequently go undiagnosed [1,25,27]. LS is an acquired
event in the form of loss of heterozygosity involving and not a congenital condition, even though it may appear
genes that may lead to an inappropriate immune reaction early in infancy. The lesions are distributed on the limbs
Table 35.1 Lichen striatus clinical characteristics, including age, sex ratio, localization of the lesions, mean duration from the review of the largest LS series
n Male : female Mean age Seasonality Localization Atopy Mean Relapses

ratio (range) duration
Sittart et al., 1989 [22] 53 1 : 2.3 2.5 yr Spring and summer Limbs 92% 20% — —
SECTION 6: OTHER
(1–40 mo)
Taïeb et al., 1991 [1] 18 1 : 1 3 yr — Limbs 66% 33% 9.5 mo 5%
(0.5–14 yr) Trunk 33% (6/18) (4 wk–4 yr) (1/18)
Kennedy and Rogers, 1996 [23] 61 1 : 2 2.9 yr Spring and summer Limbs 77% — 12 mo —
(0.8–9 yr) Trunk 11% (4 mo–4 yr)
Zhang and McNutt, 2001 [28] 37 1 : 1.6 17.5 yr — Limbs 76% — — —
(1.3–49 yr)
Hofer, 2003 [29] 18 1 : 2 44 yr — Trunk 77% — 8.7 mo 28%
(adults only) Limbs 55%
Taniguchi et al., 2004 [27] 89 1 : 3 — Spring Limbs 85% 20% — —
(1 mo–14 yr) Trunk 10%
Patrizi et al., 2004 [25] 115 1 : 2.1 4.4 yr Cold seasons Limbs 62% 61% 6 mo 4.3%
(1 mo–13 yr) Trunk 25% (70/115) (5/115)
Head 15%
Paramiquel et al., 2006 [24] 24 1 : 1 3.4 yr Spring and summer Limbs 73% 48% 8.5 mo —
(1 mo–2 yr)
c35.indd 410 9/7/2019 2:34:49 AM

in two thirds of the cases, with a slight preponderance of

lesions on the inferior limbs (Fig. 35.2) compared to the
upper limbs (Fig. 35.1), on the trunk (Fig. 35.3) in around
20% of cases, and on the face (Fig. 35.4) in the remaining
5–10% of cases (Table 35.1) [49]. Pruritus can be moderate
but is uncommon, reported by about 10% of the patients.
Clinical features of atopy and minor signs of atopic der-
matitis may be associated; more rarely psoriasis or viti-
ligo is a feature (Fig. 35.5). The mean duration is 6–12
months (range 4 weeks to 10 years; median around 8
months). Relapses may occur within the first 4 years in
about 5% of cases in children and more frequently in
adults [1,25].
The most characteristic feature is the linear arrange-
ment of inflammatory lesions, ranging in extent from a Fig. 35.3 Lichen striatus on the trunk.
few centimetres to an entire limb or half of the trunk. The
lesions consist of pink, erythematous or skin‐coloured,
flat‐topped papules, with a frequent lichenoid appear-
ance (Fig. 35.6) and sometimes vesicular with eczematous
features [40]. Wickham’s striae are absent. A perforating
variant has been described [50].
The linear eruption appears in 2–3 weeks and usually
disappears in several months, leaving transient or pro-
longed depigmentation in about 50% of cases (Fig. 35.7) [1].
Hyperpigmentation has also been noted [51]. The lesions
may form in a single line or occur in grouped divided lines.
Streaks may be discontinuous. Hemicorporeal forms with
SECTION 6: OTHER
multiple involved lines occur rarely, and bilateral forms Fig. 35.4 Facial lichen striatus.
(Fig. 35.8) appear exceptionally [52]. Facial involvement is
more common than previously thought [25] but can be dif-
ficult to diagnose if a limited portion of a Blaschko’s line is
involved because of less frequent access to biopsy. In a
Fig. 35.2 Lichen striatus on the posterior aspect of the inferior limb, here
with a double erythematous line. Fig. 35.5 Association of lichen striatus and vitiligo in a young girl.
Fig. 35.6 Lichen striatus – skin‐coloured flat‐topped papules with rarely

encountered linear vesicular lesions.
SECTION 6: OTHER
Fig. 35.8 Lichen striatus with multiple involved lines of Blaschko on the
trunk of an infant. This clinical form of LS (or blaschkitis) is characterized
by a shorter course and complete healing.
dystrophy that may be associated with longitudinal lines

or nail groove, onychorrhexis, koilonychias and distal
onycholysis. Linear papules may coexist near the nail fold.
Nail involvement may appear before typical cutaneous
lesions have been observed, or can be isolated, and can
persist after healing of the skin lesion [53–56]. Follicular
involvement with transient focal hair loss may also exist.
Prognosis. Lichen striatus is a benign disease. Resolution

begins in a few weeks to a few months. Residual hypopig-
mentation may constitute a cosmetic problem in darkly
pigmented skin.
Differential diagnosis. Lichen striatus, with its character-

istic linearity and history of acquired onset, is a distinc-
tive cutaneous disorder. Box 35.1 lists the major differential
diagnoses. Biopsy may be helpful to differentiate LS from
the other disorders.
The lesions of LS differ from the pruritic and usually
monomorphic keratotic papules of lichen planus, which
Fig. 35.7 Hypopigmented skin lesion as a sequela of lichen striatus. can also occur in a linear distribution [57,58]. In contrast,
pruritus is rare in LS. Lichen planus usually eventuates in
series of facial LS, it was noted that the average age and sex hyperpigmentation, and LS more frequently in hypopig-
ratio of facial LS was similar to that of LS of the limbs, with mentation [59]. Clinical variants of linear lichen planus,
a similar natural history [49]. Nail involvement (Fig. 35.9) including vesicular lichen planus and linear lichen plano-
is not uncommon and consists of linear, segmental or total pilaris, have been described [60,61].
Fig. 35.10 Typical linear psoriasis on the trunk and right upper limb in a
young girl, with hyperkeratotic papules surrounded by a hypochromic halo.
Linear porokeratosis is a chronic disease, and the

characteristic rim of dyskeratosis around the primary
circular or oval lesions is easily detected, especially using
dermoscopy. Linear Darier disease also has a chronic
course and typical histopathological features. Linear
lupus erythematosus is extremely rare and has not been
described in children.
In examining patients with the hypopigmented stage of
Fig. 35.9 Skin‐coloured linear papules on the dorsal part of the hand with LS, hypomelanosis of Ito and linear vitiligo must be
considered [61]. However, a history of a previous inflam-
SECTION 6: OTHER
partial involvement of the right thumbnail.
matory stage will suggest the correct diagnosis. At the
onset of the eruption, cutaneous larva migrans could be
Box 35.1 Lichen striatus: differential diagnosis confused with LS.
The linear eruptions that have been described as
• Linear lichen planus
blaschkitis or Blaschko dermatitis in adults are character-
• Linear lichen nitidus
ized both clinically and histologically by eczematous
• Linear psoriasis
changes. Adult blaschkitis shows a tendency to relapse. LS
• Inflammatory linear verrucous epidermal naevus (ILVEN)
probably belongs within the spectrum of blaschkitis [62].
• Linear atopic dermatitis
• Linear porokeratosis
• Linear Darier disease Histology findings. Lichen striatus lacks specific patho-
• Linear lupus erythematosus
logical findings, but pathological examination typically
• Hypomelanosis of Ito* (hypopigmented stage)
shows a combination of spongiotic epidermal signs and
• Linear vitiligo* (hypopigmented stage)
lichenoid interface dermatitis with a perivascular and
• Cutaneous larva migrans
periadnexal lymphocytic infiltrate [66]. The largest study
* Blaschkitis is not considered as a distinct entity but as part of the LS of the pathology of LS included 41 childhood cases [67].
spectrum. The authors concluded that histological examination
could lead to a diagnosis of LS in about 50% of cases. In an
older study of 23 cases, Reed et al. considered that histo-
Linear lichen nitidus is characterized by minute pap- pathological examination was not sufficient to differenti-
ules [62]. However, a histological overlap between lichen ate LS from lichen nitidus and lichen planus [68]. More
striatus and lichen nitidus has been noted [41]. Linear precisely, the diagnosis should be based on the following
psoriasis [63] and ILVEN are characterized by larger, lin- features: (i) a focal band‐like infiltrate with (ii) variable
ear papulosquamous streaks and a psoriasiform histolog- exocytosis and (iii) a collection of histiocytes in the d
ermal
ical pattern not seen in lichen striatus (Fig. 35.10). papillae. Slight acanthosis and focal parakeratosis,
Linear atopic dermatitis [64] has been described in a together with satellite cell necrosis, have been described.
young girl. The patient presented with a linear arrange- Additional features of interest include perivascular lym-
ment of nummular lesions that recurred during phoid aggregates and the alignment of the infiltrate along
generalized flares of the disease. Muñoz Garza et al.
hair follicles and eccrine ducts that are particularly
reported two cases of linear morphoea of the forehead distinctive of LS [1,2,28,66]. Occasionally, a dense deep
and nose with lesions that were initially diagnosed dermal lymphocytic infiltrate [28,69] and intraepidermal
clinically and histologically as LS, and hypothesized that vesicles filled with Langerhans cells and CD8+ T lympho-
LS may precede or simulate linear morphoea [65]. cytes may be present. CD8+ intraepithelial lymphocytes
are sometimes scattered but are most often located in 16 Gianotti F, Frugis F. Il lichen striatus. Aspetti clinici ed istologici di
nove casi. Giorn Ital Derm 1963;48:307–22.
clusters around necrotic keratinocytes, thus supporting
17 Jackson R. The lines of Blaschko: a review and reconsideration.
the hypothesis of a cytotoxic process directed towards Observations of the cause of certain unusual linear conditions of the
keratinocytes [1]. Most of the small lymphocytes in the skin. Br J Dermatol 1976;95:349–60.
upper dermis and epidermis are positive for CD7 [2]. 18 Blaschko A. Die Nervenverteilung in der Haut in ihrer Beziehung zu
den Erkrankungen der Haut. Beilage zu den Verhandlungen der
According to Gianotti et al. [2], the age of the lesion does Deutschen Dermatologischen Gesellschaft VII. Congress, Breslau,
not influence the ratio of nonspecific to diagnostic histo- Braumüller, Wien und Leipzig, 1901.
logical changes. In 50% of cases, nonspecific findings 19 Grosshans E. Lichen et éruptions lichénoides. Ann Dermatol
were noted. Vénéréol 1989;116:925–9.
20 Grosshans E, Marot L. Blaschkite de l’adulte. Ann Dermatol
Vénéréol 1990;117:9–15.
Treatment. Usually no treatment is required. 21 Johnson M, Walker D, Galloway W et al. Interface dermatitis along
Careful explanation of the benign and self‐limited nature Blaschko’s lines. J Cutan Pathol 2014;41:950–4.
22 Sittart JA, Pegas JR, Sant’Ana LA, Pires MC. Lichen striatus.
of this disorder is extremely important, with mention of Epidemiologic study. Med Cutan Ibero Lat Am. 1989;17:19–21.
complete healing without skin sequelae in most cases. 23 Kennedy D, Rogers M. Lichen striatus. Pediatr Dermatol
Tacrolimus ointment has been shown to hasten the 1996;13:95–9.
resolution of the disease and can be proposed on facial 24 Peramiquel L, Baselga E, Dalmau J et al. Lichen striatus: clinical and
epidemiological review of 23 cases. Eur J Pediatr 2006;165:267–9.
skin and on coloured skin in order to reduce the risks of 25 Patrizi A, Neri I, Fiorentini C et al. Lichen striatus: clinical and labo-
residual hypopigmentation. Topical tacrolimus has also ratory features of 115 children. Pediatr Dermatol 2004;21:197–204.
been considered for early treatment of multiple and 26 Markouch I, Clérici T, Saiag P, Mahé E. Lichen striatus avec dystrophie
unguéale chez un nourrisson. Ann Dermatol Venereol 2009;136:883–6.
spreading LS [70], but its usefulness in those with multiple 27 Taniguchi Abagge K, Parolin Marinoni L, Giraldi S et al. Lichen striatus:
areas of blaschkitis is difficult to prove because multiple description of 89 cases in children. Pediatr Dermatol 2004;21:440–3.
blaschkitis is thought to heal rapidly. Pimecrolimus has 28 Zhang Y, McNutt NS. Lichen striatus. Histological, immunohisto‐
also been proposed in cases of relapsing and itchy LS in chemical, and ultrastructural study of 37 cases. J Cutan Pathol
2001;28:65–71.
adults [71]. Because of interface changes mimicking lupus 29 Hofer T. Lichen striatus in adults or ’adult blaschkitis’?. There is no
erythematosus, Lee et al. proposed hydroxychloroquine need for a new naming. Dermatology 2003;207(1):89–92.
in cases of facial LS, which demonstrated reasonably 30 Patrizi A, Neri I, Fiorentini C et al. Simultaneous occurrence of lichen
striatus in siblings. Pediatr Dermatol 1997;14:293–5.
good results [72]. Finally, in a recently published series
SECTION 6: OTHER
31 Smith SB III, Smith JB, Ellis LE et al. Lichen striatus: simultaneous
of 12 patients, 308‐nm excimer laser treatment was occurrence in two nonrelated siblings. Pediatr Dermatol 1997;14:43–5.
considered effective for treating hypopigmentation after 32 Racette AJ, Adams AD, Kessler SE. Simultaneous lichen striatus in
LS, with good safety profiles [73]. siblings along the same Blaschko line. Pediatr Dermatol 2009;26:50–4.
33 Karempelis PS, Cely SJ, Davis LS. Lichen striatus in a mother and son.
Int J Dermatol 2014;53:e366.
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416
CHA PTER 3 6
Pityriasis Rosea
Antonio A.T. Chuh1,2 & Vijay Zawar3,4
1
Department of Family Medicine and Primary Care, The University of Hong Kong and Queen Mary Hospital, Pokfulam, Hong Kong
2
JC School of Public Health and Primary Care, The Chinese University of Hong Kong and the Prince of Wales Hospital, Shatin, Hong Kong

3
Skin Diseases Centre, Nashik, India

4
Department of Dermatology, MVP’s Dr Vasantrao Pawar Medical College and Research Centre, Nashik, Maharashtra, India

Abstract Many children exhibit atypical variants of this exanthem. Vali-

dated diagnostic criteria are available and are particularly appli-
cable for children with marginal symptoms. Classification systems
Pityriasis rosea is a self‐limited exanthem likely to be related to
are available for delineating subclasses, and allow for choice of
viral infections, particularly endogenous reactivation or primary
treatment modalities as well as subgroup analyses in laboratory‐
infection of human herpesviruses 7 and 6.
based and clinical investigations.
A prodrome of coryzal symptoms is common. In around 20–
Pityriasis rosea usually does not have significant impacts on
30% of childhood cases, a herald patch is seen. The secondary
children and adolescents. Symptomatic treatments usually suffice.
generalized eruption then occurs 2–3 weeks later, with usually
The benefits of active interventions with antiviral agents are being
smaller macules with peripheral collarette scaling on the trunk
actively investigated.
and proximal aspects of the extremities. The orientation of most
lesions follows lines of skin creases. Spontaneous remission then
occurs 2–12 weeks after the eruption of the herald patch or the
generalized eruption.
Key points • Diagnostic criteria and two versions of classifications are

SECTION 6: OTHER
available. These tools are useful clinically and in research

settings.
• Pityriasis rosea is highly likely to be caused by viral infections.
• Active interventions are unnecessary for most children with this
• Endogenous reactivations or primary infections of human
exanthem. Many clinical trials are being conducted.
herpesviruses 7 and 6 are highly to be the cause of many, but
not all, cases of this exanthem in children and adolescents.
intermediate variety between pityriasis simplex and pity-

Definition and history. Pityriasis rosea is a subacute
riasis rubra [3]. However, he only described the macular
self‐limited eruption mainly affecting children and
variety of pityriasis rosea, not the usual annular variety,
young adults. It is characterized by a distinctive skin
which was first described by the French dermatologist
eruption with a herald patch at the onset followed by
Pierre‐Antoine‐Ernest Bazin (1807–1878) in 1862 [3].
secondary eruptions oriented along the lines of skin
Jean Baptiste Emile Vidal (1825–1893), another French
cleavage presenting as smaller, discrete, round to oval
dermatologist, described a similar condition termed
skin lesions with collarette scaling. The lesions mainly
pityriasis circiné et marginé in 1882 [3]. Some dermatolo-
affect the trunk and proximal aspects of extremities.
gists consider this clinical entity to be a special form of
Spontaneous remission usually occurs within 6–12
pityriasis rosea, with fewer and larger lesions often local-
weeks of onset of the rash. Pityriasis rosea is suspected
ized at the axillae or groins [4], while others maintained
to be related to viral infections, especially human her-
that pityriasis circinata and pityriasis circinata et margin-
pesvirus (HHV)‐7.
ata should be synonyms of pityriasis rosea [2]. Louis‐
Anne‐Jean Brocq drew attention to the ‘primitive patch’
History. The French dermatologist Camille‐Melchior in 1887 [5]. Alfred Blaschko described peripheral collar-
Gibert (1797–1866) is generally credited with the first ette scaling in 1899 [5]. Colcott Fox reported five children
accurate description of pityriasis rosea in 1860 [1], with pityriasis rosea in 1884 [2].
although Robert Willan (1757–1812) and Erasmus Wilson
(1809–1884), both British dermatologists, described sim-
ilar rashes termed erythema annulatum and lichen Epidemiology. Pityriasis rosea is very common. The inci-
annulatus serpiginosus respectively [2]. Gibert described dence ranges from 0.39 [6] to 4.8 [7] per 100 dermatology
five varieties of pityriasis: simple, rosea, rubra, versi- patients. The overall incidence upon pooling data from 18
color and nigra, and considered pityriasis rosea to be an studies [6–23] is 0.64 per 100 dermatology patients.
Chapter 36 Pityriasis Rosea 417
The occurrence of pityriasis rosea in children is similar Most of these studies were performed in adult patients.
to that in young adults [24,25]. Pityriasis rosea can occur in In a previous study on three children with pityriasis
infants [26]. The youngest reported patient was 3 months rosea, no virological evidence of HHV‐7 and ‐6 primary
old [27]. Most patients are between the age of 10 and 35 infection or endogenous reactivation was found [65],
[28]. The incidence for paediatric patients has been while a recent study found that most children with pity-
reported as 1.02 per 100 paediatric dermatology patients riasis rosea have serological findings of previous HHV‐7
(below 14 years) [11]. For adolescents and young adults (61%) and ‐6 (84%) infections. For those children who
(10–29 years), the prevalence was reported to be 0.6% [15]. have IgM against HHV‐7 (9%) and ‐6 (16%) detected,
most have viraemia of these viruses [66]. Moreover, for
Aetiology. The aetiology of pityriasis rosea is unknown. children who have viraemia [66], the virus loads are
An infectious agent is suspected owing to the apparently higher than those of adults with pityriasis rosea [48].
programmed clinical course of the disease: prodromal Autoimmunity has been suspected to play a role in the
symptoms, primary herald patch, secondary eruptions pathogenesis [67]. In adults, T‐lymphocytotoxic antibodies
followed by complete spontaneous remission. [68], anti‐nuclear antibodies [69], rheumatoid factor [23],
Particularly strong clinical evidence for a viral aetiol- anti‐Ro autoantibodies (SS‐A) [69], thyroglobulin autoanti-
ogy is that most sufferers do not have a second eruption bodies [69], thyroid peroxidase antibodies [69] and riboso-
in their lifetime, and, for the small proportion of patients mal P protein [69] have been reported to be more prevalent
who do have a relapse, virtually all do not exhibit the her- in patients. Autoimmune diseases associated with pityriasis
ald patch [29]. This is highly suggestive of immunological rosea include undifferentiated connective tissue disease,
memory after the first episode of this eruption. autoimmune thyroiditis and chronic autoimmune urticaria
Particularly strong epidemiological evidence for an [69]. The role of autoimmunity in the immunopathogenesis
infectious aetiology is the detection of significant tempo- of pityriasis rosea in children is as yet unknown.
ral [30,31] and spatial–temporal [16] clustering of patients Studies on the association of atopic dermatitis and
with pityriasis rosea. asthma with pityriasis rosea revealed controversial find-
Various viruses (cytomegalovirus [32,33], Epstein– ings [17,24,70]. The pertinence of atopy and genetic pre-
Barr virus [32,33], influenza and parainfluenza viruses disposition to atopy in this eruption is unknown.
[33,34], adenovirus [33], respiratory syncytial virus
SECTION 6: OTHER
[33], parvovirus B19 [35], picornavirus [36–39]) and Pathology. Lesional histopathological changes are nonspe-
bacteria (Legionella longbeachae, L. micdadei, L. pneu- cific for pityriasis rosea. They include focal caps of spongi-
mophila [40,41], Mycoplasma pneumoniae [33,41–43], osis, perivascular lymphocytic infiltrates, vascular dilation
Chlamydia pneumoniae [41]) have been suspected to be and patchy parakeratosis [28] (Fig. 36.1). These changes are
associated with pityriasis rosea. However, evidence for similar for the herald patch and the generalized eruption.
these microbes having a causative association with pit- Intraepidermal dyskeratotic cells with aggregations of
yriasis rosea is not definitive. tonofilaments, numerous vacuoles and intracytoplasmic
Endogenous reactivation, and, to a lesser extent, pri- desmosomes were reported to be rather specific features
mary infection with HHV‐7 and ‐6 are particularly signifi- [71]. These cytological changes are akin to those seen in
cant as the likely aetiology of pityriasis rosea. HHV‐7 viral infections such as herpes simplex and varicella zoster,
DNA was detectable by nested polymerase chain reaction and are therefore believed to substantiate the suggestion of
in the skin, plasma and peripheral blood mononuclear viruses being the culprit [72]. Lesional histopathological
cells of all patients with pityriasis rosea in two reports changes in children are similar to those in adults.
[44–46]. HHV‐like particles have been detected by elec-
tron microscopy in lesional biopsies of patients with the
eruption [47]. HHV‐7 pp85 antigen expression has been
detected in lesional biopsies of patients [48]. A significant
inverse correlation was also reported between HHV‐7
virus neutralizing antibody titres and high HHV‐7 virus
load in the plasma of patients [48]. In the absence of virus
seroconversion, which is accepted to be the gold standard
for primary herpesvirus infections, these serological find-
ings indicate endogenous reactivation of HHV‐7.
More evidence for the relevance of these viral infections
in adults with pityriasis rosea comes from the detection of
high virus loads of HHV‐7 and ‐6 in patients with persis-
tent pityriasis rosea [49], and the association of endoge-
nous reactivation of HHV‐7 and ‐6 in miscarrying women
with pityriasis rosea [50].
Other studies [51–64] have reported conflicting results on
the detection of herpesvirus‐7 and ‐6 DNA in lesional biopsies, Fig. 36.1 Lesional biopsy of a secondary lesion in pityriasis rosea, revealing
plasma and peripheral blood mononuclear cells in patients. focal spongiosis with perivascular lymphocytic infiltrates (periodic acid–Schiff
The negative results of these studies are not yet explained. stain, ×400).
The herald patch is a primary lesion of pityriasis rosea are typically spared in children. The orientation of lesions
and presents as an erythematous large plaque with a is typically along lines of skin cleavage (Fig. 36.3) [76].
characteristic collarette scale. This is often misdiagnosed Oral and pharyngeal involvement in children (35%) is
as dermatophytic infection. more common than in adults (9%) (risk ratio: 2.19, 95%
In the peripheral blood in affected adults, elevated confidence interval [CI]: 1.30–3.69; calculated by the
erythrocyte sedimentary rate, decreased T lymphocytes authors of this chapter) [66].
and increased B lymphocytes have been reported [24]. Forty eight percent of children with pityriasis rosea have
Similar changes were noted for children with pityriasis systemic symptoms, as compared to 69% of adults (risk
rosea [65]. Autoantibodies were reported to be associated ratio: 0.70, 95% CI: 0.55–0.89) [66]. Most children do not
with pityriasis rosea in adults [68,69]. These findings were experience intense pruritus [74]. The impact of the rash on
not reported for children [65]. The roles of inflammatory the quality of life of children with pityriasis rosea is signifi-
mediators in pityriasis rosea are also being explored [73]. cantly less than for children with atopic dermatitis [75].
The total rash duration for children (average of 16 days) is
Clinical features. Pityriasis rosea in children is very simi- significantly shorter than that for adults (average of 45
lar clinically to the presentation in adults [66,74]. A herald days) [66]. Complications are rare in children and adoles-
patch is present in less than half of all sufferers. However, cents. When complications do occur, they are more likely
the time lapse between the herald patch and the second- to be related to the drug treatments rather than the disease
ary eruption (around 4 days) might be much shorter for [15]. Most children have no relapse in their lifetime.
children as compared to that in adults (around 2 weeks)
[66]. The exact incidence of the herald patch in children is Atypical presentations. Atypical features include atypical
not known. The herald patch is a solitary round to oval rash morphology (vesicular, purpuric, haemorrhagic and
lesion most commonly affecting the trunk and upper urticarial), atypical rash size (pityriasis rosea gigantea for
arms. It is annular in configuration with a raised border of exceptionally large lesions, papular pityriasis rosea for
fine, adherent scales (Fig. 36.2) [28]. exceptionally small lesions), atypical rash distribution
The secondary eruption occurs 1–3 weeks after onset of (distal aspects of extremities), atypical number of lesions,
the herald patch. Secondary lesions have a similar mor-
phology to the herald patch, although they are usually
SECTION 6: OTHER
smaller. Collarette scaling is a characteristic feature of

lesions. The scaling is circinate or oval, and fine fragments
of scales are attached only at the periphery of lesions. In
children, the centre of the lesions might also be covered
with fine scales which are lichenoid‐like with diagonal
lines [75].
In children with typical pityriasis rosea, only the trunk
and proximal aspects of the four extremities are involved.
This distribution pattern is traditionally termed a T‐shirt‐
and‐shorts or bathing suit pattern [18]. Palms and soles
Fig. 36.2 Herald plaque of a child with pityriasis rosea, which presents as Fig. 36.3 Truncal lesions of pityriasis rosea in an adolescent boy showing
an erythematous large plaque with a characteristic collarette scale. This is scaly round and oval plaques on the trunk. The herald patch is arrowed in
often misdiagnosed as dermatophytic infection. red. Orientation of the lesions is along lines of skin creases.
Box 36.1 The diagnostic criteria of pityriasis rosea [78,79]. Box 36.2 The classification of pityriasis rosea. This classification is
These diagnostic criteria are applicable to infants and children applicable to infants and children with pityriasis rosea
with pityriasis rosea
Axis 1 – Prodromal symptoms and herald patch
A patient is diagnosed as having pityriasis rosea if:
Prodromal symptoms – Present (coryza, fever, generalized muscle
• On at least one occasion or clinical encounter, he/she has all the
pain, fatigue, malaise, arthralgia, gastrointestinal symptoms),
essential clinical features and at least one of the optional
transient/barely noticeable, absent or unreliable history from patient
clinical features, and
• On all occasions or clinical encounters related to the rash, he/she Herald patch – Absent, obscure, single, multiple, gigantic, lonely
does not have any of the exclusional clinical features (herald patch as the only manifestation)
The essential clinical features are: Axis 2 – Number and distribution of lesions

• Discrete circular or oval lesions
• Scaling on most lesions, and Number – Few lesions (less than five, oligolesional), many lesions,
• Peripheral collarette scaling with central clearance on at least two suberythrodermic, erythroderma due to pityriasis rosea
lesions Distribution – Relatively unilateral, absolutely unilateral, localized,
regional, mucosal (mainly oral and genital), acral, pityriasis rosea
The optional clinical features are:
inversus (mainly involving the flexures), shoulders and hips (limb‐girdle
• Truncal and proximal limb distribution, with less than 10% of
pityriasis rosea), fewer but larger lesions localized to axillae and
lesions distal to mid‐upper‐arm and mid‐thigh
groins (pityriasis circinata et marginata of Vidal), actinic (photodis-
• Orientation of most lesions along skin cleavage lines, and
tributed), photospared
• A herald patch (not necessarily the largest) appearing at least 2
days before eruption of other lesions, from history of the patient
Axis 3 – Size, morphology and orientation of lesions
or from clinical observation
Size – Gigantic (pityriasis rosea gigantea of Darier) against miniature
The exclusional clinical features are:
Morphology – Papular, papulo‐squamous, papulo‐vesicular, vesicular,
• Multiple small vesicles at the centre of two or more lesions
lichenoid, urticarial, erythema multiforme‐like, punctate/purpuric/
• Two or more lesions on palmar or plantar skin surfaces, and
haemorrhagic, follicular
• Clinical or serological evidence of secondary syphilis
SECTION 6: OTHER
Orientation – Typical (along the skin creases), atypical (not along the
skin creases), scattered, blaschkoid (along lines of Blaschko),
segmental (along dermatomes)
atypical site of lesions (oral cavity) and atypical severity
of symptoms. Atypical rashes are fairly common in adults Axis 4 – Symptoms and clinical course
[77] but are uncommon in children [75]. Papular pityriasis
rosea is the most common atypical feature in children. Symptoms – Severely pruritic (pityriasis rosea irritata), slightly pruritic,
moderately pruritic, nonpruritic, asymptomatic
Diagnostic criteria and classification. Validated diag- Clinical course – Too short (less than 2 weeks), too long (more than 6
nostic criteria are available for the diagnosis of children months)
with marginal clinical features [78,79] (Box 36.1), and Recurrent pityriasis rosea
adoption of these might enhance diagnosis as well as
assure high homogeneity when recruiting children for Axis 5 – Seasonal morphological variations
noninterventional studies [80]. Two modern classifi- Psoriasiform in summer/crusted/haemalis form in winter
cations [81,82] (Box 36.2) also cater for children with
pityriasis rosea.
Drug‐induced pityriasis rosea‐like rashes. Numerous

patients, adults and children alike, have been reported to stages of erythema multiforme, guttate hypomelanosis
have pityriasis rosea‐like eruption. The clinical manifesta- and pityriasis lichenoides [84].
tions of these patients usually do not fulfil the diagnostic Papular pityriasis rosea in children has to be differenti-
criteria. These rashes should not be confused with pityria- ated from viral rashes including roseola infantum and
sis rosea, typical or atypical, which fulfils the diagnostic rubella. Vesicular pityriasis rosea is uncommon in
criteria [83]. These patients should not be recruited to children. Differential diagnoses of this variant include
laboratory or clinical studies and clinical trials. The man- pompholyx, bullous erythema multiforme, chickenpox,
agement should follow that for drug eruptions. dermatitis herpetiformis, linear immunoglobulin A dis-
ease and pemphigus vulgaris [77].
Differential diagnosis. Typical pityriasis rosea in children
should be diagnosable clinically. Common differential Treatment. Pityriasis rosea in children and adolescents
diagnoses for children and adolescents include guttate is a self‐limited disease. Unlike their adult counterparts,
psoriasis, lichen planus, nummular dermatitis, parapso- this eruption usually has little to no impact on the qual-
riasis, pityriasis versicolor, tinea corporis, viral rashes and ity of life of children [74]. The aim of treatment is thus
drug eruptions [28]. Uncommon differential diagnoses mainly to relieve pruritus, not to modify the course of
are secondary syphilis for adolescents, and the early the disease.
Oral aciclovir, in various dosages, has demonstrated 21 Ayanlowo O, Akinkugbe A, Olumide Y. The pityriasis rosea calendar:
a 7 year review of seasonal variation, age and sex distribution. Nig Q
efficacy in treating adults with pityriasis rosea [72,85–91].
J Hosp Med 2010;20:29–31.
The results of studies on the use of macrolides for adult 22 Ganguly S. A clinicoepidemiological study of pityriasis rosea in
patients vary [92–96]. In any case, macrolides are likely to South India. Skinmed 2013;11:141–6.
be of lower efficacy than aciclovir [87,89,97]. The efficacy 23 Özyürek GD, Alan S, Cenesizoğlu E. Evaluation of clinico‐
epidemiological and histopathological features of pityriasis rosea.
of ultraviolet radiation is inconclusive [98,99], and it Postepy Dermatol Alergol 2014;31:216–21.
should not be a conventional treatment modality for chil- 24 Björnberg A, Hellgren L. Pityriasis rosea. A statistical, clinical and
dren with pityriasis. laboratory investigation of 826 patients and matched healthy controls.
For children with little or no pruritus and a limited Acta Derm Venereol 1962;42(suppl 50):1–50.
25 Jawade SA, Chugh VS, Gohil SK et al. A clinico‐etiological study of
number of lesions, no treatment is generally required. For dermatoses in pediatric age group in tertiary health care center in
those with moderate pruritus, topical calamine lotion South Gujarat Region. Indian J Dermatol 2015;60:635.
and/or topical emollients might be considered. For chil- 26 Hendricks AA, Lohr JA. Pityriasis rosea in infancy. Arch Dermatol
1979;115:896–7.
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oral sedating antihistamines might be given as a single 1960;77:364.
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31 Chuh A, Molinari N, Sciallis G et al. Temporal case clustering in pity-
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J Dermatol 2000;143:795–8. 85 Drago F, Vecchio F, Rebora A. Use of high‐dose acyclovir in pityriasis
60 Offidani A, Pritelli E, Simonetti O et al. Pityriasis rosea associated rosea. J Am Acad Dermatol 2006;54:82–5.
with herpesvirus 7 DNA. (correspondence) J Eur Acad Dermatol 86 Castanedo‐Cazares JP, Lepe V, Moncada B. Antivirals for pityriasis
Venereol 2000;14:313–14. rosea. Photodermatol Photoimmunol Photomed 2004;20:110.
61 Chuh AAT, Chiu SSS, Peiris JSM. Human herpesvirus 6 and 7 DNA 87 Ehsani A, Esmaily N, Noormohammadpour P et al. The comparison
in peripheral blood leukocytes and plasma in patients with pityria- between the efficacy of high dose acyclovir and erythromycin on
sis rosea by polymerase chain reaction – a prospective case control the period and signs of pitiriasis rosea. Indian J Dermatol 2010;
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62 Wong WR, Tsai CY, Shih SR, Chan HL. Association of pityriasis rosea 88 Rassai S, Feily A, Sina N, Abtahian S. Low dose of acyclovir may be
SECTION 6: OTHER
with human herpesvirus‐6 and human herpesvirus‐7 in Taipei. an effective treatment against pityriasis rosea: a random investiga-
J Formos Med Assoc 2001;100:478–83. tor‐blind clinical trial on 64 patients. J Eur Acad Dermatol Venereol
63 Karabulut AA, Kocak M, Yilmaz N, Eksioglu M. Detection of human 2011;25:24–6.
herpesvirus 7 in pityriasis rosea by nested PCR. Int J Dermatol 89 Amatya A, Rajouria EA, Karn DK. Comparative study of effective-
2002;41:563–7. ness of oral acyclovir with oral erythromycin in the treatment of
64 Yildirim M, Aridogan BC, Baysal V, Inaloz HS. The role of human pityriasis rosea. Kathmandu Univ Med J (KUMJ) 2012;10:57–61.
herpes virus 6 and 7 in the pathogenesis of pityriasis rosea. Int J Clin 90 Ganguly S. A randomized, double‐blind, placebo‐controlled study of
Pract 2004;58:119–21. efficacy of oral acyclovir in the treatment of pityriasis rosea. J Clin
65 Chuh AA, Peiris JS. Lack of evidence of active human herpesvirus 7 Diagn Res 2014;8:YC01–4.
(HHV‐7) infection in three cases of pityriasis rosea in children. Pediatr 91 Das A, Sil A, Das NK et al. Acyclovir in pityriasis rosea: An
Dermatol 2001;18:381–3. observer‐blind, randomized controlled trial of effectiveness,
66 Drago F, Ciccarese G, Broccolo F et al. Pityriasis rosea in children: safety and tolerability. Indian Dermatol Online J 2015;6:181–4.
clinical features and laboratory investigations. Dermatology 92 Sharma PK, Yadav TP, Gautam RK et al. Erythromycin in pityriasis
2015;231:9–14. rosea: a double‐blind, placebo‐controlled clinical trial. J Am Acad
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Br J Dermatol 1970;82:549–60. 93 Rasi A, Tajziehchi L, Savabi‐Nasab S. Oral erythromycin is ineffec-
68 Hosokawa H, Horio S, Takiuchi Y et al. Naturally occurring T lym- tive in the treatment of pityriasis rosea. J Drugs Dermatol
phocytotoxic antibody in viral and related skin diseases. Acta Derm 2008;7:35–8.
Venereol 1984;64:275–80. 94 Amer A, Fischer H. Azithromycin does not cure pityriasis rosea.
69 Chuh AAT. A prospective case control study of autoimmune markers Pediatrics 2006;117:1702–5.
in patients with pityriasis rosea. Clin Exp Dermatol 2003;28:449–50. 95 Pandhi D, Singal A, Verma P, Sharma R. The efficacy of azithromycin
70 Chuang TY, Perry HO, Ilstrup DM, Kurland LT. Recent upper respira- in pityriasis rosea: a randomized, double‐blind, placebo‐controlled
tory tract infection and pityriasis rosea: a case–control study of 249 trial. Indian J Dermatol Venereol Leprol 2014;80:36–40.
matched pairs. Br J Dermatol 1983;108:587–91. 96 Bukhari IA. Oral erythromycin is ineffective in the treatment of pity-
71 Okamoto H, Imamura S, Aoshima T et al. Dyskeratotic degeneration riasis rosea. J Drugs Dermatol 2008;7:625.
of epidermal cells in pityriasis rosea: light and electron microscopic 97 Amatya A, Rajouria EA, Karn DK. Comparative study of effective-
studies. Br J Dermatol 1982;107:189–94. ness of oral acyclovir with oral erythromycin in the treatment of
72 Kempf W, Burg G. Pityriasis rosea – a virus‐induced skin disease? pityriasis rosea. Kathmandu Univ Med J (KUMJ) 2012;10:57–61.
An update. Arch Virol 2000;145:1509–20. 98 Arndt KA, Paul BS, Stern RS, Parrish JA. Treatment of pityriasis
73 Drago F, Ciccarese G, Broccolo F et al. The role of cytokines, rosea with UV radiation. Arch Dermatol 1983;119:381–2.
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423
C HA PTER 37
Pyodermas and Bacterial
Toxin‐mediated Syndromes
James R. Treat1, Christian R. Millett2, Warren R. Heymann3 & Steven M. Manders3
1
Children’s Hospital of Philadelphia and Dermatology Section, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
2
Forefront Dermatology, Vienna, VA, USA
3
Division of Dermatology, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, Camden, NJ, USA
Pathophysiology, 423 Localized cutaneous staphylococcal and Toxin‐mediated staphylococcal and

Epidemiology, 425 streptococcal infections: pyodermas, 426 streptococcal disease, 430
Abstract recognized clinically. SA and GAS most commonly cause localized

cutaneous infections but can lead to serious systemic diseases such
as cellulitis, staphylococcal skin syndrome and necrotizing fasciitis.
Cutaneous bacterial infections in children are common but
It has become more important to consider culturing the skin to
important to recognize as they can lead to significant sequelae.
establish bacterial sensitivities due to the increase in SA that is
Staphylococcus aureus (SA) and Group A Streptococcus (GAS) are
meticillin resistant.
the most common causes of infection. Skin infection with these
bacteria typically presents with pustules and crusting and can be
Key points • Staphylococcus aureus and group A streptococci can release

toxins that lead to widespread erythema and, in the case of toxic
shock, severe systemic sequelae.
• Superficial bacterial skin infections often present with pustules,
• Staphylococcal scalded skin syndrome is differentiated from
bullae or crusting, and swab cultures can help establish antibiotic
SECTION 7: BACTERIAL SKIN

Stevens–Johnson syndrome by the lack of mucosal involvement
sensitivities.
in staphylococcal scalded skin syndrome.
INFECTIONS
Pathophysiology
exotoxins, which are particularly potent virulence factors
Streptococci because they function as superantigens. Unlike traditional
Group A Streptococcus (GAS) is a common infectious agent antigens, superantigens have the ability to stimulate
in children, having a large number of virulence factors immune cells without undergoing antigen processing
responsible for a broad range of disease. It is a Gram‐ and presentation by antigen‐presenting cells (APCs) [3].
positive organism that is seen in chains on Gram stain. Conventional antigens are processed within the APC, and
On blood agar, GAS displays characteristic β‐haemolysis protein fragments of the antigen are then expressed on
due to the haemolysin streptolysin S. GAS has numerous the cell surface in the groove of the major histocompati-
surface and extracellular factors that confer virulence, of bility type II complex (MHCII). The antigen–MHCII com-
which the cell surface M protein is the main antigenic plex then interacts with the T cell receptor in a very
determinant. It aids in adherence but most importantly specific, antigen‐restricted fashion. The segment of T cells
enables the bacterium to evade phagocytosis. GAS classi- bearing the receptor that corresponds to the antigen is
fication is based on genotyping of the M protein. There then activated, with resultant cytokine production and
are currently approximately 180 emm sequence types and specific immune activation.
800 emm subtypes described, but new types and subtypes Whereas conventional antigens require recognition of
are still being identified [1]. all five elements of the T cell receptor (Va, Ja, Vb, Db, Jb),
Invasive GAS disease is defined by the isolation of the recognition sequence for superantigens is almost
GAS from a normally sterile body site, and includes entirely dependent on Vb only. Because only a limited
entities such as streptococcal toxic shock syndrome and amount of Vb genes exist, a given superantigen–T cell
necrotizing fasciitis [2]. These infections depend in large interaction may lead to the activation of 5–30% of the
part on the ability of the bacteria to produce streptococcal entire T cell population, whereas conventional antigens
424 Section 7 Bacterial Skin Infections
activate approximately 0.01–0.1% of the body’s T cells. syndrome (SSSS) and bullous impetigo [5]. TSST‐1,
This large‐scale activation of T cells by superantigens among other toxins produced by Staph. aureus, can also
leads to massive cytokine production, especially that of cause TSS, an acute life‐threatening illness.
tumour necrosis factor (TNF)‐α, interleukin (IL)‐1 and Staph. epidermidis is a commensal organism on the skin.
IL‐6. These cytokines, especially TNF‐α and IL‐1, have Although it cannot lead to purulent infections, it is an
been shown to mediate clinical effects such as fever, ery- important cause of neonatal sepsis and central line infec-
thematous rash, emesis, hypotension, tissue injury and tions, especially in immunosuppressed hosts.
shock. Certain superantigen‐mediated illnesses appear
to induce a large‐scale depletion of particular Vb sub- Meticillin‐resistant Staphylococcus
sets; this may result from apoptosis of initially activated aureus (MRSA)
T cells [4]. In 1942, the first penicillin‐resistant Staph. aureus isolate
Host antibacterial and antitoxic immunity to GAS is an was observed, and in 1961, Staph. aureus developed meti-
important aspect in the pathogenesis of cutaneous and cillin resistance due to the acquisition of the mecA gene. It
systemic infections. Antibacterial immunity is related to has been suggested that MRSA originated in vivo through
the type‐specific M component of GAS. For example, the horizontal transfer of the mecA gene between two
infection with type 4 Streptococcus is followed by staphylococcal species. During the last 45 years, various
development of specific neutralizing antibody for M type hospital‐associated MRSA (HA‐MRSA) clones have dis-
4‐bearing organisms, but not against heterologous types. seminated worldwide. In addition, community‐associated
Antitoxic immunity follows exposure to erythrogenic tox- MRSA (CA‐MRSA) clones have become much more prev-
ins such as the streptococcal pyrogenic exotoxins (SPEs). alent [6]. Skin and soft tissue infections, especially due to
Most commonly, these toxins produce the exanthem and MRSA, have increased, leading to more hospitalizations [7].
constitutional manifestations of scarlet fever; rarely they Meticillin resistance occurs by the presence of the
may cause toxic shock syndrome (TSS). A child with anti- mecA gene, which encodes penicillin‐binding protein 2a.
bacterial immunity to a strain with a particular M type Penicillin‐binding protein is a transpeptidase that restores
will not develop clinical disease. Conversely, in the cell wall biosynthesis of MRSA in the presence of β‐lactams.
absence of M‐type specific immunity, an infected child The mecA gene is carried on the staphylococcal methicillin
will develop scarlet fever if he or she lacks immunity to resistance gene cassette, or staphylococcal cassette chro-
the specific erythrogenic toxin. Furthermore, failure to mosome mec (SCCmec). CA‐MRSA and HA‐MRSA have
produce an adequate humoral immunity to toxins can different types of cassettes and antibiotic resistance.
lead to recurrent toxin‐mediated disease. CA‐MRSA typically has SCCmec type IV, and is generally
The immune response to various streptococcal exo- susceptible to most non‐β‐lactam antibiotics. In contrast,
products has been used in several diagnostic serological HA‐MRSA usually carries SCCmec types I, II or III, and is
tests, most notably the response to streptolysin O. The resistant to aminoglycosides, clindamycin and macrolides.
INFECTIONS
antistreptolysin O (ASO) titre is generally elevated in Infection with HA‐MRSA can occur in the community so
patients recovering from a recent streptococcal infection. Staph. aureus susceptibilities can no longer be reliably
This test may be useful in certain settings to confirm or predicted without culturing the bacteria.
support a diagnosis. In addition, there are two important A cloned strain of CA‐MRSA called USA300 defies this
late sequelae of GAS infections that appear 1–3 weeks generalization of antibiotic resistance. USA300 carries the
later: glomerulonephritis and rheumatic fever. The patho- genes that encode resistance to macrolides, lincosamides,
genesis remains poorly understood, and appears to be streptogranin B, tetracycline, doxycycline and mupirocin
best explained by an abnormal immune response or [8]. The USA300 strain has predominated in outbreaks
hypersensitivity to streptococcal antigens. throughout the USA, suggesting that it possesses viru-
lence or transmissibility factors that confer unusual path-
Staphylococci ogenicity. Recent sequencing of the complete genome of
Staphylococci are Gram‐positive cocci found in clusters this strain identified a mobile genetic element, termed
on Gram stain. Staphylococcus aureus is usually a tran- arginine catabolic mobile element (ACME). It has been
sient pathogenic organism on the skin, and can asymp- hypothesized that the products of this gene cluster
tomatically colonize the nasal mucosa. In certain enhance the capacity of USA300 strains to survive at low
situations, however, Staph. aureus can cause skin or pH on human skin and within phagocytic cells [9].
invasive infections via expression of a wide array of Other toxins produced by MRSA also contribute to the
virulence factors, including wall teichoic acid (TA) and pathogenesis of skin and soft tissue infections. Panton–
surface proteins. These promote adherence to damaged Valentine leukocidin (PVL) is a cytotoxin of CA‐MRSA
tissue and diminish neutrophil function and immune involved in the development of abscesses, cellulitis and
response. Staph. aureus also secretes exotoxins and furuncles. PVL lyses leucocytes by facilitating calcium
enzymes that can contribute to a variety of cutaneous channel opening and pore formation, and increases IL‐8
and systemic infections, including four haemolysins (a‐, secretion which leads to an inflammatory response and
b‐, d‐ and g‐toxins). Staphylococcal exfoliative toxins tissue necrosis. The genes that encode PVL have been
(ETs), including ETA, ETB and ETD, disrupt desmo- found in almost all CA‐MRSA isolates [8].
glein‐1, a desmosomal cadherin expressed in the upper Risk factors for acquisition of HA‐MRSA include a his-
epidermis. This results in staphylococcal scalded skin tory of hospitalization, surgery, dialysis or residence in a
Chapter 37 Pyodermas and Bacterial Toxin‐mediated Syndromes 425
long‐term care facility within 1 year before the MRSA 9 Gorwitz R. A review of community‐associated methicillin resistant
Staphylococcus aureus skin and soft tissue infections. Pediatr Infect
culture date, presence of an indwelling device at the time
Dis J 2008;27:1–7.
of culture, or a previous history of MRSA infection or 10 Stryjewski M, Chambers H. Skin and soft tissue infections caused by
colonization. CA‐MRSA has been defined by some as an community‐acquired methicillin‐resistant Staphylococcus aureus.
MRSA infection with onset in the community in a patient Clin Infect Dis 2008;46:S368–77.
11 Patel, A, Hill E, Simpson, E, Hanafin J. Reversion of methicillin‐
lacking established HA‐MRSA risk factors. However, it is resistant Staphylococcus aureus skin infections to methicillin‐
generally not possible to determine with certainty where susceptible. AMA Dermatol 2013;149:1167–71.
MRSA was initially acquired [9]. Staph. aureus can persist 12 Fritz SA1, Hogan PG, Camins BC et al. Mupirocin and chlorhexidine
as a colonizer for years, leading to misclassification of the in Staphylococcus aureus in patients with community‐onset skin and
soft tissue infections. Antimicrob Agents Chemother 2013;57:559–68.
source. Indeed, some ‘community‐onset’ infections may 13 Milstone AM, Elward A, Song X et al. Daily chlorhexidine bathing to
in fact be caused by hospital‐acquired strains, leading to reduce bacteraemia in critically ill children: a multicentre, cluster‐
a blurring of the distinction between CA‐MRSA and randomised, cross‐over trial. Lancet 2013;381:1099–106.
HA‐MRSA. Nevertheless, SCCmec type IV and PVL
have been useful molecular markers to identify true Epidemiology
CA‐MRSA strains.
Infections caused by CA‐MRSA predominantly affect Streptococci
children and young adults. Direct contact with infected In the past two decades, there has been a re‐emergence of
patients, colonized subjects or a contaminated environ- serious streptococcal infections. Surface proteins, host
ment is implicated in the transmission of CA‐MRSA infec- factors and toxin production have all contributed to the
tion. Crowding and sharing of personal items appear to renewed virulence of these bacteria. The re‐emergence of
be important factors. Transmission has occurred through invasive GAS infections, such as necrotizing fasciitis and
activities in which direct contact is common and, although streptococcal TSS, has been closely linked with the
originally proven in people such as football players, wres- renewed prevalence of GAS bearing M‐1 and M‐3 surface
tlers and military personnel, it is now recognized that any proteins. Host factors in the general population appear to
activity involving direct skin contact can lead to transmis- be partially responsible for the re‐emergence of strepto-
sion [10]. Nasal colonization has also been identified as a cocci as major pathogens. Very young or immunocompro-
risk factor for infection [9]. mised persons are at high risk for infection with these
Culture of purulent material establishes the diagnosis bacteria. However, a large percentage of patients who
and allows susceptibility testing to guide therapy. Patients have serious disease are otherwise healthy. This is postu-

infected with MRSA can have reversion to meticillin‐ lated to be due to the absence of previous exposure to
susceptible Staph. aureus so re‐culturing should be con- these more virulent strains of bacteria, as an absence of
sidered with each infection [11]. Subsequent cultures of protective antibody appears to predispose persons to
the nares and perianal area can also determine carrier infection. Bacterial toxin production has also been shown
INFECTIONS
states. There are many regimens that have been used for to be a highly important factor in the increased frequency
decolonization but none has proven universally success- of serious streptococcal and staphylococcal disease, with
ful. A large meta‐analysis of MRSA eradication showed toxins such as streptococcal pyrogenic exotoxin‐A (SPEA)
that mupirocin applied topically to the nasal area for being linked with the increased prevalence of serious
1 week was highly successful at eradicating nasal carriage, invasive GAS infections in the USA [1].
but this does not necessarily indicate clearance of the Around the world, there are an estimated 1.7 million
throat and anal colonization. Combining application of new cases per year and 500 000 deaths per year from seri-
mupirocin to the nasal and anal area with chlorhexidine ous GAS disease. In addition, there are over 100 million
gluconate washes may be more effective at eradicating cases of less serious skin infections per year. Since the
MRSA [12,13]. 1980s, severe GAS diseases have been increasing in inci-
dence and severity. The incidence of invasive GAS dis-
References ease in most industrialized countries is between 2.5 and
1 Steer A, Danchin M, Carapetis J. Group A streptococcal infections in 3 per 100 000, and mortality rates vary between 10% and
children. J Pediatr Child Health 2007;43:209–13. 20%. The burden of severe GAS disease is predominantly
2 Martin J, Green M. Group A streptococcus. Semin Pediatr Infect Dis
2006;17:140–8. in developing countries and impoverished populations.
3 Burnett A, Domachowske J. Therapeutic considerations for children It is estimated that more than 660 000 cases of invasive
with invasive group A streptococcal infections: a case series report and disease resulting in more than 160 000 deaths occur glob-
review of the literature. Clin Pediatr 2007;46:550–5.
ally each year, most in developing countries. The peak
4 Manders S. Toxin‐mediated streptococcal and staphylococcal dis-
ease. J Am Acad Dermatol 1998;39:383–98. incidence of these infections occurs in infants and the
5 Iwatsuki K, Yamasaki O, Morizane S, Oono T. Staphylococcal cutane- elderly [2].
ous infections: invasion, evasion, and aggression. J Dermatol Sci
2006;42:203–14.
6 Deurenberg R, Stobberingh E. The evolution of Staphylococcus aureus. Staphylococci
Infect Genet Evol 2008;8:747–63. The incidence and prevalence of MRSA infections have
7 Lopez MA, Cruz AT, Kowalkowski MA, Raphael JL. Trends in resource also been increasing. Over the last 20 years, there have
utilization for hospitalized children with skin and soft tissue infec-
been reports from many healthcare facilities documenting
tions. Pediatrics 2013;131:e718–25.
8 Kil E, Heymann W, Weinberg J. Methicillin‐resistant Staphylococcus increasing numbers of CA‐MRSA infections treated at the
aureus: an update for the dermatologist. Cutis 2008;81:227–32, 247–52. facility, increasing proportions of all MRSA infections that
are community associated, and increasing proportions of (impetigo contagiosa) is the most common form of pyo-
all community‐acquired Staph. aureus infections that are derma and is usually due to GAS, whereas bullous impe-
meticillin resistant. To date, reported CA‐MRSA infec- tigo is usually due to Staph. aureus [1]. Nonbullous impetigo
tions have disproportionately affected children, young represents a host response to the infection, whereas
adults and low socioeconomic groups [3]. Nasal coloni- staphylococcal exfoliative toxin causes bullous impetigo.
zation can be an important source of reinfection with Impetigo most often affects children 2–5 years of age,
Staph. aureus. Colonization with Proteobacteria and although it can occur in any age group. Impetigo is the
Corynebacterium spp. seems to be protective against Staph. most common bacterial skin infection among children
aureus colonization [4]. Eradication of Staph. aureus coloni- and is more common in those receiving dialysis. The
zation is challenging because the throat, perineum and diagnosis usually is made clinically and can be confirmed
nares can all be colonized. In one study the throat was the by Gram stain and culture. The infection usually heals
most common site colonized followed by perineum and without scarring and can resolve within several weeks
then nares [5]. In addition to humans, pets can be colo- even if left untreated [2].
nized and can become a source of reinfection. Dogs were Impetigo usually is transmitted through direct contact.
found to be most commonly colonized in their mouth [6]. In many cases there is antecedent cutaneous trauma, such
Between 1998 and 2004, 44.9% of non‐intensive care unit as an insect bite or minor scratch. Bacterial colonization of
Staph. aureus strains were meticillin resistant. Furthermore, the nares, axilla or perineum may serve as a reservoir for
the percentage of meticillin resistance among patients in infection. Impetigo is more common in tropical climates
intensive care units infected with Staph. aureus was 59.5% and in crowded living conditions, and can be associated
in 2003, an 11% increase in resistance from 1998 to 2002. with poor hygiene. Certain dermatoses, most notably
Meticillin resistance has also spread to the outpatient set- atopic dermatitis, are associated with higher Staph. aureus
ting, and between 1998 and 2004, 25% of Staph. aureus colonization rates, leading to frequent bacterial superin-
infections were meticillin resistant [7]. There has also been fection. Outbreaks of impetigo may also occur in the new-
an increase in resistance to topical therapies. There is born nursery setting.
geographical variability in resistance patterns but one Nonbullous impetigo begins as an erythematous mac-
paediatric study showed that Staph. aureus resistance ule or papule, which can progress to pustules and ero-
rates to mupirocin and retapamulin were 9.8% and 9.5% sions. Serous and purulent drainage forms a characteristic
respectively [8]. honey‐coloured crust. Any serum that extrudes to the sur-
face and dries can appear honey coloured. Therefore the
References serous drainage from exuberant contact dermatitis such

1 Manders S. Toxin‐mediated streptococcal and staphylococcal disease. as from urushiol (poison ivy or oak) is often mistaken for
J Am Acad Dermatol 1998;39:383–98. impetigo. Individual lesions of impetigo can enlarge to 1
2 Steer A, Danchin M, Carapetis J. Group A streptococcal infections in
or 2 cm, but satellite lesions typically appear in the vicin-
INFECTIONS
children. J Pediatr Child Health 2007;43:209–13.

3 Gorwitz R. A review of community‐associated methicillin resistant ity due to spread by autoinoculation. Coalescence of these
Staphylococcus aureus skin and soft tissue infections. Pediatr Infect lesions may produce wider areas of crusted involvement.
Dis J 2008;27:1–7.
The face, especially around the mouth and nares, and the
4 Johnson RC, Ellis MW, Lanier JB et al. Correlation between nasal
microbiome composition and remote purulent skin and soft tissue perineum are the most common sites. Recently, a strain of
infections. Infect Immun 2015;83:802–11. enterovirus (coxsackie A6) has been recognized to cause a
5 Kumar N, David MZ, Boyle‐Vavra S et al. High Staphylococcus aureus similar picture wherein widespread small vesicles with
colonization prevalence among patients with skin and soft tissue infec-
tions and controls in an urban emergency department. J Clin Microbiol
individual crusts can simulate impetigo. The eruption can
2015;53:810–15. be especially widespread when it superinfects pre‐
6 Iverson SA, Brazil AM, Ferguson JM et al. Anatomical patterns of colo- existing atopic dermatitis [3]. Although typically localized,
nization of pets with staphylococcal species in homes of people with widespread impetigo may occur, especially in the setting of
methicillin‐resistant Staphylococcus aureus (MRSA) skin or soft tissue
infection (SSTI). Vet Microbiol 2015;176:202–8. underlying atopic dermatitis or immunosuppression.
7 Kil E, Heymann W, Weinberg J. Methicillin‐resistant Staphylococcus Itching and mild discomfort may occur with impetigo, but
aureus: an update for the dermatologist. Cutis 2008;81:227–32, 247–52. systemic complaints are rare.
8 McNeil JC, Hulten KG, Kaplan SL, Mason EO. Decreased suscepti-
bilities to retapamulin, mupirocin, and chlorhexidine among
Bullous impetigo is mainly caused by toxin‐producing
Staphylococcus aureus isolates causing skin and soft tissue infections phage group II Staph. aureus. It is a localized form of SSSS,
in otherwise healthy children. Antimicrob Agents Chemother with subcorneal epidermolysis caused by one of the two
2014;58:2878–83. staphylococcal exfoliative toxins. These toxins are local-
ized to the area of infection and Staph. aureus can be cul-
tured from the blister contents (unlike the denuded skin
Localized cutaneous staphylococcal
and erosions in generalized SSSS). Superficial vesicles
and streptococcal infections:
progress to rapidly enlarging, flaccid bullae with sharp
pyodermas
margins. Ruptured bullae are replaced with yellow crust-
Impetigo ing. The peripheral peeling at the perimeter of the crust
Pyoderma refers to a localized purulent infection of the (caused by desmoglein‐1 cleavage) is very helpful in mak-
skin and soft tissues. Impetigo is a common type of super- ing the clinical diagnosis. Bullous impetigo is most fre-
ficial pyoderma that is characterized by inflammation and quently seen in infants and favours moist intertriginous
infection localized in the epidermis. Nonbullous impetigo areas such as the perineum, axillae and neck folds. It
appears to be less contagious than nonbullous impetigo, The clinical lesions of folliculitis begin as small pustules
and cases usually are sporadic. in follicular orifices, often accompanied by a halo of
Impetigo has an excellent prognosis. The infection may perifollicular erythema. Pustules may rupture followed
be self‐limited, but it can spread and persist on the skin, by crust formation at the follicular opening. The papulo-
remaining contagious to others. Acute poststreptococcal pustular eruption is often regionalized, and lesions are
glomerulonephritis is an uncommon but serious compli- typically located on the trunk, buttocks and extremities.
cation of nonbullous impetigo. Treatment with antibiotics Pruritus is the most common symptom of folliculitis.
does not seem to have any effect on this risk. Other rare Although prominent excoriations are usually not seen,
but potential complications include sepsis, osteomyelitis, children may excoriate each pustule leaving behind only
arthritis, endocarditis, pneumonia, cellulitis, lymphade- papules and crusts. Systemic signs and symptoms are rare.
nitis, guttate psoriasis, Henoch–Schönlein purpura, ery- The histopathology of folliculitis reveals neutrophilic
thema nodosum, TSS and SSSS [2]. pustules within the hair follicle. A perifollicular infiltrate
Treatment of impetigo is appropriate to achieve a composed of lymphocytes and histiocytes may also be
faster resolution of infection, prevent more serious com- present. Folliculitis may be acute or chronic with a ten-
plications and limit the spread of infection to others. dency for recurrence. The prognosis for superficial folli-
Patients with localized disease may be treated with topi- culitis is excellent, and the process may be self‐limited.
cal antiseptics, mupirocin, bacitracin and retapamulin. Deeper forms of folliculitis can result in dermal scarring
Oral antibiotics are recommended for more extensive and alopecia. Although uncommon, folliculitis can lead to
disease. Given the relative prevalence of staphylococcal cellulitis or lymphadenitis. Rarely, folliculitis caused by
impetigo, non‐β‐lactamase penicillins such as amoxicillin toxigenic staphylococcal strains can produce TSS.
and penicillin VK are not good choices for oral therapy In normal hosts, folliculitis may resolve spontaneously
unless the impetigo is culture proven to be exclusively without systemic treatment. Good hygiene is the best way
due to GAS. The most appropriate oral antibiotics for the to prevent this type of infection. For superficial and lim-
majority of cases of impetigo include penicillinase‐ ited folliculitis, topical antiseptics (e.g. chlorhexidine) or
resistant penicillins, cephalosporins or clindamycin. topical preparations of erythromycin or clindamycin are
Staphylococcal resistance is increasing so cultures and usually effective. Mupirocin ointment is also effective, but
sensitivities should dictate therapy, especially in immu- the rate of mupirocin resistance is increasing in proportion
nosuppressed patients or those with recalcitrant, widely to its use in mild cutaneous infections which has a nega-
disseminated disease. tive impact on its important role in elimination of nasal

Ecthyma is considered to be an ulcerated form of MRSA carriage. Widespread or deep inflammatory follicu-
impetigo, and can be a consequence of failure to effec- litis usually requires oral antistaphylococcal antibiotics.
tively treat impetigo. The infection extends into the
dermis to produce shallow ulcerations that may heal Furunculosis
INFECTIONS
with scarring. It is mainly caused by GAS. Because GAS Deep folliculitis with extensive perifollicular inflammation
can lead to small vesicles, pustules and erosions, it can and abscess formation produces a furuncle (boil). Isolated
simulate herpes simplex infections, especially in patients furuncles are common, and the term ‘furunculosis’ refers to
with atopic dermatitis. Treatment for ecthyma usually a condition with multiple, recurrent furuncles. Furuncles
requires systemic antibiotics such as β‐lactamase‐resistant are inflammatory nodules associated with a hair follicle
penicillins or cephalosporins in order to cover for the that extend into the dermis and the subcutaneous tissue.
possibility of coinfection with Staph. aureus. Systemic They usually affect moist, hairy, friction‐prone areas of
therapy is recommended because ecthyma is more the body, such as the face, axilla, neck and buttocks. These
commonly seen in patients with underlying immuno- lesions are firm and tender, and may spontaneously
deficiency or widespread atopic dermatitis as well as drain purulent material. Fever and other constitutional
in those living under poor hygienic conditions. GAS symptoms are rarely present. The most common causa-
ecthyma may also be an underrecognized source of tive microorganism is Staph. aureus.
rheumatic heart disease [4]. When the subcutaneous infection extends to involve
multiple furuncles, the lesions are called carbuncles. This
Folliculitis multiseptate coalescence can be painful, and constitu-
Bacterial folliculitis is a specialized form of pyoderma in tional signs and symptoms, including fever and malaise,
which the infection is anatomically confined to the hair are often present. Severe complications, such as bacterial
follicle and perifollicular structures. By far the most com- endocarditis, have been reported. If systemic involve-
mon bacterial pathogen in cases of childhood folliculitis ment of any type is suspected, evaluation should include
is Staph. aureus. Superficial staphylococcal folliculitis is blood cultures as well as Gram stain and culture of puru-
very common and is also known as Bockhart impetigo. lent material [5].
Predisposing conditions that increase the number of skin Smaller furuncles can be treated with the application of
surface bacteria, such as occlusion, overhydration and warm, moist towels. Incision and drainage is usually
maceration, may lead to the development of folliculitis. required for larger furuncles and carbuncles. In addition,
Similar to impetigo, folliculitis is more common in tropi- the increased incidence of MRSA dictates a consideration
cal climates and in settings characterized by crowded of empirical coverage of MRSA in these infections in addi-
living conditions and poor hygiene. tion to incision and drainage. Antibiotic choices include
clindamycin, doxycycline (in children older than 9 years) report of erysipelas complicating a microcystic lymphatic
and trimethoprim–sulfamethoxazole (TMP‐SMX). Patients malformation [7].
who have recurrent furuncles may require eradication Prompt, aggressive treatment is indicated for erysipe-
of Staph. aureus from the nares, axilla and perineum with las, and parenteral antibiotics are generally preferred for
antibacterial cleansing agents such as chlorhexidine in initial management. Once stabilized, patients can be
addition to mupirocin ointment or oral clindamycin to treated with oral therapy. Penicillin remains the treatment
decrease risk for future infection. of choice for erysipelas, but numerous alternatives are
available, including the β‐lactamase‐resistant penicillins
Cellulitis and erysipelas and cephalosporins.
Cellulitis is an infection of the dermis and subcutaneous
fat that typically manifests as warm, tender, poorly Botryomycosis
demarcated areas of erythema. Occasionally, bullae and Botryomycosis is a chronic suppurative granulomatous
even necrosis may be present. Constitutional symptoms bacterial infection of the skin and subcutaneous tissue. It
may include malaise, fever and chills. In adults, cellulitis presents with clinical and histological features similar to
is often caused by Staph. aureus or Strep. pyogenes and is actinomycosis or mycetoma, although the causative
typically located on the lower extremities. In paediatric organism is usually Staph. aureus. The bacteria become
patients, cellulitis is most often caused by Staph. aureus encapsulated, which not only protects them from systemic
and frequently affects the face and neck, although other antibiotics but also prevents proliferation to a full patho-
areas can be involved. Multiorganism cellulitis with logical state. The bacterial inoculum usually remains low
anaerobes and Gram‐negative bacteria tends to occur in enough that abscesses do not develop but a chronic granu-
patients with chronic ulcers secondary to diabetes, venous lomatous reaction develops with sinuses, fistulas and
insufficiency or pressure. ulceration. Small yellow granules may be noted in the exu-
Small breaks in the skin, as can occur with minor date, and the causative bacteria are embedded within
trauma, injection drug use, body piercing or bites, serve these granules. The extremities are most commonly
as portals of entry for bacteria. Tinea pedis is a common affected, while head and neck involvement is unusual [8].
fungal infection that predisposes to bacterial cellulitis. The term ‘botryomycosis’ came from the Greek botrys,
Haematogenous spread of bacteria from other sites to the meaning bunch of grapes, because of the characteristic
skin occurs most commonly in the immunosuppressed groups of granules that resemble grapes, and mycosis,
patient. Lymphadenitis, subacute bacterial endocarditis because the origin of the disease was first thought to be a
and glomerulonephritis are potential, but uncommon, fungus. However, botryomycosis is mainly caused by
complications of cellulitis. In most cases, the clinical pres- Staph. aureus, with Pseudomonas aeruginosa ranking second
entation is sufficient for an accurate diagnosis. Blood cul- in frequency. Most cases are reported in hospitalized
tures and cultures of bullae or ulcers should be obtained patients with concomitant diseases. The major associated
INFECTIONS
but may not always yield the pathogen. Imaging is not predisposing factors are skin trauma, previous surgery,
usually necessary, but can be helpful in distinguishing diabetes mellitus, liver disorders, systemic steroids, alco-
cellulitis from more severe infections such as necrotizing holism and cystic fibrosis.
fasciitis [6]. If necrotizing fasciitis is suspected, emergent Whenever botryomycosis is suspected, a Gram stain
surgical consultation is warranted. should be used to look for bacterial masses. Two cultures
Treatment in immunocompetent patients involves oral should be done: one for fungi and one for bacteria. A
antibiotic therapy targeting Staph. aureus and Strep. pyogenes. biopsy should be taken for histopathological examination
Options include cephalexin, clindamycin and dicloxacillin and to determine the shape and staining characteristics of
(for Staph. aureus). In those who are more severely ill, initial the granule, which differentiate it from actinomycosis
intravenous antibiotics are indicated, such as cefazolin, and mycetoma [9]. Histopathological findings of botryo-
clindamycin, oxacillin or vancomycin [5]. Gram‐negative mycosis include eosinophilic granules in a suppurative
bacteria and opportunistic organisms should be consid- focus. The centre of the granules is basophilic, but the
ered in immunocompromised individuals and people periphery is eosinophilic. They are usually 1–3 mm and
with diabetes. When multiorganism cellulitis is suspected, stain with periodic acid–Schiff (PAS), Gram and Giemsa
broad‐spectrum antibiotics should be instituted [6]. stains. A chronic inflammatory response composed of
Erysipelas is a distinctive superficial variant of cellulitis, neutrophils, lymphocytes, eosinophils, plasma cells,
characterized by striking erythema and a firm, well fibroblasts and histiocytes is present [8].
defined, advancing border. It is primarily caused by GAS. Treatment of botryomycosis traditionally involves a
Infants, young children and older adults are most com- combination of antibiotic and surgical therapy. Antibiotic
monly affected by erysipelas. Fever, chills, nausea and treatment should be prolonged, usually for weeks, and
vomiting are frequent, and may be associated with bac- based on the causal agent isolated. Surgical excision and
teraemia. Although most common on the lower legs, drainage of lesions can speed resolution.
erysipelas may occur in any location. It is particularly
dangerous on the face due to the risk of septic sinus Blastomycosis‐like pyoderma
thrombosis. Recurrent erysipelas most frequently occurs Blastomycosis‐like pyoderma is a rare chronic pyoderma
in lymphoedematous extremities. Disrupted lymphatics that presents as verrucous plaques with multiple draining
put patients at higher risk of erysipelas; there is a recent sinuses, and heals with a cribriform scar [10]. Typical
vegetating skin lesions are difficult to distinguish tissue. Early surgical intervention for fasciotomy and
clinically from blastomycosis. Staph. aureus is the most debridement, along with an aspirate for Gram stain
common cause but β‐haemolytic streptococci, Pseudomonas and culture, is usually indicated. Antibiotic choices
spp., Proteus mirabilis and E. coli have also been reported should cover the variety of potential causative organisms,
[11]. Blastomycosis‐like pyoderma probably represents unless a definite bacterium can be isolated. The mortality
an excessive tissue reaction in the context of altered rate for NF ranges from 35% to 40%; however, prompt
immunity. It has been reported in patients with systemic intervention lowers the rate to 12% [14].
immunosuppression due to malnutrition, alcoholism,
lymphoma, chronic myeloid leukaemia and human Blistering distal dactylitis
immunodeficiency virus (HIV) [10]. The initial lesion Blistering distal dactylitis (BDD) is an infection mani-
usually begins at sites of trauma, and presents as large fested by acral pustules and bullae on erythematous bases
verrucous plaques with multiple pustules and elevated and, classically, as an individual bulla on the distal finger.
borders. Histology shows pseudoepitheliomatous hyper- This helps differentiate it from herpetic whitlow which is
plasia and multiple abscesses [11]. Cultures and biopsy usually a multiloculated honeycomb blister. BDD typi-
may be helpful in distinguishing blastomycosis‐like cally occurs on the proximal phalanx, palm or sole, and
pyoderma from blastomycosis. can present as multiple individual bullae. The bullae are
Treatment for blastomycosis‐like pyoderma includes typically oval and 1–3 cm in diameter and evolve into ero-
topical and systemic antibiotics, intralesional corticoster- sions when they denude. A culture of the blister fluid is
oids, surgical excision and local ablative measures such diagnostic. It most commonly occurs in infants and chil-
as electrodesiccation and curettage or carbon dioxide dren; cases in adults have mainly been reported in immu-
laser. There are also several case reports of response to nosuppressed patients and those with diabetes.
acitretin [10]. GAS is the most frequently reported cause of BDD,
although occasional cases are linked to Staph. aureus, espe-
Necrotizing fasciitis cially if multiple bullae or erosions are present. BDD is
Necrotizing fasciitis (NF) is an aggressive soft tissue infec- associated with very low morbidity. When it is suspected,
tion involving the subcutis and fascia, with a rapid and ful- treatment is with incision, drainage and culture of bullae
minant progression. NF in adults is frequently polymicrobial, and a course of β‐lactamase‐resistant antibiotics [15].
but in children it is usually a monomicrobial infection most
commonly caused by GAS. Because of a significant mortal- Perianal streptococcal dermatitis

ity rate, early diagnosis and initiation of aggressive surgical Perianal streptococcal dermatitis is an infection that pre-
and supportive therapy are critical for survival. Any suspi- dominantly affects younger children and is most fre-
cion of NF warrants immediate hospitalization, surgical quently caused by GAS. It has a male preponderance, and
consultation and critical care support [12]. the typical age group is between 6 months and 10 years.
INFECTIONS
Predisposing conditions for the acquisition of NF The signs and symptoms of PSD include rectal pain, pru-
include trauma, previous surgery, diabetes mellitus, ritus ani, painful defaecation, rectal bleeding and enco-
immunosuppression, renal failure, arteriosclerosis, odon- presis. The cutaneous findings in acute infections are
togenic infection and malignancy. In infants, the risk fac- patchy or plaque‐like, sharply demarcated, moist ery-
tors include omphalitis, mastitis, fetal scalp monitors, thema in a uniform perianal distribution extending
mammitis and necrotizing enterocolitis [13]. 2–4 cm from the anal verge. Satellite pustules may also be
Although NF usually involves an extremity, it can often observed. Perianal bacterial cultures can confirm the
involve the trunk in children. Localized painful erythema diagnosis. Staphylococcal perianal dermatitis can occur,
and oedema rapidly progress over hours to days, with but is far less common than streptococcal perianal derma-
development of cyanosis, blistering and necrosis. titis. Perianal streptococcal dermatitis is an underrecog-
Untreated, NF may progress to deep gangrene and nized cause of flares of guttate psoriasis.
sloughing of tissue. Systemic signs and symptoms include Oral therapy with penicillin V is considered first‐line
high fever, anxiety, altered mental status, tachypnoea, therapy. Alternatives include cefalexin, erythromycin
tachycardia and hypocalcaemia [14]. Vesiculation, ecchy- or other macrolides. A duration of therapy from 14 to
mosis, crepitus, anaesthesia and necrosis are indicative of 21 days is recommended. Additional topical antiseptics
advanced disease. Severe pain out of proportion to skin (e.g. chlorhexidine) may accelerate bacterial clearance [16].
findings, rapidly spreading oedema, bullae formation,
mental status changes, marked leucocytosis or elevated Streptococcal intertrigo
creatinine kinase level all suggest NF more than cellulitis. Intertrigo is caused by friction of opposing skin surfaces
Anaesthesia of overlying skin may be present prior to the in a moist environment. Young infants are especially sus-
appearance of skin necrosis [12]. ceptible because of their abundant skinfolds. Secondary
In cases of suspected NF, an MRI scan of the affected infection with Candida albicans is common, but GAS must
extremity can help in diagnosis but should not delay sur- also be considered. A sharply demarcated, intensely ery-
gical consultation if there is high suspicion. MRI typically thematous, weeping eruption in intertriginous areas is
shows widespread soft tissue oedema and subfascial gas characteristic of both candidal and GAS intertrigo. Certain
formation. Frozen tissue sections show massive polymor- clinical features can help to differentiate these two condi-
phonuclear infiltrate in the fascia and subcutaneous tions. The appearance of satellite lesions surrounding the
main eruption favours Candida infection, whereas the In all of these cases, the source location and dose of
presence of pain, bright red colour and a foul odour sug- toxin have been shown to directly influence the clinical
gests GAS intertrigo. GAS can occur in multiple skinfolds response. In addition, host factors such as local pH, glu-
including the neck, axillae, inguinal folds and popliteal cose level, oxygen level, age, and presence or absence of
fossae simultaneously. Patients with GAS intertrigo may antibodies will have a direct impact on the clinical expres-
also be irritable or have low‐grade fevers. Bacterial cul- sion of toxin‐mediated illness. Certain physical signs are
ture can establish the diagnosis. frequently present in toxin‐mediated illness. These
Simple intertrigo will respond to measures that mini- include strawberry tongue, acral erythema with desqua-
mize moisture and reduce friction, such as drying of the mation, and an erythematous eruption with frequent per-
skinfolds, barrier creams or zinc pastes. Candidal inter- ineal accentuation. These signs have been described in
trigo can be treated with topical anti‐yeast medications TSS, scarlet fever and recurrent perineal erythema, among
such as ketoconazole or nystatin. For GAS intertrigo, a others. The frequent clinical overlap between toxin‐medi-
10‐day course of penicillin successfully eliminates the ated diseases has been attributed to the significant degree
infection in most instances. Recurrences may occur and of sequence homology not only between toxins produced
require retreatment [17]. by the same bacterial strain, but also due to the similari-
ties at a molecular level between many streptococcal and
References staphylococcal toxins. Ultimately, though, the phenotypic
1 Steer A, Danchin M, Carapetis J. Group A streptococcal infections in expression of a given toxin‐mediated disease is depend-
children. J Pediatr Child Health 2007;43:209–13.
ent not only on the toxin itself, but also on host factors [1].
2 Cole C, Gazewood J. Diagnosis and treatment of impetigo. Am Fam
Physician 2007;75:859–64.
3 Mathes EF, Oza V, Frieden IJ et al. “Eczema coxsackium” and unusual Staphylococcal scalded skin syndrome
cutaneous findings in an enterovirus outbreak. Pediatrics 2013;132: SSSS is a potentially life‐threatening, toxin‐mediated
e149–57.
4 Parks T, Smeesters PR, Steer AC. Streptococcal skin infection and
manifestation of localized infection with certain strains of
rheumatic heart disease. Curr Opin Infect Dis 2012;25:145–53. staphylococci. The syndrome is characterized by bright
5 Lopez F, Lartchenko S. Skin and soft tissue infections. Infect Dis Clin red, tender skin, especially periorificial and in the neck,
North Am 2006;20:759–72. axillary and inguinal folds, that denudes with lateral
6 Kroshinsky D, Grossman M, Fox L. Approach to the patient with pre-
sumed cellulitis. Semin Cutan Med Surg 2007;26:168–78. pressure (Nikolsky sign). In more severe cases, fever,
7 Neri I, Montanari F, Baraldi C et al. Erysipelas as a superinfection of tachycardia and hypotension may be present.
an oral lymphangioma. J Pediatr 2014;165:205. SSSS is predominantly a disease of infancy and early
8 Ellerbe D, Parsons D, Cook P. Botryomycosis: improved therapy for a
childhood, with most cases seen before the age of 5 years.

difficult infection. Int J Pediatr Otorhinolaryngol 1997;41:363–9.
9 Bonifaz A, Carrasco E. Botryomycosis. Int J Dermatol 1996;35:381–8. This age distribution may be due to renal immaturity
10 Nguyen R, Beardmore G. Blastomycosis‐like pyoderma: successful leading to decreased clearance of the toxin or lack of pro-
treatment with low‐dose acitretin. Australas J Dermatol 2005; tective antibodies against the toxin. Adults with SSSS
INFECTIONS
46:97–100.
11 Sawalka S, Phiske M, Jerajani H. Blastomycosis‐like pyoderma. Indian
have rarely been reported; predisposing factors in this
J Dermatol Venereol Leprol 2007;73:117–19. population include renal failure, malignancy, immuno-
12 Bingol‐Kologlu M, Yildiz R, Alper B et al. Necrotizing fasciitis suppression, chronic alcohol abuse or HIV infection.
in children: diagnostic and therapeutic aspects. J Pediatr Surg Most toxigenic strains of Staph. aureus causing SSSS
2007;42:1892–7.
13 Hsieh WS, Yang PH, Chao HC, Lai JY. Neonatal necrotizing fasciitis: belong to phage group II, types 71 and 55. SSSS results
a report of three cases and review of the literature. Pediatrics from the effects of one of the exfoliative (also known as
1999;103:e53. epidermolytic) toxins (ETs). As noted previously, bullous
14 Manders S. Toxin‐mediated streptococcal and staphylococcal disease.
impetigo results when toxin is produced and exerts its
15 Scheinfeld N. Is blistering distal dactylitis a variant of bullous impe- effect locally. In generalized forms of SSSS, the toxin dif-
tigo? Clin Exp Dermatol 2007;32:314–16. fuses from an infected focus and, in the absence of specific
16 Jongen J, Eberstein A, Peleikas H et al. Perianal streptococcal dermati- antitoxin antibody, spreads haematogenously to produce
tis: an important differential diagnosis in pediatric patients. Dis Colon
Rectum 2008;51:584–7. its widespread effects. In children the infectious focus is
17 Honig P, Frieden I, Kim H, Yan A. Streptococcal intertrigo: an usually in the nasopharynx or conjunctivae; therefore, if a
underrecognized condition in children. Pediatrics 2003;112:1427–9. primary source of infection cannot be found, the nares
and rectum should be cultured to establish antibiotic sus-
ceptibilities. An appropriate antibody response to ET
Toxin‐mediated staphylococcal
appears to limit clinical disease expression to bullous
and streptococcal disease
impetigo; an inadequate humoral immune response may
Children commonly present with exanthems. Although predispose patients to development of SSSS.
viral exanthems account for the majority, staphylococcal Childhood cases of SSSS are primarily associated with
and streptococcal toxin‐mediated diseases are important solely ETA production, but the frequency of the different
disorders to identify. Early recognition and treatment of toxins in adult cases is unclear [1]. Both ETs produce blis-
these syndromes can significantly reduce the morbidity tering and denudation by disruption of the epidermal
and potential mortality. In this section, staphylococcal granular cell layer. ETs have been shown to be glutamate‐
scalded skin syndrome (SSSS), staphylococcal TSS, strep- specific serine proteases that specifically bind and cleave
tococcal TSS, streptococcal scarlet fever and recurrent desmoglein‐1. Desmogleins are cadherin‐type cell–cell
toxin‐mediated erythema will be discussed. adhesion molecules found in desmosomes, and play a
critical role in maintaining epithelial integrity. Desmogleins which occurs in a variety of clinical settings and has a ten-
are also affected in the autoimmune blistering disease dency to recur [5]. Currently, the incidence of nonmen-
pemphigus. Desmoglein‐1 is targeted by IgG autoanti- strual TSS exceeds that of menstrual TSS. Most cases of
bodies in pemphigus foliaceus, which shows superficial nonmenstrual TSS occur in the postoperative setting but
epidermal blisters with identical histological findings TSS has also been described in association with influenza,
to SSSS [2]. sinusitis, tracheitis, intravenous drug use, HIV infection,
Clinical features of SSSS include fever, irritability, skin cellulitis, burn wounds, allergic contact dermatitis, gynae-
tenderness and scarlatiniform erythema with accentua- cological infection and the postpartum period.
tion in flexural areas. Within 24–48 hours, flaccid blisters In both settings, TSS occurs when infection with toxin‐
and erosions develop. These blisters are caused by the producing strains of Staph. aureus induces a systemic
toxin and thus are sterile. The Nikolsky sign is character- inflammatory response in those lacking protective
istically present. Mucosal lesions do not occur because antibodies.
desmoglein‐3 is compensatory in the mucosa and not tar- TSST‐1 is one of the significant mediators of patho-
geted by the ETs. However, involvement of the kerati- genicity in TSS, and it is generated by strains from virtu-
nized external lip with crusting and fissuring is frequently ally all menstrual and many nonmenstrual cases of TSS.
encountered. The lack of mucosal involvement is the However, nonmenstrual cases of TSS can be due to strains
main differentiator from Stevens–Johnson syndrome of Staph. aureus that do not produce TSST‐1 but instead
(SJS). SJS is also typically caused by medicines and a produce staphylococcal enterotoxins. TSST‐1 and staphy-
rare disease in infancy. In contrast to SSSS, SJS produces lococcal enterotoxin B act as superantigens, and can lead
full‐thickness epidermal necrosis and histologically to large‐scale activation of T cells as well as massive
demonstrates subepidermal separation, rather than the cytokine production.
intraepidermal split characteristic of SSSS. Clinically, both menstrual and nonmenstrual TSS have
Sepsis is rare in children but common in (immunocom- similar features. Fever, rash, desquamation, hypotension
promised) adults. and multiple organ involvement are the hallmarks of both
Therapy for SSSS should be directed towards eradica- variants. The eruption of TSS is defined as ‘diffuse macu-
tion of staphylococci from the focus of infection, which lar erythroderma’; however, a scarlatiniform eruption,
generally involves intravenous penicillinase‐resistant often with flexural accentuation, is frequently present.
penicillins. Usually, oral antibiotic therapy can be substi- Erythema and oedema of palms and soles, hyperaemia of
tuted within several days. In addition to antibiotics, topi- conjunctiva and mucous membranes, and strawberry

cal supportive skin care and appropriate attention to fluid tongue are often noted. Desquamation of the palms and
and electrolyte management in the face of disrupted bar- soles, as seen in many bacterial toxin‐mediated disorders,
rier function will usually ensure rapid recovery. The mor- usually follows the onset of the illness by 1–2 weeks.
tality rate is low in children (3%) but exceeds 50% in Importantly, in nonmenstrual TSS caused by a postopera-
INFECTIONS
adults, especially in the setting of immunocompromise tive infection, the classic signs of localized infection such
[1]. Recent studies have documented that SSSS is more as erythema, tenderness and purulence may be absent
commonly caused by meticillin‐susceptible Staph. aureus from the site of infection, thereby making clinical diagno-
than would be predicted based on local antibiotic sensi- sis challenging. Multiple organ involvement may include
tivities. In addition, a higher percentage of clindamycin the gastrointestinal, muscular, renal, hepatic, haemato-
resistance was found. Therefore, if clindamycin is initi- logical or central nervous systems [1].
ated in order to decrease toxin production, a penicillinase‐ Intense conjunctival hyperaemia is a very frequent and
resistant penicillin or cephalosporin should be used to characteristic finding in TSS, but it also occurs in Kawasaki
provide double coverage until susceptibilities can be disease, erythema multiforme, Rocky Mountain spotted
established [3,4]. fever and adenoviral and enteroviral infections. These
It is vital to recognize the potential for epidemic SSSS in diseases, along with streptococcal toxic shock syndrome
newborn nurseries, and identification of healthcare work- (STSS) and early SSSS, constitute the differential diagno-
ers who are colonized or infected with toxigenic Staph. sis of TSS. In children, the distinction between Kawasaki
aureus is an integral part of management. Control meas- disease and TSS can be very difficult, especially early in
ures should be applied, including strict enforcement of the course of illness. The characteristic thrombocytosis
chlorhexidine handwashing, oral antibiotic therapy for and lymphadenopathy of Kawasaki disease are the most
infected workers, and mupirocin ointment for eradication helpful distinguishing features, but may not always be
of persistent nasal carriage. present.
Prompt intervention is the key to the successful man-
Staphylococcal toxic shock syndrome agement of the multiorgan involvement in TSS. Removal
Toxic shock syndrome (TSS) is defined as an acute and of infected foreign bodies, drainage of infected sites and
potentially fatal illness characterized by high fever, a dif- institution of penicillinase‐resistant antistaphylococcal
fuse erythematous rash, hypotension, involvement of antibiotics are essential to eradicate the focus of toxin‐
three or more organ systems and desquamation of the producing organisms. Massive volume replacement may
skin 1–2 weeks after onset. TSS is usually classified into be needed in the setting of severe intravascular volume
two categories: menstrual TSS, originally described in depletion. Cardiovascular support may be necessary,
association with tampon use; and nonmenstrual TSS, including both inotropic and antiarrhythmic measures.
Paediatric patients may require ventilatory support for more than 50% of patients with STSS, as compared with
respiratory distress more often than adult patients. less than 15% in TSS. In addition, mortality rates are more
Metabolic acidosis, hypomagnesaemia, hypocalcaemia than five times higher in STSS.
and hypophosphataemia may accompany renal disease, Management of STSS is similar to that of TSS.
requiring aggressive monitoring and management. Supportive therapy, vasopressors and antibiotics are the
cornerstones of treatment. The increasingly reported clin-
Streptococcal toxic shock syndrome ical resistance of streptococci to penicillin, as well as the
In the late 1980s, a disease similar in appearance to TSS, difficulty in distinguishing STSS from TSS in some cases,
yet caused by invasive streptococci, was recognized. This suggests the need for adequate antimicrobial coverage for
streptococcal toxic shock syndrome (STSS) was found to both staphylococci and penicillin‐resistant streptococci.
share many clinical features with staphylococcal TSS, Consideration should be given to clindamycin, erythro-
including multiorgan involvement, toxicity, conjunctival mycin, cephalosporins or other agents as deemed appro-
hyperaemia and profound hypotension. In the majority of priate by clinical presentation and culture results [1].
cases, toxin‐producing group A streptococci have been Surgical drainage, debridement, fasciotomy or amputa-
isolated, with SPE‐A production being most closely linked tion may be necessary.
with invasive disease. However, group A streptococci
producing SPE‐B, SPE‐C, streptococcal superantigen and Streptococcal scarlet fever
mitogenic factor, as well as non‐group A streptococci, Scarlet fever is caused by pyrogenic exotoxin‐producing
have been found to be causative in individual cases of group A β‐haemolytic streptococcal infections. Epidemics
STSS as well. In a similar manner to classic TSS, the clini- of scarlet fever occurred in the first half of the twentieth
cal signs of STSS are postulated to be mediated by mas- century, but it is no longer the major public health threat
sive cytokine release as a result of toxin/superantigen that it was in the past. Morbidity, mortality and sequelae
activity. In addition, streptolysin O, produced by 100% of are much less serious today, not only because of the
streptococcal strains associated with STSS, has been dem- development of antibiotics, but also because of changes
onstrated to act synergistically with SPE‐A [1]. in the streptococci responsible for the majority of cases of
The majority of cases of STSS have occurred in young, scarlet fever. Whereas the bacteria that caused scarlet
otherwise healthy persons between 20 and 50 years of fever in the past primarily produced the more virulent
age. Most are associated with invasive streptococcal infec- SPE‐A toxin, currently SPE‐B and SPE‐C are produced by
tions with virulent (i.e. M types 1 and 3) strains causing most Strep. pyogenes organisms isolated from patients
extensive soft tissue infections and leading to bacterae- with scarlet fever.
mia. (In contrast with STSS, staphylococcal TSS typically Scarlet fever remains primarily a disease of children,
is associated with occult or minor focal infections.) The with most cases occurring between the ages of 1 and 10
factors that determine whether infections with SPE‐A years. SPEs have been shown to elicit the cutaneous
INFECTIONS
lead to STSS or classic scarlet fever are uncertain. The manifestations of scarlet fever by enhancing delayed‐
host’s immune status for the infecting strain’s M type and type hypersensitivity to streptococcal products, thereby
toxin type is clearly important. It appears that lack of requiring previous exposure for expression of disease.
immunity to both streptococcal M type and toxin is This explains the rarity of cases of scarlet fever in infancy:
required for both scarlet fever and STSS. most infants have not had previous exposure to these
Clinically, STSS shares many features with TSS. Fever, streptococcal toxins and therefore have not generated
hypotension, myalgias, liver abnormalities, diarrhoea, antitoxin antibody. Clinical findings include the abrupt
emesis, renal dysfunction and haematological abnormali- onset of fever, sore throat, headache and chills.
ties may be present in TSS caused by either staphylococci Mucocutaneous findings include a finely papular erythe-
or streptococci. Diffuse macular erythroderma likewise matous ‘sandpaper’ rash on the trunk and extremities,
is frequently present in disease caused by both bacteria, with circumoral pallor. Pastia’s lines represent linear
and is often accompanied by mucous membrane findings, petechial streaks found especially in flexural locations
such as conjunctival injection and delayed desquamation such as the antecubital fossae, the axillae and the ingui-
of palms and soles. Nonetheless, certain important dif- nal region. Erythema and oedema of the pharyngotonsil-
ferences exist between STSS and TSS. The skin is often lar area, punctate erythematous and petechial macules
the portal of entry in STSS, with soft tissue infections on the palate, and strawberry tongue are commonly pre-
developing in 80% of patients. The initial presentation of sent. Large, thick sheets of skin may desquamate from
STSS is often localized pain in an extremity, which rapidly the hands and feet, especially in the convalescent phase.
progresses over 48–72 hours to manifest both local and Uncommon complications include pneumonia, pericar-
systemic signs of STSS. Cutaneous signs may include ditis, meningitis, hepatitis, glomerulonephritis and rheu-
localized oedema and erythema, a bullous and haemor- matic fever. Recurrence rates of scarlet fever have been
rhagic cellulitis, necrotizing fasciitis or myositis, and gan- reported to be as high as 18%.
grene. Soft tissue involvement of this nature is distinctly Diagnosis of scarlet fever is usually apparent clinically,
uncommon in staphylococcal TSS. STSS may uncom- but can be further confirmed by supportive serologies
monly occur in the absence of cutaneous involvement; and isolation of group A streptococci from the pharynx.
in these cases differentiation from staphylococcal TSS First‐line treatment is with penicillin; cephalosporins,
becomes more difficult. Blood cultures are positive in erythromycin and other macrolides are alternatives [1].
Recurrent toxin‐mediated (perineal) bacterial pharyngitis, isolated episodes of toxin‐mediated

erythema erythema without recurrences, and patients with episodic
Recurrent toxin‐mediated perineal erythema (RPE) is mild hypotension, fever and typical mucocutaneous find-
caused by the action of toxins produced by both staphylo- ings in the absence of full criteria for TSS have been
cocci and streptococci. Due to a homology at the molecu- described. The common feature, aside from a large degree
lar level between the toxins produced by these bacteria, of clinical overlap, has been the repeated ability to isolate
there is a substantial clinical overlap. Furthermore, a sin- toxin‐producing bacteria from normally sterile sites.
gle bacterial toxin acting as a superantigen can lead to a Given the clinical variations, it is more appropriate to
broad spectrum of clinical diseases. Testing for these tox- refer to this group of entities as ‘toxin‐mediated erythema’
ins in cases of RPE has revealed streptococcal pyrogenic although most cases are recurrent with a propensity for
exotoxins A and B as well as TSST‐1 [6]. perineal involvement [1].
The hallmark of RPE is a striking diffuse macular ery-
References
thema in the perineum occurring within 24–48 hours 1 Manders S. Toxin‐mediated streptococcal and staphylococcal disease.
after a bacterial pharyngitis. Oral mucosal changes, such J Am Acad Dermatol 1998;39:383–98.
as strawberry tongue, as well as erythema, oedema and 2 Anzai H. Production of low titers of anti‐desmoglein 1 IgG autoanti-
bodies in some patients with staphylococcal scalded skin syndrome.
convalescent desquamation of the hands and feet are

usually present as well. Systemic signs such as fever or 3 Li MY, Hua Y, Wei GH, Qiu L. Staphylococcal scalded skin syndrome
hypotension are absent; however, diarrhoea may occur. in neonates: an 8‐year retrospective study in a single institution.
Recurrences are frequent, occurring as many as 40 times. Pediatr Dermatol 2014;31:43–7.
4 Braunstein I, Wanat KA, Abuabara K et al. Antibiotic sensitivity and
Culture of the pharynx during the acute episodes reveals resistance patterns in pediatric staphylococcal scalded skin syn-
toxin‐producing Staph. aureus or Strep. pyogenes. drome. Pediatr Dermatol 2014;31:305–8.
It has become clear that RPE is part of an expanding 5 Iwatsuki K, Yamasaki O, Morizane S, Oono T. Staphylococcal cutane-
clinical spectrum of toxin‐mediated skin diseases that do ous infections: invasion, evasion, and aggression. J Dermatol Sci
2006;42:203–14.
not easily fit into previously described clinical entities. 6 Patrizi A, Raone B, Savoia F et al. Recurrent toxin‐mediated perineal
Recurrent erythroderma associated with a preceding erythema. Arch Dermatol 2008;144:239–43.

INFECTIONS
434
CHA PTER 3 8
Cutaneous Manifestations of

Gram‐negative Infections
Saul N. Faust1, Diane Gbesemete1 & Robert S. Heyderman2
NIHR Southampton Clinical Research Facility, University of Southampton and University Hospital Southampton NHS Foundation Trust, Southampton, UK
1
University College London, London, UK

2
Meningococcal disease, 434 Gram‐negative soft tissue Gram‐negative folliculitis, 451

Pseudomonal skin disease, 446 infections, 450
Abstract Neisseria meningitidis is a common human nasopharyngeal

commensal. In a minority of individuals it causes invasive, life‐
threatening disease. The cutaneous features are often recognizable
Gram‐negative infections are a rare but potentially life‐threatening
at presentation and may cause significant morbidity.
cause of cutaneous lesions, often requiring urgent recognition and
Pseudomonas aeruginosa can cause both localized primary skin
treatment. This chapter discusses the pathophysiology, clinical
lesions and systemic infection with cutaneous manifestations.
features and management of the most common Gram‐negative
Pseudomonal skin infections are more commonly, but not exclu-
infections.
sively, seen in immunocompromised individuals.
Key points • Early diagnosis, early antibiotics and good supportive care are
crucial in the management of meningococcal disease.
Meningococcal disease Pseudomonal skin disease
• Neisseria meningitidis, a small encapsulated Gram‐negative • Pseudomonas aeruginosa is a Gram‐negative aerobic rod that is
diplococcus, is the aetiological agent of meningococcal disease. widely distributed in the environment, particularly in aqueous
• Asymptomatic nasopharyngeal carriage is common with a peak environments.
in carriage in adolescence. • It is a common opportunistic pathogen that is responsible for
• Transmission is predominantly via respiratory droplets shed significant morbidity and mortality in immunocompromised
INFECTIONS
from asymptomatic close contacts. hosts but can also cause disease in previously fit and well
• Neisseria meningitidis causes invasive disease in a minority of individuals with a normally functioning immune system.
colonized individuals, usually soon after acquisition. • It has intrinsic resistance to many first‐line antibiotics and
• Most infections are due to serogroups A, B or C. often develops resistance to broad‐spectrum or second‐line
• Vaccines are available for serogroups A, C, W‐135, Y and, more antibiotics.
recently, serogroup B. • Skin manifestations of pseudomonal infection can be localized
• Meningococcal disease remains a major health problem worldwide primary infections or secondary manifestations of pseudomonal
and can occur as sporadic cases, outbreaks or epidemics. septicaemia.
• Although meningococcal disease can occur at any age, children • Primary, localized pseudomonal skin infection can occur in
under 5 years of age are predominantly affected with a second immunocompetent individuals who have a disruption in the
smaller peak in incidence amongst adolescents. normal skin defences against infection.
• Mortality from meningococcal disease is approximately 5–10% and • Pseudomonas septicaemia is strongly associated with
there are long‐term sequelae in up to 25% of those who survive. immunocompromise and has a very high mortality.
• The skin rash is characteristically petechial but may blanch and • Ecthyma gangrenosum is the characteristic cutaneous lesion
resemble a viral exanthem in the early stages of infection. associated with pseudomonal sepsis.
Meningococcal disease
and mortality [2,5]. Meningococcaemia is characterized
Introduction. Neisseria meningitidis is one the most by the development of a widespread purpuric rash and
common causes of severe infection in childhood [1–3]. the progression to vascular collapse and death in up to
First described by Vieusseux [4] in 1806 following an out- 20% of cases. In his description of the rapid onset and ful-
break of epidemic meningitis in Geneva, meningococcal minant progression of meningococcal disease, Herrick [6]
disease remains an important cause of both morbidity remarked that ‘no other infection so quickly slays’. Nearly
Chapter 38 Cutaneous Manifestations of Gram‐negative Infections 435
100 years later, improved awareness, the availability of by inhibitory flora, and mucosal and systemic immunity
highly active antibiotics and advances in intensive care [22–29]. No increased risk of invasive meningococcal dis-
management have failed to alleviate our fear of meningo- ease is associated with human immunodeficiency virus
coccal infection. (HIV) infection [30,31].
Aetiology. The aetiological agent N. meningitidis is a small Epidemiology. Meningococcal disease remains a major
Gram‐negative diplococcus that is surrounded by an health problem worldwide although there is substantial
outer polysaccharide capsule, an outer membrane and an geographical variation in incidence. It is endemic in most
underlying peptidoglycan layer. The cell wall is rich in countries but occurs in small outbreaks and epidemics in
lipopolysaccharide (LPS) which, together with outer both developing and industrialized countries [3,5,14].
membrane proteins, is released as vesicles or ‘blebs’. The incidence and predominant strains seen in particu-
These blebs are thought to facilitate immune avoidance lar geographical locations change significantly over time
by binding antibodies that would otherwise bind to with cyclical epidemics occurring in some regions. Part of
whole organisms and also mediate endotoxic shock. the reason for this dynamic epidemiology is thought to be
N. meningitidis is an obligate human commensal which antigenic variability with the organism capable of capsular
causes disease in a minority of those who carry the switching and other noncapsular antigenic changes [14].
organism [7,8]. The ‘meningitis belt’ of sub‐Saharan Africa has the
Different strains of N. meningitidis may be distinguished highest incidence with large epidemics occurring every
by their serogroups, which are based on the 13 recognized 5–10 years [32–35], affecting up to 1% of the population at
variations in capsular polysaccharide antigens (A, B, C, D, their peaks [14]. There is seasonal variation in incidence,
E, H, I, K, L, W135, X, Y, Z) [8,9]. Worldwide, most infec- rising dramatically towards the end of the dry season and
tions are due to organisms of serogroup A, B or C, falling with the onset of the rains [3,32]. Serogroup A is
although Y, W135 and X are becoming more prevalent predominant although serogroups C, Y and W135 and
[8,10–12]. N. meningitidis may be further serotyped, sero- more recently X are also seen. The incidence in North
subtyped and immunotyped on the basis of outer mem- America is currently unusually low with a predominance
brane protein and LPS expression. The bacterial genome of serogroups B and C although Y and W135 are also seen.
can be characterized using multilocus sequence typing European countries and Australasia have a predominance
(MLST) [13]. These tools are often used in conjunction of serogroup B, especially following the introduction of
when analysing the epidemic spread of disease [14]. routine vaccination against serogroup C [14]. In temper-

ate climates a seasonal peak in incidence can be seen in
Meningococcal carriage the first quarter of the year [3].
Transmission of N. meningitidis is predominantly via res- Although meningococcal disease can occur at any age,
piratory droplets shed from asymptomatic close contacts. children under 5 years of age are predominantly affected,
INFECTIONS
This may result in transient acquisition, prolonged car- with the highest attack rates being seen in those less than
riage in the nasopharynx (colonization) or invasive dis- 1 year old. In many countries, a second smaller peak in
ease [8]. A recent meta‐analysis looking at nasopharyngeal incidence has also been observed among teenagers aged
carriage in European countries showed that the preva- 15–19 years [3,36].
lence of carriage increased from 4.5% in infants, with a At the beginning of the twentieth century when the
sharp rise in adolescence, peaking at 23.7% at 19 years of only treatment available was a crude horse serum, the
age before gradually decreasing again throughout adult- mortality among patients with meningococcal septicae-
hood [15]. Nasopharyngeal carriage results in the produc- mia was often over 90% [5,37]. With the introduction of
tion of antibodies [7]. sulfonamides and penicillin in the late 1930s and 1940s,
there was a dramatic reduction in this mortality in coun-
Invasion tries around the world [5]. Until the mid 1990s the mortal-
In a minority of cases N. meningitidis penetrates the ity associated with meningococcal infection remained
mucosal layer, reaches the bloodstream and causes inva- unchanged at around 10% overall, rising to between 40%
sive disease. This usually happens in the first 2 weeks fol- and 70% in those patients in severe shock [5,37]. More
lowing acquisition [8] and is rare following prolonged recently, in industrialized countries where early disease
carriage. A number of hypervirulent strains are responsi- recognition and aggressive intensive care have become
ble for the majority of invasive disease, with the presence common, the mortality even in children presenting in
of a capsule being a particularly important virulence fac- shock has decreased to between 5% and 10% [2,38]. Up to
tor [14]. Other bacterial properties that might influence a quarter of those who survive an episode of meningococ-
invasion include the presence of pili, outer membrane cal disease may have significant ongoing sequelae [39].
proteins and immunoglobulin (Ig) A1 proteases [16–19].
The most important host factor conferring protection Pathophysiology. Between 1947 and 1976, the cutaneous
from invasive disease is the presence of serum bacteri- manifestations of fulminant meningococcal septicaemia
cidal activity [20,21]. Host factors implicated in the devel- were investigated in a series of postmortem and skin
opment of invasive disease include poor socioeconomic biopsy studies [40–46]. Although the appearances
circumstances, overcrowding, secretor status, smoking, described probably represent the final common pathway
respiratory tract infection, nasopharyngeal colonization for a number of possible pathogenic mechanisms, a wide
Endothelial Vasoconstriction
injury
Collagen tPA
exposure
Serotonin ADP aPC

nϕ thromboxane A2 PS TM
GAG nϕ
nϕ TAFI
loss Platelet PAI Haemostatic
release nϕ tPA
reaction, plug
aggregation
and fusion
Platelet
TF Plasmin
phospholipid
mϕ mϕ AT
TFPI
a
Xa a
TFPI Xa Fibrin
Va Xa Vllla Thrombin Vllli
a Xa X Va a
IXa Vi
X IXa AT PS
TF Xa Xa ll aPC
nϕ E
PC E aPC P
TM P C
TM C R
THROMBIN R
generation by Protein S circulates
SELECTINS amplification in a free form (the
tether monocytes and initiated by active inhibitor) or
platelets(attached to tissue factor Activation bound to C4bBP
neutrophils) to endothelium via Xa
to provide further surface Inhibition or
area for complex formation
a = activated i = inactivated
Fig. 38.1 The molecular pathogenesis of disseminated intravascular coagulation of bacterial septicaemia. ADP, adenosine 5’‐diphosphate; aPC, activated
protein C; AT, antithrombin; EPCR, endothelial protein C receptor; GAG, glycosaminoglycan; PAI, plasminogen receptor inhibitor; PC, protein C; PS, protein
S; TAFI, thrombin activatable fibrinolysis inhibitor; TF, tissue factor; TFPI, tissue factor pathway inhibitor; TM, thrombomodulin; tPA, tissue plasminogen
INFECTIONS
activator.
spectrum of histological changes were observed. These A haemostatic imbalance occurs following the activa-
ranged from fibrin–platelet thrombi, endothelial swelling tion of coagulation and dysfunction or dysregulation
and necrosis, and granulocytic infiltrates to occlusion of of the natural regulatory pathways (Fig. 38.2) [52–54].
blood vessels, extravasation of red blood cells and exten- Endothelial prostacyclin production and the expression
sive full‐thickness necrosis. In recent years, our under- of anticoagulant glycosaminoglycans may be impaired
standing of the mechanisms underlying meningococcal [59,60]. Patients with meningococcal disease have
sepsis has improved. It has become apparent that much of increased monocyte tissue factor activity [61], decreased
the disease process that follows meningococcal invasion is tissue factor pathway inhibitor [62], a deficiency of
not due to direct toxicity by the meningococcus itself but antithrombin, protein C and protein S, and significant dis-
results from the release of endotoxin into the circulation. ruption of the fibrinolytic pathway [50,57,63–68]. We have
This triggers the activation of inflammatory cells and demonstrated that disruption of the endothelial activa-
the elaboration of a wide range of cytokines and other tion of protein C in meningococcal sepsis is caused by
mediators [47–52]. This intense inflammatory response downregulation of thrombomodulin and endothelial pro-
is commonly associated with platelet consumption, a tein C receptor on the endothelial cell surface (Figs 38.3
coagulopathy and intravascular thrombosis, which are and 38.4) [57].
all important markers of disease progression and a poor This dysregulation of the coagulation and fibrinolysis
prognosis [53]. However, the coagulopathy and the micro- pathways occurs together with activation of inflamma-
vascular consequences of meningococcal sepsis are more tory pathways including innate, cell‐mediated and
complex than originally thought (Fig. 38.1) [54]. With the humoral immunological processes, involving the comple-
appreciation that the vessel wall is not simply an inert con- ment cascade, the kallikrein–bradykinin system, mono-
duit [55] but performs a wide range of important homeo- cytes, neutrophils and cytokines (Fig. 38.5) [52,54,69–73].
static functions, it has become recognized that dysfunction The pathways are linked at many levels [52], together
of the vascular endothelium is key to the development leading to the capillary leak, defects in vascular tone,
and progression of both the haemostatic and inflamma- hypoperfusion, myocardial dysfunction and focal throm-
tory disorders associated with severe sepsis [54,56–58]. bosis that are responsible for the tissue damage
TFPI
PAI
Plasma
AT PC, PS
Fig. 38.2 The coagulation and fibrinolytic Production Plasmin

AT function
pathways rely on the function of endothelial APC
proteins and protein complexes. Dysfunctional
regulatory mechanisms in meningococcal disease
include endothelial (protein C pathway) and
plasma (tissue factor pathway inhibitor [TFPI],
antithrombin, plasminogen receptor inhibitor tPA
PGl2 GAGs
[PAI]) factors. AT, antithrombin; CS, chondroitin Endothelial CS, HS, DS PC
sulphate; DS, dermatan sulphate; EPCR, surface TM, EPCR
endothelial protein C receptor; GAGs,
glycosaminoglycans; HS, heparan sulphate; PC,
protein C; PGI2, prostacyclin; PS, protein S; TM,
thrombomodulin; tPA, tissue plasminogen
activator.
remains uncertain. Large numbers of meningococci can

(a) be detected in the dermal vessels of purpuric skin lesions
[40,43,46,74] and may not only be directly toxic but act as
a focus for both the inflammatory and haemostatic
responses on the vessel wall [73,75–77]. Endothelial colo-
nization has recently been demonstrated in an experi-
mental model of human skin grafted onto immunodeficient
mice. This adherence was mediated by type 4 pili and
resulted in the pathological features of thrombosis, vessel

occlusion, red blood cell extravasation and tissue necrosis
[78–80]. We have identified meningococci in a number of
different cellular environments expressing key virulence
factors (Fig. 38.6) [74].
INFECTIONS
While many single‐gene defects are known to affect the
immune and coagulation responses to infection [81], a
combination of genetic predisposition and bacterial
(b) (c)
virulence factors is likely to be responsible for any one
individual’s susceptibility to invasive disease. In menin-
gococcal disease, many such single‐nucleotide polymor-
phisms have now been identified. Genetic variants of
mannose‐binding lectin might account for nearly one
third of cases of invasive disease [82] and an innate anti‐
inflammatory cytokine profile contributes to the likeli-
hood of death [83]. A specific Fc‐γ receptor polymorphism
may be essential in protecting against fulminant menin-
Fig. 38.3 Skin biopsy specimen from a patient with meningococcal sepsis.
A biopsy specimen from a purpuric lesion shows areas containing
gococcal infection [84]. Although the factor V Leiden
thrombosed vessels (right‐hand arrow in (a) and arrow in (b)) and a mutation confers a specific genetic predisposition to
perivascular infiltrate (left‐hand arrow in (a)) (haematoxylin and eosin, thrombotic disease [85], it has not been shown to be asso-
×100 (a) and ×400 (b)). (c) shows inflammatory cells (arrow) around ciated with increased mortality in meningococcaemia,
unthrombosed vessels (haematoxylin and eosin, ×400). The cellular although patients with this mutation may be at higher
infiltrate consisted of both neutrophils (identified by neutrophil‐elastase risk of thrombotic complications such as amputations and
staining) and monocytes and macrophages (identified by CD68 staining).
skin grafting [86]. An increased PAI‐1 response to tumour
necrosis factor (TNF)‐α has been associated with death in
commonly observed in association with fulminant menin- meningococcal septicaemia [87], demonstrated to be due
gococcal sepsis [52]. to a polymorphism in the PAI‐1 gene [67,68].
The release of meningococcal lipopolysaccharide has
been understood for some time to be an important trigger Clinical features. Meningococcal meningitis is the most
for the inflammatory and haemostatic processes seen in common form of the disease, is indistinguishable from
fulminant disease [8,49]. However, the importance of other forms of childhood bacterial meningitis, usually
direct bacterial invasion of the skin by the organism responds rapidly to antibiotics and is associated with
(a) (b)
(c) (d)
INFECTIONS
(e)
Fig. 38.4 Thrombomodulin immunostaining (immunoperoxidase stain, ×200) of skin biopsy specimens from a patient with acute meningococcal sepsis
during the initial infection (a) and 3 months later (b) is shown. The same sequence is shown for a second patient (c, d). (e) Another initial specimen from
the second patient. The arrows in (a) and (e) show unthrombosed vessels with reduced thrombomodulin staining, and the arrow in (c) shows a thrombosed
vessel with reduced thrombomodulin staining. Partial recovery of thrombomodulin expression (arrows in (b) and (d)), together with some residual
inflammatory infiltrate, is seen in both patients after 3 months.
little long‐term morbidity [88]. Meningococcal septicae- 80–90% of patients [90]. The rash usually occurs within
mia with shock is more devastating, commonly present- 12–36 hours of the onset of the disease and is characteris-
ing with nonspecific symptoms of fever, vomiting, tically petechial but may blanch early in the course of the
headache, abdominal pain and muscle aches. The rash of infection. In the classic presentation of meningococcal
meningococcal septicaemia may be very subtle in the septicaemia, the petechiae are irregular, small and often
early stages (Fig. 38.7) and its recognition is imperative if have raised centres (Fig. 38.8). Lesions commonly occur
this life‐threatening condition is to be diagnosed early on the limbs and trunk but may be found on the head,
and treated effectively. palms, soles and mucous membranes. They may also
In the early stages of meningococcal infection the rash occur on areas subjected to friction or under pressure
may resemble a viral exanthem such as rubella (see by clothing.
Fig. 38.7). This erythematous maculopapular rash is non- Progression of the rash of meningococcal septicaemia
purpuric, nonpruritic and often very transient [40,89]. has been shown to relate to the severity of the coagu-
Following a diligent search of all areas of the body, the lopathy and prognosis [45,53,91–94]. As the disease
purpuric lesions of meningococcal septicaemia are seen in becomes more fulminant, lesions coalesce to form large
Sepsis usually considered contraindicated when the clinical

diagnosis is meningococcal septicaemia or is often
n delayed when a characteristic rash suggests meningococ-
io
In
at cal meningitis, as it is frequently associated with clinical
fl
l
gu
am
a deterioration and death [2,96]. Nasopharyngeal swabs
m
Co
at
may provide evidence of meningococcal infection. Biopsy
io
n
material and aspirates from the characteristic purpuric
skin lesions of meningococcal disease provide a rich
Endothelial
injury source of organisms and have been advocated by some
workers for rapid diagnosis, but this is not usually con-
Organ sidered routine owing to the advent of modern molecular
Death
failure
techniques now available [95,97–101].
An array of rapid tests is now available to detect
N. meningitidis group A, B, C, Y and W135 antigens from
Fibrinolysis blood, CSF and urine, which may establish the diagnosis
although the sensitivity is poor [102,103]. The highly sen-
sitive polymerase chain reaction (PCR) of blood (or CSF
Fig. 38.5 The inflammatory, coagulation and fibrinolytic pathways are
linked at many levels, leading to organ failure and eventually death. where available) can make the diagnosis in an additional
60% of cases in which no positive culture has been obtained
[104–107]. The sensitivity of the new WB‐Taqman PCR on
ecchymoses and become haemorrhagic and bullous (see EDTA‐treated samples of whole blood has been demon-
Fig. 38.8). These areas of extensive skin involvement strated to be 87%, increasing case confirmation compared
may progress to gangrene of the digits or whole limbs with previous PCR techniques from 72% to 94% [107].
(Fig. 38.9). In such severe purpura fulminans, the gangre-
nous regions are gunmetal grey or blue‐black and are Management of acute meningococcal septicaemia. The
well demarcated [41]. The arterial pulses are usually management of meningococcal disease has been reviewed
intact but the capillary perfusion is very poor. Thrombosis, in detail elsewhere [2,90] and is detailed in Fig. 38.11.
extensive skin involvement, venous congestion and tissue However, a number of important management points
oedema may lead to the development of a limb compart- will be emphasized.

ment syndrome (see Fig. 38.9). Severe tissue destruction may
be associated with muscle infarction and rhabdomyolysis. Recognition and initial therapy
The development of shock associated with meningo- It is crucial that, in the absence of another diagnosis, any
coccal septicaemia may be insidious, and is manifested febrile, ill child with a petechial rash should be considered
INFECTIONS
initially by poor peripheral perfusion, confusion and an to have meningococcal septicaemia, and treatment should
increased respiratory rate. Hypotension is a late sign as be commenced without awaiting further confirmation.
children and young adults may maintain their blood Although the majority of children may not appear desper-
pressure by vasoconstriction, despite severe hypovolae- ately ill when first seen, they may deteriorate suddenly
mia [2]. It is important to recognize meningococcal shock and therefore should be observed carefully during the first
in the early phases, well before hypoxia, acidosis and 48 hours, ideally on a paediatric intensive care unit.
hypovolaemia lead to multiorgan failure (Fig. 38.10). An
algorithm for the early recognition and management of Choice of antibiotic
meningococcal infections is given in Fig. 38.11. Penicillin remains the treatment of choice for meningo-
coccal sepsis. However, since other infections may also
Differential diagnosis. Bacteraemia with Haemophilus occasionally cause shock and a petechial rash, a third‐
influenzae, Streptococcus pneumoniae, Pseudomonas spp. and generation cephalosporin should be employed until the
overwhelming viral and fungal infections may all rarely diagnosis has been confirmed. Penicillin‐resistant strains
present with shock and purpuric rash (Fig. 38.12). Other of N. meningitidis have become a problem in Spain and
congenital and immune causes of a purpura fulminans may South Africa [108–110] but fortunately only a handful of
present with the characteristic rash but these patients are insensitive strains have been detected in the UK, the rest
rarely cardiovascularly compromised (see Chapter 146). of Europe and North America [111–118].
Laboratory diagnosis. Meningococci are very sensitive to Supportive care

chilling or drying and must be inoculated and cultured Children who present in meningococcal shock need
soon after collection. Cerebrospinal fluid (CSF) examina- immediate resuscitation, restoration of circulating vol-
tion and culture are likely to provide confirmation of the ume and adequate oxygenation [2]. In those patients with
diagnosis of meningococcal meningitis in about 80–90% concomitant meningitis, cerebral oedema and raised
of cases [95]. However, blood cultures are positive in only intracranial pressure may occur. Elective ventilation, con-
one third to one half of untreated patients, even when trol of the PCO2 and improvement of cardiac output and
accompanied by a characteristic rash or positive CSF thus cerebral perfusion are important aspects of treatment
microscopy and culture [95]. Lumbar puncture is now of such patients.
(a) (b)
INFECTIONS
(c)
Fig. 38.6 Skin biopsy specimen from a patient with meningococcal septicaemia. (a, b) Gram‐stained sections reveal meningococci associated with a
leucocyte (a, electronically enlarged) and within blood vessels (b, electronically enlarged). Figures were processed with Adobe Photoshop and illustrator
software. Arrows indicate Gram‐stained meningococci. (c) Immunohistochemical staining of N. meningitidis in a skin biopsy sample from a patient with
meningococcal disease showing PorA‐stained bacteria in the interstitium and blood vessel. V, blood vessel. Arrows indicate immunoperoxidase‐positive
staining of meningococci (brown) with the appropriate specific mouse monoclonal antimeningococcal antibody (nuclei were counterstained in
haematoxylin).
Management of the skin lesions angrene is seen in a ‘glove and stocking’ distribution.

g
Although the majority of purpuric skin lesions heal well However, there is no clinical trial supporting its use and,
following the resolution of meningococcal sepsis, in ful- when used in large doses, this agent may cause further
minant disease it is important to prevent the extensive hypotension [54,59].
skin damage, limb loss and associated multiorgan failure Faced with a devastating illness, and the prospect of
that often occur despite prompt antibiotic therapy. limb loss and death in young children, many clinicians
Although there is no evidence from randomized con- have felt justified in attempting to utilize experimental
trolled trials, fresh frozen plasma (FFP) infusions are used treatments outside controlled trials. Purified inhibitors
to correct hypofibrinogenaemia and specific clotting such as antithrombin, fibronectin, protein C or variants
factor deficiency, and to reduce the risk of haemorrhage of α1‐antitrypsin have been advocated by a number of
[54,119]. Cryoprecipitate may be used in patients where authors [63,120–126], as have blockers of the initial phases
hypofibrinogenaemia persists despite multiple FFP of coagulation [127–129]. Others have suggested fibrino-
infusions. In addition, prostacyclin has been used to try lytic agents [130]. Heparin has been promoted in the past
to reverse some vasoconstriction where impending as rational therapy for disseminated intravascular
[136] and recombinant bactericidal permeability‐increasing

protein [137]. Although previous trials of steroids in sepsis
have been disappointing [138,139] and a very old study
suggested a worse prognosis in meningococcaemia [140],
more recent data have renewed interest in low‐dose steroid
therapy [141]. A phase III trial of recombinant activated
protein C was initially shown to reduce the mortality in
adult sepsis [142], although a phase III trial in childhood
sepsis did not show similar benefit [143] and the drug has
since been withdrawn from the market globally because it
failed to show any survival benefit in subsequent adult
trials [144]. On the basis of small pharmacological series
using unactivated protein C concentrate, some have advo-
cated using this form of the drug [126,145,146]. However, it
is currently not possible to predict which patients who
have been administered protein C concentrate will be able
to activate the drug [57,145]. Even when activated protein
C is detectable in the plasma, there is evidence of an acti-
vation defect in the dermal vascular endothelium and a
theoretical risk that unactivated protein C in excess may
displace activated protein C at the endothelial protein C
receptor and thus worsen dermal vessel thrombosis [57,147].
Finally, although the use of recombinant tissue plasmi-
nogen activator (tPA) to treat severe meningococcaemia
has an apparently sound theoretical basis [65,67,68,87], in
a retrospective European study of 62 children with menin-
gococcal disease treated with tPA, 8% suffered serious
intracerebral bleeding and its use cannot now be recom-
(a) mended [148]. The adverse clinical experience demon-

strated in evaluating tPA and the lack of benefit of most of
the other adjunctive therapies used to treat severe sepsis
strongly reinforce the need for new or experimental
agents to be introduced only after properly controlled
INFECTIONS
randomized clinical trials.
Surgical intervention
Small vessel thrombosis, vascular insufficiency and com-
partment syndrome can lead to peripheral ischaemia and
soft tissue necrosis, predominantly in the lower limbs [149].
In the acute phase, fasciotomy may be beneficial in
selected cases to reduce peripheral ischaemia caused by
increased pressure rather than small vessel thrombosis
[149–151] (Fig. 38.13).
(b)
As discussed more fully in Chapter 146, surgical inter-
Fig. 38.7 Early stages of meningococcal septicaemia. (a) Fine maculopapu- vention to remove necrotic skin or amputate limbs or dig-
lar rash with one early purpuric lesion on the forearm of a young infant.
its is generally not indicated during the acute phase of the
(b) Fine maculopapular rash with a few early purpuric lesions on the trunk
of a young child with septic shock.
disease but should be should be carried out once the lim-
its of tissue damage have been definitively established
[149,151]. During recovery, surgery to repair damaged
coagulation (DIC) [43,131,132]. However, the agent has skin and extremities may be required in up to 72% of
failed to produce obvious benefit in a limited number of patients [152]. These procedures range from skin grafting
open clinical trials [44,133,134] and has been associated and local debridement to microvascular flaps and ampu-
with uncontrolled bleeding. tations [152–154]. Multiple grafting procedures and scar
In recent years, understanding of the pathophysiology revision may also be required [153–156] (see Fig. 38.13).
of the coagulation and inflammatory abnormalities has The use of negative pressure wound therapy has been
led to a number of large randomized controlled trials of suggested to decrease the time from initial infection to
adjunctive agents in adult and childhood sepsis and in skin grafting, as well as reducing the invasiveness and
meningococcal disease. No survival or morbidity benefit frequency of dressing changes [149].
has been demonstrated for most of these agents, including Nutritional support and the avoidance of nosocomial
antithrombin [135], antiendotoxin monoclonal antibody wound infection are essential in the management of such
(a)
(b) (d)
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(c)
(e)
Fig. 38.8 Purpuric lesions of meningococcal sepsis. (a) Purpuric lesions on trunk and limbs. (b) Close‐up of abdominal purpuric lesions. (c) Haemorrhagic
rash with central necrosis. (d) Severe purpura fulminans. (e) Bullous formation on a large ecchymotic area.
patients [153]. A new microsurgical technique has been Outcome of skin disease
proposed to benefit outcome, but this remains to be tested A large study from The Netherlands showed the inci-
in a larger study or reported from other centres [157]. dence of long‐term skin scarring to be 48% and of ortho-
Later surgical complications may arise several years paedic sequelae 14% in children surviving meningococcal
after the original infection. Ongoing orthopaedic follow‐ sepsis. Although the severity of these sequelae varied,
up may be required to allow early recognition and thus children with more severe scarring or who had suffered
optimal management of these late sequelae such as orthopaedic sequelae were demonstrated to have had
physeal growth plate arrest with associated limb length more severe disease [159]. A group of UK children who
discrepancy, and joint malalignment [151,158]. had suffered amputation were studied from a daily living
(a)

(b)
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(d)
(e)
(c)
Fig. 38.9 Extensive cutaneous involvement in meningococcal sepsis. (a) Severe digital hypoperfusion in the early stages of meningococcal septicaemia.
(b) Digital hypoperfusion that has progressed to gangrene with demarcation 2 weeks after onset of the illness. (c) Gangrene over a proximal ecchymotic
area associated with dermal vascular thrombosis. (d) A child with septicaemic shock in the first 24 hours of the illness, showing purpura fulminans,
severe bilateral lower limb ischaemia and bilateral compartment syndromes. (e) Extensive gangrene with marked venous thrombosis of superficial and
deep vessels.
to an intense mononuclear infiltration of the basal layer

with overlying atrophy. Meningococcal antigen, anti-
meningococcal antibody and complement (C3) have been
demonstrated in the skin and synovium of these patients.
Greenwood et al. [164] suggested that these skin lesions
occur as a result of Arthus‐like immune complex deposi-
tion. Prolonged antibiotic therapy offers no benefit to
patients with this allergic phenomenon and the use of
systemic corticosteroids has not been evaluated in con-
trolled trials.
Chronic meningococcaemia
In addition to meningitis and fulminant septicaemia,
occasional cases of meningococcal infection may present
as chronic meningococcaemia, pneumonia, arthritis or
ophthalmitis [165,166]. More common in teenagers and
adults [165], chronic meningococcaemia has become a
rare entity since the widespread use of antibiotics.
Untreated, the disease was often self‐limiting with a small
mortality associated with supervening meningitis or
endocarditis. Underlying immunological disorders, other
chronic diseases or specific bacterial virulence factors
have not been confirmed in the pathogenesis of this syn-
drome [165,167]. However, some have suggested that
chronic infection may be caused by less virulent menin-
gococci producing a milder host immune response [168].
Fig. 38.10 Severe meningococcal sepsis associated with a capillary leak Chronic meningococcaemia is an insidious disease,
syndrome and multiorgan failure. This child had widespread purpuric classically presenting with a low‐grade fever lasting for
lesions, poor peripheral perfusion and marked tissue oedema and required at least 1 week, flitting arthralgias or, less commonly,
mechanical ventilation, inotropic support and peritoneal dialysis. arthritis [165]. The rash is recurrent and may be maculo-
papular, nodular or petechial. There is little systemic tox-
icity and no significant coagulopathy, and the presence of
functions and quality of life perspective for 3–5 years meningeal signs suggests that the disease has become
INFECTIONS
following their disease. Importantly, the degree of ampu- fulminant [165,166]. Histology shows a perivascular
tation did not predict the functional outcome, and most infiltration of lymphocytes, macrophages and a few neu-
children were reported to have effective compensation trophils. Vessel wall destruction has not been reported.
strategies with a generally good quality of life [160]. Meningococci are rarely detected in the cutaneous
However, others report considerable lasting effects on lesions. Multiple blood cultures are required for the diag-
health and health‐related quality of life 2 years following nosis of chronic meningococcaemia and may not be posi-
severe meningococcal sepsis [161]. tive until between 2 and 8 weeks into the illness. Chronic
meningococcaemia responds rapidly to systemic antibi-
Allergic complications otics and therefore should always be considered in the
Approximately 5 days after the presentation of acute differential diagnosis of vasculitic disorders, particularly
meningococcal disease, between 1.7% and 4.7% of patients Henoch–Schönlein purpura, acute rheumatic fever and
may develop a vasculitic rash that may be accompanied infective endocarditis [165,166].
by arthritis or episcleritis [162,163]. Typically, the rash
occurs either as a single lesion or as crops on the trunk, Prevention
lower limbs, deltoid areas and dorsum of the hand. Often Chemoprophylaxis
associated with persistence of fever, the lesions appear At present, recommendations are that household mem-
as darkened skin with a blistered edge and are slightly bers and hospital workers who have come into close con-
swollen, warm and tender. These lesions progress to tact with secretions and the index case (unless already
sterile bullae containing red cells and leucocytes which treated with ceftriaxone) should receive single‐dose cip-
ulcerate but usually heal quickly. A few patients develop rofloxacin [169] chemoprophylaxis [90,170–172]. In the
tender warm nodules similar to Osler’s nodes. UK, routine prophylaxis for day nursery contacts is not
Histologically, the dermal lesions appear oedematous recommended. It is important to recognize that eradica-
and consist of dilated small blood vessels with poly- tion of the meningococcus is not always successful and
morph and mononuclear infiltrates. Thrombosis, necrosis that recolonization of the nasopharynx may occur after
and haemorrhage may be seen in association with these initial clearance. Rifampicin can be used where ciproflox-
changes and typically organisms are neither seen nor acin is contraindicated. Chemoprophylaxis should be
cultured. The epidermal changes range from hyperkeratosis followed by vaccination where possible.
Chapter 38 Cutaneous Manifestations of Gram‐negative Infections
445
Fig. 38.11 Early management of meningococcal disease in children. Source: Reproduced with permission from the Meningitis Research Foundation. © Meningitis Research Foundation (www.meningitis.org).

INFECTIONS
However, the immunological response to these polysac-

charides does not provide complete protection for all age
groups, and does not induce immunological memory
(immunity lasts for a maximum of 3 years). Following the
outstanding successes of the H. influenzae type b vaccine
[174,175] a conjugate vaccine against the group C menin-
gococcus has been introduced successfully in the UK and
in other European countries [176–180]. Quadrivalent con-
jugate ACW135Y vaccines have been licensed for use in
the USA and Europe [181].
The development of a vaccine for group B has been
more complicated because of its poorly immunogenic
capsule and potential cross‐reactivity [12,39]. Two vac-
cines have recently been developed. 4CMenB (Bexsero,
Fig. 38.12 Differential diagnosis of meningococcal sepsis. The hand of a GSK) is a four‐component vaccine licensed for use from
child with Streptococcus pneumoniae septicaemia. Although this infancy and is part of the national immunization schedule
presentation is rare, the confluent purpuric lesions, tissue oedema and in the UK. Trumenba (Pfizer) is a protein‐based vaccine
compartment syndrome are very similar to those seen in meningococcal now licensed in the USA and Europe for use in
septicaemia.
adolescents and adults [20].
Pseudomonal skin disease

Introduction. Pseudomonas aeruginosa is a common oppor-
tunistic pathogen that is responsible for significant mor-
bidity and mortality in immunocompromised hosts,
particularly in those with underlying neoplastic disease.
It causes particular concern as it has intrinsic resistance to
many first‐line antibiotics and often develops resistance
to broad‐spectrum or second‐line antibiotics. The progno-
sis of pseudomonal sepsis in an immunocompromised

individual is particularly poor.
The reported incidence of opportunistic pseudomonal
infection is increasing. This is because of increasing levels
INFECTIONS
of immunocompromise due to more invasive and

(a) immune‐modifying treatments and procedures, with
increased survival from illnesses affecting the immune
system [182]. Localized outbreaks have been seen in hos-
pitals. Infections in healthy hosts have also increased
due to changes in lifestyle such as the use of hot tubs and
contact lenses. The increased use of broad‐spectrum anti-
biotics has also allowed for the selection of this organism
due to its high levels of intrinsic and acquired antimi-
crobial resistance. A recent survey showed a dramatic
increase in the rate of antimicrobial resistance and among
isolates of P. aeruginosa from hospitalized children in the
USA between 1999 and 2012, with multidrug resistance
(more than three classes) increasing from 15.4% to 26%
and carbapenemase resistance increasing from 9.4% to
20% over this time [183].
(b) Although P. aeruginosa is most commonly identified as
Fig. 38.13 Surgical intervention in meningococcal sepsis. (a) Fasciotomy a potential pathogen in the immunocompromised host, it
following the development of a compartment syndrome in a child with can also cause disease in previously fit and well individu-
purpura fulminans. (b) Extensive skin necrosis following meningococcal als with a normally functioning immune system.
septicaemia requiring multiple grafting procedures. P. aeruginosa can cause infections of many different
body systems although the most common site of infection
Vaccines is the lower respiratory tract. Other sites include the
Bivalent (A and C) and tetravalent (A, C, W135, Y) bloodstream, localized skin and soft tissue, ears and eyes.
polysaccharide vaccines have been shown to be both Skin manifestations of pseudomonal infection can be as
safe and effective in containing small outbreaks and more localized primary infections or as secondary manifesta-
widespread epidemics of meningococcal disease [173]. tions of pseudomonal septicaemia. Skin presentations
athogen and frequent cause of nosocomial infections. It

p
has been found as a contaminant in hospital water sys-
tems and can easily be transferred on the hands of health-
care workers [184], allowing for easy spread within the
vulnerable population of hospitals. It is an important
cause of a variety of nosocomial infections including
bloodstream infections (the third most common Gram‐
negative pathogen grown in blood cultures) [186], hospi-
tal‐acquired pneumonia, ventilator‐associated pneumonia
and surgical site infections [187]. It is a common pathogen
in burn and wound infections – the most common Gram‐
negative pathogen isolated from infected burns [188].
Pathophysiology. P. aeruginosa is an opportunistic organ-

ism that rarely penetrates the first line of host defence of
intact skin or mucosal surfaces. It therefore rarely causes
Fig. 38.14 Ecthyma gangrenosum. Source: Dr John C. Browning, Baylor disease in the immunocompetent host. Once it has been
College of Medicine and Children’s Hospital of San Antonio, Texas, USA. allowed to gain entry it has a large variety of virulence fac-
tors that allow it to adhere to host tissues, avoid the host
vary greatly, ranging from the classical and more easily innate and acquired immune defences, become invasive
recognizable lesions of ecthyma gangrenosum (Fig. 38.14) and cause disease. The interplay of these virulence factors
to more subtle or localized infections that may imitate and the host defence systems allows colonization, local
fungal or other bacterial infections, potentially leading to infection or systemic infection to result (Table 38.1).
a delay in diagnosis and treatment. Colonization of host tissues is helped by the ability to sense
a biochemically favourable environment (chemotaxis) and
Aetiology. P. aeruginosa is the main human pathogen move towards it (motility). Organisms also need to be able
of the family Pseudomonadaceae. It is a strictly aerobic to adhere to host surfaces. The main virulence factors that
Gram‐negative rod with a polar flagellum allowing P. aeruginosa uses for these processes are pili and flagella.
motility. It is nonfastidious in terms of its nutritional and Pili and flagella are complex bacterial cell surface struc-

environmental requirements for growth, can be easily tures that project away from the cell surface [188].
cultured on routine and selective media and will tolerate A key mechanism used by P. aeruginosa is the ability to
a wide range of temperatures. It is able to survive even grow in vivo primarily in biofilm rather than as single,
in distilled water hence it is often found in water‐related
INFECTIONS
environmental reservoirs [184].
Colonies of P. aeruginosa are irregular, fluoresce under Table 38.1 Pseudomonas aeruginosa – virulence factors
Wood’s light and have a characteristic metallic blue‐green [182,184,185,188,191–193]
appearance and grape‐like odour. A variety of pigments
are produced by Pseudomonas species. Pyoverdin is a Virulence factor Location Roles
green‐yellow pigment responsible for fluorescence
which is also produced by other species of Pseudomonas. Pili Cell surface Chemotaxis
Pyocyanin is only produced by P. aeruginosa and is respon- Motility
sible for the characteristic blue‐green colour of colonies Adhesion
Biofilm production
[182,184]. Other pigments include pyorubin, pyomelanin
Flagella Cell surface Chemotaxis
and trimethylamine, the last of which is responsible for Motility
the characteristic odour [182]. Biochemically, colonies Adhesion
produce a positive oxidase test and are unable to ferment Alginate Cell surface Adhesion
carbohydrates [184]. Biofilm formation
Colonization
Carriage. P. aeruginosa is not usually a commensal of Avoidance of host immune
response
healthy individuals although it can be found in the gas-
Lipopolysaccharide Cell surface Avoidance of host immune
trointestinal microbiome of a small proportion of the pop- response
ulation, particularly in hospitalized individuals [185]. It is Systemic inflammatory response
widely distributed in the environment, particularly in Type 3 secretion Cell surface Form protein bridge for injection
aqueous environments, and in humans it frequently colo- system of toxins into host cells
nizes areas of impaired host defence (e.g. burns) or the Type 3 secretion Injected into Host cell disruption and invasion
respiratory tract of ventilated individuals or those with system toxins host cell
Secreted enzymes Extracellular Avoidance of host immune
cystic fibrosis or bronchiectasis.
and toxins response
Invasion
Epidemiology. P. aeruginosa’s ability to survive and grow Pigments Extracellular Iron scavenging
is an important factor in its role as an opportunistic
free‐floating ‘planktonic’ bacteria. Bacterial biofilms are persistently moist areas of skin, allowing the survival and
associated with specific bacterial phenotype and metabo- growth of the organism. Any local disruption in the integ-
lism associated with surface aggregation and the produc- rity of the skin can allow further invasion and disease.
tion of a specific matrix. Biofilms are more tolerant to Other pathogens can also cause similar localized skin
antibiotics and can evade host immune responses. infections which can cause diagnostic uncertainty and the
Chronic infections of the skin and wounds are due to bac- risk of initial empirical treatment not including cover
teria in biofilms [189,190]. against Pseudomonas.
Intact skin and mucosal membranes are the first line of Distinguishing characteristics of pseudomonal infec-
defence against potential pathogens and are usually suf- tion include the presence of a green exudate, which fluo-
ficient to prevent infection. P. aeruginosa is not a usual resces under Wood’s light, and a characteristic fruity
commensal of dry healthy skin although it may be found grape‐like odour [182]. Localized infection usually has a
in moist areas of skin in a minority of healthy individuals. good prognosis.
Colonization of the stratum corneum is prevented by the
lack of water, continual shedding and presence of antimi- Toe web infections
crobial lipids. These local host defence strategies can be Infection of the toe webspaces can occur due to recurrent
hindered by an area of skin being exposed to a persis- recreational or occupational immersion and inadequate
tently moist or humid environment, by frequent immer- drying, prolonged occlusion with non‐breathable foot-
sion in water or by occlusion by dressings, etc., allowing a wear, high humidity or hyperhidrosis [182]. Fungal infec-
build up of sweat. The normal skin commensals have a tions are the most common cause but P. aeruginosa can
role in the prevention of colonization by potential patho- also be a cause, usually as a bacterial superinfection
gens, and any change to the normal flora such as by the where there is underlying chronic yeast infection. This
use of antiseptics or antibiotics can allow colonization by causes erythema and erosion or maceration of the local
organisms that would otherwise be present only tran- area with pustules and hyperkeratosis with local
siently, including P. aeruginosa. This often results in local- discomfort or pain [184].
ized superficial infection. Any disruption to the continuity
of the skin barrier can allow organisms to colonize the Green nail syndrome
exposed surface and invade deeper structures. This can Pseudomonal infection of the soft tissues around nails can
occur with dermatitis and excoriation, ulceration, trauma, cause a chronic paronychia and/or onycholysis. The
burns, or following medical or surgical procedures. The accumulation of pyocyanin results in a characteristic dis-
ubiquitous nature of P. aeruginosa and its ability to grow colouration of the nailfold, known as green nail syndrome
in nutritionally poor environments means that it is a fre- or chloronychia, which can help to distinguish pseu-
quent causative pathogen in wound infections, particu- domonal infection from the commoner fungal pathogens.
larly in burns or where poorly perfused or necrotic tissue Although characteristically green, it can be blue‐grey or
INFECTIONS
is present. Colonization of burned skin requires a tiny nearly black in colour and cannot be removed by wash-
inoculum of P. aeruginosa in comparison to the inoculum ing. Any underlying abnormality of the nail or nailbed
required to colonize healthy skin [194]. such as trauma or psoriatic change can predispose to
pseudomonal infection [182,184].
Antibiotic resistance Management of these conditions involves the avoid-
P. aeruginosa has inherent resistance to multiple antibiotic ance or removal of predisposing factors where possible,
classes and has the ability to quickly gain resistance to and on occasion may require topical antibiotic treatment
others. In 2013 the Centers for Disease Control (CDC) or nail removal [182].
classified multidrug‐resistant P. aeruginosa as a serious
threat with approximately 13% of severe pseudomonal Otitis externa
healthcare‐associated infections being resistant to multi- P. aeruginosa colonizes the external auditory canal of a
ple antibiotics, including aminoglycosides, cephalospor- small minority of healthy individuals but is commonly
ins, fluoroquinolones and carbapenems [195]. Biofilm present if there is a breakdown of the host defences
phenotypes specifically increase antibiotic tolerance and with pre‐existing inflammation, trauma (for example
make chronic pseudomonal infections hard to treat with following ear piercings) or persistent moisture. Infection
conventional antibiotics [196]. results in tenderness, pain on movement, swelling and
a purulent discharge [182,184]. Treatment includes
Clinical features. P. aeruginosa is associated with several removal of any debris in the external canal and topical
well‐defined skin manifestations ranging from a simple antibiotics [182].
localized skin infection to cutaneous manifestation of a Necrotizing or malignant otitis externa is a potentially
life‐threatening systemic infection. life‐threatening, invasive infection of the external ear pre-
senting with severe peri‐auricular tenderness, purulent
Primary skin infections discharge and localized lymphadenopathy. Bacterial
Primary, localized pseudomonal skin infection can occur invasion into nearby blood vessels and soft tissues can
in immunocompetent individuals who have a disruption lead to localized necrosis and can progress to mastoiditis,
in the normal skin defences against infection. This can cranial nerve abnormalities, osteomyelitis and sepsis
be due to prolonged exposure to contaminated water, or [182,184]. It is classically seen in elderly patients with
underlying diabetes mellitus but has also been described Pseudomonal sepsis can cause diffuse eruptions with a
in children with underlying immunodeficiency [197]. variety of lesions including macules, papules, vesicles,
Intravenous antibiotics and surgical debridement of petechiae or ecchymoses. Subcutaneous nodules occur
affected tissues are required [182]. rarely – these are deep fluid‐filled nodules that are often ten-
der and may spontaneously rupture, releasing fluid from
Folliculitis which the organism can be cultured [182]. Skin and soft tis-
Direct contact with water contaminated with P. aeruginosa sue infections such as cellulitis, gangrenous cellulitis and
can cause a characteristic folliculitis with discrete, large necrotizing fasciitis can be primary lesions caused by infec-
papules or pustules that are erythematous and pruritic or tion with P. aeruginosa or secondary to bacteraemia [182].
painful [182,184]. These lesions appear 8–48 hours after
immersion [198] and are distributed in areas of skin that Ecthyma gangrenosum
have been in contact with the water surface or at specific Ecthyma gangrenosum (Fig. 38.14) is the characteristic
areas of abrasion allowing inoculation of the organism, cutaneous lesion associated with, although not pathogno-
e.g. the plantar surface of the foot following abrasion on a monic for, pseudomonal sepsis. It is seen in approximately
pool floor (hot‐foot syndrome) [184]. Hot tubs and swim- 28% of those with Pseudomonas bacteraemia [191,204]. It
ming pools are frequent sources of infection hence the initially appears as an erythematous or purpuric macule
term ‘hot‐tub folliculitis’. P. aeruginosa is a frequent con- which evolves rapidly, over 12–24 hours, forming a blue‐
taminant of such water sources and is difficult to eradi- black haemorrhagic bulla or pustule that bursts, leaving
cate because it can withstand high temperatures and an ulcer with a necrotic centre, covered by a black scab,
chlorination [182]. Folliculitis often occurs in an otherwise and with a surrounding rim of erythema [182,191,202,205].
healthy host and usually self‐resolves within 7–10 days so These lesions can be found anywhere on the skin but
treatment with antibiotics is not usually indicated are particularly associated with moist areas such as the
[182,184,198]. There may be some systemic symptoms groin, axilla and perianal regions [182]. They almost
associated with infection such as fever and malaise but always result from haematogenous spread but can occa-
systemic spread does not usually occur in healthy hosts sionally occur in the absence of bacteraemia, presumably
[182]. Changes in local host defences (e.g. trauma, under- secondary to local inoculation.
lying skin disease or chronic tetracycline use) can increase There are case reports of previously healthy children
the risk of infection. Immunocompromised hosts are at presenting with pseudomonal sepsis and ecythma gan-
risk of progression to ecthyma gangrenosum, and treat- grenosum [202,206] and with ecythma gangrenosum as

ment with systemic antibiotics may be considered [184]. an isolated lesion [207], although it is normally associated
Other organisms such as Aeromonas species have rarely with significant immunodeficiency. Apparently healthy
been implicated in cases of ‘hot‐tub folliculitis’ [199,200]. children should be investigated for potential underlying
Other forms of Gram‐negative folliculitis are discussed in immunodeficiency.
INFECTIONS
the following paragraphs. The histological features of ecthyma gangrenosum
include vasculitic changes in the dermis with bacterial
Omphalitis invasion of the adventitial and medial layers but not the
Infection of the umbilical stump in the neonatal period intima or lumen, without inflammatory changes or neu-
can be caused by a number of organisms, including trophil invasion. P. aeruginosa can be cultured from the
Pseudomonas spp., and is more commonly seen in associa- lesion itself and usually also from the blood [182].
tion with poor cord care and in settings with limited Although characteristically associated with P. aerugi-
resources. It can initially present with an area of erythema nosa, ecthyma gangrenosum has been reported in associa-
and tenderness around the umbilicus and a purulent dis- tion with infection with other species of Pseudomonas
charge but may progress to pustules on the surrounding [205], other Gram‐negative bacteria such as Escherichia
skin and then necrosis of the surrounding soft tissues. The coli, Aeromonas hydrophilia, Vibrio vulnificus, Klebsiella pneu-
direct entry of bacteria into the bloodstream will result in moniae, Citrobacteri freundii, Morganella morganii and
systemic infection and sepsis. Appropriate intravenous Stenotrophomonas maltophilia [182] and occasionally Gram‐
antibiotics should be commenced at presentation and in positive bacterial, nontuberculous mycobacterial and fun-
cases of soft tissue necrosis surgical debridement will be gal infections [205].
required [182,201].
Treatment. Treatment depends on the severity of infec-
Cutaneous manifestations of systemic infection tion and antibiotic sensitivity profile of the bacteria. It is
Pseudomonas septicaemia is strongly associated with essential to culture the bacteria if at all possible in order to
immunocompromise and has a very high mortality use the correct antibiotics due to the high incidence of
[182,184]. It has also been reported to occur in apparently antibiotic resistance in Pseudomonas and other Gram‐
immunocompetent children [202] and infants [203]. negative bacteria.
Cutaneous manifestations occur in 1.3–13% of cases [182],
and a variety of manifestations occur, some of which are Burn wound infections
very typical of pseudomonal infection and some of which Partial and full thickness burns result in disruption of the
may be mistaken for other bacterial infections, potentially mechanical barrier of the skin, and depress local and sys-
delaying appropriate treatment. temic immune responses. The presence of necrotic tissue
provides an ideal environment for pathogen survival and index of suspicion is essential, particularly in those with
proliferation and the impairment of blood supply results risk factors such as underlying immunocompromise, as a
in inadequate delivery of systemic immune mediators large proportion of these infections are diagnosed and
and antimicrobial drugs. These factors result in a high treated as simple cellulitis in the early stages [217].
risk of bacterial colonization and infection of burn
wounds, with a high associated mortality and morbidity. Clinical features
Burn wounds will become colonized within a few days, Early clinical features suggestive of complicated infection
initially with Gram‐positive bacteria from the patient’s include pain and tachycardia out of proportion to the ini-
own commensal flora, and later by Gram‐negative tial appearance, with raised inflammatory markers and
organisms and fungi [208]. P. aeruginosa is one of the lead- biochemical abnormalities and other signs of systemic
ing pathogens responsible for burn wound infections, involvement such as fever and cardiovascular compro-
although other Gram‐negative organisms can also be mise. However, a lack of systemic symptoms at presenta-
responsible [208,209]. The acute management of burn tion does not exclude a necrotizing infection [211,217].
wounds should include measures to clean the wound to Local features of progressive infection include oedema
reduce the risk of secondary bacterial infection such as surrounding the involved area, subcutaneous gas, blister-
early and adequate debridement and strict infection con- ing or bullous changes, ecchymoses and then visibly
trol practices, as well as active surveillance with regular necrotic tissue. The speed of onset can be variable depend-
clinical monitoring, inspection of the wound surface, sur- ing on the organism responsible, but is often rapid [211].
face swabs or biopsy cultures. Prophylactic topical antibi-
otic dressings have been found in a recent meta‐analysis Diagnosis
to increase burn wound infections; the role of systemic The diagnosis of a necrotizing infection is based on clini-
antibiotic prophylaxis remains unclear despite many cal suspicion of severe infection, or sepsis, with or with-
local and regional burn management clinical guidelines out the specific clinical features mentioned previously
recommending antibiotics to prevent infection [210]. and/or the presence of a risk factor such as immunocom-
Distinguishing between infection and colonization can be promise. A scoring system (the Laboratory Risk Indicator
challenging as local and systemic inflammatory reactions for Necrotizing Fasciitis or LRINEC score) has been devel-
may be due to the initial burn wound, and surface micro- oped by Wong et al [218] as an early indicator of necrotiz-
biology may be positive in either case. Rapid eschar sepa- ing fasciitis based on laboratory values. Imaging studies
ration, changes in surrounding viable tissue, progression may reveal thickening and enhancement of the affected
tissue layers, fluid collections and visible free gas [211]. A
of burn depth and systemic signs of sepsis are suggestive

of infection. Adequate debridement and appropriate anti- recent study has suggested that computed tomography
biotic treatment should be commenced as soon as possi- (CT) is superior to plain radiography in the detection of
ble when infection is suspected as it can rapidly invade these changes [219].
INFECTIONS
the surrounding and deeper tissues and progress to sepsis Positive microbiology samples will help to confirm the
and multiorgan failure [208]. diagnosis and guide antimicrobial treatment but only
76.5% of wound and 35.2% of blood cultures were posi-
Gram‐negative soft tissue infections tive in a recent review [217]. A wide variety of organisms
can be implicated, with Gram‐positive cocci found in the
Necrotizing skin and soft tissue infections majority of monomicrobial infections. However, many
Necrotizing infections can involve the more superficial cases are polymicrobial and a number of Gram‐negative
skin layers, resulting in gangrenous cellulitis, or the organisms such as E. coli, Acinetobacter spp., P. aeruginosa
deeper layers resulting in necrotizing fasciitis [211]. These and Klebsiella spp. are among those that have been cul-
aggressive infections may start insidiously but then pro- tured [211,217,220].
gress rapidly resulting in necrosis and destruction of the Macroscopic features of necrosis will be seen at the time
affected layers of skin with severe systemic effects includ- of surgical debridement with tissue appearing grey and
ing multiorgan failure and high rates of mortality of up to noncontractile and being easily dissectible with minimal
40% [211–213]. The majority of cases occur in those with resistance and a lack of bleeding. Vessel thrombosis will
significant underlying immunocompromise [184,214]. be evident on histological examination [211].
Varicella infection can be a predisposing factor in children
[215], particularly in association with the use of nonsteroi- Treatment
dal anti‐inflammatory drugs [216]. The prognosis of necrotizing soft tissue infections depends
Uncomplicated skin and soft tissue infections caused upon early recognition of disease and immediate and effec-
by Gram‐positive organisms are common and frequently tive treatment. Good supportive care with adequate fluid
managed in an outpatient setting. Complicated, or resuscitation is vital. Empirical antimicrobial treatment
necrotizing skin and soft tissue infections are much rarer, should be commenced immediately with broad‐spectrum
can be caused by a wider range of organisms including antibiotics covering Gram‐positive, Gram‐negative and
many Gram‐negative organisms and require prompt and anaerobic bacteria according to local antimicrobial
aggressive medical and surgical management. The initial guidelines.
clinical presentation can be similar, with localized skin Surgical debridement of affected tissue should be car-
swelling, erythema and pain. This means that a high ried out as soon as possible, and should be complete with
a wide margin of normal healthy tissue. A delay of 6 Herrick W. Extrameningeal meningococcal infections. Arch Intern
Med 1919;23:409–18.
debridement beyond 12 hours of presentation has been
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Gram‐negative folliculitis meningococcal disease during the Hajj, 2000. Emerg Infect Dis

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456
CHA PTER 3 9
Pitted Keratolysis, Erythrasma and Erysipeloid

Zhe Xu, Yuanyuan Xiao, Ying Liu & Lin Ma
Department of Dermatology, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health, Beijing, China
Pitted keratolysis, 456 Erythrasma, 458 Erysipeloid, 460
Abstract the groin, axilla, gluteal crease or inframammary regions, and inter-
digital spaces of the feet. Erythrasma is frequently confused with
dermatophyte infections (i.e. tinea corporis), with which it may
Pitted keratolysis (PK) is a superficial bacterial infection that
occasionally coexist. However, it can be differentiated from tinea
affects the plantar stratum corneum and is caused most frequently
infection by the characteristic ‘coral‐red’ fluorescence under Wood’s
by Corynebacterium spp., Kytococcus sedentarius, Dermatophilus
lamp illumination. Erythrasma can be treated with topical antibiot-
congolensis, Actinomyces keratolytica and Streptomyces spp. PK is
ics, including erythromycin or clindamycin. Recalcitrant cases can
not limited to barefooted populations in tropical areas but has a
be treated with oral antibiotics such as tetracyclines or macrolides.
worldwide distribution. The infection is characterized by circular,
Erysipeloid is an acute skin infection caused by Erysipelothrix
shallow erosions and pits. Areas of greater pressure, friction and
rhusiopathiae, mostly subsequent to cutaneous trauma. It is
hyperhidrosis are more commonly affected. Topical antibiotics such
characterized clinically by an erythematous oedema, with well‐
as erythromycin and clindamycin are the first‐line treatment while
defined and raised borders, usually localized to the back of one
elimination of predisposing factors such as hyperhidrosis and pro-
hand and/or fingers. Vesicular, bullous and erosive lesions may
longed contact with water is also helpful.
also be present. In addition to cutaneous infection, E. rhusiopathiae
Erythrasma is a superficial bacterial infection of the skin caused
can cause endocarditis. The diagnosis of localized erysipeloid is
by Corynebacterium minutissimum. It is characterized by asymp-
based on the patient’s history and clinical features.
tomatic, well‐demarcated, reddish brown, slightly scaly patches in
Key points
• It can be differentiated from tinea infection by the characteristic

‘coral‐red’ fluorescence seen when viewed under Wood’s lamp
illumination.
Pitted keratolysis:
• Erythrasma may be treated with topical antibiotics. Oral
• Pitted keratolysis is a superficial bacterial infection that affects
antibiotic therapy is also very effective.
INFECTIONS
the plantar epidermis.

• The clinical diagnosis of pitted keratolysis can be made by the
crateriform pitting primarily affecting the pressure‐bearing Erysipeloid:
areas of the soles and the malodour. • Erysipeloid is an occupational, acute skin infection caused by
• Symptoms include hyperhidrosis, maceration and fetidness. Erysipelothrix rhusiopathiae.
• Multiple organisms have been isolated from these lesions. • It occurs primarily in individuals who handle animals and animal
• Therapy is simple and efficacious. Topical antibiotics such as products, especially fish, shellfish, meat and poultry.
erythromycin and clindamycin are safe and systemic treatment • It is characterized clinically by an erythematous oedema, with
with erythromycin has been successful. well‐defined and raised borders, usually localized to the back of
• Reducing hyperhidrosis also plays an important role in disease one hand and/or fingers.
management. • Diagnosis of localized erysipeloid is based on the patient’s
history (occupation, previous traumatic contact with infected
animals or animal products) and clinical features (typical skin
Erythrasma:
lesions, lack of severe systemic features and rapid remission
• Erythrasma is a superficial bacterial infection of the skin caused
after treatment with penicillin or cephalosporin).
by Corynebacterium minutissimum.
• It is characterized by asymptomatic, well‐demarcated, reddish
brown, slightly scaly patches in moist, occluded, intertriginous areas.
Pitted keratolysis bacterial infection of the plantar stratum corneum [1], often
diagnosed in barefooted individuals in tropical climates.
Brief introduction/history. Pitted keratolysis (PK), first Castellani [2] first reported this condition from Sri Lanka in
described as keratolysis plantare sulcatum (also known as 1920 and termed it ‘keratoma plantare sulcatum’. Although
keratolysis sulcata, ringed keratolysis and keratolysis plan initially thought to be a condition found only in tropical
tare sulcatum), is a descriptive title for a common s uperficial climates, it has also been described in temperate zones. The
Chapter 39 Pitted Keratolysis, Erythrasma and Erysipeloid 457
term ‘pitted keratolysis’ was coined by Zaias et al. [3] in seen more commonly in tropical areas. On the palms, the
1965 and is universally accepted. lesions may present as scaly collarettes instead of pits
[9,12]. In addition to bacterial infection, sweat retention
Epidemiology and pathogenesis. PK is a condition that and water immersion are important cofactors for the
occurs worldwide and can be seen in both temperate and development of PK. Patients may experience hyperhidro
tropical environments [4]. Prevalence rates of the disease sis, foot odour, maceration and sometimes itching or
range from 1.5% for Korean industrial workers to burning while walking, although most cases are asympto
42.5% for paddy field workers in South India [5,6]. PK matic. Painful lesions have been described with erythe
is common in physically active individuals because matous to violaceous tender plaques in children [9,13].
pathological microbes thrive in their warm, sweaty shoes. The exact reason for the pain in some patients is not
Hyperhidrosis of the feet brings a softening of stratum known. In one review of 53 patients with PK, hyperhidro
corneum, thus facilitating invasion by the corynebacte sis was present in 51 patients (96.2%) and malodour in
rium. The aetiology of PK is attributed to a Gram‐positive 47 patients (88.7%) [14]. A mixture of thiols, sulphides and
bacterial infection. It is characterized by superficial thio‐esters has been shown to be the cause of the unpleas
erosions and crater‐like pits measuring 1–3 mm in diameter ant odour [14]. Yellowish‐brown discolouration of
which are located primarily along the sole. The causative involved skin has also been reported [15].
agents are Gram‐positive bacteria, e.g. Corynebacterium
spp., Kytococcus sedentarius, Dermatophilus congolensis and Histology and microbiology. Histological examination of
Streptomyces spp. [7–9]. These microorganisms produce the lesion would show multiple superficial erosions
proteases that enable them to digest the keratin and confined to the upper layers of the stratum corneum. These
dissolve the stratum corneum, thereby producing the shallow, crater‐like defects have sharply inclined walls and
characteristic pits or craters [10]. Predisposing factors a flat base consisting of a thin layer of stratum corneum. The
include hyperhidrosis, prolonged use of occlusive foot pathogenic microorganisms penetrate the hydrated stratum
wear, increase in skin pH, humid climate, poor foot corneum. They are rarely seen with potassium hydroxide
hygiene, obesity and immunodeficiency. preparation but are more easily demonstrated on Gram‐
stained scrapings or thin tissue sections [15]. As PK is an
Clinical features. PK occurs in both sexes and in most age acquired, superficial bacterial infection of the skin, multiple
groups. The physical examination mostly reveals multi organisms have been isolated from these lesions, including
ple circular, discrete and coalescing superficial erosions various species of Streptomyces and Corynebacterium,

on the soles and undersurface of the toes (Fig. 39.1). In Dermatophilus congolensis, Micrococcus sedentarius and
addition to the circular pits, some patients manifest small K. sedentarius [16–19]. Specific proteases of K. sedentarius
stratum corneum defects along the lateral plantar surface. account for the degradation of corneal callus in PK [20].
The lesions primarily affect the weightbearing aspects of
INFECTIONS
the feet, such as the toes, balls of the feet and the heels. Diagnosis. The diagnosis can be made clinically [21]. PK
The skin‐coloured, punched‐out, shallow depressions is characterized by typical malodour and pits in the
measure 1–3 mm in diameter. However, involvement of hyperkeratotic areas of the soles. It is more common in
non‐weightbearing areas has been described. The areas barefooted individuals in tropical areas, or those who
involved were the instep of the foot and dorsal aspect of have to wear occlusive shoes, such as soldiers, sailors
the toes [11]. Palmar involvement rarely occurs and is and athletes. PK is frequently accompanied by plantar
(a) (b)
Fig. 39.1 (a) Pitted keratolysis presenting as multiple crater‐like shallow plantar pits and a macerated area. (b) Dotted blue fluorescence in the sole area on
Wood’s light examination. Source: Courtesy of Dr Hongwei Wang from Huadong Hospital affiliated to Fudan University.
yperhidrosis. The weightbearing metatarsal parts of the

h 3 Zaias N, Taplin D, Rebell G. Pitted keratolysis. Arch Dermatol
1965;92:151–4.
feet are mostly affected. Histological examination of the
4 Eetam I, Aytimur D, Yuksel SE. Isolation of Kytococcus sedentarius
lesion shows multiple superficial erosions confined to the from a case of pitted keratolysis. Ege Tip Dergisi 2005;44:117.
upper layers of the stratum corneum. The pathogenic 5 Eun HC, Park HB, Chun YH. Occupational pitted keratolysis. Contact
microorganisms can be cultured on an appropriate Dermatitis 1985;12:122.
6 Shenoi SD, Davis SV, Rao S et al. Dermatoses among paddy field work
medium if specific identification is desired. ers–a descriptive, cross‐sectional pilot study. Indian J Dermatol
Venereol Leprol 2005;71:254–8.
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manifestations in 53 cases. Br J Dermatol 1997;137:282–5.
include tinea pedis, verrucae, punctate palmoplantar ker
8 Tamura B, Cuce LC, Souza RL et al. Plantar hyperhidrosis and pitted
atoderma type 1 and basal cell naevus syndrome [22]. A keratolysis treated with botulinum toxin injection. Dermatol Surg
potassium hydroxide stain and Wood’s light examination 2004;30:1510–14.
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facultative bacteria. Clin Infect Dis 1999;29:713–23.
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taneously [23]. Dermoscopy usually reveals abundant infective cause of foot odor. CMAJ 2015;187:519.
pits with well‐marked verrucae. Punctate palmoplantar 11 Takama H, Tamada Y, Yokochi K et al. Pitted keratolysis: a discussion
keratoderma type 1 (PPKP1, OMIM #148600) is a rare of two cases in non‐weight‐bearing areas. Acta Dermatol Venereol
1998;78:225–6.
form of palmoplantar keratoderma that is autosomal 12 Zaias N. Pitted and ringed keratolysis: a review and update. J Am
dominantly inherited [24]. PPKP1 is clinically character Acad Dermatol 1982;7:787–91.
ized by multiple punctate hyperkeratotic papules affect 13 Lamberg SI. Symptomatic pitted keratolysis. Arch Dermatol
1969;100:10–11.
ing the palmar and plantar skin. The lesions typically 14 Nordstrom KM, McGinley KS, Cappiello L et al. Pitted keratolysis: the
start to appear in early adolescence but sometimes role of Micrococcus sedentarius. Arch Dermatol 1987;123:1320–5.
develop later in life. Pitting associated with the basal cell 15 Sehgal VN, Ramesh V. Crateriform depression – an unusual clinical
naevus syndrome, which is an autosomal dominant syn expression of pitted keratolysis. Dermatologica 1983;166:209–11.
16 Gill KA, Buckels LJ. Pitted keratolysis. Arch Dermatol 1968;98:7–11.
drome that causes pitting of the palms and soles, multiple 17 Gillum RL, Qadri SM, Al‐Ahdal MN et al. Pitted keratolysis: a mani
basal cell carcinomas, jaw cysts and skeletal abnormali festation of human dermatophilosis. Dermatologica 1988;177:305–8.
ties, can be distinguished by the specific clinical features 18 Woodgyer AJ, Baxter M, Rush‐Munro FM et al. Isolation of
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seen in this syndrome [25].
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19 Ertam I, Aytimur D, Yuksel SE. Isolation of Kytococcus sedentarius
Treatment and prevention. Therapy for PK is simple and from a case of pitted keratolysis. Ege Tip Dergisi 2005;44:117–18.
efficacious. Treatment generally consists of a combination 20 Longshaw CM, Wright JD, Farrell AM et al. Kytococcus sedentarius,
the organism associated with pitted keratolysis, produces two kera
of hygienic measures and antimicrobials. In the past, vari tin‐degrading enzymes. J Appl Microb 2002;93:810–16.
ous treatments (20% aluminium chloride, formalin oint 21 Martin AG, Kobayashi GS. Bacterial diseases with cutaneous involve
ment, various topical antibiotics and imidazoles) were ment. In: Freedberg IM, Eisen AZ, Wolff K et al. (eds) Dermatology in
INFECTIONS
General Medicine, 5th edn. New York: McGraw Hill, 1999:2203–4.

used with some success. A variety of studies used a com
22 Pranteda G, Carlesimo M, Pranteda G et al. Pitted keratolysis,
bined approach in the treatment of the disease, consisting erythromycin, and hyperhidrosis. Dermatol Ther 2014;27:101–4.
of the management of provoking factors (such as hyperhi 23 Schlappner OL, Rosenblum GA, Rowden G. Concomitant erythrasma
drosis) and the management of the bacterial infection and dermatophytosis of the groin. Br J Dermatol 1979;100:147–51.
24 Pohler E, Mamai O, Hirst J et al. Haploinsufficiency for AAGAB
[26]. Topical antibiotics such as sodium fusidate, clinda causes clinically heterozygous forms of palmoplantar keratoderma.
mycin and erythromycin are the first line of medical treat Nat Genet 2012;44:1272–6.
ment. Imidazole antifungal agents are also effective 25 Cohen PR. Axillary basal cell carcinoma in patients with Goltz‐Gorlin
because they have antibacterial activity. Mupirocin oint syndrome: report of basal cell carcinoma in both axilla of a woman
with basal cell nevus syndrome and literature review. Dermatol
ment has been found to be effective when conventional Online J 2014;17:20(8).
therapy has failed [27], but its use should be restricted to 26 Garcia GR, Nunez PY, Arrese EJ. Queratolisis punctata emergente en
elimination of meticillin‐resistant Staphylococcus aureus los Andes Cusco‐Peru. Med Cutan Iber Lat Am 2006;34:223.
27 Vazquez‐Lopez F, Perez‐Oliva N. Mupirocine ointment for sympto
(MRSA). Systemic treatment with erythromycin is likely matic pitted keratolysis. Infection 1996;24:55.
to be effective, but it is only rarely required [28]. 28 Eetam I, Aytimur D, Yuksel SE. Isolation of Kytococcus sedentarius
Decreasing sweat production by topical aluminium from a case of pitted keratolysis. Ege Tip Dergisi 2005;44:117.
hydroxide should be considered, and even botulinum
toxin has been used in two patients with refractory PK
due to prominent hyperhidrosis. Tamura et al. [8] per Erythrasma
formed subcutaneous injection of low‐dose botulinum
toxin into multiple sites in the plantar region to induce Brief introduction/history. Erythrasma is a superficial
anhidrosis; however, this therapy should only be consid bacterial infection of the skin caused by Corynebacterium
ered when traditional therapies have proved ineffective. minutissimum. The skin lesions show a characteristic
‘coral‐red’ fluorescence when viewed under Wood’s light.
Before 1960, the aetiological agent of erythrasma was
References presumed to be a fungal organism. Lagana [1] first iso
1 Naik CL, Singh G. Clinicoepidemiological study of pitted keratolysis. lated a diphtheroid bacterium from an erythrasma lesion.
Indian J Dermatol 2007;52:35.
2 Castellani A. Keratoma plantare sulcatum. J Ceylon Br Med Assoc In 1961, Sarkany et al. [2] confirmed that C. minutissimum
1920;1:12–14. was the cause of erythrasma.
Epidemiology and pathogenesis. C. minutissimum, the

aetiological agent of erythrasma, is a short, Gram‐positive
rod with subterminal granules which often colonizes the
nose, pharynx, bulbar conjunctiva, ear canal and skin sur
face. Erythrasma begins as a proliferation of C. minutissi-
mum within the stratum corneum. Organisms can be
found both extracellularly and intracellularly. Whether
the associated scaling precedes and allows the infection to
occur or is the result of heavy colonization of the stratum
corneum is still a matter of debate.
Predisposing factors include warm, humid climate,
poor hygiene, hyperhidrosis, obesity, diabetes mellitus,
advanced age and compromised host status. The infec
tion is more common in tropical than in temperate cli
mates. A disciform variant exists which occurs outside the
classically involved intertriginous areas. This generalized
Fig. 39.2 Erythrasma. Well‐demarcated brownish scaly plaque in bilateral
form is most commonly seen in diabetics. It can be the intracrural areas of the groin of an adolescent boy. Source: Courtesy of Dr
presentation of type 2 diabetes mellitus and can also be Hongwei Wang from Huadong Hospital affiliated to Fudan University.
secondary to tinea pedis [3].
Clinical features. Erythrasma occurs in all age groups and

in both sexes. It is much more common in adults than in
children [4] with around 15% of cases occurring in
children between 5 and 14 years of age. The incidence is
notably higher among institutionalized children and
children in boarding schools as well as people living a
communal lifestyle [5].
Erythrasma occurs most commonly in moist, occluded
intertriginous areas that favour the growth of C. minutis-

simum. The common locations for erythrasma are the
axilla, groin, toe webs, intergluteal and crural folds and
inframammary areas. Occasionally, it occurs on mucous
INFECTIONS
membrane such as on the labia [6]. However, disciform
erythrasma, a more generalized form, occurs in noninter
triginous areas as well as intertriginous areas and is more
commonly seen in the tropics [7]. Although most lesions Fig. 39.3 Coral fluorescence in areas of plaque on Wood’s light examina-
are asymptomatic, mild pruritus may be present. In tion. Source: Courtesy of Dr Hongwei Wang from Huadong Hospital
patients with pruritus, irritation of lesions by scratching affiliated to Fudan University.
may cause secondary changes of excoriations and
lichenification. ifferentiating these entities. However, both erythrasma
d
The characteristic skin lesions are well‐demarcated, and tinea infection may be present simultaneously [10].
irregular, reddish‐brown scaly patches in the genitocru Tinea versicolor may resemble erythrasma but does not
ral, axillary and inframammary regions (Fig. 39.2). tend to localize to body folds. Similarly, erythrasma and
However, in the toe webs, erythrasma frequently presents tinea versicolor may coexist and become difficult to diag
as asymptomatic, chronic maceration with fissuring or nose [4].The disciform type may be confused with lichen
scaling of interspaces or blisters [8]. Lesions of disciform sclerosis et atrophicus and plaque‐type parapsoriasis [7].
erythrasma may have a shiny, atrophic‐appearing surface It also can be in the differential diagnosis of vulvar
and may resemble lesions of parapsoriasis en plaque or mucosal rashes [6].
lichen sclerosis et atrophicus [9]. Mild, subclinical cases
are not uncommon and are diagnosed only by the typical Histology findings. The finding of bright coral‐red fluores
fluorescence on Wood’s light examination (Fig. 39.3). cence under Wood’s light examination (the result of porphy
rin production by the bacteria) is the best way to make the
Differential diagnosis. Erythrasma must be distinguished diagnosis. Gentle scraping of the lesions may yield scale that
from tinea cruris, intertrigo and seborrhoeic dermatitis can be stained with methylene blue or Gram stain. Coccoid
when it occurs in the genitocrural regions and from tinea and rod‐like organisms with long filaments will be seen
pedis or other bacterial infections when it occurs in the under the oil immersion lens. Corynebacterium organisms
interdigital areas. The main differentiating symptom of exhibiting coral‐red fluorescence can be cultured on tissue
erythrasma is its lack of pruritus. A potassium hydroxide culture medium, but culture is not routinely performed in
stain and Wood’s light examination are valuable in clinic. Skin biopsy is rarely indicated but may be p
erformed
when the lesions are atypical in morphology and distribu Erysipeloid

tion, as may be seen with disciform erythrasma.
On histological examination, corynebacteria are seen in Brief introduction. Erysipeloid, named in the past as
the horny layer in small numbers as Gram‐positive rods Rosenbach disease, Baker–Rosenbach disease, pseudoery
and filaments. Electron microscopic examination of thin‐ sipelas, erythema serpens, erythema migrans, erysipelas
sectioned skin from patients with erythrasma has also chronicum, swine erysipelas, diamond skin disease and
demonstrated ‘diphtheroids’ in the horny layer [2]. crab cellulitis [1–5], has been recognized since the late
1800s. It was initially described by Tilbury Fox, who
Treatment and prevention. Erythrasma responds quickly named the c ondition erythema serpens in 1873. In 1876
to treatment with a variety of topical preparations and to Robert Koch first isolated a strain of Erysipelothrix from a
topical and systemic antibiotics. The subclinical form mouse inoculated with putrefying blood and termed the
may remain asymptomatic for years or undergo periodic organism E. muriseptica. In 1884 Anton Rosenbach discov
exacerbations. Relapses may occur even after successful ered an organism similar to Koch’s in a patient with local
treatment. ized cutaneous lesions and named the condition
Multiple options are available for treating erythrasma, erysipeloid. In 1909 E. rhusiopathiae was isolated from
including oral and topical therapies [11]. The most effec cutaneous lesions of erysipeloid [6].
tive treatment is erythromycin (250 mg, four times daily
for 14 days) with cure rates (both clinical and bacte
Epidemiology and pathogenesis. Erysipeloid is most
riological) as high as 100% [12]. A single 1 g dose of
commonly seen in fishermen and meat handlers but can
clarithromycin has been reported to be effective as well
occur in anyone coming into contact with the appropriate
[13]. In patients with interdigital involvement or hidden
infectious agents. The incidence of this disease was about
reservoirs, some form of local therapy is recommended,
0.3% in the past [7], but only occasional sporadic cases are
such as clindamycin applied once daily during the course
reported now because of technological advances in ani
of oral therapy and continued for 2 weeks after the phys
mal‐handling industries. It is uncommon in the paediatric
ical clearance of these areas [12].
population.
Antibacterial soaps can be used initially, and prophy
E. rhusiopathiae is a rod‐shaped, Gram‐positive, faculta
lactically once the infection has cleared. Topical treat
tive aerobic, nonmotile, nonsporulating bacterium. It is
ments with 10–20% aluminium chloride, 2% clindamycin
found worldwide in soil, contaminated water from infected
HCl solution, erythromycin, miconazole cream or
animals and food products. It can survive in soil for several
Whitfield ointment have all been shown to be effective. It

weeks. In pig faeces, the survival period of this bacterium
was reported that photodynamic treatment can be used to
ranges from 1 to 5 months. E. rhusiopathiae produces neu
treat erythrasma in adults [14].
raminidase and hyaluronidase, the latter contributing to its
INFECTIONS
capacity for dissemination within infected tissue.

References
Erysipeloid is transmitted by several animals, particularly
1 Lagana L. Contribution to the study of the pathogenic agent of swine (up to half of healthy pigs), fish, crab and shellfish.
erythrasma and its therapy (in Greek). Acta Microbiol Hellen E. rhusiopathiae (previously named E. insidiosa) has been
1960;5:69–75. found in several dozen species of mammals and other ani
2 Sarkany I, Taplin D, Blank H. Erythrasma—common bacterial infec
tion of the skin. JAMA 1961;177:130–2. mals, such as sheep, rabbits, chickens, turkeys, ducks, emus,
3 Inci M, Serarslan G, Ozer B et al. The prevalence of interdigital eryth pigeons, cows, guinea pigs, cats, dogs [8] and kakapo [9].
rasma in southern region of Turkey. J Eur Acad Dermatol Venereol The bacterium penetrates the skin through tiny breaks.
2012;26:1372–6.
4 Karakatsanis G, Vakirlis E, Kastoridou C et al. Coexistence of pity-
The incubation period is 2–7 days. At present, strains of
riasis versicolor and erythrasma. Mycoses 2004;47:343–5. Erysipelothrix are classified as serotypes 1–26 with sero
5 Somerville DA, Seville RH, Cunningham RC et al. Erythrasma in a types 2, 7 and 16 being the most commonly involved in
hospital for the mentally subnormal. Br J Dermatol 1970;82:355–60. the pathogenesis of human erysipeloid [10].
6 Wilson BB, Wagenseller A, Noland MM. An atypical presentation
of erythrasma. J Am Acad Dermatol 2012;67:e217–18.
7 Gorani A, Oriani A, Falconi Klein E et al. Erythrasmoid pityriasis
Clinical features. Three forms of human disease have
versicolor. Mycoses 2001;44:516–17.
8 Sariguzel FM, Koc AN, Yagmur G et al. Interdigital foot infections: been described.
Corynebacterium minutissimum and agents of superficial mycoses. The first is the localized cutaneous form (‘true’ erysip
Braz J Microbiol 2014;45:781–4. eloid). It initially begins on the dorsal hands or fingers as
9 Tchen JA, Ramsdell WM. Disciform erythrasma. Cutis 1983;31:541–7.
10 Morales‐Trujillo ML, Arenas R, Arroyo S. Interdigital erythrasma:
an inflammatory plaque with well‐defined raised borders
clinical, epidemiologic, and microbiologic findings. Actas (Fig. 39.4). However, lesions can occur elsewhere and have
Dermosifiliogr 2008;99:469–73. been reported on the palms, forearms, arms, face and legs
11 Chodkiewicz HM, Cohen PR. Erythrasma: successful treatment after [11–13]. The colour is characteristically bright red to pur
single‐dose clarithromycin. Int J Dermatol 2013;52:516–18.
12 Holdiness MR. Erythrasma and common bacterial skin infections. ple and lesions may assume a ‘diamond’ shape. Vesicular,
Am Fam Physician 2003;67:254. bullous and erosive lesions have also been described [14].
13 Wharton JR, Wilson PL, Kincannon JM. Erythrasma treated with sin The entire lesion tends to spread centrifugally. Swelling of
gle‐dose clarithromycin. Arch Dermatol 1998;134:671–2.
14 Darras‐Vercambre S, Carpentier O, Vincent P et al. Photodynamic
the fingers is often substantial, leading to the common
action of red light for treatment of erythrasma: preliminary results. terms ‘whale finger’ and ‘seal finger’. The lesion may be
Photodermatol Photoimmunol Photomed 2006;22:153–6. slightly pruritic or painful. Fever, arthralgia, lymphadenitis
(a) (b)
Fig. 39.4 (a and b) Erysipeloid characterized by marked erythematous oedema on the right hand of a woman. Source: Courtesy of Dr Hongwei Wang from
Huadong Hospital affiliated to Fudan University.
and lymphangitis may occur [15]. Erysipeloid is often self‐ Polymerase chain reaction (PCR) assays have recently
limited and resolves spontaneously. been described for the diagnosis of human erysipeloid.
The diffuse cutaneous or generalized form is much Their specificity and sensitivity seem to be high, although
rarer than the cutaneous form. It is characterized clini only a few cases of human erysipeloid infection have
cally by multiple lesions with central clearing of the skin. been tested to date [17].
The presence of systemic symptoms is characteristic,
including fever, lymphadenitis, arthralgia and myalgia.
Diagnosis. The diagnosis of erysipeloid is based on: (i)
This form of the disease is also self‐limited, but the clinical
the patient’s occupation; (ii) previous traumatic contact

course is longer and recurrences more common.
with infected animals or their products; (iii) typical
The most serious manifestation of erysipeloid is the
skin lesions (erythematous oedema with well‐defined
systemic or ‘septic’ form. Cutaneous lesions may be
and raised b orders, or vesicular–bullous–erosive
found consisting of red papules, some of which exhibit
INFECTIONS
lesions on an erythematous base, usually localized to
necrosis and ulceration. Systemic clinical manifestations
the back of one hand and/or fingers); (iv) lack of severe
may include septic arthritis, osseous necrosis, cerebral
systemic features; (v) slight laboratory abnormalities;
infarction or abscess, pulmonary effusion, encephalitis,
and (vi) rapid remission after treatment with penicillin
meningitis, renal failure, peritonitis and bacterial endo
or cephalosporin.
carditis which may be acute or subacute [16]. Morbidity
and mortality (38%) are greatly increased in those who
manifest endocarditis. Differential diagnosis. The clinical differential diagnosis
includes erysipelas, cellulitis and acute irritant/allergic
Laboratory findings. Serological investigations may reveal contact dermatitis. Erysipelas is characterized clinically
leucocytosis, slightly increased serum gammaglobulins by the acute appearance of erythematous and oedema
and an increase in inflammatory markers (erythrocyte tous lesions, usually localized on the face or legs, often
sedimentation rate, C‐reactive protein and α‐1 acid glyco accompanied by pain, fever and general malaise.
protein). Anti‐E. rhusiopathiae antibodies can also be Cellulitis is more common on the face and trunk with
detected by agar gel precipitation test [10]. Histopathological painful diffuse swelling on the skin accompanied by
findings are nonspecific. Varying degrees of spongiosis severe systemic symptoms such as high fever, chills and
and intraepidermal vesiculation have been shown in the rigors and generalized malaise. Bacterial culture with
upper and mid dermis; a polymorphous infiltrate of Gram staining can help identify the pathogen and con
neutrophils, lymphocytes, eosinophils and plasma cells is firm the clinical diagnosis. Irritant and allergic contact
seen in the dermis. Gram staining of tissue sections usually dermatitis often occur on both hands as erythematous,
does not demonstrate the organism, possibly because the vesicular and pruritic lesions. The clinical course is often
organism is believed to reside in the reticular dermis and chronic and recurrent.
may be missed if skin biopsy is performed superficially. In addition to these conditions, atypical cutaneous
Another possibility is that the bacteria have lost their cell leishmaniasis should be considered by clinicians in the
walls, reverting to ‘L’ forms. differential diagnosis because histopathology and culture
Isolation of E. rhusiopathiae is very often difficult. may be negative. However a smear from the lesion show
E. rhusiopathiae grows slowly in media enriched with blood ing a number of amastigotes in the intracellular and extra
and incubated in an atmosphere containing 5–10% CO2. cellular area can identify the disease [18].
4 Varella TC, Nico MM. Erysipeloid. Int J Dermatol 2005;44:497–8.

Treatment and prevention. E. rhusiopathiae is sensitive to 5 Veraldi S, Girgenti V, Dassoni F et al. Erysipeloid: a review. Clin
a number of common a ntibiotics, including penicillins, Exp Dermatol 2009;34:859–62.
6 Shin SJ, Gwak WG. Erysipelothrix rhusiopathiae peritonitis in
cephalosporins (cefotaxime, ceftriaxone), tetracyclines
a patient undergoing continuous ambulatory peritoneal dialysis.
(chlortetracycline, oxytetracycline), quinolones (cipro J Korean Med Sci 2010;25:1234–6.
floxacin, pefloxacin), clindamycin, erythromycin, linco 7 Parsons DW. Treatment of the septic hand. Proc R Soc Med
mycin, imipenem and piperacillin. It is resistant to 1962;55:445–7.
8 Brooke CJ, Riley TV. Erysipelothrix rhusiopathiae: bacteriology,
vancomycin, chloramphenicol, daptomycin, gentamicin, epidemiology and clinical manifestations of an occupational
netilmicin, polymyxin B, streptomycin, teicoplanin and pathogen. J Med Microbiol 1999;48:789–99.
trimethoprim–sulfamethoxazole [19]. 9 Werner K, Gartrell B, Norton SA. Erysipeloid (Erysipelothrix rhusi
Although the cutaneous forms of the disease are self‐lim opathiae infection) acquired from a dead kakapo. Arch Dermatol
2011;147:1456–8.
ited in many instances, all patients should receive antibiot 10 Molin G, Söderlind O, Ursing J et al. Occurrence of Erysipelothrix
ics to prevent progression to systemic disease and rhusiopathiae on pork and in pig slurry, and the distribution of spe
endocarditis. Penicillins and cephalosporins are the first cific antibodies in abattoir workers. J Appl Bacteriol 1989;67:347–52.
11 Veraldi S, Rizzitelli G, Schianchi‐Veraldi R. Occupational cutaneous
line of treatment. A 7‐day course is appropriate, and clinical infections. Clin Dermatol 1992;10:225–30.
improvement is usually observed 2–3 days after the begin 12 Razsi L, Sanchez MR. Progressively enlarging painful annular plaque
ning of the treatment. Incision and drainage of skin lesions on the hand. Arch Dermatol 1994;130:1314–15.
is contraindicated because surgery has been noted to pro 13 Hamilton JF. Recurrent erysipeloid cellulitis of the lower extremities;
with case reports. South Med J 1954;47:778–83.
long the duration of the erysipeloid lesions [20]. Direct skin 14 Connor MP, Green AD. Erysipeloid infection in a sheep farmer with
contact with pork and fish and other aquatic products coexisting orf. J Infect 1995;30:161–3.
should be avoided to prevent accidental p uncture of the 15 Nelson E. 500 cases of erysipeloid. Rocky Mt Med J 1955;52:40–2.
16 Simerkoff MS, Rahal JJ Jr. Acute and subacute endocarditis due to
skin. Improved hygiene during meat processing and aqua
Erysipelothrix rhusiopathiae. Am J Med Sci 1973;266:53–7.
culture is also helpful to decrease erysipeloid prevalence. 17 Brooke CJ, McLaughlin V, Mee BJ, Riley TV: An investigation of ‘cray
fish poisoning’ in Western Australia. Med J Aust 1999;170:288.
References 18 Mnejja M, Hammami B, Chakroun A et al. Unusual form of cutaneous
1 Gilchrist TC. Erysipeloid with a record of 329 cases of which 323 were leishmaniasis: erysipeloid form. Eur Ann Otorhinolaryngol Head
caused by crab bites or lesion produced by crabs. J Cutan Dis Neck Dis 2011;128:95–7.
1904;22:507–19. 19 Boyd AS, Ritchie C, Fenton JS. Cutaneous Erysipelothrix rhusi
2 Klauder JV, Righter LL, Harkins MJ. A distinctive and severe form of opathiae (erysipeloid) infection in an immunocompromised child.
erysipeloid among fish handlers. Arch Dermatol 1926;14:667–78. Pediatr Dermatol 2014;31:232–5.
3 Barnett JH, Estes SA, Wirman JA et al. Erysipeloid. J Am Acad Dermatol 20 Lamphier TA. Erysipeloid infection of digits. J Fla Med Assoc
1983;9:116–23. 1971;58:39–41.
INFECTIONS
463
C HA PTER 40
Lyme Borreliosis
Susan O’Connell
Formerly Lyme Borreliosis Unit, Health Protection Agency Microbiology Laboratory, Southampton University Hospitals NHS Trust, Southampton, UK
Abstract
manifestation, mainly in older people. Borreliae can disseminate
Lyme borreliosis is caused by several Borrelia burgdorferi geno- and affect other tissues. The most common paediatric neurologi-
species transmitted by Ixodes (hard‐bodied) ticks. Common tick cal presentations are facial and/or other cranial nerve palsies and
bite sites include skinfolds and scalp. Erythema migrans, a rash viral‐like meningitis. Painful radiculopathy is common in adults.
spreading from a tick attachment site, is the most common pres- Encephalomyelitis is a rare severe presentation. Lyme arthritis
entation, occurring in 80–90% of patients studied prospectively. affects large joints, particularly the knee, causing large effusions.
Myalgias and arthralgias can also occur. Borrelial lymphocytoma Carditis is uncommon, usually presenting with heart block. All in-
is an uncommon early feature, usually located on earlobe, nip- fection stages respond to antibiotics but clinical recovery can be
ple or scrotum. Acrodermatitis chronica atrophicans is a rare late incomplete if severe damage had occurred prior to treatment.
Key points • Antibody response to Borrelia burgdorferi infection takes

several weeks to develop. Antibody tests are not indicated
• Erythema migrans is the most common clinical presentation of routinely for the diagnosis of erythema migrans but should be
Lyme borreliosis. used to confirm later‐stage presentations.
• Erythema migrans rashes can vary in appearance, related to • Long‐term outcomes of patients appropriately treated in early
infecting genospecies and duration of infection. Lyme borreliosis are excellent. Oral antibiotics (usually amoxicillin
• A history of tick exposure rather than specific tick bite should or doxycycline) are recommended as first‐line agents for most
be sought, as ticks are tiny and easily overlooked, especially if clinical presentations. Recovery may be slow or incomplete in
attached in skinfolds or on the back or scalp. some patients with later‐stage disease.

Definition and cause. Lyme borreliosis (Lyme disease) is which was isolated initially from Ixodes scapularis ticks
INFECTIONS
a multisystem spirochaetal infection caused by Borrelia (deer ticks) and then from skin biopsies, blood and cere-
burgdorferi sensu lato, transmitted by hard‐bodied ticks of brospinal fluid (CSF) of affected patients [2].
the Ixodes ricinus complex. Similar rashes following tick bites, termed erythema
migrans or erythema chronicum migrans, had been
History. The term Lyme arthritis was used initially in the recognized in European countries for many years, and
mid‐1970s, after a cluster of cases of juvenile arthritis clinicians had noted associations of tick bites with neuro-
occurred in the area of Old Lyme and neighbouring com- logical presentations such as facial palsy, meningitis and
munities in rural Connecticut. Two mothers became con- radiculoneuritis. Many physicians suspected an infec-
cerned about the extremely high rate of ‘juvenile tious cause, and some had used empirical penicillin
rheumatoid arthritis’ diagnosed in the locality and alerted treatment, with good results [3].
the local public health authorities, prompting investiga- Another skin condition, acrodermatitis chronica
tions by clinicians and scientists from Yale University [1]. atrophicans, had been described by German, Swedish
They noted that the arthritis had been preceded by tick and Austrian clinicians from the late nineteenth century
bites and slowly spreading erythematous skin lesions in a onwards, and was also found to be responsive to empiri-
significant number of patients, thus raising suspicions of cal penicillin treatment. In the early 1980s Swedish
a tick‐transmitted infection. It also became apparent that researchers, using culture media developed by the
the disease could affect other organs and systems includ- American workers, established that B. burgdorferi was the
ing the nervous system and the heart. The term Lyme cause of acrodermatitis chronica atrophicans, erythema
disease was used to denote this expanded clinical spec- migrans and a third skin manifestation also seen in
trum. The causative organism was a previously unknown Europe, borrelial lymphocytoma. The disease is now gen-
spirochaete, subsequently named Borrelia burgdorferi, erally known in Europe as Lyme borreliosis [2,3].
continents there is considerable variation in incidence,

Epidemiology and ecological factors. Lyme borreliosis
with focal areas of hyper‐endemicity.
(LB) is the most common arthropod‐borne infectious
Hard‐bodied ticks of the Ixodes ricinus complex are the
disease in temperate areas of the northern hemisphere
only vectors for Lyme borreliosis. In North America the
[2,4]. Its incidence is strongly dependent on ecological
infection is transmitted by the black‐legged or deer tick
and climatic factors affecting vector ticks and the small
I. scapularis (formerly called I. dammini) and I. pacificus in
mammals and birds that are reservoir hosts for B. burg-
the Pacific coastal states [2,5]. The main European vector is
dorferi, and on human behavioural factors leading to risk
I. ricinus (commonly called the deer, sheep or castor bean
of tick bite. In North America the regions of highest LB
tick) [2,10]. In Russia and the Baltic republics the range of
incidence are north‐eastern and mid‐Atlantic seaboard
I. ricinus overlaps with that of another vector, I. persulcatus
states, from Maine to Virginia, the upper mid‐west states
(the taiga tick), which is also widespread throughout tem-
of Wisconsin and Minnesota, and some coastal areas of
perate Asia to the Far East, including Japan.
northern California. About 37 000 cases were reported in
Ixodid ticks are very susceptible to desiccation and
2015, but the true incidence may be over 300 000, based
require a high relative humidity [10]. The most favourable
on data obtained from commercial laboratories and
tick habitats are forested areas and heathland where leaf
medical insurance claims [5]. Reported incidence in
litter and undergrowth provide protection against dry-
Canada is low but increasing, with 315 cases in 2012, and
ing. These habitats also support animals and birds that
environmental studies indicate an expanding geograph-
are the natural feeding hosts for ticks [2,10]. Ticks have a
ical range [6]. In Europe the infection occurs in wood-
three‐stage lifecycle (larva, nymph and adult), usually
land and forested regions mainly between latitudes
over 2–3 years (Fig. 40.1). At each stage they take a single
62° and 42° North (southern Scandinavia to northern
blood meal lasting from 3 to 7 days. The common feeding
Mediterranean countries), with an increasing incidence
hosts for larvae and nymphs are small and medium‐sized
from west to east. There is no standardized case‐report-
mammals such as field mice, voles, squirrels and hares,
ing system for Europe, but a review of numerous data
and ground‐feeding birds including blackbirds, robins
sources suggests that there are over 200 000 European
and pheasants. These creatures are reservoir‐competent
cases annually [4,7]. Prospective studies in several high‐
hosts for B. burgdorferi. Ticks can become infected during
endemic areas showed that about 90% are likely to be
the course of a blood meal taken from a spirochaetaemic
erythema migrans [8,9]. Within endemic regions of both
Larva feeds
on host 1
Larvae seek
new host
INFECTIONS
Fully fed larva

Eggs hatch drops to ground
to larva
Host 1
Eggs laid
by female Larva moults
to nymph
Fully fed female Life cycle

drops from host of the deer tick
to ground (Ixodes ricinus)
Host 3 Host 2
Female attaches Nymph attaches

and feeds on and feeds on
host 3 host 2
Nymph moults
to adult
Fig. 40.1 Lifecycle of Ixodes ricinus ticks (after Professor Jeremy Gray and Mr Bernard Kaye). The relative size of the animals approximates their significance
as hosts for the different lifecycle stages in a typical woodland habitat.
Chapter 40 Lyme Borreliosis 465
animal and in turn can transmit infection to hosts during Male : female incidence ratios seem to be about equal or
feeds at later stages in their lifecycle, thus maintaining the with a slight preponderance of cases in males in some
spirochaetal reservoir in nature [2]. Spring and early studies [2,5,8,9]. The major risk factors for infection are
summer is the peak period for tick feeding and there can residential or recreational activities in tick habitats.
be a secondary peak during autumn. There can be a low
level of tick feeding activity on mild winter days in some
regions, resulting in occasional cases of erythema migrans Causative organisms and pathogenetic factors. At least
occurring outside the peak periods, as demonstrated by 20 genospecies of B. burgdorferi sensu lato have been identi-
the case illustrated in Fig. 40.3. This child had sustained a fied; the majority are not pathogenic. Until recently the only
tick bite on her scalp in late December. pathogenic genospecies found in North America was
Deer are strongly associated with the presence of ticks. B. burgdorferi sensu stricto, however another genospecies,
They are preferred feeding hosts for adult female ticks, B. mayonii, has been identified in a few cases of LB with
who mate after feeding, drop back into the undergrowth unusually high spirochaetaemia [12]. A wider range of
and lay between 1000 and 2000 eggs before dying. Deer pathogenic genospecies is found in Europe, p redominantly
are important in the maintenance and expansion of tick B. garinii and B. afzelii, but B. burgdorferi sensu stricto occurs
populations because of their feeding role at the tick’s in some areas [7]. All pathogenic strains can cause erythema
reproductive stage but they are not competent reservoir migrans, the early skin lesion. There is evidence for some
hosts for B. burgdorferi. Increased numbers and geograph- genospecies‐dependent variations associated with later
ical ranges of deer in some regions of Europe and North manifestations and for within‐ genospecies variation in
America have been linked to significant increases in tick pathogenicity [7,13]. B. burgdorferi sensu stricto is strongly
populations and Lyme borreliosis incidence. linked with arthritic and neurological complications,
Human beings can be incidental feeding hosts for ticks. B. garinii and B. bavariensis with neuroborreliosis, and
Larval ticks pose minimal risk for borrelial transmission B. afzelii with acrodermatitis chronica atrophicans (ACA).
as they are rarely, if ever, infected transovarially. Nymphal Occasional cases of erythema migrans are caused by
ticks are most likely to transmit infection to people, as B. spielmanii and there have been only rare reports of disease
they are very small (about the size of a poppy seed) and linked to B. valaisiana and B. lusitaniae. Genospecies differ-
may not be noticed, even after feeding. Their major feed- ences also have implications for vaccine development.
ing period is during late spring and early summer, when Variations in the geographical distribution of European
human outdoor recreational activity is also likely to be at borrelial genospecies affect the incidence and types of

its peak. The larger adult ticks are more likely to be spot- clinical presentations of later disease seen in different
ted and removed before completing their feeds (Fig. 40.2). locations. For example, ACA occurs more frequently in
Most ticks do not carry borreliae. Infected I. ricinus ticks Scandinavia and central Europe, where B. afzelii is com-
are unlikely to transmit infection in the first 18 hours of feed- monly found. The condition is infrequently seen in the
INFECTIONS
ing and I. scapularis ticks within the first 36 hours, but trans- UK, where B. afzelii is less common. The most commonly
mission risk rises steadily as feeding continues. Early identified pathogenic genospecies in the UK is B. garinii,
removal of attached ticks greatly reduces human infection and acute neuroborreliosis is the main complication seen
risk [7,11]. There is some evidence that transmission may there. A high proportion of infected ticks in the UK carry
take place at an earlier stage during I. persulcatus blood meals. B. valaisiana, which is essentially nonpathogenic. This
Most cases of Lyme borreliosis are reported in the sum- may have some bearing on the lower overall incidence of
mer months, between May and September, but some clinically significant disease there compared to other
patients with disseminated and late presentations are parts of Europe where a higher proportion of infected
diagnosed at other times of the year. In many studies ticks carry more pathogenic genospecies.
there is a bimodal age distribution, with higher incidences B. burgdorferi is an obligate parasite with limited bio-
in the 5–19 year age group and in people over age 40. synthetic ability, relying on its host for many nutrients [2].
It does not possess the virulence factors such as toxins,
lipopolysaccharides and enzymes that are associated
with many bacterial pathogens [2]. Borreliae are highly
motile and can disseminate through tissues and bind
closely to host cell surfaces, affecting their function [2,14].
Borreliae must adapt to life in very different environ-
ments: the midgut of the tick vector at ambient tempera-
ture and the mammalian or avian natural reservoir host
from about 35 ° to 39 °C. They vary in gene expression,
leading to production of different protein components.
Some help the organisms to evade the initial defences of
the host’s innate immune system, others contribute to
evasion of the subsequent acquired immune response, at
least for some time. For example, borreliae express an
outer surface protein (Osp), called OspA within the tick,
but OspC is preferentially expressed during the early
Fig. 40.2 Ixodid tick on nail of little finger. stages of mammalian infection. Expression of another
protein, VlsE, which has an elaborate system for extensive

variation over time, is required to maintain persistent
infection. Synthesis of VlsE starts at about the time that
OspC production ceases and helps the organism to evade
the host’s humoral immune response, at least for some
time [2,14].
Many clinical manifestations of Lyme borreliosis occur
largely as a consequence of the human immunopatholog-
ical response to infection. Some borrelial lipoproteins can
activate a variety of cells, including macrophages, B cells,
dendritic cells and endothelial cells, triggering inflamma-
tory responses that contribute to pathogenesis [2,7,13,15].
There is also some in vitro evidence that antibodies
produced in response to B. burgdorferi infection may also
bind to human neural and other antigens [14].
Ixodid tick bites
Ixodid ticks attach to their hosts by barbed mouth parts.
Their saliva contains anaesthetic, anti‐inflammatory and
anticoagulant substances that allow them to attach and
complete their feed without their hosts becoming aware
of their presence [16]. Borreliae can bind immunosup-
pressive tick salivary proteins to their surfaces which can
aid the establishment of infection in the skin [2,7]. The
bites are not usually significantly painful or itchy,
although some people who have had many bites over a
prolonged period, such as forestry workers, can become
sensitized to tick saliva and develop itchy skin reactions.
This can provide some protection against B. burgdorferi
infection, by drawing early attention to the tick before Fig. 40.3 Erythema migrans in a child.
there is significant risk of spirochaetal transmission.

tick attachment and undisturbed blood meals which can
Clinical features. result in borrelial transmission include skinfolds (e.g.
INFECTIONS
B. burgdorferi infection can be asymptomatic or mini- groins, armpits, backs of knees, waistband area, under
mally symptomatic, as shown by prospective studies in breasts), back and scalp. Tick bites are more frequent
areas of high prevalence [8,9,17,18]. Clinically significant around the head and neck areas (particularly the scalp) of
disease has been customarily divided into three children than adults.
stages – early localized, early disseminated and late Most EM rashes become evident within about 5–14
Lyme borreliosis – but the process should be regarded as days (range 3–30 days) of a bite. They are usually round
a continuing pathological evolution in some untreated or oval but some can have a more triangular or linear
patients rather than having distinct phases or processes. appearance, presumably determined in part by lines of
Progression to later‐stage disease is not inevitable. The skin tension. A central punctum may be present at the tick
most frequently affected tissues and organs are the skin, attachment site. The leading edge can have a stronger col-
nervous system and joints. Case definitions have been our, giving the appearance of an outer ring or border, but
published, primarily for epidemiological purposes in the is not significantly raised [7,21]. They are not usually par-
USA and for clinical use in Europe [19,20]. ticularly pruritic or painful [21]. Very itchy or painful
lesions should raise suspicion of other conditions, includ-
Skin manifestations ing severe insect bite reactions or pyogenic infections.
Erythema migrans (Figs 40.3, 40.4) Most EM rashes are homogeneous in the early stages, but
Erythema migrans (EM) is the most characteristic presen- with longer duration some can develop an area of central
tation of Lyme borreliosis, occurring in about 90% of clearing, giving a so‐called ‘bull’s‐eye’ or target‐like
symptomatic infections [8,9,21,22]. It is an erythematous, appearance. Very pale lesions may be seen more easily
usually annular lesion spreading slowly from the site of a when the skin is warm, e.g. after exercise or bathing. If left
tick bite (often unnoticed) that had occurred 2 or more untreated, EM rashes eventually resolve over weeks to
days previously [7]. This lag phase occurs because spiro- months, and usually clear within a few days of commenc-
chaetal replication is relatively slow by comparison to ing appropriate treatment.
pyogenic bacteria. Localized redness appearing within a There can be variations in EM appearance, related to
few hours of a tick bite is likely to be caused by an imme- the infecting genospecies. In North American‐acquired
diate inflammatory response or hypersensitivity reaction infections, caused by B. burgdorferi sensu stricto, rashes
and usually fades within several days. Common sites for tend to evolve more quickly, are less likely to have central
Fig. 40.4 Erythema migrans in adults. Source: Courtesy of the late Dr John White.
clearing than European‐acquired infections caused by

B. afzelii, and are more likely to be accompanied by sys-
temic symptoms and signs including malaise, myalgia,
arthralgia, headache, fever and regional lymphadenopa-

thy [23]. Some have central vesiculation, which can cause
difficulties in differentiation from cellulitis, arthropod
bites or herpesvirus infections [24]. Some EM lesions
caused by B. afzelii develop slowly, with little systemic
INFECTIONS
upset, and can reach large sizes with high rates of central
clearing [23]. Infections caused by B. garinii seem to be
more virulent than those caused by B. afzelii, with more
homogeneous and faster evolving rashes and a higher
likelihood of systemic symptoms and signs [25].
Multiple erythema migrans can occur, principally in
infections caused by B. burgdorferi sensu stricto. Affected
patients have multiple smaller lesions resulting from
haematogenous spread of spirochaetes from the initial Fig. 40.5 Borrelial lymphocytoma.
lesion. They usually have significant systemic symptoms
and may also have other objective extracutaneous mani- European Lyme borreliosis, mainly associated with B afzelii
festations of Lyme borreliosis, which include facial nerve infection; only rare cases have been reported in the USA.
palsy, meningitis, carditis and arthritis [26]. It may develop several weeks to months after a tick bite
Differential diagnosis of EM includes reactions to tick and occurs more frequently in children than adults [7,20]. It
bites or other arthropod bites, urticaria, cellulitis, granuloma presents as a bluish‐red tumour‐like skin infiltrate most
annulare, ringworm, herpes simplex or zoster, fixed drug commonly on the earlobe, ear helix, nipple or scrotum
eruptions or contact dermatitis [7,23,27]. The histological [7,30–32]. If untreated it can persist for months but usually
appearance of erythema migrans is characterized by patchy resolves over some weeks following antibiotic treatment.
perivascular infiltrates, predominantly lymphocytic, with Histological examination shows dense lymphocytic and
plasma cells, mast cells and occasionally eosinophils, mainly histiocytic infiltrates, frequently with germinal centres [33].
affecting the superficial dermis. Immunohistochemical Borrelial lymphocytoma lesions have occasionally been
staining may demonstrate occasional spirochaetes, but misdiagnosed as B‐cell lymphomas.
silver staining is prone to artefact [28,29].
Acrodermatitis chronica atrophicans (Fig. 40.6)
Borrelial lymphocytoma (Fig. 40.5) Acrodermatitis chronica atrophicans (ACA) is an uncom-
Borrelial lymphocytoma (also termed lymphadenosis mon manifestation of longstanding infection, seen almost
benigna cutis) is an uncommon early manifestation of exclusively in European‐acquired infections. It occurs
Nervous system manifestations

Neuroborreliosis is a common complication of European‐
and North American‐acquired Lyme borreliosis, mainly
presenting within a few weeks to months of infection, in
about 10% and 20% of previously untreated patients,
often with concurrent or recent EM. It can affect both
peripheral and central nervous systems. The most com-
mon manifestation in children is isolated facial nerve
palsy without clinical signs of meningitis, although CSF
examinations of some patients show mononuclear pleio-
cytosis [39,40]. It has been postulated that the higher rate
of tick bites occurring on the head and neck region of
young children causes a relatively higher incidence of facial
palsies in children than in adults [41]. Other neurological
Fig. 40.6 Acrodermatitis chronica atrophicans. Source: Courtesy of the presentations in children include ‘viral‐like’ meningitis
late Dr John White. with or without facial or other cranial nerve palsies, includ-
ing sixth nerve palsy [39,40]. Rare cases have been reported
mainly in older people, more frequently in women, with of children with previously untreated Lyme neuroborrelio-
only rare reports of ACA‐like lesions in children [7,22,34]. sis presenting with raised intracranial pressure and very
Almost all cases are caused by B. afzelii infection. ACA high CSF protein levels, leading to sight‐threatening
usually occurs on extensor sites of the extremities, most complications [40,42]. Other uncommon complications

commonly on the lower legs, causing localized livid red include meningoencephalitis and encephalopathy.
colour changes, doughy swelling and induration of the Garin–Bujadoux–Bannwarth (GBB) syndrome is the
affected skin. Untreated lesions may progress over years, most common neurological complication in adults.
with development of hyperpigmentation and atrophy, Features include facial palsy, meningitis and radiculoneu-
giving a cigarette paper‐like appearance with loss of ritis, usually presenting as a painful radiculopathy simi-
body hair, connective tissue and fatty tissue [7,35]. There lar to that of shingles or mechanical radiculopathy. It was
may be an associated peripheral neuropathy, with numb- originally described by French physicians in 1922 and a
ness, paraesthesias and allodynia [7]. If severe, this can German neurologist in 1941 [43,44]. A more indolent pres-
lead to joint damage secondary to the neurological defi- entation of radiculopathy occurs in some European
cit. The differential diagnosis depends on the duration of patients, mainly in older age groups, who present with a
the condition and includes vascular insufficiency, acro- gradual onset of pain increasing over months after
cyanosis, livedo reticularis, lymphoedema or chilblains. infection acquisition. This may result from direct spiro-
INFECTIONS
The infection responds to treatment but completeness of chaetal invasion of peripheral nerves from the initial skin
clinical recovery depends on the degree of underlying inoculation site, gradually extending to the nerve roots,
tissue damage. Histological appearance depends on the in contrast to the more rapid onset and wider effects
duration of the lesion, with earlier inflammatory lesions seen in classic GBB syndrome, resulting from haematog-
showing perivascular infiltrates of lymphocytes and enous spread [14]. Some patients may retrospectively
plasma cells, dermal oedema and telangiectasia. recall a preceding EM. In both situations radicular pain
Epidermal atrophy and loss of epidermal appendages can be very severe and patients may require opiates, but
are characteristic findings in late‐stage ACA [29,35]. analgesia requirements usually reduce very significantly
within a short time of commencing antibiotic treatment.
Other skin manifestations Painful radiculopathy is rare in children.
Several other skin conditions, including morphoea and Meningoencephalitis is an uncommon complication in
lichen sclerosis et atrophicus, have been linked to both children and adults. Encephalomyelitis is rare,
B. burgdorferi infection in a few case reports and small mainly seen in older adults. It appears to affect white
studies, predominantly from high‐endemic areas of Europe. matter disproportionately and its clinical presentation

Other European and North American studies have shown may be confused with multiple sclerosis or, if particularly
no link with these conditions. These mainly early reports acute, with acute disseminated encephalomyelitis.
should be interpreted cautiously, as the laboratory tests Virtually all patients have an inflammatory CSF and
used in support of some cases relied on methods such as intrathecal production of B. burgdorferi antibodies, indi-
silver staining, which is prone to artefact, or IgM antibody cating the diagnostic value of CSF examination [20,45].
tests, which are known to have a significant risk of false‐ European experts have estimated that it occurs in less
positive reactions. Positive serology, especially in areas of than one in 1000 cases of untreated infection [46].
high prevalence (where background seroprevalence in the
population can be as high as 10–20%), should not be inter- Musculoskeletal manifestations
preted as evidence for causation of atypical lesions without Myalgias and arthralgias are common features of early
additional support from direct detection of the organism. disseminated Lyme borreliosis. Frank arthritis with
More recent studies and reviews suggest that B. burgdorferi synovitis was the presentation that initially drew atten-
is rarely associated with these presentations [29,36–38]. tion to the infection in Connecticut. As with other later
manifestations, it has become less common in recent Recommendations for treatment of Lyme borreliosis
years, probably because high awareness of Lyme borrelio- in pregnant women are the same as those for nonpreg-
sis in endemic areas has led to earlier recognition and nant adults, with the exception that doxycycline is
treatment. contraindicated [7,52,53].
Arthritis is strongly associated with infection caused by
B. burgdorferi sensu stricto, but other pathogenic genospe- Diagnosis. Diagnosis of EM is primarily clinical, based on
cies also cause occasional cases in Europe [47]. Patients recognition of the characteristic skin lesion in a patient
present initially with migratory arthralgias, developing who has had recent exposure to ticks. A specific history of
later into an asymmetrical mono‐ or oligoarthritis, most tick bite is not an essential criterion, as many tick bites go
commonly affecting the knee. Other large joints are less unnoticed. No later‐stage manifestation of Lyme borrelio-
frequently affected, and small joints of the hands and feet sis is unique to the infection; supporting evidence from
are rarely involved. Synovial effusion can cause marked the laboratory should be obtained to confirm a diagnosis
joint swelling, out of proportion to the degree of pain. of disseminated or late infection [20,52].
Patients do not have symptoms suggesting acute sepsis,
and serum inflammatory markers are usually only mildly Direct detection methods
elevated [20,48,49]. Tests for serum IgG antibodies to Direct detection methods include borrelial culture and
B. burgdorferi are almost always very strongly positive, DNA detection. Culture is not routinely available for
and laboratory examination of synovial fluid usually diagnostic purposes, as it requires complex culture media
demonstrates a polymorphonuclear infiltrate and pres- and may take 3–6 weeks. It is valuable in providing iso-
ence of borrelial DNA in patients who have not received lates of proven pathogenicity for research purposes. It has
antibiotics. Antibiotic treatment is usually effective in an overall success rate of about 70% when applied to skin
eradicating infection from the affected joint(s) but inflam- biopsies from patients with untreated EM or ACA, but
mation may not resolve completely by the end of treat- much lower rates (<10%) from CSF or blood, unless large‐
ment, taking weeks or months for complete resolution. volume (30–40 mL) blood cultures are taken. Synovial
A minority of patients have persistent arthritis even fluid culture has rarely been successful [7,54].
after re‐treatment, without objective evidence of active Nuclear amplification methods, usually polymerase
infection. This has been termed ‘antibiotic‐refractory’
chain reaction (PCR), for DNA detection are more valua-
arthritis and appears to have an autoimmune component. ble in providing timely results, and a variety of target
Patients with antibiotic‐refractory arthritis are more likely DNA sequences are available [2,7,55]. Positive results

than those with antibiotic‐responsive arthritis to have should be confirmed by probe hybridization or sequenc-
HLA‐DR molecules that bind B. burgdorferi outer surface ing of the amplicate, also allowing genospecies identifi-
protein A163–175, and in some patients there is also an asso- cation [7]. Overall sensitivities for skin biopsies appear to
ciation with intra‐articular steroid use prior to antibiotic be about 70% for samples from patients with EM and
INFECTIONS
treatment [50]. An early longitudinal study of 21 patients over 90% from those with ACA. In patients with acute
who did not receive any antibiotics showed that they neuroborreliosis, PCR positivity on CSF samples has
had attacks of arthritis for a median of 43 months (range been reported to range from about 70% in some American
4–76 months) [48]. A later study of patients who received studies to 30% in European patients, probably reflecting
antibiotic treatment showed that those with antibiotic‐ variations in pathogenicity associated with different
responsive disease had episodes of arthritis during a borrelial genospecies and in duration of disease prior to
median total time period of 4 months (range 1–51 months) sampling. Synovial tissue or fluid samples from patients
and those with antibiotic‐refractory disease had episodes with untreated Lyme arthritis have DNA detection rates
for a median total period of 16 months (range 4–73 around 70–90%, and these tests can occasionally be useful
months), suggesting that antibiotic treatment reduces the in assessing the need for additional antibiotic treatment
duration of inflammation even in antibiotic‐refractory in patients with refractory arthritis [50]. As with any
arthritis [50]. Nonsteroidal anti‐inflammatory agents are DNA detection test, care must be taken to avoid labora-
also helpful. tory contamination, as PCR methods are extremely sensi-
tive and are vulnerable to false‐positive results from
Lyme disease in pregnancy extraneous target DNA [56].
Three cases of maternal‐to‐fetal transmission of B. burg-
dorferi were documented in early reports, with the babies Indirect diagnostic methods
stillborn or dying within the first 48 hours after delivery. Antibody tests remain the mainstay of laboratory support
The mothers had received inadequate or no treatment for for the diagnosis of Lyme borreliosis [2,7,55,57–59]. The
EM during pregnancy. Since then several large studies antibody response to B. burgdorferi infection is slow to
have shown no increased rates of adverse outcomes of develop compared to many other bacterial or viral infec-
pregnancies and no excess of congenital abnormalities in tions, reflecting the organism’s slow replication cycle, and
Lyme‐endemic areas by comparison to nonendemic areas. early treatment can abrogate an antibody response.
An extensive review of published data concluded that an Antibody positivity rates in EM range from 30% to 80%,
adverse fetal outcome due to maternal infection with depending on duration of infection prior to treatment
B. burgdorferi at any point during pregnancy in humans is and, to a certain extent, on infecting genospecies [54].
rare [51]. Infection with B. burgdorferi sensu stricto appears to
enerate a brisker antibody response than the other

g neuroborreliosis. Examination of CSF can also give valu-
pathogenic genospecies. About 70–90% of patients with able additional supporting evidence including lympho-
early disseminated infection are seropositive at clinical cytic pleiocytosis and raised CSF protein levels [20,45,46].
presentation, and the remainder usually seroconvert
within several weeks. Patients with late‐stage Lyme bor- Diagnostic tests that are not recommended
reliosis are very rarely seronegative; seropositivity is in A number of poorly standardized and unvalidated meth-
excess of 99%. The great majority of patients with late‐ ods are marketed, mainly from commercial ‘Lyme disease
stage infections, including ACA, Lyme arthritis and late specialty’ laboratories. They include antigen detection
neuroborreliosis, are very strongly seropositive, with tests in body fluids, PCR of urine, lymphocyte transfor-
antibodies to a wide range of borrelial antigens [7,20,54,55]. mation tests (LTTs), CD57 lymphocyte measurements and
Most current antibody screening tests are based on immunoblots performed as single‐stage tests or inter-
enzyme‐linked immunosorbent assay (ELISA) methods. preted using nonstandard criteria. They have contributed
There are significant issues related to specificities of these to many misdiagnoses in North America and Europe
tests, especially older tests based on whole‐cell‐sonicate [7,55,57,61,64].
antigens, related to the complex antigenic structure of B.
burgdorferi sensu lato. Some antigens are shared with other
spirochaetes and other flagellated organisms. False‐posi- Treatment of Lyme borreliosis. Evidence‐based guide-
tive reactions can occur in tests on sera from patients with lines and consensus documents for the treatment of Lyme
syphilis, leptospirosis and enteric bacteria, presumably borreliosis in adults and children have been published by
caused by high levels of antibodies produced to common a number of American and European specialist societies
flagellin antigens. Nonspecific reactions, especially in and expert groups [7,52,53,58,59,65–67]. These will
IgM tests, have been well documented to occur in the undergo regular review. There are only minor variations
presence of other acute infections and also with some in drug choice, dose and duration between the guidelines.
autoimmune conditions. The most commonly recommended antibiotics for oral
Newer ELISAs based on recombinant or synthetic use are doxycycline, amoxicillin and cefuroxime axetil.
peptide antigens are easier to standardize and have better Cefuroxime axetil is generally recommended only if there
performance characteristics, but some specificity prob- are contraindications to doxycycline and amoxicillin.
lems remain. Accordingly, authorities in North America Macrolides should be used only if the other oral agents
and Europe currently recommend using a two‐stage are contraindicated because there is a significant risk of
treatment failure, especially with erythromycin, which
testing process to minimize risk of false‐positive results

[2,7,20,54,57]. Serum samples are screened in a first‐stage has been superseded by azithromycin in more recent
test, using a sensitive ELISA method. Specimens giving recommendations. Ceftriaxone is the preferred agent for
reactive or indeterminate results are then tested with a parenteral use, as it can be given once daily, facilitating
INFECTIONS
second method, usually immunoblot (western blot), outpatient use.

which allows an evaluation of the sample’s reactions to a Oral treatment is recommended for EM, BL, arthritis
broad range of B. burgdorferi antigens. This assessment and ACA. Most authorities recommend oral treatment
minimizes the risk of false‐positive results overall. for isolated facial palsy without other neurological mani-
Adherence to the two‐stage recommendation is impor- festations and parenteral antibiotics for other nervous
tant, as some screening ELISAs have specificities of less system presentations. However, there is increasing inter-
than 95% and the predictive value of positive results can est in the use of oral doxycycline for neuroborreliosis fol-
be very low when tests are applied in a situation where lowing a well‐conducted Norwegian study that showed
there is a low prior probability of B. burgdorferi infection, noninferiority of outcome in adult patients treated with
leading to misdiagnosis [7,20,55]. Unfortunately, this is a doxycycline compared with those who received standard
frequent occurrence. Numerous studies have shown that therapy with ceftriaxone, confirming the findings of an
misdiagnosis is a major cause of nonresponse to treat- earlier Swedish study and providing additional evidence
ment for presumed Lyme borreliosis, usually resulting to support the use of doxycycline for neuroborreliosis
from false‐positive tests or from the application of poorly [58,68–70].
specific clinical diagnostic criteria [56,60–63]. See Tables 40.1 and 40.2 for recommendations.
An important additional factor to be considered when
evaluating serological results is the high background Prognosis. Several studies have shown excellent outcomes
seroprevalence in populations living in highly endemic for patients with appropriately treated EM [71–76]. A large
areas, reflecting residual antibodies to a previous infec- prospective study performed in Connecticut showed
tion, which may have been asymptomatic, so it is impor- excellent long‐term outcomes of children who received
tant that positive antibody results are carefully assessed appropriate treatment for EM and other manifestations
for current clinical relevance [2,7,55]. [75]. European studies have shown similar results [71,76].
Antibody tests are also useful in CSF assessment. Most Most patients with acute neuroborreliosis who receive
patients with acute neuroborreliosis have detectable anti- appropriate treatment also have very good long‐term out-
bodies to B. burgdorferi in CSF at time of presentation, and comes, but full recovery can take some weeks or months,
intrathecal antibody synthesis can also be assessed. This as seen in other conditions such as viral meningitis or
is particularly useful in the evaluation of suspected late meningoencephalitis. Patients with facial palsy may have
Table 40.1 Commonly recommended antibiotics and doses for treatment of Lyme borreliosis
Agent Route Adult dose Child dose Notes
Doxycycline Oral 100 mg 12‐hourly 4 mg/kg/day (max. 100 mg/dose) Contraindicated in children <9 years
(or 200 mg daily) (12 years in UK)
Amoxicillin Oral 500 mg–1 g 50 mg/kg/day in three divided
8‐hourly doses (max. dose 500 mg)
Cefuroxime axetil Oral 500 mg 12‐hourly 30 mg/kg/day in two divided
doses (max. dose 500 mg)
Ceftriaxone Parenteral 2 g daily 50–100 mg/kg/day as single dose
Cefotaxime Parenteral 2 g 8‐hourly 150–200 mg/kg/day in three
divided doses
Benzylpenicillin Parenteral 18–24 mIU daily in 200 000–400 000 IU/kg/day in six
six divided doses divided doses (max.
18–24 mIU/day)
Azithromycin (careful follow‐up Oral 500 mg daily 5 mg/kg/day (max. 500 mg) 5‐ to 10‐day course for EM. Not
required, see text and references recommended for disseminated or late
for further details) infection. Careful follow‐up required
Table 40.2 Indications, routes of administration and duration of treatments estimated to occur in 5–10% of patients with dissemi-
for Lyme borreliosis nated infection and is less common in children than in
adults. Six randomized controlled trials have shown no
Treatment indication Route Duration evidence of persistent borrelial infection in patients
with post‐Lyme symptoms, and no sustained benefit
Erythema migrans Oral 14 days
(range 10–21)
from prolonged antibiotic treatments, which can cause
Borrelial lymphocytoma Oral 14 days significant risks [81–83].
(range 10–21)
Isolated facial nerve Oral or parenteral 14 days ‘Chronic Lyme disease’
palsy (range 14–21) This term has been used to denote a variety of patient
Early or late Parenteral (or oral – see 14 days

groups, including those with post‐Lyme syndrome and
neuroborreliosis text and references) (range 10–28)
Acrodermatitis chronica Oral 21 days
patients with incomplete clinical recovery following treat-
atrophicans (range 14–28) ment of late Lyme borreliosis, as described earlier in the
Arthritis Oral 28 days chapter. The majority of patients given a diagnosis of
INFECTIONS
Arthritis (if re‐ Oral 28 days ‘chronic Lyme disease’ include those who have had
treatment indicated) B. burgdorferi infection at some time in the past but whose
current clinical presentation is due to another unrelated
See references 7,50,52,53,58,59,65–67 for more detailed information and condition, and patients who have never had B. burgdorferi
additional recommendations for complicated cases.
infection but have been misdiagnosed through the use of
poorly specific case definitions or false‐positive results,
some residual paresis, which is usually mild [77]. Some, frequently from nonstandard laboratory tests. Studies
mainly older, patients with radiculopathies can have from referral centres have shown that many patients
persistent paraesthesias [78]. given this diagnosis fulfil criteria for conditions such
The degree of clinical recovery of patients with late‐ as chronic fatigue syndrome or fibromyalgia, and some
stage manifestations such as ACA or late neuroborreliosis have other serious conditions for which specific treat-
depends in part on the severity of damage incurred prior ments are indicated [61–63,81].
to treatment [7,78]. Antibiotics can eradicate the infection
but full recovery may not be possible if tissue damage has Prevention. No vaccine is currently available.
been severe. However, a historical study of untreated
patients with neuroborreliosis showed good functional Education, awareness and personal protection measures
results in the majority of the study group [79]. Public education is needed to heighten awareness of ticks
and their potential for disease transmission. This is
Persistent symptoms following treated Lyme borreliosis particularly important with the increasing popularity of
A minority of patients have nonspecific symptoms such outdoor recreational activities such as hiking, camping
as fatigue, musculoskeletal pain or cognitive com- and mountain biking, involving urban dwellers who may
plaints persisting after receiving appropriate treatment have little prior knowledge of the potential natural haz-
of their infection. This condition has been termed ‘post‐ ards to which they might be exposed. The main preven-
treatment Lyme syndrome (PTLS) [2,7]. It seems to be tion measures are directed at avoidance of tick bites and
similar to fatigue syndromes documented following early removal of attached ticks, as transmission of borre-
other infections and correlates with severity of disease liae from an infected tick is very unlikely to occur in the
at presentation and with delayed treatment [80,81]. It is first few hours of a tick feed [7,52,84]. Simple measures
include wearing light‐coloured long‐sleeved shirts with and has a mortality rate of about 1% [89]. A TBE vaccine is
buttoned cuffs and long trousers, using DEET‐based available. Powassan virus has caused cases of menin-
insect repellents, frequent checks of exposed skin for goencephalitis in North America. Co‐infections with
attached ticks during the day and a thorough check of the Lyme borreliosis can occur with any of these infections
body, including skinfolds (armpits, groins, backs of knees, and may produce modified disease presentations, which
under breasts, waistband area, etc.), at the end of each day can cause clinical diagnostic difficulties if the possibility
in a tick‐infested area. It is important to check the head of co‐infection is not considered.
and neck area, including the scalp, of young children.
Permethrin‐impregnated clothing can be useful for peo- Southern tick‐associated rash illness (STARI)
ple who have heavy prolonged exposure to ticks, such as This condition, also known as Masters disease, is associ-
forestry workers. Permethrin kills ticks on contact, but is ated with bites of Amblyomma americanum, the Lone Star
not suitable for application directly to the skin. tick. It presents as an EM‐like rash that is smaller and
more circular and has a greater degree of central clearing
Tick removal than that of EM. Affected patients seem to be less likely to
Attached ticks should be removed using fine‐pointed have significant systemic symptoms than those who have
tweezers, grasping the mouth parts as close to the skin as Lyme borreliosis [90]. The causative agent has not been
possible and pulling gently and steadily upwards [85]. identified. The condition has been identified predomi-
A skin disinfectant can be applied after removal to reduce nantly in Missouri but the tick vector has a broad range
risk of pyogenic infection. Retained mouth parts do not through the southeastern USA and its range appears to
increase risk of borrelial transmission, but may occasion- have increased in recent years, appearing as far north as
ally cause a foreign body reaction. The site of tick attach- Maine [91].
ment should be monitored for possible development of
rash, but it is also important to recognize that infection
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INFECTIONS
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475
C HA PTER 41
Bartonella Infections
Sonia Kamath1 & Minnelly Luu2,1
Department of Dermatology, Keck School of Medicine of University of Southern California, Los Angeles, CA, USA
1
Division of Pediatric Dermatology, Children’s Hospital Los Angeles, Los Angeles, CA, USA
2
Introduction, 475 Cat scratch disease, 478

Bacillary angiomatosis, 475 Bartonellosis, 480
Abstract vascular papules and nodules with lobular vascular proliferations

of plump endothelial cells on histology. Lesions generally respond
The spectrum of Bartonella infections includes cat scratch disease well to therapy with erythromycin. Lastly, bartonellosis is caused
(CSD), bacillary angiomatosis, trench fever and bartonellosis (or by B. bacilliformis and transmitted from person to person by sand-
Carrion disease). In immunocompetent individuals, B. henselae flies in certain regions of Peru, Colombia and Ecuador. Bartonel-
infection results in CSD, characterized by self‐limited regional losis is characterized by acute and chronic presentations. The acute
lymphadenopathy after a cat scratch or bite distal to the affected Oroya fever phase may lead to severe, life‐threatening anaemia
node. Histologically, CSD manifests as a granulomatous process. and requires treatment with chloramphenicol. The chronic verruga
By contrast, B. henselae or B. quintana infection in immunocom- peruana phase is associated with less morbidity and responds well
promised hosts results in bacillary angiomatosis, comprised of to rifampicin (rifampin).
Key points • Caused by B. henselae, cat scratch disease is a common self‐

limiting cause of lymphadenopathy in immunocompetent
• The majority of Bartonella infections are caused by three children and is characterized by an inoculation lesion followed
species: Bartonella henselae, Bartonella quintana and Bartonella by regional lymphadenopathy.

bacilliformis. • Bartonellosis, caused by B. bacilliformis, is geographically
• Bacillary angiomatosis consists of vascular papules or nodules limited to parts of South America and consists of an acute phase
caused by B. henselae and B. quintana, occurs primarily in (Oroya fever) and eruptive phase (verruga peruana), which
immunocompromised patients, and generally responds to respond to treatment with chloramphenicol and rifampicin,
INFECTIONS
treatment with erythromycin. respectively.
Introduction B. bacilliformis, is limited geographically to certain areas of

Peru, Colombia and Ecuador [3].
The genus Bartonella includes more than 30 different species
of facultative intracellular Gram‐negative bacilli. A variety
of mammals, including cats, rodents and humans, serve as Bacillary angiomatosis
reservoirs for Bartonella species, and the bacteria are often
transmitted via vectors, such as sandflies, body lice, fleas History. Compared to other Bartonella infections, bacillary
and ticks. Over fifteen of these species have been described angiomatosis was described relatively recently; however,
to cause human infections; however, three species account the research on bacillary angiomatosis has led to consid-
for the majority of Bartonella‐related pathology in humans: erable advances in the understanding of Bartonella
Bartonella henselae, Bartonella quintana and Bartonella bacilli- infections in general. In 1983 Stoler et al. described the
formis [1]. The clinical manifestations associated with first case of bacillary angiomatosis in a patient with
Bartonella infection depend largely on the host’s immune acquired immunodeficiency syndrome (AIDS) and sub-
status. The more benign, self‐limited cat scratch disease, cutaneous nodules. On biopsy, these nodules showed a
caused by B. henselae, occurs in immunocompetent hosts, lobular proliferation of capillary channels. Tissue cultures
while the more severe bacillary angiomatosis, caused by failed to reveal a causative organism, but Warthin–Starry
B. henselae and B. quintana, occurs more often in immuno- stains showed diffuse infiltration of small bacillary forms
compromised hosts [2]. Lastly, bartonellosis, caused by [4]. Cockerell et al. then reported five similar cases in
patients with human immunodeficiency virus (HIV), Both B. quintana and B. henselae are now known to cause
describing the condition as ‘epithelioid angiomatosis’ [5]. bacillary angiomatosis. B. quintana is also the aetiological
Soon after, AIDS patients with lesions histologically simi- agent of trench fever, an illness initially described in
lar to those described by Stoler et al. were found to have a troops during World War I, which recently has re‐emerged
positive reaction to antisera from the cat scratch disease in homeless inner‐city populations and has been reported
bacillus, and the term bacillary angiomatosis along with in children [25,26]. Humans are the main reservoir for
criteria for diagnosis of the condition was defined [6]. B. quintana with human body lice (Pediculus humanus
Subsequent studies sought to better characterize the humanus) and possibly head lice (Pediculus humanus
infectious agent responsible for bacillary angiomatosis, capitis) as vectors [27–29].
but culture of the organism proved to be difficult. In By contrast, cats have been identified as a major reser-
1990, polymerase chain reaction (PCR) studies of infected voir for B. henselae. A case‐control study found that trau-
tissue samples revealed a previously uncharacterized matic cat exposure, such as a bite or scratch, was strongly
organism closely related to Rochalimaea quintana (the associated with bacillary angiomatosis [30,31]. Affected
cause of trench fever) [7]. Shortly after, a new species, patients were more likely to own a kitten than a cat [31].
Rochalimaea henselae, was identified as a cause of Further studies have found B. henselae bacteraemia in pet
persistent fever with bacteraemia, peliosis hepatis and cats of affected patients and in approximately 40% of ran-
bacillary angiomatosis in patients with HIV [8–10]. domly screened cats [32]. Fleas from infected cats also
Koehler et al. then isolated both R. henselae and R. quin- carry the bacteria [32]. Still, many patients with bacillary
tana from cutaneous bacillary angiomatosis lesions and angiomatosis have no history of cat exposure, suggesting
successfully cultured the organisms on solid agar with an that the organism may be acquired from other sources,
endothelial cell monolayer [11]. such as arthropod vectors like fleas and ticks [14,27].
The original descriptions of the causative organisms of The pathogenesis of bacillary angiomatosis occurs via
bacillary angiomatosis refer to the genus Rochalimaea, multiple mechanisms, including immune evasion, bacte-
which was previously categorized in the family rial replication, erythrocyte and endothelial cell parasit-
Rickettsiaceae and order Rickettsiales. At the time, ism, and induction of angiogenesis. Bartonella may
B. bacilliformis was the only Bartonella species that had successfully evade the host immune system due to several
been described and was categorized in the family characteristics. The B. henselae lipopolysaccharide (LPS) is
Bartonellaceae within the order Rickettsiales. A seminal subinflammatory, resulting in at least 1000‐fold less
paper by Brenner et al. reported that the four Rochalimaea potent toll‐like receptor (TLR) 4 activation compared to
species were much more closely related to Bartonella than LPS from Salmonella [27]. B. quintana LPS may also p ossess
previously thought. Thus, they were reclassified under antagonistic properties for TLR4, resulting in downregu-
the genus Bartonella (B. quintana, B. henselae, B. elizabethae lation of cytokines in monocytes that are normally
and B. vinsonii), and the family Bartonellaceae was produced by TLR4 [33]. Finally, B. henselae can avoid

INFECTIONS
removed from the Rickettsiales order altogether [12]. The lysosomal fusion and acidification after invading

full spectrum of Bartonella infections is now well under- endothelial cells and macrophages, thus avoiding the
stood to include bacillary angiomatosis, cat scratch normal endocytic pathway and conferring an intracellu-
disease, trench fever and bartonellosis [13]. lar survival advantage [33,34].
Both B. quintana and B. henselae parasitize erythrocytes,
Epidemiology and pathogenesis. Bacillary angiomatosis causing chronic intraerythrocytic bacteraemia [27]. Within
primarily occurs in immunocompromised patients, such endothelial cells, they have been shown to induce pro‐
as those with HIV/AIDS or on immunosuppressive angiogenic mediators such as vascular endothelial growth
therapy; however, there have been rare reports of the factor (VEGF) and interleukin (IL)‐8 [27]. The bacteria
condition in immunocompetent patients as well [14]. In also replicate locally within the extracellular matrix and
children, bacillary angiomatosis appears to be extremely utilize BepA effector proteins to impede apoptosis of
rare. There are very few reports of HIV‐associated bacil- endothelial cells [33,35,36]. Additionally, B. quintana and
lary angiomatosis in paediatric patients; however, the B. henselae can colonize foci distant from the primary site
diagnosis should be considered in children with HIV in of infection with preference for highly vascularized tis-
the appropriate clinical setting [15–17]. There have been sues such as the liver and spleen, which has been sup-
rare reports of bacillary angiomatosis occurring in paedi- ported by an immunocompromised murine model [27,37].
atric solid organ transplant recipients and in a child The exact reasons why B. henselae and B. quintana cause
undergoing chemotherapy for leukaemia [18,19]. Few angiogenesis more often in immunocompromised hosts
reports exist of bacillary angiomatosis occurring in immu- but cat scratch disease and trench fever in immunocom-
nocompetent children [20]. Bacillary angiomatosis has petent hosts are still poorly understood.
been reported in pregnancy, and a recent case report
provided evidence that B. henselae can be transmitted to Clinical features. Patients with bacillary angiomatosis
children in utero or during caesarean section from a may exhibit both cutaneous and extracutaneous manifes-
mother with chronic B. henselae bacteraemia [21–23]. tations of disease. Skin eruption is considered to be the
Additionally, B. henselae was found to be viable in red most common manifestation of bacillary angiomatosis,
blood cell units after storage at 4 °C for 35 days, raising and several cutaneous morphologies have been described
the possibility of infection through blood transfusion [24]. [38]. Most commonly, lesions are described as red or
Chapter 41 Bartonella Infections 477
iolaceous dome‐shaped papules, which can evolve into

v response consistent with a Jarisch–Herxheimer reaction.
larger friable nodules or tumours that bleed profusely Pretreatment with an antipyretic medication may be help-
with trauma. These lesions often ulcerate with associated ful, and these symptoms are likely to improve over time
serosanguinous exudate [13]. Less commonly, patients with continued antibiotic therapy [11,18].
have deeper subcutaneous masses, which clinically appear
as large flesh‐coloured or dusky nodules that are often
Differential diagnosis. The differential diagnosis of the
tender and may appear cellulitic. These lesions may be
cutaneous lesions of bacillary angiomatosis includes
mobile or fixed to underlying structures, and involvement
infectious and non‐infectious entities. Noninfectious dis-
of the underlying bone is common [13]. Plaque‐like lesions
orders include pyogenic granuloma, cherry angioma,
and suppurative ulcers have also been reported [14].
dermatofibroma and haemangioma. Solitary lesions can
Although in general patients with cutaneous bacillary
be difficult to distinguish clinically from pyogenic granu-
angiomatosis present with multiple lesions, the majority
loma and may require biopsy for diagnosis [39]. Kaposi
of paediatric case reports of bacillary angiomatosis have
sarcoma (KS) is perhaps the most important diagnosis to
described isolated lesions, such as a crusted violaceous
differentiate from bacillary angiomatosis, as they are both
papule or nodule [15,17,19,20,39–41]. Cutaneous lesions
more common in the immunocompromised patient.
are most often located on the trunk and extremities, but
Clinically, cutaneous bacillary angiomatosis more often
there have been unusual reports of localized bacillary
presents as a bright‐red round papule, nodule or tumour.
angiomatosis in the oral cavity [42,43]. Patients with skin
Plaque‐type lesions are more rare compared to KS in
disease alone may have associated constitutional symp-
which patients often present with macules, patches and
toms such as fever, chills, malaise and anorexia [13].
plaques. On pathology, bacillary angiomatosis is more
In addition to the skin, bacillary angiomatosis may
sharply demarcated compared to KS, the vascular spaces
involve a number of internal organs, leading to associated
are more round compared to slit‐like in KS, and the
complications and a possibly fatal course. Patients with
endothelial cells in bacillary angiomatosis are plump
extracutaneous disease generally have associated consti-
compared to spindled in KS [14].
tutional symptoms and other systemic symptoms
With respect to the infectious differential diagnosis, the
depending on the organs involved. Hepatic involvement
eruptive phase of bartonellosis very closely resembles
may present as blood‐filled cystic spaces, also known as
bacillary angiomatosis clinically; however, this infection
bacillary peliosis hepatis. Splenic peliosis has also been
occurs almost only in endemic areas in South America.
observed and may require splenectomy [44]. Patients
Other infections on the differential diagnosis include

usually present with gastrointestinal symptoms such as
atypical Mycobacterium infections, tuberculosis, coccidioi-
anorexia, nausea, vomiting, diarrhoea, abdominal disten-
domycosis, cryptococcosis, histoplasmosis and sporotri-
sion and weight loss. Clinical examination often reveals
chosis [39].
fever and hepatosplenomegaly [39]. Patients often have
INFECTIONS
cytopenias and elevated serum levels of liver enzymes,
including γ‐glutamyltransferase (GGT), alkaline phos- Laboratory and histology findings. Diagnosis of cutane-
phatase, and aspartate aminotransferase (AST) [14,38]. ous bacillary angiomatosis is most often based on sugges-
Peliosis hepatis or peliosis of the spleen may be compli- tive clinical features confirmed by histology. Biopsies of
cated by organ rupture with haemoperitoneum [44]. skin lesions of bacillary angiomatosis demonstrate a
Involvement of many other organs has been reported lobular proliferation of small blood vessels lined by large,
with bacillary angiomatosis, including the heart, lungs, plump endothelial cells that protrude into the vessel
muscles and soft tissues, gastrointestinal tract, bone lumen (Fig. 41.1) [6,18]. Granular clumps of purplish
marrow, bone and brain [39]. Lymphadenopathy may be material are present, around which there is prominent
the sole manifestation in approximately 20% of patients neutrophilic infiltrate with leucocytoclastic debris [39].
[38]. A case report by Rostad et al. described two paediatric Staining of these granular clumps with Warthin–Starry
solid organ transplant recipients who both presented reveals masses of small bacilli (Fig. 41.2) [18]. Electron
with unilateral lymph node swelling confirmed as microscopy demonstrates pleomorphic bacilli with a
bacillary angiomatosis by biopsy [18]. Laryngeal and Gram‐negative trilaminar wall [4,6]. Histological exami-
endobronchial lesions may cause obstruction and nation of bacillary peliosis hepatis demonstrates dilated
respiratory compromise [14,45]. Bony involvement may capillaries or multiple blood‐filled cystic spaces with foci
be asymptomatic or present as focal bone pain, and of necrosis and a myxoid stroma with similar granular
radiological examination often reveals osteolytic lesions clumps and inflammation admixed [14,44,47].
[46]. Some patients may develop bacteraemia without Both B. henselae and B. quintana can be isolated from
focal infection and generally present with associated blood using tubes containing ethylenediaminetetraacetic
malaise, fatigue, anorexia and weight loss [9,10]. acid (EDTA) and from cutaneous tissue by cultivation on
Once the diagnosis of bacillary angiomatosis is made, solid agar in the presence of an endothelial cell mon-
prompt treatment is required to avoid potential morbid- olayer [8,11]. Furthermore, Bartonella DNA from tissue
ity and mortality, and appropriate antibiotic therapy usu- or blood can be amplified by PCR, which has been found
ally leads to the resolution of cutaneous lesions and to be more sensitive than culture at detecting Bartonella
visceral disease [14]. Upon initiation of treatment, some [48]. Indirect fluorescence assay (IFA) and enzyme
patients may abruptly develop fever with a systemic toxic immunosorbent assay (ELISA) have also been tested for
bacillary peliosis hepatis, the recommended treatment

duration is 4 months [50]. For bacillary peliosis hepatis, the
recommended treatment duration is 4 months [50]. Therapy
should be guided by clinical response and extended
beyond clinical clearance of lesions to help decrease the
likelihood of relapse. In severe or refractory cases, a combi-
nation of doxycycline and rifampicin (rifampin) can be
used. Patients should be monitored closely for relapse after
cessation of therapy, which probably requires a longer
duration of or indefinite antibiotic therapy [1].
Cat scratch disease

History. In 1889, Parinaud described a constellation of
symptoms including fever, conjunctival granulomas and
Fig. 41.1 Haematoxylin and eosin stain of a lymph node biopsy shows preauricular lymphadenopathy, known as oculoglandu-
diffuse proliferation of small blood vessels (original magnification, ×200). lar syndrome [52]. The first official report of cat scratch
Source: Reproduced from Rostad et al., 2012 [18]. Reproduced with disease came in 1950 in patients with a history of cat con-
permission of John Wiley & Sons Ltd. tact followed by regional adenitis that spontaneously
resolved [53]. Epidemiological features of the disease
suggested an infectious aetiology; however, the infectious
agent proved to be difficult to isolate, and studies initially
implicated Afipia felis as the causative agent [54,55].
At the same time, investigators noted similarities
between the organisms causing cat scratch disease and
bacillary angiomatosis and speculated that they might be
the same. Serological evidence linked B. henselae to cat
scratch disease when sera from 36 of 41 patients (88%)
with suspected cat scratch disease were found to have

high titres of antibodies to B. henselae antigens [30].
Additionally, sera with high titres of B. henselae antibod-
ies did not cross‐react with A. felis, and only 24% of
INFECTIONS
patients with cat scratch disease had detectable A. felis

antibodies, suggesting that A. felis might not be the pri-
mary causative agent [30]. Other reports confirmed the
positive serologies to B. henselae in patients with cat
Fig. 41.2 Warthin–Starry stain demonstrates aggregates of small scratch disease and found that 81% of the cats owned by
coccobacilli (original magnification, ×400). Source: Reproduced from Rostad patients with cat scratch disease had serum antibodies
et al., 2012 [18]. Reproduced with permission of John Wiley & Sons Ltd.
that reacted with B. henselae [56]. Subsequently, B. hense-
lae has been isolated from the lymph nodes of patients
serological diagnosis of B. henselae and B. quintana; with cat scratch disease [57].
however, difficulties with serology include suboptimal
sensitivity and false‐positive tests due to cross‐reactivity Epidemiology and pathogenesis. B. henselae is now
between Bartonella, Coxiella and Chlamydia species. widely accepted as the primary cause of cat scratch dis-
Additionally, serologies are not reliable in immunosup- ease [14]. There have also been reports of cases caused by
pressed patients [48]. As a result, PCR is preferred as a B. clarridgeiae [58,59]. Generally, cat scratch disease occurs
faster, more sensitive and more specific test [33]. in immunocompetent patients of all ages; however, 80%
are under 21 years of age [60]. It is considered the most
Treatment. The treatment of choice for bacillary angioma- common cause of chronic benign lymphadenopathy in
tosis and bacillary peliosis hepatis is erythromycin [49]. In children and adolescents. More than 90% of patients have
children, erythromycin ethylsuccinate can be used at a history of some type of contact with cats, and 60% have
40 mg/kg per day divided into four doses (maximum 2 g a preceding cat scratch [13,14]. Patients are significantly
per day). An alternative therapy depending on the age of more likely than healthy cat‐owning controls to have at
the patient is doxycycline 100 mg twice daily [50]. An least one kitten aged 12 months or younger, to have been
observational study in HIV patients found no statistical scratched by a kitten and to have at least one kitten with
difference in the cure or relapse rate in patients treated fleas [56]. There have been rare cases of cat scratch disease
with erythromycin compared to those treated with doxy- after skin injury from a foreign body, and fleas and ticks
cycline [51]. A treatment duration of at least 3 months has may also be vectors [1]. Family outbreaks have been
been recommended for bacillary angiomatosis, and for described, often in households with cats or kittens [61].
As discussed previously, B. henselae has been found to be manifestations aside from the primary inoculation lesion
viable in stored red blood cell units, suggesting the occur in 5% of patients and include a transient morbilli-
possibility of transmission by blood transfusion [24]. form eruption, erythema nodosum, erythema multiforme,
Clinical manifestations of cat scratch disease may be leucocytoclastic vasculitis and thrombocytopenic pur-
due to an immunological reaction in the lymph nodes. pura [66]. Although patients with cat scratch disease are
Although PCR assays are often positive with acute not usually systemically ill, up to 14% of cases may have
disease, culture of bacteria from the lymph nodes of
systemic or severe disease [50]. Less common findings
patients with cat scratch disease is difficult as there are include fatigue, headache, hepatosplenomegaly, nausea,
probably few viable B. henselae bacilli present [48]. vomiting, myalgias and arthralgias [63].
Historically, the Th1 immune response has been impli- Various other organs may be involved, including heart,
cated in cat scratch disease, as evidenced by the Bartonella lung, brain, eyes, liver, spleen, kidneys, bone and thy-
skin test, which represents a classic delayed type hyper- roid. B. henselae endocarditis has been reported, particu-
sensitivity reaction [33]. Further studies have shown larly in patients with pre‐existing damage to heart valves
increased production of Th1 cytokines, including [67]. Lung involvement manifests as pleural effusion,
interferon‐γ (IFN‐γ) and IL‐12 [62]. pneumonia and, least commonly, pulmonary nodules
[68]. Neurological changes are relatively rare and present
Clinical features. The primary cutaneous lesion in cat approximately 2 weeks after the onset of cat scratch dis-
scratch disease is most often a papule, pustule or nodule, ease. Encephalopathy, the most common neurological
usually less than 1 cm in size. This lesion occurs at the site manifestation, may present as headache, seizures, coma,
of inoculation after an incubation period that ranges from transient combative behaviour, ataxia, expressive apha-
a few days to a month [13]. Over time, the lesion may sia, transient hemiplegia or hearing loss [69,70]. Other
undergo ulceration. Approximately half of patients pre- neurological findings may include neuroretinitis, periph-
sent with the hand or arm as the site of inoculation [13]. eral neuritis, Guillain–Barré syndrome, and chronic
Other sites include the eye, mucous membranes and scalp inflammatory demyelinating polyradiculopathy (CIDP)
[63]. The primary lesion may last for a few days to months [69,71–73]. Parinaud oculoglandular syndrome is an
and usually resolves without treatment. atypical form of cat scratch disease that presents as a
Several weeks after inoculation (range 5–50 days), conjunctival granuloma at the site of inoculation with
regional lymphadenopathy proximal to the inoculation preauricular lymphadenopathy [63].
site develops, which is the hallmark of the disease In the liver and spleen, necrotizing granulomas may

(Fig. 41.3) [63]. In most patients, lymphadenopathy occurs develop, and microabscesses in the kidneys have been
in the head, neck or upper extremity. Although the major- reported [47,74]. Other atypical manifestations of cat
ity of patients present with regional enlarged lymph scratch disease include osteolytic lesions and septic
nodes, approximately 30% of them have involvement of arthritis [63,75]. Lastly, a single case report recently
INFECTIONS
multiple anatomical sites with generalized lymphade- described a paediatric patient who developed autoim-
nopathy in severe cases [60]. The lymphadenopathy is mune thyroiditis associated with cat scratch disease [76].
initially tender, and up to 20% of patients develop sup-
purative lymphadenopathy, which may require drainage Differential diagnosis. The differential diagnosis of cat
or removal [64,65]. It typically resolves spontaneously scratch disease includes various causes of lymphadenop-
within 2–4 months [13]. athy, ranging from infectious to malignant. Tender lym-
Associated signs and symptoms include fever and phadenopathy may be more suggestive of a different
malaise in at least 30% of patients [63]. Dermatological infectious aetiology, such as Staphylococcus aureus, group
A β‐haemolytic streptococci, anaerobes, atypical myco-
bacteria, Mycobacterium tuberculosis, Francisella tularensis
or Brucella. Fungal aetiologies such as histoplasmosis,
sporotrichosis, toxoplasmosis and nocardial infection
may also need to be considered. Viral infections, such as
cytomegalovirus, HIV and Epstein–Barr virus, usually
cause generalized lymphadenopathy, which is less com-
mon in cat scratch disease. Noninfectious diagnoses to
consider include sarcoidosis, congenital and acquired
cysts, Kawasaki disease and Kikuchi disease. Lastly,
malignancy may need to be ruled out, especially in
patients with symptoms that are slower to resolve [66].
Laboratory and histology findings. The diagnosis of cat

scratch disease is primarily clinical. Historically, the diag-
nosis could be made if three of the following four criteria
Fig. 41.3 Inoculation lesion of cat scratch disease on the right cheek and were met: history of cat exposure with presence of a
associated submandibular lymphadenopathy in an infant. Source: Courtesy scratch or primary dermal, ocular or mucous membrane
of Dr. Andrew Margileth. lesion; a positive cat scratch disease skin test; negative
studies for other causes of lymphadenopathy; and a when an outbreak of severe anaemia and fever occurred in
characteristic biopsy sample [77]. In general, the sensitivity workers constructing a railway from Lima to Oroya [81]. The
of culture and PCR is low for detecting B. henselae in patients disease subsequently became known as Oroya fever, but the
with cat scratch disease (13% and 30%), whereas serological aetiology remained unknown. Then, in 1885, a Peruvian
diagnosis reaches up to 90% sensitivity [48]. Recent studies medical student named Daniel Carrion inoculated himself
have focused on more specific methods of serological diag- with material from a verruga peruana lesion. He died after
nosis, including an IgG ELISA that uses sarcosin‐soluble developing symptoms of Oroya fever, now known as the
proteins of B. henselae which reached almost 98% specificity acute phase of bartonellosis. Carrion’s experiment suggested
[78]. Still, it is recommended that serological studies be used that both Oroya fever and verruga peruana were two phases
as an adjunct to clinical findings. of a disease caused by one p athogen, leading to the eponym
Histological findings in the primary cutaneous inocula- Carrion disease [82]. The infectious agent was finally discov-
tion site include necrosis in the dermis with multiple sur- ered in 1905, when Alberto Barton identified B. bacilliformis
rounding layers of palisading histiocytes and epithelioid within erythrocytes [82].
cells and a peripheral zone of lymphocytes. In lymph
nodes, the findings may be nonspecific depending on the Epidemiology and pathogenesis. B. bacilliformis is a
stage of disease. Initially, lymphoid hyperplasia is present. small, motile, pleomorphic coccobacillus [83]. Unlike
Subsequently, stellate granulomas may form with similar B. henselae and B. quintana, B. bacilliformis is a flagellated
morphology to those in the skin. Lastly, microabscesses organism. Although the flagella may play a role in host
develop and may become confluent. Warthin–Starry stain- colonization, its importance has not yet been clearly dem-
ing demonstrates pleomorphic bacilli within areas of onstrated [27]. B. bacilliformis exhibits a preference for
necrosis in the cutaneous and lymph node lesions [13]. colonizing cooler areas of the body, such as the vascular
bed of the skin [27].
Treatment. Cat scratch disease is usually a self‐limited Humans are the main reservoir for B. bacilliformis, and
infection with an excellent prognosis. Patients usually do person‐to‐person transmission occurs via phlebotomine
not require antibiotic therapy, and symptoms resolve sandflies (Lutzomyia species) [1]. Cases of bartonellosis are
within 2–4 months [66]. For immunocompetent mildly ill geographically limited to areas in Peru, Colombia and
patients, recommended management includes ruling out Ecuador. In outbreaks of bartonellosis, the paediatric popu-
other causes and providing supportive care. Suppurative lation has been most affected with the highest mortality rate
lymph nodes can be treated with needle aspiration or compared to other age groups [80]. When the acute phase of
removal if necessary. Alternatively, for children with bartonellosis occurs during pregnancy, higher mortality has
large, bulky lymphadenopathy, therapy can be consid- been reported in both mother and fetus, and vertical trans-
ered with azithromycin at 10 mg/kg on day one followed mission from mother to baby has been reported [80,84].
by 4 days at 5 mg/kg per day dosing [50]. A single pro- Additionally, bartonellosis was reported as the cause of
INFECTIONS
spective randomized double‐blind placebo‐controlled death in an aplastic anaemia patient who developed shock
trial demonstrated a more rapid reduction in lymph node and died after receiving numerous transfusions [85].
volume with the use of azithromycin compared to p lacebo Compared to B. henselae and B. quintana, the intraeryth-
in the first month of treatment [79]. Treatment with rocytic phase of infection is relatively short but much
trimethoprim–sulfamethoxazole, rifampicin, ciprofloxa-
more severe, leading to a potentially life‐threatening drop
cin or gentamicin has been observed to be efficacious as in haematocrit. Deformation factor, or deformin, helps
well [77]; however, a recent meta‐analysis combining the B. bacilliformis establish erythrocyte tropism by causing
results from both studies found that treatment had no pitting and invagination of the cell membranes.
significant effect in terms of time to achieve cure or cure Additionally, B. bacilliformis expresses haemolysin and an
rate, because all patients in both arms were cured [51]. invasion‐associated gene, which help with erythrocyte
For complicated cat scratch disease, including neurore- tropism [27]. B. bacilliformis is known to cause a transient
tinitis and encephalopathy, a combination of doxycycline cellular immunosuppression due to alterations in the
and rifampicin for 4–6 weeks is recommended [1]. number and function of T cells, which predisposes to
Suspected Bartonella culture‐negative endocarditis should infections like salmonellosis, toxoplasmosis, tuberculosis,
be treated with a 2‐week course of intravenous (IV) gen- reactivated tuberculosis and pneumococcal pneumonia
tamicin and 6‐week course of IV ceftriaxone with or without [80]. The pathogenesis of the eruptive phase of bartonel-
doxycycline for 6 weeks. Documented culture‐positive losis is not well characterized, but the current under-
B. henselae endocarditis requires similar courses of doxy- standing is that verruga peruana is characterized by
cycline and IV gentamicin [50]. angioblastic hyperplasia, loss of cell‐to‐cell contact, acti-
vation of Langerhans cells and positive factor VIII in
Bartonellosis endothelial cells [80]. Recently, a new Bartonella species,
B. ancashensis, has been isolated from the blood of two
History. Bartonellosis was described in Peru in the pre‐ verruga peruana patients [86].
Colombian era, and the first written reports of the disease
were by Spanish conquerors in the 1500s, describing lesions Clinical features. Bartonellosis exhibits two clinical
now typical of verruga peruana [80]. All references to the dis- phases: an acute phase (Oroya fever) and an eruptive
ease mentioned only cutaneous manifestations until 1870, phase (verruga peruana). The acute phase results from
invasion of the bloodstream by B. bacilliformis. Clinically, Verruga peruana usually appears 2–8 weeks after the
this manifests with fever, hepatosplenomegaly, pallor, patient has recovered from Oroya fever, but many patients
jaundice, lymph node enlargement and a systolic present with no prior symptoms. The cutaneous lesions in
murmur. Laboratory evaluation demonstrates severe
verruga peruana display three potential morphologies
haemolytic anaemia, leucocytosis, thrombocytopenia (Figs 41.4–41.6). First, miliary lesions present as multiple,
and hepatic involvement. Almost 70% of patients with small, pruritic, erythematous papules, most commonly
acute‐phase bartonellosis experience at least one located on the lower extremities. Involvement of the mucous
complication [82]. Complications may include menin- membranes may also occur. Second, nodular lesions are
geal signs, seizures, infections, arthralgias, hyperbiliru- larger and fewer in number. Lastly, mular lesions are
binaemia in newborns, congestive heart failure, typically isolated, erythematous, deep‐seated lesions that
myocarditis, pericarditis and multiorgan dysfunction may bleed easily [82]. The most common associated signs
[80]. Weight loss and severe malnutrition are common and symptoms in the eruptive phase include bleeding
in children, and respiratory infections have been found of the lesion, fever, malaise, arthralgias, pallor, fever and
to be the most common paediatric complication of lymphadenopathy [80].
Oroya fever [80]. The acute phase of bartonellosis can be
fatal in 10% of patients [82].
Differential diagnosis. Acute Oroya fever should be
istinguished from other systemic haemotropic bacterial
d
infections. The differential diagnosis for verruga peruana
includes bacillary angiomatosis, Kaposi sarcoma, pyo-
genic granulomas and acquired angiomas [82].
Laboratory and histology findings. Available diagnostic

tests for bartonellosis include blood culture, IFA, soni-
cated immunoblot, PCR, ELISA, thin blood smear and
western blot. Thin blood smear is the fastest and least
expensive method; however, a recent systematic review

(a)
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(b)
Fig. 41.4 (a and b) Isolated facial lesions of verruga peruana in Peruvian Fig. 41.5 Multiple vascular papules of verruga peruana on the legs of a
children. Source: Courtesy of Dr. Hector Caceres‐Rios, Instituto de Salud 15‐year‐old boy from Peru. Source: Courtesy of Dr. Hector Caceres‐Rios,
del Niño, Lima, Peru. Instituto de Salud del Niño, Lima, Peru.
having symptoms, suggesting that IFA may be better for

detecting past infection [87].
Histology of verruga peruana reveals capillary and
endothelial proliferation, similar to pyogenic granuloma
(Fig. 41.7) [88]. An inflammatory infiltrate with neutro-
phils, histiocytes, plasma cells, lymphocytes and mast
cells is present (Fig. 41.8). Despite use of special stains,
organisms are usually not detected on histology.
Immunohistochemical staining reveals strong positivity
for factor VIII‐related antigen [88]. Electron microscopy
demonstrates B. bacilliformis extracellularly in the stroma,
although it has been reported to be phagocytosed in neu-
trophils, histiocytes and endothelial cells [89].
Treatment and prevention. Chloramphenicol (dose of

75 mg/kg per day divided into 4 doses for 14 days) with a
β‐lactam is the treatment of choice for Oroya fever. In
children aged 7–12, ciprofloxacin can be used at 250 mg
Fig. 41.6 Conjunctival lesion of verruga peruana in a girl from Peru. Source: twice daily for 10 days. For verruga peruana, the pre-
Courtesy of Dr. Hector Caceres‐Rios, Instituto de Salud del Niño, Lima, Peru.
ferred treatment is rifampicin 10 mg/kg per day for
2 weeks [50]. An observational study compared treatment
with rifampicin and streptomycin and found no statisti-
cally significant difference in achievement of good
response; however, the intramuscular route of adminis-
tration of streptomycin makes its use problematic in
children [50,51]. Blood transfusions and other supportive
measures are necessary for severely anaemic patients.
Prevention of the disease is mostly through insecticides
for control of sandflies.
Acknowledgement
We would like to thank Diana B. McShane, Heidi H. Kong
and Sarah A. Myers for their contributions and acknowl-
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edge use of material from their chapter in the third e dition

entitled ‘Bartonella Infections: Bacillary Angiomatosis, Cat
Fig. 41.7 Histopathology of verruga peruana skin lesion showing pyogenic
Scratch Disease and Bartonellosis’.
granuloma‐like appearance. Source: Courtesy of Dr. Hector Caceres‐Rios,
Instituto de Salud del Niño, Lima, Peru.
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INFECTIONS
485
C HA PTER 42
Mycobacterial Skin Infections

G. Sethuraman1, Tanvi Dev1 & V. Ramesh2
Department of Dermatology, All India Institute of Medical Sciences, New Delhi, India
1
Department of Dermatology, Vardhman Mahavir Medical College & Safdarjung Hospital, New Delhi, India
2
Introduction, 485 Leprosy in children, 496 Nontuberculous mycobacterial

Cutaneous tuberculosis, 486 infections, 497
Abstract isseminated lesions are quite common in children compared to

d
adults. Systemic infection is also frequent in children. Several
unusual patterns of skin tuberculosis are recognized in the paedi-
Mycobacterial skin infections are important to recognize in the
atric population. Leprosy in children is still prevalent (>100 cases a
paediatric population as they can cause serious morbidity. They
year are reported) in some of the African countries, the Dominican
include tuberculosis, leprosy and various nontuberculous myco-
Republic, the eastern Mediterranean and the western Pacific
bacterial infections. Of these, both tuberculosis and leprosy have
region, especially Micronesia. Borderline tuberculoid leprosy and
caused a heavy disease burden among children, especially in devel-
indeterminate leprosy are the two common forms seen in children
oping countries, owing to several factors such as malnutrition,
and the lesions are usually macular. Nontuberculous mycobacterial
poverty, poor living conditions and emerging human immunodefi-
infections are related to environmental bacteria. The incidence of
ciency virus (HIV) infection. Cutaneous tuberculosis, mostly caused
these infections is increasing, especially in tropical climates. They
by Mycobacterium tuberculosis, can have varied clinical manifesta-
cause several clinical syndromes such as cervical lymphadenopa-
tions depending on the host immune response. Children usually
thy, skin and soft tissue infections following injury and systemic
acquire the infection from infected adults. Skin tuberculosis in
diseases.
children can be severe with a protracted course. Multifocal and
Key points

unusual variants are common in children. Scrofuloderma
progressing to scrofulous gumma, a localized disseminated form
and coexistence of several forms of tuberculosis are frequent in
• Cutaneous tuberculosis and leprosy are two important
children. Drug resistance is also an emerging problem.
mycobacterial infections in children.
• An underlying systemic focus of tuberculosis is more frequent in
INFECTIONS
• Skin tuberculosis is widely prevalent in South‐East Asian
children compared to adults.
countries, especially those that are underdeveloped.
• Leprosy in children commonly presents as the macular form, and
• Scrofuloderma is the most frequent form of skin tuberculosis,
borderline tuberculoid leprosy is frequent.
followed by lupus vulgaris. The occurrence of tuberculids, in
• Nontuberculous mycobacteria cause a spectrum of clinical
particular lichen scrofulosorum, has increased in recent years.
syndromes including cervical lymphadenopathy, injury‐related
• Compared to adults, children with skin tuberculosis have severe
skin infections and soft tissue infections. Buruli ulcer occurs
disease with significant morbidity and disability. Multifocal
mostly in Africa.
involvement with dissemination is common in children. Several
Introduction M. tuberculosis and M. bovis [1]. Besides human and bovine

Mycobacteria are slender aerobic rods that stain weakly types, MTC also includes M. africanum and M. microti.
positive with Gram stain. They have a waxy cell wall Among the MTC, M. tuberculosis is responsible for
composed of mycolic acid, which makes them acid fast, most cases of tuberculosis in humans. M. bovis can be
i.e. they retain the staining even on treatment with a mix- pathogenic for animals, especially dairy cows. Hence,
ture of acid and alcohol. This acid‐fast nature is demon- consumption of unpasteurized milk can lead to develop-
strated by the Ziehl–Neelsen stain. Broadly, the genus ment of oropharyngeal and intestinal tuberculosis.
Mycobacterium is divided into Mycobacterium tuberculosis M. africanum infection is common in tropical Africa [1,2].
complex (MTC), Mycobacterium leprae and atypical or M. leprae causes leprosy, a chronic granulomatous
nontuberculous mycobacteria (NTM) (Table 42.1). MTC infection of the skin and peripheral nerves [3]. NTM, on
consists of two important tubercular bacilli, namely the other hand, encompass a variety of species which are
Table 42.1 Classification of mycobacteria Table 42.2 Classification of skin tuberculosis in children
Organism Disease Primary tuberculosis

Tuberculous chancre
Mycobacterium tuberculosis complex Miliary tuberculosis
Multibacillary
M. tuberculosis Tuberculosis Secondary tuberculosis
M. bovis Tuberculosis Scrofuloderma
Mycobacterium leprae Leprosy Tuberculous gumma
Nontuberculous mycobacteria Orificial tuberculosis
Rapid growers Lupus vulgaris Paucibacillary
M. abscessus Localized nodules, abscesses, draining sinuses, Tuberculosis verrucosa cutis

M. fortuitum injection abscess, infection of the surgical Tuberculids
M. chelonae wounds Micropapular – lichen scrofulosorum
Slow growers Papular – papulonecrotic tuberculid
M. marinum Swimming pool granuloma Nodular – nodular tuberculid (erythema
M. ulcerans Buruli ulcer induratum)
M. avium complex Cervicofacial lymphadenopathy, disseminated
infections in HIV cases
M. haemophilum Cervicofacial lymphadenopathy, skin and soft
tissue infection
M. scrofulaceum Cervicofacial lymphadenopathy
especially lichen scrofulosorum, have been emerging as
M. kansasii Skin and soft tissue infection the second most common form of skin tuberculosis in the
M. szulgai Skin and soft tissue infection recent years, especially in developing countries [8,16].
Classification. Cutaneous tuberculosis may occur as a

ubiquitous in nature. Infections with these mycobacteria result of exogenous inoculation (tuberculous chancre,
have a wide spectrum of presentation, including lymphad- tuberculosis verrucosa cutis and rarely lupus vulgaris) or
enopathy, pulmonary, skin and soft tissue infections, and endogenous spread. The latter may develop either from
even disseminated disease, especially in immunosup- contiguous (scrofuloderma, tuberculosis orificialis cutis),
pressed individuals [1]. haematogenous (acute military tuberculosis, tuberculous
In this chapter, the skin infections caused by these three gumma, lupus vulgaris) or lymphatic spread. Based on
major groups of mycobacteria will be discussed. the bacterial load it can be divided into multibacillary or
paucibacillary forms. The simple working classification of
Cutaneous tuberculosis paediatric skin tuberculosis is true tuberculosis and tuber-
culids. True tuberculosis is further subdivided into pri-
INFECTIONS
Cutaneous tuberculosis is an uncommon form of extrapul- mary and secondary forms depending on previous
monary tuberculosis. It is most commonly caused by sensitization to M. tuberculosis [7,17] (Table 42.2).
M. tuberculosis and rarely by M. bovis [4]. The clinical spec-
trum of paediatric skin tuberculosis is diverse. Most cases Lupus vulgaris
of skin tuberculosis in children have been reported from Lupus vulgaris (LV) is the most common form of skin
developing countries, in particular the South Asian tuberculosis [15]. However, in many paediatric skin
Association for Regional Co‐operation (SAARC) nations tuberculosis series it is the second most common type
and African countries. Skin tuberculosis in children is reported [7–10,12,15,16]. LV occurring as a result of
quite severe with significant morbidity and disability. systemic haematogenous spread of M. tuberculosis affects
the head and neck region. In tropical countries like India,
Epidemiology. Cutaneous tuberculosis accounts for about LV can also develop due to exogenous inoculation on the
0.5% of the dermatoses in Europe [4], 1.3% in Ethiopia [5], gluteal region, knees, feet and hands [7,17].
2% in Morocco [6], 0.1–0.5% in India [7–10] and 0.066– LV classically presents as slowly progressive, irregular
0.04% in Hong Kong [11]. In Ethiopia, paediatric skin and infiltrative plaques with characteristic central
tuberculosis accounted for 24% of all cutaneous tubercu- atrophic scarring and advancing margins (Figs 42.1–42.3).
losis cases [5]. In Morocco, 60% of skin tuberculosis cases The erythematous elevated edge of the lesion may show
were under the age of 30 years [6]. In Pakistan, 45% of several soft, translucent, erythematous papules and/or
cutaneous tuberculosis patients were children <10 years coalescent plaques, which on diascopy reveal yellow‐
of age, and another 37% were aged between 10 and brown apple‐jelly nodules. These nodules represent
20 years [12]. In Japan, cutaneous tuberculosis was microscopic granulomas. This particular subtype, also
observed in all age groups before 1980. Interestingly, no known as plane LV, predominantly affects the head and
case has been reported in the age group 0–19 years neck [15].
between 1981 and 2002 [13]. In India, skin tuberculosis in LV occurring on the extremities and buttocks due to the
children accounts for 18.7–54% of all cases of skin tuber- exogenous route may show longstanding larger lesions
culosis [8,14–16]. with excessive hyperkeratosis. The epidermal hyperpro-
The two most common forms of paediatric skin tuber- liferation in keratotic or psoriasiform LV is possibly due
culosis are scrofuloderma and lupus vulgaris. Tuberculids, to immunological events influenced by the presence of
Chapter 42 Mycobacterial Skin Infections 487
Fig. 42.1 Lupus vulgaris: large erythematous and infiltrated plaques with Fig. 42.2 Lupus vulgaris: large erythematous and hyperkeratotic plaque
keloidal scarring. involving bilateral gluteal region causing anal stricture.

INFECTIONS
(a) (b)
Fig. 42.3 (a and b) Lupus vulgaris: multifocal involvement involving bilateral gluteal region and left knee.
concomitant chronic pyogenic infections in hot and Genital involvement is usually associated with scarring,
humid tropical climates [15]. mutilation and ulceration [15].
The natural course of LV is characterized by its chronic Several unusual variants of LV have been described.
indolent behaviour. The lesions of LV can progress to The authors have described symmetrical LV involving
become very large, sometimes affecting the entire ana- both the knees, possibly due to exogenous inoculation of
tomical region. During its course, chronic secondary mycobacteria, and also symmetrical LV developing in the
infections are common, resulting in crusting and ulcera- vicinity of a scrofuloderma sinus due to autoinoculation
tion. Such lesions may heal with hypertrophic, keloidal or tuberculosis [18,19]. Other variants include sporotrichoid,
atrophic scarring (Fig. 42.2). Sometimes, LV may result in kissing LV involving the gluteal cleft, and multifocal
irreversible contractures, such as deformities of nasal or lesions [7,17,20]. Rarely LV can also develop following
ear cartilage, flexion contractures of extremities, etc. bacillus Calmette–Guérin (BCG) vaccination [21].
Rarely, squamous cell carcinoma may develop in long- Histopathology of LV usually reveals psoriasiform epi-
standing LV [8,15,16]. dermal hyperplasia and a diffuse upper dermal granu-
Involvement of the genitalia is uncommon. Both vulval lomatous reaction composed predominantly of epithelioid
and scrotal involvement has been described in children. cells. Acid‐fast bacilli (AFB) are usually not detected [7,17].
Scrofuloderma with extensive swellings, ulcers and sinus tracts forming

Scrofuloderma (SFD) is the most common pattern of skin finger‐like extensions leading to a condition known as
tuberculosis in children. It is due to the contiguous spread scrofulous gumma, which is mostly reported from India
of tuberculous infection from an underlying focus. Lymph (Fig. 42.8) [15].
nodes are the most frequently associated focus followed The authors have described symmetrical SFD involving
by bone and joints, testes and lacrimal glands. Among the bilateral ankles with underlying tuberculosis of the bones
lymph nodes, cervical and inguinal groups are often [19]. Disseminated SFD affecting the left leg and foot,
involved. Other lymph nodes such as supraclavicular, right hand and inguinal region has been reported in a
axillary, occipital, parasternal, submandibular and malnourished child who also had widespread tubercu-
epitrochlear groups may also be affected [7,17]. lous infection of several joints, lungs and cold abscess
SFD begins as a subcutaneous cold abscess (Fig. 42.4) [22]. SFD occurring in a segmental pattern is uncommon
which, over a period of time, ruptures to form an ulcer or (Fig. 42.9). Tuberculous cold abscess or SFD developing
sinus tracts (Fig. 42.5). These ulcers are typically shallow in association with other forms of skin tuberculosis such
with bluish margins and undermined edges (Fig. 42.6). as LV (Fig. 42.10), tuberculosis verrucosa cutis and lichen
There may be one or several ulcers in the affected area scrofulosorum is also recognized [7,17].
(Fig. 42.7). These ulcers and sinus tracts may heal sponta- An underlying systemic focus, including lymph nodes,
neously and leave behind the characteristic puckered lungs, intestine and bones, has been reported in about
scars that are the hallmark of healed SFD. In some cases 46% of cases of paediatric skin tuberculosis [8,23].
several adjoining groups of lymph nodes are involved A skin biopsy should be taken from the edge of the
ulcer or the sinus tract. It shows mixed cell granulomas
composed of epithelioid cells admixed with acute
inflammatory cells. Necrosis is often identified, which
may show AFB on Ziehl– Neelsen (ZN) staining [17].
INFECTIONS
Fig. 42.4 Scrofuloderma: tuberculous cold abscess on the anterior neck.
Fig. 42.6 Scrofuloderma: a large shallow ulcer with bluish margin on the

clavicular area.
Fig. 42.5 Scrofuloderma: tuberculous cold abscess with multiple sinuses Fig. 42.7 Scrofuloderma: multiple ulcers overlying a tuberculous
on the inguinal region. osteomyelitic focus on the wrist.
(b)
(a)

INFECTIONS
(c) (d)
Figs 42.8 (a–d) Scrofulous gumma. Tuberculous cold abscesses involving inguinal, cervical and axillary groups of lymph nodes with extensive swellings,
ulcers and sinus tracts forming finger‐like extensions.
Tuberculosis verrucosa cutis also occur in children. It is often difficult to distinguish it

Tuberculosis verrucosa cutis, otherwise known as warty from the hypertrophic variant of LV. However, there is
tuberculosis, accounts for 12–15% of paediatric skin tuber- much more verrucosity, whereas there is much less mutila-
culosis. It occurs as a consequence of exogenous inoculation than in LV [7,15,17].
tion of M. tuberculosis in previously sensitized individuals.
Clinically, it is characterized by the presence of warty or Tuberculous gumma
verrucous plaques on the acral extremities (Fig. 42.11). Tuberculous gumma, also known as tuberculous meta-
Rarely, the scrotum and gluteal region can also be affected. static abscess, results from haematogenous dissemination
The surface may show fissuring that may extrude pus, and of the organism from a primary focus during periods of
there is often perilesional erythema. Lesions can be unilat- lowered resistance. It is often seen in malnourished and
eral or bilateral. A preceding history of trauma is often immunocompromised children. It is considered as a severe
present. Tuberculosis verrucosa cutis is mostly solitary, variant of SFD as the gummatous lesions resemble SFD
however bilateral, multifocal or segmental patterns can clinically, histologically and bacteriologically. Typically
Orificial tuberculosis
Orificial tuberculosis occurs as a result of autoinoculation
of M. tuberculosis in sputum or stool onto the skin. It is
often seen in immunocompromised children. Clinically it
presents as painful and refractory necrotic ulcers in the
perioral and perianal regions. Underlying pulmonary
and intestinal tuberculosis is usually associated [7,17].
Sporotrichoid cutaneous tuberculosis

Sporotrichoid tuberculosis is a rare form of skin tuberculo-
sis that has been reported in 3% of all cases with cutaneous
tuberculosis. It mimics the subcutaneous linear lymphang-
itic form of sporotrichosis and sporotrichoid NTM.
Fig. 42.9 Scrofuloderma in a segmental pattern over the right thoracic Sporotrichoid tuberculosis occurs mainly by lymphatic
chest wall (T4). spread, which would explain the linear arrangement of
the lesions in the same limb. In all the published reports,
the sporotrichoid lesions have been described mostly in
children and at times in young adults. The efficient lym-
phatic drainage in children and their physical activity pre-
disposing them to trauma may be responsible for this rare
lymphangitic form of skin tuberculosis [20,24,25].
Sporotrichoid tuberculosis is called inverse sporotrichoid
when the proximal half of the lower limb is affected due
to retrograde lymphatic spread from the inguinal lymph
nodes [20].
Tuberculids
Tuberculids are considered to be delayed hypersensitivity
reactions to M. tuberculosis in individuals with strong
immunity. Children with tuberculids often have an under-

lying focus of tuberculosis. The key diagnostic criteria
include the following: (i) absence of the organisms in the
lesional smear or culture; (ii) strongly positive Mantoux
INFECTIONS
Fig. 42.10 Unilateral tuberculosis showing cold abscess involving the groin reaction; (iii) presence of concomitant or past tuberculo-
and multifocal lupus vulgaris on the sole. sis; and (iv) clinical resolution with antitubercular treat-
ment. Although M. tuberculosis is not identified in either
smear or culture, polymerase chain reaction (PCR) tech-
niques have demonstrated mycobacterial DNA in lesional
biopsies of tuberculids [7,17].
Tuberculids can be broadly divided into true and facul-
tative tuberculids. Lichen scrofulosorum and papulone-
crotic tuberculids are true tuberculids, in which M.
tuberculosis significantly contributes to the disease patho-
genesis. Facultative tuberculids (erythema induratum
and erythema nodosum) have diverse aetiological factors
and M. tuberculosis is one of them [7,17].
Lichen scrofulosorum
Lichen scrofulosorum (LS) is characterized by lichenoid
eruption of minute papules in children and adolescents
with tuberculosis. Hebra initially described it in 1868.
Subsequently, many investigators have reported several
Fig. 42.11 Tuberculosis verrucosa cutis on the sole showing verrucous cases of LS across the world. Most LS cases are due to
plaques. pulmonary or extrapulmonary infection with M. tubercu-
losis [26,27]. It has also been reported after BCG vaccina-
tion. Rarely atypical mycobacteria such as M. szulgai and
tuberculous gumma is characterized by multiple, non- M. avium‐intracellulare complex can also cause LS [28].
tender, subcutaneous nodules that may break down to LS was a rare tuberculid, but according to reports from
form deep punched‐out ulcers and sinuses (Figs 42.12 developing countries, the prevalence of LS is increasing.
and 42.13) [7,15,17]. In two different studies from India, LS was the second

INFECTIONS
Fig. 42.12 (a and b) Tuberculous gumma showing multiple punched‐out ulcers with undermined edges and bluish margins.
most common pattern of paediatric skin tuberculosis, have also been described, and may be a marker of
seen in 23.5% and 33% respectively [8,16]. isseminated systemic tuberculosis (Fig. 42.16) [32].
d
Clinically, LS is characterized by an asymptomatic In a large prospective study of 39 cases of LS, 82% were
eruption of lichenoid or skin‐coloured follicular and patients younger than 15 years. Twenty two (56.4%) were
perifollicular papules, ranging from 0.5 to 3 mm in diam- boys while 17 (43.6%) were girls. The trunk was the com-
eter (Figs 42.14 and 42.15). They are mostly seen over monest site affected. An underlying tuberculous focus
the abdomen, chest, back and proximal extremities. was observed in 28 (72%) cases. Of these, 13 (33%) had
Occasionally other body sites such as genitalia, palms and lymph node tuberculosis (submandibular and cervical),
soles can also be affected. The lesions may last several 11 (28%) had pulmonary involvement, three had tubercu-
months and heal spontaneously without any scarring. loma of the brain, and one had spinal tuberculosis along
Several unusual variants such as micropustular, nodulo‐ with paravertebral cold abscess. Six patients (15%) also
ulcerative, and annular discoid plaques have been had associated cutaneous tuberculosis. All the patients
reported [26,27,29–31]. Widespread psoriasiform plaques had a strongly positive Mantoux reaction [27].
Fig. 42.13 Tuberculous gumma with ocular involvement.
Fig. 42.15 Lichen scrofulosorum showing large lichenoid scaly plaques.

INFECTIONS
(a)
Fig. 42.14 Lichen scrofulosorum showing lichenoid follicular papules on

the trunk.
Histologically, LS reveals noncaseating, epithelioid cell

granulomas in the upper dermis and also around the der-
mal appendages.
Papulonecrotic tuberculids
Papulonecrotic tuberculid (PNT) is a rare entity of tuber- (b)
culids. Most cases of PNT have been reported from South Fig. 42.16 (a and b) Lichen scrofulosorum showing psoriasiform plaques
Africa. In the largest series of 91 cases of PNT seen over a with pustules.
(a) (b)
Fig. 42.17 (a and b) Papulonecrotic tuberculid showing papulonecrotic ulcers and varioliform scars over trunk and extremities.
vulva, perineum and trunk [35]. PNT occurring in associa-

tion with disseminated LV has also been described [36].
The vast majority of children with PNT have associated
pulmonary tuberculosis or phlyctenular conjunctivitis.

Histologically, early lesions show leucocytoclastic vascu-
litis with a wedge‐shaped dermoepidermal infarct. Older
lesions may show noncaseating ill‐formed granulomas
along with lymphohistiocytic vasculitis. Immunologically,
INFECTIONS
PNT is considered as an Arthus reaction followed by a
delayed‐type hypersensitivity reaction to the intravascular
release of M. tuberculosis. During the process of immuno-
logical reactions, bacillary emboli are opsonized with anti-
bodies and complement. The subsequent complement
activation and polymorphonuclear leucocyte activation
results in the release of proteolytic enzymes leading to vas-
cular necrosis. The consequent mononuclear cell response
Fig. 42.18 Papulonecrotic tuberculid involving the glans penis with a destroys the bacilli. Sometimes the tubercle bacilli may sur-
healed sinus and a punched‐out scar. vive, leading to the development of LV [33].
period of 17 years, 26% of the cases were younger than 10 Erythema induratum of Bazin
years of age, and 21% were between 11 and 20 years [33]. Erythema induratum of Bazin (EIB) is rare in children.
However, Jordaan et al. were the first group from the The pathogenesis appears to be similar to that of PNT, but
same region to describe in detail the clinicopathological EIB affects larger vessels. Clinically, it presents on the calf
findings of eight children with PNT [34]. as deep‐seated reddish blue nodules that break down to
PNT affects children and young adults. Typically the form an ulcer that heals with atrophic scarring [37].
lesions are distributed symmetrically on the acral extremi- Simultaneous occurrence of PNT and EIB has been
ties, ears and extensor aspect of the joints. Clinically, the described in a child [38]. Histologically, EIB shows a lobu-
lesions are papulonecrotic and/or crusted ulcers, measur- lar panniculitis with vasculitis. In about 50% of the cases
ing 1–5 mm, which may heal with atrophic or varioliform mycobacterial DNA can be isolated by PCR [37].
scars over several weeks (Fig. 42.17a and b). Continuous Nodular tuberculid is a variant in which there is
crops of new lesions may develop over a period of several involvement of deep dermis and superficial fat, in con-
months or years [34]. Involvement of genitalia is not trast to the deeper involvement in EIB. The inflamed ves-
uncommon with deep punched‐out ulcers healing with sels in nodular tuberculid are present in the superficial fat
disfigurement (Fig. 42.18). Ramdial et al. described PNT in at the dermoepidermal junction, whereas in EIB they are
a child who had adult-pattern involvement of the face, situated at a deeper level [37].
Erythema nodosum than 2 years, diagnosis of tuberculous infection should

Erythema nodosum is a nonspecific entity characterized therefore not rely on the result of IGRA alone [40].
by painful subcutaneous nodules on the shins that last
for about 2 weeks and heal with hyperpigmentation. Histopathology
Histology shows septal panniculitis without vasculitis. The characteristic histological features of cutaneous
Several aetiological factors are associated with erythema tuberculosis include the presence of tuberculoid granulo-
nodosum [7,17] (see Chapter 102). mas consisting of epithelioid cells, giant cells and lym-
phocytes. The overall clinicopathological concordance is
BCG and cutaneous tuberculosis noted in 64–85% of the cases. In general, the presence of
The BCG vaccine is a live attenuated vaccine derived from diffuse dermal epithelioid cell granulomas along with
M. bovis. It is given soon after birth and is recommended in epidermal hyperplasia suggests either LV or tuberculosis
all tuberculosis endemic countries excluding the USA and verrucosa cutis. These are paucibacillary forms in which
parts of Europe [21]. Usually it is safe to administer BCG; AFB are often not seen. In SFD and gummatous tubercu-
however local reactions are known to occur. Rarely there losis, there would be dermal mixed cell granulomas com-
may be persistent ulceration, infection, abscess and keloid posed of epithelioid cells and histiocytes admixed with
formation. A few cases may develop maculopapular rash neutrophils and eosinophils. Necrosis is often seen and
and erythema nodosum. Paradoxically, a few children AFB can be detected [7,17].
may develop LV, SFD and tuberculids [7,17].
Studies have shown that the BCG vaccine prevents Culture
approximately 50% of pulmonary tuberculosis and Culture positivity varies from 5% to 55% [17]. Vashisht
50–80% of severe and disseminated tuberculosis, includ- et al. identified the organism in 36.8% and 13.6% of biop-
ing meningeal involvement. Studies on skin tuberculosis sies in SFD and LV respectively [16]. With the use of mul-
have shown no difference in the clinical spectrum or out- tiple media and Kirchner’s liquid medium for storing the
come of skin tuberculosis in BCG‐vaccinated and unvac- tissue biopsy, the yield of organisms is better. In a com-
cinated children [7]. parative study of the radiometric BACTEC™ 460 TB cul-
ture system and Lowenstein–Jensen (LJ) medium for the
isolation of M. tuberculosis in 35 patients with cutaneous
Diagnosis. Diagnosis is usually based on the classical tuberculosis, 26 isolates of the organism were identified.
clinical morphology and supported by laboratory investi- Of these, four (11.4%) grew on LJ medium, 17 (48.5) on the
gations [39]. Demonstration of M. tuberculosis in the tissue
BACTEC™ system, and five on both the media. It was

smear or biopsy is the gold standard in the diagnosis of found that the sensitivity of BACTEC™ system was sig-
skin tuberculosis. In general, all children with skin tuber- nificantly better than that of LJ medium (62.8% vs. 25.7%,
culosis should be investigated for a tuberculous focus in P <0.002). The combined sensitivity for isolation on both
INFECTIONS
the lungs, lymph nodes, bone and joints, nervous system the media was 74.3% [41].
and other relevant organs. Fine needle aspiration cytology (FNAC) is a simple and
rapid diagnostic procedure. The aspirated air‐dried smear
Screening tests can be stained with Giemsa and ZN stain. The cytomor-
The tuberculosis skin test (TST, formerly the Mantoux test) phological features in LV include cohesive epithelioid cell
is a good screening test to detect the presence or absence of granulomas along with chronic inflammatory cells, while
tuberculous infection. The test consists of an intradermal in SFD there will be predominant caseous necrosis with or
injection of 0.1 mL (5 TU) of purified protein derivative on without granulomas along with acute inflammatory cells
the volar aspect of the forearm, and reading is performed [42]. With FNAC, the identification of AFB is easier, espe-
after 48 hours. An induration of 10 mm or more is sugges- cially in SFD and lymph node tuberculosis. In an Ethiopian
tive of infection or disease. Strongly positive reactions or study of 143 cases (including children) with SFD, AFB
bullous reactions are seen in tuberculids. The test may be were identified in all the cases by ZN staining [5]. In
negative in disseminated military tuberculosis or coexist- another study of 19 cases of SFD, AFB were identified in
ent human immunodeficiency virus (HIV) infection. 79% of cases in the aspirate compared to only 16% in the
False‐positive results are observed in BCG‐vaccinated biopsy specimens [42]. Hence, FNAC can be used as an
children. Interferon‐γ release assays (IGRA) are based on alternative diagnostic test in cutaneous tuberculosis, par-
the release of interferon by blood monocytes and lympho- ticularly SFD associated with lymph node tuberculosis.
cytes upon stimulation by highly specific antigens of
M. tuberculosis. They are equally sensitive but more specific PCR
than TST and can thus avoid false‐positive results due to PCR amplification may be a useful tool for the detection
BCG vaccination or exposure to NTM. Combination of of mycobacterial DNA and is particularly helpful to dif-
TST and IGRA may increase the detection rate of children ferentiate tuberculosis from other granulomatous condi-
at high risk of progression from tuberculous infection to tions such as sarcoidosis, fungal granulomas and NTM.
tuberculous disease [40]. In children >5 years IGRA are However, there are conflicting reports of its usefulness in
applicable in all situations where TST is indicated. the diagnosis of skin tuberculosis. Several of the common
However, the sensitivity of IGRA in younger children is forms of skin tuberculosis have been confirmed by
currently not sufficiently established. In children younger PCR by various investigators. IS6110 based conventional
Table 42.3 Antitubercular therapy (ATT)
Drug Dosage/kg/day Side‐effects Monitoring
First‐line drugs
Isoniazid (H) 10 (7–15) mg/kg/day, Hepatotoxicity Liver function test
max. 300 mg/day Peripheral neuropathy
Ataxia
Acne
Rifampicin (R) 15 (10–20) mg/kg/day, Hepatotoxicity Liver function test
max. 600 mg/day Orange‐coloured body fluids
Pruritus
Drug interactions (P450)
Pyrazinamide (Z) 35 (30–40) mg/kg/day, Hyperuricaemia Renal function test
max. 2000 mg Hepatotoxicity
Arthralgia
Rash, photosensitivity, pruritus
Ethambutol (E) 20 (15–25) mg/kg/day, Retrobulbar neuritis Fundus examination (contraindicated
max. 2000 mg Rash in younger children)
Second‐line drugs
Amikacin 15 mg/kg /day Ototoxicity Renal and auditory function test
single dose IM or IV Nephrotoxicity
Kanamycin 15/kg/day IM
one or two divided doses
Streptomycin 20–40 mg/kg/day IM
Max. 1000 mg/day
Ciprofloxacin 15–30 mg/kg/day PO in two GI (nausea, vomiting, abdominal CNS evaluation and
doses discomfort, diarrhoea) electrocardiographic monitoring,
Levofloxacin 10 mg/kg/day CNS (headache, dizziness, rarely blood sugar levels
Ofloxacin 10 mg/kg/day in two doses hallucinations, delirium and seizures)
Gatifloxacin 10 mg/kg/day single oral dose Skin rash/ photosensitivity
Prolongation of QT interval
Drugs for nontuberculous mycobacteria

Clarithromycin 15 mg/kg/day q. 12 hourly oral GI intolerance No evaluation required
Cotrimoxazole 5–8 mg/kg of TMP and Haematological side‐effects, GI intolerance, Haemogram, liver and renal
(trimethoprim [TMP]– 25–50 mg/kg of SMZ per hypersensitivity reaction, vasculitis, renal functional tests
sulfamethoxazole [SMZ]) day q. 12 hourly oral damage, CNS disturbance rarely
INFECTIONS
Doxycycline 5 mg/kg/day q. 12 hourly oral GI intolerance, photosensitivity, hepatic Liver and renal function tests
(not in children <8 years) and renal toxicity, discolouration of teeth
Max. 200 mg/day Cutaneous pigmentation with minocycline
Minocycline 4 mg/kg/day q. 12 hourly (not
in children <8 years)
Max. 200 mg/day
CNS, central nervous system; GI, gastrointestinal; IM, intramuscular; IV, intravenous; PO, per os (oral).
PCT/nested PCR has been found to be useful in the diagnosis treatment with ATT [7,17]. Dosing schedule, side‐effects
of skin tuberculosis and superior to 16S rRNA gene based and monitoring evaluation are given in Table 42.3.
PCR [43,44]. However, others have not found PCR to be a
useful complement to the clinical and histological diagno- Drug resistance
sis [45]. Hence, the sensitivity and specificity of PCR need Multidrug resistance (MDR) is an emerging problem in
better validation in order to recommend it for diagnosing children with skin tuberculosis. Multidrug‐resistant
cutaneous tuberculosis in the routine clinical setting. strains are isolates that are resistant to rifampicin and
INH on drug sensitivity testing, with or without resist-
Treatment. The standard antitubercular therapy (ATT) ance to other drugs. MDR should be suspected in children
for skin tuberculosis consists of an initial 2 months of with poor or no response to first‐line ATT with clinical
intensive‐phase regimen with four drugs (ethambutol [E], deterioration and where other causes of treatment failure
isoniazid [INH, H], rifampicin [R] and pyrazinamide [Z]), are not proven. The predisposing factors include high dis-
followed by 4 months of maintenance with two drugs ease burden, endemicity of tuberculosis and emerging
(HR) (2 EHRZ/4HR). Pyridoxine (10–25 mg/day) should HIV co‐infection.
also be given in order to prevent INH‐related neuropathy. MDR has been reported in all common forms of skin
Children with underlying bony or other organ tuberculo- tuberculosis, namely LV, SFD and tuberculosis verrucosa
sis or associated HIV infection need longer periods of cutis [46–48]. Aggarwal et al., in their study of drug
s usceptibility testing conducted in Chennai, South India, Table 42.4 The proportion of childhood leprosy cases reported in different
showed resistance to one or more ATT for 12 (46.2%) of tropical countries
the 26 mycobacterial isolates. Of the 15 isolates from LV,
six resistant isolates were identified, and of the nine iso- Region Period of Age group Proportion
reporting (years) of childhood
lates from SFD, five resistant isolates including four MDR
leprosy (%)
were identified [41].
Culture and drug susceptibility testing should be done India
in all suspected cases of MDR cutaneous tuberculosis and • South India [51,52] 1990–1995 <14 33–34
these patients should be treated with second‐line ATT for • Delhi [53] 1992–2003 <15 7.71
a period of 18 months (Table 42.3). • Delhi [54] 2000–2009 <14 9.6
• Chandigarh [55] 2001–2011 <18 4.8
Brazil (Aracaju) [56] 2001–2012 <15 8.3
Leprosy in children Colombia [57] 1994–2000 <15 7
Southern Ethiopia [50] 1999–2011 <15 7.4
Leprosy is a chronic infectious disease caused by M. lep-
rae, which is a Gram‐positive obligate intracellular organ-
ism that has an affinity for Schwann cells and cells of the
reticuloendothelial system, where it occurs in clumps or reported in different tropical countries are summarized
globi. Leprosy affects mainly the skin and peripheral in Table 42.4 [50–57].
nerves, leading to physical disabilities. Clinically it mani- A history of familial contact has been reported in 0.66–
fests itself along a spectrum with two poles, namely 47% of cases [58]. This may be a concern as it implies con-
tuberculoid and lepromatous, and borderline forms in tinuing transmission of the disease.
between [2,3].
Clinical spectrum of leprosy in children. In India, hypo-
pigmented macules are the most commonly observed
Epidemiology. Leprosy has been a major public health skin lesions. Plaques are also seen, but nodular lesions are
problem but with implementation of multidrug therapy uncommon. All five types defined under the Ridley–
in 1985, the prevalence of leprosy reduced drastically by Jopling classification, namely TT, BT, BB, BL and LL, can
as much as 45%. With strong and effective control meas- occur in children (Box 42.1 and Figs 42.19–42.25). However
ures by the World Health Organization (WHO) and the most common form of leprosy reported in various
national‐level programmes worldwide, the goal of elim- studies from India is BT leprosy [51–55,58,59]. In a series
ination of leprosy (defined as a reduction of leprosy of 59 cases, BT leprosy was seen in 67.8%, followed by LL
prevalence to <1 case per 10 000 population) was in 12% and BL in 10%. Twenty three cases (39%) had a
achieved at global level by the year 2000. Most countries single skin lesion, 2–5 lesions were seen in 12 (20%), and
INFECTIONS
also reached the goal of elimination at national level by >5 lesions or diffuse infiltration in 22 (37%) of the cases.
2005 [49]. Thickened nerves were observed in 48 (81.4%), of whom
The global leprosy prevalence at the end of the first 44% had single nerve and 56% had more than one nerve
quarter of 2014 was 0.32 per 10 000 population, with the trunk involvement. Disability was noted in 24 (40%) chil-
maximum prevalence of 0.62 per 10 000 population in the dren [55]. In another series of 138 cases from South India,
South East Asia Region (SEAR). The new case detection BT leprosy was seen in 66%, followed by indeterminate
rate (during 2013) globally was 3.81 per 100 000 popula- leprosy (IL) in 19.4% and TT in 10% [59]. In Brazil, pauci-
tion. SEAR has the highest number of new cases and bacillary leprosy (182, 68.4%) is more common than multi-
accounts for 72% of the global leprosy burden. Fourteen bacillary leprosy (84, 31.6%). Tuberculoid (95, 35.7%) and
main endemic countries, which include six each from IL (92, 34.6%) forms are the two most commonly reported.
SEAR and Africa and one each from America and the A total of 24 children had deformities [56]. In southern
western Pacific region, reported >1000 new cases in 2013. Ethiopia, multibacillary leprosy was the most common
India reported the highest number of new leprosy cases type, seen in 95% of the children and 84% of adolescents.
(126 913) followed by Brazil (31 044) and Indonesia Six (27.3%) children and 18 (28.6%) adolescents had
(16 856). India alone accounts for 58.85% of the global deformities [50].
leprosy burden [49]. Overall clinicopathological concordance is seen in 76%
The percentages of children among new leprosy cases of the cases. Slit skin smear positivity ranges from 5% to
in countries reporting ≥100 cases in the different WHO 25%. Lepra reactions have been reported in 1–30% (type 1
regions are as follows: African region – Comoros 29%, reactions, 1.2–28%; type 2 reactions, 0.2–5.8%). However,
Niger 0.9%; America – Dominican Republic 9.4%, in some studies reactions are not reported. Relapse can
Argentina and Mexico 0.6%; eastern Mediterranean occur in 1–7% of the cases [58,60].
region – Yemen 12.3%, Sudan 2.1%; SEAR – Indonesia
11.9%, Nepal 4.1%; western Pacific region – Micronesia Diagnosis. Diagnosis is based on the classical clini-
39.5%, China 1.5% [49]. cal morphology supported by slit skin smear and
Overall, several epidemiological studies indicate histopathology. Serological tests (anti‐phenolic gly-

that childhood leprosy accounts for about 5–10% of the colipid I, PGL‐I) are often used to screen for subclinical
cases [50]. The proportions of childhood leprosy cases infections [61].
Box 42.1 Spectrum of leprosy
Tuberculoid leprosy (TT) • As the disease progresses, the macules may show infiltration or
papulonodules, especially on the face and ears.
• TT affects skin and peripheral nerves. However TT seldom leads to
• Peripheral nerve involvement is asymmetrical and nerve tenderness
peripheral nerve damage or disability.
and damage is less pronounced than in BT.
• Lesions are dry, anaesthetic and hypopigmented with sharply defined
• Cases of BL that might have downgraded from BT may show features
infiltrated margins and loss of appendages. Erythema may be seen in
of nerve damage or concurrent lesions of BT.
fairer skin types.
• Lesions are usually single or few.
Lepromatous leprosy (LL)
Borderline tuberculoid leprosy (BT) • Numerous small symmetrically distributed normoaesthetic and shiny
macules become more and more infiltrated with disease progression,
• The lesions resemble TT but the marginal definition is less
leading to a waxy appearance.
pronounced, possibly with pseudopodia or satellite lesions. The
• Sites of predilection for infiltration include the face, particularly
lesions may also show a palpable feeder nerve.
forehead, zygoma, chin and earlobes, and also the cooler dorsal areas
• Number of lesions may be up to 10 or 20.
of the body.
• Hypopigmentation, dryness and anaesthesia tend to be less pronounced.
• Infiltration may lead to loss of skin creases and extreme cases may
• In contrast to TT, nerve damage is severe and much more widespread
result in ‘leonine’ facies.
as reaction is more frequent.
• Immune zones or the warmer areas of the body such as axillae, groin,
• Untreated BT leprosy may continue with episodes of reaction or
midline of back, perineum and scalp are preferentially spared.
deformities, which might eventually heal or may progress towards the
• Symmetrical enlargement of the peripheral nerves with glove and
LL spectrum.
stocking sensory impairment occurs in later stages of disease
progression.
Mid‐borderline leprosy (BB)
• Signs of nerve damage such as wasting of muscles and/or deformities
• This is the unstable part of the spectrum and usually manifests as are an indicator of downgraded spectrum.
reactional states, either upgrading or downgrading. • Systemic involvement can be seen as there is a high bacterial load and
• Has dimorphous features with ‘punched‐out’ inner and sloping outer bacillaemia.
margins (inverted saucer appearance). Sometimes present as
‘geographical’ lesions. Indeterminate leprosy (IL)

• Lesions tend to occur in symmetry.
• Presents as one or few slightly hypopigmented ill‐defined macules on
• Nerve damage is variable.
the face, buttocks or extensor aspect of extremities.
• In most cases IL lesions heal spontaneously without any sequelae.
Borderline lepromatous leprosy (BL)
• A few cases may progress either to tuberculoid or lepromatous poles.
INFECTIONS
• Earlier lesions are multiple, ill‐defined shiny macules, which are
distinct and tend to show symmetry. The intervening skin is clinically
as well as bacteriologically normal.
Treatment. The WHO recommendations for multidrug

Nontuberculous mycobacterial
therapy in children (10–14 years) are given in Table 42.5. infections
The appropriate dose for children under 10 years of age NTM are a group of AFB which encompass all mycobac-
is as follows: rifampicin, 10 mg/kg monthly; clofazimine, terial species other than M. tuberculosis complex and M.
1 mg/kg daily and 6 mg/kg monthly; dapsone, 2 mg/kg leprae. Unlike the other two groups of mycobacteria,
daily. which are pathogenic to humans, the NTM are mostly
found in soil and water. Most of these organisms are
BCG vaccination and leprosy. The role of the BCG vaccine in nonpathogenic; however some can cause infections in

leprosy was first described by Fernandez in 1939 who humans. Based on their cultural characteristics, they are
observed lepromin conversion among lepromin‐negative broadly divided into rapid growers and slow growers
healthy children following BCG administration. Subse- (Table 42.1). The major clinical syndromes associated with
quently several studies have been published with varying NTM infections include: lymphadenitis, pulmonary dis-
ranges of protective efficacy (20–90%). In a meta‐analysis on ease, disseminated disease and skin and soft tissue infec-
the protective aspect of BCG vaccine in the prevention of tions. Of the various skin infections, fish tank or swimming
leprosy, the author has reported that 13 (54.2%) studies dem- pool granuloma caused by M. marinum and Buruli ulcer
onstrated >50% efficacy/effectiveness and five (20.9%) stud- caused by M. ulcerans are the two species‐specific NTM
ies showed >75% protection against leprosy. Since familial disorders [1,2,63,64].
contacts play an important role in transmission in children,
a simple and inexpensive measure like BCG vaccination Epidemiology. The incidence of NTM infections has
may partly help to halt the transmission of the disease [62]. increased in the last two decades owing to increasing
Fig. 42.19 Borderline tuberculoid leprosy on the face. Source: Courtesy of

Neena Khanna.
Fig. 42.21 Borderline tuberculoid leprosy in reaction on the face, showing
annular erythematous and oedematous plaque with scaling. Source:
Courtesy of Saurabh Singh.
INFECTIONS
Fig. 42.20 Borderline tuberculoid leprosy with reaction. Source: Courtesy

of Neena Khanna.
nonsurgical cosmetic and implant procedures, wide-

spread use of immunosuppressive therapy and HIV
infection. Most of the published data relating to NTM are
available for adult populations in the developed coun-
tries [1]. Data for the epidemiology of NTM in children
are scarce. The overall incidence of NTM infections in
children varies between 0.3 and 1.9 per 100 000 [65]. In
Fig. 42.22 Borderline tuberculoid leprosy in downgrading reaction
developed countries, epidemiological studies have showing erythematous and oedematous plaques along with multiple
focused mainly on cervicofacial lymphadenitis, which is mid‐borderline (BB) lesions showing inverted saucer appearance on the
the most common clinical syndrome associated with extremities.
Fig. 42.23 Mid‐borderline (BB) leprosy showing multiple annular plaques

with inverted saucer appearance on the buttocks. Source: Courtesy of Fig. 42.25 Indeterminate leprosy showing a hypopigmented macule with
Saurabh Singh. ill‐defined margin on the forehead. Source: Courtesy of Saurabh Singh.

INFECTIONS
(a) (b)
Fig. 42.24 (a and b) Borderline lepromatous leprosy in reaction showing multiple erythematous, oedematous and infiltrated plaques over face and ear.
Source: Courtesy of Saurabh Singh.
NTM in children [1]. Blyth et al., in their Australian of the cases had lymphadenopathy, mostly in the cervical
study of 102 children with NTM infection, reported region (87%). Of the 27 children who had a positive cul-
lymph node disease to be the most frequent (66.6% of the ture result, M. avium was isolated in 67% [66]. In Sweden,
cases), followed by skin and soft tissue infection and pul- the annual incidence of NTM infection varied from a min-
monary disease in 13.7% each. M. avium intracellulare is imum of 0.06 to a maximum of 5.7 per 100 000 children
the most frequently isolated species (48.5%) among the under 5 years. During the study period from 1969 to 1990,
NTM infections. Rapid growers such as M. abscessus, M. 390 culture‐confirmed cases were studied. The most fre-
chelonae, M. fortuitum and M. peregrinum were responsible quent disease was lymph node and soft tissue infection,
for 66.6% of skin and soft tissue infection, 50% of pulmo- and M. avium intracellulare was the aetiological agent in
nary disease and all bacteraemias [65]. In another pro- 317 (81.28%) cases. In most of the cases the cervicofacial
spective study of 61 children from the Netherlands, 92% group of lymph nodes was involved. Granulomatous
Table 42.5 World Health Organization multidrug therapy for leprosy in children aged 10–14 years
Rifampicina Dapsoneb Clofaziminec Duration
Paucibacillary leprosy 450 mg monthly 50 mg once daily – 6 months

Multibacillary leprosy 450 mg monthly 50 mg once daily 150 mg monthly + 50 mg alternate days 12 months
For younger children the dose is calculated as follows:

a
10–20 mg/kg once a month;
b
1–2 mg/kg/day;
c
1 mg/kg/day and 4–6 mg/kg once a month.
skin infection due to M. marinum was seen in four cases

(1.02%) and another child had M. avium intracellulare
infection [67].
Clinical spectrum of NTM infections

Cervicofacial lymphadenopathy
Cervicofacial lymphadenopathy is the most frequent
manifestation of NTM infection in immunocompetent
children. The portal of entry of infection is the orophar-
ynx via contaminated water or soil. Typically it affects
children below 5 years of age with unilateral lymphade-
nopathy. The commonly affected lymph nodes are the
Fig. 42.26 Buruli ulcer: a large deep ulcer with undermined edges
jugulodigastric, parotid, preauricular, submandibular involving the lower part of the shin along with oedematous infiltration of
and posterior triangle group. Rarely, the inguinal and the ankle region. Source: Courtesy of Bessie D.
axillary group of nodes is affected. The lymphadenopa-
thy may resolve spontaneously or progress through
the following stages in about 50% of the cases: stage 1, Buruli ulcer
painless firm lymphadenopathy; stage 2, fluctuant Buruli ulcer is one of the most devastating infections
lymphadenopathy due to liquefaction; stage 3, violaceous caused by M. ulcerans and is the third most common
discolouration and thinning of the overlying skin; stage 4, mycobacterial infection worldwide after tuberculosis and
INFECTIONS
rupture of the swelling leading to fistula or sinus tract leprosy. It is mostly seen in the swampy rural areas of
formation [1,66,67]. western and central Africa [69]. It is estimated that more
Most of the cases are due to M. avium intracellulare and than 7000 people develop Buruli ulcer annually with the
some cases are caused by M. haemophilum, especially in highest incidence in Benin, West Africa [70]. Overall, cases
older children. In the latter, multiple groups of lymph have been reported from at least 32 different countries in
nodes are affected [1]. M. scrofulaceum infection accounts Africa, Australia, South‐East Asia, China, the western
for 60% of cases of cervical lymphadenopathy due to Pacific and Central and South America [63]. Risk factors
NTM in India [68]. for Buruli ulcer include living in proximity to slow‐flowing
In immunocompromised cases, lymphadenopathy water bodies, poor wound care and not wearing protective
is often accompanied by disseminated mycobacterial clothing [63]. The organisms may be directly transmitted
disease [1]. from the environment to the wounded skin or indirect
Whenever NTM lymphadenitis is suspected, complete transmission by an insect vector [1].
diagnostic surgical excision is recommended, which is In Africa, most cases (75%) occur in children 15 years
also curative at the same time. The sensitivity of bacterial or younger, and the lower extremities are often affected
culture is suboptimal (41–80%) while PCR in the lymph [69]. Buruli ulcer begins as preulcerative nodules, plaques
node sample has a sensitivity of up to 72%. For M. haemo- or oedematous infiltrations which later develop into
philum, the media needs to be supplemented with iron deep necrotic ulcers with undermined edges (Fig. 42.26).
sources [1]. Typically the ulcers are painless. The lesions may spread
to an entire limb and the adjoining bones become devital-
Skin and soft tissue infections ized and necrotic with the development of sequestra and
The various NTM that cause localized infections of the osteomyelitis. Local or metastatic osteomyelitis has been
skin and soft tissue include M. fortuitum, M. abscessus, reported in 10% of the cases [69–73]. In a recent large
M. chelonae, M. ulcerans and M. marinum. Of these, Buruli series of 1227 laboratory‐confirmed cases of Buruli ulcer,
ulcers caused by M. ulcerans and fish tank or swimming 57% of patients were younger than 15 years of age.
pool granuloma due to M. marinum are the two species‐ Ninety six percent had one localization and 36% had
specific disorders. The other rapid growers produce lesions of >15 cm in diameter. The clinical spectrum
several nonspecific clinical morphologies [64]. included: ulcers in 805 (66%); plaques in 668 (54%);
oedema in 307 (25%); nodules in 42 (3%); and osteomyeli- duration of therapy varies from 6 months to 12 months,
tis in 82 (7%). Permanent residual sequelae were noted in depending on the anatomical sites of involvement,
229 of 1043 (22%) cases who had a follow‐up record; severity and potential toxicity [63].
there was a significant association with multiple lesions
and osteomyelitis [69]. References
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503
C HA PTER 43
Rickettsial Disease
Arun C. Inamadar & Aparna Palit
Department of Dermatology, Venereology & Leprosy, Sri B.M. Patil Medical College, Hospital & Research Centre, BLDE University, Vijayapur, Karnataka, India
Abstract tiorgan involvement contributes to the morbidity and mortality.

The specific diagnostic test is detection of rising antibody titre in
paired sera by immunofluorescence assay or enzyme‐linked immu
Rickettsial organisms have a worldwide distribution. They are the
nofluorescence assay (ELISA). The drug of choice is doxycycline,
causative agents for typhus fever and rickettsial spotted fever. The
irrespective of patient age. Rickettsial diseases are difficult to

organisms have a complicated lifecycle in lower vertebrates and
diagnose during the first week because of the lack of specific clini
blood‐sucking arthropods. Human beings are infected accidentally
cal features and absence of specific diagnostic tests. As the disease
and human‐to‐human transmission does not occur. These organ
is most responsive to antibiotics during this period, a high index
isms are ‘vasculotropic’, causing selective damage to endothe
of suspicion and empirical therapy with doxycycline is essential to
lial cells, termed ‘rickettsial vasculitis’. The classic presentation is
prevent mortality.
with high fever, headache, myalgia and petechial skin rash. Mul
• Sensitive and specific diagnostic tests are not available in the

Key points early phase of illness.
• The few ancillary laboratory findings that may diagnose
• Rickettsial infections are zoonotic illnesses with a worldwide rickettsial illness during the early phase (<7 days) are: normal or
distribution. low total leucocyte count with band cells in peripheral blood
• The prototype illnesses are Rocky Mountain spotted fever smear, thrombocytopenia, hyponatraemia, hypoalbuminaemia
(R. rickettsii) and Mediterranean spotted fever (R. conorii) in the and raised hepatic enzymes.
‘spotted fever group’, and epidemic typhus (R. prowazeki) and • A high index of suspicion is required to diagnose rickettsial fever
endemic typhus (R. typhi) in the ‘typhus group’. at presentation, even in endemic areas.
• The organisms target vascular endothelial cells causing inflam • Doxycycline is the treatment of choice in rickettsial illnesses,

mation, apoptosis and capillary leakage, collectively known as even in children.
‘rickettsial vasculitis’. • In case of doubt, empirical therapy with doxycycline can be
• Rickettsial infections present with nonspecific signs and started at presentation in all suspected cases of rickettsial fevers.
symptoms such as fever, headache, myalgia and petechial • In uncomplicated cases the patient should become afebrile
INFECTIONS
skin rash. within 48 hours of administration of doxycycline. If this is not
• Multisystem involvement with pneumonia, meningoencephalitis, the case, the physician should reconsider the initial diagnosis.
acute renal failure and ‘disseminated intravascular coagulation’‐ • Personal protection and environmental treatment are the
like features is often present. important preventive measures.
determined by the then ongoing epidemic of louse‐borne

Introduction. Rickettsial organisms are heterogenous,
typhus fever [1].
causing febrile illnesses with variable clinical features
The upsurge of rickettsial diseases in recent years is a
ranging from mild to life‐threatening. Epidemic typhus
threat to human health and a problem for the medical
caused by louse‐borne Rickettsia prowazeki is of great
fraternity. Diagnosis of these infections is challenging
historical importance. The first epidemic of typhus fever
because of lack of ‘tell‐tale’ clinical features. Moreover,
was recorded during the fifth century, in Athens, Greece
there is no laboratory test to confirm the disease during
[1]. Napoleon’s victory march to Russia was curtailed by
the first week of illness. Although low‐cost specific therapy
the then ongoing typhus epidemic in the country which
is available, rickettsial illnesses continue to remain a
affected his troops [1]. It became a scourge during the
menace to health in many endemic areas.
First World War when >30 million people were infected
and nearly 3 million lost their lives [1–3]. It was aptly
remarked by Vladimir Lenin (1919) during the Russian Epidemiology. Rickettsial illnesses occur worldwide and
Revolution that ‘Either socialism will defeat the louse or there are endemic foci of infection in which sporadic cases
the louse will defeat socialism’ [1]. Many historians and occasional outbreaks occur. In suitable environmen
believe that the destiny of twentieth‐century warfare was tal conditions there is re‐emergence of the infection with a
resultant epidemic. Business or recreational travel to causative agent for scrub typhus [5,7]. There has been
various places may transport the disease to new geo documented emergence of new species such as R. parkeri
graphical areas. Decade‐wise frequency estimation of (2002) and R. slovaca in the spotted fever group.
Rocky Mountain spotted fever by passive surveillance Various species of Rickettsia, the vectors, hosts and
demonstrates a gradual increase in annual incidence rate reservoirs, the diseases caused by them and their geo
(1.7 cases per million person‐years in 2000 to 14.3 cases graphical distribution, are presented in Table 43.1. These
per million person‐years in 2012) [4]. organisms are probably able to adapt to new ecosystems,
completing their lifecycle through new arthropod hosts
Agent and maintaining their virulence [8]. R. prowazekii has the
The genus Rickettsia in the family Rickettsiaceae includes ability to persist in the human reticuloendothelial system
a special group of microorganisms with properties tran during convalescence as a subclinical infection and may
sitional between bacteria and viruses. These are aerobic, manifest later as recrudescent typhus (Brill–Zinsser
strictly obligate, intracellular organisms with coccobacil disease) [9].
lary morphology [5]. They have variable Gram staining
properties but are mostly Gram negative and take on a Host
purple colour on Giemsa staining [5]. Rickettsia are una Human rickettsioses are considered to be zoonoses. The
ble to grow in cell‐free media and have fastidious growth natural hosts of Rickettsia are lower mammals, some
requirements. Laboratory culture of these organisms is vertebrates and arthropods. Blood‐sucking ectoparasites
undertaken in the yolk sac of developing chick embryos, such as ticks, fleas, mites and lice constitute the arthropod
and in continuous cell lines such as mouse fibroblast, hosts as well as vectors [5]. They acquire the infection
HEp‐2, HeLa, Detroit 6, etc. [5]. Isolation from patient following a blood meal from an infected/reservoir verte
samples is better performed in animal models like guinea brate host. The ectoparasites become infective within
pigs and mice [5]. 1 week (when the organism has multiplied in their
There are more than 20 validated species; in a current alimentary canal) and remain so until they succumb to
classification system, these have been categorized into the infection [5]. Wild rats and household mice are the
four groups [6]. Orientia is another genus in the same commonest mammal hosts [5]. Human beings are not
family, and the organism Orientia tsutsugamushi is the actually involved in the natural lifecycle of rickettsial
Table 43.1 Various rickettsial species, related vectors, hosts and reservoirs, diseases caused by them and geographical distribution [3,7]
Species Disease Vector Host/vertebrate Distribution

reservoir
INFECTIONS
A. Ancestral group (tick‐borne): R. bellii, R. canadensis

B. Typhus group
R. prowazekii Epidemic typhus Human body louse; rarely, Human, flying Central, north and south America,
Recrudescent typhus (Brill–Zinsser head louse squirrels central Africa, Asia
disease)
R. typhi Murine typhus (endemic typhus) Rat flea, (Xenopsylla cheopis) Rat Worldwide tropical and subtropical
possibly some ticks regions
C. Spotted fever group
R. rickettsii Rocky Mountain spotted fever Tick (Dermacentor variabilis) Dogs, rabbits, birds North, central and south America
R. conorii Mediterranean spotted fever Tick Rodents, dogs Southern Europe, South and West
(boutonneuse fever), Indian Asia, India, Africa
tick typhus
R. japonica Japanese spotted fever Tick ?Rodents Japan
R. slovaca Tick‐borne lymphadenopathy Tick Lagomorphs, rodents South and East Europe, Asia
(TIBOLA), Dermacentor‐borne
necrosis, erythema and
lymphadenopathy (DEBONEL)
Other organisms in the spotted fever group (tick‐borne): R. aeschlimannii, R. africae, R. heilongjiangensis, R. helvetica, R. honei, R. massiliae, R.
montanensis, R. parkeri, R. peacockii, R. rhipicephali, R. sibirica
D. Transitional group
R. akari Rickettsial pox Gamasid mite Domestic mouse, wild Soviet Union, South Africa, Korea,
rodents Turkey, Balkan countries, North
and South America
R. felis Cat‐flea rickettsiosis Cat flea Domestic cat, rodents, Europe, North and South America,
opossum Asia
R. australis Queensland tick typhus Tick Bush rodents Tasmania, Australia
Other organisms
Orientia Scrub typhus (chigger‐borne Trombiculid mites (transmitted Rodents, birds Asia Pacific region from maritime
tsutsugamushi typhus) by mite larvae/chiggers) Russia and China to Indonesia and
North Australia to Afghanistan
Chapter 43 Rickettsial Disease 505
organisms. Human disease is accidental, occurring due to epidemic typhus are mediated by human‐to‐human
an arthropod bite [3,5]. transfer of the ectoparasites [5].
There is a close inter‐relationship between the vector,
vertebrate hosts, human activities and the transmission of Pathogenesis. In mammals, rickettsial organisms have
disease. Travel and outdoor activities such as hunting, a tropism for the vascular endothelium of small and
fishing, camping, trekking and dog‐walking increase the medium‐sized blood vessels [3]. R. rickettsii rarely may
chances of acquiring infection [7]. Epidemic typhus is infect the smooth muscle cells, where they multiply in
prevalent in particular populations such as nomads and in the cytoplasm [12]. At the site of the first host–pathogen
refugee colonies, army barracks, etc., where risk of body interaction, i.e. in eschar, mononuclear phagocytes are
louse infestation is increased [7]. The rat flea (Xenopsylla the first group of defence cells to become infected [3].
cheopis), the vector for endemic typhus, remains in an A series of events takes place thereafter, resulting in
infective stage for a long time and bites human beings clinical manifestations.
only when the natural hosts are not available [10].
Adhesion and entry into host cells
Environment Rickettsial organisms possess genetically encoded surface
Rickettsial organisms are present ubiquitously irrespec cell antigens (Sca) that encode autotransporter‐like pro
tive of geographical variations. The vector for scrub teins and are involved in host cell adhesion and/or inva
typhus, the trombiculid mite, resides in scrub jungle and sion [3]. Well‐identified antigens include Sca0 (OmpA),
tall‐grass areas [5,7]. These mites reside in a well‐defined Sca1, Sca2 and Sca5 (OmpB). Spotted fever group (SFG)
area of soil with a favourable microecosystem, designated organisms possess two well‐characterized Sca, OmpA
as ‘mite islands’ [5]. Humans contract infection through and OmpB; typhus fever group (TG) organisms possess
chigger‐bites when accidentally entering these areas. only OmpB [3]. These Scas play varied roles in the organ
This is of importance for the movement of soldiers during ism–host interaction which may differ species‐wise. In
warfare [5,7]. R. conorii, Sca1 acts as an adhesin without playing a role
Disease is common in spring and summer as ticks and in invasion and Sca2 mediates interaction with the target
fleas remain most active during these seasons [7]. April host cell membrane [3,9]. In R. parkeri, Sca2 acts as a
to September are the common months for the occurrence ‘formin‐like mediator of actin‐based motility’ and inter
of Rocky Mountain spotted fever (>90% cases) [9,10]. acts with host proteins to promote survival of the organ
Endemic typhus occurs throughout the year in the USA ism [3,9]. Sca4 (all rickettsial species) co‐localizes with

with a peak during April to June [9]. Having domestic host cell vinculin at the site of adhesion and binds to and
cats/dogs and forest around the residence confers a higher activates vinculin through two vinculin‐binding sites [3].
risk of infection [9]. Rickettsial pox, the reservoir host for
which is domestic mice, prevails in urban areas [5,7,9]. Role of host cells
INFECTIONS
Multiple interactions between host cell receptors and
Transmission outer membrane ligands of Rickettsia take place for inter
The arthropod vectors acquire the infection by ingesting a nalization [3]. Host cell nuclear DNA‐dependent protein
blood meal from an infected small mammal host. In kinase Ku70 (also located in plasma membrane and cyto
arthropod hosts rickettsiae can maintain their lifecycle plasm) acts as the receptor for OmpB and helps in entry of
through trans‐ovarial and trans‐stadial transmission [5,7]. R. conorii [3]. In rickettsia‐infected hosts, at the site of entry,
The larvae of trombiculid mites (chiggers) harbour the ubiquitination of Ku70 occurs by recruitment of ubiquitin
organisms rather than adults and infect humans by ligase c‐cbl. Integrins (α2β1) on the host cell surface act as
repeated asymptomatic biting. receptors for OmpA [3]. Actin polymerization in host cells
Tick‐borne diseases are transmitted to a human host is another mechanism for rickettsial internalization. There
through tick saliva. Flea and lice defaecate while feeding is evidence that endocytosis, mediated by clathrin and
on hosts (flea‐feeding reflex) [11]. Entry of organisms claveolin‐2, may play a part in this process [3].
through human skin is facilitated by rubbing of infective The rickettsial membranolytic proteins haemolysin C
faecal pellets onto microtraumatized areas of skin and and phospholipase D cause rupture of phagosomal mem
mucosa while scratching [11]. Rare modes of transmission branes and thus entry to host cytosol [3,9]. A phospholi
in typhus fevers are inhalation of dried faeces of louse or pase A2‐like activity may also facilitate entry of R. typhi
ticks (aerosols) or conjunctival inoculation [5,7]. Food that to host cells [3,13]. In vivo, these organisms preferentially
has recently been contaminated with rat urine may be a invade the endothelial cells of small and medium‐sized
source of infection [5,7]. Very rare modes of transmission blood vessels, causing vascular damage [3].
are blood transfusion and organ transplantation [8].
In addition to tick bites, Rocky Mountain spotted Intracellular movement and cell‐to‐cell dissemination
fever can be transmitted by deeper contact via a crushed This process varies for different species. Spotted fever
or incompletely removed tick [10]. Human‐to‐human group organisms develop a ‘polar actin tail’ which helps
transmission does not occur. Body lice are temperature their intracellular movements and intercellular passage,
sensitive. They leave the body of a febrile human host in thus promoting dissemination, a key factor in pathogenesis
search of a normothermic one. In communities or geo [3,9]. R. typhi develop a shorter polar actin tail, resulting
graphical areas with high lice infestation, outbreaks of in limited, erratic motility. RickA, a Wiskott–Aldrich
syndrome protein (WASP), regulates actin‐based motility in a blood smear. Procoagulant properties of the activated
via activation of actin nucleation and Arp2/3 complex endothelial cells result in platelet adhesion, leucocyte
recruitment [3,9]. R. prowazekii undergoes intracellular chemotaxis and consumption of coagulation factors
replication by binary fission and the infected cells bulge resulting in a clinical picture similar to disseminated
with loaded organisms resulting in necrotic cell lysis [3]. intravascular coagulation [13]. Fig. 43.1 illustrates various
Intracellular Rickettsia secrete various membrane‐associated steps in the pathogenesis of rickettsial illnesses.
transporter systems and effector proteins to modulate
host cell functions. Clinical features. Symptomatology‐wise, rickettsial
diseases are categorized into SFG and TG. The main ill
Host immune response nesses in SFG are Rocky Mountain spotted fever (RMSF),
The selective vasculotropism of rickettsial organisms Mediterranean spotted fever (MSF) and rickettsial pox. In
predisposes mammal hosts to events such as inflamma TG, epidemic and endemic typhus are the main illnesses
tion of the vessel wall, loss of vascular integrity and of clinical importance. Recrudescent typhus (Brill–Zinsser
increased vascular permeability. This conglomerate effect disease) is an illness of epidemiological importance in this
of rickettsial infection is known as rickettsial vasculitis group. Scrub typhus is a closely related disorder caused
[3,9]. Simultaneously, the host immune system mounts an by genus Orientia.
anti‐inflammatory response to curb the damage caused Elicitation of a detailed history about outdoor activi
by rickettsial vasculitis. ties, travel to endemic areas in the recent past, pets in the
In response to rickettsial infection endothelial cells family, tick/mite exposure within 15 days of illness and
undergo activation from a relatively quiescent state to other affected family members is of great importance [12].
an ‘activated phenotype’ with pro‐inflammatory and The presence of any of these helps to make an early tenta
procoagulant properties (normally constituting an anti‐ tive diagnosis, but absence does not exclude it. Mite and
inflammatory and anticoagulant barrier) [9]. In vitro tick bites are typically painless, hence the site (eschar)
studies demonstrate an array of local changes: altered may remain obscure. Bites by nymphal stages of ticks
surface adhesiveness of platelets, increased expression of result in multiple, small erythematous papules simulating
tissue factors such as interleukin (IL)‐1α, intercellular and mosquito bite rather than an eschar [12]. The clinician
vascular cell adhesion molecules, E‐selectin, increased must search for an eschar or attached tick or mite after
synthesis of plasminogen activator inhibitor‐1, and adequate stripping [13]. Clothing should also be checked
release of von Willebrand factor from Weibel–Palade bod for ticks or body lice [13].
ies of endothelial cells [9]. Infection with R. prowazekii The incubation period of all rickettsial diseases ranges
induces secretion of prostaglandins E2 and I2 [9]. Vascular between 5 and 15 days after a bite by the vector [6]. Any
endothelial insults eventually lead to expression of genes age group may be affected. High‐grade fever is the usual
dependent on the nuclear factor (NF)‐κB family of tran
INFECTIONS
presenting feature in all forms of rickettsiosis and some

scription factors. This results in activation of NF‐κB and variants present with skin rash. Multisystem involvement
there is upregulation of NF‐κB binding sites in promoter and a fatal course may ensue if the disease is not treated
regions of the organisms. NF‐κB has antiapoptotic activity; at an early stage.
this maintains mitochondrial integrity of host cells and
prevents infection‐induced apoptosis of endothelial cells Cutaneous features
by preventing the activation of caspase‐8 and ‐9 [9]. There High fever and chills are the presenting features in spot
is secretion of interferons (IFN), IFN‐α and ‐β, which have ted fevers. In some spotted fevers, e.g. African tick bite
shown inhibitory action on the growth of R. prowazekii fever or MSF, one or more eschar(s) may be demonstrable
in in vitro studies [9]. The killing of intracellular organ [14]. A faint erythematous skin rash evolves 3–5 days
isms in endothelial cells, macrophages and hepatocytes after the onset of fever. Rose‐red, discrete, blanchable
depends upon the concentration of IFN‐γ, IL‐1β, RANTES macules start at the wrists and ankles and spread to proxi
and tumour necrosis factor (TNF)‐α [9]. mal extremities, trunk and face (centripetal spread)
Rickettsia‐infected vascular endothelium produces (Fig. 43.2a and b). Palms and soles are classically involved
reactive oxygen species (ROS), superoxide radical (O2−) [10,12] (Fig. 43.3a and b). In dark‐skinned patients, the
and hydrogen peroxide (H2O2), which put the host cells rash may be difficult to appreciate initially. In RMSF the
under oxidative stress [9]. There is widespread dilatation rash may sometimes be evanescent or localized, or totally
of intracellular membranes, mostly of rough endoplasmic absent (20%) [12,13,15,16]. The rash gradually turns pete
reticulum, loss of osmoregulatory control and cell lysis chial (Fig. 43.4) or may become maculopapular. Confluent
occurring by 5–6 days of infection [9]. There is increased purpuric lesions may be seen as the disease advances and
vascular permeability due to PGE2 and PGI2 resulting indicate severe illness [12]. Ecchymotic and gangrenous
in the inflammatory oedema found during rickettsial areas simulating purpura fulminans may appear, espe
infections [9]. cially in body areas with end‐vasculature: tip of nose,
Widespread vascular injury and capillary leak caused helix of ear, scrotum and digits [13] (Fig. 43.5). Rarely,
by rickettsial organisms affects nearly all organ systems, digital gangrene simulating ‘peripheral symmetrical
lungs, kidney, liver, spleen, meninges, brain and testes, gangrene’ may occur [13] (Fig. 43.6a and b). Periorbital
resulting in complications. There are limited organisms in oedema (Fig. 43.7) and swelling of hands and feet
the peripheral circulation and these are not demonstrable (Fig. 43.8) usually accompany the skin lesions [10].
R1= SFG organism

R2= TG organism
R1 R2
= OmpA
= OmpB
R1 =SFG organism with

polar actin tail
INTEGRIN =Group of TG
Ku70 organisms multiplied
Ku70 R1 by binary fission
R1
Internalization R2
Effector proteins to modulate
R1,R2 host
host cell function
cellfunction Replication
by
endocytosis Spread of TG
Cell organisms
R1 Activated endothelial cell with bulging
Spread of SFG procoagulant & proinflammatory & lysis
R1 property
organism
cell
R1 R1 Maintains mitochondrial integrity
NF-κB
Prevents activation of caspase
upregulation pathway
Cell
R1
HOST IMMUNE
SYSTEM RESPONSE
IL-1α, IFN-γ, Prevents
Adhesion molecules IL-1β, infection-induced
Reactive E-selectin RANTES, apoptosis
oxygen Plasminogen activator inhibitor-1 TNF-α
v-WF
Prostaglandins E2 & l2
Killing of
intracellular
organism
CELL LYSIS Inflammation of
endothelial cells

RICKETTSIAL EFFECT ON HOST CELLS
INFECTIONS
Fig. 43.1 Various steps in the pathogenesis of rickettsial infection.
(a) (b)
Fig. 43.2 (a and b) Initial faint erythematous rash of rickettsial spotted fever.
(a)
Fig. 43.5 Ecchymotic spots on helix of the ear.

INFECTIONS
(a)
(b)
Fig. 43.3 (a and b) Rash on palms and soles.
(b)
Fig. 43.4 Petechial skin rash. Source: Image courtesy of Dr Atul Kulkarni, Fig. 43.6 (a) Gangrene of fingertips and ecchymotic areas on palm. (b)
Paediatrician. Ecchymotic areas on sole with peripheral symmetrical gangrene of feet.
Fig. 43.9 Maculopapular rash on the trunk in a case of typhus fever.
Fig. 43.7 Periorbital swelling and faint skin rash on face. Eschars are painless ulcers with central, dark, adherent
crusts with surrounding erythema or scaling and regional
lymphadenopathy. Usually eschar is solitary but multiple
lesions may be present [10].
Systemic features
There is abrupt‐onset high fever, occasionally with morn
ing remission [13]. Shaking chills, headache, myalgia,
nonproductive cough, dyspnoea, nausea and vomiting,

calf pain and tenderness may accompany the fever at
presentation. Headache is typically frontal [13]. It is a
consistent feature and may be severe. Myalgia commonly
involves the muscles of the lumbar area, thigh and calf,
INFECTIONS
resulting in lower‐back and lower‐limb pain [13]. Rare
and unusual complications of MSF fever are haemophago
cytic lymphohistiocytosis and acute pancreatitis [18,19].
In scrub typhus, headache and conjunctival injection
are the common initial presentation. Hepatosplenomegaly
and generalized lymphadenopathy are seen in most of
Fig. 43.8 Ecchymotic skin lesions on sole with swelling of the foot. the patients [13]. Multiorgan involvement may manifest
by the end of 1 week. Pneumonia is the commonest
Patients with typhus fever also present with a febrile systemic manifestation. Others include hepatitis, renal
illness. In both epidemic and endemic typhus, the skin failure, myocarditis and meningoencephalitis. Severe
rash is morphologically similar but milder in the latter. In neurological manifestations in this illness (photophobia,
contrast to SFG, the eruption starts on the trunk and blurring of vision, drowsiness, disorientation, delirium and
thereafter spreads in a centrifugal distribution (Fig. 43.9). stupor) are the origin of the name ‘typhus’ (cloudiness)
Face, palms and soles are spared in this disease [10]. [13]. Septic shock or acute respiratory distress syndrome
Rickettsial pox is characterized by a varioliform skin (ARDS) may complicate the disease course [10].
eruption. The fever is preceded by eschar formation at Immediate and long‐term residual complications (beyond
the site of mite adherence. A generalized papulovesicular 1 year) in patients suffering from rickettsial illnesses are
eruption sparing the palms and soles is characteristic of presented in Table 43.2 [12,13,20].
this disease [5,10]. The lesions heal with black crusting
and resolve without scarring. This is the mildest of the Childhood disease
rickettsial illnesses. Children may be affected by any type of rickettsial illness.
The incubation period of scrub typhus is 1–3 weeks An earlier notion that RMSF is more common in children
[10]. These patients lack a generalized skin rash. However, was not substantiated in later studies [12]. However, in a
an eschar (tache noir) at the site of a bite by chiggers recent report on an explosive outbreak of RMSF in tribal
may be noticed at presentation and is the pointer to lands of Arizona, nearly 50% of the cases were ≤10 years of
the diagnosis [10,17]. Common body sites to search for age and this was attributed to ‘dog handling’ by children,
eschars are neck, axillae, chest, abdomen and groin. tick‐infested dogs being the reservoir of infection in that
Table 43.2 Long‐term complications of the main rickettsial diseases [12,13,20]
Disease Early complications Late complications
Rocky Mountain • Interstitial pneumonia • Partial paraplegia

spotted fever (RMSF) • Pulmonary oedema • Bell’s palsy
• Acute respiratory distress syndrome • Digital/limb gangrene requiring amputation
• Abdominal pain • Deafness and blindness
• Meningoencephalitis • Loss of bladder and bowel control
• Disseminated intravascular coagulopathy‐like • Movement disorders
symptoms and peripheral gangrene • Difficulty in speech
• Hepatic failure These have been reported in patients with RMSF who had prolonged hospital
• Myocarditis stay and some of these complications developed beyond 1 year of illness
Mediterranean spotted • Haemophagocytic lymphohistiocytosis
fever (MSF) • Acute pancreatitis
Scrub typhus • Constipation
• Meningoencephalitis
• Photophobia and blurring of vision
• Acute renal failure
area [21]. The overall case fatality rate of RMSF in children at any time during the course of the illness. The
aged 5–9 years has been found to be high in the USA [22]. abdominal pain may be severe enough for the clinician
Clinical features of rickettsial infections in children to consider causes of acute abdomen, most likely acute
similar to those in adults. There are few case series appendicitis [12].
reporting rickettsial fever in paediatric patients [23–25].
The youngest patient among the reported cases was 16 Diagnosis. Diagnosis of rickettsial diseases during the
months old. Continuous, high‐grade fever extending initial few days is easily missed because of nonspecific
beyond a week and skin rash strikingly involving palms clinical features simulating viral exanthema. Even in
and soles are the consistent features in this age group. endemic areas, approximately 60–75% patients with
Onset of rash may be earlier in children as compared RMSF are diagnosed as having some other illness at first
to adults [12]. Headache is uncommon in younger visit to a doctor [12]. A history of tick bite may be avail
children but, if present, is often not manageable with able in less than half of the cases [13]. As the bite by an
analgesics [13]. Calf pain and tenderness are common in ectoparasite is usually painless, the sufferer may not be
children [13]. Puffiness of the face, periorbital oedema aware of an eschar. Absence of fever or rash in a patient at
INFECTIONS
and oedematous extremities are common features; gen presentation should not deter the clinician from making a
eralized oedema with ascites and hydrothorax may be diagnosis of rickettsial fever, as the patient may be in the
present. Various systemic features reported in paediat evolving phase of the disease; moreover, fever and even
ric patients are conjunctival injection (Fig. 43.10), altered rash may be absent in these patients [15,21]. A compli
sensorium, seizures, hepatosplenomegaly, abdominal cated case of rickettsial fever may present with shock‐
pain, arthralgia and pneumonia, which may manifest related hypothermia [21].
‘Case definitions’ for diagnosis of rickettsial diseases
formulated by the Indian Council of Medical Research
(ICMR) in 2015 are listed in Box 43.1 [17].
Box 43.1 Case definitions for diagnosis of rickettsial diseases

formulated by the Indian Council of Medical Research (ICMR) in 2015
[17]
• Suspect/clinical case: Acute‐onset fever of unknown origin for a duration

of ≥5 days, ± the presence of eschar. In the presence of eschar, scrub
typhus can be suspected even if the fever duration is <5 days. Skin rash,
headache, myalgia and other systemic features may be associated.
• Probable case: A suspect/clinical case with positive Weil–Felix test
(≥1:80 titre for all three antigens) and positive enzyme‐linked
immunofluorescence assay (ELISA) for IgM antibody (>0.5 optical
density).
• Confirmed case: Detection of rickettsial DNA from sample of eschar
or polymerase chain reaction (PCR)of whole blood; or demonstration
of rising antibody titre in acute and convalescent sera by indirect
immunofluorescence assay/indirect immunoperoxidase assay.
Fig. 43.10 Conjunctival injection in an adolescent with rickettsial fever.
Laboratory tests high concentration of agglutinins is also demonstrable in

Leucocytosis, thrombocytopenia and elevated serum nonrickettsial infections [17]. However, good correlation
transaminase levels are detected during the early phase of between a positive Weil–Felix test and raised IgM antibody
the disease. In RMSF, the total leucocyte count may be by IFA has been seen [13]. It is a useful option for making
normal or borderline low with immature band cells in the probable diagnoses of rickettsial diseases (spotted fever or
peripheral blood smear [12,13]. Thrombocytopenia is pre typhus) in resource‐poor countries [17]. The test becomes
sent in 60% patients [13]. The erythrocyte sedimentation reactive after 5–7 days of onset of fever. A 1 : 80 titre is indic
rate is usually high. ative of possible rickettsial infection; however, this should
Hyponatraemia and hypoalbuminaemia resulting from be standardized in each endemic region [17]. Paired sera
capillary leak syndrome may be features in the acute can be tested for a fourfold rise in titre, or a single high titre
stage [12,13]. Hepatic transaminases are often raised. In (>1 : 320) can be considered diagnostic [13].
the presence of respiratory symptoms, a chest radiograph
should be obtained and may show a bilateral interstitial Skin biopsy
infiltrate or lobar consolidation. In the presence of menin Histopathology. A skin biopsy should be obtained from
gitis, cerebrospinal fluid analysis shows polymorphonu the purpuric skin rash. In patients with RMSF a haema
clear or lymphocytic pleocytosis (<100 cells/μL) [12]. toxylin and eosin‐stained specimen shows a dense mono
nuclear cell infiltrate around the dermal vasculature [27].
Immunofluorescence assay (IFA). This is considered a
‘gold‐standard’ test for the diagnosis of rickettsial infec Immunohistochemical staining. This is performed on skin/
tion [12,17]. The sensitivity of the test depends on the involved organ biopsy specimens. Immunohistochemical
duration of disease; usually it becomes positive beyond staining from skin biopsy specimens in patients with
7–10 days. Sensitivity of IFA assay rises to 94–100% RMSF has 70% sensitivity and 100% specificity. The presence
beyond 14 days of illness, higher than any other sero of rickettsial antigen in skin may be focal, limiting consist
logical test for rickettsial infection [12]. It is ideal to test ent detection.
the paired sera (acute and convalescent) at an interval of Rathi et al. have developed the Rathi, Goodman, Aghai
2–3 weeks, to demonstrate a greater than fourfold rise in (RGA) scoring system, which utilizes clinical, laboratory
titre of IgM and IgG. Availability of this test is limited to and epidemiological parameters to diagnose SFG
certain centres and it is not useful during the first week of illnesses [26]. The RGA scoring system has a total of

illness. In RMSF, the IgM antibody wanes by 3–4 months 35 points. It has been reported to have a sensitivity of 96.1%

and IgG by 7–8 months [12]. In endemic areas the value of and specificity of 98.8% for diagnosing spotted fever at
detection of IgM and IgG antibodies against rickettsial score 14 [28].
organisms may not be very specific; anti‐R. conorii IgM
has been found to cross‐react with bacterial antigens such Differential diagnosis. The commonest differential
INFECTIONS
as Legionella spp. and Coxiella burnetii, giving rise to false diagnoses of rickettsial fever in children include various
positivity [26]. classical viral exanthems of childhood (measles, rubella,
erythema infectiosum, roseola infantum) and drug rash.
Demonstration of antibodies by ELISA. ELISA is used The chronological order in which the fever and skin rash
more frequently in the diagnosis of rickettsial infections. appear, progress and subside in these illnesses is usually
IgM capture assay of serum confirms recent infection but distinctive. Constitutional symptoms are milder and the
the significant baseline titre needs to be determined in risk of systemic involvement is usually low. Moreover,
each endemic region [12]. the character of the rash is mostly maculopapular rather
than purpuric in these conditions. Other viruses causing
Indirect immunoperoxidase assay. This is considered transient exanthematous illness in children are coxsacki
equivalent to IFA assay and is another gold‐standard test evirus, echovirus and Epstein–Barr virus. Various differ
in the diagnosis of rickettsial fever. However, its availability ential diagnoses of rickettsial illnesses and the points of
is limited and it is mostly used for research purposes [17]. differentiation are presented in Table 43.3.
PCR. Detection of rickettsial antigen by PCR can be used Risk factors and prognosis. Rickettsioses are usually benign
for early and rapid diagnosis. Blood is not a very suitable infectious illnesses but 10% of patients may develop severe
sample, and a skin or organ biopsy specimen should be complications [23]. The clinical severity depends upon
utilized for this purpose. However, this facility is again the virulence of the organism as well as host factors
available only in specific laboratories. Treatment with such as older age, black ethnicity, male gender, chronic
doxycycline decreases the sensitivity of PCR [12]. alcoholism and presence of co‐morbid illnesses [12,29].
National surveillance data (1999–2007) from the USA
Weil–Felix test. This is a heterophile antibody test. The regarding case fatality rate in RMSF have revealed that
basis of this test is sharing of antigens between Rickettsia native Americans had more fatal outcome of the disease
and Proteus species (P. vulgaris: OX19, OX2; P. mirabilis: than other races [22,30]. Tick‐borne illnesses are more com
OXK) and demonstration of agglutinins to these organisms mon in males, probably because of higher occupational and
in a ‘suspect case’ of rickettsial fever. This test lacks the recreational exposures in tick‐infested areas [4,29]. Children
sensitivity and specificity of a good diagnostic test as a are also at higher risk when playing outdoors.
Table 43.3 Differential diagnoses of rickettsial fevers in children [10,13]
Disease Clinical features/laboratory tests Clinical features/laboratory tests not in favour of rickettsial illness
similar to rickettsial illness
Infections
Scarlet fever Fever, skin rash, vomiting, Rash characteristics: generalized, fine, punctate and erythematous; described as
lymphadenopathy, often ‘sunburn with goose pimples’; transverse streaks at skinfolds, ‘Pastia’s lines’; subsides
myocarditis and meningitis with desquamation; flushing of face with perioral pallor; white strawberry tongue
Staphylococcal toxic Fever, skin rash, vomiting, myalgia, Initially, faint skin rash present on first day, with diffuse erythema, disappears by 3 days.
shock syndrome marked oedema of hands and Further maculopapular and purpuric rash appears in second week. Characteristic
feet, thrombocytopenia desquamation of palms and soles by 10–21 days. Mucosal and conjunctival erythema
Dengue fever High fever with maculopapular skin Rash characteristics – ‘islands of normal skin in sea of red’; joint pain; haemorrhagic
rash, myalgia, thrombocytopenia symptoms and shock
Meningococcaemia Febrile child with petechial skin rash Rapid progression of illness
Meningitis CSF analysis: very low glucose level, neutrophilic pleocytosis; Gram stain: Gram‐negative
diplococci; blood culture: growth of N. meningitidis
Secondary syphilis Lesions on palms and soles Afebrile patient
Lesions on palms and soles are either hyperpigmented macules or hyperkeratotic, scaly
papules
Positive serological tests for syphilis
Colorado tick fever High biphasic fever, severe Absence of skin rash
neurological involvement,
leucopenia, thrombocytopenia
Enteric fever High fever and rose spots Rash appearing in second week of fever
Noninfectious illness
Kawasaki disease High fever, maculopapular rash, Cheilitis, nonexudative conjunctivitis, strawberry tongue, periungual and perineal
lymphadenopathy desquamation
Erythema multiforme Fever, involvement of palms and soles Target lesions
Lesions on palms and soles are pruritic and tender
Stevens–Johnson Fever, involvement of palms and Temporal correlation with drug intake
syndrome soles Typical/atypical target lesions
Lip and mucosal involvement
Drug‐induced Fever, maculopapular rash Temporal correlation with drug intake

maculopapular rash Rash is devoid of haemorrhagic component
Henoch–Schönlein Purpuric skin lesions starting at ankles Palpable purpura, usually involving lower limbs; arthralgia/arthritis
purpura Fever may be present, renal Immunofluorescence of skin biopsy specimen demonstrates IgA deposit at dermal vessel
INFECTIONS
involvement, acute abdomen walls

Histopathology of skin lesions:
inflammation around dermal vessels
Thrombotic Petechial skin lesion,
thrombocytopenic thrombocytopenia
purpura
Epidemic typhus is considered one of the most severe organism and host risk factors in certain populations such
infectious diseases of human beings, the mortality rate as alcoholism and patients with concomitant illnesses
ranging from 10% to 60% [9]. Mortality directly correlates such as acute renal failure and hyperbilirubinaemia [32].
with patient age, being lower in young adults (10%) and Scrub typhus usually runs a self‐limiting course [29].
higher in patients >50 years (60–70%) [29]. Complications However, the risk of mortality ranges from 1% to 35%,
are rare in endemic typhus, which has a mortality rate depending upon the virulence of the organism, adverse
of 1% [29]. host factors and time of initiation of therapy [29].
RMSF is the most severe SFG in developed countries
and untreated cases may have 20–30% mortality by the Treatment. Approximately 50% of patients with rickettsial
second week [9]. Delay in diagnosis and initiation of infections with major systemic symptoms require hospitali
treatment with the appropriate antibiotic is associated zation and a multidisciplinary approach.
with 4% mortality [31]. Glucose‐6‐phosphate dehydroge Currently, doxycycline is the treatment of choice in
nase (G6PD) enzyme deficiency is directly proportional patients of any age suffering from rickettsial fever. It is
to the severity of RMSF and fatality ensues within 5 days a rickettsiostatic drug [12]. Initially, there was reluc
of the onset of fever [29]. tance among paediatricians to use this drug empirically
In general, MSF is considered to be a milder disease in in children suffering from rickettsioses [24]. However, in
humans that runs a benign course. However, at present children a single 5–7 day exposure to doxycycline (as in
R. conorii has a wide geographical distribution and it the treatment of rickettsial infections) is not associated
appears that the clinical course is increasing in severity. with discolouration of teeth [33]. The American Academy
This may be related to changes in the virulence of the of Pediatrics Committee for Infectious Diseases has
recommended doxycycline as a life‐saving drug in the Protective clothing. Long clothing with socks and closed
treatment of ‘suspect’ or ‘confirmed’ rickettsial infection shoes prevents tick/mite adherence. Light‐coloured
in children [34]. It is also recommended in pregnant clothing is preferable in order to see a crawling ectoparasite.
women in whom there is high suspicion of rickettsial
disease [12]. It must be started early as antibiotic therapy Tick removal. Periodic inspection of the entire body for
is most effective during the initial phase of the disease hidden, attached ticks should be performed daily in endemic
when the organism is multiplying. In a ‘suspect’ case, areas. Frequent checking and removal is beneficial as the tick
doxycycline should be started empirically [21]. If there may remain quiescent for several hours (from 2 to 20 hours)
are complicating features, doxycycline should be started before injecting the organism into a human body. An
prior to referral to a tertiary centre [17]. These measures attached tick must be removed with mouth parts intact by
prevent disease‐related morbidity and death [17]. Consi gentle traction using fine forceps. If the mouth parts break
dering all these factors, early administration of doxycycline off in the skin they should be removed. Use of the fingers for
is a judicious step towards the goal of patient survival. this purpose and crushing of the tick is not recommended to
Oral doxycycline at 4.5 mg/kg bodyweight in two prevent undue contamination and risk of conjunctival inoc
divided doses is administered in children <45 kg [17]. ulation. The bite wound should be disinfected.
In an uncomplicated case without organ dysfunction, the
child becomes afebrile within 24–48 hours of starting the Use of insect repellents. N,N‐diethyl‐m‐toluamide (DEET)
drug and this may be taken as indirect evidence of rickett can be used on exposed skin and clothing. For children,
sial infection [13]. Failure to respond in this way may a 20–30% concentration is recommended by the American
prompt the clinician to reconsider the diagnosis [12]. Academy of Pediatrics [36]. Both DEET and benzyl ben
Children >45 kg should be given the adult dosage of zoate have miticidal action [37]. Malathion is effective
100 mg orally twice daily. The optimum duration of oral against the rat flea [37]. A spray‐on preparation of perme
treatment for outpatient/inpatient cases has not been thrin can be applied evenly to outer clothing and dried
established. Two recommendations for uncomplicated before wearing to kill ectoparasites.
cases are until 3 days after remission of fever and a
minimum total period of 5–7 days [12]. Cases with com Protection of pets
plications may require longer duration of treatment. Pet dogs must be treated with acaricides at periodic inter
Intravenous doxycycline may be administered in hospi vals. Their bodies should also be checked for the presence
talized children with critical illness. The calculated dose of ticks at periodic intervals to minimize the risk of human

is added to 100 mL of normal saline and slowly infused exposure.
over a period of 30 minutes. This is followed by oral
dosage for a total duration of 7–15 days. Depletion of natural hosts
Other drugs that can be used are fluoroquinolones, Vegetation around human habitats must be cleared peri
INFECTIONS
chloramphenicol and azithromycin [17,23]. Fluoro odically to reduce the load of ectoparasites in the environ
quinolone has been used at a dosage of 20–30 mg/kg ment [10]. Rodenticides and mouse traps should be
per day [23]. The dose of chloramphenicol is 50–100 mg/kg regularly used on farms and in households [10].
per day (maximum 3 g/day) administered 6 hourly. Use
of chloramphenicol is nowadays limited because of its Role of prophylactic antibiotic
life‐threatening adverse effects, enhancing the risk of In patients who have had an accidental tick bite but who
mortality in these patients. The dosage of azithromycin have no symptoms of illness, prophylactic antibiotics are
in children is 10 mg/kg bodyweight as a single dose for not indicated [12]. This is because, in an endemic area,
5 days [17]. This is the drug of choice in the presence of only 1–3% of the vector ticks are infected and <1% have
doxycycline resistance [35]. confirmed disease [12,38]. Hence, the chance of acquiring
Sulfonamides should not be administered in ‘suspect’ infection merely by a tick bite is low. Moreover, it has
cases of rickettsial fever as these may directly enhance the been shown that prophylactic antibiotics may delay the
growth of the organism. This, in combination with delay onset of symptoms of RMSF in a patient exposed to infec
in institution of specific therapy, increases morbidity and tion, but do not prevent it [12,39].
mortality [13,17].
Role of vaccine
Prevention
Rickettsial vaccines are not yet available.
Personal protection
When visiting areas endemic for rickettsial diseases or
Notification of cases
tick‐infested geographical areas, adoption of personal
A physician diagnosing and treating a case of rickettsial
protective measures is of immense importance.
illness should notify it to the local health authorities. This
is especially relevant in naive areas for rickettsial infec
Avoidance of tick habitats. Walking on cleared trails and
tions to prevent an outbreak of the disease.
avoiding brushing against uncut grass and weeds is
advised, especially during peak seasons for tick activity.
Children may be prevented from playing in backyards Future directions. Some inherent properties of rickettsial
with vegetation – clear ground is preferred. organisms make them suitable for illegitimate use as
bioterrorism weapons [2,3]. Some nations have field‐ 16 Kirkland KB, Wilkinson WE, Sexton DJ. Therapeutic delay and
mortality in cases of Rocky Mountain spotted fever. Clin Infect Dis
tested weaponized rickettsial organisms [2]. The compli
1995;20:1118–21.
cated arthropod‐dependent lifecycle of the organisms is 17 Rahi M, Gupte MD, Bhargava A et al. DHR‐ICMR Guidelines for
an obstacle to such attempts [2]. However, the ease of diagnosis and management of rickettsial diseases in India. Ind J
spread of diseases like epidemic typhus and spotted Med Res 2015;141:417–22.
18 Cascio A, Giordano S, Dones P et al. Haemophagocytic syndrome and
fevers, the associated lethality and the potential to destroy Rickettsial diseases. J Med Microbiol 2011;60:537–42.
humankind en masse should put endemic countries on 19 Rombola F. Mediterranean spotted fever presenting as an acute
constant alert for such eventualities. pancreatitis. Acta Gastroenterol Belg 2011;74:91–2.
Vaccines against rickettsial organisms are not currently 20 Nilsson K, Wallménius K, Hartwig S et al. Bell’s palsy and sudden
deafness associated with Rickettsia spp. Infection in Sweden. A retro
available and remain an area to be explored. The possibil spective and prospective serological survey including PCR findings.
ity of antibiotic‐resistant rickettsial strains developing Eur J Neurol 2014;21:206–14.
should be checked periodically. Current advances in the 21 Traeger MS, Regan JJ, Humpherys D et al. Rocky Mountain spotted
fever characterization and comparison to similar illnesses in a highly
understanding of the pathogenesis of rickettsial disease endemic area—Arizona, 2002‐2011. Clin Infect Dis 2015;60:1650–8.
have paved the way for development of novel therapies 22 Dahlgren FS, Holman RC, Paddock CD et al. Fatal Rocky Mountain
[3,9]. This knowledge can be exploited to develop patho spotted fever in the United States, 1999‐2007. Am J Trop Med Hyg
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23 Murali N, Pillai S, Cherian T et al. Rickettsial infections in south
associated with the illness [9]. The reactive oxygen radicals India – How to spot the spotted fever? Indian Pediatr 2001;
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pediatric patients. Pediatr Infect Dis J 2000;19:871–4.
26 McQuiston JH, Wiedeman C, Singleton J et al. Inadequacy of IgM
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515
C HA PTER 44
Endemic Treponematoses: Yaws, Pinta

and Endemic Syphilis
Herman Jan H. Engelkens
Department of Dermatology and Venereology, Ikazia Hospital, Rotterdam, The Netherlands
Abstract Emergency Fund (UNICEF) and World Health Organization (WHO)

supported mass treatment campaigns in the 1950s and 1960s,
The treponemal infections that occur in humans are venereal the incidence of the endemic treponematoses has been greatly
syphilis and the endemic treponematoses (yaws, endemic syphilis reduced. However, these diseases have not been eradicated. Latent
and pinta). The endemic treponematoses, all of which are chronic cases are still prevalent and millions of people continue to be at
relapsing tropical diseases, have similar natural histories. Young risk of acquiring the endemic treponematoses from individuals
children are at the highest risk of acquiring these nonvenereal with relapsing disease.
treponematoses. Nearly all of the new cases are found in children In 2012, WHO launched a new initiative for the eradication of yaws
less than 15 years of age. As a result of United Nations Children’s by 2020.
Key points • Children younger than 15 years are predominantly affected.

• Late‐stage sequelae may lead to severe handicap.
• There is a new 2012 WHO initiative for eradication of yaws.
• The endemic treponematoses are yaws, pinta and endemic
syphilis.
Endemic syphilis (bejel, firjal or loath) is assumed to

Definition and aetiology. The treponemal infections that
have originated before 8000 bce, probably as a result of
occur in humans are venereal syphilis and the endemic
a mutation of the (ancestor) treponeme, or as an adapta
treponematoses (yaws, pinta and endemic syphilis). The
tion to new epidemiological factors [11–14]. The sexually
causative organisms of the endemic treponematoses
INFECTIONS
transmitted form of treponematosis, venereal syphilis,
are listed in Table 44.1. These organisms belong to the
emerged in a later millennium, at a time when bodily
order Spirochaetales, family Treponemataceae and genus
contact among adults was largely restricted to sexual

Treponema. In the case of T. carateum, propagation in an
contact [11,14].
animal model has not yet been achieved; this is consid
According to Hackett [11], four different treponemal
ered to be a separate species [1,2]. At present the causa
diseases exist, but the different treponemes share a
tive agents of the different treponematoses cannot be
common biological ancestor, probably an animal path
distinguished serologically or morphologically [1–5].
ogen. However, it has also been suggested that the four
The endemic treponematoses, all of which are chronic
clinical entities that are recognized today are, in fact, a
relapsing tropical diseases, have similar natural histo
single disease caused by T. pallidum (unitary theory).
ries [6–10]. Young children are at the highest risk of
Changing environmental conditions are held responsi
acquiring these nonvenereal treponematoses. Nearly all
ble for the different epidemiological patterns of the
of the new cases are found in children less than 15 years
treponematoses [13].
of age.
In 1905, Castellani [15] discovered the presence of spi
rochaetes in ulcers from patients with parangi (yaws) in
History. It has been postulated that treponematoses orig Ceylon. The microorganisms resembled those observed by
inated some 22 000 years ago on the Eurasian–African Schaudinn and Hoffmann, who described the causative
landmass [11,12]. Pinta (carate, mal del pinto, azul) is agent of venereal syphilis earlier that year. As the cutane
believed to be the first treponematosis occurring in ous lesions in yaws frequently resemble raspberries, the
humans. Yaws (framboesia tropica, pian, parangi, paru, disease was called ‘framboesia tropica’ and skin lesions
buba) probably arose around 10 000 bce on the Afro‐Asian were called ‘frambesiomas’. The causative agent of pinta
landmass from a mutant form of pinta. This mutated was first believed to be a fungus. In 1938, a spirochaete,
organism was more adapted to tropical circumstances. T. carateum, was recognized as the causative organism.
Table 44.1 The causative agents of the endemic treponematoses

Aetiology. Direct personal skin–skin contact is the major
Yaws Treponema pallidum ssp. pertenue (T. pertenue) route of transmission of yaws. Breaks in the skin provide
Pinta Treponema carateum (T. carateum) a site of entry for the treponemes. Transmission is facili
Endemic syphilis Treponema pallidum ssp. endemicum (T. endemicum) tated under overcrowded conditions, where open skin
lesions are common and in areas where no protective
clothing is worn. Infectivity is highest in humid tropical
climates. The mode of transmission of pinta is not well
The World Health Organization (WHO) and the United defined. Transmission most probably occurs through
Nations Children’s Emergency Fund (UNICEF) supported direct skin or mucous membrane contact. The disease is
mass treatment campaigns against the endemic trepone transmitted among children [7]. Endemic syphilis is most
matoses. These were executed with great success in the probably transmitted directly or indirectly by skin–skin
1950s and 1960s [6–10]. As a result of penicillin treatment or mouth–mouth contacts with infectious lesions [8].
during these mass campaigns, the incidence of the Theoretically, indirect transmission of treponemal disease
endemic treponematoses has been greatly reduced [16– by fomites and insects is probable, but no direct evidence
20]. However, these diseases have not been eradicated. for this mode exists [7,8].
Latent cases are still highly prevalent and millions of peo Serological evidence indicates that there is a reservoir
ple continue to be at risk of acquiring the endemic for yaws in West African baboons (Papio cynocephalus)
treponematoses from individuals with relapsing disease [44,45]. However, the significance of this reservoir for
[16–20]. In recent years, an increasing incidence of infec humans is not known. As a rule, sexual transmission does
tion is being reported from endemic regions [6–10,19,20]. not have a pathogenetic role in endemic treponematoses.
In 2012, WHO launched a new initiative, the Morges
strategy, for the eradication of yaws by 2020 [21].
Pathology
Yaws
Distribution The histopathological appearance of yaws is varied. In
Yaws early yaws, papillomatous epidermal hyperplasia is
Yaws is prevalent in rural areas of warm tropical regions the main feature. In addition, there is focal spongiosis
with high humidity and heavy rainfall. The main reser and neutrophils migrating into the epidermis may
voirs of infection are located throughout Africa [6,19–23]. give rise to intraepidermal microabscesses. There is a
An alarming resurgence of yaws has been observed in the dense dermal perivascular infiltrate [46,47]. In contrast
tropical countries of West and Central Africa. In Ghana, with venereal syphilis, blood vessels are usually only
Benin, Togo and the Central African Republic, the preva mildly affected, and little proliferation of endothelial
lence of yaws resembles that seen in the precampaign era cells is found [47]. Epidermal changes, similar to those
INFECTIONS
[24]. An increase in seroreactivity has also been reported seen in condylomata lata, can occur. Hyperkeratotic
in Nigeria, Ivory Coast and Mali. In areas of South‐East lesions f requently show nonspecific characteristics
Asia and the Pacific Islands (e.g. Indonesia, Timor‐Leste, (acanthosis, hyperkeratosis and parakeratosis) and
Papua New Guinea, Solomon Islands and Vanuatu), foci only a mild infiltrate [48,49]. With silver impregnation
of infection persist. Only a few countries in the Americas or immunofluorescent staining techniques (Figs 44.1
continue to report sporadic cases. In several endemic and 44.2), treponemes can be demonstrated [48,50,51].
areas, the current extent of yaws is not fully known, and Characteristic for yaws is the epidermotropic character
there is presumably considerable underreporting in many of T. pertenue [48–51].
affected areas [25–29]. In 1995, when WHO last issued
estimates, there were at least 2.5 million cases of endemic
treponematoses, mostly yaws [26].
Pinta
Pinta is still prevalent in remote rural regions in tropical
Central and South America [8,30]. Unfortunately, precise
figures on the prevalence of this disease are difficult to
obtain [6,21,31–33]. Serological surveys in these areas are
essential for estimating the current magnitude of this
treponemal reservoir.
Endemic syphilis
Endemic syphilis still exists, especially among isolated
closed communities living under primitive, crowded and
unhygienic conditions [6,19,34–40]. Infectivity is particu
larly present in the arid climates of the eastern hemisphere,
among nomads and seminomads in Saudi Arabia and in Fig. 44.1 Numerous treponemes (Treponema pertenue) visualized by the
Sahel countries in Africa [34–43]. Steiner silver staining method.
Chapter 44 Endemic Treponematoses: Yaws, Pinta and Endemic Syphilis 517
Fig. 44.2 Treponema pertenue in the epidermis (immunofluorescent

staining).
Pinta
The histopathological changes in pinta are largely similar
to those in yaws [49,50,52], except that ulcer formation
does not occur [49]. In the early lesion, only mild acan
thosis is present, with migration of some lymphoid cells
into the epidermis. Basal cells show loss of melanin and
liquefaction degeneration. In early‐stage lesions, melano
phages may be seen in the upper dermis [50]. A moderate Fig. 44.3 Early (primary) yaws: infectious skin lesions on the leg.
dermal inflammatory infiltrate consists mainly of plasma
cells and lymphocytes. Histiocytes and neutrophils may initial skin lesions, but are greater in both number and
be seen. Occasionally, slight swelling of endothelial cells size. In the tertiary stage, deformities can occur. An

is present [49,50]. In the late stage, irregular acanthosis or overlap between the stages is often noted. A more prac
epidermal atrophy can occur. Pigmentary changes vary tical system of classification defines an early stage with
with the colour of skin lesions. A lymphocytic infiltrate contagious skin lesions, and a late stage, in which the skin
and numerous melanophages may be present in the lesions are less contagious [44]. Early yaws includes the
INFECTIONS
dermis. Treponemes can sometimes be visualized in the primary and secondary stage; late yaws is equivalent to
epidermis by means of silver staining methods or immu the tertiary stage.
nofluorescent techniques. Dyschromic late skin lesions Early stage skin lesions, often pruritic, appear after
may contain treponemes and show an inflammatory an incubation period of 9–90 days, with an average of
infiltrate, but achromic late skin lesions lack both of these 3 weeks [6]. Classically, the initial presentation of yaws
features [50]. consists of one or more nontender papules which later
become crusted and ulcerated (Fig. 44.3). The lower
Endemic syphilis
extremities are a site of predilection. The early papules
The histopathological picture closely resembles that of
can evolve into ulcerated and papillomatous lesions,
venereal syphilis. In the early stage, the dermal infiltrate
containing numerous treponemes.
is primarily perivascular, and plasma cells and lympho
Disseminated lesions may occur together with or after
cytes predominate. Slight vascular changes may be
the disappearance of primary lesions. These are some
present. In early endemic syphilis, granulomas consisting
times preceded or accompanied by malaise, fever and
of epithelioid cells and multinuclear giant cells are seen
generalized lymphadenopathy. These early (secondary)
[50]. Silver or immunofluorescent staining methods may
stage skin lesions often resemble the initial lesions
assist in visualization of the treponemes in the early
(Fig. 44.4). Macules, papules and nodules can occur. Palms
stage. In the late stage, treponemes are rarely seen.
and soles often show hyperkeratosis (crab yaws). In the
early stage, bone and joint manifestations, particularly
Clinical features osteitis and periostitis, may already be noted [53]. Lesions
Yaws in the early stage of yaws usually disappear spontane
Historically, several systems have been used to classify ously, sometimes leaving slight pigmentary changes.
the clinical stages of yaws [6]. The most frequently used However, severe secondary infection can be life‐threatening
system defines four stages (primary, secondary, tertiary and scarring is common. In the warm and rainy seasons,
and latent), equivalent to those seen in venereal syphilis. cutaneous lesions are more florid and abundant than
In the primary stage, skin lesions develop at the site of during drier periods of the year. During the dry season,
infection. Secondary stage skin lesions, a result of the patients may present with atypical macular cutaneous
widespread dissemination of treponemes, resemble the lesions.
Fig. 44.5 Sabre tibia. This irreversible condition is caused by chronic untreated

periostitis. Source: Perine et al. 1984 [6]. Reproduced with permission of WHO.
Fig. 44.4 Multiple ulcerocrustopapillomatous skin lesions in early

(secondary) yaws. Dark‐field examination revealed the presence of many
treponemes.
After the early skin manifestations have subsided, a

INFECTIONS
latent period of variable duration follows. The presence

of latent infection can be detected by the presence of a
positive serological test. This period may be interrupted
by one or more relapses of skin lesions. In the majority of
patients latency is lifelong. However, an estimated 10%
of patients develop a destructive late stage after 5–10
years or longer. Irreversible lesions of bone, cartilage,
soft tissue and the skin then develop. Manifestations
of late yaws include gangosa (destructive ulcerative
rhinopharyngitis), gummata, juxta‐articular nodes, con
tractures and sabre tibiae (Figs 44.5 and 44.6). Gondou,
the rarely occurring exostoses of nasal and adjacent
bones, can also develop early in the course of the dis
ease. Hyperkeratotic lesions may be observed in both
late and early yaws [6].
It has been generally assumed that no neurological or
cardiovascular involvement occurs in yaws. However, a
review in 1986 suggested that cardiovascular and neuro
logical disease, similar to that in syphilis, may be seen in
patients with yaws [22,54,55]. In one study, ocular and
neurological abnormalities were described in patients
with late yaws [55]. Cerebrospinal fluid abnormalities,
optic atrophy, abnormal pupils and perivascular sheath
ing were noted. As confusion between yaws and other
treponematoses is possible, and as there is no serological Fig. 44.6 Gummatous osteoperiostitis. Monodactylitis is characteristic of
test to differentiate between these diseases, additional late yaws bone lesions. Deformity of the fingers may result. Source: Perine
research is required [54]. et al. 1984 [6]. Reproduced with permission of WHO.
Pinta most common manifestations. Condylomata lata, compa

The early stage of pinta includes the development of rable to those in yaws and sexually transmitted syphilis,
initial lesions and more generalized secondary lesions; occur frequently. In the early stage, a painful osteoperios
the late stage includes a tertiary and late latent phase. titis, similar to yaws, may be observed. After early lesions
There may be considerable overlap between stages. After have subsided, the patient enters latency. In this stage,
an incubation period of several weeks to months, the ini treponemal infection can only be detected by positive
tial lesion, usually a papule or an erythematosquamous serological tests. In some patients, the late stage may
plaque, develops on exposed skin. This primary lesion develop at a young age [36,42]. In this stage, involvement
may become pigmented, hyperkeratotic and scaly, and of skin, bones and cartilage may lead to severe destruc
may be accompanied by local lymphadenopathy. Primary tion, especially of the nose and palate. The larynx may
lesions of pinta disappear spontaneously. be solely affected [43]. In patients with nasopharyngeal
After several months or even years, more extensive and involvement, gummata may progress to destructive
generally smaller lesions may appear, which are similar in chronic ulceration, similar to rhinopharyngitis mutilans.
morphology to the initial lesions. These so‐called ‘pintids’ Neurological and cardiological involvement is extremely
may persist for years or resolve and then recur. Striking rare or perhaps nonexistent [42,43,56,57].
changes in skin pigmentation may result [6].
In late (tertiary) pinta, disfiguring pigmentary changes, Differential diagnosis. The diagnosis of endemic trepone
achromia, skin atrophy and hyperkeratoses are common. matosis must be based on clinical, geographical, epidemi
The pigmentary alteration may vary from lesion to lesion, ological and laboratory findings. At this point in time, it is
resulting in a sometimes lifelong mottling of the skin not possible to distinguish between the causative agents of
(Fig. 44.7). Skin lesions may turn red, white, bluish, violet the different treponemal diseases on serological, morpho
or brown. Severe mutilation does not occur; it is assumed logical or biochemical grounds. Positive serological tests
that the skin is the only organ affected by this chronic in all but the very early stage, the presence of treponemes
treponemal disease [6]. Pinta is considered the most in dark‐field examination of exudates of cutaneous lesions
benign of the endemic treponematoses, with a good and the histopathological features confirm the diagnosis.
prognosis. No cardiological or neurological symptoms Diagnosis can be difficult in geographical regions where
have been described [6,7,55]. There is no known congeni venereal syphilis and/or endemic treponematoses are
tal form [7]. simultaneously prevalent, particularly for patients who
are in latency and the late stage (Table 44.2). Several other

Endemic syphilis diseases in the tropics can resemble yaws, pinta and
Endemic syphilis may be divided into an early and a late endemic syphilis (Tables 44.3–44.5).
stage. The early stage includes primary and secondary
symptoms, and the late stage includes tertiary and late Laboratory tests. For the endemic treponematoses, the
INFECTIONS
latent disease. In contrast with the other treponematoses, same treponemal and nontreponemal tests designed
and perhaps because of the small inoculum, primary for the serodiagnosis of venereal syphilis are used. The
lesions may go unrecognized. In the primary phase, the treponemal tests are the T. pallidum haemagglutination
oropharyngeal mucosa is frequently involved. Frequently, assay (TPHA), the fluorescent treponemal antibody‐
endemic syphilis first manifests in the secondary stage absorbed test (FTA‐abs) and most enzyme‐linked immu
and resembles secondary venereal syphilis. Patches on nosorbent assay (ELISA) tests. The nontreponemal tests
the mucous membranes, angular stomatitis, nonpruritic are the rapid plasma reagin (RPR) test and the Venereal
skin eruptions and generalized lymphadenopathy are the Disease Research Laboratory (VDRL) test. In remote regions,
only the nontreponemal tests are practical. In reference
Table 44.2 Some characteristics of treponematoses
Venereal Yaws Endemic Pinta

syphilis syphilis
Source of Sexual School, School, Social

infection partner house house
Age Adults 2–15 years 2–15 years 10–30 years
Type of climate All Humid/warm Dry/warm Dry/warm
Early genital Often Rare Rare Very rare
lesions
Neurological Sometimes No? No? ?
complications
Cardiovascular Sometimes No? No? ?
complications
Congenital Occasional No? No? ?
disease
Fig. 44.7 Pigmentary changes in pinta.
Table 44.3 Differential diagnosis of yaws laboratories, the treponemal tests can be used to confirm
reactive nontreponemal tests. In the field, the most prac
Skin lesions Venereal syphilis tical means for collecting and transporting blood for
Endemic syphilis serological tests is the filter paper method [58]. The
Pinta temporal relation between infection and reactivity, and
Leprosy
the persistence of positive serologies after treatment, are
Impetigo
Ecthyma the same in the endemic treponematoses and sexually
Tungiasis transmitted syphilis.
Tropical ulcers Recent progress in DNA technology, using Escherichia
Chromomycosis coli‐derived recombinant T. pallidum proteins, has led to
Cutaneous leishmaniasis the development of tests that can be used for sexually
Sarcoidosis, psoriasis
transmitted syphilis as well as for the endemic trepone
Vitamin deficiencies
Scabies
matoses [59–61]. However, shared antigens give rise to
Viral infections such as mollusca contagiosa cross‐reactive antibodies common to all treponemal
or plantar warts diseases, precluding a differentiation of these diseases
Bone lesions Venereal syphilis on the basis of serological tests.
Endemic syphilis Demonstration of treponemes by dark‐field examination
Tuberculosis of exudates from early stage skin lesions can assist in diag
Bacterial osteomyelitis
nosing treponemal disease, but there are no differentiating
Sickle cell anaemia
Rhinopharyngeal lesions Espundia (mucocutaneous leishmaniasis)
morphological criteria among the treponematoses.
Rhinosporidiosis
Rhinoscleroma Treatment. The drug of choice is long‐acting penicillin.
Tuberculosis Treatment consists of 600 000 U benzathine penicillin for
Leprosy all patients and contacts (for children under 10 years) and
South American blastomycosis
1 200 000 U (for older individuals) by single intramuscular
injection. No other drug is effective in a single dose.
Family members, contacts of patients and patients with
Table 44.4 Differential diagnosis of the skin lesions of pinta
latent infection should receive the same dose as those
with active disease [62]. For patients who are allergic to
Venereal syphilis, yaws and endemic syphilis penicillin, alternative therapies are tetracycline and eryth
Skin disorders with changes in pigmentation (vitiligo, pityriasis versicolor, romycin [63]. The newer tetracycline and erythromycin
pityriasis alba, erythema dyschromicum perstans, Riehl melanosis, analogues have not yet been tested on a large scale for the
chloasma, discoid lupus erythematosus) treatment of endemic treponematoses.
INFECTIONS
Eczema, psoriasis, tinea corporis, chronic pellagra, leprosy Change in titre of quantitative nontreponemal tests is
the major parameter used to measure response to therapy.
Treponemal tests may remain positive for life despite
Table 44.5 Differential diagnosis of endemic syphilis treatment. Strains of T. pallidum that are resistant to peni
cillin have not yet been reported [63,64].
Skin lesions Venereal syphilis Endemic treponematoses are still prevalent in various
Yaws and pinta regions of the world, especially among people living in
Psoriasis unhygienic circumstances in inaccessible regions with
Eczema inadequate medical facilities [8,19,65]. Public health
Pityriasis rosea
concern about the endemic treponematoses diminished
Lichen planus
Leprosy, mycoses
after the mass campaigns, and a resurgence of endemic
Herpes simplex treponematoses has been documented [19,65,66]. Millions
Condylomata acuminata of people are again at risk of contracting these infections.
Perlèche and aphthae Owing to the ever‐increasing frequency of worldwide
Many diseases presenting with a generalized rash travel and migration, nonvenereal treponematoses can
Late stage Malignancies (carcinoma, mycosis fungoides, easily be transported to nonendemic areas, confronting
leukaemias, Bowen disease)
the local healthcare provider with a diagnostic dilemma.
Lupus vulgaris
Toxicodermas
A positive treponemal test result in a person originating
Bromoderma and iododerma from an endemic region must arouse the suspicion of one
Infiltrated types of rosacea and lupus of the non‐sexually‐transmitted treponemal infections [67].
Erythematosus, facial granuloma In the modern era, yaws and endemic syphilis may pre
Nasopharyngeal lesions Yaws sent in a milder ‘attenuated’ form or an atypical form
Venereal syphilis [38,68–73] with less florid skin lesions. In areas with a low
Leishmaniasis
prevalence, solitary, small, flat, dry and hidden lesions of
Histoplasmosis
Rhinoscleroma short duration are seen. It has been argued that endemic
Rhinosporidiosis treponematoses demonstrate extremely variable disease
severity, depending on the frequency of infection in a
given community [68]. This phenomenon may be caused Early recognition and treatment of patients with endemic
by the widespread use of antibiotics, the improvement of treponematoses can prevent patients from developing
social conditions, a mutation or an adaptation of the later stage manifestations. Without institution of therapy,
causative organism or altered immune responses of the late‐stage sequelae may lead to severe handicap.
host. A modified form of pinta has not yet been reported.
The rarity or absence of congenital infection and of neu References
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523
C HA PTER 45
Tropical Ulcer
Vibhu Mendiratta & Soumya Agarwal
Department of Dermatology, Lady Hardinge Medical College and associated hospitals, New Delhi, India
Abstract vesicle/pustule at the site of trauma most occur on the lower leg)
followed by ulceration with perilesional oedema, purulent discharge
and pain. Untreated, the ulcer shows necrotic slough and invasion
Tropical ulcer (TU) is a synergistic bacterial infection caused by
of deeper subcutaneous tissues, fascia and bone. Histopathology is
Bacillus fusiformis and Treponema spp. A high prevalence of TU
necessary to exclude malignancy in the chronic stage. Complications
is recorded in Africa, South‐East Asia and South America. Current
include septicaemia, osteomyelitis, contractures and squamous cell
trends show a declining prevalence owing to better awareness of
carcinoma development. Treatment includes local cleaning with
environmental and personal hygiene, health education and avail
soap and water/hydrogen peroxide, nonadherent antiseptic
ability of effective antimicrobial treatment. Aetiological factors
dressings, penicillin/macrolide antibiotics, metronidazole and, if
include minor, superficial trauma to skin, exposure to muddy
necessary, skin grafting.
water, poor hygiene and malnutrition. Clinically TU begins as a
Key points • Diagnosis is mainly based on clinical grounds. It can be

confirmed by dark‐field examination and culture of the causative
• Tropical ulcer (TU) is a painful, acute infective ulcer caused by organisms. Histopathology is required in chronic cases to rule
synergistic bacterial infection of Fusobacterium, spirochaetes out malignancy.
and/or anaerobic bacteria. • TU should be differentiated from other infective (Buruli ulcer,
• The incidence of TU is currently declining due to improved yaws, leishmaniasis, leprosy, deep fungal infections) and
socioeconomic conditions and better hygiene practices. The noninfective (traumatic, sickle cell anaemia, atherosclerosis,
prevalence is high in certain areas of Africa and South‐East Asia. vasculitis, drug‐induced) causes of leg ulceration.
• Predisposing factors include minor, superficial trauma to skin, • TU can be complicated by secondary bacterial infection, osteo

exposure to muddy water, poor hygiene and malnutrition. myelitis, malignant transformation, deformity and lymphoedema
• The disease has no sex predilection in childhood, but males due to scarring.
are more commonly affected in the adult age group. The most • The mainstay of treatment is systemic antibiotics including
common age group involved is 5–20 years. penicillin, streptomycin and metronidazole. It should be
INFECTIONS
• The most common site affected is the lower legs. TU starts as a supplemented with repeated antiseptic dressings, adequate
tiny vesicle/pustule that breaks down rapidly to form a tender, rest, improved nutrition and local cleaning with soap, water
round–oval, foul‐smelling ulcer that bleeds easily on touch. and/or hydrogen peroxide.
in the Transvaal in southern Africa. This author demon-

Introduction
strated the presence of Vincent’s bacilli alone or in asso-
Definition
ciation with Spirillum in the pus from ulcers affecting
Tropical skin ulcer (TU), also known as Naga sore, ulcus
mineworkers and hypothesized that some local infection
tropicum, Aden ulcer, Jungle rot, Malabar ulcer, and tropi-
of a minor wound was responsible for the ulcers [1].
cal phagedena, is a painful and disabling condition of the
Similar mixed isolates comprising fusiform bacilli,
lower leg and foot affecting primarily adolescents and
spirochaetes and staphylococci were obtained from TU
young adults. TU is defined as a painful, acute inflamma-
in a series of 38 patients in India [2].
tory, rapidly spreading ulceration of skin and subcutaneous
TU has been referred to by different names in the past
tissue affecting the lower extremities which is accompanied
such as ‘Naga sore’ by Fox [3], ulcus tropicum by Panja [4]
by necrosis, sloughing oedema and foul‐smelling discharge.
and tropical phagedenic ulcer by MacAdam [5]. Both
The ulcer is characterized by an undermined edge and
Burnie and MacAdam suspected that infection had a
considerably raised margins [1–5].
causative role and both demonstrated that it was possible
to produce a TU by inoculating pus from affected indi-
History viduals into healthy volunteers [6]. TU was considered
Vinson was the first to mention tropical ulcers when epidemiologically important during World Wars I and II
describing them in 1857 as occurring in slaves aboard when returning European troops got infected, and reporting
a ship. Later, features of tropical ulcers that affected of these cases by treating doctors diverted medical
mineworkers were studied by Spencer Lister in an epidemic attention to the subject [7]. Early reports from the 1930s to
1950s are on record from South Africa and India that including many aerobes such as Staphylococcus aureus, can
described TU as acute, painful, inflammatory ulceration also be found. The reservoir of F. ulcerans is not fully
over the lower legs that was associated with great known, but it has been isolated from mud and stagnant
morbidity [4]. Earlier reports may lack evidence as to the water in endemic areas [13].
design but TU was first recognized as a distinct clinico- Panja [4] claimed that the identification of fusiform
morphological entity in tropical areas. The aetiology is bacilli in granulation tissue confirms that they cause
multifactorial, and still not known completely. Historical ulceration in TU. In a later study, Panja experimentally
suggestions throughout the literature support the belief produced TU in 11 volunteers after injecting pure cultures
that TU occurs only in people who are undernourished of fusiform bacilli obtained from ulcer swabs, further
and live in poor conditions [8,9]. In 1936, Clements supporting his theory that infection was truly responsible
described them as ‘one of the diagnostic garbage heaps for ulceration [4]. Results of the four‐country survey
of tropical medicine’ and argued that this was ‘a definite performed in the 1980s also indicated that fusobacteria
disease with its own signs and histopathology’ [8]. In were actively involved in the aetiology of tropical ulcera-
1963, Loewenthal defined a tropical phagedenic (meaning tion [18]. Further laboratory experiments found that these
‘to eat’) ulcer as ‘an acute, specific, localised necrosis of organisms produced acidic butyrate as a metabolite and
skin and subcutaneous tissues endemic in, but not con- were cytotoxic to cells in vitro, which might contribute
fined to, the tropical regions’. After the acute stage a to ‘rapid tissue destruction and ulcer formation’ [19].
chronic, nonspecific ulcer may persist [9]. Later, Tumwine Electron microscopy of the epidermis and dermis of
et al. gave a more detailed clinical definition of TU [10]. TU biopsies revealed fusobacteria deep in the dermis,
supporting Panja’s findings [4,20]. Gross destruction of
Epidemiology. TU is worldwide in distribution and collagen was observed, particularly near clusters of bacte-
cases are found in almost all tropical and subtropical ria. Oedema and huge numbers of polymorphonuclear
areas. A higher prevalence is noted in Nigeria, Uganda, leucocytes supported the suspicion that necrosis was
Democratic Republic of Congo, West Africa, the Bantu of caused by toxins released from fusobacterium [20].
southern Africa, Sri Lanka, Indonesia, Java, Papua New Factors like poor hygiene, exposure to muddy water
Guinea, the Pacific Islands, Madagascar and South and and malnutrition seem to predispose to the bacterial
Central America.The disease occurs mostly in sporadic infection and also facilitate spread of the ulcer. A wet trop-
and endemic forms, although outbreaks of almost ical climate is conducive to the easy spread of infection. In
epidemic proportions have been noted from Assam,
the presence of a susceptible host who sustains superficial
Cochinchina, Malaya, certain parts of Africa, the Solomon skin trauma through a scratch/insect bite or abrasions
Islands and Melanesia [11]. India was among the initial from thorns/tall grass, the bacteria are inoculated into
regions to report TU; however, there has been a steady the skin leading to acute, painful ulcerations of the skin
decline in numbers over the last decade. (Box 45.1). TU is encountered more commonly in rural
INFECTIONS
All age groups from the age of 5 to 70 years can have areas where improperly clad farmers go to the fields and
TU; however, the majority of cases of TU are between bear a high occupational risk of sustaining minor skin
5 and 20 years. The disease shows no sex predilection in injuries. Contamination of minor abrasions sustained dur-
childhood, but occurs more commonly in men in adults ing farming by muddy water, dirt, or local applications of
in most countries. A review of 230 cases of TU from a cow dung, tobacco or many other locally available indig-
hospital in Haiti between 1963 and 1973 found ulcers enous products, promotes secondary infection by other
affecting both men and women (males more than females) bacteria, which produces chronic inflammation and
with a median age of 21 years, median duration of 2 years resultant lack of healing of the ulcers.
and healing time of 2 days to 18 years [12]. Robinson et al.
described 170 patents with 241 ulcers affecting the lower Clinical features. The clinical presentation of TU is similar
legs in predominantly male children aged between 5 and in all geographical locations. TU begins as a tiny vesicle
14 years. On the other hand, women were more com- that turns into a pustule over a couple of days. The vesiculo-
monly affected in Papua New Guinea. In the majority, the pustule ruptures to form a round to oval ulcer usually
ulcers were of less than 6 months’ duration [13]. Other located below the knee on the anterolateral side of the leg
retrospective data from Cook Island and from Zimbabwe or the ankle.The rapid breakdown of the initial preulcerative
recorded the predominance of ulcers in 10‐ to 19‐year‐old
males [10,14]. An epidemiological survey from Ethiopia
confirmed the age and sex distribution of TU in 6‐ to 15‐
Box 45.1 Tropical ulcer: predisposing factors
year‐old males [15]. A declining trend has been noted in
the prevalence of TU, but certain geographical areas still Hot and humid climate
continue to register significant numbers of cases. Trauma
Lack of footwear
Pathogenesis. TU is a synergistic bacterial infection that Malnutrition
Deficiency of micronutrients (e.g. zinc)
occurs secondary to invasion of skin by at least two
Overcrowding
organisms, one of which is a Fusobacterium spp., usually Poor socioeconomic conditions
F. ulcerans, while others include spirochaetes or some Poor hygiene
anaerobic bacteria [16,17]. In chronic TU, different bacteria,
Chapter 45 Tropical Ulcer 525
papule to form a TU constitutes one of the characteristic equinovarus. The tibia and fibula may become thin and
features of TU [13]. atrophic. Lymphoedema can result from scarring.
The ulcer bleeds easily on touch. It has circular, oedem-
atous margins that are raised above the surrounding skin.
Diagnosis. The diagnosis of TU is based on clinical his-
The ulcer base is granulomatous and shows a foul‐smelling
tory and examination. The presence of a round to oval,
grey slough (Fig. 45.1). Edges become rolling, along with
painful ulcer over the lower third of the leg discharging
evident perilesional pigmentation in the chronic stage.
pus and blood and covered with greyish slough should
There is usually no regional lymphadenitis.
arouse clinical suspicion of TU. Bacillus fusiformis and
The majority of TU remain confined to the skin only.
Borrelia vincentii have been found in more than 30% of TU.
Some may rapidly invade deeper tissues such as subcuta-
B. fusiformis is a cigar‐shaped Gram‐negative organism
neous tissue, fascia, tendons, muscles and bones in a span
that grows on an anaerobic medium containing serum
of a few weeks to months if neglected. Untreated ulcers
agar or serum broth. B. vincentii is a delicate organism,
can assume a large size of up to 15 cm. The duration of the
5–10 µm in length, with three to eight irregular spirals.
ulcer may range from 6 months to 15 years.
It is motile, Gram‐negative and stains with silver impreg-
nation. It is best demonstrated by dark–field examination
Complications (Box 45.2)
and is cultured on anaerobic medium consisting of serum
Superimposed secondary bacterial infections, septicae-
agar or broth. Many other Gram‐negative and ‐positive
mia and gangrene are acute complications. Malignant
bacteria can also be isolated in the chronic stage of a TU.
degeneration is rare before 20 years of ulcer duration, but
Histopathological examination of the ulcer shows a
may occur in about 2–9% of chronic TU. Squamous cell
chronic inflammatory infiltrate with necrosis and fibrosis.
carcinoma with lymph node spread is known to arise in
Features of vasculitis are absent. Pseudoepitheliomatous
the ulcer and has been reported. It may also develop at
hyperplasia is prominent in the late stage and simulates
the site of a healed ulcer scar. Healing of the ulcer may be
squamous cell carcinoma. Imaging (radiography/ ultra-
followed by flexion deformity of the knee and talipes
sonography) of the limb will reveal soft tissue thickening
and a periosteal reaction that later produces a thickened
sclerotic layer known as ivory osteoma.
Differential diagnosis. TU mimics a host of other tropical

infections that cause leg ulcers. Buruli ulcer caused by
Mycobacterium ulcerans is common in children but they are
in good health and there is no pain. Yaws and cutaneous
leishmaniasis should also be differentiated.
INFECTIONS
Castellani’s ‘tropicaloid’ ulcer is caused by Corynebacterium
spp. and closely mimics TU.
Veldt sores or Barcoo rot and leg ulcers in sickle cell
anaemia over the inner side of the leg near the ankle also
should be differentiated from TU (Box 45.3).
Treatment. There is a dearth of literature on the treatment

of TU. General measures such as resting the affected
part, elevation of the limb and institution of adequate
diet are some important steps. Simple protective meas-
ures such as wearing clothing that fully covers the body
and boots to cover the feet are helpful in prevention.
Minor abrasions/cuts sustained during farming or acci-
dentally must be cleansed with clean water (which should
be preferably boiled for 15 minutes as for drinking) and
Fig. 45.1 A large chronic tropical ulcer with oedematous margins, serous
followed by the application of gentian violet. This will
discharge and unhealthy base over the lateral malleolus. help get rid of the infection. It is imperative also to treat
any other underlying chronic disease.
The patient with a TU should preferably be admitted
Box 45.2 Tropical ulcer: complications to hospital. While the results of the antibiotic sensitivity
are awaited, penicillin and streptomycin 1 g daily should
Severe debilitating pain in the acute phase be given for about 7–10 days [21]. Long‐chain penicillins
Scarring and contractures resulting in crippling deformities can be given once/twice a week to minimize injections.
Lower limb amputation
Alternatively, an oral tetracycline or erythromycin in
Squamous cell carcinoma at ulcer site
Hepatitis infection
divided doses can be used in children (after development
Septicaemia if untreated of the permanent dentition in the case of tetracyclines) or
in patients who cannot be admitted. Metronidazole also
All patients are seen on at least four occasions and

Box 45.3 Tropical ulcer: differential diagnosis
hospitalized patients require a minimum of 15 days’ ther-
Acute leg ulcers
apy compared to 10 days if lesions are grafted early. Skin
grafting produces excellent responses but the drop‐out
Traumatic ulcer rate is high. There is a strong need for a uniform approach
Impetigo to the management of ulcerated skin lesions along with
Ecthyma ready access to grafting facilities to reduce the require-
Cellulitis ment for long‐term dressings and the risk of chronic
Drug‐induced (hydroxycarbamide, ergotamine, iododerma) ulcer
ulceration.
Radiation‐induced ulcer
Prevention of minor abrasions seems to be vital in
preventing TU and the wearing of long‐legged trousers
Chronic leg ulcers
is recommended. If a minor trauma occurs, first aid
Buruli ulcer including thorough cleansing of the lesion with soap
Veldt sore and water should be performed followed by an occlusive
Cutaneous leishmaniasis dressing.
Tuberculosis
Leprosy
References
Pyoderma gangrenosum
1 Lister FS. Aetiology of tropical ulcer. Transvaal Med J 1911;7:25–6.
Deep fungal infections 2 Rao RV, Kini MG, Subrahmanyan KS. Tropical ulcers in Madras city.
Yaws Ind Med Gaz 1949;84:88–92.
Vasculitis 3 Fox ECR. Naga sore. Ind J Med Res 1920;8:694–8.
4 Panja G. Aetiology and treatment of ulcus tropicum. Ind J Med Res
Squamous cell carcinoma
1945;33:11–16.
Sickle cell anaemia 5 MacAdam I. Tropical phagedenic ulcer in Uganda. J Roy Coll Surg
Venous/arterial ulcer Edinb 1966;11:196–205.
6 Burnie RM. Observations on tropical ulcer. West Afr Med J
1931;4:77–86.
7 Smyth EA. The treatment of tropical ulcer. J Royal Army Medical
has similar efficacy and can be used as a single therapeutic Corps 1946;87:141–2.
agent in a dose of 250 mg every 8 hours for 10 days. TU 8 Clements FW. Tropical ulcer with special reference to its aetiology.
Med J Australia 1936;2:615–44.
responds quickly with relief of pain and appearance of 9 Loewenthal LJ. Tropical phagedenic ulcer: a review. Int Rev Trop
healthy granulation tissue [22]. Combination therapy Med 1963;2:267–91.

with metronidazole and amoxicillin–clavulanic acid can 10 Tumwine JK, Dungare PS, Tswana SA, Maoneke WR. Tropical
ulcers in a remote area in Zimbabwe. Cent Afr J Med 1989;
also be used [23]. 35:413–16.
Various other treatment modalities have been reported 11 Roy DN. Tropical ulcer. Brit Encyl Med 1949;12:320.
INFECTIONS
to be successful for TU: 12 Ariyan S, Krizek TJ. Tropical ulcer. Plast Reconstr Surg 1975;55:
• Antibiotics: in the early stages, penicillin or metronidazole 324–9.
13 Robinson DC, Adriaans B, Hay RJ et al. The clinical and epidemio-
is used in combination with topical antibiotics or antisep- logical features of tropical ulcer (tropical phagadenic ulcer). Int J
tics such as framycetin sulfate, neomycin, polymyxin B, Dermatol 1988;27:49–53.
bacitracin, nitrofurazone and povidone–iodine. 14 Kubersi T, Koteka G. An outbreak of tropical ulcer in the Cook Islands.
Am J Trop Med Hyg 1980;29:291–7.
• Improved nutrition and vitamins.
15 Bulto T, Muskel FH, Fisseha G. Skin lesions in resettled and indige-
• Nonadherent dressings. nous populations in Gambela with special emphasis on the etiology
• Large infected ulcers may require debridement under of tropical ulcer. Ethiopian Med J 1993;35:75–82.
anaesthesia. 16 Adriaans B, Hay RJ, Drasar B et al. The infectious aetiology of tropi-
cal ulcer–a study of the role of anaerobic bacteria. Br J Dermatol
• Skin grafting may be helpful in advanced cases to 1987;118:31–7.
ensure the lesion does not progress to the chronic stage. 17 Citron DM. Update on the taxonomy and clinical aspects of the genus
• In extreme cases, amputation is necessary. fusobacterium. Clin Infect Dis 2002;35(suppl 1):S22–7.
In the late stages of the ulcer, after infection has been ade- 18 Adriaans B, Drasar BS. The isolation of fusobacteria from tropical
ulcers. Epidemiol Infect 1987;99:361–72.
quately treated, pinch grafting of the skin is a good alternative 19 Adriaans B, Garelick H. Cytotoxicity of Fusobacterium ulcerans.
to secondary intention healing. The procedure is simple and J Med Microbiol 1989;29:177–80.
can be easily carried out by health workers in rural areas [24]. 20 Adriaans B, Hay R, Lucas S et al. Light and electron microscopic
features of tropical ulcer. J Clin Pathol 1987;40:1231–4.
In specialized centres, wide excision of the infected 21 Ngu VA. Tropical ulcer. BMJ 1967;1:283–5.
bone and tendon can be carried out in chronic cases with 22 Yesudian P, Thambiah AS. Metronidazole in the treatment of tropical
associated underlying osteomyelitis. A split‐skin graft or phagedenic ulcers. Int J Dermatol 1979;18:755–7.
a full‐thickness pedicle graft is used to provide cover for 23 Aribi M, Breuillard F, Poirriez J. Guess what! Eur J Dermatol 1999;
9:321–2.
the resulting defect [25]. 24 Morris GE, Hay RJ, Srivastava A et al. The diagnosis and management
Watkinson et al. [26] conducted a double‐blind trial of tropical ulcer in East Sepik province of Papua New Guinea. J Trop
on the use of oral zinc supplements as an adjunctive Med Hyg 1989;92:215–20.
25 Goodacre TEE. Plastic surgery in a rural African Hospital: spectrum
treatment for TU and concluded that, although zinc sup-
and implications. Ann R Coll Surg Engl 1986;68:42–44.
plements significantly elevated plasma concentrations of 26 Watkinson M, Aggett PJ, Cole TJ. Zinc and acute tropical ulcers in
zinc, they had no effect on ulcer healing. Gambian children and adolescents. Am J Clin Nutr 1985;41:43–51.
527
C HA PTER 46
Superficial Fungal Infections

Peter Mayser1 & Yvonne Gräser2
Clinic of Dermatology, Allergology and Venereology, Justus Liebig University (UKGM), Giessen, Germany
1
The National Reference Laboratory for Dermatophytes, Universitätsmedizin – Charité, Institute of Microbiology and Hygiene, Berlin, Germany
2
Introduction, 527 Candidosis (candidiasis), 545 Less common superficial fungal

Dermatophytoses, 527 Malassezia‐associated diseases, 550 infections, 556
Abstract carriers. Onychomycosis, although uncommon in children, increases

with age. Risk factors are sporting activities and infected parents.
Superficial mycoses are among the most common skin infections. Recalcitrant candidosis may be indicative of immune deficiency. Among
Molecular methods can accelerate diagnosis. In childhood, tinea children in the tropics, pityriasis versicolor is not an uncommon disease.
capitis, especially caused by anthropophilic dermatophytes, is of Furthermore Malassezia yeasts seem to be associated mainly with the
rising importance. Oral therapy is essential. Index cases due to head, neck and face types of atopic eczema/dermatitis syndrome, cor-
T. tonsurans, T. violaceum and M. audouinii warrant screening of all responding to the numerous sebaceous glands found in this region,
family members and close contacts and treatment of asymptomatic but it remains to be clarified whether this is also applicable to children.
Key points • Tinea capitis, especially when caused by anthropophilic

dermatophytes, is of rising importance in childhood. For
eradication of the organism, resulting in both clinical and
• Superficial mycotic infections are among the most common skin
mycological cure as quickly and safely as possible and reduction
infections in childhood.
of transmission to others, oral therapy is essential.
• Molecular methods can accelerate diagnosis.
Introduction skin and keratinized tissues such as hair and nails. The
severity of the infection depends on the dermatophyte
Superficial fungal infections are common in both temperate species involved and the immunological response of the
SECTION 8: FUNGAL SKIN

and tropical climates and although the majority occur in host. The clinical appearance of the lesions varies accord
all age groups, some are seen only rarely in children. For ing to the site of infection and the causative organism.
these superficial infections, fungal invasion is restricted
INFECTIONS
to the skin, hair, nails and mucous membranes. In the
skin, these fungi are found only in the stratum corneum History. The first recognition that a fungus could be
and, very exceptionally, in the epidermis. Some of these the cause of an infection was in 1837, when Remak [1]
fungal infections show characteristic and diagnostic clini observed the presence of filaments and spores in material
cal features but, in others, laboratory procedures are from favus, a chronic infection of the scalp. In 1839,
required to differentiate them from other dermatoses. The Schoenlein [2] described the filaments as being those of
principal infections and their causative agents are listed moulds, and when the fungus was isolated by Remak [3]
in Table 46.1. The taxonomy of dermatophytes has been in 1845, he classified it in the genus Achorion and named it
renewed recently. The taxonomic names applied in this A. schoenleinii (now Trichophyton schoenleinii). In 1841,
chapter are based on current species conceptualizations. Gruby [4] also published on the fungal nature of favus; he
Table 46.2 shows the old and new species concepts in this recognized the different types of hair invasion in cases of
group of fungi. tinea capitis, giving the name Microsporum audouinii to
the fungus causing ectothrix‐type infection. In 1910,
Sabouraud [5] published his classic book Les Teignes,
Dermatophytoses representing the accumulation of his work on taxonomy,
morphology, diagnosis and treatment of dermatophy
Definition. Dermatophytoses are infections caused by a toses. The dermatophytes were classified into four
specialized group of fungi, the dermatophytes, which are genera – Achorion, Epidermophyton, Microsporum and
able to invade and colonize the stratum corneum of the Trichophyton – on the basis of the clinical manifestations of
528 Section 8 Fungal Skin Infections
Table 46.1 Principal superficial infections and their causative agents A further development in taxonomy was the discovery of
the sexual states of some dermatophytes [7], which placed
Infection Agent the dermatophytes in their correct systematic position.
They are classified as Euascomycetes, order Onygenales
Dermatophytosis Microsporum spp.
and family Arthrodermataceae. Recently, molecular
Trichophyton spp.
Epidermophyton spp.
methods have been introduced to re‐evaluate the taxonomy
Nannizzia spp. of these three genera [8,9] and according to the new poly
Pityriasis versicolor Malassezia spp. phasic species concept in dermatophytes, the number of
Tinea nigra Hortaea werneckii recognized species is now about 40. Not all cause human
White piedra Trichosporon spp. infections, as most of them have been isolated only from
Black piedra Piedraia hortae soil or other keratin‐containing substrates. The applica
Neoscytalidium infections Neoscytalidium dimidiatum
tion of molecular methods in the last 20 years has revolu
Neoscytalidium hyalinum
tionized fungal taxonomy, and phylogeny is nowadays
the mainstay for systematics. Extensive application of
Table 46.2 New and old species concept within the dermatophytes several gene markers has shown that the main topology
of the Arthrodermataceae seems to be stable, but does not
New species Synonymized taxa entirely correspond with morphology [8,9]. Therefore in
concept 2017 de Hoog et al. [9] confined Trichophyton, Microsporum
and Epidermophyton to mainly anthropophilic and zoo
Mammal‐associated dermatophytes philic species located in derived clusters while the highly
Trichophyton T. mentagrophytes var. granulosum, A. benhamiae diverse geophilic species were located in the middle and
benhamiae
the bottom of the tree and were reclassified in Nannizzia,
T. bullosum Identical
T. concentricum Identical
Lophophyton and Arthroderma.
T. equinum All varieties of T. equinum A notable event in the study of dermatophytes was the
T. erinacei T. mentagrophytes var. erinacei report by Gentles [10] in 1958 of the successful treatment
T. eriotrephon Identical of experimental dermatophytoses in guinea pigs by the
T. interdigitale T. mentagrophytes var. interdigitale, goetzii, oral administration of griseofulvin. Subsequent clinical
nodulare, T. krajdenii trials proved the efficacy of griseofulvin in human derma
T. mentagrophytes T. mentagrophytes var. mentagrophytes,
tophyte infections, and it remained the only systemic
granulosum, T. verrucosum var. autotrophicum,
A. vanbreuseghemii
therapy available for many years.
T. quinckeanum T. mentagrophytes var. quinckeanum, T. langeronii,
T. sarkisovii Aetiology, epidemiology and pathogenesis. The most
T. rubrum T. fischeri, T. kanei, T. raubitschekii frequent dermatophyte species reported from human
T. schoenleinii Identical infections comprise three each in the genera Microsporum
T. simii A. simii
and Nannizzia, 17 in the genus Trichophyton and one

T. soudanense T. gourvilii, T. megninii
T. tonsurans All varieties of T. tonsurans
Epidermophyton species. Dermatophytes are not part of
T. verrucosum Remaining varieties of T. verrucosum the normal skin flora but have had a long‐lasting associa
INFECTIONS
T. violaceum All varieties of T. violaceum, T. yaoundei tion with the human host. They can be divided into three
Epidermophyton Identical groups depending on their natural habitat.
floccosum • anthropophilic species, which affect only humans
Microsporum M. langeronii, M. rivalieri • zoophilic species, whose normal hosts are animals but
audouinii
which also infect humans
M. canis M. distortum, M. equinum, A. otae
M. ferrugineum Identical
• geophilic species, which are found in soil and are only occa
sionally pathogenic for humans and animals (Box 46.1).
Main geophilic dermatophytes
Nannizzia gypsea M. appendiculatum, M. gypseum, A. gypseum
N. incurvata M. gypseum, M. incurvatum, A. incurvatum
N. fulva K. longifusus, M. boullardii, M. ripariae, M. fulvum, Box 46.1 Ecology of dermatophytes
A. fulvum
Anthropophilic Zoophilic Geophilic
E. floccosum M. canis N. fulva
M. audouinii N. gypsea
the diseases they caused as well as the morphological
M. ferrugineum T. equinum N. incurvata
characteristics of the fungi. In subsequent years, many T. concentricum T. erinacei
new species and genera were described, separated only T. interdigitale
on the grounds of small differences in fungal morphology T. rubrum T. mentagrophytes
or by the type of lesions they produced. T. soudanense T. benhamiae
By 1934, over 300 species in 40 genera had been pro T. schoenleinii T. simii
T. tonsurans T. verrucosum
posed. However, in 1934, Emmons [6] found that, on the
T. violaceum T. quinckeanum
basis of spore morphology, the dermatophytes could T. eriotrephon
be divided naturally into three genera, Microsporum, T. bullosum
Trichophyton and Epidermophyton, comprising 19 species.
Chapter 46 Superficial Fungal Infections 529
isolated from African immigrants in the UK and other

Epidemiology. Changes in the prevalence of infections
parts of Europe while the indigenous population rarely
caused by different species are important because infec
becomes infected by these two organisms. Whether racial
tions caused by these species vary in virulence and in
differences play a role in the epidemiology of geographi
response to therapy. The two most widely distributed
cally restricted species is not understood. T. schoenleinii
anthropophilic species are Trichophyton rubrum and
was previously considered as a cosmopolitan anthropo
Trichophyton interdigitale. Of these, T. rubrum, since its
philic species and was widespread in Europe but is now
introduction from the Far East to Europe and other coun
mainly isolated from parts of Africa and the Near East.
tries after World War II, has become the most common
Before the 1960s, M. audouinii was the dominant cause
cause of skin and nail infections in most countries. In con
(over 50%) of fluorescent scalp infections in Europe, the
trast, Trichophyton concentricum, the cause of tinea imbri
USA and parts of Africa. Subsequently, the number of
cata, is endemic only in the South Pacific, the south‐eastern
M. audouinii infections markedly decreased in both Europe
periphery of Asia and parts of Latin America and Mexico,
and America. In a survey covering the years 1979–1981
and cases of this infection are rarely seen elsewhere
in the USA [12], it accounted for only 0.3% of the total
(Tables 46.3 and 46.4).
isolations of dermatophytes. It has been suggested that
The aetiology of tinea capitis worldwide is known
this decline reflects the success of griseofulvin in treating
to change periodically. Microsporum ferrugineum is an
infections caused by this fungus. In parts of Africa,
example of an anthropophilic agent of tinea capitis
however, M. audouinii remains endemic and skin infec
whose distribution changed. In Japan, where prior to the
tions, as well as scalp infections, are common.
1970s M. ferrugineum predominated, the zoophilic species
Trichophyton violaceum and Trichophyton tonsurans,
Microsporum canis is now isolated more frequently. M. fer-
although recognized as cosmopolitan, are far more com
rugineum remains a common cause of infection in Korea,
mon in some parts of the world than others. T. violaceum
parts of China and north‐west Africa. Children of Korean
has always been the dominant cause of scalp infection in
immigrants to eastern Europe after World War II who had
the Indian subcontinent. It is also prevalent in North and
tinea capitis were found to be affected by M. ferrugineum,
East Africa, where 10–30% of the child population is
but this species appears not to have spread to the indig
infected [13], and due to immigration is found with
enous population [11]. Similarly, the anthropophilic
increasing incidence in Europe [14].
species Trichophyton soudanense was originally considered
Over the last 40 years, T. tonsurans has become the
geographically restricted to West Africa, and is now
most common causative agent of tinea capitis in the
USA, particularly in African‐American children living in
Table 46.3 Cosmopolitan dermatophytes urban areas. One report from Chicago [15] found that this
species accounted for 96% of all cases seen from 1976 to
Fungus Site of infection 1980. This was confirmed in a large survey from 1999 to
2002 by Foster et al. who found that T. tonsurans achieves
Anthropophilic E. floccosum Foot, groin, nail

near exclusionary proportions as the causal agent of tinea
T. interdigitale Foot, groin, nail
capitis in the USA [16].
T. rubrum Foot, nail, groin, body
T. tonsurans Scalp, body T. tonsurans is endemic in Mexico, Puerto Rico and
INFECTIONS
Zoophilic M. canis Scalp, body other Latin American countries, and it has been suggested
T. benhamiae Scalp, body that it was spread to the USA by immigrants from such
T. mentagrophytes Scalp, body areas. The fungus is also now endemic among the aboriginal
T. verrucosum Scalp, beard, body populations of parts of Australia [17]. The aetiology of
Geophilic N. fulva Scalp, body
tinea capitis in Europe has shown significant changes
N. gypsea Scalp, body
N. incurvata Scalp, body
during the last 30 years. In the 1980s, the dominant patho
gens were zoophilic, with M. canis predominant. In the
early 1990s, a rise in the number of anthropophilic derma
tophytes causing scalp ringworm was noticed in some
Table 46.4 Geographically limited species urban areas of north‐western Europe, particularly those
with large communities of Caribbean or African ancestry.
Fungus Site of Distribution
This trend has continued, and a survey performed under
infection
the auspices of the European Confederation of Medical
M. audouinii Scalp Africa
Mycology [18] confirmed a dramatic change from pre
M. ferrugineum Scalp Far East, Africa dominantly zoophilic to anthropophilic infections in a
T. concentricum Body Western Pacific, South‐East Asia, South number of major European cities. The children involved
America are predominantly of African ancestry, but they are not
T. erinacei Body Europe, New Zealand, Asia, Africa recent immigrants; in fact the vast majority were born in
T. quinckeanum Body Asia, Africa, Europe Europe. Several anthropophilic species are involved.
T. soudanense Scalp Africa, Asia
In the UK and in Amsterdam, T. tonsurans is dominant.
T. schoenleinii Scalp Asia, Africa
T. violaceum Scalp, body, Africa, Asia In a 25‐year survey in Bristol, UK, the contributions of
nail T. tonsurans and T. violaceum to total dermatophyte isola
tions increased tenfold, and in 2003 both accounted for
Table 46.5 Animal hosts of zoophilic dermatophytes scalp infections. Some of the asymptomatic carriers may
later develop clinical infections. Parents of children with
Fungus Major animal host(s) tinea capitis are also likely to be asymptomatic carriers of
the infecting fungus [23,24]. In the study by White et al.
M. canis Cats, dogs, horses
[25] of 209 household contacts of patients with tinea capi
T. equinum Horses
T. erinacei Hedgehogs
tis caused by T. tonsurans, 44.5% had silent fungal carriage
T. mentagrophytes Rodent, cats, sheep on the scalp. Therefore all household contacts of patients
T. quinckeanum Camels, rodent with tinea capitis should be offered screening to eradicate
T. benhamiae Guinea pigs, rabbits a potential reservoir of infection.
T. simii Monkeys Constant exposure to possible infection may also influ
T. verrucosum Cattle ence the incidence of disease. In closed communities, it
T. bullosum Donkeys
has been shown that the number of cases of tinea pedis
increases with the time of exposure to possible sources of
infection. For example, in one study carried out in a resi
86% of all dermatophytes isolated from tinea capitis. In dential school, it was found that the incidence of toe space
contrast, M. canis prevalence decreased by 90% [19]. infections increased with the number of years the boys
In Paris and its environs, however, T. soudanense and had been in the school [26]. New boys on entering the
M. audouinii predominate [18]; the incidence of the latter school had a 5% prevalence of infection; after 1 year, this
also increased in Switzerland [20]. had risen to 19% and after 2 years to 36%, whereas 54% of
Human infections caused by zoophilic species are the boys were infected if they had been at the school for
restricted to areas where the host animal is present. 4 years or more.
M. canis, commonly associated with cats and dogs, has
always been a worldwide cause of human infection. In Pathogenesis. Dermatophytes penetrate keratinized tis
many parts of Europe, and even in rural areas of countries sues by a combined enzymatic and physical attack on
that have seen such a dramatic rise in anthropophilic host tissues. They have been shown to produce enzymes,
infections in the major cities, this organism remains the such as keratinases, and in vitro invading dermatophyte
most frequent cause of tinea capitis. The countries report hyphae have been shown to be flattened, branched fronds
ing the highest incidence of M. canis infections are mainly adapted to force themselves between keratinocytes [27].
in the Mediterranean but also bordering countries such as Infection is transmitted by arthroconidia, spores formed
Austria, Hungary, Germany and Poland [21]. Other zoo by segmentation of fungal filaments (hyphae) that adhere
philic species with a wide distribution include Trichophyton to the skin, germinate and invade the stratum corneum.
benhamiae (guinea pigs, rabbits and other rodents) [22] For this infection to occur, some slight trauma or abrasion
and T. mentagrophytes (with a large range of animal hosts is necessary. Other factors that may play a role in the
inclusive of cats), T. verrucosum (mainly cattle) and T. equi- establishment of infection are skin surface factors such as
num (horses). pH and carbon dioxide tension; a rise in the latter has
By contrast, T. quinckeanum seems to occupy the same been shown to promote growth of fungi. Once established
distribution area as T. schoenleinii does [8]. Thus this spe on glabrous skin, the hyphae grow centrifugally to form
INFECTIONS
cies is very rare in Europe and other parts of the world. ‘ringworm‐like’ lesions. Different disease patterns are
Similarly, Trichophyton simii, found on monkeys in India, determined by the site of infection and the causative fun
produces human infection only in these countries gus. The pathogenesis of experimentally induced and
(Table 46.5). naturally acquired scalp infections has been studied by
Kligman [28]. After initial infection of the scalp skin, the
Transmission and source of infection. Transmission of hyphae grow down into the space between the hair shaft
infection is usually indirect, occurring through infected and follicle wall. The hair is then invaded at about mid‐
skin scales and hairs shed from infected human or animal follicle level. The intrapilary hyphae grow down towards
hosts in which the infective spores (arthroconidia) may the hair bulb but stop at the upper limit of the keratoge
remain viable for many months. Scalp infections may also nous zone, known as Adamson’s fringe. Hyphae within
be acquired through the use of contaminated combs and the hair are carried upwards by the growth of the hair, but
hairbrushes. Clothing, towels and bed linen are all possi the newly keratinized shaft is invaded by the fungus as
ble sources of infection. It is not difficult to isolate fungi soon as it is formed, at a rate of about 0.3 mm daily. When
from the floors of showers, changing rooms and dormito the invading fungus is one that produces an ectothrix
ries. It has been shown that in schools with outbreaks of infection (e.g. M. audouinii), the intrapilary hyphae
tinea capitis, many children in the same classroom as an emerge through the hair surface and fragment into masses
infected child carry the causative fungus on their scalps. of spores. The infected hair grows upwards and usually
This scalp carriage is believed to represent contamination breaks off a few millimetres above the scalp surface. In an
by spores shed from the infected child. It is usually tran endothrix infection (e.g. T. tonsurans), the intrapilary
sient, as once clinical cases are removed from the school, hyphae break up to form spores, which become rounded
the carrier rate decreases and then disappears. Never and fill the cortex of the hair. The invaded hairs break off
theless, these findings illustrate that there is widespread close to the scalp surface because of the greater degree of
dissemination of fungal spores from children who have shaft damage (‘black dot ringworm’). Favus is the name
given to a chronic type of endothrix invasion of the hair within the epidermis can be observed [34]. Certain unsat
caused by T. schoenleinii in which the hyphae grow irregu urated fatty acids present in sebum are inhibitory to the
larly down the hair shaft and do not fragment into masses growth of some dermatophytes in vitro. Their presence in
of spores. The shaft is not weakened and long lengths of postpubertal sebaceous secretions is thought to be an
infected hair are carried beyond the follicle by the growth important factor in preventing tinea capitis in adults.
of the hair. Degeneration of the hyphae leads to the for Tinea capitis in children may clear spontaneously at
mation of elongated air spaces in the hair. puberty, a time when greater quantities of sebum are
Infection of skin, hair and nails can persist only if the formed. Cell‐mediated immunity is thought to play an
fungus can grow into newly formed keratin as quickly as important role in defence against dermatophyte infection
old keratin is shed. Fungus‐specific factors may include [35]. Zoophilic and geophilic dermatophytes induce a
adaptation to the host, release of enzymes, production of delayed‐type hypersensitivity cell‐mediated response,
toxins and/or release of immune modulating agents. In which usually results in recovery and subsequent protec
general, the better the fungus is adapted to its host, the tion against re‐infection. Clinically this might be repre
milder the inflammatory response tends to be. Since sented by the characteristic healing from the centre of a
dermatophytes are almost exclusively localized in kerati classic ringworm lesion. The response is characterized by
nized tissues, this may require particular metabolic elevated levels of the key cytokines IL‐12 and interferon
activities. The spectrum of acidic proteases secreted by (IFN)‐γ, which trigger T‐helper 1 (Th1) cells for the activa
dermatophytes is similar to that of Aspergillus, but differs tion of macrophages as effector cells. In contrast,
by multiple endoprotease members of the S8 (subtilisins), anthropophilic species (e.g. T. rubrum, T. interdigitale and
M35 (deuterolysin) and M36 (fungalysins) families [29,30]. T. tonsurans) tend to be associated with less inflammatory
Surprisingly, most of the proteases secreted in vitro dur but more chronic and persistent infections. These infections
ing keratin digestion in protein media were not detected are correlated with poor specific delayed‐type hypersen
in vivo during the establishment of an infection. sitivity, elevated specific IgE and IgG4, and IgE‐mediated
Transcriptome analysis from guinea pigs infected by the immediate hypersensitivity (IH), with the production of
dermatophyte T. benhamiae and proteomic analyses of Th2 cytokines by mononuclear leucocytes [27,36].
proteins extracted from infected nail beds of patients with Infections by dermatophytes have been usually associ
onychomycosis by T. rubrum revealed that Sub1, Sub2, ated with extrinsic conditions such as immunosuppres
Sub7 and especially Sub6, not detected in vitro, were the sion, diabetes mellitus, advanced age, environmental
major proteases during infection [31,32]. Additional factors (e.g. humidity, occlusive footwear), contaminated
secreted proteases, including the closely related Sub7 and objects and surfaces as well as direct transmission by
the dipeptidyl peptidase DppV, were found. These results infected individuals or animals. However, it is well
from in vivo experiments are of particular interest since known that people are not equally susceptible to infec
Sub6 and DppV in T. rubrum were previously identified tion, even when they have the same risk factors. There is
and described as the major dermatophyte allergens, Tri r2 some evidence for a familial or genetic predisposition to

and Tri r4, respectively [33].Tri r2 induces delayed‐type dermatophytosis [37]. The observations include special
hypersensitivity (DTH) reactions, which are assumed to forms of the disease in small isolated communities (e.g.
be associated with highly inflammatory lesions in derma tinea imbricata in Polynesians) and a high incidence of
INFECTIONS
tophytosis. In addition to a protective role of endogenous tinea in certain families, suggesting genetic susceptibility.
microbiota, host factors that play a role in the inflamma Specific defects in molecules that are important in innate
tion process include the site of entry, nonspecific defence and adaptive immunity have been shown for the Dectin‐1
mechanisms and both the adaptive and innate immune receptors, the caspase recruitment domain‐containing
response [27]. In more detail these factors comprise an protein 9, the transcription factor signal transducer and
increase in cell proliferation, the production of noncellular activator of transcription, the major histocompatibility
antimicrobial agents derived from epidermal keratino complex class II genes and the DEFB4 (defensin beta 4
cytes, complement‐related mechanisms and a specific gene) [37].
immune response involving the activation of immune‐
competent cells and a subsequent increase in Langerhans Pathology. Most dermatophyte infections are confined to
cells, T‐cell‐mediated delayed immune reaction and the the stratum corneum, nails and hair. In general, three dif
production of antibodies. Innate immunity in superficial ferent changes in the stratum corneum can be associated
dermatophytosis implies the action of keratinocytes, with dermatophyte infections: the presence of neutro
neutrophilic granulocytes and macrophages. Keratino phils, compact orthokeratosis and the presence of the
cytes may induce an acute and early response to infection, ‘sandwich sign’, which refers to the presence of hyphae
releasing a variable spectrum of cytokines upon initial ‘sandwiched in’ between an upper but normal bas
interaction with a dermatophytic agent. These include ketweave stratum corneum and a lower layer of recently
interleukin (IL)‐8, a potent chemoattractant for neutrophils produced stratum corneum which is abnormal in being
which can kill dermatophytes, and the pro‐inflammatory compact orthokeratotic and parakeratotic in type [38].
tumour necrosis factor (TNF)‐α. Following an inflammatory In noninflammatory scaling lesions, hyperkeratosis
reaction, damage can be observed within the epidermal with little dermal infiltrate is present. In more inflamma
barrier, epidermal proliferation is enhanced, and enhanced tory lesions, in the early phase, there is a dense neutrophil
expression of keratinocyte‐derived antimicrobial peptides accumulation in the stratum corneum and around the
hair follicles. When there is hair follicle invasion, fungal shows a characteristic type of endothrix invasion in which
fragments are surrounded by phagocytes or giant cells in hyphae and air spaces are found in the hair but very few
the dermis. spores are present. Another feature of scalp infections that
helps to distinguish the invading fungi is the bright‐green
Clinical features. The clinical features of dermatophyte fluorescence of infected hairs seen under an ultraviolet
infection depend on the body site infected, the causative (UV) lamp with maximal emission at 365 nm (Wood’s lamp)
organism and the immune status of the host. The degree of when Microsporum species are responsible. However, nega
inflammation of the epidermis results from an immunologi tive fluorescence does not exclude Microsporum infection.
cally mediated reaction to the diffusion of fungal antigens Favus‐infected hairs fluoresce a dull green, but hairs invaded
from the stratum corneum. The amount of scaling is the result by other Trichophyton species show no fluorescence.
of increased epidermal replacement following inflammation.
Dermatophyte infections are commonly described Small‐spored ectothrix infections
using the Latin word ‘tinea’ followed by the Latin name When the causative fungi are anthropophilic (e.g.
of the site; for example, scalp ringworm is ‘tinea capitis’. M. audouinii, M. ferrugineum), slowly extending circular
patches with partial hair loss occur in the scalp, with only
Tinea capitis mild erythema and scaling (Fig. 46.1). More inflammatory
Scalp ringworm is primarily a disease of childhood. The lesions with a greater degree of scaling occur when zoo
incidence among adults is low, but adult cases of T. ton- philic or geophilic species are responsible (e.g. M. canis,
surans infection may be seen, for example in adults with N. gypsea) (Fig. 46.2).
acquired immune deficiency syndrome (AIDS). Although
the clinical appearance is in part dependent on the fungus Large‐spored ectothrix infections
responsible for the infection, there is always hair loss, with These infections are produced by the zoophilic species
varying degrees of scaling and erythema. Inflammation is T. mentagrophytes, T. benhamiae, T. quinckeanum and
generally more intense when zoophilic fungi are responsi T. verrucosum and are usually more inflammatory than
ble. However, an inflammatory lesion that becomes swol those caused by M. canis. Solitary lesions are typical
len and pustular, referred to as a kerion, may be produced with swollen and pustular areas (kerion) containing loose
by both zoophilic and anthropophilic fungi. With the hairs (Fig. 46.3).
exception of the two species Epidermophyton floccosum and
T. concentricum, all dermatophytes are able to invade hair, Endothrix infections
although T. rubrum is rarely reported as a cause of tinea Circular patches of alopecia with mild scaling and ery
capitis in countries with a temperate climate. Scalp infec thema are characteristic. The infected hairs break off at
tions may be classified by the way in which dermato the surface of the scalp and in dark‐haired subjects give
phytes form spores after invading the hair shaft. a ‘black dot’ appearance (Fig. 46.4). In some patients,
In ectothrix infections, the spores are seen predomi scaling becomes widespread with a generalized erythema
nantly outside the hair shaft and may be either small resembling seborrhoeic dermatitis and leading to progres
(2–3 µm) and arranged in masses, or larger (3–5 or 5–10 µm) sive hair loss.
and usually occurring in straight chains on the surface of Sometimes a kerion develops followed by scarring and
INFECTIONS
the hair. Small‐spored ectothrix invasion is produced by permanent alopecia; this has been seen most frequently
Microsporum species and the larger ectothrix by T. menta- when T. violaceum was the invading organism but also
grophytes, T. benhamiae and T. verrucosum respectively. In occurs in cases of T. tonsurans infection (Fig. 46.5).
endothrix infections, the spores (4–8 µm) are found within
the hair shaft, and this type of infection is produced by
Trichophyton spp., e.g. T. tonsurans (Table 46.6). Favus, a
chronic form of tinea capitis caused by T. schoenleinii,
Table 46.6 Types of hair invasion
Species Spore arrangement Size (µm)
Microsporum M. audouinii Ectothrixa

Nannizzia M. canis Ectothrixa
N. gypsea Ectothrixa 2–3
M. ferrugineum
Trichophyton T. quinckeanum Ectothrix 3–5
T. verrucosum Ectothrix 5–10
T. soudanense Endothrix
T. tonsurans Endothrix 4–8
T. violaceum Endothrix
T. schoenleinii Endothrixa
Infected hairs fluoresce under Wood’s lamp.

a
Fig. 46.1 Tinea capitis caused by Microsporum audouinii.
Fig. 46.2 Tinea capitis caused by M. canis and fluorescence under Wood’s lamp.

INFECTIONS
Fig. 46.3 Tinea capitis caused by Trichophyton mentagrophytes. Fig. 46.5 Tinea capitis with kerion caused by T. tonsurans.
Favus, a chronic scalp disease mainly caused by

T. schoenleinii, is characterized by crusted, cup‐shaped
lesions (known as scutula) consisting of hyphae and
spores, which develop around follicular openings
(Fig. 46.6). Infections frequently produce considerable
scarring and alopecia and, unlike other forms of tinea
capitis, may persist into adult life. Patients are frequently
seen in families, with different generations being infected.
Tinea capitis is generally more common in boys than
girls, possibly because shorter hair allows easier access
for infecting fungal spores. However, in a survey of
fungal infections in the USA, more girls (59%) than
boys (41%) were found to have tinea capitis caused by
T. tonsurans [15].
The prevalence of a particular dermatophyte as the
Fig. 46.4 Tinea capitis caused by T. violaceum. cause of tinea capitis varies from country to country
Fig. 46.7 Tinea facei caused by T. mentagrophytes.

Fig. 46.6 Favus of the scalp.
Box 46.2 Geographical distribution of principal dermatophytes causing tinea capitis
Europe North and South America Australia Africa Middle East Asia
M. canis T. tonsurans M. canis T. violaceum M. canis T. violaceum
T. tonsurans M. canis T. tonsurans T. soudanense T. schoenleinii M. ferrugineum
T. tonsurans
M. audouinii
(Box 46.2). It should be noted, however, that children

whose parents and grandparents were immigrants from
other countries tend to be infected with the causative
fungi from their country of origin, irrespective of how
long they have been resident in their adopted country.
Tinea faciei
The face is an unusual site for a fungal infection except

when representing spread from another site, particularly
INFECTIONS
the scalp. Lesions are similar to those found on other

parts of the body (Fig. 46.7). They have been reported in
newborns and infants, and may be caused by anthropo
philic or zoophilic species. In the USA, it has been reported
that the face was the most common site for skin lesions of
the body caused by T. tonsurans [15].
Tinea corporis
This term is used for infections of the trunk and limbs,
which are characterized by circular lesions arising by
centrifugal spread of the fungus from the initial site
of infection. The degree of inflammation depends on
whether the fungus is zoophilic or anthropophilic. A zoo
philic species such as M. canis produces erythematous Fig. 46.8 Tinea corporis caused by M. canis.
scaly circinate lesions, often with a raised border and
pustules; hairs in the involved area may become infected the infant’s family or infected pets are usually the source
(Fig. 46.8). In contrast, fungi of human origin such as of infection.
T. rubrum or T. tonsurans cause scaly and not very erythe
matous lesions, although there is usually a clearly defined Tinea incognito
margin. Children of all ages can be infected, and rare Tinea incognito describes an infection in which the usual
cases have been recorded in the newborn. Many different clinical signs of tinea have been altered by the application
fungi have been implicated, including M. canis [39], of potent topical corticosteroids. The active margin of the
T. mentagrophytes [40] and T. tonsurans [15]. Members of lesion may be lost, pruritus may be decreased or absent,
Fig. 46.9 Tinea imbricata.
scaling may be absent, and the rash typically becomes

widespread. Pustules and papules are prominent [41].
Fig. 46.10 Tinea pedis caused by T. interdigitale.
Tinea imbricata
This is a type of chronic tinea corporis caused by T. con-
centricum. The fungus, and the disease it produces, has a
very restricted geographical distribution, being found
only in the western Pacific area (e.g. Papua New Guinea),
South‐East Asia and Amazonia. The infection is often
acquired during infancy and occurs in all ages. It is most
frequently observed on the trunk and limbs. The lesions
are very characteristic, consisting of extensive and persis
tent rings of concentric scales (Fig. 46.9).
Tinea cruris
This infection is rare before puberty but is frequently seen
in adolescent males. The clinical features are erythema

tous and scaly lesions extending symmetrically from the
groin down the inner surface of the thighs with a margin
ated edge sometimes containing pustules; lesions are
INFECTIONS
often very itchy. The infection may spread to the perianal
area and buttocks. The causative fungus is T. rubrum, T.
interdigitale or E. floccosum. The last is almost always the
cause of outbreaks in groups of sportspeople or in people
living in close communities (e.g. boarding schools) and
Fig. 46.11 Tinea pedis in an infant caused by T. rubrum.
using shared bathing facilities. Under these circum
stances, it is not difficult to isolate the causative fungus
from towels, bedding or clothing. clinical features depend on the fungus responsible. When
Annular rashes in the napkin area may also be caused T. interdigitale is the causative organism, small clear vesi
by dermatophytes and have to be distinguished from cles may develop which eventually rupture, dry and
other forms of napkin dermatitis [42]. form an irregular scaly edge. Fine, dry scaling on the
soles is typical of T. rubrum infections. These tend to
Tinea pedis (athlete’s foot) become chronic and widespread, affecting the heels,
This is the most common form of tinea in temperate cli sides and dorsa of the feet.
mates. The causative fungi are all anthropophilic, and T. The incidence of tinea pedis in children before the age
rubrum is now the most common species isolated in the of puberty is low, although there are reports of cases in
majority of countries, having in the past three decades children less than 4 years old [43] (Fig. 46.11). Surveys of
supplanted T. interdigitale and E. floccosum. schoolchildren in the UK have recorded incidences rang
The infection usually starts in the toe spaces, often ing from 2.2% in 7‐ to 10‐year‐old boys to 6.6% in 11‐ to
between the fourth and fifth toe, and is characterized by 14‐year‐old boys [44]. In Denmark, 15‐year‐old children
peeling, maceration and fissures (Fig. 46.10). In the acute showed an incidence of tinea pedis of 3.7% [45]. A 20‐year
phase, the lesions are usually itchy. Spread of the infection survey of tinea pedis in children between 3 and 13 years
may occur to the toes and soles of the feet, where the of age in Italy found only 80 cases compared with over
2500 cases in adults studied concurrently, children there established, the nail plate becomes friable and thickened.
fore representing only 3.1% of cases [46]. A study in France In developed countries, T. rubrum is the most common
looking at dermatophytosis in children over a 5‐year cause; in areas where T. tonsurans, T. violaceum or T. sch-
period recorded only two cases of tinea pedis in infants oenleinii is endemic [54], these fungi may produce similar
less than 2 years old but 19 cases among children aged infections.
between 2 and 10 years [47]. In Korea, a study over a
3‐year period examined 102 children with foot dermatitis Superficial white onychomycosis. This is an uncommon
and identified 21 cases of tinea pedis, based on positive type of nail damage produced by a fungus invading the
direct microscopy [48]. Seven of the children were less superficial surface of the nail plate, with minimal penetra
than 4 years old and eight were between the ages of 5 and tion of the nail. White patches that are easily removed by
9 years. The reason for the different incidences in children scraping are produced in the nail. This type of infection
and adults is not known. Risk factors such as frequent use is mainly seen on toenails and is usually caused by
of swimming baths are the same in both age groups. T. interdigitale.
Parents of children with tinea pedis are frequently found
to have chronic dermatophyte infections. As in adults, Proximal subungual onychomycosis. Fungal invasion
tinea pedis occurs more frequently in males than in females. occurs from the skin to the proximal nail bed and white
The clinical features in children are similar to those found spots occur under the nail; these may extend distally to
in adults, although vesicular lesions are perhaps more involve all layers of the nail (Fig. 46.12). It is more often
common and bullous lesions can also occur [49]. seen with yeast infection and rarely caused by a dermato
phyte, but it has been particularly associated with patients
Tinea manuum with AIDS [55].
This is again rare in children. Lesions usually follow a
primary foot infection and T. rubrum is the usual cause. Endonyx onychomycosis. This is seen with infection due
Diffuse hyperkeratosis and peeling of the palms and to dermatophytes that cause endothrix scalp infections,
fingers are the most common features, often affecting notably T. soudanense. The nail plate is scarred with pits
only one hand, for reasons that are not understood. and lamellar splits. Invasion occurs from the top surface
Spread may occur to the dorsum of the hand when lesions but the fungus penetrates deeply into the nail plate [56,57].
have a more marked edge.
Total dystrophic onychomycosis. The entire nail plate is
Tinea unguium destroyed, leaving a thickened and abnormal nail bed.
Onychomycosis is uncommon in children, the incidence This may occur as a consequence of any of the three types
increasing with age. In a British study, only one case of of onychomycosis. Although the majority of toe‐ and fin
tinea unguium was found in a survey of 494 schoolchil gernail infections in children are caused by anthropophilic
dren aged 5–10 years, an overall prevalence of 0.2% [50]. fungi (Fig. 46.13), occasionally zoophilic species such as
In the USA, a 3‐year survey of children under 12 years M. canis [58] and T. equinum [59] are responsible.
revealed 26 cases of onychomycosis [51]. Six children also
had tinea pedis. In France, a survey reported four cases of Mykids
INFECTIONS
onychomycosis in children up to 2 years old and a further An ‘id’ reaction is a secondary immunological reaction to
41 cases in children between 2 and 10 years [47]. Ninety circulating antibodies or activated T lymphocytes that are
nine cases of onychomycosis in children and adolescents directed against microbial antigens [60]. Superficial
were diagnosed in North Poland, representing 19.8% fungal infections are the most common cause of so‐called
of all mycologically confirmed superficial mycoses (500
cases). Fingernail onychomycosis was recognized pre
dominantly in children under 3 years of age (52 cases)
while 47 patients were affected by toenail onychomycosis,
mostly due to T. rubrum. The incidence increased steadily
with age [52].
As distinct from adults, most cases of onychomycosis in
children show no sign of infection in the adjacent skin sites.
However, the parents of children with tinea unguium are
frequently found to be infected and therefore are the most
likely source of infection [52,53]. Children with infection of
a fingernail by an anthropophilic organism causing tinea
capitis should be examined for scalp infection.
There are five types of nail involvement.
Distal and lateral subungual onychomycosis. This is the

most common form of fungal nail dystrophy. Invasion
starts at the distal end and side of the nail and then Fig. 46.12 Proximal subungual onychomycosis caused by T. mentagrophytes,
spreads proximally up the nail. As the infection becomes assisted by the habit of thumb sucking.
1 Diagnosis based on clinical impression only is often

misleading. Clinically indistinguishable lesions may be
produced by organisms that are not always responsive
to the same form of therapy. For example, T. rubrum and
Neoscytalidium dimidiatum may cause clinically identical
infections of the skin and nails but the former is sensi
tive to griseofulvin, whereas the latter is resistant.
2 The administration of oral antimycotics without identi
fication of the aetiological agent is questionable.
3 Therapy options for Trichophyton spp. and Microsporum
spp., as well as for anthropophilic and zoophilic
species, may be different.
4 Identification of a zoophilic dermatophyte species
allows conclusions on the animal source of infection,
Fig. 46.13 Tinea unguium caused by T. rubrum.
which also has to be treated.
5 Early start of causative therapy.
6 For epidemiological reasons.
‘mykids’. Two major types of dermatophytids, a mykid
caused by a dermatophyte, have been described: (i) Collection of specimens
generalized lichenoid eruptions of grouped or scattered Skin lesions are best collected using a blunt scalpel.
follicular papules on the chest, trunk and back, mainly in Infected hairs (minimum of 10) may be removed with
children during the course of tinea capitis (‘lichen tricho flat‐ended forceps and infected hair stumps by scraping
phyticus’); and (ii) dyshidrotic and vesicular eczema on with a scalpel. Nails (3 mg or 20 small clippings) are often
the hands (palms and/or fingers) associated with tinea thickened and nail clippers are necessary to cut through
pedis (mainly caused by T. interdigitale). Other forms the whole thickness; subungual debris may also be
include nodular erythema/erythema nodosum, diffuse removed with a scalpel. The scalp may be sampled using
erythema and pustule formation. A set of diagnostic criteria either a shampoo brush or a toothbrush [63] when scaling
were defined to identify a dermatophytid reaction: is the predominant sign (mainly in cases of infection with
1 Primarily there is a proven focus of dermatophytic anthropophilic species).
infection elsewhere.
2 Fungal forms are not present in the site of the mykid. Microscopy
From this site, culture assays remain sterile and direct Samples are placed in a drop of 20–30% potassium or
mycological examinations as well as histopathological sodium hydroxide (KOH/NaOH) or tetra‐ethylammoni
preparations are negative. umhydroxide (TEAH) on a microscope slide. Softening of
3 The dermatophytid symptoms spontaneously resolve

the tissue can be hastened by incubation in a wet chamber
after an acute course, provided that the primary focus for 20–30 min (1–2 h for nails) at room temperature. The
of fungal infection is eliminated. incorporation of dimethyl sulphoxide (DMSO) in KOH
4 The patients are sensitized to dermatophyte antigens
INFECTIONS
(DMSO 40 mL, distilled water 60 mL, KOH 30 g) may per
and show a positive skin test response to an extract pre mit more rapid examination without heating. Unstained
pared from cultures of fungi of the genus Trichophyton preparations are generally satisfactory for the demonstra
(‘Trichophytin’). tion of fungi in keratin, but chlorazole black E may be
A dermatophytid may worsen after effective, mainly sys added to DMSO to aid in the differentiation of hyphae
temic antimycotic therapy has been initiated and should from common artefacts such as cotton fibres, elastic fibres
not be confused with a drug reaction [60]. Topical (or or ‘mosaic fungus’. The last is an artefact caused by depo
occasionally, if very severe, oral) corticosteroids may pro sition of cholesterol and other material around the periphery
vide symptomatic relief. of the epidermal cells. Calcofluor white (10–40 mg
Blankophor®, 95 mL NaOH 0.5 M, 5 mL DMSO), a stain
Diagnosis. The diagnostic procedures for superficial that fluoresces green on excitation with UV light, can also
fungal infection are changing. At present the microscopic be added to an equal volume of KOH. The stain is selec
observation of fungal elements in specimens of infected tive for fungi and is helpful for the detection of scanty
skin, hair or nail followed by species identification using fungal elements in clinical material. The preparation must
culture is still widely used. However, molecular methods be examined with a fluorescence microscope.
to diagnose the causative agent play an increasing Infected skin scrapings show branching hyphae, often
role. Polymerase chain reaction (PCR) techniques and segmenting into chains of arthroconidia (Fig. 46.14).
matrix‐assisted laser desorption/ionization time‐of‐flight If hairs are infected, the size and arrangement of the
(MALDI‐TOF) analysis [61,62] are able to detect dermato spores will contribute to the identification of the derma
phyte and nondermatophyte species directly from clinical tophyte species involved (Figs 46.15–46.18) (see Table 46.6)
specimens or from a grown culture, respectively [61,62]. but an accurate species identification is not possible.
It is important to establish the correct diagnosis for the It should be noted that microscopy of skin, hair and nails
following reasons: is more often positive than culture.
Fig. 46.17 Endothrix invasion of hair by T. tonsurans (30% KOH).

Fig. 46.14 Hyphae and arthroconidia of dermatophyte in skin (30% KOH).
Fig. 46.18 Favus hair showing hyphae and air spaces infected by

T. schoenleinii (30% KOH).
(peptone 1%, dextrose 2–4%, agar 1.5%, pH 5.6). It is

recommended that the clinical material is inoculated on
INFECTIONS
Fig. 46.15 Small‐spored ectothrix invasion of hair by M. canis (30% KOH). two agar plates, one without (for moulds) and one with
gentamicin or chloramphenicol (0.005%) which is added
to reduce bacterial contamination and the medium is
made selective for dermatophytes by adding cyclohex
imide (0.05%). Dehydrated media are commercially
available that include these antibiotics either incorpo
rated in the agar powder (Mycobiotic Agar, Difco/Gibco;
Mycosel™, BBL™) or in separate vials (Dermasel™,
Unipath). Dermatophyte test medium (DTM) or so‐called
Taplin agar are not real alternatives because the alkalini
zation of the media (red colour) is also induced by geo
philic dermatophytes (e.g. A. terrestre) or moulds.
The macro‐ and micromorphology of the dermatophyte
colony is used for species identification, inclusive of the
texture of the colony, the surface colour and production of
pigments seen on the reverse side of the Petri dish. The
Fig. 46.16 Large‐spored ectothrix invasion of hair by T. verrucosum (30% KOH). three genera of dermatophytes are characterized by the
type of multicellular spores (macroconidia) produced on
culture (Fig. 46.19):
Culture 1 Microsporum and Nannizzia genus: fusiform
Petri dishes are satisfactory for the culture of dermato macroconidia;
phytes but quite time consuming (2–6 weeks). Sabouraud 2 Trichophyton genus: cylindrical macroconidia;
dextrose agar (SDA) is the medium most commonly used 3 Epidermophyton genus: pyriform macroconidia.
(a) (b)
(c)

Fig. 46.19 (a) Microsporum, (b) Trichophyton and (c) Epidermophyton macroconidia.
The shape and arrangement of unicellular spores
INFECTIONS
(microconidia) and the presence of other structures such other members of the T. rubrum complex) are not reliably
as chlamydoconidia, spirals and so on are other features differentiated by any molecular target, inclusive of mark
that aid in the identification of a dermatophyte [64]. ers with high discriminatory power, such as microsatellites
[65]. These factors should be kept in mind by anyone per
Molecular diagnostics forming dermatophyte identification or reading the results.
A review on the new species concept of dermatophytes by In the past, an increased number of PCR strategies were
de Hoog et al. is available [9]. The taxon names applied in published and manufactured kits were developed which
this chapter are based on the new species concept. Table 46.2 can be applied in routine diagnostics to detect dermato
shows the old and new species concepts in this group of phytes directly from clinical specimens. In general, the
fungi. It is recommended to strictly rely on the new con selection of the right molecular technique depends on its
cept, at least when molecular methods for identification are analytical sensitivity and specificity, corresponding inter
used. For instance, routine laboratories that entirely rely on nal controls (positive, negative, extraction and amplifica
conventional diagnostics are unable to further differentiate tion controls) and last but not least on effective DNA
between species of the T. mentagrophytes complex, i.e. T. extraction methods [66]. At the moment, commercially
mentagrophytes, T. benhamiae, T. interdigitale, T. erinacei and available kits for the detection of T. rubrum, T. interdigitale,
T. quinckeanum. Furthermore, it has been shown that E. floccosum (the main agents of onychomycosis and tinea
misidentifications are possible when using phenotypic fea pedis), M. canis, M. audouinii and N. gypsea at species level
tures. Given that the former T. mentagrophytes complex are useful. Other pathogens of dermatophytoses are identi
consists of species that are distinguished at many molecu fied at genus level only (e.g. Trichophyton spp.). In addition,
lar targets, it would be very confusing to use the name a detection reaction that identifies the dermatophytes as a
T. mentagrophytes for all isolates. The question would arise: group (Arthrodermataceae) should be included for the
which T. mentagrophytes is meant? In turn, species that have identification of new species and of geophilic dermato
been synonymized (e.g. T. raubitschekii, T. megninii and phytes that are nonpathogenic [67].
Comparision of conventional and molecular Tinea cruris

diagnostic methods Tinea cruris should be differentiated from flexural pso
Many studies have compared the sensitivity and speci riasis, seborrhoeic dermatitis, erythrasma and Candida
ficity of microscopy, culture and molecular methods intertrigo.
(conventional and real‐time PCR). The results uniformly
reveal that even at species level molecular methods are up Tinea pedis
to 21% more sensitive than direct microscopy and culture Other causes of interdigital scaling are Candida infection,
[68,69]. erythrasma and Gram‐negative and staphylococcal
A further advantage of molecular methods is the very infections.
short time period needed to diagnose the pathogen and
to start the appropriate therapy (24–48 hours compared Tinea manuum
to 2–6 weeks when using culture). The results of any Tinea manuum should be distinguished from eczema and
mycological detection system (culture and molecular) psoriasis.
need to be discussed against the background of clinical
plausibility. Saprophytic fungi without any clinical rele Tinea unguium
vance may be detected in culture if the medium is suit Psoriasis, eczema and Candida infection of the nails should
able. Using molecular methods, the detection of such be considered in the differential diagnosis of tinea
microorganisms will succeed only when specific prim unguium. Features of psoriasis of the nail are involvement
ers/probes have been developed. Thus rarely occurring of the same nails of the opposite hand or foot, pitting of the
dermatophyte species as well as yeast and moulds which nails and onycholysis; psoriasis is often present elsewhere.
are potential pathogens in about 5% of onychomycosis
cases may be identified using appropriate methods, e.g. Treatment. Although certain forms of dermatophytosis
the microarray technique. are self‐limiting, most types require treatment. Topical
In summary, PCR strategies supplement conventional therapy is used for localized lesions not involving hair or
methods at present but will be able to substitute for nails. Oral therapy is essential for chronic and widespread
microscopy and culture in the near future. infections and for those involving the scalp or nail.
The main antifungal drugs used in the treatment of der
Further methods for the differentiation matophyte infections include the following.
of dermatophytes
The identification of dermatophyte species grown in Griseofulvin
culture is possible using MALDI‐TOF analysis [61,62]. This is an antifungal antibiotic derived from a number of
Identification of dermatophytes directly from clinical Penicillium species. It is fungistatic and affects nuclear
specimens is not possible. A prerequisite for identification division by binding to microtubular proteins. It also acts
using this method is that MALDI‐TOF platforms have as an inhibitor of nucleic acid synthesis. It is selectively
been validated by a sufficient number of strains of all rele concentrated in the stratum corneum, where it inhibits
vant dermatophyte species. The differentiation of phylo fungal growth sufficiently to prevent invasion of newly
genetically closely related species is, however, difficult, formed keratin. Griseofulvin was the first oral drug avail
INFECTIONS
e.g. T. tonsurans/T. equinum, T. mentagrophytes/T. interdig- able for the treatment of dermatophytosis. Its activity is
itale or M. canis/M. ferrugineum. restricted to the dermatophytes and its clinical use is
limited to infections caused by these fungi. Given the
superior activity obtained with newer agents, griseoful
Differential diagnosis
vin is rarely used now except for some scalp infections.
Tinea capitis
Scalp scaling without hair loss occurs in a number of con Azoles
ditions. Seborrhoeic dermatitis, psoriasis or pityriasis These are synthetic drugs that act by inhibition of ergos
amiantacea may appear similar to tinea capitis. In pityria terol biosynthesis by fungal cytochrome P450 enzymes.
sis amiantacea, large numbers of thick scales are present Ergosterol is an essential constituent of the fungal cell
around hairs, which do not break. In alopecia areata, membrane. The imidazoles comprise a large number of
where there are patches of hair loss, there is usually no compounds primarily for topical use such as clotrima
scaling and a number of broken tapering hairs (‘exclama zole, miconazole, econazole, bifonazole, isoconazole,
tion mark’ hairs) are present. Dermoscopy may be helpful oxiconazole, sulconazole, terconazole, tioconazole, fenti
in differentiating tinea capitis (‘comma hairs’) from alope conazole and ketoconazole. They have a broad spectrum
cia areata (exclamation mark hairs) [70]. of antifungal activity including dermatophytes and yeasts
such as Candida and Malassezia species. Some also show
Tinea corporis activity against Gram‐positive bacteria.
Tinea corporis may be mistaken for other annular lesions The triazoles itraconazole and fluconazole are used
such as eczema, annular erythemas, psoriasis and granu orally for the treatment of superficial fungal infections,
loma annulare. Dermatophyte infections usually have a having a broad spectrum of activity similar to the imida
distinct edge where scaling is more obvious, and the zoles. In many countries they are not licensed at present
lesions itch. for use in children.
Allylamines dosages of griseofulvin (>18 mg/kg daily). When broken

These synthetic compounds block the formation of ergos down by species, the mean efficacy rates for Trichophyton
terol in the cell membrane by inhibition of squalene epox spp. and Microsporum spp. were 67.6% ±
9% and
idase. They have a broad spectrum of activity in vitro. 88.1% ± 5% respectively [72]. The drug should be taken
Naftifine shows antifungal activity against both dermato after meals. An oral suspension is available in some
phytes and yeasts and is used topically in the treatment of countries.
superficial fungal infections. It also has anti‐inflammatory Adverse reactions that have been reported with gri
activity. Terbinafine is available for topical and oral use. seofulvin include drowsiness, headache and nausea;
Although topically effective against both yeasts and photosensitivity and urticarial reactions are also occa
dermatophytes, terbinafine, when given orally, is effective sionally observed. The use of selenium sulfide shampoo,
only against dermatophytes. Against these fungi, it shows 2.5% twice weekly, has been shown to reduce the frequency
primary fungicidal activity. Oral terbinafine is licensed of positive cultures from scalps when used with griseo
for use in children only in some countries. It is available fulvin [73]. Ketoconazole shampoo may also be helpful
as a cream, a solution, a 250 mg tablet, and in the form of in conjunction with griseofulvin.
packaged granules. A 125 mg tablet is now available in The use of the allylamine terbinafine and the triazoles
some countries for treating children. itraconazole and fluconazole in the treatment of tinea
capitis has been reviewed by Gupta et al. [74], who
Morpholines summarized many of the open study and trial data.
These compounds strongly inhibit ergosterol biosynthesis These drugs generally appear to have equal efficacy
at two different enzymatic stages specific for fungal cells with griseofulvin, and are effective with shorter courses
(the reductase and isomerase stage). Amorolfine, a phenyl of therapy.
propyl morpholine derivative, has in vitro activity against Few significant adverse effects have been reported. As
a variety of fungi including dermatophytes and yeasts; it active levels of drug remain in the keratinized tissues for
has fungicidal activity against dermatophytes. It is inac weeks after therapy has ceased, pulse and intermittent
tive when given systemically and is thus only available therapy have been reported to be successful with itracon
for topical use. azole and fluconazole.
Terbinafine has been shown to be effective in the treat
Miscellaneous ment of tinea capitis caused by Trichophyton spp. The fol
Other miscellaneous compounds available for topical treat lowing dosages are commonly recommended:
ment include tolnaftate, ciclopiroxolamine, haloprogin • children weighing <20 kg, 62.5 mg
and derivatives of undecylenic acid. • children weighing 20–40 kg, 125 mg
• children weighing >40 kg, 250 mg.
Treatment of specific conditions With T. tonsurans, doses are generally given once daily
Tinea capitis. The British Association of Dermatologists’ for 4 weeks. Some reports suggest that a 2‐week course

guidelines for the management of tinea capitis were may be effective. The experience with terbinafine in
published in 2014 [71]. They also include a patient infor infants and neonates is been limited [75,76]. Terbinafine
mation leaflet (available on the British Association of is well tolerated in children between 2 and 17 years of
INFECTIONS
Dermatologists’ [BAD] website, http://www.bad.org.uk). age, with few adverse events. Gastrointestinal discom
Oral therapy is essential to achieve the aims of treatment: fort and skin rashes have been reported. There is some
1 Eradication of the organism, resulting in both a clinical evidence that terbinafine is less effective in infections
and mycological cure as quickly and safely as possible; caused by Microsporum spp. and that these may need
2 Alleviation of symptoms; longer courses of therapy and higher doses [77–81]. In a
3 Prevention of scarring; and comparative study of a new paediatric formulation of
4 Reduction of transmission to others. terbinafine hydrochloride oral granules with griseofulvin
Adjuvant therapies such as antifungal shampoos or oral suspension, clinical cure was higher for terbinafine
topical antimycotics should be routinely combined. At than for griseofulvin, but the difference was not found to
present, griseofulvin is the only antifungal licensed for be statistically significant. Subgroup analyses revealed
oral use in tinea capitis in most parts of the world. that terbinafine was significantly better than griseofulvin
However cumulative evidence now demonstrates that among patients with T. tonsurans and vice versa with
newer antifungal agents have higher response rates and M. canis [82].
are safe and more cost‐effective. Itraconazole is also not yet licensed for oral use in tinea
Griseofulvin (10–15 mg/kg daily) should be given for capitis in many countries but has been used quite exten
at least 6 weeks. In some cases, particularly with T. ton- sively in open studies and trials. It is available in capsule
surans infections, longer courses and sometimes higher form or as a suspension. It should not be given with a
doses (20 mg/kg daily) of griseofulvin therapy may be meal and can cause diarrhoea because of the presence of
needed [24]. M. canis infections may also need longer cyclodextrin. For continuous therapy, itraconazole is gen
courses [71]. In a meta‐analysis of clinical trials of griseo erally given as 3–5 mg/kg per day for 4–6 weeks. In the
fulvin use in tinea capitis, the overall mean effective cure majority of the studies, the efficacy was high. In one study,
at 4–6 weeks post treatment was 73.4% ± 7%. Higher effi 50 children from six countries with tinea capitis caused by
cacy rates appeared to be reported with the use of higher either M. canis or T. tonsurans were included. The majority
of cases were treated with 100 mg of itraconazole daily for for 2 weeks and the patients were assessed at 4 weeks
approximately 5 weeks [83]. In total, 38 patients (76%) and, if clinically indicated, a further 1 week of treatment
were considered healed at the end of the study. Another was given. Terbinafine was given as follows: >40 kg,
study [84] compared 100 mg daily itraconazole and 250 mg per day; 20–40 kg, 125 mg per day; and <20 kg,
500 mg daily griseofulvin in the treatment of tinea capitis. 62.5 mg per day. The itraconazole dose was 5 mg/kg per
There were 17 patients in each group and the majority of day and fluconazole 6 mg/kg per day. At 12 weeks’ follow‐
infections were caused by M. canis. Treatment was given up, effective treatment was seen in 92% of the griseofulvin
for 6 weeks, and at follow‐up 8 weeks after the end of ther group, 94% of the terbinafine group, 86% of the itracona
apy, 80% of patients in each group were cured. However, zole group and 84% of the fluconazole group. Overall,
another study in which 25 patients with T. tonsurans infec 6 weeks of griseofulvin therapy appears similar in efficacy
tion completed a course of 4 weeks of 100 mg itraconazole to 2–3 weeks’ therapy with the newer antifungals.
daily together with selenium sulfide shampoo resulted in Additional measures include the following [25,71]:
only 10 cures (40%) [85]. In one study, 163 children with 1 Children receiving appropriate therapy should be
tinea capitis caused by M. canis and previously unsuc allowed to attend school or nursery.
cessful therapy with terbinafine were treated with 5 mg/ 2 Index cases due to anthropophilic species, especially
kg per day given in a continuous regimen either as a cap T. tonsurans, T. violaceum and M. audouinii, warrant
sule or an oral suspension. In all children, there was both screening of all family members and close contacts and
clinical and mycological cure after a mean treatment treatment for positive cases.
period of 39 ± 12 days [86]. In infants, itraconazole proved 3 In asymptomatic carriers (no clinical infection, culture
to be a safe and effective treatment option for M. canis‐ or PCR positive) with a high spore load, systemic treat
induced tinea capitis [87]. ment is generally justified. If the spore load is low,
Pulse therapy has been reported to be successful. In a carriage may be eradicated with topical treatment
small study involving 10 children [88], the subjects took alone, but close follow‐up is needed, with repeated
5 mg/kg itraconazole daily for 1 week followed by 2 weeks pathogen detection, to ensure that treatment has been
off between consecutive pulses. One, two or three pulses effective. In an outbreak, additional infection control
resulted in clinical cure in one, six and three patients measures include antifungal shampoo use, exclusion of
respectively. A subsequent larger study produced a myco identified cases for a short period, removal of shared
logical and clinical cure in 30 of 37 patients (81%) [89]. items, and enhanced decontamination of fomites [94].
Few data are available for the use of fluconazole in See Table 46.7 and Box 46.3 for therapeutic recommenda
tinea capitis. In one study, 48 patients with Trichophyton tions for tinea capitis.
tinea capitis were treated with 6 mg/kg daily for 2 weeks,
followed by 2 weeks without treatment. At 4 weeks Tinea corporis. Unless there is widespread infection,
after the start of therapy, they were examined and those lesions usually respond well to a topical imidazole, such
with persistent clinical signs were given a further week’s as clotrimazole, or to ciclopiroxolamine, amorolfine or
treatment. Follow‐up at 12 weeks resulted in clinical terbinafine. These compounds are available as creams
and mycological cure in 37 of 42 patients (88%) [90]. A and lotions and most will be effective after once or twice
subsequent larger study, including patients with both daily application for 2–4 weeks. Terbinafine cream is
INFECTIONS
Trichophyton and Microsporum infections, comprised 61 effective after 7 days of treatment applied once daily [95].
children, dosed at 8 mg/kg once weekly. At follow‐up,
complete clinical and mycological cure was seen in Tinea cruris. Topical therapy is the same as for tinea
60 patients; of these, 47 were treated for 8 weeks, 10 for corporis.
12 weeks and three for 16 weeks. In total, three patients
suffered a mild, reversible gastrointestinal complaint and Tinea pedis. Tinea pedis will usually respond to topical
one patient showed an elevated liver function test, but treatment with one of the compounds mentioned under
this was asymptomatic and reversible [91]. In another Tinea corporis. The antifungal should be applied twice
study, fluconazole at two different doses (6 mg/kg per daily to the interdigital areas for at least 2 weeks; longer
day for 3 weeks followed by 3 weeks of placebo, flucona treatment is sometimes required. However, a compara
zole 6 mg/kg per day for 6 weeks) was compared with tive study of 1 week of terbinafine 1% cream versus
standard‐dose griseofulvin (11 mg/kg per day microsize 4 weeks of clotrimazole 1% cream found the former
formulation) in tinea capitis caused mainly by T. tonsurans
(86%, 11% M. canis). At the end of treatment, both regi
mens produced low mycological and clinical cure rates. Table 46.7 Recommendations for the oral therapy of tinea capitis
Mycological cure rates for fluconazole at 3 weeks and according to [71]: choice of drug according to organism isolated
6 weeks were 44.5% and 49.6% respectively. For griseoful

Trichophyton tonsurans Terbinafine
vin the mycological cure rate was 52.2% [92].
Trichopython violaceum, soudanense Terbinafine
A study compared griseofulvin with terbinafine, itra Microsporum canis Griseofulvin or itraconazole
conazole and fluconazole in the treatment of Trichophyton Microsporum audouinii Griseofulvin or itraconazole
tinea capitis [93]. In total, 200 patients were randomized
to the four groups. Griseofulvin therapy was 20 mg/kg Source: Fuller et al. 2014 [71]. Reproduced with permission of John Wiley
per day for 6 weeks; the remaining antifungals were given & Sons.
therapy in one infant and 19 children aged 8 years and

Box 46.3 Recommendations for the oral therapy of tinea capitis
older resulted in a complete cure rate of 80.0% (n = 20).
according to [71]: dosage of oral antifungals. (NB Terbinafine,
itraconazole and fluconazole are not licensed for oral use
The efficacy and safety profiles of terbinafine, itracon
in childhood in many countries)
azole, griseofulvin and fluconazole in children were
similar to those previously reported for adults. When
Griseofulvin oral therapy is contraindicated, application of an anti
fungal nail lacquer could be considered. Ciclopirox nail
>50 kg 1 g/day (single or divided dose) for 6–8 weeks
lacquer applied once daily for up to 6 months produces
<50 kg 15–20 mg/kg per day (single or divided dose) for 6–8 weeks
varying mycological cure rates from about 30% up to
Doses up to 25 mg/kg per day may be required in some cases 85.6% [100].
Alternatively, amorolfine 5% nail lacquer applied once
Terbinafine or twice weekly for up to 6 months produces cure in
approximately 40–55% of patients with mild onychomy
<20 kg 62.5 mg/day for 2–4 weeks
cosis without nail matrix involvement. Studies in adults
20–40 kg 125 mg/day for 2–4 weeks
>40 kg 250 mg/day for 2–4 weeks
suggest that even better responses can be obtained by
combining amorolfine with either terbinafine or itracona
zole [101].
Itraconazole
50–100 mg/day for 4 weeks, or 5 mg/kg per day for 2–4 weeks

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94 Gray RM, Champagne C, Waghorn D et al. Management of a C. dubliniensis. Apart from C. glabrata, which, like C. albicans,
Trichophyton tonsurans outbreak in a day‐care center. Pediatr is a commensal yeast, and C. dubliniensis, which is associ
INFECTIONS
Dermatol 2015;32:91–6. ated predominantly with AIDS patients, the other species
95 Evans EGV, James IGV, Joshipura RC. One week treatment of tinea
corporis and tinea cruris with terbinafine (Lamisil) 1% cream: a pla are often isolated from natural sources. However, fre
cebo controlled study. J Dermatol Treat 1992;3:181–4. quent isolation of C. dubliniensis in caries‐active children
96 Korting HC, Kiencke P, Nelles S, Rychlik R. Comparable efficacy and was reported recently [6]. Candida spp. may also be iso
safety of various topical formulations of terbinafine in tinea pedis
irrespective of the treatment regimen: results of a meta‐analysis. Am
lated from the hospital environment such as floors, wash
J Clin Dermatol 2007;8:357–64. basins, bedding and other surfaces in wards [7]. However,
97 Ortonne JP, Korting HC, Viguié‐Vallanet C et al. Efficacy and Candida cells show poor survival on dry surfaces and
safety of a new single‐dose terbinafine 1% formulation in patients transmission of infection by dry fomites is therefore
with tinea pedis (athlete’s foot): a randomized, double‐blind,
placebo‐controlled study. J Eur Acad Dermatol Venereol 2006; unlikely [8]. The success of C. albicans, the most prevalent
20:1307–13. and best studied Candida spp., as both commensal and
98 Hay RJ, McGregor JM, Ryatt KS et al. A comparison of 2 weeks terbi human pathogen depends on its genetic, biochemical and
nafine 250 mg/day with 4 weeks itraconazole 100 mg/day in plantar
morphological flexibility, which facilitates adaptation to a
type tinea pedis. Br J Dermatol 1995;132:604–8.
99 Gupta AK, Paquet M. Systemic antifungals to treat onycho- wide range of host niches. In addition, formation of bio
mycosis in children: a systematic review. Pediatr Dermatol 2013;30: films provides additional protection from adverse envi
294–302. ronmental conditions. Furthermore, in many host niches
100 Gupta AK, Fleckman P, Baran R. Ciclopirox nail lacquer topical solu
tion 8% in the treatment of toenail onychomycosis. J Am Acad
Candida cells coexist with members of the human microbi
Dermatol 2000;43(4 suppl):S70–80. ome. The resulting fungal–bacterial interactions have a
101 Baran R, Sigurgeirsson B, Berker D et al. A multicentre, rand major influence on the success of C. albicans as commensal
omized, controlled study of the efficacy, safety and cost‐effective and also influence disease development and outcome [9].
ness of a combination therapie with amorolfine nail lacquer and
oral terbinafine compared with oral terbinafine alone for the treat As the most important source of Candida spp. in human
ment of onychomycosis with matrix involvement. Br J Dermatol disease is endogenous, many studies have been carried
2007;157:149–57. out on the yeast flora of the mouth, rectum, vagina and
skin of healthy subjects and of patients. The reported There have been many reports in the literature about
prevalence of Candida spp. from these sites depends the pathogenicity of the hyphal stage as opposed to the
largely on the sampling methods used. Imprint cultures yeast phase of C. albicans. The hyphal phase was consid
or mouthwash samples are found to give more positive ered to be the pathogenic or parasitic phase and the yeast
findings of oral carriage than swabs. Odds [7] has calcu phase the saprophytic form. It is now known that the
lated from published data that the carriage rate of C. albi- transition from the oval, budding yeasts to parallel‐sided
cans in the mouths of healthy subjects ranges from 2% to hyphae is associated with adhesion to and penetration of
41%, whereas in hospitalized patients the range is from host cells and the temperature, pH and other environ
6% to 70%, as determined by mouth swabs. Oral Candida mental factors. The ability to invade tissues and to induce
carriage also varies according to age. The mean carriage an inflammatory response is a characteristic of the species
rate of yeasts was calculated to be 17.3% in neonates, and not of a particular growth form. On body surfaces,
46.3% in infants aged 1 week to 18 months and 15.1% in the normal growth form of the organism is a yeast. Once
children over 18 months. Studies in neonatal intensive colonization and invasion of tissues have occurred, the
care units evaluating preterm infants found gastrointesti proportion of hyphal elements increases with the age of
nal colonization rates of 23% in 2157 infants [10] and the lesion. In superficial cutaneous candidosis, the yeasts
79.6% in 54 neonates [11]. The mean carriage rate in adults and hyphae are restricted to the stratum corneum. The
was found to be 25.1% [7]. main changes in the early stages of Candida invasion are
In the vagina, the carriage rate of C. albicans in normal the infiltration of the epithelium by neutrophils with
females is rarely found to be more than 20%. The vaginal some hyper‐ and parakeratosis. There is upper dermal
carriage of yeasts is more prevalent in pregnant than in infiltration of lymphocytes and plasma cells.
nonpregnant women, with the highest prevalence being
in the third trimester of pregnancy. The influence of oral Clinical features
contraceptives depends on the oestrogen dosage [7]. Oral candidosis
The change from a commensal status to a pathogenic This condition can be divided into a number of distinct
one is associated with a number of underlying host condi clinical forms [14]: (i) acute pseudomembranous candi
tions. Factors predisposing to Candida infections include dosis; (ii) acute erythematous atrophic candidosis; (iii)
the following: chronic erythematous candidosis; and (iv) chronic hyper
• age plastic candidosis (Candida leucoplakia).
• pregnancy
• local occlusion and maceration Acute pseudomembranous candidosis (thrush). This
• antibiotic therapy presents with white plaques on the buccal mucosa and
• endocrine disease lateral borders of the tongue. These gradually coalesce
• immune defects and become confluent (Fig. 46.20). Lesions may spread to
• immunosuppressive therapy the throat, leading to serious dysphagia.
• iron and zinc deficiency. This type of oral candidosis is common in infants with
Newborn infants, especially premature infants, are very an incidence of between 4% and 8%. It is also the form
susceptible to Candida infection, probably reflecting their seen in patients who are immunocompromised, such as
INFECTIONS
immature mucosal immunity [12]. The occlusive effects

of napkins are a cause of candidosis in babies [13], and
thumb sucking may lead to maceration of the nailfolds
and subsequent infection by Candida.
Disturbance of the normal bacterial flora by the admin
istration of antibiotics facilitates the growth of Candida
spp. Endocrine disorders such as diabetes mellitus,
Cushing syndrome, hypoparathyroidism, hypothyroid
ism and autoimmune polyendocrinopathy syndromes
(such as APECED) favour the development of candidosis.
Immune defects, particularly in T‐lymphocyte function,
predispose to superficial forms of candidosis, and chronic
mucocutaneous candidosis is often associated with
defects in cell‐mediated immunity [12]. In patients with
neutropenia, the development of Candida infections
reflects the inability to eliminate yeasts that have already
penetrated the skin or mucous membranes.
Pathology Successful colonization and infection by Candida

begins with the adherence of commensal organisms to
mucosal cells or keratinocytes. Adherence must take place
before the yeasts can germinate to produce germ tubes and
hyphal elements, which can penetrate host tissues. Fig. 46.20 Oral candidosis with lesions extending on the tongue surface.
those with AIDS. The cumulative prevalence of oral

Candida infection was found to be 72% of 99 children with
perinatally acquired human immunodeficiency virus
(HIV) infection examined longitudinally for oral lesions
[15]. HIV‐positive children show the same range of
Candida spp. reported for adults who are HIV positive,
and C. dubliniensis has been isolated in several studies
[16,17]. Resistance to azole antifungals has also been dem
onstrated in clinical C. albicans isolates from HIV‐infected
children [18,19].
Acute erythematous atrophic candidosis. This entity is

characterized by small or large erythematous and atrophic
areas. Any part of the oral mucosa may be affected,
although the most common site is the tongue. This is a rare
condition and is usually associated with broad‐spectrum
antibiotic treatment [20] but may also develop in HIV‐
Fig. 46.21 Napkin candidosis.
positive patients.
Chronic erythematous candidosis. This is the most com discoloured brown or green and is often ridged. The nail
mon form of oral candidosis, usually associated with oral becomes friable and detached from the nail bed.
prostheses such as those used in orthodontics. Presenting Paronychial infection can occur in infants with a long
signs are persistent erythema and oedema of the portion of history of finger sucking, leading to a breakdown of the
the palate that is in contact with dentures. It is frequently cuticle and invasion of Candida. The fingers become red
accompanied by angular cheilitis, but this condition can with proximal and lateral nailfold swelling [25]. Candida
develop in association with any form of oral candidosis. onychomycosis has also been reported in a 5‐day‐old
neonate [26], and also at 5 weeks in a preterm infant
Chronic hyperplastic candidosis (Candida leucoplakia). with suspected C. albicans sepsis [27]. In both cases, the
This presents with lesions ranging from small translucent mothers had vaginal candidosis before delivery.
white areas to large dense opaque plaques, which cannot
be easily detached from the affected areas of the mouth or Congenital cutaneous candidosis
tongue. This condition is seen mainly in adults and is This is a rare condition in newborn infants whose mother
associated with smoking. However, hyperplastic nodules, had an intrauterine Candida infection prior to delivery.
particularly on the tongue, are often found in children The disease is characterized by multiple papules on an

with chronic mucocutaneous candidosis (CMC) (see erythematous base. The lesions occur on the face, neck,
Chronic mucocutaneous candidosis). trunk and limbs. This form of candidosis is believed to
occur after yeasts ascend from the vagina and penetrate
INFECTIONS
Napkin (diaper, nappy) dermatitis the amniotic membranes [28]. Odds [7] found that in 40%
Napkin dermatitis leads to approximately 20% of all of 54 cases, the pregnancy was associated with a foreign
childhood dermatology visits. Common causes include body in the uterus, either a contraceptive device or cervi
allergic contact dermatitis, irritant contact dermatitis, cal suture. Inflammation of the fetal membranes may be
infection and psoriasis [21]. Rashes due to Candida on the present at birth with focal yellow lesions containing
buttock and in the perianal area of babies, associated with yeasts on the umbilical cord and placenta [29]. Full‐term
wearing napkins, present with erythema, scaling and infants with congenital cutaneous candidosis generally
characteristic satellite pustules (Fig. 46.21). exhibit a benign course and respond well to topical therapy;
The relationship between the presence of cutaneous some may even clear spontaneously. However, in prema
candidosis in infants and the faecal carriage of Candida ture and low‐birthweight infants this is a serious infection,
has been frequently recorded [13,21,22]. The precise role frequently complicated by systemic involvement [30].
of Candida in napkin rash is still unclear. Candida as a pri Inborn errors of caspase recruitment domain‐containing
mary invader of an irritant dermatitis has been favoured protein 9 (CARD9) immunity are predisposing factors for
by some investigators [23], whereas others have found invasive candidosis [12,31].
that C. albicans was a common secondary invader of many
types of napkin dermatitis [24]. (See also Chapter 20.) Chronic mucocutaneous candidosis
Chronic mucocutaneous candidiasis (CMC) is character
Paronychia and onychia ized by recurrent or persistent infections of the skin, nails,
These are acute or chronic infections of the nailfolds and oral and genital mucosae with Candida spp., mainly
nails caused by Candida spp. The nailfold becomes swol C. albicans. In recent years, inborn errors of human IL‐17
len, erythematous and painful with a discharge of pus. immunity have been demonstrated to underlie primary
Nail plate invasion may follow, infection beginning in immunodeficiencies with CMC. Various defects in recep
the proximal portion of the nail. The nail plate becomes tors responsible for sensing of C. albicans or downstream
signalling to IL‐17 may lead to susceptibility to Candida Other infections. Other chronic skin infections such as
infection. While CMC is common in patients with pro warts and dermatophytosis can occur in patients with
found T‐cell immunodeficiencies, CMC can also form CMC [33].
part of other immunodeficiencies in syndromic CMC, or
occur as a separate entity [12,31,32]. Prognosis. Prognosis of candidosis depends largely on
the type and severity of the predisposing factors or asso
Oral lesions. These are usually of the pseudomembra ciated disease. Oral and congenital cutaneous candidosis
nous type but may develop into chronic hyperplastic in the newborn may clear uneventfully but other forms,
lesions that present with white, adherent plaques affect for example CMC, are difficult to treat and will not clear
ing any mucosal surface, including the lateral borders of spontaneously.
the tongue. Angular cheilitis may be present. Oral lesions
occur in more than 90% of all CMC patients [7]. Diagnosis. In all cases of suspected candidosis, micro
scopic and culture confirmation is necessary. Smears from
Skin lesions. These progress from erythema to hyper mucosal surfaces may be examined as unstained wet
keratosis and crusted plaques (candida granuloma) preparations in saline or KOH. Heat‐fixed preparations
(Fig. 46.22). Granulomatous lesions predominate on the may be stained by Gram (Fig. 46.24) or by periodic acid–
scalp and face but can also occur on other parts of the Schiff (PAS) stain. Skin and nail specimens should be
body. placed in 30% KOH under a coverslip. Softening of the
tissue can be hastened by gentle heating. Specimens
Nails. Fingernails become affected but rarely toenails should be examined for the presence of round or oval
(Fig. 46.23). Nail involvement is characterized by severe budding yeast cells of 2–4 µm in size. Long hyphae with
dystrophic changes with thickening, distortion and frag yeasts at points of constriction are also present (Fig. 46.25).
mentation of the nail plate. Material should be inoculated onto SDA. Chloram
phenicol may be incorporated to reduce bacterial contam
ination, but cycloheximide should be omitted as many
yeast species are sensitive to this antibiotic. Incubation is
at 37 °C for 2–5 days and plates are discarded as negative
INFECTIONS
Fig. 46.24 Smear showing hyphae and yeasts (Gram stain).

Fig. 46.22 Candida granuloma.
Fig. 46.23 Chronic mucocutaneous candidosis affecting a thumb nail. Fig. 46.25 Hyphae and yeasts in skin (30% KOH).
if no growth appears after 7 days. Colonies should be

Box 46.4 General recommendations for the treatment of candidosis
examined by microscopy for typical budding yeast cells.
Selective and chromogenic media for the isolation of • Topical therapy (polyenes = nystatin, amphotericin B; azoles;
yeasts and their identification are now available com amorolfine) in a suitable formulation is usually sufficient.
mercially. They include CandiSelect™ 4 (Bio‐Rad, USA), • Griseofulvin is not effective.
an isolation medium on which C. albicans appear pink to • Oral candidosis: nystatin or amphotericin B oral solution.
purple and other yeasts turquoise, and BBL CHROMagar™ • Cutaneous candidosis: above‐mentioned antifungals in a cream or
Candida (Becton Dickinson, Europe; Mast Diagnostics, paste formulation.
UK), an isolation medium on which colonies of C. albicans • Chronic mucocutaneous candidosis: oral azole antifungals
according to sensitivity testing.
appear green, C. tropicalis blue, C. krusei pink and others
white to pink.
Tests for the identification of Candida spp. involve the
investigation of isolates for their ability to ferment sugars
and also to assimilate various sources of carbohydrates Oral candidosis
and nitrates. Commercial identification kits are available Oral candidosis in infants generally responds quickly to
and include API™ 20C Aux and ID 32C (both BioMerieux, topical treatment. Nystatin oral suspension (100 000 U/mL)
USA) and AuxaColor 2™ (Bio‐Rad, France). or amphotericin oral suspension (100 mg/mL) should
be given at 4–6 hourly intervals. In older children, the
Molecular diagnostics dose of amphotericin and nystatin oral suspension can
For the identification of Candida spp. directly from clinical be increased to 1 mL at 6 hourly intervals for 2–3 weeks.
specimens, the same methods are used as for dermato Nystatin and amphotericin B lozenges can also be used.
phyte fungi (real‐time or conventional PCR in combina These compounds have a bitter taste and miconazole oral
tion with sequencing or hybridization to species‐specific gel is sometimes better tolerated. In children under 2
probes). In addition, fluorescence in situ hybridization years, 2.5 mL at 12 hourly intervals should be given, chil
and nucleic acid sequence‐based amplification of dren between 2 and 6 years of age should have 5 mL at 12
extracted yeast cell RNA combined with species‐specific hourly intervals and those over 6 years 5 mL at 6 hourly
probes have been applied to detect Candida yeast cells intervals. The gel should be retained in the mouth for as
mainly from blood or blood cultures (for review see [34]). long as possible and treatment should be continued for at
As target genes for the differentiation of Candida yeasts, least 48 hours after all symptoms have disappeared.
the 26S and the ITS 1/2 region of the rDNA have been Oral candidosis occurring in immunosuppressed chil
established. Even phylogenetically closely related spe dren may require systemic therapy, such as itraconazole
cies, e.g. C. dubliniensis and C. albicans, are delineated by solution or fluconazole or the newer azoles posaconazole
these targets. Commercially available tests are designed and voriconazole, and prophylaxis should be introduced,
to identify Candida spp. from systemic infections (mainly for example in children with acute lymphocytic leukae
blood).

mia [35].
Differential diagnosis. Oral candidosis should be Cutaneous candidosis

distinguished from lichen planus, leucoplakia, herpes
INFECTIONS
Most infections respond to topical nystatin, azoles or
stomatitis, aphthous stomatitis and erythema multiforme. amorolfine. Napkin dermatitis associated with Candida
Napkin dermatitis caused by C. albicans may resemble other infection may be treated with low‐potency corticosteroid
forms of dermatitis and psoriasis [21]. Staphylococcal preparations (1% hydrocortisone cream) in addition to a
and Gram‐negative nailfold infections are similar to topical antifungal [36]. Congenital cutaneous candidosis
Candida paronychial infections, and Candida nail infec responds well to topical antifungals such as nystatin or an
tions should be differentiated from dermatophytosis, azole except in infants who are premature or low birth
psoriasis and eczema. weight who typically require systemic therapy.
Congenital cutaneous candidosis may resemble neona
tal bacterial infections (staphylococcal infections), tran Paronychia and onychia
sient neonatal pustulosis and congenital syphilis. Topical application of an azole cream or solution to the
nailfold may be helpful; control of the predisposing fac
Treatment. The majority of the antifungal drugs tor, such as finger sucking, may lead to a spontaneous
described for dermatophytosis are also effective for the cure [37]. Nail infections occurring in infants have also
treatment of most superficial forms of candidosis. been reported as recovering without therapy.
However, in addition, the polyenes, complex macrolide
substances derived from Streptomyces spp. that act by Chronic mucocutaneous candidosis
selectively binding to the fungal cell membrane, are Oral and cutaneous lesions will respond to short courses
useful topically for oral and vaginal candidosis. The of antifungal therapy, but longer courses are needed to
main polyene drugs are amphotericin B, nystatin and clear nail infections. Improvement is often transient and
natamycin. Resistance to these compounds is rare and recurrence is common. Therapy with itraconazole and
toxicity, a problem with parenteral use, is not seen with fluconazole may be helpful. Especially in systemic disease,
local application. See Box 46.4. the newly developed azoles (voriconazole, posaconazole)
or the echinocandins (caspofungin, anidulafungin, 28 Chapel TA, Gagliardi C, Nichols W. Congenital cutaneous candidosis.
micafungin) offer some advantages as they have a broader
29 Whyte RK, de Hussain Z, Sa D. Antenatal infections with Candida spe
spectrum and a higher sensitivity against otherwise cies. Arch Dis Child 1982;57:528–35.
resistant pathogens [35]. 30 Darmstadt GL, Dinulos JG, Miller Z. Congenital cutaneous candidia
sis: clinical presentation, pathogenesis, and management guidelines.
Pediatrics 2000;105:438–44.
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2 Langenbeck B. Auffindung von Pilzen aus der Schleimhaut der 32 Sparber F, LeibundGut‐Landmann S. Interleukin 17‐mediated host
Speiseröhre einer Typhus‐Leiche. Neue Not Geb Natur‐U Helik defense against Candida albicans. Pathogens 2015;4:606–19.
(Froriep) 1839;12:145–7. 33 Shama SK, Kirkpatrick CH. Dermatophytoses in patients with chronic
3 Bennett JH. On the parasitic vegetable structures found growing in mucocutaneous candidiasis. J Am Acad Dermatol 1980;2:285–94.
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4 Zopf W. Die Pilze in morphologischer, physiologischer, biologischer tion and typing of pathogenic Candida yeasts. Biomed Pap Med Fac
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7 Odds FC. Candida and Candidosis, 2nd edn. London: Baillière Dermatologists’ guidelines for the management of onychomycosis
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8 Kashbur IM, Ayliffe GAJ, George RH. The survival of Candida albicans
in moist and dry environments. J Hosp Infect 1980;1:349–51.
9 Polke M, Hube B, Jacobsen ID. Candida survival strategies. Adv Malassezia‐associated diseases
Appl Microbiol 2015;91:139–235.
10 Saiman L, Ludington E, Dawson JD et al. The National Epidemiology The genus Malassezia currently comprises 17 species of
of Mycoses Study Group. Risk factors for Candida species colonisa
tion of neonatal intensive care unit patients. Pediatr Infect Dis J
lipophilic yeasts (M. pachydermatis, M. furfur, M. yama-
2001;20:1119–24. toensis, M. sympodialis, M. caprae, M. dermatis, M. slooffiae,
11 Gagneur A, Sizun J, Vernotte E et al. Low rate of Candida parapsilosis‐ M. japonica, M. nana, M. equina, M. obtusa, M. restricta,
related colonisation and infection in hospitalised pre‐term infants: a M. globosa, M. cuniculi, M. brasiliensis, M. psittaci, M.
one‐year prospective study. J Hosp Infect 2001;48:193–7.
12 Netea MG, Joosten LA, van der Meer JW et al. Immune defence arunalokei). These species belong to the resident flora of
against Candida fungal infections. Nat Rev Immunol 2015;15:630–42. human and animal skin; they are also associated with
13 Dixon PN, Warin RP, English MP. Alimentary Candida albicans and common skin diseases, but their pathogenesis is still not
napkin rashes. Br J Dermatol 1972;86:458–62.
fully elucidated (for review see [1,2]).
14 Lehner T. Classification and clinico‐pathological features of Candida
infections in the mouth. In: Winner H, Hurley R (eds) Symposium on
Candida Infections. Edinburgh: Livingstone, 1966:119–37.
15 Katz MH, Mastrucci MT, Leggott PJ et al. Prognostic significance of Pityriasis versicolor
oral lesions in children with perinatally acquired human immunode
ficiency virus infections. Am J Dis Child 1993;147:45–8. Definition. Pityriasis versicolor is a chronic, mild and
16 Jabra‐Rizk MA, Falkler WA, Enwonwu CO. Prevalence of yeast
among children in Nigeria and the United States. Oral Microbiol
usually asymptomatic infection of the stratum corneum.
It is produced by the proliferation of lipid‐dependent
INFECTIONS
Immunol 2001;16:383–5.
17 Brown DM, Jabra‐Rizk MA, Falkler WA et al. Identification of Candida yeasts of the genus Malassezia, which are part of the nor
dubliniensis in a study of HIV‐seropositive pediatric dental patients. mal flora of human skin. The infection is characterized by
Pediatr Dent 2000;22:234–8.
18 Muller FM, Weig M, Peter J et al. Azole cross‐resistance to ketocona the development of erythematous scaly macules in
zole, fluconazole, itraconazole and voriconazole in clinical Candida sebum‐rich areas of the skin, especially on the trunk, arms
albicans isolates from HIV‐infected children with oropharyngeal and neck. Occasionally, the face and groin are involved.
candidosis. J Antimicrob Chemother 2000;46:338–40.
The lesions may be followed by long‐lasting depigmenta
19 Pelletier R, Peter J, Gonzalez C et al. Emergence of resistance of
Candida albicans to clotrimazole in human immunodeficiency virus‐ tion known as pityriasis versicolor alba (PVa). The disease
infected children: in vitro and clinical correlations. J Clin Microbiol is distributed worldwide but is more prevalent in tropical
2000;38:1563–8. areas, where extensive lesions are common. It can occur at
20 Lehner T, Ward RG. Iatrogenic oral candidosis. Br J Dermatol
1970;83:161–6.
any age but is most commonly seen in young adults and
21 Klunk C, Domingues E, Wiss K. An update on diaper dermatitis. Clin is comparatively rare in children.
Dermatol 2014;32:477–87. The term ‘tinea versicolor’ is inaccurate and should not
22 Rebora A, Leyden JJ. Napkin (diaper) dermatitis and gastrointestinal be used as the causative agent is not a dermatophyte.
carriage of Candida albicans. Br J Dermatol 1981;105:551–5.
23 Leyden JJ, Kligman AM. The role of microorganisms in diaper derma
titis. Arch Dermatol 1978;114:56–9. History. The disease was first recorded by Eichstedt [3] in
24 Dixon PN, Warin RP, English MP. The role of Candida albicans infection 1846 and also described by Sluyter [4] in 1847. Both
in napkin rashes. BMJ 1969;2:23–7.
25 Raimer SS, Petrusick TW. Superficial fungal infections in children.
authors called the infection ‘pityriasis versicolor’ but did
Dermatol Clin 1984;2:57–65. not propose a name for the causative organism. In 1853,
26 Plantin P, Jouan N, Calligaris C et al. Onychomycosis in a newborn Robin [5] named the fungus Microsporum furfur and called
due to Candida albicans with neonatal infection. Ann Dermatol the disease ‘tinea versicolor’ because he thought the fun
Vénéréol 1992;119:213–15.
27 Abraham Z, Sujov P, Blazer S et al. Candida onychomycosis in a pre gus resembled the dermatophyte Microsporum audouinii.
term infant. Mykosen 1986;29:357–9. Malassez [6], in 1874, described yeast‐like cells from scalp
lesions and in dandruff and called them ‘spores’. In Reports on the distribution of the newly recognized
1889, Baillon [7] created a new genus, Malassezia, for species suggest that M. globosa and M. restricta [21–23] are
these organisms. the most common species on normal adult skin. However,
The fastidious nutritional requirements of these lipid‐ these studies are flawed because the majority relied on
dependent yeasts made their isolation difficult, and some swabbing for sampling, and this method is unlikely to
of the early reports of their culture may be suspect. yield accurate quantitative data. Sites examined and
Castellani and Chalmers [8] cultured a yeast from human media used varied as well. This may also explain the
skin in 1913, which they named Pityrosporum ovale, fol different results obtained concerning the colonization of
lowing the lead of Sabouraud [9] who, in 1904, assigned children by Malassezia yeasts. Studies based on molecular
the yeasts seen in dandruff and sebaceous dermatitis to a techniques showed that M. restricta overwhelmingly pre
new genus, Pityrosporum, as P. malassezii. In the same year, dominated at ages over 16–18 years in males and 23–29
Kraus [10], using a medium supplemented with lanolin, years in females. M. globosa and M. restricta together
also reported in vitro isolation of the yeasts, although accounted for more than 70% of Malassezia spp. regardless
the lipophilic nature of Malassezia was first described of gender [24].
by Benham [11] only in 1939. The isolation of P. ovale by The incidence of Malassezia on clinically normal
Panja using Petroff’s egg medium is also widely regarded skin from the back of newborn infants and those aged
as genuine [12]. In 1951, Gordon [13] isolated a round, 6 months, 1 year, 5 years, 10 years and 15 years was inves
double‐contoured, lipophilic yeast‐like fungus and called tigated by Faergemann and Fredriksson [25]. They were
it Pityrosporum orbiculare, suggesting that it might be unable to demonstrate M. furfur in children less than
the causative fungus of pityriasis versicolor. Subsequent 1 year of age. In contrast, several later studies suggest that
studies by Keddie and co‐workers [14,15] demonstrated neonatal and infant carriage of Malassezia yeasts is not
both morphological and antigenic relationships between unusual. In a report from Thailand, Malassezia yeasts were
P. orbiculare cultured from infected scales and the M. furfur isolated from the normal skin of 47% of 150 1‐ to 5‐day‐
cells found in skin scales. old infants [26], and 37% of infants hospitalized in inten
For a number of years there was controversy between sive care units in the USA were found to harbour Malassezia
those who believed that P. ovale and P. orbiculare repre on the skin [27]. A study of 245 neonates and 42 infants in
sented two distinct species and those who believed that a neonatal and medical unit demonstrated that 41 out of
the oval and round cells were aspects of a single species. the 42 infants were colonized with Malassezia yeasts on
This was apparently resolved in 1984 when Yarrow and admission. None of the neonates was colonized immedi
Ahearn [16] placed both of these lipophilic organisms into ately after birth, but 78 (31.8%) became colonized during
a single species. As the generic name Malassezia given the study. In both infants and neonates, the ear was the
by Baillon had priority over Pityrosporum given by most common site of colonization [28].
Sabouraud, the organism was named Malassezia furfur, With respect to older children, a survey on the scalp
and this applied to both yeast and hyphal phases of carriage of Malassezia species in healthy schoolchildren

growth. Subsequently, Simmons and Gueho described a aged between 7 and 17 years showed that prepubertal
second lipid‐dependent species which was a normal resi children yielded yeasts less often than older or sexually
dent on human skin, Malassezia sympodialis [17]. The mature children [29]. This study of nearly 600 children
INFECTIONS
situation was further complicated when a detailed study also found that Caucasians harboured yeasts more often
using morphological, physiological and molecular tech than black children. In a study that examined skin from
niques showed that the yeasts classified as M. furfur actu the forehead of healthy children, 119 out of 138 children
ally comprised a number of different species and a further (87%) gave positive cultures. Children producing the
four species – M. globosa, M. slooffiae, M. restricta and highest number of colonies were those aged between 2
M. obtusa – were added to the genus [18]. By means of and 23 months and those over 9 years old [30]. In the
conventional and molecular methods, today 17 species of study of children comparing 5‐, 10‐ and 15‐year‐olds by
lipophilic yeasts (M. pachydermatis, M. furfur, M. yama- Faergemann and Fredrikson [25], the highest prevalence
toensis, M. sympodialis, M. caprae, M. dermatis, M. slooffiae, (93%) was in 15‐year‐old children.
M. japonica, M. nana, M. equina, M. obtusa, M. restricta, M. A number of factors influencing the appearance of pity
globosa, M. cuniculi, M. brasiliensis, M. psittaci, M. arunalokei) riasis versicolor have been described [31,32]. It is well
are distinguished (for review, see [1,2]). known that the incidence of the disease is higher in warm
and humid climates, and sweating may be one factor
Aetiology and pathogenesis. The recognition of new spe associated with increased growth of Malassezia, leading to
cies of Malassezia makes many of the preceding studies of signs and symptoms of infection. Systemic corticosteroid
the genus difficult or even impossible to interpret, as the therapy is related to an increased incidence of pityriasis
yeast strains used have not been maintained in culture and versicolor [19]. It is also associated with Cushing syn
cannot be related to the new species. The yeasts are part of drome [33] and immunosuppression associated with
the normal flora of the skin. Early studies found that 97% of transplantation but not with AIDS. To some extent,
clinically normal people may carry the yeast on the scalp genetic factors may play a role, as the disease occurs more
and 92% on the trunk [19,20]. The oval form was more frequently among first‐degree family members [34].
common on the scalp (‘M. ovale’), whereas the spherical However, the pathogenesis of pityriasis versicolor is not
forms were more frequent on the trunk (‘M. orbiculare’). clearly understood. Being most frequently isolated from
the lesions, M. globosa is discussed as the causative agent hyperkeratosis may be present but there are few or no
of pityriasis versicolor but the clinical phenomena, espe signs of inflammation (‘seemingly normal skin’).
cially fluorescence and change in skin colour, are not
explained. M. furfur has been shown to produce a great Clinical features. Pityriasis versicolor classically presents
number of indole pigments and fluorochromes when as asymptomatic scaly hypo‐ or hyperpigmented macular
grown with tryptophan (Trp) as sole nitrogen source, lesions which, in adults, mainly occur on the upper trunk
which may explain several clinical features of pityriasis and arms. The macules frequently coalesce, producing
versicolor [2]. In the plant pathogen Ustilago maydis, a patches of varying shapes and sizes. The colour of the
fungus phylogenetically closely related to Malassezia spp., lesions varies: in pale‐skinned individuals, the lesions
it was recently shown that the biosynthetic pathway lead appear fawn or brown‐coloured or occasionally red
ing to pigment production from Trp was based on the (Fig. 46.26), whereas after sun tanning they appear paler
activity of a single enzyme, Tam 1 [35]. It is a Trp ami or hypopigmented in comparison with the surrounding
notransferase that converts Trp to indolepyruvate (IP). tanned skin. In dark‐skinned subjects, the rash is usually
Furthermore, it was found that the indole pigments can hypopigmented (Fig. 46.27) but may be hyperpigmented.
develop spontaneously from IP and Trp without the These pigmentary changes are thought to be due to the
action of any additional enzymes. Thus, synthesis of a inhibition of melanin formation by dicarboxylic acids,
multitude of pigments produced from Trp is catalysed by such as azelaic acid, produced by the enzyme activity of
a single biosynthetic step, the activity of Tam 1. This sug the yeasts. However, given the characteristic occurrence
gests that utilization of spontaneously generated meta of pityriasis versicolor only under special conditions such
bolic by‐products might constitute an important step in as high air humidity and excessive sweating and the fact
the pathophysiology of pityriasis versicolor. This was that Malassezia yeasts belong to the normal cutaneous
underlined by a rapid impressive effect of the topically flora, the regularly produced dicarboxylic acids cannot
applied transaminase inhibitor cycloserin on the clinical serve as the sole explanation why pityriasis versicolor
course of pityriasis versicolor [36]. (alba) does not occur whenever the organism is found on
Although M. globosa is nowadays considered the main the skin [45,46].
pathogen in pityriasis versicolor, it is not able to produce Other sites of infection include the face, neck, abdo
pigment in vitro. Hypothetically, M. globosa might have men and thighs. More extensive lesions occur in tropical
the genetic potency to produce pigment in vivo, but the
prerequisites for induction in vitro remain to be deter
mined. Investigations based on the genome of M. globosa
might help clarify this discrepancy [37]. The comparative
rarity of pityriasis versicolor in children under 10 years of
age might suggest that physiological changes in skin
lipids during puberty could enhance fungal pathogenic
ity [19]. Pityriasis versicolor is most commonly seen in

young adults with an almost equal sex distribution.
Although much less common, it does occur in children
INFECTIONS
[38–40]. Of 305 children examined in Poland, 33 (10.8%)

were found to have pityriasis versicolor. Their ages
ranged from under 1 year to 10 years old, with the highest
number affected being between the ages of 8 and 10 years;
two patients were under 1 year of age [38]. A report
from Tunisia [33] analysed retrospectively the results of
Fig. 46.26 Pityriasis versicolor. Hyperpigmented lesions.
a 5‐year study. Of 1379 cases of pityriasis versicolor,
164 (11.8%) were in children aged 5 months to 14 years. In
children, the face is often involved, in contrast to the rar
ity with which facial lesions occur in adults [40–42]. In a
series of 57 cases of pityriasis versicolor in children,
Terragni et al. [40] found that the face was the only site of
involvement in 18 patients (31.6%). Similarly, in the
Tunisian study, of the 164 children diagnosed, 78 (47.5%)
had facial lesions. Among children in the tropics, pityria
sis versicolor is not an uncommon disease. There is a sud
den resurgence of cases in the hot monsoons and even
infants are not spared [43]. The infection has also been
recorded in neonates [44].
Pathology. The yeasts and hyphae are restricted to the

outermost layers of the stratum corneum, where hyphae
invade both between and inside corneocytes. Mild Fig. 46.27 Pityriasis versicolor. Hypopigmented lesions.
climates, covering many sites on the body surface. erythrasma (generally restricted to intertriginous areas)
Occasionally slight irritation may be noted by patients, and pinta also need to be considered.
but medical attention is generally sought for cosmetic rea
sons. Examination of lesions under a Wood’s light reveals Molecular diagnostics
a golden‐yellow fluorescence in the majority of cases and The 17 species described currently within the genus
may reveal the presence of lesions not obviously visible to Malassezia are differentiated by sequence analysis of the
the naked eye. This fluorescence might be explained by D1/D2 domain of the 26S and the ITS 1/2 region of the
the Trp‐derived compound pityrialactone [2]. rDNA. Several conventional and real‐time ‘in‐house’ PCRs
have been developed targeting these genes to identify
Diagnosis. Pityriasis versicolor is easily diagnosed by Malassezia spp., even quantitatively [1,2]. For routine
microscopic examination of skin scales mounted in 30% diagnostics, however, the delineation of the animal‐
KOH. Both yeasts and hyphae fluoresce very strongly associated species M. pachydermatis (source of infection)
with the calcofluor technique (‘spaghetti and meatballs’; from the remaining species is necessary.
Fig. 46.28). It is the hyphae that are diagnostic of pityriasis
versicolor. In the majority of instances, the yeasts associ Treatment. Treatment is usually successful with either
ated with the hyphae are round, budding on a narrow topical or systemic antimycotic therapy within 2 weeks or
base, with morphology typical of M. globosa, and this less, but widespread disease and frequent relapses may
yeast is widely accepted as the main species associated be of some concern [49]. For example, the condition can
with pityriasis versicolor [21–23]. However, occasionally, be treated effectively with 2.5% selenium sulfide suspen
and more frequently in the tropics, oval yeasts are seen sion as a shampoo applied to the skin, left on overnight
with the hyphae, suggesting that more than one species of and washed off the next morning. One or two applica
Malassezia may be associated with the disease [47]. Culture tions are usually sufficient. It also responds to most
is not helpful as the organisms are part of the normal skin topical imidazoles (such as clotrimazole, miconazole,
flora. If required, Malassezia yeasts can be grown on a econazole) for 1–2 weeks as well as ketoconazole sham
medium enriched with lipids, such as Dixon’s agar or poo (two or three applications).
Leeming’s medium [1,2]. Incubation should be at 32–35 °C It should be noted that, as Malassezia yeasts are part of
for 2 weeks. Hypopigmented lesions may be confused the normal flora of the skin, relapses occur very fre
with vitiligo but there is no scaling in vitiligo and the quently. Any skin discolouration may take several months
lesions are white and usually symmetrical. In contrast to to revert to normal, and patients should be reassured that
vitiligo, there is no sunburn after exposure to UV light, this is normal and that further treatment is not required.
which might be explained by the action of the UV filter
pityriacitrin [48]. Other Malassezia (Pityrosporum) infections
Although the trunk may be affected, other sites Malassezia (Pityrosporum) folliculitis
involved include wrists, ankles, knees and hands. Other This condition is seen primarily in teenagers or young

pigmentary disorders, such as chloasma, in which hyper adult males. Lesions consist of papules or pustules, often
pigmented macules without scaling affect the face but not widely scattered on the shoulders and back [50,51]
the trunk or limbs, should also be excluded. Pityriasis (Fig. 46.29). Numerous, often round, budding Malassezia
INFECTIONS
rosea, like pityriasis versicolor, has a predilection for the yeasts are found in affected follicles, surrounded by
trunk but is more acute and rapidly spreading after the inflammatory cells, suggesting that M. globosa may again
appearance of a herald patch. Seborrhoeic dermatitis, be of significance in many instances [21]. Some workers
have suggested that follicular occlusion may be the primary
event in the development of folliculitis and that over
growth of Malassezia is a secondary occurrence [52]. It is
Fig. 46.28 Thick‐walled yeasts and short angular hyphae in skin

(‘spaghetti and meatballs’; calcofluor preparation). Fig. 46.29 Pityrosporum folliculitis.
not associated with a single Malassezia species [53]. It has homologous human self‐antigens [66]. The human
to be distinguished from acne as it does not respond to proteins are capable of inducing positive skinprick and
the same treatment. Oral ketoconazole or ketoconazole atopy patch tests in patients sensitized to the Malassezia
shampoo is the most effective treatment. proteins, indicating a role of IgE‐mediated autoreactivity
in the pathogenesis of AD in a subset of patients. A com
Malassezia (Pityrosporum) yeasts in seborrhoeic parative analysis of Malassezia flora between adults and
dermatitis children with AD showed that M. restricta was the pre
In adults, Malassezia yeasts are found in large numbers dominant species in the children with AD, while both
in the scales of seborrhoeic dermatitis and dandruff. M. restricta and M. globosa predominated in the adults.
Seborrhoeic dermatitis is characterized by yellowish‐red The adults showed increased sensitization in terms of
lesions in seborrhoeic areas covered with greasy scales anti‐Malassezia‐specific IgE responses in the sera to
and associated with mild itching. The relationship both M. globosa and M. restricta in comparison with the
between infantile seborrhoeic dermatitis and these yeasts children [67]. In the study by Lange et al. sensitization of
is less well established. The finding of oval yeasts in infan 141 children with AD against a mixture of three Malassezia.
tile seborrhoeic dermatitis was first reported by Devred spp. (M. sympodialis, M. globosa and M. restricta; Pharmacia
et al. [54] in 1985. Ruiz‐Maldonado et al. [55] found P. ovale Immunocap m227) showed no significant correlation to
in 73% of infants with seborrhoeic dermatitis and in 53% age, duration or onset of the disease, but a higher risk for
of healthy infants, whereas Broberg and Faergemann [56] sensitization was found with increasing total IgE levels
cultured P. ovale significantly more often from children with [68]. Malassezia yeasts seem to be associated mainly with
seborrhoeic dermatitis (90%) than healthy children (20%). the head, neck and face type of atopic eczema/dermatitis
Since the recognition of the new species of Malassezia, a syndrome (AEDS) (head and neck dermatitis), corre
study in Japan compared 52 patients with infantile sebor sponding to the numerous sebaceous glands found in
rhoeic dermatitis and 47 healthy 1‐month‐old infants. this region. This is supported by the demonstration of
Direct counts of yeasts in skin samples from the cheek Malassezia‐specific IgE antibodies, skinprick testing and
found significantly more yeasts in the seborrhoeic derma atopy patch test, but in particular by the results of clinical
titis group. Cultures from the other cheek also yielded studies in which antimycotics were applied topically or
M. furfur and M. globosa at significantly higher rates than systemically for treatment of head and neck dermatitis
the seborrhoeic dermatitis group [57]. However, although [65]. It remains to be clarified whether these results are
it appears that these Malassezia yeasts are found in the also applicable to children with AD.
skin of infantile seborrhoeic dermatitis sufferers more fre
quently than in healthy children, the importance of these Malassezia fungaemia and invasive infection
yeasts as pathogens is still unclear. Treatment of infected Malassezia spp. are rare causes of invasive infections in crit
infants with 2% ketoconazole cream has given good ically low‐birthweight ill infants and in immunocompro
response rates [55,58] but, as this condition has a good mised children and adults [69,70]. The clinical spectrum
prognosis without treatment, placebo studies are neces ranges from asymptomatic infection to life‐threatening
sary before the role of Malassezia in infantile seborrhoeic sepsis and disseminated disease, with intravascular cath
dermatitis can be established with certainty. eters and administration of lipid‐supplemented parenteral
INFECTIONS
nutrition acting as the main risk factors. The overwhelm

Neonatal cephalic pustulosis ing majority of invasive infections reported in the literature
Malassezia yeasts have been linked to a nonfollicular pus have been associated with M. furfur and M. pachydermatis.
tulosis of the face in neonates, first reported by Aractingi Most patients had a serious underlying disease affecting
et al. [59]. Several subsequent reports have supported the overlapping components of host responses, had indwell
view that this condition is directly related to the presence ing vascular access, and had received parenteral nutrition
of these yeasts [60–62], and some have reported a clinical containing lipid emulsions.
response to antifungal treatment. However, only a pro While invasive infections may occur sporadically, in the
portion of pustule smears in these reports revealed the last decade nosocomial outbreaks of neonatal M. furfur
presence of Malassezia yeasts, and positive cultures also and M. pachydermatis infections have been widely
did not show complete correlation between pustules and reported. As shown by molecular typing methods, infants
isolation of yeasts [63,64]. Considering the now convinc become colonized by skin contact with parents or health
ing evidence that the normal skin of neonates may be rap care workers, who may further transmit the organism
idly colonized by Malassezia yeasts in the first weeks of from an infected or colonized infant to others via their
life, more evidence is required to confirm the significance hands [71,72]. Malassezia spp. can be detected in blood
of these yeasts in this condition. and other specimens by direct microscopic examination,
by culture and by molecular methods. Detection is
Atopic dermatitis complicated by the organism’s lipid‐dependent nature as
Malassezia yeasts have been shown to act as allergens in most routinely used media do not support its growth [69].
atopic dermatitis (AD), and 13 allergens have been cloned, Use of lipid‐supplemented media may be warranted in
characterized and produced as recombinant proteins certain specimens, especially if cultures appear sterile
from Malassezia species [65]. Some of these recombinant on routine media and yeasts have been observed on
allergens show a high degree of sequence identity to microscopy.
There is general consensus that the management of 30 Bergbrant IM, Broberg A. Pityrosporum ovale. Culture from the forehead
of healthy children. Acta Dermatol Venereol (Stockh) 1994;74:260–1.
Malassezia‐related fungaemia and sepsis requires the
31 Crespo‐Erchiga V, Florencio VD. Malassezia yeasts and pityriasis ver
prompt removal of any indwelling catheter in addition sicolor. Curr Opin Infect Dis 2006;19:139–47.
to intravenous antifungal therapy and, less clearly, the 32 Gupta AK, Batra R, Bluhm R et al. Pityriasis versicolor. Dermatol Clin
temporary discontinuation of parenteral nutritional lipid 2003;21:413–42.
33 Canizares O, Shatin H, Kellert AJ. Cushing’s syndrome and dermato
solutions. mycosis. Arch Dermatol 1959;80:701–12.
34 He SM, Du WD, Yang S et al. The genetic epidemiology of tinea versi
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INFECTIONS
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isolated from patients with seborrheic dermatitis, atopic dermatitis, rheique du nourrisson. Ann Dermatol Vénéréol 1985;112:211.
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24 Wu G, Zhao H, Li C et al. Genus‐wide comparative genomics of Pityrosporum ovale in infantile seborrhoeic dermatitis. Pediatr
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on human skin. Acta Dermatol Venereol (Stockh) 1980;60:531–3. 57 Nakabayashi A, Sei Y. Relationship between Malassezia yeast and
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Quaderni di Cooperazione Sanitaria, 1991:63–9. 58 Taïeb A, Legrain V, Palmier C et al. Topical ketoconazole for infantile
27 Powell DA, Hayes J, Durrell DE et al. Malassezia furfur skin colo seborrhoeic dermatitis. Dermatologica 1990;181:26–32.
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1987;111:217–20. par Malassezia furfur. Ann Dermatol Venereol 1991;118:856–8.
28 Ashbee HR, Leck AK, Puntis JWL et al. Skin colonisation by Malassezia 60 Rapelanoro R, Mortureux P, Couprie B et al. Neonatal Malassezia fur-
in neonates and infants. Infect Cont Hosp Epidemiol 2002;23:212–16. fur pustulosis. Arch Dermatol 1996;132:190–3.
29 Noble WC, Midgley G. Scalp carriage of Pityrosporum species: the 61 Niamba P, Weill FX, Sarlangue J et al. Is common neonatal cephalic
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16:229–32. Dermatol 1998;134:995–8.
62 Bernier V, Weill FX, Hirigoyen V et al. Skin colonisation by Malassezia

species in neonates. A prospective study and relationship with neona
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63 Bergman JN, Eichenfield LF. Neonatal acne and cephalic pustulosis. Is
Malassezia the whole story? Arch Dermatol 2002;138:255–7.
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by Malassezia species: relationship with neonatal cephalic pustulosis.
65 Darabi K, Hostetler SG, Bechtel MA, Zirwas M.The role of Malassezia
in atopic dermatitis affecting the head and neck of adults. J Am Acad
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2007;157:1178–82.
68 Lange L, Alter N, Keller T et al. Sensitization to Malassezia in infants
and children with atopic dermatitis: prevalence and clinical character Fig. 46.30 White piedra hair showing nodules containing arthroconidia
istics. Allergy 2008;63:486–7. (30% KOH).
69 Marcon MJ, Powell DA. Human infections due to Malassezia spp.
Clin Microbiol Rev 1992;2:101–19.
70 Tragiannidis A, Bisping G, Koehler G, Groll AH. Minireview: nodules of white piedra are seen to be composed of
Malassezia infections in immunocompromised patients. Mycoses hyphae fragmented into rectangular or round arthrospores
2010;53:187–95.
and budding yeasts (Fig. 46.30). Infected hairs can be
71 Chang HJ, Miller H, Watkins N et al. An epidemic of Malassezia pachy-
dermatis in an intensive care nursery associated with colonization of cultured on SDA with chloramphenicol but without
health care workers’ pet dogs. N Engl J Med 1998;338:706–11. cycloheximide; yellowish or cream colonies are produced
72 Chryssanthou E, Broberger U, Petrini B. Malassezia pachydermatis fun within 2–3 days.
gaemia in a neonatal intensive care unit. Acta Paediatr 2001;90:323–7.
Black piedra
Less common superficial fungal This is caused by Piedraia hortae, a filamentous fungus.
infections The disease occurs in humid, wet tropical parts of the
world and is found on primates as well as humans. The
Piedra
natural habitat of this fungus is not known. Black piedra
This is an infection limited to hair shafts and is character
is most commonly seen in young adults [5].
ized by nodular lesions composed of fungal elements.
There are two varieties: white and black piedra.
Clinical features. Black piedra is usually found only on
scalp hair. Infection is characterized by asymptomatic
White piedra
fusiform black nodules firmly attached to the hair shaft;
Until recently, the yeast‐like fungus Trichosporon beigelii
the cortex of the hair shaft is not penetrated. The nodules

was thought to be the causative organism. This organism
are variable in size, often visible to the naked eye, and are
is found in soil, lake water and on plants, and is occa
rough and granular to the touch.
sionally seen as part of the normal flora of the human
INFECTIONS
skin and mouth. However, genetic analysis has shown

Diagnosis. This is readily confirmed by microscopy in
that this taxon actually represents a mixture of six distinct
30% KOH. Infected hairs show firmly adherent, black and
species [1,2]. Those associated with infection of genital or
hard, gritty nodules composed of regularly arranged,
scalp hairs are Tr. mucoides, Tr. inkin, Tr. asahii and Tr. ovoides.
thick‐walled cells and hyphae held together by a cement‐
The disease occurs in both temperate and tropical
like substance (Fig. 46.31). Dark‐brown to black velvety
regions. White piedra can affect males and females of all
colonies are produced on culture. The nodules could be
age groups, but infection of the genital hairs is thought to
confused with trichonodosis or trichorrhexis nodosa.
be more common in young men [3]. However, a survey
from equatorial Africa found that, of 449 females exam
ined, 18% of inguinal hairs were infected by white piedra; Treatment. For both types of piedra, cutting or shaving
in the youngest age group (15–20 years), white piedra off all affected hairs is the simplest form of treatment.
was seen in 32 of 221 patients (14.5%) [4]. Infection may recur and the topical application of an imi
dazole cream is recommended. One case of black piedra
Clinical features. The presence of irregular, soft, white successfully treated with oral terbinafine has been
nodules along the hair shafts is characteristic of white pie reported [6].
dra. Scalp hairs may be involved as well as beard and
axillary hairs but infection is mainly seen in genital hairs. Tinea nigra
The surrounding skin is unaffected. This is an infection of the palmar or plantar skin, charac
terized by brown to black macules with well‐defined bor
Differential diagnosis. The nodules produced on pubic ders. It is mainly seen in the tropics but can occur in
hair shafts may be confused with pediculosis or tricho Europe and the USA. It is more prevalent under the age of
bacteriosis axillaris. When examined microscopically, the 20 years. Females are three times more likely to be affected
(a) (b)
Fig. 46.31 (a) Black piedra hairs with dark nodules. (b) Hair in 30% KOH showing nodule consisting of regularly arranged, thick‐walled cells and hyphae.

INFECTIONS
Fig. 46.32 Tinea nigra. Fig. 46.33 Infected skin scales showing brown, septate, irregularly
branched hyphae (30% KOH).
than males, the reason for this being unknown; one case
has been reported in a 20‐month‐old girl [7]. Predisposing yellowish or light‐brown hyphae, which are septate and
factors associated with the condition are hyperhidrosis branched, in 30% KOH preparations (Fig. 46.33). Colonies
and presence in coastal areas or hypersaline environ of Hortaea werneckii grow on a standard medium within
ments, where the causative agent may be picked up from 5–8 days. They are initially black with a creamy appear
the natural habitat [8]. ance and later become filamentous.
The disease is caused by the halophilic, melanized,
yeast‐like fungus Hortaea werneckii (Horta) Nishimura Treatment. This consists of daily application of an imi
and Miyaji, which is found in the soil and on decompos dazole for 2–3 weeks to avoid recurrence.
ing plant material.
Neoscytalidium infections
Neoscytalidium dimidiatum, a plant pathogen found in
Clinical features. Tinea nigra usually presents as an tropical and subtropical parts of the world, and N. hyali-
asymptomatic dark patch of skin on the palm of one hand num, a colourless form of the same fungus with lower
(Fig. 46.32) or on the sole. The lesion is solitary, with an virulence [9,10], which has only been isolated from
irregular, sharply defined margin. There is no erythema humans, cause infections of the hand and foot indis
and only rarely is fine scaling present. tinguishable from the dry‐type infections caused by
T. rubrum; nail infection also occurs.
Differential diagnosis. The main differential diagnosis is In endemic areas, surveys have shown that N. dimidia-
an acral melanoma or naevus. Diagnosis of tinea nigra is tum is a not uncommon cause of foot infections in adults,
confirmed by the presence of hyaline, light‐coloured but only a few cases have been recorded in children.
Fig. 46.35 Neoscytalidium hyphae in skin (30% KOH, phase contrast).
is also fast growing with fairly high aerial mycelium,

which is white or buff cream in colour. Chains of hyaline
arthroconidia are observed on microscopy. Cultures
must be set up on SDA without cycloheximide, to which
these fungi are sensitive [16]. Infections must be distin
guished from dermatophyte lesions as they are unre
sponsive to the majority of antifungal drugs.
Fig. 46.34 Neoscytalidium infection of the palm.
Treatment. These nondermatophyte fungi do not respond

In Nigeria, of 64 cement workers with culture‐positive tinea to griseofulvin. Although they exhibit in vitro sensitivity
pedis, N. dimidiatum was the causative organism in 23% of to miconazole, clotrimazole, voriconazole and ampho
cases and N. hyalinum in 8%. Family members of workers tericin B, there is insufficient evidence at present to
were also examined, and N. dimidiatum was isolated from know whether or not these compounds will prove useful
toe web lesions in two children whose fathers had this clinically [17]. These infections are extremely refractory to
infection [11]. A case of N. dimidiatum infection in a child has treatment and no consistently effective therapy can be
also been reported from a survey of children attending a recommended.
paediatric dermatology clinic in Sri Lanka [12]. Outside
endemic areas, the majority of cases recorded have been in Acknowledgements

immigrants. However, a few cases have been reported in The authors acknowledge use of material from the
patients who have not visited endemic areas [13,14]. excellent chapter in the 2nd edition entitled ‘Superficial
INFECTIONS
fungal infections’ written by Yvonne M. Clayton and

Clinical features. The infection presents with scaling of Mary K. Moore.
the soles and palms (Fig. 46.34) and cracking between the
toes. Nail dystrophy is common and, in the fingernails, References
onycholysis without significant thickening is present; in 1 Gueho E, Improvisi L, De Hoog GS et al. Trichosporon on humans: a
practical account. Mycoses 1994;37:3–10.
addition, nailfold swelling may occur [15]. N. dimidiatum 2 Chagas‐Neto TC, Chaves GM, Colombo AL. Update on the genus
and N. hyalinum produce similar clinical features. Lesions Trichosporon. Mycopathologia 2008;166:121–32.
may be asymptomatic. 3 Kalter DC, Tschen JA, Cernock PL et al. Genital white piedra: epidemi
ology, microbiology and therapy. J Am Acad Dermatol 1986;14:982–93.
4 Therizol‐Ferly M, Kombila M, Gomez de Diaz M et al. White piedra
Diagnosis by morphology. Microscopic examination of and Trichosporon species in equatorial Africa. I. History and clinical
infected material in 30% KOH shows hyphae resembling aspects: an analysis of 449 superficial inguinal specimens. Mycoses
those of a dermatophyte but with more variation in 1994;37:249–53.
5 Coimbra CEA, Santos RV. Black piedra among the Zoro indians from
width along their length and a double‐contoured appear Amazonia (Brazil). Mycopathologia 1989;107:57–60.
ance due to retraction of cytoplasm from the hyphae 6 Gip L. Terbinafine for black piedra. Lancet 1993;341:1164.
cell wall (Fig. 46.35). Cultures of N. dimidiatum are of 7 Palmer SR, Bass JW, Mandojana R et al. Tinea nigra palmaris and
two forms. They may be fast growing, producing a high, plantaris: a black fungus producing black spots on the palms and
soles. Pediatr Infect Dis 1989;8:49–50.
cotton‐like aerial mycelium after 3–4 days at 26 °C, ini 8 Bonifaz A, Badali H, de Hoog GS et al. Tinea nigra by Hortaea wer-
tially white but darkening to grey or black as the colony neckii, a report of 22 cases from Mexico. Stud Mycol 2008;61:77–82.
ages. Alternatively, the colonies may be slower growing 9 Machouart M, Menir P, Helenon R et al. Scytalidium and scytalidiosis:
what’s new in 2012? J Mycol Med 2013;23:40–6.
and velvety, without the development of aerial myce
10 Ruíz‐Cendoya M, Madrid H, Pastor FJ et al. Development of murine
lium. Both are easily identified by the chains of brown models of disseminated infection by Neoscytalidium dimidiatum.
one‐ or two‐celled arthroconidia they produce. N. hyalinum Med Mycol 2010;48:681–6.
11 Oyeka CA, Gugnani HC. Skin infections due to Hendersonula toru- 15 Hay RJ, Moore MK. Clinical features of superficial fungal infections
loidea, Scytalidium hyalinum, Fusarium solani and dermatophytes in caused by Hendersonula toruloidea and Scytalidium hyalinum. Br J
cement factory workers. J Mycol Med 1992;2:197–201. Dermatol 1984;110:677–83.
12 Perera J, Perera C. Fungal skin infections in a paediatric dermatology 16 Midgley G, Moore MK, Cook JC et al. Mycology of nail disorders.
clinic. Ceyl Med J 1993;38:75–7. J Am Acad Dermatol 1994;31:S68–74.
13 Elewski BE, Greer DL. Hendersonula toruloidea and Scytalidium hyali- 17 James JE, Santhanam J, Lee MC et al. In vitro antifungal susceptibility
num. Arch Dermatol 1991;172:1041–4. of Neoscytalidium dimidiatum clinical isolates from Malaysia.
14 Frankel DH, Rippon JW. Hendersonula toruloidea infection in man. Mycopathologia 2017;182:305–13.
Mycopathologia 1989;105:175–86.

INFECTIONS
560
CHA PTER 4 7
Deep Fungal Infections

María Teresa García‐Romero
Department of Dermatology, National Institute for Pediatrics, Mexico City, Mexico
Introduction, 560 Systemic mycoses, 564

Subcutaneous mycoses, 561 Opportunistic mycoses, 569
Abstract infections. The diagnosis of deep fungal infections should be made

promptly in order to decrease morbidity and mortality. As globali-
Deep fungal infections are uncommon in children and are divided zation occurs and fungal infections, previously restricted to certain
into subcutaneous and systemic mycoses. Subcutaneous mycoses locations, are found outside those areas, and acquired immune
mainly occur in tropical climates and the causal fungi are usually deficiencies have become more common due to infections or ther-
acquired from the environment. Systemic mycoses are divided into apies related to oncological and autoimmune diseases, all physi-
those that occur in specific endemic areas and those that primar- cians should be acquainted with the presentation of deep fungal
ily occur in immunocompromised patients, called opportunistic infections in children.
Key points which occur mainly in Latin America; their treatment is

completely different.
• Sporotrichosis is a subcutaneous mycosis that occurs mainly • Opportunistic infections caused by Mucorales are increasing
in tropical climates and in children presents frequently as due to more severe immunosuppression associated with
one verrucous plaque on the face or acrally as nodules with chemotherapy regimens in children, and should be differentiated
lymphatic spread. from aspergillosis because their treatment is based on
• Mycetomas can be caused by fungi (eumycetomas), more intravenous amphotericin B and surgical debridement instead of
common in Africa and Asia, or actinomycetes (actinomycetomas) voriconazole.
Introduction from where the fungus can disseminate by haematoge

Fungal infections are common in humans, and they nous and, eventually, lymphatic involvement, and reach
include the frequent superficial infections as well as the the skin and other organs. Opportunistic mycoses are
INFECTIONS
rarer, more severe and even potentially fatal deep and seen in all climates, as their main determinant is an under
systemic infections [1,2]. Deep fungal infections are lying defect in the immune response that predisposes to
uncommon and are divided into subcutaneous and sys infection. Their causal agents are considered to have low
temic mycoses. pathogenicity, but can produce disseminated and fatal
The subcutaneous mycoses mainly occur in tropical infections if not treated early [1,3]. The causal fungi exist
climates and are usually confined to the skin and subcuta as saprophytes in the environment in the form of free
neous tissue but may extend deeper, even to bone. The spores and filaments and can be inoculated through
causal fungi are usually from sources in the environment occupational exposure or during leisure activities, which
such as soil or plants, and they rarely culminate in sys makes human‐to‐human transmission exceptional. The
temic infection. severity of the infection is determined by the extent of the
Systemic mycoses are generally divided into those that exposure to the organism and by the immune status of
occur in specific endemic areas (endemic or respiratory the patient [3,4].
mycoses) that can infect anyone irrespective of their Globalization has made international travel much
immune status, and those that only occur in the immuno easier and more accessible, and so fungal infections

compromised patient, called opportunistic infections restricted to certain geographical regions can be found in
[1–3]. The endemic or respiratory mycoses are caused by travellers returning from those areas [2].
the inoculation of fungal particles, usually through the This chapter will cover the spectrum of deep fungal
respiratory tract but occasionally by direct inoculation, infections as well as two nonfungal diseases that were
Chapter 47 Deep Fungal Infections 561
formerly considered mycoses and share clinical similari form is fixed cutaneous (30% of cases) [7] which presents
ties with them: nocardiosis and actinomycosis. as a plaque, nodular, verrucous or ulcerated lesion [13,14].
Other less frequent presentations include dacryocystitis
[15], earlobe infiltration and deformity [16], nasal lesions
Subcutaneous mycoses [17], palpebral lesions [18] and osteolytic lesions [19].
Sporotrichosis The differential diagnoses include leishmaniasis, cuta
neous tuberculosis and other atypical mycobacteriosis,
Introduction. Sporotrichosis is a subacute or chronic cutaneous nocardiosis, tularaemia, chromoblastomycosis
infection caused by the dimorphic fungus Sporothrix and mycetoma.
schenckii complex, found in vegetation and organic matter
in temperate climates. It is the most common subcutane Laboratory and histological findings. Direct examination
ous mycosis in Latin America. Most cases involve skin in this condition is not useful because fungal structures
and subcutaneous tissues, but disseminated sporotricho are not usually observed with routine tests, but periodic
sis can occur in immunosuppressed patients. acid–Schiff (PAS) stain or fluorescent techniques can be
performed. The definitive diagnosis is made by fungal
Epidemiology and pathogenesis. The disease is common culture in Sabouraud dextrose agar (SDA). In cultures,
in children and young adults [5], particularly in some colonies are creamy white initially and then become
geographical locations such as Peru where 60% of cases brown‐black and membranous with radiating growth; the
occur in patients younger than 14 years old, with an inci characteristic microscopic features are sympodial conid
dence of 1 per 1000 [6]. An equal sex distribution occurs. iae resembling daisy flowers. Histopathological findings
Many outbreaks have been described and the fungus has include hyperplastic epidermis and suppurative granulo
been isolated in and transmitted by fauna, especially mas including cigar‐shaped yeasts and asteroid bodies,
rodents and cats [5–11]. which are fungal elements, surrounded by eosinophilic
Traditionally sporotrichosis was considered an occupa material resulting from antigen–antibody reaction
tional disease, particularly of males, with the highest proteins [5,13]. Other techniques have been developed in
incidence in gardeners, florists, labourers and farmers association with outbreaks, such as enzyme‐linked immu
who acquire the fungus through penetration of the skin; nosorbent assay (ELISA), with excellent accuracy in
however, in a high percentage of patients there is no
paediatric patients [20].
history of trauma [7].
Treatment and prevention. Therapeutic options include
Clinical features and differential diagnosis. There are local hyperthermia, saturated solution of potassium
four clinical forms: lymphocutaneous, fixed cutaneous, iodide (SSKI), azoles (ketoconazole, itraconazole and flu
multifocal or disseminated, and extracutaneous (affecting conazole) and other antifungals such as terbinafine and
lungs and joints) which is rare and usually acquired by amphotericin B (for systemic disease). SSKI is the first‐

inhalation of the fungus. Overall, the most common form line treatment in many developing countries because of
is lymphocutaneous (70–75%) [12], characterized clini its effectiveness and low cost; the dose for children is
cally by an indurated papular lesion that develops about 1.5–3 g/day administered continuously until the lesions
INFECTIONS
1–4 weeks after inoculation. It subsequently turns into a are cleared and then continued for 2–4 weeks more [5,21–
nodule with or without ulceration, and further nodules 23]. Itraconazole is the azole of choice: the paediatric dose
appear following a lymphatic spreading pattern that may is 5 mg/kg per day for 3–6 months [13]. Terbinafine has
ulcerate or suppurate (Fig. 47.1). Regional lymph nodes also been shown to be effective. Other therapeutic alter
are involved and may ulcerate. The most commonly natives include co‐trimoxazole and griseofulvin. The cure
involved areas are the upper and lower extremities and rate of sporotrichosis is high [5,7,14].
the face. In paediatric patients facial lesions are frequent
(in up to 90% of cases) [5] and the most common clinical Chromoblastomycosis
Introduction. Chromoblastomycosis is an important

s ubcutaneous mycosis that occurs worldwide, although it
is more common in the tropics. It is not fatal, but tends to
be very chronic and difficult to treat with potential seri
ous complications such as lymphatic damage, scarring
and neoplastic transformation. It is caused by traumatic
implantation into the skin of dematiaceous fungi of the
genera Fonsecaea, Cladophialophora and Phialophora that are
present in soil, decaying vegetation and wood.
Epidemiology and pathogenesis. Chromoblastomycosis is

caused by fungi of the genera Fonsecaea, Cladophialophora and
Phialophora such as Fonsecaea pedrosoi, F. compacta, F. nubica,
Fig. 47.1 Lymphatic spread of sporotrichosis in a child. F. monophora, Phialophora verrucosa, Cladophialophora carrionii
and Exophiala jeanselmei – all saprophytes in soil and plants. examination with 10% potassium hydroxide of scrapings
It is distributed worldwide, especially in tropical and sub taken from the lesion, the pathognomonic sclerotic or
tropical regions of Latin America, the Caribbean, Africa and fumagoid cells (Medlar bodies, copper pennies) can be
Asia. F. pedrosoi is the most common agent found in tropical found, which are small, oval, dark, thick‐walled cells
forests with high rainfall such as the Amazon and elsewhere with septation or binary fission. Cultures can be grown
in Latin America. C. carrionii is the most important agent in in SDA and the microscopic characteristics depend on
dry and desert regions, such as Australia and South Africa. the species; however, since these are slow‐growing fungi,
The disease occurs frequently in young men, especially in the culture can be inconclusive. Polymerase chain reac
rural areas. Some cases and series of affected children have tion (PCR) assays have been developed for the identifica
been described (86% are males), with a mean age of 11 years tion of Fonsecaea species and C. carrionii. Histopathological
[24]. It is a disease with a prolonged evolution time (10 years findings are marked epitheliomatous hyperplasia, gran
or more) and therefore many adult patients could have ulomatous infiltrates with multinucleate giant cells and
acquired it during childhood. More than half of the children the presence of sclerotic bodies intermixed with the infil
reported with chromoblastomycosis had a close relative trate [14,24–27].
affected, which suggests a genetic susceptibility to develop
the disease [24]. In paediatric cases the most frequent causa Treatment and prevention. Treatment is difficult as the
tive agent has been found to be C. carrionii [24,25]. disease has variable cure rates and is recalcitrant,
although paediatric cases have higher cure rates (86%)
Clinical features and differential diagnosis. Lesions of [24]. Management depends on the aetiological agent,
chromoblastomycosis start as erythematous, verrucous size and extent of lesions, and consists of long courses
papules and plaques that can progress and eventually, (6 months) of antifungal drugs combined with physical
after many years, ulcerate or become cauliflower‐like; treatments such as thermotherapy, surgery, electrodessi
necrotic plaques have been described in infancy. The most cation or liquid nitrogen [26,27]. Itraconazole and terbi
frequent location in children is the upper limbs (whereas nafine followed by surgery have shown good efficacy
in adults it is the lower limbs) [24], followed by the back for localized lesions [26]; other options are oral 5‐fluoro
and lower limbs [24]. As the lesion increases in size or cytosine, 5‐fluorouracil (5FU) [24], SSKI, intralesional
heals, the central area becomes scar‐like and atrophic and amphotericin B, thiabendazole [14], vitamin D [26] and
can be severely disfiguring [25–28] (Fig. 47.2) Skin lesions ajoene in some areas of South America [24,26]. Local
may be mildly pruritic or asymptomatic unless complica heat therapy using pocket warmers for 6 months has
tions develop, including ulceration, secondary infection also been found to be effective, because temperatures
and lymphoedema. Rarely, chronic lesions have been over 40–42 °C kill the causative fungi [26]. The response
complicated by malignant transformation into squamous also depends on the fungal species causing the condition:
cell carcinoma. Chromoblastomycosis stays confined to C. carrionii and P. verrucosa respond better to a ntifungals
the skin and rarely invades underlying muscle or bone, than F. pedrosoi [25,26].
except in the context of immunosuppression [27].

The differential diagnoses are tuberculosis verrucosa Mycetoma
cutis, sporotrichosis, psoriasis and squamous cell carci Mycetomas are unique chronic granulomatous subcuta
INFECTIONS
noma, which can develop in chronic ulcerated lesions [26]. neous infections caused by actinomycetes (actinomyceto
mas) and by fungi (eumycetomas). Differentiating
Laboratory and histological findings. Microbiological between these two categories is essential for treatment
confirmation of the diagnosis is key to differentiate and prognosis. They affect the skin but can also compro
chromoblastomycosis from other conditions. On direct mise fascia, tendons, muscles and bones, giving rise to
significant morbidity and disability. Mycetoma is
amongst the most common of the subcutaneous mycoses
with a worldwide distribution, predominantly in tropical
and subtropical countries (the so‐called mycetoma belt)
where this poses a significant burden on global health
[29,30]. Actinomycetomas are more common in Mexico,
Central and South America, and eumycetomas in Africa
and India [31,32].
Eumycetoma
Introduction.
Eumycetoma is, along with sporotrichosis, the most com
mon subcutaneous mycosis worldwide. It is not frequent
in children, and there is a possible role for hormones in its
development that could explain this, as could the fact that
Fig. 47.2 Verrucous scar‐like plaque typical of chromoblastomycosis. it is a very slowly progressing condition that might go
Source: Courtesy of Prof. Roberto Arenas MD, Mexico City. unnoticed until adulthood [31].
the new posaconazole and voriconazole are effective, but

Epidemiology and pathogenesis. At least 30 species of
should be given for 12–24 months [14], a costly option in
fungi are associated with eumycetomas, and they are
low‐resource settings. Terbinafine for 24–48 weeks has
classified according to the type of grains found in

been effective in some reports [31,36]. The combination of
secretions: black or white‐grey grains. More than 90% of
itraconazole and terbinafine for 6–12 weeks before surgi
eumycetomas worldwide are caused by Madurella myce-
cal removal and continued until remission of the disease
tomatis, M. grisea, Pseudoallescheria boydii and Leptosphaeria
is very effective and easier for compliance [31,32,34].
senegalensis. The distribution depends on the geographical
Given the high rates of drug resistance, routine drug
location: Acremonium spp. and M. grisea are common in
susceptibility testing should be used when available [32].
South America, and M. mycetomatis has an extensive distri
bution in India and Africa. Soil is the natural reservoir of
Actinomycetoma
most agents and the disease begins with the traumatic
introduction of the fungus through the skin. The evolution
Introduction. Actinomycetoma is a chronic subcutane
of the disease is very slow and most patients seek medical
ous infection caused by aerobic branching actinomycetes.
help after many years [31]. There is a male predominance,
It is endemic in tropical climates with the highest inci
and the affected patients are usually young adults,
dence occurring in Asia, Africa, Mexico, Central and
although in some regions of the world such as Sudan, a
South America.
significant number of cases in children are described
[31,33] with an incidence between 3% and 4.5% [34]. In the
Epidemiology and pathogenesis. Worldwide, 60% of
largest series reported, most children were male (73.5%),
mycetomas are caused by actinomycetes, but in Mexico
between 10 and 14 years of age, and students (79.6%). The
and Central and South America 90% of mycetomas are
average duration of the disease was 2 years [34].
actinomycetomas. The most frequent causative agents are
Nocardia brasiliensis, N. asteroides, Actinomadura madurae,
Clinical features and differential diagnosis. Mycetomas
A. pelletieri and Streptomyces somaliensis [39].
present as tumour‐like lesions, gradually developing
Actinomycetomas are uncommon in children (4.5–9.8%
nodules, abscesses and sinus tracts that drain a mucopu
of all cases) [40,41] and only a few cases and series are
rulent discharge in which fungal colonies in the form of
reported in the literature. The role of hormones in disease
grains are found. The grains can be observed with the
susceptibility may explain the fewer cases of mycetoma in
naked eye in some cases or microscopically, and their
children. The median age in a paediatric series was
morphology and colour contribute to their identification
11.2 years, the mean duration of disease was 1 year, and
[31]. The most frequent location is the foot, followed by
there was male predominance (80%) and a frequent
the hands, legs and back [34]; mycetomas in the oral
history of farm work [40].
mucosa, face and scalp have been reported [33,35–37].
Mycetomas can progress to osteomyelitis and require
Clinical features and differential diagnosis. Actinomy
amputation in severe cases [38].

cetomas are similar to eumycetomas but the clinical
The differential diagnosis includes foreign body granu
picture is more inflammatory. There is induration and

lomas, sporotrichosis, chromomycosis, leishmaniasis or
increased volume, causing deformity of the affected area
cutaneous tuberculosis. In children the diagnosis of soft
INFECTIONS
with the presence of nodules, scar tissue, abscesses, fistulae
tissue neoplasia should be ruled out [33].
and purulent exudate that contains the granules (Fig. 47.3).
The most commonly affected sites in all ages are the legs,
Laboratory and histological findings. Diagnosis is con followed by the back and chest [40]. In children there is
firmed by direct microscopy, histopathology and cul often a milder presentation, even in longstanding cases,
ture. Direct microscopic observation of the grains can
contribute to identification of the causative fungus.
Culture of the secretion and grains in SDA will yield the
causative agent’s colony and PCR can also be used for
identification if culture fails. Histologically, pseudoepi
theliomatous hyperplasia with abundant granulation
tissue and granulomatous inflammation are found, with
grains in the centre of the abscesses. Disease extent can
be assessed by radiology, ultrasonography or even
helical computed tomography (CT) [14,31,32].
Treatment and prevention. Eumycetomas usually

respond less well to drug treatment and therefore
combined medical and surgical treatment is the standard
therapy, achieving better cure rates in shorter periods.
Drug treatment is given before surgery to decrease lesion
size and continued afterwards to ensure complete remis Fig. 47.3 Actinomycetoma in a child. Note the marked inflammation and
sion [32]. Azoles such as ketoconazole, itraconazole and volume increase with tumefaction and fistulization.
with one or two draining sinuses, little or no swelling and cutaneous infection occurs after traumatic or accidental
seldom bone involvement (minimycetoma) [40,42,43]. inoculation, and disseminated disease is seen in the
The differential diagnosis includes eumycetoma, spor immunocompromised [14].
otrichosis, tuberculosis, osteomyelitis, botryomycosis,
phaeohyphomycosis and neoplasias of the bone and soft Epidemiology and pathogenesis. Coccidioidomycosis
tissues [39]. occurs predominantly in the western hemisphere, mainly
in the southern area of the USA and northern states of
Laboratory and histological findings. Direct microscopic Mexico. It is also endemic in some regions of Central and
examination with 10% KOH or saline reveals the size and South America such as Guatemala, Venezuela, Colombia
morphology of the grains, which help to identify the and Argentina.
causative agent. Isolation of the actinomycete is achieved The causative agent is Coccidioides, either immitis or
by culture of the discharge using Sabouraud or blood posadasii, a dimorphic fungus characterized by a sapro
agar. Colonies grow slowly and their characteristics vary phytic or infecting phase in the form of arthrospores and
depending on the agent. On histology, suppurative a parasitic phase with spherules containing endospores in
granulomatous inflammation is found and within this their interior. It is found in the soil and vegetation of semi‐
infiltrate the grains of the specific agent are present arid areas and introduction to the body occurs through
(Fig. 47.4) [4]. the respiratory tract, although most infected individuals
Imaging studies are useful in delineating the extent of are asymptomatic [45,46]. In endemic areas, both genders
the lesions in bone and neighbouring tissues [39]. and all ages are equally affected [47] but two peaks have
been described: in children under 5, and in adults over
Treatment and prevention. Treatment should be only 45 years of age [48]. There is an ethnic predisposition to
medical, as surgical interventions may disseminate the severe infection, with higher rates of dissemination in the
condition. There are several regimens available: the most Philippines and in African Americans (10–175 times
effective includes co‐trimoxazole alone [39] or in combi higher), although the reason is not completely under
nation with other antibiotics such as dapsone alone or stood [49]. In large case series of coccidioidomycosis in
combined with rifampicin for 6 months to 2 years [42], children, 60% were male with a median age at diagnosis
depending on the clinical response [40]. Other regimens of 5 years, ranging from 6 months to 17 years of age
include amoxicillin/clavulanate [40] or the combination [50,51]. There has been an increase in incidence in the last
of meropenem or imipenem with or without amikacin for decade with rates as high as 15 per 100 000 [52], as well as
3 weeks and repeated after a 6‐month interval, which has an increase in hospitalization rates due to the disease [53],
shown very good results [32,44]. with health‐related costs becoming a public health chal
lenge [48,49,54–56]. Also, with intensive treatments for
patients with haematological malignancies becoming
Systemic mycoses
more common, disseminated coccidioidomycosis is being
Coccidioidomycosis
seen frequently in these patients who live in endemic

areas, warranting special attention to diagnose, effec
Introduction. Coccidioidomycosis, also known as San tively treat and appropriately adjust chemotherapy plans
INFECTIONS
Joaquin Valley fever, is an endemic mycosis caused by to minimize immunosuppression [57].

two distinct species, Coccidioides immitis and C. posadasii,
both saprophytes of soil found in desert areas. The most Clinical features and differential diagnosis. In children,
frequent presentation is pulmonary; however, primary the most common clinical presentation is pneumonitis
and mediastinitis [50,51]. Infected individuals are asymp
tomatic in 60–75% of cases, the remaining presenting a
nonspecific upper respiratory infection 1–3 weeks after
inoculation [45]. Only 1–5% develop a chronic pulmonary
infection and/or disseminated infection of other organs,
especially – but not exclusively – in the context of an
altered immune system [46]. Symptomatic patients pre
sent with fever, chills, asthenia, anorexia, productive
cough and occasionally chest pain, all of which disappear
in about 8 weeks. In almost 5% of cases, a chronic infec
tion develops with pulmonary infiltrates, pleural dis
charge, cavernous lesions and coccidioidomas (fungus
balls). When the disease disseminates it affects lymph
nodes, skin, bones, joints, heart, liver, spleen, kidneys, the
central nervous system and occasionally the retina [49,58].
Symptoms vary depending on the affected site. Cutaneous
findings include abscesses, fistulae, verrucous lesions,
Fig. 47.4 Histology of an actinomycetoma showing a grain characteristic ulcers, and keloid scars [14]. Central nervous system
of Nocardia brasiliensis surrounded by a mixed inflammatory infiltrate. involvement causes headache, confusion, hydrocephaly
and diverse neurological syndromes [14]. Musculoskeletal immunosuppression, should receive amphotericin B
infection can occur in 10–50% of children with extrapul [69] or posaconazole, which has shown efficacy in
monary infection [59], manifesting as painful osseous patients with chronic refractory meningitis [70]. The
masses usually without preceding pulmonary infection, combination of voriconazole and caspofungin salvage
the most common location being the foot and the knee therapy for refractory paediatric coccidioidomycosis
[45,46,60]. There are reports of intraocular infection simu has shown excellent results [71]. For musculoskeletal
lating neoplasms [61,62], and abdominal and pelvic and sometimes thoracic disease, treatment should be a
masses simulating appendicitis and tumours [63]. combination of medical and surgical approaches
The differential diagnosis includes lung cancer, viral [46,59,72]. The duration of therapy varies on the site
infections, mycoplasma, tuberculosis, parasitic abscesses and severity of disease. Duration of 3–6 months is
[64], North American blastomycosis, histoplasmosis, asper preferred for primary pulmonary disease, with follow‐up
gillosis, sporotrichosis and cryptococcosis. Musculoskeletal for at least 1 year after diagnosis. In contrast, chronic
infection can be confused with osteomyelitis and sarcomas, pulmonary disease warrants lifelong therapy to pre
and intra‐abdominal infection can be confused with serve lung function and avoid damage [49].
tumours, abscesses and appendicitis. Development of a vaccine against Coccidioides spp. is
under way, with cost‐effectiveness analysis showing a
Laboratory and histological findings. The diagnosis is substantial public health benefit [53].
confirmed by the identification of the parasitic or sapro
phytic form of the fungus. The saprophytic form are 10‐ to Histoplasmosis
100‐µm sized spherules contained by a refractile double
wall and can be seen by direct KOH examination or by Introduction. Histoplasmosis (also known as American
PAS stain of exudate, pus or cerebrospinal fluid. Special histoplasmosis, Darling disease or Ohio Valley fever) is a
stains such as PAS, Gridley and Gomori facilitate the common infection produced by the dimorphic fungus
identification of the fungus, especially when the spher Histoplasma capsulatum var. capsulatum. It is endemic to
ules are scarce. Culture of any specimen such as sputum certain zones and affects primarily the lungs, but skin
or tissue requires Sabouraud medium; it should be manifestations can occur as the result of haematogenous
processed in a level III security bell because accidental spread or direct inoculation. Another type of histoplas
infection may occur in laboratory personnel. C. immitis mosis in humans is caused by Histoplasma capsulatum var.
grows in 7–14 days as a white, downy colony but it can duboisii, also called African histoplasmosis because it is
present variations in texture and colour [14,49]. endemic to that continent. In this chapter we will refer
Histological findings include granulomas with a poly only to American histoplasmosis.
morph nuclear infiltrate, plasma cells, macrophages,
giant cells, areas of necrosis and the presence of spherules Epidemiology and pathogenesis. Histoplasmosis is the
with a double refractive outer wall that vary from 10 to most common endemic mycosis causing human infection

100 µm in diameter [65]. [73]. Histoplasma capsulatum is a dimorphic saprophytic
Antigens such as coccidioidin (obtained from the myce soil fungus with a worldwide distribution. The endemic
lial phase) and spherulin (from the spherular phase) can areas are the Mississippi and Ohio river valleys of the
INFECTIONS
be used to evaluate previous exposure to the disease and USA, the rural regions of tropical Central and South
response to treatment. Coccidioidin is more widely America, and some areas in the eastern USA, southern
available and commonly used. Serological tests can detect Europe, Africa and South‐East Asia [73–77]. In the USA
antibodies in the first phase of the infection; the most population histoplasmin skin testing is positive in 80%
reliable is the immunodiffusion test which can be used [14]. The spores are found in soil contaminated with
both in serum and cerebrospinal fluid. Complement‐ chicken, pigeon or bat feathers or droppings (guano).
fixation serological tests determine the level of IgG Activities associated with this infection include: mining;
antibodies against the antigens of C. immitis [14,49]. landscaping; cleaning debris from attics, bridges or barns;
Imaging studies such as chest radiograph, CT scans tearing down structures; and hobbies such as speleology
and magnetic resonance imaging (MRI) help visualize the and caving [73,75,76,78].
extent of the fungal infection. Histoplasmosis affects all races and ages, with infants
and children commonly having the acute pulmonary or
Treatment and prevention. For pulmonary disease, disseminated form [77–79]. Histoplasmosis is usually
a ntifungal therapy is frequently not required, but pro acquired by inhalation, but there have been rare cases of
longed courses of antifungals are generally needed in transmission from fomites, direct inoculation, solid organ
disseminated disease. The first line of therapy is with transplant, sexual contact and wood‐burning [77,80,81].
triazole antifungals: either fluconazole or itraconazole H. capsulatum is an intracellular pathogen with the abil
has been effective for various forms of coccidioidomy ity to remain viable in tissues for years in a latent state;
cosis, including meningitis [66]. Clinical evidence sug thus, if cell‐mediated immunity wanes, the organism can
gests that itraconazole is equivalent or superior to reactivate and cause disease [73,81]. In patients with
fluconazole in treating osteoarticular infections in rates human immunodeficiency virus (HIV)‐acquired immune
of cure and recurrence [67,68]. Patients with dissemi deficiency syndrome (AIDS) the frequency of infection is
nated or refractory disease, especially in the context of higher than in the immunocompetent host, with a greater
risk for life‐threatening, disseminated infections, and

histoplasmosis is considered a marker of the disease

[79,82]. In paediatric patients who received solid organ or
haematopoietic cell transplants, the 12‐month cumulative
incidence rate for histoplasmosis is 0.102%, and the risk of
infection continues for years after transplant [83].
Children with primary or drug‐induced immunodefi
ciency are also at a higher risk of acquiring severe forms
of the disease [84,85].
Clinical features and differential diagnosis. Histoplasmosis

is a systemic infection that can compromise multiple tis
sues; however, in the majority of cases the lungs and reticu
loendothelial system are affected. Illness may occur within
a few weeks following heavy exposure, or months to years
Fig. 47.5 Disseminated histoplasmosis in an immunocompromised teenager.
later following low‐inoculum exposure or even due to
reactivation of old infection during immunosuppression.
Up to 95% of affected individuals have asymptomatic dis characterized by a chancre‐like lesion and regional lym
ease that is discovered by radiography of the lungs (hilar phadenopathy that resolves in several months with no
calcification) or positive skin tests to histoplasmin but 5% treatment. Widespread primary cutaneous disease has
can develop systemic illness, particularly immunocompro been described but is exceptional.
mised patients [75,85]. Histoplasmosis produces four major The differential diagnosis of acute pulmonary histo
groups of clinical manifestations: (i) acute pulmonary plasmosis is acute pulmonary blastomycosis and atypical
form; (ii) chronic pulmonary form; (iii) disseminated forms; community‐acquired pneumonias. The differential
and (iv) traumatic primary cutaneous form. The most com diagnosis of chronic pulmonary histoplasmosis includes
mon forms of histoplasmosis in children are severe acute tuberculosis, nontuberculous mycobacterial infections,
pulmonary histoplasmosis, mediastinal adenitis and other endemic fungal infections and sarcoidosis.
progressive disseminated histoplasmosis [77,78].
Acute pulmonary histoplasmosis usually follows a Laboratory and histological findings. The fungus can be
heavy inoculum exposure. It is the most common initial isolated from a variety of samples such as saliva, cerebro
form and manifests as a flu‐like febrile disorder, with spinal fluid, blood, bone marrow, pus and biopsies. In
cough, malaise, chest pain, low‐grade fever, upper res direct examination of these smears stained with Wright or
piratory symptoms and pulmonary infiltration lasting for Giemsa stains, intracellular yeasts of 3–4 µm in size can be
several weeks or months. In approximately 5% of patients seen. Culture of blood, sputum or skin material in
it is accompanied by rheumatological and/or dermato Sabouraud or blood agar grows smooth cotton‐like white
logical manifestations, such as erythema nodosum and or brownish colonies in up to 4–6 weeks. Microscopic
erythema multiforme, and arthritis and arthralgias. examination of the colonies is necessary for positive iden
INFECTIONS
Chronic pulmonary histoplasmosis resembles tubercu tification and shows abundant tuberculate macroconidia
losis clinically and radiographically and can also present and microconidia [14]. PCR on paraffin‐embedded tissue
with erythema nodosum and erythema multiforme. also allows the identification of the fungus.
Disseminated histoplasmosis is rare and affects mostly Biopsy of skin stained with Gomori’s methenamine sil
young children and older individuals, as well as immu ver or PAS stains demonstrates a granulomatous reaction
nocompromised hosts. It has become more frequent with with epithelioid and giant cells, macrophages and histio
the AIDS epidemic. Fulminant disease is seen during cytes, with or without caseous necrosis. Small (1–3 µm),
childhood, especially in the first year of life. This form of round budding encapsulated yeasts are found within
histoplasmosis presents with high fever, anaemia, hepat macrophages and grouped in extracellular masses [65].
osplenomegaly, lymphadenomegaly, diarrhoea and Serological tests (complement fixation and immunodif
weight loss. Mucosal and cutaneous lesions are due to fusion) play an important role in the diagnosis of acute
haematogenous spread of the fungus and can be papules, pulmonary, chronic cavitary pulmonary and chronic
nodules, molluscoid lesions, indurated granulomatous or progressive disseminated histoplasmosis. However, in

vegetating plaques; they frequently become ulcerated immunosuppressed patients, serology is rarely useful.
and are usually multiple (Fig. 47.5). Both assays have a sensitivity of about 80%. A false‐
Other less common forms of infection in children are negative test is seen during the first month following
cerebral [86], meningeal [87], granulomatous pleuritis acute infection, and a false‐positive test may occur in
[88] and endocarditis [89]. patients with other fungal infections and granulomatous
Primary cutaneous histoplasmosis is extremely rare processes. The histoplasmin skin test demonstrates the
and seen especially in laboratory workers. It can also be immune response of the host to the fungus, but is of little
the result of accidental inoculation of the fungus into value in endemic areas [77,90].
the skin of a patient with immunodeficiency. In the Measuring the cell‐wall polysaccharide antigen of
immunocompetent host, this form of histoplasmosis is H. capsulatum is a sensitive diagnostic tool for patients
who have disseminated infection, and urine is preferred infected by group 2 present with isolated pulmonary
for testing because of enhanced sensitivity. Antigen involvement and constitutional symptoms, with similar
detection is also helpful in monitoring efficacy of therapy findings replicated in a paediatric cohort [95,96].
and detecting relapses [73,90]. Examination of faecal Blastomycosis affects mainly adult men in rural areas,
mucus to detect yeast cells of the fungus has shown to be and there have been outbreaks associated with dogs,
quick and cost‐effective for diagnosing disseminated which can also be infected by the fungus. Certain ethnici
disease in children [91]. ties seem to have a greater incidence of the disease, such
as African Americans, Canadian aboriginals and Asian
Treatment and prevention. Mild to moderate acute Hmong [93,94,97]. Patients of all ages are susceptible but
ulmonary histoplasmosis in children does not usually
p children are rarely infected by this agent: only 3–11% of
warrant treatment, but itraconazole for 6–12 weeks is reported cases occur in patients under 20 years of age
recommended for patients who continue having symp [93,95], and the youngest reported surviving patient was
toms for 1 month after the infection. For moderate or 4 months of age [98].
severe pulmonary infection amphotericin B deoxycholate Rare human‐to‐human transmission has been observed
1 mg/kg daily is well tolerated, or itraconazole 5–10 mg/kg in female sexual partners of men with blastomycosis
daily in two divided doses. For progressive disseminated disseminated to the prostate gland, in post mortem trans
infection treatment with amphotericin B deoxycholate mission at autopsy and perinatal infection of newborns
1 mg/kg daily for 4–6 weeks is recommended, or the [98]. In contrast to other fungal infections usually seen in
same dose for 2–4 weeks followed by itraconazole immunocompromised patients, B. dermatitidis is a true
5–10 mg/kg daily in two divided doses to complete pathogen that often infects immunocompetent individu
3 months of therapy. Longer therapy may be needed for als [65,95].
patients with severe disease, immunosuppression or pri
mary immunodeficiency syndromes. Lifelong suppres Clinical features and differential diagnosis. The clinical
sive therapy with itraconazole 5 mg/kg daily may be spectrum of blastomycosis ranges from asymptomatic
required in immunosuppressed patients and in those subclinical infection to disseminated or even fulminant
who relapse despite adequate treatment [74]. Voriconazole disease.
and posaconazole are considered second‐line agents Following an incubation period of 2–6 weeks, pulmonary
because there are no treatment trials as yet using these blastomycosis develops, although asymptomatic infection
agents [92]. occurs in at least 50% of cases. Acute pulmonary disease
Most cases of histoplasmosis resolve spontaneously and mimics community‐acquired bacterial pneumonia with
have a good prognosis, with minimal pulmonary calcifica uni‐ or bilobal infiltrates, and typically resolves spontane
tion, but disseminated histoplasmosis carries a serious ously. Chronic pulmonary blastomycosis is an indolent pro
prognosis with a mortality rate as high as 95%, especially cess that tends to progress insidiously with fever, weight
in young infants or immunocompromised hosts. loss and night sweats and cavitary or mass‐like lesions on

radiographs. It is indistinguishable from tuberculosis, other
Blastomycosis fungal infections and cancer. Only a few patients experience
disseminated disease, where the skin and subcutaneous
INFECTIONS
Introduction. Blastomycosis, also known as Gilchrist tissue are the most common sites of extrapulmonary

isease or North American blastomycosis, is a chronic
d involvement, followed by bones and joints, the genitouri
granulomatous disease of the lungs, skin and subcutane nary tract and the central nervous system [93].
ous tissue produced by the dimorphic fungus Blastomyces Cutaneous lesions occur in 60% of patients with
dermatitidis. extrapulmonary blastomycosis and may be single or mul
tiple and affect any part of the body [99,100]. They tend to
Epidemiology and pathogenesis. Blastomycosis is seen be nodules or plaques that enlarge and ulcerate or become
most frequently in the central eastern and mid‐western verrucous or crusted, sometimes developing abscesses
USA and Canadian provinces, and occasionally in Central and fistulizing through the overlying skin. Erythema
and South America and isolated regions of Asia and nodosum may be associated with pulmonary blastomy
Africa. Within endemic areas the annual incidence can be cosis [93].
up to 101.3 per 100 000 [93,94]. The fungus grows as a Primary cutaneous blastomycosis (also known as inoc
nonpathogenic mould in soil and decaying wood and its ulation blastomycosis) is a rare infection resulting either
conidia convert to pathogenic yeasts in the tissues. from laboratory accidents or animal bites. After inocula
Occupational and recreational activities that involve tion, an erythematous, indurated area with a chancre
disruption of soil or wood, frequently along streams or associated with painful lymphadenopathy appears in
rivers, can result in exposure to the conidia. These are 1–2 weeks, but spontaneously heals [93].
inhaled and phagocytosed by macrophages and neutro In children, the disease tends to present as acute pneu
phils in the lungs, but some can become yeasts evading monia, but extrapulmonary dissemination is common
the immune response, become pathogenic and dissemi (38%) with skeletal involvement as well as cutaneous and
nate causing systemic infection [93,95]. Two species of central nervous system manifestations being frequent,
Blastomyces have been identified: group 1 (B. gilchristii), associated with higher morbidity and mortality rates
and group 2 (B. dermatitidis). The majority of patients [93,95,101–103].
The diagnosis of blastomycosis is difficult and frequently It is also known as South American blastomycosis or Lutz–
delayed, which highlights the importance of the dermatol Splendore–de Almeida disease.
ogist recognizing blastomycotic skin lesions, which, along
with pneumonia unresponsive to treatment, are highly Epidemiology and pathogenesis. Paracoccidioidomycosis
suggestive of the disease in endemic areas [95,97,101]. is endemic in Mexico and South America, with most cases
The differential diagnosis of cutaneous blastomycosis occurring in Brazil (where the reported incidence is 1–10
is wide and includes scrofuloderma, lupus vulgaris, squa cases per 100 000 per year, making the disease an impor
mous cell carcinoma, keratoacanthoma, tertiary syphilis, tant public health concern), Colombia and Venezuela.
leprosy, bacterial pyoderma, pyoderma gangrenosum, Even though both sexes are equally exposed to the fun
leishmaniasis and other fungal infections. gus, paracoccidioidomycosis is more common in males in
a 15 : 1 ratio [106,107]. Approximately 10 million people
Laboratory and histological findings. Direct examination are infected, 2% of whom will develop the disease. It
with potassium hydroxide of the purulent discharge from occurs more frequently in adults, although in a large
a lesion or sputum often demonstrates the characteristic series up to 18.5% of patients were children, and 9.7%
thick double‐walled, round yeast with wide‐based bud were younger than 4 years [106,108].
ding. Fungal cultures require a 1‐ to 4‐week incubation Transmission is through inhalation of the fungal spores,
period for growth of a slow‐growing brown, wrinkled but the skin and oropharyngeal mucous membranes can
yeast colony at body temperature (37 °C) and a mycelial be inoculated after trauma with contaminated materials.
form at room temperature (25 °C), producing a white, There is no evidence of human‐to‐human transmission. The
fluffy colony on SDA. incubation period is variable, from weeks to years. There
Histopathological examination of tissue specimens is a correlation of T‐cell depression with the severity of
with use of Gomori’s methenamine silver or PAS stain paracoccidioidomycosis, and hormonal, genetic and
demonstrates a suppurative noncaseating granulomatous nutritional factors all play a role in the development of
reaction with the distinctive yeasts inside macrophages: the infection and clinical disease [108,109].
round to oval, 8–15 µm in diameter, with a thick refractile
wall located intra‐ and extracellularly [65]. An enzyme Clinical features and differential diagnosis. Two clinical
immunoassay (EIA) for the detection of a polysaccharide forms of paracoccidioidomycosis are currently recog
cell‐wall antigen in urine, serum, bronchoalveolar lavage nized: the acute juvenile form, and the chronic adult form.
and cerebrospinal fluid has improved rapid diagnosis of The acute juvenile form occurs in 25% of cases and
blastomycosis, with high sensitivity but low specificity affects mainly children and adolescents [106]. It is charac
because of cross‐reactivity. Serological testing has poor terized by disseminated infection that progresses rapidly
sensitivity and specificity, but an EIA using the BAD‐1 with reticuloendothelial system involvement and a Th2
antigen of the fungus is promising. Real‐time PCR assays immunological response. Skin lesions are infrequent, and
for rapid diagnosis are being used with very high sensi the only mucocutaneous manifestations are gingival
tivity and specificity [93,104]. oedema with recession and tooth loss, or infiltrated viola
ceous plaques reminiscent of sarcoidosis [110]. Mortality
Treatment and prevention. Current guidelines empha is as high as 5–11% [14,108,111,112].
INFECTIONS
size that all patients with blastomycosis should receive Most adult patients affected by paracoccidioidomyco
antifungal treatment because of the high likelihood of sis have the chronic form, characterized by a Th1 response,
progression or recurrence of the infection. Itraconazole is which is the result of primary pulmonary infection and
first‐line therapy for mild to moderate disease for a can be indolent and self‐limiting (75%) or chronic and
minimum of 6–12 months. Other options are fluconazole, progressive. It initially presents with mucosal nodules,
voriconazole or posaconazole, which have been used suc vegetations or ulcers (called mulberry‐like stomatitis),
cessfully in a few reports. For moderately severe to severe which can progress to tissue destruction and ulceration
blastomycosis, treatment should be with amphotericin B and respiratory obstruction [108,113].
until improvement is noted in 1–2 weeks, followed by The main differential diagnoses of the acute juvenile
itraconazole or voriconazole for 12 months. For acute res disease are lymphoproliferative disorders or sarcoidosis
piratory distress syndrome (ARDS), methylprednisolone [110,111]; for the classic chronic adult form with oral
can be added or extracorporeal membrane oxygenation lesions, squamous cell carcinoma, leishmaniasis, tubercu
provided. Central nervous system disease and infection losis, syphilis, sarcoidosis and Wegener granulomatosis
in immunosuppressed patients should be treated as may be considered.
severe blastomycosis [105]. Overall, mortality is 4–6%,
but if ARDS occurs it can be as high as 89% [93]. Laboratory and histological findings. Diagnosis is
mainly clinical. Mycological direct examination shows
Paracoccidioidomycosis (South American yeast‐like cells with a helm‐like arrangement (Fig. 47.6).
or Brazilian blastomycosis) Histology shows pseudoepitheliomatous hyperplasia
with intraepithelial microabscesses and a granulomatous
Introduction. Paracoccidioidomycosis is the most frequent reaction. Spores of P. brasiliensis are round, 6–20 µm in
systemic mycosis in Latin America and is caused by the ther diameter, and develop multiple buds in their periphery
mally dimorphic fungus Paracoccidioides brasiliensis complex. that give the characteristic ‘pilot’s wheel’ configuration.
Epidemiology and pathogenesis. All species of Candida

are distributed widely in nature, but C. albicans, the most
frequent one, is an endosaprophyte of mammal and bird
gastrointestinal tract, C. tropicalis is found in oropharynx
and C. glabrata in vagina. They become pathogenic when
cellular immunity fails and/or when the normal flora is
altered. The incidence of invasive candidiasis has steadily
risen because of increasing use of multiple antibiotics and
invasive procedures such as parenteral nutrition and cen
tral venous catheters. Any source of immune compromise
(e.g. primary immunodeficiency, haematological malig
nancy, solid organ or stem cell transplantation, HIV‐AIDS
or medication) is associated with disseminated infection by
this yeast [119]. Incidence rates have decreased signifi
Fig. 47.6 Direct examination of exudate showing spherical spores with cantly in the general population following strict protocols
multiple buds in a pilot’s wheel configuration characteristic of P. brasiliensis. for central line insertion, but in the paediatric population
Source: Courtesy of Prof. Alejandro Bonifaz, Mexico City. >1 year of age they have increased from 2.0 to 2.4 per
100 000 person‐years in a period of 5 years in the USA [120].
Worldwide there is a shift from C. albicans towards non‐
They are found frequently in multinucleated giant cells, albicans species such as C. parapsilosis and C. tropicalis, with
but also inside the microabscesses [65,108]. an associated increase in mortality and antifungal resist
P. brasiliensis grows very slowly in special media with ance. In large studies, the median age for disseminated
antibiotics. Serological examination by immunodiffu candidiasis in children was 3.5 years and the most common
sion or complement fixation and skin intradermal tests underlying diagnoses were oncological, gastrointestinal
with paracoccidioidin are used mainly for epidemio and cardiac diseases. The organs most commonly affected
logical studies or to monitor treatment [114]. The were lung, liver, kidney, brain, spleen, eye and heart [121].
technique of double immunodiffusion, because of its Independent risk factors that have been identified are per
sensitivity of over 80% and specificity of over 90%, has sistently positive blood cultures for Candida spp. with a
been considered the main tool for the diagnosis of para central venous catheter in place, immunosuppression and
coccidioidomycosis. A latex immunoassay for the gp43 a stay in the intensive care unit) [122].
antigen of the f ungus has shown high diagnostic accu
racy, low cost and reduced assay time [115]. Molecular
Clinical features and differential diagnosis. In patients
identification of P. brasiliensis has been successfully
with altered cell‐mediated immunity, systemic candidae
achieved by immunohistochemistry and PCR amplifi
mia is the most frequent presentation and has a high mor

cation of ribosomal DNA.
tality if not treated promptly. The second in frequency is
chronic disseminated candidiasis (7%), followed by
Treatment and prevention. The first line of treatment is mucocutaneous candidiasis (particularly in patients with
INFECTIONS
itraconazole, followed by fluconazole and, less preferred, HIV). Patients with systemic or disseminated candidiasis
ketoconazole, until clinical remission with 50% of the present with persistent unexplained fever, various degrees
dose continued for 1 year thereafter. Sulphonamide deriv of multiorgan dysfunction that can progress to severe
atives can also be used, such as co‐trimoxazole every sepsis or shock, and skin lesions [123]. The skin lesions are
12 hours until clinical remission and 50% of the dose for commonly erythematous papules, pustules or nodules that
1 year thereafter. Voriconazole has been trialed compared often coalesce; crusty and erosive lesions can also be found
to itraconazole, with good results. Amphotericin B is the (Fig. 47.7) [121,124,125]. Patients with chronic dissemi
drug of choice for severe or recalcitrant cases nated candidiasis present with persistent fever unrespon
[14,107,108,116]. Efforts are under way to develop a thera sive to broad‐spectrum antibiotics, abdominal distention
peutic vaccine using peptides, purified antigens, attenu and hepatosplenomegaly. The diagnosis is usually delayed
ated yeast cells and/or monoclonal antibodies [117]. as imaging studies are not always helpful [126].
Other clinical presentations include meningitis, endo
carditis, endophthalmitis, ecthyma gangrenosum‐like
Opportunistic mycoses lesions and renal candidiasis in neonates [124,127,128].
Candidiasis The differential diagnosis should be made with bacte
rial infections and opportunistic fungal infections such as
Introduction. Candida spp. is the most common pathogen aspergillosis, fusariosis or cryptococcosis.
causing disseminated infection in immunocompromised
children, especially those with primary immunodeficien Laboratory and histological findings. Direct examination
cies that involve CARD9 deficiency [118]. The most with KOH or iodide of any exudate or secretion will show
common isolated species is C. albicans, but resistant strains abundant yeasts of 2–4 µm in diameter and pseudohy
of C. kruzei and C. glabrata are increasing in frequency. phae or real hyphae. Culture on Sabouraud medium at
Cryptococcosis
Introduction.
Cryptococcosis (also known as torulosis, European blasto
mycosis or Busse–Buschke disease) is an invasive fungal
infection caused by an encapsulated yeast, Cryptococcus neo-
formans. The organism produces infection following inhala
tion, disseminates haematogenously, and manifests with a
great variety of signs, both cutaneous and extracutaneous.
Cryptococcus neoformans var. neoformans is associated
with immune cellular depression and has become an
increasingly prevalent pathogen among immunocompro
mised patients. Cryptococcus neoformans var. gattii infects
immunocompetent individuals more frequently than
Fig. 47.7 Chronic disseminated candidiasis in a malnourished child. immunosuppressed hosts [132]. Mortality is high, espe
cially when diagnosis is delayed [133,134]. Several forms of
non‐neoformans cryptococci (C. laurentii, C. albidus) have
rarely been associated with human infection [135,136].
room temperature should be done quickly, and smooth
shiny white creamy colonies that eventually become
rugged or membranous will grow. On microscopic exami Epidemiology and pathogenesis. Cryptococcus neoformans
nation of the colonies, spherical or ovoid budding yeast is an encapsulated round or oval yeast, 3–10 µm in diame
with mycelia will be found (only C. glabrata does not pro ter. Although more than 30 species are included in the
duce hyphae). Biochemical testing methods such as genus Cryptococcus, the pathogenic yeasts involved in
CHROMagar™ Candida are based on specific enzymes of cryptococcosis are C. neoformans var. neoformans, C. neofor-
the various species and allow the identification of the mans var. gattii and C. neoformans var. grubii. The environ
most common species as well as other yeasts such as mental reservoir for C. neoformans is primarily pigeon
Rhodotorula, Cryptococcus, Trichosporum and Geotrichum. droppings. C. gattii is found predominantly in eucalyptus
On histopathology findings include pseudoepitheli and other trees such as firs and oaks. Because of its
omatous hyperplasia, granulomatous abscesses and environmental reservoir, infection by C. neoformans occurs
blastospores that are best seen with PAS, Gomori–Grocott worldwide, whereas the distribution of C. gattii and
or methenamine silver stain. C. grubii is more limited to tropical and subtropical regions.
There are multiple available diagnostic molecular Cryptococcosis is uncommon in infancy, with a calculated
techniques such as specific DNA probes, electrophoresis, incidence of 1 in 100 000 in the general paediatric popula
enzyme restriction analysis, PCR and in situ hybridiza tion and 47 in 100 000 in HIV‐infected children, which is
tion. PCR is the most sensitive analysis available and is much lower than in adults. A bimodal peak in incidence
used widely for the diagnosis of disseminated or systemic has been described, affecting children <1 year of age and
candidiasis [4]. the 5–10 years age group. Paediatric patients with HIV‐
INFECTIONS
AIDS and cryptococcosis are usually severely immuno

compromised with low CD4 counts [137]. Cryptococcal
Treatment and prevention. Amphotericin B remains
infection in immunocompetent children is much less
the first choice in critically ill children, at 0.6–1 mg/kg
common, even though a high proportion of children

per day intravenously [123]. Echinocandins such as
are seropositive to the fungal proteins by the age of 2
caspofungin or micafungin are also used with good
[132,134,138–141]. Neonatal cryptococcosis due to vertical
results; paediatric doses are 25–50 mg/m 2 daily and
or peripartum transmission has also been reported,
3–10 mg/kg daily, respectively. After initial intensive
although it is very rare [142].
treatment, fluconazole at 6–12 mg/kg daily for several
weeks should follow [4,127]. Treatment should be
initiated promptly after blood cultures are taken and Clinical features and differential diagnosis. The portal of
susceptibility patterns identified. Voriconazole has entry is primarily through inhalation of the fungus from
been used as salvage treatment of invasive candidiasis the environment, although direct inoculation into tissue
that was resistant to other azoles with a response rate following trauma occasionally occurs. Once the fungus
of 56% [129]. There are reports of adjunctive use of enters the human body, it can produce either latent infec
interferon‐γ immunotherapy in cases of primary tion or acute disease. In many circumstances, the yeast
immunodeficiencies [130]. Catheters and intravascu can remain dormant for years in hilar lymph nodes or
lar devices should be cultured and replaced [124]. pulmonary foci in an asymptomatic individual, and then
Even with appropriate treatment, mortality remains grow and disseminate outside these sites when the local
high at 40–50%. cellular immunity is suppressed.
Vaccine development is under way, using live attenu Disseminated cryptococcosis with cutaneous or
ated strains, proteins, cell‐wall extracts, and combination mucocutaneous manifestations occurs in 10–15% of cases
of polysaccharides with proteins [131]. following primary pulmonary disease, especially in
immunocompromised patients. It is one of the most

Treatment and prevention. Untreated cryptococcosis is
common opportunistic infections in individuals with

fatal in 90% of patients. Treatment of C. neoformans and
HIV‐AIDS. Other conditions that favour the spread of
C. gattii is determined by the host’s immune status and
cryptococcosis are acute leukaemia, solid organ trans
organ involvement and includes the use of antifungal
plantation, diabetes mellitus, connective tissue diseases,
agents, CSF drainage and occasionally surgical resec
chronic pulmonary diseases and treatment with corticos
tion [134].
teroids or immunosuppressive monoclonal antibodies
Fluconazole, itraconazole and amphotericin B in com
[143–146].
bination with flucytosine (5FC) are effective therapies for
Cryptococcosis has a predilection for the central
cryptococcosis [150]. Treatment must be started early in
nervous system (CNS), producing meningitis, menin

order to improve the prognosis. Another option is to
goencephalitis and abscesses of the brain. The CNS and
combine amphotericin B and 5FC for 2 weeks and then
respiratory tract are the organs most commonly involved
continue treating with fluconazole for a minimum of

in C. neoformans and C. gattii infections. Other affected
10 weeks [4]. Isavuconazole has been used with good
organs include prostate, eye, bone, urinary tract, biliary
results [151,152].
tract and blood [147].
Cryptococcal infection cannot be eradicated in patients
Cutaneous cryptococcosis is the third most common
with HIV‐AIDS unless the immune status improves with
clinical presentation and can be either a primary cutane
antiretroviral therapy. Fluconazole prophylaxis has been
ous infection from direct inoculation, or a secondary
shown to be effective for preventing cryptococcosis in
lesion as part of disseminated disease. Primary crypto
AIDS patients who have low CD4 counts [<100 cells/μL],
coccosis manifests as a nodule or abscess after trauma
and it is also effective for preventing relapses of crypto
[148] and secondary cryptococcosis presents mainly on
coccosis [139].
the face and scalp, with papules mimicking acne or mol
Vaccines and/or immune therapies to induce protection
luscum contagiosum. On rare occasions, cryptococcosis
and improve the host’s immune response to C. neoformans
presents as deep abscesses or vegetating ulcerations,
are under development [139].
nodules, vesicles, pustules, sinuses, cellulitis and even
panniculitis [134,149].
Differential diagnosis includes molluscum contagio Zygomycosis
sum and acne, pyoderma gangrenosum, and other oppor
tunistic infections, mainly systemic candidosis. Introduction. Zygomycosis infection is associated with
fungi of the Zygomycetes class and the order Mucorales
Laboratory and histology findings. Direct microscopic (the term mucormycosis should be discouraged because
examination for the presence of encapsulated yeasts using Mucor spp. are rarely the cause of zygomycosis). Most of
an India ink preparation is a rapid and inexpensive diag the species involved in these infections are saprophytes
nostic test. This simple technique is 80% sensitive in that live in the soil or in plants or animals and acciden
tally infect the human body under special conditions

AIDS‐related meningitis and 50% in immunocompetent
hosts [132,139]. (opportunistic infections). Zygomycosis or phycomycosis
Culture in SDA grows smooth mucoid white colonies also includes another type of mycosis, the entomophtho
ramycoses caused by members of Entomophthoraceae
INFECTIONS
developing in 24–48 hours.
On histopathology, a dermal and hypodermal inflam [4]. These are rare and mostly endemic to tropical regions,
matory granulomatous infiltrate is found, with rounded not opportunistic infections; thus they will not be covered
PAS‐positive budding yeast cells with capsules, 2–20 µm in this chapter.
in size, found within clear mucoid spaces [65]. Stains such
as methenamine silver, Alcian blue or mucicarmine help Epidemiology and pathogenesis. Opportunistic infec
visualize the yeast cells [4]. tions due to the Mucorales are caused by species of
Cryptococcus polysaccharide capsular antigen can be Mucor, Rhizopus, Absidia, Rhizomucor, Saksenaea, Mortierella,
detected in most fluids and tissues of the body by a latex Cunninghamella and Syncephalastrum. These fungi are
agglutination test. The sensitivity of this test is reported to ubiquitous in nature and can be found in vegetation,
be 93–100% and it has a specificity of 93–98%. A latex bread and soil. Classically, they infect patients with dia
agglutination test in CSF or serum is rapid, specific, non betic acidosis [153], extensive burns and/or malnutrition,
invasive and virtually diagnostic of meningoencephalitic but in the past decades they have become an increasing
or disseminated cryptococcosis if high titres are found. cause of infection in patients with neutropenia due to
Latent asymptomatic individuals can be discovered haematological malignancies who are treated prophylac
through positive cryptococcal skin testing for delayed tically with voriconazole against aspergillosis [154]. They
hypersensitivity to Cryptococcus or through a serological are also more common in patients with corticosteroid or
test for the fungus. Serum cryptococcal antibodies are not immunosuppressive therapy, organ transplantation and
helpful in diagnosing and deciding treatment for crypto HIV‐AIDS [155], and even in immunocompetent patients
coccosis, because of the poor sensitivity and specificity of [156–158]. They affect both genders and all ages equally
this method. Its positivity can appear later during the [159]. Along with aspergillosis, they are the second or
treatment, or it can be negative in patients with disease third most frequent fungal infection after candidiasis in
confined to the skin [134,139]. immunosuppressed patients [156,160]. The most common
route of infection is through inhalation of spores but, in inflammation, necrosis, vascular invasion and different
diabetic acidosis and burns, infection can develop under degrees of thrombosis, and collections of broad, ribbon‐
occlusive bandages or after trauma; and there have been like, nonseptated hyphae branching at 90° angles
outbreaks in hospitals and large institutions [161,162]. (Fig. 47.9). Tissue should be sent for direct examination
The most frequently observed organisms are Rhizopus and fungal culture in order to identify the specific
arrhizus, R. oryzae and R. microsporus, Absidia corymbifera, fungus causing the infection and its susceptibility

A. ramosa and Mucor pusillus [159,163,164]. patterns. Culture of infected tissue in Sabouraud’s agar
grows colonies in 1–5 days. The diagnosis by culture
Clinical features and differential diagnosis. Opportunistic alone is difficult because of the widespread nature of
zygomycosis caused by Mucorales is a serious, fulminant these agents as contaminants [172].
infection responsible for rapid death in susceptible hosts.
It can affect many different organs: rhinocerebral, pulmo Treatment and prevention. Treatment should be started
nary, gastrointestinal, cutaneous or disseminated. The promptly. Ideally it should combine surgical debridement
rhinocerebral form is the most common; infection starts at and antifungal treatment with intravenous amphotericin
the nasal mucosa and then disseminates to the orbit and B or posaconazole [153,159]. Isavuconazole has been tried
brain. Necrotic ulcers of the palate are an important sign, and has comparable results with amphotericin B [173].
as is facial cellulitis. The fungi have a predilection to The echinocandins and other triazoles such as ravucona
invade blood vessels, leading to thrombosis, haemor zole and voriconazole are considered inactive against
rhage, necrosis and infarction [159,163,165]. Mucorales [174]; however, there are reports of successful
The primary cutaneous form usually follows inocula combined treatment with caspofungin and posaconazole
tion or contact with contaminated material after trauma, or amphotericin B, suggesting that they have additional
natural disasters or accidents. It is a rapidly progressive or synergistic antimucoral effects [175]. Relapses can
infection characterized by tissue destruction and blood occur after successful treatment [176]. It is necessary to
vessel invasion. Skin lesions are usually tender erythema simultaneously correct the predisposing abnormalities
tous or purpuric nodules or patches that rapidly progress and monitor patients closely.
to necrosis and invade peripheral tissues (Fig. 47.8) [166]. Zygomycosis caused by Mucorales is a serious, life‐
Haematogenous dissemination is not rare, and the threatening disorder that leads to death in most
mortality rate, although lower than in other forms of
disseminated cases. Early diagnosis is the cornerstone of
mucormycosis, is high even after treatment has been successful treatment, increasing survival from approxi
started (up to 32%) [155,156,167]. mately 40–80% [177].
Rare presentations such as acute bilateral renal artery
thrombosis in a healthy young adult [168], a pulsatile Aspergillosis
nodule [169], renal mass [170] and mediastinal mass have
been described [171]. Introduction. Aspergillus spp. are ubiquitous fungi that
The differential diagnosis is with pyoderma gangreno very frequently cause opportunistic infections in
sum, septicaemia, bacterial cellulitis, necrotizing fasciitis immunocompromised patients, especially those with
and meningitis. leukaemias and lymphomas. It is the second most
INFECTIONS
frequent opportunistic fungal infection, after candidia

Laboratory and histological findings. The diagnosis is sis. In immunocompetent people, Aspergillus spp. can
made histologically from a skin or tissue biopsy. induce allergic responses such as sinusitis and asthma
The
typical findings are suppurative granulomatous [178,179].
Fig. 47.9 Skin biopsy stained with Gomori’s methenamine silver showing

Fig. 47.8 Purpuric plaque that rapidly progressed into a necrotic ulcer in a broad, ribbon‐like, nonseptated hyphae branched at 90° angles typical of
child with acute leukaemia and zygomycosis. Mucorales fungi.
Epidemiology and pathogenesis. Members of the Laboratory and histological findings. Clinical suspicion
Aspergillus genus can be found in fomites, the atmosphere is crucial, but the definitive diagnosis is histological and
and organic materials, with a worldwide distribution. mycological through culture of tissue. On histological
Aspergillus fumigatus is the most common species isolated examination of a biopsy stained with Gomori’s methena
from cultures (50–60%), followed by A. flavus, A. niger and mine silver, septate hyphae that branch at acute angles are
A. terreus (10–15% each); other rare Aspergillus spp. repre found within a suppurative granulomatous infiltrate and
sent less than 2% of isolates. Inhalation is the most com the deep arterial vessels of the skin; however, sensitivity is
mon route of entry of Aspergillus spores. Primary cutaneous not high. Immunoperoxidase staining using the monoclo
aspergillosis is rare, following either direct physical nal antibody EB‐A1 on formalin‐fixed, paraffin‐embedded
inoculation or occlusive dressing at the site of indwelling tissue permits detection of Aspergillus spp. even when
catheters. More often the skin is involved due to haema cultures remain negative. Aspergillus grows rapidly in

togenous dissemination from a pulmonary focus. cultures in SDA, but this is not conclusive because of fre
Aspergillosis has emerged as an important morbid quent contamination with this ubiquitous agent. Thus,
ity‐ and mortality‐causing agent in immunocompro diagnosis must rely on noninvasive and indirect methods
mised children with deficiencies of phagocytic cells, such as fungal antigen detection and amplification of fun
especially those receiving myelosuppressive antineo gal nucleic acid sequences. PCR assays have a sensitivity
plastic chemotherapy for acute leukaemias, recipients and specificity of 84%, but these increase when at least two
of haematopoietic stem cell or solid organ transplants, positive specimens are used [194]. Aspergillus antigen
or patients with primary immunodeficiencies such as detection was a synonym for the galactomannan ELISA
chronic granulomatous disease [178–184]. Large studies until the modern 1,3 β‐glucan test was developed.
report that up to 75% of paediatric invasive aspergillo Circulating galactomannan antigens may be present in the
sis cases occur in this setting, increasing mortality rates blood in detectable levels very early in the course of inva
from 1% to 21% [184]. Secondary, acquired or induced sive aspergillosis in immunosuppressed patients and can
deficiencies of T‐cell‐dependent defence mechanisms be detected by enzyme immunoassay in serum [184].
and comorbidities such as cytomegalovirus disease are Specific DNA can be detected by PCR assay
also involved but appear to be less important [184]. [178,179,182,189,195]. There are conflicting results con
Patients with cystic fibrosis have increased rates of cerning sensitivity and specificity of all these assays in
allergic bronchopulmonary aspergillosis and Aspergillus children because data are limited, but the galactomannan
bronchitis [185]. assay has acceptable sensitivity and specificity [181,184].
Other studies include pulmonary CT scan, which in
Clinical features and differential diagnosis. Invasive children should be used selectively, and bronchoalveolar
aspergillosis principally involves the respiratory tract. lavage.
Facial swelling, epistaxis, proptosis, cranial nerve abnor

malities or bone erosion are signs of fungal sinusitis. Treatment and prevention. Mortality is high if aspergillosis
Fever, cough and dyspnoea are frequent nonspecific find is not treated promptly, so treatment should be started
ings of pulmonary aspergillosis. Poorly controlled based on risk profile and available diagnostic testing. The
INFECTIONS
Aspergillus infection may lead to extension to local struc gold standard of systemic antifungal treatment is voricona
tures and haematogenous dissemination that can involve zole 8–14 mg/kg per day divided in two doses as the
any organ. primary therapy for invasive aspergillosis [189] or ampho
Cutaneous aspergillosis can be primary, secondary tericin B 1–1.5 mg/kg per day for at least 6–12 weeks to
through haematogenous spread from a distant focus (up avoid recurrence [182]. For children under 2 years of age,
to 11% of these patients have skin manifestations) or only liposomal amphotericin B is approved at 3 mg/kg per
affected by spread from contiguous tissues (e.g. nasal day. Choices for second‐line treatment in patients older
septum abscesses). Lesions usually arise around catheters, than 2 years include amphotericin B lipid complex, ampho
oxygen saturation monitors, intravenous lines or sites that tericin B colloidal dispersion and caspofungin [184].
were covered with tape or dressings. Clinically, lesions are Combination therapy with two antifungal agents such as
erythematous plaques or nodules that can develop into voriconazole and liposomal amphotericin B has shown
necrotic eschars or purpuric bullae. Disseminated second good results with higher survival rates [196]. However, the
ary aspergillosis of the skin is similar to meningococcae use of voriconazole significantly increases the risk of cuta
mia, with scattered purpuric nodules and papules over neous squamous cell carcinoma, and the risk increases as
the entire surface of the body [121,186–189]. the duration of the treatment increases, so special attention
Some less frequent clinical presentations of aspergillo should be given to these patients and they should be coun
sis are laryngeal [190], orbital [180], bronchial following selled appropriately [197]. Prophylactic treatment with
foreign body aspiration [191], osteomyelitis [192] and posaconazole or itraconazole significantly improves sur
otomycosis [193]. vival and reduces the risk of invasive aspergillosis in
Aspergillosis must be differentiated from other dis patients with leukaemia and post stem cell transplantation
eases causing nodules and ulceration, such as bacterial [182,184,195]. Early debridement of localized aspergillosis,
septicaemia, systemic candidosis, nocardiosis, fusariosis, such as sinusitis, cutaneous disease and osteomyelitis,
zygomycosis and vasculitis. should be performed for a better prognosis. Invasive
a spergillosis caused by A. terreus has a worse prognosis

Epidemiology and pathogenesis. Actinomycosis is a
than non‐terreus species, regardless of treatment used [198].
ubiquitous disease. Its incidence has decreased due to
better oral hygiene. It affects both genders with a slight
Nocardiosis predominance in females, and all ages equally.
Predisposing factors include dental procedures, dental
Introduction. Nocardiosis is a disease caused by aerobic cavities, intrauterine devices and bad dental hygiene. The
actinomycetes, particularly Nocardia asteroides, N. brasilien- most frequently implicated agent is Actinomyces israelii
sis and N. otitidis‐caviarum. Primary cutaneous nocardiosis (80%); less frequent are A. naeslundii, A. viscosus, A. odon-
is rare in both children and adults, and is usually associ tolyticus, Arachnia propinica and Bifidobacterium eriksonii
ated with an underlying immunological condition, [4,14,201].
although it can present in healthy patients [199].
Clinical features and differential diagnosis. The infec
Epidemiology and pathogenesis. Nocardiosis is a cosmo tion may involve both bone and soft tissues. There are
politan disease, affecting mainly adult males, and is different types according to the location: cervicofacial,
acquired by inhalation or through cutaneous inoculation. pulmonary, abdominal and pelvic.
There is usually a history of trauma, and the interval Cervicofacial actinomycosis is the most frequent. It is
between this and the appearance of the lesion is very vari rare in childhood but several cases have been reported.
able. Nocardiosis affects healthy individuals and those who Trauma or dental disease can usually be implicated. In
are immunodeficient due to any cause. The most common children tooth eruption may provide a portal of entry and
species isolated are N. asteroides and N. brasiliensis [4,199,200]. infection spreads slowly to contiguous tissue. It is charac
terized by an increase in volume, tissue deformity and
Clinical features and differential diagnosis. Clinical sinus tract formation with purulent discharge that con
manifestations are primarily pulmonary as acute or tains parasitic forms called ‘sulphur granules’ (Fig. 47.10).
chronic pneumonia in 70%. Dissemination to the CNS The pulmonary form manifests as fever, cough and
occurs in one quarter of cases and causes brain abscesses expectoration. The abdominal and pelvic forms are com
or meningeal symptoms. Skin lesions are nodules or monly mistaken for appendicitis, and in chronic cases the
plaques with abscesses and fistulae. Primary cutaneous skin is involved with abscesses and purulent draining
nocardiosis is exceptional and occurs after trauma. It is sinuses [4,14,201].
characterized by pustules or nodules that spread with a The differential diagnosis should be made with tuber
lymphangitic (sporotrichoid) pattern away from the inoc culosis, mycetoma, lymphomas and odontogenic sinus
ulation site. They are very tender and inflammatory, and tracts.
the patients are frequently febrile [4,199,200].
Laboratory and histological findings. The diagnosis
Laboratory and histological findings. The diagnosis is can be established through a direct examination of the
made by direct examination of the discharge from lesions exudate and visualization of the sulphur granules,
or sputum with Gram and Ziehl–Neelsen stains, where which are multilobulated masses of yellow‐white
partially acid‐fast filamentous branching structures will micromycelia. A biopsy should be stained with Gram,
INFECTIONS
be found. Culture of material obtained from the lesions in PAS or Gomori–Grocott as in all chronic, purulent and
SDA yields characteristic white cerebriform colonies. granulomatous processes. The granules can be distin
Histologically, there is pseudoepitheliomatous hyperpla guished from Nocardia spp. with Ziehl–Neelsen stain
sia and suppurative granulomatous inflammation. With because Actinomyces granules are not acid fast. Culture
Gram and Ziehl–Neelsen stains the filaments of Nocardia confirms the species but must be done in an anaerobic
spp. are demonstrated [4,199,200]. medium [4,14].
The differential diagnosis includes pulmonary tuberculo
sis, blastomycosis, coccidioidomycosis, and histoplasmosis;
cutaneous lesions can be confused with actinomycosis,
mycetoma and botryomycosis.
Treatment and prevention. The treatment of choice is co‐

trimoxazole in doses of 10 mg/kg per day for 3 months.
Other antibiotics employed are minocycline, amikacin,
cephalexin, erythromycin and imipenem [4,199,200].
Actinomycosis
Introduction. Actinomycosis is a chronic, suppurative

endogenous infection caused by filamentous anaerobic
actinomycetes that reside in the oral mucosa, dental cavi Fig. 47.10 Increased volume and tumefaction of the right mandibular
ties, tonsil crypts and vagina. area, characteristic of cervicofacial actinomycosis.
27 Ameen M. Chromoblastomycosis: clinical presentation and manage

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579
C HA PTER 48
Molluscum Contagiosum
Joachim J. Bugert1, Ali Alikhan2 & Tor Shwayder3
1
Institut für Mikrobiologie der Bundeswehr, München, Germany
2
University of Cincinnati, Department of Dermatology, Cincinnati, OH, USA
3
Department of Dermatology, Henry Ford Hospital, Detroit, MI, USA
Abstract and 77% in different geographical locations and subpopulations,

s uggesting many infections are either subclinical or not reported.
MC is normally self‐limiting with few lesions disappearing sponta-
Molluscum contagiosum (MC) is the most common poxvirus infec-
neously without need for treatment. Extensive cases are seen in
tion circulating in humans. Prevalence/incidence studies indicate
immunosuppressed individuals and those with atopic dermatitis.
the infection is frequently seen in general practice with a case
MC can persist for years, and treatment should be considered in
incidence rate of 1295/100 000 person‐years in the UK. Mollus-
those cases.
cum contagiosum virus (MCV) seroprevalences vary between 6%
Key points • MC lesions are, once detected, cleared by an overwhelming

immune response.
• MCV enters basal keratinocytes and causes hyperproliferation
• Molluscum contagiosum (MC) is a self‐limiting poxviral infection
of epidermal cells.
caused by molluscum contagiosum virus (MCV).
• MCV is secreted through the umbilicated lesion centre onto the
• MCV induces an antibody response which does not prevent
skin surface and then transmitted by smear infection.
re‐infection.
• Diagnosis can be made by clinical inspection, extrusion of papule
• MC seroprevalence is between 6% and 77% depending on
contents and histopathology.
enzyme‐linked immunosorbent assay (ELISA) format, and
• Destructive treatment methods including laser/cryotherapy,
population studied.
topical cytotoxins, and curettage are not adequately evaluated
• MC lesions persist for up to 3 years because they are temporarily
to be included in the 2013 Cochrane report.
shielded from immune effectors through sequestration and
• Imiquimod is ineffective.
production of immune evasive molecules, including inhibitors of
signalling pathways and apoptosis.
detected [3,4]. A Turkish study detected MCV‐1 in 100%

Aetiology. Molluscum contagiosum (MC) is a benign
(61/61) of cases examined [5]. In Japan, MCV‐1 and ‐3
self‐limiting infection of the skin caused by a member
are most commonly found, whereas MCV‐2 and ‐4
of the poxvirus family, molluscum contagiosum virus
occur in only 2% of cases [6]. MCV‐2 occurs primarily
(MCV). MCV‐1/80–U60315 is the type member of the
in sexually transmitted MC [7]. There may also be vari-
genus Molluscipoxvirus and has a linear double‐
SECTION 9: VIRAL SKIN

ation in prevalence of the subtypes in those infected with
stranded DNA genome of approximately 190 000 base
the human immunodeficiency virus (HIV) compared
pairs [1]. The infection appears to be specific to the
with immunocompetent individuals [8].
INFECTIONS
human host, and MCV cannot be grown in tissue
culture or embryonated chicken eggs. Unlike human
papillomaviruses or herpesviruses, it does not inte- Epidemiology. MC is a common infection, occurring
grate into the host genome or develop a latent state. worldwide and demonstrating variation in geographical
Restriction endonuclease analysis of the genomic distribution of viral subtypes [3,4,6]. The exact prevalence
DNA from various sources has revealed four closely is not known, but an increase in sexually transmitted MC
related viral subtypes, MCV‐1–4. There is no appar- was reported in both the UK and USA between 1960 and
ent relationship between viral subtype, morphology 1980 [9]. Incidence has been previously reported at
or anatomical distribution [2,3]. However, there between 2% and 10% [10,11], and the incidence rate in
appears to be marked geographical variation in the dis- those 14 years or younger in a large British study was
tribution of subtypes. MCV‐1 and its variants account 1265/100 000 person‐years [12]. Of note, in the USA, visits
for 98% of cases in the USA, while MCV‐1 and ‐2 pre- to dermatologists comprised the majority (71%) of healthcare
dominate in the UK, with MCV‐3 only rarely being utilization units for MC [13].
580 Section 9 Viral Skin Infections and Opportunistic Infections
Local outbreaks of MC occur and have been reported

in children attending swimming pools [14,15] and on
one occasion among 34 children from a kibbutz [16].
High incidence usually reflects increased exposure to
the virus. Sexual transmission from skin to skin surface
suggests that close contact is required to facilitate
spread of infection. MC rarely occurs before the age of
1 year, perhaps because of less direct contact with other
children [14], but this might also be explained by mater-
nally transmitted immunity to the infant or a prolonged
incubation period. Nonetheless, congenital transmis-
sion has been reported, presenting as lesions on the
extremities and scalp [7].
Age (young school‐aged children), living in close prox-
imity, skin‐to‐skin contact, sharing of fomites, residence
in tropical climates and swimming pool use are associ- Fig. 48.1 Seventeen‐year‐old white male with a subtle immune defect
with widespread molluscum and flat warts.
ated with higher rates of MC, while the child’s sex, sea-
sonality and hygiene do not show an association [10].
Viral transmission via fomites inside the pool (e.g. kick- Concomitant atopic dermatitis must not be confused
boards) or outside the pool (e.g. bath towels), or both, with new‐onset dermatitis that may occur around the
may explain the general correlation between MC and mollusca [28]. It is unclear whether application of topical
swimming pool exposure [10]. corticosteroids encourages the infection to flourish [29],
A prospective community cohort study by Olsen and or reduces the numbers of lesions [27]. Inflammation of
co‐workers in 2015 described MC as one of the 50 most MC lesions may indicate immune responses leading to
prevalent diseases worldwide with very little epidemio- viral clearance.
logical information available. The authors found a rate of Other immunosuppressants such as tacrolimus [30,31],
MC consultations in primary care for children aged 0–14 pimecrolimus [32] and methotrexate [33] can also facili-
years of 9.5 per 1000. In one in ten children with MC, the tate spread of an infection. Extensive and persistent MC
condition is likely to have a substantial effect on their also occurs in the immunosuppressed, including organ
quality of life [17]. allograft recipients and patients infected with HIV [34–36].
In a 2014 systematic literature review by the same In the latter group, facial involvement is common
authors, most epidemiological data on MC were found to (Fig. 48.1) [37]. Of children with acquired immune deficiency
be of poor quality. However, the picture emerging is that syndrome (AIDS) in a Romanian orphanage, 74% had MC
children aged between 0 and 14 years have an incidence of the head or face [38]. These observations support the
rate of 12–14 episodes per 1000 per year, with a point importance of cell‐mediated immunity in eliminating or
prevalence in children aged 0–16 years of between 5.1% controlling spread of the infection.
and 11.5% as per meta‐analysis. Children aged 1–4 years
exhibit the highest incidence. Swimming and eczema are Pathology. The virus enters the basal keratinocytes,
associated with the presence of MC, but the causal rela- where it causes an increase in cell turnover that extends to
tionships are unclear [18]. the suprabasal region. Higher in the stratum spinosum,
Recent enzyme‐linked immunosorbent assay (ELISA)‐ the mitotic rate decreases as viral DNA synthesis increases.
based studies show that seroprevalences in general popu- Proliferating cells within the follicular epithelium in par-
INFECTIONS
lations vary from 6% in Japan [19] to 14.8% in Germany ticular form lobulated epithelial masses compressing the
[20], while seroprevalences up to 77% are observed in dermal papillae.
immunosuppressed individuals [21,22]. However, the basal layer is not disrupted. Cytoplasmic
aggregations of viral material appear as large hyaline
Relation to disease state bodies (molluscum bodies), and these eventually destroy
Clinical impressions suggest that MC occurs commonly the cells, particularly at the centre of each lobule. In a fully
in those with atopic dermatitis [23,24]. In large epidemio- developed lesion, a cavity develops in which there are
logical studies, up to 24.2% of MC patients were diag- large numbers of molluscum bodies (Fig. 48.2).
nosed with concomitant atopic dermatitis [25,26]. Little inflammatory infiltrate is seen in the adjacent der-
MCV seroconversion was more common in dermato- mis, although in chronic MC a granulomatous infiltrate
logical and autoimmune disorders than in immunocom- may occur, possibly secondary to the discharge of papule
promised patients or patients with multiple sclerosis [20]. contents into the upper dermis [39]. Scanning electron
A retrospective medical chart review of 696 patients microscopy revealed a number of different gross mor-
(mean age, 5.5 years) with MC found that 259 patients phologies of molluscum but all had a dense distribution
(37.2%) had a history of atopic dermatitis. Patients with of small protrusions with similar ultrastructure [40].
atopic dermatitis had higher numbers of MC lesions and In a synopsis of observations available so far, the MCV
an increased likelihood of molluscum dermatitis (50.6% lifecycle (Fig. 48.3) starts with attachment of virus particles
vs. 31.8% [27]). to keratinocytes, probably followed by macropinocytosis
Chapter 48 Molluscum Contagiosum 581
structural gene products and assembly are extremely

efficient in vivo and sequestered in the ‘viral colony sac’, a
cellular membrane compartment in the cytoplasm of
infected cells observed on electron microscopy [48].
Cellular organelles are pushed to the side and eventually
disappear altogether in the spinous layer of infected
epidermis. The final step of viral egress is a destructive
process characterized by disintegrating cells, with virus
particles, membranous vesicles and other cellular debris
forming a characteristic plug‐like debrisome in the umbil-
icated centre of MC lesions (Fig. 48.2). This plug can be
extruded by pressure, leading to release of infectious
virus and autoinoculation as well as transmission through
smear infection. This process is similar to holocrine secre-
tion from sebaceous glands and possibly associated with
hair follicles, leading to the hypothesis that the initially
(a) infected cells are follicular stem cells [21]. Reattachment
and reinfection of MCV in neighbouring skin areas may
then occur, producing further MC lesions.
Immune response
Good correlation was found between the presence of
antibodies to MCV and clinical infection [49,50]. More
recently, ELISAs were found to be specific and sensitive in
the detection of antibodies to MCV [20,51]. However, as
with viral warts, it seems that depressed cell‐mediated
immunity (Th1), secondary to anti‐inflammatory viru-
lence factors produced by the MCV, rather than humoral
immunity (Th2) is of greater importance in disease
control [45,52].
MCV may evade detection and destruction by encod-
ing proteins suppressing the immune system, including
chemokine inhibitors (mc148 [53]), IFN‐β inhibitors
(mc160 [54]), FLICE/apoptosis inhibitors (mc066/mc159
(b)
[55,56]), as well as homologues of CD150/SLAM, which
Fig. 48.2 (a and b) Haematoxylin and eosin stained section of a fully is involved in signalling pathways essential to viral
developed molluscum lesion. Proliferating cells within the follicular
immunity (mc002, mc161 and mc162 [57]). The pathologi-
epithelium form lobulated epithelial masses. Cytoplasmic aggregations of
viral material appear as large hyaline bodies (molluscum bodies).
cal appearance of the papular stage of resolving MC
shows a dense mononuclear cell infiltrate hugging the
epidermis [58], suggesting that a cell‐mediated immune

[41]. Release of the virus core leads to transcription of mechanism is involved in this process. There is evidence
early mRNA which has been observed in vitro [42]. Early for humoral immunity directed against MCV [19,20]
INFECTIONS
gene products are partially secreted, suppress innate through the ubiquitin‐proteasome system, followed by
immune responses and may have systemic effects (mc159 apoptosis [59] and complete clearance as the consequence
and 160, NF‐κB, interferon [IFN] [1]). The infection is up of an overwhelming immune response [43].
to this point undetected by the immune system and the
lesion can develop to the immunologically undisturbed Clinical features. An incubation period for MCV of
state [43]. However, leakage of virus components through 2 weeks to 6 months has been reported [60].
the basal membrane or limited viraemia [44] at any stage This is also reflected in the seropositivity rate in a
would explain polymerase chain reaction (PCR) detection cohort of 289 German adults and children aged 0–40
in serum as well as serological responses (mc084 [20]) and years; seropositivity was low in children below the age of
further control by cellular immune effectors and clear- 1 (4.5%), peaked in children aged 2–10 years (25%) and
ance [43]. If cellular immune control is missing, extensive fell again in older populations (11–40 years: 12.5% [20]).
MC is the consequence [45]. Uncoating and DNA replica- The rate of general practitioner consultations in chil-
tion are the next steps in cells now dividing due to viral dren aged 1–4 years and 5–9 years was found to be 13.1
interference with the cell cycle (mc007 [46]). This step is and 13.0 (males) and 13.0 and 13.9 (females) per 1000
not well understood and does not happen in any in vitro respectively, as compared to 9.5 per 1000 in children aged
cell culture system tested so far. A cellular factor that is 0–14 years [25].
only present/induced in infected epidermis may be In a prospective community cohort study of 306 chil-
required [47]. Viral DNA replication, translation of late dren with MC [17] the mean time to resolution was
Egress – destructive
‘Debrisome - plug’
Infection - attachment
‘Viral colony sac’
Epidermal differentiation
Macropinocytosis/core release
Late gene products
Early gene products Uncoating/DNA replication/mitosis?
Spinous cell
N
Basal cell
Basal membrane
Secreted viral factors - antigen/leak?
Virion
Viral genome
Viral core protein/lateral bodies
Early gene product
Late gene product
Viral colony sac
Intra/extracellular vesicles
Fig. 48.3 Schematic diagram of the lifecycle of molluscum contagiosum virus in human epidermis. N, nucleus.
c entre (Fig. 48.4). Lesions vary in size from 1 to 10 mm

although occasionally giant lesions are seen (primarily in
the setting of HIV infection). Growth occurs over several
weeks and eventually spontaneous remission will ensue.
Spontaneous remission is heralded by inflammation,

suppuration and crusting (Fig. 48.5) which destroys the
lesion, leaving a small atrophic scar. Unlike varicella, the
INFECTIONS
molluscum pox scar is transitory. Most cases of MC

resolve within 6–9 months, but they can occasionally per-
sist for several years. However, studies on children in Fiji
show that no individual lesion persists for more than
2 months. In rare cases, primarily in the setting of immu-
nodeficiency, widely disseminated and grossly disfiguring
MC can occur in children (see Fig. 48.1) [61].
The lesions are often distributed on sites of friction
from clothing (e.g. around the neck, axillae or trunk); in
Fig. 48.4 Classic molluscum on the upper back of a 6‐year‐old white male. one large epidemiological study, the trunk was the most
commonly reported location for lesions, and half of the
patients presented with lesions in more than one anatomical
13.3 months. Eighty (30%) of 269 cases had not resolved region (Fig. 48.6) [26]. In tropical climates, involvement of
by 18 months, 36 (13%) had not resolved by 24 months, the limbs is more common. MC does occur in the anogeni-
and transmission to other children in the household was tal region too, but this does not necessarily signify sexual
recorded in 102 (41%) of 250 cases. spread in children (Fig. 48.7). More unusual sites include
The morphology of an individual lesion is a dome‐shaped the scalp and face, although the latter distribution is com-
papule, flesh‐coloured or pearly, with an umbilicated mon in those infected with HIV [28]. On the soles and
Fig. 48.5 Inflammation of molluscum heralding resolution in a 5‐year‐old Fig. 48.7 Molluscum and human papillomavirus in a 20‐month‐old white
white female. female with eczematous reaction.
Fig. 48.8 KOH of a molluscum lesion. Low power. Note enlarged

keratinocytes in pseudo‐saccules leading to central pore.
MCV infection. Herpes simplex virus (other than the

vesicular form), human papillomavirus, benign naevi,
fibrous papules, adnexal tumours, milia, juvenile xan-
INFECTIONS
thogranuloma, pyogenic granuloma, bacillary angioma-
Fig. 48.6 Three‐year‐old white male with multiple mollusca on his chest.
tosis, histoplasmosis, sebaceous naevi, comedones,
furuncles, syringomas, Penicillium marneffei infection,
mucosal surfaces, the appearance is atypical [62–64]. basal cell carcinoma, keratoacanthoma and varicella zos-
Around 10% of patients develop eczema around the ter virus should also remain in the differential [61,69].
lesions, but this disappears as the infection resolves [65]. If diagnosis is not straightforward, other techniques
Ocular manifestations of MC include dermal lid lesions, may be of assistance. The easiest is a 10% KOH smear;
conjunctival lesions, follicular conjunctivitis, intraocular simple light microscopy will demonstrate a papule with
lesions and chronic conjunctivitis or keratoconjunctivitis pseudo‐saccules gathered symmetrically around the cen-
[66,67]. If left untreated, vascular infiltration and scarring tral pore. These pseudo‐saccules have ever‐increasing
of the peripheral cornea may occur [68]. keratinocyte cell size as one looks from the base to the
centre of the specimen (Fig. 48.8). In addition to KOH
Diagnosis. This is generally straightforward, but large smear, biopsy, real‐time PCR of swab samples (with
solitary lesions in adults may occasionally be mistaken pyrosequencing to differentiate between MCV‐1 and
for basal cell carcinoma. Expression of a white cheesy MCV‐2) [70], dermoscopy [71] and reflectance confocal
substance by lateral pressure with forceps on an individ- microscopy (RCM) [72] may also help to diagnose MC
ual lesion is characteristic. In the immunosuppressed [69]. Dermoscopy reveals a polylobular, white‐yellow,
patient, cutaneous cryptococcal infection may mimic amorphous structure in the centre surrounded by a crown
of vessels [73]. RCM demonstrates a round, well‐circum- to each lesion with the blunt, wooden end of an applicator
scribed lesion with central round cystic areas teeming stick and rinsed off after 2–6 hours, or earlier in the case of
with bright refractile material [72]. discomfort. Another study of 54 patients demonstrated a
96% improvement rate and a parental satisfaction rate of
Treatment. In minor infections, it is reasonable to await 78% [83]. Several applications may be required to success-
spontaneous resolution, as this is least distressing to a fully treat lesions. In our experience (TS), two to six visits
child. There is a risk, however, of widespread cutaneous usually cure even the most widespread cases, and cantha-
dissemination, discomfort, bacterial superinfection, acute ridin has been used safely on the face and anogenital
inflammatory and chronic granulomatous reactions and region without adverse events. Careful application of the
scar formation [28]. Spontaneously resolving lesions that cantharidin with a wooden applicator stick should be fol-
become secondarily infected may require topical antisep- lowed by immediate drying with a fan. Adjacent skin
tic application. Furthermore, left untreated, lesions can should be held apart until completely dry. If the skin is
persist for several months to several years. thin or in an intertriginous area, less contact time
Active treatments for MC include destructive methods, is needed (2 hours). The eyelids can be treated if the child
occlusion, and cytotoxic, immune‐modulating and antivi- is calm and can hold still with their eyes closed until the
ral preparations. Unlike varicella scars, molluscum scars cantharidin is completely dried. Avoid the area immediately
are usually few and resolve completely. Molluscum scar adjacent to the eye margins. Avoid at all costs dripping
keloids have not been noted in the literature. cantharidin into the eye itself. Baby shampoo is recom-
mended to wash the area afterwards to avoid the eye‐
Destructive methods stinging sensation of regular soaps.
Cryotherapy and curettage. Cryotherapy is a very effective This preparation is not available in some countries,
therapy, inducing an ice ball on the lesion itself but not on including the UK, and may have some adverse events,
the surrounding skin [60,74,75]. Application of EMLA including exaggerated blistering, pain, pruritus, tempo-
cream (a eutectic mixture of prilocaine and lidocaine) rary hypopigmentation and secondary infection [83].
1 hour before the procedure may facilitate treatment,
which should not, however, be inflicted on an unwilling Keratolytics. Keratolytics, which disintegrate des-
recipient! The use of phenol is not recommended because mosomes and hemi‐desmosomes, are also an effective
of scarring and potential toxicity/carcinogenicity. treatment for MC. However, one large study examining a
Curettage of single or a few lesions can be carried out, combination cream of salicylic acid 16.7% and lactic acid
once again using EMLA cream for local anaesthesia [76,77]. 16.7% found it to be quite irritating, resulting in only a
In order to avoid the risk of methaemoglobinaemia, the 32.1% patient and parent satisfaction rate even with the
recommended upper quantities of EMLA cream per appli- 100% cure rate by two visits [28]. Adapalene 0.1% gel [84]
cation need to be taken into consideration (see Chapter 173). and salicylic acid 12% gel [85] may also be effective treat-
In one large study of four treatments, curettage was ment options. Again, caution is necessary in order to
found to be the most effective, associated with the fewest avoid systemic toxic effects of transcutaneously absorbed
adverse effects, and rated highest for patient satisfaction salicylic acid (see Chapter 5).
among patients and parents [19]. In this study curettage
was done under general anaesthesia. Curettage had an Electrosurgery. Electrosurgery has been suggested using
80% cure rate after one visit and 96% after two visits. Of a disposable 23‐gauge or thicker bore hypodermic needle
note, in this same study, after two visits, topical canthari-
as the effective probe [86]. Pain and possible scarring

din had an 80% cure rate and topical keratolytics had a must be considered when using this modality.
100% cure rate. These treatments did not require anaes-
INFECTIONS
thesia. Another curettage study found a high risk of treat- Topical potassium hydroxide. KOH aqueous solution in
ment failure at weeks 4 and 8; risk factors for treatment concentrations of 5–20% to all lesions is another treatment
failure were the number of lesions at day 0, the number of option for MC as it effectively dissolves keratin [87].
involved anatomical sites, and concomitant atopic derma- Applied once daily at bedtime, this solution achieved
titis [78]. Furthermore, topical anaesthesia (e.g. EMLA) complete clearance after a mean period of 17 days in 27
and occasionally systemic sedation may be required to Indian children [87]. Ten percent KOH also demonstrated
perform the procedure. efficacy, with lesions in 70% of children completely clear-
Recently, a modified curettage technique has been ing in a double‐blind, placebo‐controlled study [88].
described, involving first opening the epithelial surface of
the lesion with a 30‐gauge needle followed by gently Laser treatment. Flashlamp‐pumped pulsed‐dye laser
scraping away the viral core with a fox curette [79]. This therapy is a treatment for MC [89–91], although rand-
may be less traumatic and forceful compared with tradi- omized controlled trials are lacking. In most cases, only
tional curettage. one or two treatments are needed for complete lesion
resolution. Furthermore, the face, trunk and extremities
Cantharidin. Cantharidin, a vesicant produced by can all be treated with this modality, and side‐effects are
Coleoptera, has been widely used for MC in the USA [80–82]. minimal (e.g. local pain, itching, transient hypo‐ or hyper-
In a series of 300 children [80] it was shown to be pigmentation). EMLA cream under occlusion prior to
extremely effective and well tolerated, applied carefully treatment is advisable in younger children.
Duct tape. Typically used for common warts, duct tape occlusion Other antiretroviral agents, such as zidovudine,
is also effective in treating MC [92]. It is nondestructive, lamivudine and nevirapine, have successfully cleared
painless, affordable and convenient. Complete treatment MC in those with comorbid AIDS [105]. There is no mech-
may take several weeks to months. anistic explanation for this effect.
Topical cytotoxic therapy. Topical therapy with podo- Other treatments

phyllotoxin has been found to give good results, a 0.5% These include 10% solution (v/v) of essential oil of
cream resulting in a 92% rate of resolution [93]. The epi- Australian lemon myrtle (Backhousia citriodora) [106],
dermal irritation that results is thought to disrupt the pro- 0.0001–0.1% topical diphencyprone solution [107], and
tein–lipid membrane around the molluscum, thereby photodynamic therapy with 20% 5‐aminolaevulinic
facilitating an immune response. Systemic toxicity after acid [108].
transcutaneous resorption has been reported [94]. The The 2006 Cochrane review on MC treatment, updated
substance is not licensed for use in children. in 2010 [109] stated that many treatments have been
used for MC but a clear evidence base supporting them
is lacking. Eleven studies with a total number of 495
Immune‐modulating treatments participants were evaluated, of which nine described
Immune modulators. Imiquimod, a member of the imi- the effects of topical treatments and one each described
dazoquinoline family, stimulates the release of proinflam- systemic and homeopathic interventions, respectively.
matory cytokines such as IFN‐β, IFN‐α, tumour necrosis No treatment was convincingly effective, while many
factor (TNF)‐α, interleukin (IL)‐1, IL‐3, IL‐6, IL‐8 and common treatments for MC, such as physical destruc-
IL‐10 [28] by Th1 lymphocytes and is a therapeutic ago- tion, did not fulfil the criteria to be included in the
nist of toll‐like receptor (TLR)7 [95]. Its use in molluscum Cochrane review.
infection is not recommended. In a letter to Lancet
Infectious Diseases in 2014, Kenneth Katz pointed out that
imiquimod had been tested in two large but unpublished Conclusion. MC is a common, worldwide poxvirus infec-
randomized trials (IMQ14194 and 1495‐ [2006]), and tion that usually undergoes spontaneous resolution. As a
found to be ineffective in 702 individuals 2–12 years of general rule, reports concerning MC treatment cures,
age, of whom 470 had received imiquimod 5% cream [96]. sometimes in the medical literature and almost always in
Independently, Yaldo and co‐workers reported in 2015 the lay press and on the internet, are usually without pla-
that MC lesions show no detectable expression of TLR 7 and cebo control. Multiple small controlled studies have been
8, and TLR7 agonists may therefore be ineffective [97]. conducted to support various treatments; however, the
only treatment tested in two large randomized controlled
trials, 5% imiquimod cream, was shown to be ineffective.
Candida antigen immunotherapy. This method involves Destructive methods and systemic DNA polymerase
injection of a killed yeast protein into a molluscum inhibiting antivirals are supported by mechanistic consid-
lesion, in the hope that as the immune system becomes erations. The selection of treatment for recalcitrant cases
active in this region, it will mount an immune response should take into account potential side‐effects, scarring
not only to the yeast protein but also against MCV [98]. and cost‐effectiveness [110]. Because the infection resolves
A retrospective chart review of patients treated over on its own, often in a matter of months, the decision
a 1‐year period demonstrated complete resolution in whether or not to try an intervention must ultimately be
56% and partial resolution in 28% of patients upon

made by the patient or their guardian.
follow‐up [98].
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INFECTIONS
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588
CHA PTER 4 9
Human Papillomavirus Infection

Yun Tong1, Stephen K. Tyring2 & Zsuzsanna Z. Szalai3
1
Department of Dermatology, University of California San Diego, San Diego, CA, USA
2
Department of Dermatology, University of Texas Health Science Center at Houston, Houston, TX, USA
3
Department of Pediatric Dermatology, Heim Pál Children’s Hospital, Budapest, Hungary
Abstract i nfections are asymptomatic and cleared by the immune system,

continued cutaneous manifestations including genital warts are
a sign of persistent disease. Persistent infections by highly onco-
Human papillomaviruses (HPV) are a group of viruses with
genic HPV strains can lead to anogenital and/or oropharyngeal
implications ranging from cutaneous warts to cancer. HPV is

cancers.
the most common sexually transmitted disease. Although most
Key points • Clinical appearance varies according to the type of virus,

anatomical site and host’s response to the infection.
• HPV are separated into high‐ and low‐risk types.
• Over 170 types of HPV have been identified.
• Viral DNA integration into host genome confers higher‐risk
• HPV infection occurs when the virus is able to cross the basal
lesions/tumours.
lamina through disruption of the skin barrier or establish at
• Up to two thirds of noncancerous cutaneous HPV manifestations
naturally present squamocolumnar junctions (e.g. endocervix).
may regress spontaneously within 2 years.
• Most HPV are transient without clinical symptoms.
• Multiple treatment modalities are available because no single
• HPV infection is the most common sexually transmitted
treatment has been universally successful.
disease.
• The 9‐valent vaccine immunizes against the HPV types that cause
• HPV infections are classically separated into cutaneous, mucosal
~90% of genital warts (types 6 and 11) and ~90% of cervical
and epidermodysplasia verruciformis (EV) types.
cancers (16, 18, 31, 33, 45, 52 and 58).
investigators determined the function of these genes. The

Introduction. Human papillomaviruses (HPV) are a
recognition and increasing appreciation of the fact that a
group of ubiquitous viruses that infect the basal
subset of HPV was closely associated with cervical cancer
keratinocytes of the skin and together are recognized as
led to the establishment of HPV as the new model of viral
the most common sexually transmitted disease (STD) in
tumorigenesis [2–4].
the USA. Belonging to the family Papillomaviridae (PV),
approximately 170 types of papillomaviruses have been
identified that infect humans, with most having medical Classification. The International Committee on the Taxonomy
significance. Most HPV types are asymptomatic, and of Viruses designated papillomaviruses, Papillomaviridae,
patients typically are unaware of their infection [1]. HPV as a separate family. PV are highly species specific; there
is a circular, nonenveloped, double‐stranded DNA virus. are a few hundred types of papillomaviruses. Over 170
INFECTIONS
HPV is packaged into icosahedral capsid virions that HPV types have been sequenced. A range in homology has
measure approximately 55 nm in diameter (Fig. 49.1). led to the following classifications: genus, species, type,
Warts, the common clinical manifestation of HPV, were subtype and variant. There are 12 genera, designated by
recognized as infectious diseases by the ancient Greeks the first 12 letters of the Greek alphabet, of which five gen-
and Romans. Since the early twentieth century, warts have era (α, β, γ, μ, ν) contain HPV types [2,5,6]. Historically,
been viewed as viral infections. After it was demonstrated HPV has been classified into cutaneous, mucosal and epi-
in the early 1900s that the virus was transmitted from cell‐ dermodysplasia verruciformis (EV) types. HPV types are
free filtrates of warts, papillomaviruses were identified in also separated into high or low risk based on their predis-
a number of vertebrate species. Molecular cloning led to a position to malignancy. α‐genus HPV types, which infect
scientific development which largely enhanced the study the anogenital region and oral cavity contain both high‐
of the biological and biochemical properties of papilloma- and low‐risk types. Verrucae and papilloma types from β,
viruses. Sequencing allowed the identification of the open γ, μ and ν genera are considered low risk because infection
reading frames (ORF) as putative viral genes and the generally does not progress to cancer [7].
Chapter 49 Human Papillomavirus Infection 589
After viral capsid endocytosis into the host cell, the HPV
genome travels to the host nucleus where it uses host cell
machinery to maintain low copies of itself (~200 copies/
cell) through its normal life. However, in high‐grade cervi-
cal lesions and tumours, the viral DNA is integrated into the
host genome. As the infected cells leave the basal layer, viral
E6 and E7 proteins promote cell cycle continuation.
HPV induces immunomodulation resulting in local
impairment of the immune response [11,12]. The immune
defence of the infant, HLA type, the presence of HPV anti-
bodies, and differences in the host genome may protect
the young child.
The rare autosomal recessive condition, epidermodys-
plasia verruciformis (EV), which starts in early infancy
or childhood, is associated with an abnormal immune
response to HPV [13]. Secondary immunodeficiency
states – acquired immune deficiency syndrome, malig-
nancies or organ allograft recipients as a result of immu-
nosuppressive therapy – are also associated with frequent
and persistent HPV infection [14]. Warts may have a
tendency to either disappear or be refractory to all treat-
Fig. 49.1 Structure of the human papillomavirus. ments. Resolution rates may be adversely influenced by
the HPV type (as with mosaic warts), the extent and dura-
tion of the warts and suppression of the host’s cell‐
The genome consists of approximately 8000 base pairs mediated immune response [3].
and is divided functionally into three regions: an early,
a late and a noncoding long region. The early region WHIM syndrome
contains six common ORF and encodes genes for viral This is the association of warts, hypogammaglobulinaemia,
transcription, cellular transformation and DNA replica- recurrent bacterial infections and myelokathexis. Severe
tion. The late region encodes for structural proteins, major chronic neutropenia appears with hyperplasia of the
capsid protein L1 and minor capsid protein L2 [8,9]. HPV mature myeloid compartment in the bone marrow [15].
typing is based on >10% dissimilarity in the highly con- WHIM syndrome is associated with a heterozygous
served L1 ORF nucleotide sequence [10]. The regulatory truncating mutation of the CXCR4 gene. The CXCR4
or long control region, which is located between the early receptor is bound by CXCL12, a chemokine that regulates
and late regions, contains transcription enhancer genes cardiogenesis and haematopoiesis, among others [4].
and controls viral replication and gene expression.
Mode of transmission
Epidemiology and pathogenesis. Most HPV infections Subclinical and latent forms
are transient with no clinical symptoms. A minority of Among healthy individuals, persistent subclinical infec-

HPV types can result in warts or malignancies. HPV tions can be demonstrated on mucosal surfaces by appli-
infection is responsible for 99.7% of cervical cancer cases cation of 3% acetic acid, as in the procedure of colposcopic
and is the fourth most frequent cause of death from can- examination of the cervix or genital tract. High‐risk HPV
INFECTIONS
cer in women [1]. Cutaneous infections are essentially DNA can be detected in the oral and genital mucosa
ubiquitous. About 40% of childhood warts resolve within of infants during the first 3 years of life and occasionally
2 years. The incubation period of HPV varies from several in immunocompetent and immunosuppressed individu-
weeks up to more than a year. Viral warts can occasion- als [12]. Latent papillomavirus represents the presence
ally persist for many years in otherwise healthy individu- of HPV DNA in clinically and histologically normal
als. Older individuals may have some immune resistance skin and mucosa. HPV infections might be transmitted
to infection because there is a low number of cases in this horizontally from other family members. It is important
population [3]. to remember this to decrease the number of false allega-
The human clearance of HPV involves a protective skin tions of sexual abuse. Identification of possible sexual
barrier and interactions between innate immunity and abuse is still by detailed and appropriate history taking,
acquired immunity. Early exposure to the wart virus may physical examination and correlation with the socio‐
confer a period of immunity, especially in a young child clinical context [16].
with a few asymptomatic warts that are likely to resolve HPV can often be detected in common dermatoses,
spontaneously within months. leading to speculation that it may play a role in the devel-
Infection occurs when HPV is able to access the basal opment of conditions such as psoriasis vulgaris, lichen
lamina and its layer of keratinocytes, either through skin sclerosus and naevus sebaceus [17]. EV HPV types may
barrier disruption or at anatomical places where the squa- play a role in the hyperproliferation of skin. Anti‐HPV‐5
mocolumnar junction is naturally present (e.g. endocervix). antibodies have been demonstrated in epidermal repair
processes (second‐degree burn, autoimmune skin diseases, Sexual transmission

bullous disorders, psoriasis vulgaris). The mechanism by The prevalence of childhood HPV infection varies widely
which hyperproliferative HPV types may trigger a wide- in the literature. Most children who have been sexually
spread epidermal disorder is currently unknown [18]. abused will not show carriage of the virus. The minimal
period from sexual HPV exposure to development of
Autoinoculation external genital warts (EGWs) in adolescents and adults
An important mode of spreading the virus is autoinocula- is about 3 months, but is unknown in children [28–30].
tion (Fig. 49.2). The leading sites of HPV infection are the Autoinoculation or heteroinoculation from nongenital
extremities and the face. Hand warts are transferred by warts may be a source of EGWs in children. It has been
contact to other cutaneous sites including the lips, nose recognized that the phylogenetically related mucosal
and face [19]. Infection occurs when the basal epithelial HPV types 2, 27 and 57 can be detected in cutaneous
cells of the mucosa or skin are exposed to the virus. lesions as well as oral and genital lesions [12]. HPV‐27
Trauma also facilitates the spread of viruses [20]. with HPV‐3 is commonly found as a nongenital HPV in
genital lesions of children. HPV subtypes in children do
Heteroinoculation and iatrogenic transmission not show the high degree of site specificity for either
HPV infection plays an important role in the transmission mucosal or cutaneous sites that is seen in adults [19].
of HPV DNA between family members, and may be
transmitted via saliva during an infant’s nursing. The Clinical features
mother’s warts are associated with persistent oral and HPV infections of the skin
genital HPV carriage [12]. Deficiencies in cell‐mediated The clinical appearance of viral warts varies according to
immunity cause problems with persistent infection. the type of the virus, the anatomical site involved and the
Viral warts are spread by direct contact through host’s response to the infection [14].
fomites or indirectly by contaminated surfaces [21]. Clinical appearance can be defined by morphology
Iatrogenic transmission of the virus may occur indirectly (common warts, flat warts, filiform warts, tinea versi-
through the use of inadequately sterilized instruments color‐like warts, doughnut warts, epidermal cyst‐type
[20,22]. Papillomaviruses can remain infectious for long warts, punctate warts, pigmented warts, keratoacanthoma,
periods. Viral transmission is facilitated by maceration of subclinical or latent infection) or by location (common
the skin. There is an increased risk of reinfection in those warts, palmoplantar warts, periungual warts, respiratory
who have had viral warts previously [23]. The most papillomatosis, oral papillomatosis [Heck disease], con-
frequently reported risk factors for genital HPV infec- dyloma acuminatum, verrucous carcinoma). Warts can
tions are related to sexual behaviour, the partner’s sexual also be categorized by the host immune response [4].
history and age [24–26]. Common warts occur primarily in children and repre-
sent 70% of all skin warts (Fig. 49.3). Plantar and flat
Vertical transmission warts occur in a slightly older population. Warts can be
HPV infection of normal skin is acquired very early in painful when involving the soles or located near the nails,
infancy. HPV transmission from mother to neonate may
occur either in utero or during delivery; the resulting
laryngeal papillomas or anogenital warts may become
clinically apparent only months or years later. Viraemia
has not been shown to occur with HPV [19,27].

INFECTIONS
Fig. 49.2 Autoinoculation of warts from the periungual lesion to the

mouth. Fig. 49.3 Common skin wart on the scrotum of an infant.
especially when inflammation develops. If they are carcinoma in situ) [3]. Regression of these lesions may
located on visible areas, they can be socially unaccepta- occur, which is usually heralded by inflammation. Flat
ble [31]. Common warts present in a variety of clinical wart HPV types include 3, 10, 28, 41 and 49, followed by
patterns, appearing as hyperkeratotic papules with a types 5, 8, 12, 14, 15, 17, 25 and 30.
rough, irregular surface, and can occur in almost any area Deep plantar warts/myrmecia. The name ‘myrmecia’ orig-
of the body. HPV types 2 and 4 are the most common, fol- inates from the Greek meaning ‘ant hill’. The lesions
lowed by types 1, 3, 7, 10, 26, 27, 29 and 57. Common appear as small papules and progress to deep lesions
warts may become exophytic and vary in size from tiny with a rough keratotic surface. A well‐demarcated rim of
flesh‐coloured papules to hyperkeratotic fissured masses compressed keratin surrounds a softer substance. Plantar
1–2 cm in diameter. Thrombosed capillaries are often seen warts often grow into the deeper layers of skin because of
after paring away the hyperkeratotic tissue [14]. the pressure (callus‐like warts typically involve HPV‐1,
Filiform/digitate warts are long, with a narrow base and ‐4, ‐7, ‐10). Plantar warts should be treated to lessen pain
verrucous tip, and are usually seen on the face and neck, and transmission of infection [14]. The incubation period
around the lips, eyelids or nares. These variants of com- is 1–20 months. They grow deep and tend to be more
mon warts are benign and easy to treat [4]. painful than common warts. Treatment responsiveness
Verrucae planae/plane warts/flat warts are more common is generally good. The most common type of deep
among children and young adults and develop by autoin- palmoplantar wart is HPV‐1, followed by HPV‐2, ‐3, ‐4,
oculation. They are smooth, flesh‐coloured or lightly pig- ‐27, ‐29, ‐57 and ‐63.
mented yellow‐brownish papules with hyperkeratosis, Mosaic warts are formed by smaller plantar warts, which
usually 2–4 mm in size. These lesions are common on are composing plaques. They are coalescent and are usu-
photo‐exposed areas such as the face and neck and the ally seen on the palms and soles. Mosaic warts are impor-
dorsum of the hands. The Koebner phenomenon (or, more tant for their persistence and difficulty of treatment.
properly, pseudokoebnerization) often appears (Fig. 49.4). Mosaic wart types are HPV‐1, ‐4, ‐7 and ‐10 (Fig. 49.5) [4].
HPV‐10 and ‐28 related plane warts are more hyperkera- Punctate warts (HPV‐60, ‐63, ‐65) are rare and consist of
totic and can resemble early common warts. localized endophytic hyperkeratotic papules, usually
When flat warts are spread over a wide surface area, located on the palms. Occasionally warts can present a
they may be slightly hyper‐ or hypopigmented, and may high degree of pigmentation (HPV‐60), mimicking a pri-
appear like tinea versicolor. This appearance is not usual mary melanocytic process.
and is more commonly limited to patients with EV, human Periungual and subungual warts (benign HPV‐1–4, ‐7,
immunodeficiency virus (HIV) infection or other immune ‐10; premalignant HPV‐16, ‐34) are painful; their treat-
deficiency. In EV, warts spread rapidly and may progress ment is often difficult due to the physical blockade cre-
to bowenoid papulosis or Bowen disease (squamous cell ated by the nail itself. When treating a wart in this location,
the nail matrix may incur damage (Fig. 49.6).
A cystic wart appears as a nodule on the weightbearing
surface of the sole (plantar epidermoid cyst). The nodule
is usually smooth but may become hyperkeratotic. If the
lesion is incised, cheesy material may be expressed. Cystic
wart HPV types are 60, 63 and 65 [32].
Doughnut/ring warts are seen after the use of destructive

therapies. They occur around the periphery of a wart that
has been treated previously (Fig. 49.7).
Butcher’s wart. HPV types are 1, 4, 7 and 10. These are
INFECTIONS
seen in people who frequently handle raw meat. Their
Fig. 49.4 Verrucae planae on the skin – linear appearance due to

scratching. Fig. 49.5 Mosaic wart on the sole.
develop into squamous cell cancers. There are two pre-

dominant types of lesions. Some lesions have the appear-
ance of flat warts, caused by the same HPV types that
induce flat warts in the general population (HPV‐3 and
‐10). The others are flat, scaly, red‐brown macules, associ-
ated with EV‐specific HPV types, most frequently HPV‐5
and HPV‐8 [17]. The lesions are resistant to the usual
treatment modalities. They develop on light‐exposed skin
sites in most cases. EV occurs as an inherited disorder in
about half of the affected patients, inherited in an autoso-
mal recessive pattern or X‐linked recessive inheritance.
p53 mutations are also common. The presence of EV but
not cutaneous HPV DNA in normal skin was significantly
associated with nonmelanoma skin cancer status and
may prove to be of predictive value for skin cancer risk.
The EV HPV types play a role as causal agents in skin
cancer [13,17].
HPV infections of the aerodigestive tract

Focal epithelial hyperplasia. Focal epithelial hyperplasia
Fig. 49.6 Periungual wart. (Heck disease) is an HPV infection in the oral cavity [3].
The lesions are mucosa‐coloured, flat‐topped or dome‐
morphology is similar to common warts, with a higher shaped, pink‐white papules. They are usually 1–5 mm,
prevalence of hyperproliferative cauliflower‐like lesions. with some lesions coalescing into plaques, and are seen in
Keratoacanthomas have been associated with HPV‐37 many ethnic groups but are most common in native
and ‐77, and can progress to squamous cell carcinoma. Americans and Inuit children. Persistent oral HPV car-
Bowenoid papulosis is a form of squamous cell carcinoma riage in infancy is associated with the mother’s high‐risk
in situ characterized by enlarging plaques of the genital HPV carriage [12]. Cryotherapy or carbon dioxide laser
region. It can occur in immunocompetent and immunotherapy has been helpful in these patients. Spontaneous
suppressed children. The known HPV types include 1, 16, regression follows a similar time schedule to standard
18, 33 and 34; in verrucous carcinoma, the HPV types wart resolution. Aggressive therapy should be reserved
include 1–4, 6, 11, 16 and 18 [22]. for cases with a protracted course (Fig. 49.8).
Epidermodysplasia verruciformis (EV) is a rare disorder.
Warts generally develop in childhood, become wide- Recurrent respiratory papillomatosis. Recurrent respira-
spread, do not tend to regress, and in certain cases may tory papillomatosis (RRP) in childhood occurs at an inci-
dence of 0.3–3.9/100 000 and is considered to be the most
common benign tumour that affects the larynx in chil-
dren. RRP is a life‐threatening benign tumour as it has the
tendency to grow in size and number, causing complete
airway obstruction [31]. This disease presents with

INFECTIONS
Fig. 49.7 Doughnut wart. Fig. 49.8 Oral papillomas on the mucosal part of the lip (Heck disease).
hoarseness, stridor, cough and dyspnoea and is often mis- Anogenital warts: condylomas. Anogenital warts in chil-
taken early on for asthma or laryngeal haemangioma. dren are rare, much less common than in adults. The dis-
HPV types related to respiratory papillomatosis are 6, 11, covery of EGWs in children raises concerns regarding
16 and 18. HPV‐11 is considered to be the most common sexual abuse, but it is often difficult to definitively deter-
cause of RRP [4]. Diagnosis of RRP is confirmed by direct mine. Most genital HPV infections are asymptomatic and
laryngoscopy and biopsy for tissue diagnosis. The man- transient [12]. The mean age at presentation in children
agement of RRP includes surgical removal, various lasers ranges from 2.8 to 5.6 years. Due to potentially long
and adjuvant pharmacological medical therapies with the latency periods, several possible modes of transmission
antiviral agents cidofovir or interferon [3]. may occur [31]. Most condylomas are self‐limiting and
regress spontaneously or with local treatment, but some
Genital HPV infection may persist for years.
HPV infection of the genital tract is the most common Children may present with small flesh‐coloured pap-
sexually transmitted virus. The prevalence is age depend- ules noted by their caregiver. Some warts can be a source
ent: women between 15 and 25 years have the highest of itching, burning and bleeding. It remains difficult to
prevalence, which may be about 25–40% of all infections determine with certainty the source of HPV contamina-
[16]. The majority of precursor lesions to cervical intraepi- tion in children with anogenital warts [16]. Of all cases of
thelial neoplasia (CIN), vulvar intraepithelial neoplasia genital warts, about 90% are caused by HPV types 6 or 11,
(VIN) and vaginal intraepithelial neoplasia (VaIN) are with type 6 predominating and accounting for 39–90%. It
caused by HPV infection. The five most common HPV may be possible that genital skin in children is more vul-
types in HPV‐positive women worldwide are 16, 18, 31, nerable to infection by nongenital HPV types [19]. Genital
58 and 52, representing approximately 50% of all HPV types of HPV are divided into high or low risk depending
infections [3]. High‐ and low‐risk HPV infections are on their potential for causing anogenital neoplasia.
often simultaneously observed. Persistent carriage of
high‐risk HPV types was detected in 10% of oral and Penile warts. Condylomata acuminata in boys may also
1.5% of genital mucosa specimens obtained from all develop on the penis, most commonly involving the glans
infants during their first 26 months of life [12]. HPV has penis, penile shaft and prepuce. HPV‐16 has the highest
been detected in newborn babies as well [27]. The infants prevalence, but multiple HPV types may also exist [28]
are infected by periconceptual transmission, by prenatal (Fig. 49.10).
transmission via placenta, amniotic fluid or cord blood or
by passive contamination going through the birth canal. Histology. HPV infection of the skin and mucosa results
Persistence of HPV carriage in children varies in duration in hyperkeratosis and causes squamous cell prolifera-
from 2 days to up to 3 years [33]. tion, parakeratosis and acanthosis of the epidermis.
Vulvovaginal warts. The lesions can develop rapidly into

clusters of flat, papillomatous and occasionally cauli-
flower‐like lesions (HPV types are 6 and 11) (Fig. 49.9). In
cases of children with EGWs, coexistent HPV‐16 has been
seen in cervicovaginal or intra‐anal samples, although its
oncogenic potential in children is unclear. A slow‐growing,

cauliflower‐like mass, known as giant condyloma acumi-
natum, is a regional variant of verrucous carcinoma. It is
extremely rare and occurs in adulthood [4,30].
INFECTIONS
Fig. 49.9 Condyloma of the vulva. Fig. 49.10 Condyloma on the glans and foreskin of an infant.
Characteristic histological features include vacuolation of preparations should be avoided in children because of
the keratinocytes, with inclusion bodies composed of possible systemic toxicity [38].
viral particles and abnormal keratin [14]. In cases of deep Cantharidin, derived from the blister beetle Cantharis
plantar warts, the cells are enlarged, irregular and vacu- vesicatoria, can have a cure rate of up to 80% in plantar and
olated, and eosinophilic cytoplasmic inclusions, either periungual warts [39]. Its application causes activation of
sickle‐ or ring‐shaped, are distributed throughout the proteases, which degrade desmosomal attachments lead-
entire stratum spinosum, more dense superficially. ing to acantholysis and possibly painful blister formation.
Anogenital warts are markedly acanthotic and papil- No longer available in the USA since 1992, cantharidin
lomatous with little hyperkeratosis but some parakerato- can be purchased over the counter in Canada or be com-
sis [34]. Common warts have an endophytic, papilliferous pounded by a pharmacist. Unlike salicylic acid, canthari-
architecture with an acanthotic hyperplastic epidermis din is to be applied in‐office only as oral consumption can
and prominent granular layer. Viral DNA can be detected lead to death [35,39]. Use on thin‐skinned areas such as
in suprabasal cells in which the early cytopathic effect of a the face or genital areas may produce more significant blis-
perinuclear halo is observed. These changes become pro- tering, so use at these sites should be carefully considered.
gressively more pronounced in the superficial layers of the
epidermis. Some infected cells may have characteristic Cryotherapy. Traditionally, if simple topical treatments
cytoplasmic vacuoles (‘balloon cells’ or koilocytes) [14]. fail, cryotherapy is a routine second‐line treatment. It is
often considered as a first‐line therapy for treatment of
facial or genital warts as it is inexpensive and easy to
Differential diagnosis. Pseudoverrucous nodules and
administer. It has few side‐effects but can be painful and
benign and malignant tumours must be differentiated
may induce haemorrhagic blisters. Among refrigerant
from warts. The association of the wart virus with tumour
agents, liquid nitrogen is the coldest and most effective.
development may mean that verrucous carcinomas and
Care must be taken to avoid excessive deep freezing,
warts can exist side by side.
which can damage underlying structures (tendons, inter-
phalangeal joints and peripheral nerves) and cause scar-
HPV genotyping
ring. The infecting HPV is not killed by cryotherapy, but
The methods for detecting HPV of verrucae vulgaris are
its release from the damaged cells of the treated wart will
based on polymerase chain reaction (PCR) followed by
encourage an immune response to the virus [38,40].
sequencing or hybridization [6]. A negative test does not
mean that HPV was not previously present as HPV infec-
Occlusotherapy (adhesiotherapy). Occlusion therapy
tion can be transient and the virus can be eliminated by a
using duct tape for 2 months can be effective with common
healthy immune system to undetectable levels [19].
warts. Occlusion in conjunction with other wart therapies
Multiplex PCR allows detection and typing of HPV DNA
such as salicylic acid can enhance drug efficacy. Success
simultaneously [24].
rates can be high with relatively limited side‐effects [38].
Treatment and prevention. Many noncancerous cutane- Curettage and surgical treatment. With all surgical treat-
ous manifestations of HPV may be self‐limiting and ments for warts, there is a risk of recurrence because of
regress spontaneously. Up to two thirds of warts may residual wart tissue or recrudescent latent virus adjacent
clear without treatment within 2 years [35]. Several thera- to the original wart. Electrocautery and hyfrecation can be
peutic options exist for viral warts [36,37]. No definitive used to destroy small filiform warts, especially on the
single therapy cures all warts [35]. The choice of treat- face, but run the risk of aerosolizing viral particles.
ment depends on different considerations. Patients often Pretreatment with local anaesthetic cream is effective in
INFECTIONS
have different skin types, HPV numbers, sizes, locations relieving the pain [20,41].
and durations of lesion, immune statuses, other comorbid
skin or internal diseases, different pain thresholds and Laser treatment. The most represented laser modalities in
different preferences [38]. Parents have different attitudes the literature for warts are carbon dioxide and pulsed‐dye
and timetables. lasers (PDL), which produce comparable cure rates to
multisession destructive therapy. The routine use of laser
Destructive therapies treatment is not cost‐effective and it is painful. Its higher
Destructive agents cause nonselective damage to the cost is perhaps balanced by decreased number of required
infected keratinocytes. Destructive modalities tend to treatment sessions. Compared to a carbon dioxide laser,
require multiple treatments and have high recurrence PDL is more selective by causing direct thermal damage
rates. Most destructive therapies may cause scarring. to the wart microvasculature [35]. The success of PDL
treatment depends upon adequate energy absorption
Keratolytic agents. Among the destructive methods, sali- within the capillary loops of the wart; it produces more
cylic acid has the best clinical trial data supporting its purpura but less tissue damage.
usage. Topical treatment containing salicylic acid is effec-
tive and safe; it produces a local irritant effect. A number Antiproliferative agents and antimitotics
of placebo‐controlled trials document a 50–75% rate of Systemic retinoids may have a place in the management
cure with 6 weeks’ usage [4]. The more concentrated of persistent warts in adults, but only in selected
aediatric cases. Retinoids disrupt epidermal growth and

p Intralesional agents. Intralesional therapy utilizes a
differentiation. Podophyllin is a cytotoxic agent with delayed‐type hypersensitivity response towards warts.
powerful irritant effects and is also teratogenic. Due to Interestingly, it has the potential to resolve warts distant
its cytotoxic effect, it is not routinely recommended. to those being treated [46]. Intralesional agents include
Intralesional bleomycin is unlicensed for treatment of Candida antigen, the measles–mumps–rubella (MMR)
children. 5‐fluorouracil is a chemotherapeutic agent vaccine, trichophytin and bacille Calmette–Guérin (BCG)
thought to interfere with DNA and RNA synthesis and vaccine.
needs further investigation before paediatric use can be
routinely advised. Interferon. In warts, the T lymphocyte CD4/CD8 ratio is
inverted, which improves following interferon therapy.
Virucidal therapy Locally used interferon therapy is more efficacious than
Cidofovir, an acyclic nucleoside phosphonate, acts as a systemic administration [47]. Patients administered
dead‐end substrate for DNA polymerase, stopping repli- twice‐weekly injections for up to 8 weeks saw 62% clear-
cation. Cidofovir has been used successfully in HIV‐ ance of warts versus 21% in placebo groups [46].
positive patients for the topical treatment of genital warts
[42]. Off‐label intralesional use in children for RRP has Contact sensitizers. Contact sensitizers elicit a type IV
shown partial to complete resolution of mucosal papillo- hypersensitivity reaction. Agents include diphencyprone
mas [39]. Intravenous administration of cidofovir requires (DPCP), squaric acid and dinitrochlorobenzene (DNCB)
more investigation before paediatric use. Topical use of [39]. DNCB has been shown to be mutagenic and should
compounded 1–3% formulations of cidofovir has also be avoided. A retrospective study with paediatric subjects
been reported to be effective, but care should be taken in showed that DPCP may be the preferred method for peri-
areas where skin is eroded or thin or occluded due to risks ungual warts (85% of patients saw clearance) but requires
of systemic absorption. more investigation [48]. Although these treatments may
be efficacious, limited data support their use, and they do
Immune stimulation and modulation not have any significant advantage over simpler and safer
Ingenol mebutate. Approved for actinic keratosis, treatments, except perhaps in selected cases [49].
ingenol mebutate has a dual mechanism of inducing
cell death directly and stimulating an inflammatory Systemic immune stimulation. Immunostimulatory
response against tumour cells. In a case series of 17 drugs such as levamisole and inosine pranobex, and the
patients (21–70 years old), 16 patients demonstrated H2‐receptor antagonist cimetidine, which also has immu-
complete clearance of their EGWs, 76% of whom had nomodulatory actions, proved disappointing in the man-
rapid clearance within 3–35 days [43]. Thirteen of the 16 agement of cutaneous warts. While cimetidine appears to
who had complete clearance required only a single show a trend towards improvement in paediatric patients,
treatment of ingenol mebutate; the remaining three randomized controlled trials do not demonstrate statisti-
patients cleared after a second or third application. No cally significant differences in comparison to placebo,
recurrence was noted up to 240 days on follow‐up. particularly in adults. Zinc sulfate administration orally,
Local skin irritation similar to application for actinic which can be associated with gastrointestinal adverse
keratosis was noted after 24–48 hours but ameliorated effects when used at high doses, is effective but only in
within 2–5 days. cases of zinc deficiency [14,34,37,50].

Imiquimod. Approved by the US Food and Drug Vaccination. The multivalent HPV vaccines are infection‐
Administration (FDA) in 1997 for external and perianal prevention‐focused, component vaccines made up of
INFECTIONS
warts, imiquimod is a topical immune response cream virus‐like particles produced from the L1 surface proteins
applied to the affected area, which induces production of of HPV types 16 and 18 for the bivalent (Cervarix) and
interferon‐α, tumour necrosis factor (TNF)‐α and interleu- HPV types 6, 11, 16 and 18 for the quadrivalent (Gardasil)
kin (IL)‐1, IL‐6 and IL‐8. Used for anogenital warts in vaccines. Both HPV vaccines protect against highly onco-
adults, there has been some success in its use for anogeni- genic HPV‐16 and ‐18 infections, which together account
tal warts in children [44,45]. Imiquimod is well‐suited for for more than 70% of cervical cancer cases. Gardasil also
warts in other anatomical sites in children and has the covers against HPV types 6 and 11, which are the cause of
benefit of home use [35]. 90% of anogenital warts. Just 6 years after vaccine intro-
duction, the prevalence of the four HPV types covered by
Polyphenon E (sinecatechins). Botanical polyphenol the vaccine had dropped by 64% among 14‐ to 19‐year‐
sinecatechins ointments isolated from green tea are old girls. Perhaps equally important, there has been no
approved in the USA and Europe for the treatment of indication of type replacement occurring [51].
genital warts. Polyphenon E has not been studied as A next‐generation vaccine protecting against nine HPV
extensively for cutaneous warts. An antioxidant, poly- types (Gardasil‐9) was approved in 2014 by the FDA to
phenon E, stimulates pro‐inflammatory cytokine release succeed the original Gardasil. Gardasil‐9 potentially
causing telomerase inhibition and apoptosis [39]. A 15% extends an additional 20% of coverage by including five
ointment formulation demonstrated up to 65% clearance more high‐risk HPV types: 31, 33, 45, 52 and 58 [52].
with low recurrence rate of 5.9–12% [39,46]. High‐risk HPV types are also significantly involved in
HPV‐positive cancers of the penis, vulva, vagina and External genital warts. The diagnosis of EGWs is usually
anus as well as the head and neck. a clinical one and should be differentiated from anatomi-
Clinical trials have shown that the HPV vaccines are cally normal findings. A detailed history from the child
highly immunogenic, safe and well tolerated in females and family, a thorough medical examination for cutane-
and males 9–26 years of age. Their efficacy remains high ous warts, and consideration of referral of family mem-
for at least 10 years following vaccination. Currently, bers for examination are needed. Examination of the child
the rationale for routine immunization at 11–12 years of for signs of physical injury should be undertaken. The
age is that the vaccine should be given before a child majority of children who have been sexually abused have
becomes sexually active. The vaccine is currently no genital or perineal injury on examination. A physical
administered as a three‐dose regimen in the USA, but examination is needed to exclude other STDs. Suspected
many countries including the UK have switched to a sexual abuse cases should be reported to appropriate
two‐dose regimen, which demonstrated noninferiority authorities. Children with EGWs should be treated and
[53,54]. As the HPV vaccine rate is variable and not followed up for signs of recurrence. A comprehensive,
expected to prevent infection attributable to all high‐ evidence‐based HPV educational protocol is effective
risk HPV types, cervical cancer screening recommenda- regardless of adolescent sociodemographic characteris-
tions, including Papanicolaou testing, should continue tics or risk behaviours. Written brochures and internet‐
to be followed for females who have received HPV based materials are useful. Education by school health
vaccination [25,31,55,56]. educators must include the safety and efficacy of HPV
While the purpose of the HPV vaccines has been to vaccines, recommendations for vaccination, and the
prevent primary infection, there are reports of therapeutic importance of safe sexual behaviours and continued
effect for both vaccine‐ and nonvaccine‐type HPV warts Papanicolaou screening after vaccination [19,58,59].
[57]. This might perhaps add support of cross‐protection
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INFECTIONS
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598
CHA PTER 5 0
Herpes Simplex Virus Infections

Manuraj Singh1, Helen M. Goodyear2 & Judith Breuer3
1
St George’s University Hospitals, London, UK
2
Health Education England (West Midlands), Heart of England NHS Foundation Trust, Birmingham, UK
3
Great Ormond Street Hospital, UCL Division of Infection and Immunity, London, UK
Abstract of HSV infections and latency has improved with in vitro models
and studies in rodent models. There is increasing understanding
Herpes simplex virus (HSV) belongs to the class of α‐herpesviruses about the various viral and host factors that determine latency.
which includes varicella zoster virus (VZV). HSV has a tropism for Therapy for mild HSV infections, such as aciclovir, is not generally
epithelial tissue and like VZV demonstrates latency within sensory indicated in uncomplicated infections in childhood. However, such
ganglia after primary infection. Two distinct antigenic types exist, therapy is clearly indicated and can be lifesaving in neonatal her-
known as HSV‐1 and HSV‐2. Herpes labialis and herpes genitalis pes simplex and disseminated infections such as those occurring
are typically due to HSV‐1 and HSV‐2 respectively but an increas- in eczema herpeticum and in immunocompromised patients. At
ing number of genital cases are also caused by HSV‐1. Both HSV‐1 present there is no therapeutic or prophylactic vaccine available
and HSV‐2 cause primary infections followed by the potential for for either HSV‐1 or HSV‐2, although studies to develop effective
episodes of recurrent disease. Knowledge of the pathogenesis vaccines are still ongoing.
Key points • The histological features of HSV infections are very similar to
VZV. They are characterized by varying degrees of epidermal
blistering and necrosis. The typical cytopathic features include
• Herpes simplex virus (HSV) is an alpha‐herpesvirus like varicella
nuclear enlargement, peripheral margination of chromatin,
zoster virus (VZV). There are two distinct antigenic types known
eosinophilic inclusions and multinucleation.
as HSV‐1 and HSV‐2. HSV, like VZV, undergoes latency within
• Definitive diagnosis of HSV infections is usually achieved by
sensory ganglia after primary infection.
polymerase chain reaction (PCR) or immunohistochemistry using
• HSV‐1 infection typically causes ‘herpes labialis’ whereas
specific HSV‐1 or HSV‐2 antibodies.
HSV‐2 has traditionally been responsible for ‘herpes genitalis’.
• Treatment of uncomplicated HSV in healthy children is generally
Primary oral infection is commonly asymptomatic in children.
not required. However, patients with eczema herpeticum or
Occasionally, healthy children may present with a moderate‐
severe infections such as disseminated disease occurring in the
to‐severe episode of primary gingivostomatitis. Recurrent oral
context of immunosuppression should be treated with systemic
herpes simplex is not uncommon and may be associated with
antiviral therapy such as aciclovir.
erythema multiforme. Genital herpes is much less common in
children and although it may be due to innocent inoculation,
sexual abuse must be considered.
HSV infection of humans has been documented since

Brief introduction/history. Herpes simplex virus (HSV)

ancient Greek times [5] and the name ‘herpes’ is derived
belongs to the α‐subfamily of herpesviruses, which share
from the Greek word meaning ‘to creep’ [6]. In the mid‐
the characteristic of being neurotropic and include vari-
INFECTIONS
nineteenth century, the term ‘herpes’ was restricted to

cella zoster virus (VZV) [1]. There are two antigenic types
skin disorders with a vesicular lesion, and in the early
of HSV, types 1 and 2. The virus particles consist of a
twentieth century the term ‘herpes simplex’ was intro-
central core of double‐stranded DNA, a 100 nm diameter
duced to include ‘herpes facialis’ and ‘herpes genitalis’.
icosahedral capsid (containing 162 capsomeres) sur-
HSV‐1 and ‐2 may affect any cutaneous site [3] and lesions
rounding the core, an envelope on the outside consisting
are characterized by grouped vesicles on an erythema-
of a lipid bilayer with glycoproteins embedded in it and a
tous background.
tegument (amorphous material filling the space between
the capsid and the envelope) [1–3]. The glycoproteins
have an important role in infectivity and also allow anti- Epidemiology and pathogenesis. Humans are the only
genic recognition by the host. The DNA molecule of natural host of HSV and the viruses do not survive for
HSV‐1 and ‐2 has a molecular weight of approximately long periods in the external environment [7]. The lipid
100 × 106 Da and the complete virus measures about glycoprotein envelope is needed for HSV to be infectious,
150–1200 nm in diameter [4]. Over 50% of the DNA and this rapidly becomes desiccated in the low ambient
sequences in HSV‐1 and HSV‐2 are homologous [3]. humidity of the atmosphere [8]. Primary infection is
Chapter 50 Herpes Simplex Virus Infections 599
acquired when a nonimmune child is exposed to contam- functions appear to be important. Natural killer cells,
inated saliva or secretions from the pharynx, genitalia or macrophages, CD4 and CD8 T lymphocytes and various
eyes, usually exchanged in close personal contact. The cytokines (interferon‐α, ‐β and ‐γ, interleukins IL‐2 and
virus must come into contact with mucosal surfaces or IL‐18 and leucocyte migration inhibition factor) are
abraded skin. Sources of infection are individuals with thought to be important in protection against HSV
an obvious clinical lesion and those with asymptomatic infection. This explains the more severe and extensive
viral shedding, which may occur whether or not there presentation of mucosal or cutaneous HSV infections in
is a history of clinical herpes. The amount of virus shed patients with suppressed cell‐mediated immunity such as
is thought to be 100–1000 times less if an individual is transplant recipients and human immunodeficiency virus
asymptomatic [9]. Viral shedding has been found in (HIV)‐infected individuals. HSV can have a markedly
18–20% of young children [10,11]. Although most recur- suppressive effect on immune mechanisms during acute
rent infections are due to reactivation of virus, exogenous episodes of infection and may enhance suppressor T cell
re‐infection may also occur [12]. activity, decrease cytokine production, decrease expres-
The highest rate of HSV infections is in the first 5 years sion of major and minor histocompatibility antigens and
of life and then after the onset of sexual maturity. Most inhibit cytotoxic effector cell function. The cell‐mediated
children will be asymptomatic or have a trivial illness immune response to HSV antigen has been noted to
associated with HSV exposure. HSV infections are uncom- be both low [24–26] and high [26,27] at the time of
mon under 6 months of age due to passive transfer of HSV recurrence.
maternal antibodies [13,14]. Acquisition of HSV antibod- Humoral immunity is important in limiting the extent
ies by children depends on socioeconomic conditions. of recurrences, but the role of antibodies in primary
Between 20% and 50% of children have HSV antibodies infections is less well defined. Antibodies assist in the
by 5 years of age, and up to 90% of children in crowded destruction of cells infected with virus by complement
underdeveloped areas will have antibodies by 10 years of and natural killer cells and by the process of antibody‐
age [10,14]. The majority of cases of herpes labialis are dependent cell‐mediated cytotoxicity. Antibodies have a
caused by HSV‐1 and the majority of herpes genitalis cases protective effect when an individual is exposed to HSV of
were due to HSV‐2. However more recent epidemiological either type, and patients with previous exposure to HSV‐1,
studies have shown that a higher number of cases (up to usually oral infection, have a less severe genital infection
50%) of genital herpes are attributable to HSV‐1 [15,16]. with HSV‐2. A stronger and broader spectrum of antibody
reactivity to viral polypeptides is present in recurrent HSV
Pathogenesis. In primary infections, HSV‐1 and ‐2 both infection compared with primary HSV infection [28].
replicate at the site of viral inoculation. The virus binds to However, the importance of these HSV antibodies is illus-
heparan sulphate proteoglycan (HSP) molecules which trated by the fact that neonatal HSV infections are reduced
act as receptors for the virus [17]. This binding is depend- and less severe in mothers who are seropositive. Therefore
ent on the viral glycoproteins C and D interacting with a primary genital HSV infection, near the time of labour in
HSP moieties for HSV‐1; for HSV‐2 the main interacting a seronegative mother, is a high risk for neonatal herpes
protein is glycoprotein B [18]. In addition to HSP, two simplex [29,30]. Recurrent HSV infection occurs, however,
other cell surface receptors, herpesvirus entry mediator despite high antibody titres [31–33]. Aciclovir has been
(HVEM) and nectin‐1, have been shown to interact with found to delay antibody development to some of
glycoprotein D and facilitate entry of HSV‐1 [19]. Viral the HSV glycoproteins when used to treat genital infec-

replication occurs within the nucleus and is divided into tions, although a full antibody complement is present
three main stages, known as immediate early (IE), early 6–12 months after initial infection [34,35]. It is important to
and late viral gene synthesis. The tegument part of the realize that a state of adequate immunity does not prevent
INFECTIONS
HSV virus particle contains several proteins including the development of recurrent lesions. However, a lack of
VP16/UL48 [20], ICP0 [21] and ICP4 [22] that are key both humoral and cell‐mediated immunity is associated
facilitators of viral gene transcription. The tegument with more severe and atypical presentations of recurrent
proteins are delivered into the cytoplasm after the virus disease. In particular, a lack of humoral immunity is

envelope fuses with the host cell membrane. After the associated with an increased risk of dissemination and
tegument proteins enter the nucleus, the first round of encephalitis, and such patients should be considered for
HSV transcription occurs. After the primary infection, prophylactic aciclovir therapy.
HSV, similar to VZV, is transported from cutaneous sites In recurrent infections [9,14], an inflammatory infiltrate
in a retrograde fashion by neurons to dorsal root ganglia consisting of macrophages and T lymphocytes appears
of sensory nerves. Latency is then established within mainly in the dermis, at least 2 days after virus first
these dorsal root ganglia. Subsequent reactivation is reaches the skin. CD4 lymphocytes predominate in the
associated with the virus travelling down the associated early stages of infection, followed by an increase in CD8
sensory nerve to re‐infect epithelial tissue including
lymphocytes 2 days later. Neutrophils and macrophages
adnexal structures at the end of the nerve endings. infiltrate advanced necrotic lesions. Expression of major
histocompatibility complex (MHC) class II DR antigens is
Immunology. Cell‐mediated immunity has a central role subsequently seen in basal cells, keratinocytes, Langerhans
in recovery from primary and recurrent HSV infections cells, endothelial cells and most infiltrating mononuclear
[23]. Both non‐ and HSV‐specific cellular immune cells. Some of the mononuclear cells produce the antiviral
cytokine interferon‐γ. p63 Gene expression, which plays a The exact mechanisms underlying reactivation from
pivotal role in the development and maintenance of latency remain unresolved but the Wilcox laboratory has
epithelial stratification, is increased in HSV‐1 and HSV‐2 demonstrated that removal of nerve growth factor (NGF)
infections and induces apoptosis when overproduced [36]. results in HSV‐1 reactivation [61–63]. Further studies have
HSV has developed several mechanisms to evade the shown that the mechanism of NGF‐mediated latency
innate antiviral immune system. HSV recognition by involves the PI3K‐Akt‐mTORC‐1 (phosphatidylinositol
toll‐like receptor 2 (TLR2) on cell membranes is inhibited 3‐kinase protein kinase B‐mammalian target of rapamy-
by the HSV viral protein ICP0. This leads to a decrease in cin [mTOR] complex 1) pathway. NGF removal inhibits
NF‐κB and interferon‐regulatory factor translocation into mTORC‐1 and induces HSV‐1 reactivation [64].
the nucleus and reduced secretion of antiviral molecules, Immune mechanisms also play a pivotal role in main-
such as interferons and cytokines. HSV also interferes taining latency; they involve CD8+ T cells, NK cells
with cell viability. It has different effects in different cell and interferon (IFN)‐γ produced by these cells [65].
types. For example, in epithelial cells apoptosis is blocked There is now also evidence for viewing HSV‐1 reactiva-
due to several viral proteins such as ICP0, UL41 (virion tion as a three‐step process involving epigenetic regula-
host shutoff protein) and gD. In contrast, HSV induces tion and divided into animation, exit from latency and
apoptosis of dendritic cells and natural killer (NK) cells. finally release of infective virions [66]. The animation
The HSV viral proteins, ICP0 and ICP27, have also been phase describes uncoordinated generalized transcription
shown to decrease induction and secretion of antiviral resulting in the production of viral genes that map
type‐1 interferons. Another mechanism of immune eva- throughout the entire genome. This phase is independ-
sion involves blocking the function of the C5 component ent of the HSV viral protein, VP16/UL48, a key activator
of complement mediated by glycoprotein C. HSV has also of lytic infection. Further DNA replication, during the
been shown to interfere with innate immune cells by exit from latency phase, and progression through reacti-
reducing the activation of NK and natural killer T (iNKT) vation with production of infectious virus is dependent
cells [37,38]. on VP16/UL48 [67,68].
Whereas HSV‐1 and ‐2 reactivation is often recurrent
and occurs in a younger population, VZV reactivation is Clinical features. HSV infections may be subclinical or
seldom recurrent and more prevalent in the elderly [39]. asymptomatic, in particular orolabial infections.
HSV‐1 DNA exists in a non‐integrated form within Approximately 90% of HSV‐1 infections and 75% of HSV‐2
human trigeminal ganglia [40]. The DNA is for the most infections are initially asymptomatic [69]. Transmission of
part transcriptionally silent and exists as genome con- both HSV‐1 and ‐2 occurs through exposure to contami-
catemers or as circular episomes of genomic unit length. nated secretions such as saliva on mucosal surfaces or
In latently infected ganglia, the most abundantly detected traumatized skin. Primary infection with HSV‐1 usually
HSV‐1 gene transcripts are those that map antisense to occurs in children and is mild. After primary infection,
ICP0/RL2 [41]. The most abundant latency associated similar to the other α‐herpesvirus, VZV, HSV travels along
transcripts (LATs) are two stable introns (1.5 and 2.0 kb) sensory nerves in a retrograde fashion to remain latent
spliced from the unstable primary 8.3 kb LAT [42–46]. within sensory ganglia. This is primarily trigeminal
Although LATs are dispensable for establishment of ganglia for herpes labialis and sacral ganglia for herpes
latency they do have antiapoptotic properties and facili- genitalis. Reactivation of both viruses results in similar
tate latency by epigenetic modification of HSV‐1 lytic gene painful lesions at the site of initial infection or asympto-
promoters. They also function as a primary micro‐RNA matic shedding of infectious viral particles. Asymptomatic
(miRNA) precursor that encodes at least four miRNAs in shedding is common for HSV‐2 infections [70].
HSV‐1‐infected cells [47–50]. miRNAs are small RNAs
INFECTIONS
that bind to complementary RNA sequences resulting in Primary herpes gingivostomatitis or herpes labialis
their destruction and ultimate inhibition of protein transla- This is the most common clinical manifestation of
tion. Seven of the 16 miRNAs identified in HSV‐1‐infected primary HSV infection in children and is usually due to
cells are present in latently infected mouse or human gan- HSV‐1 [2,71–74] (Fig. 50.1). Primary infection refers to a
glia [51–53]. Three of these miRNAs reduce the expression first infection occurring in a seronegative nonimmune
of key virus proteins such as ICP4, ICP34.5 and ICP0/RL2 individual. The severity of symptoms in normal healthy
which are involved in gene transcription, n eurovirulence children varies widely. Initially, children tend to have
and evasion of innate antiviral pathways respectively malaise and fever and subsequently develop small
[54,55]. Further support for the important role of LAT‐ grouped vesicles typically on an erythematous base.
encoded miRNAs in maintaining latency comes from These may be present on the hard and soft palate, gingiva,
studies showing a steady state decrease of HSV‐1 miRNA lips, buccal mucosa, tongue, floor of the mouth and phar-
levels as the virus reactivates [56–58]. ynx. Perioral lesions may occur and may extend some dis-
It is important to note that other miRNAs including viral tance away from the mouth. The vesicles form shallow
and host encoded transcripts are also involved in maintain- ulcers with a yellow exudative base and an erythematous
ing latency. Viral miRNAs may also interfere with host halo and lesions may coalesce. Numerous ulcers may be
factors to facilitate latency and host miRNAs expressed in present. Associated symptoms include tender cervical
a neuronal specific manner have been shown to reduce lymphadenopathy and halitosis. Excessive dribbling may
expression of lytic virus genes such as ICP0 [59,60]. occur in the younger child. The lips and gingiva may be
Fig. 50.2 Herpetic whitlow.

Fig. 50.1 HSV primary gingivostomatitis with multiple lesions on the lips
and tongue. The gums are red and swollen.
recurrences [75,76]. In 80% of cases, a single area of
involvement is present and less than 5% of patients will
swollen and red and bleed easily when touched. Lesions have two or more areas involved.
tend to be painful and commonly sting or itch, causing One quarter of individuals experiencing recurrences
the child to be irritable and to refuse food or drink. will have two or more episodes per year. The most com-
Tonsillitis or posterior pharyngitis with exudative ulcera- mon factors that have been implicated in reactivation
tive lesions on the pharynx, tonsils and buccal mucosa include ultraviolet light, local trauma, fever, wind, con-
may be the presenting feature, especially in older chil- current infections – classically described with a pneumo-
dren. The fever lasts for 2–7 days and then subsides. Oral coccal chest infection – HIV infection, local dental or
lesions may persist for 2–3 weeks. surgical procedures, stress, pregnancy and menstruation.
Complications include herpetic whitlows, spread to
other areas of the face or eye and transfer of infection to Herpetic whitlow and hand lesions
other body sites by scratching, including the genital HSV infection of the digits is most commonly described
areas. When lesions are widespread, the clinical diagno- as herpetic whitlow, herpetic paronychia or felon [77–79]
sis is not usually in doubt. Differential diagnosis of less (Figs 50.2 and 50.3). Lesions may occur anywhere on
severe HSV oral infection and pharyngitis includes aph- the hand, and ‘herpes manus’ has been suggested as an
thous stomatitis, herpangina due to enteroviruses, infec- appropriate name.
tious mononucleosis, streptococcal infection, diphtheria, Herpetic whitlows tend to occur in young children
erythema multiforme and Stevens–Johnson syndrome. with primary HSV gingivostomatitis due to autoinocula-
tion from finger/thumb sucking, and multiple digits may
Recurrent herpes gingivostomatitis or herpes labialis be involved [80,81]. Autoinoculation may occur in older

Between 20% and 40% of the population, at some stage, children due to nail biting [82], and in teenage children
will have recurrent orolabial HSV lesions [2,71]. Lesions whitlows may be present in association with primary
INFECTIONS
are usually on the lips rather than intraoral and are collo- genital infection [83,84]. HSV infection of the digits less
quially referred to as ‘cold sores’. The site most commonly commonly occurs as a result of a contact who has HSV
affected is the mucocutaneous junction of the lips. The (usually a close adult relative with recurrent HSV labialis),
lesions of HSV‐1 are more frequently recurrent than those kissing an affected digit [11] or toe [84] or after physical
of HSV‐2 [73]. In comparison with the initial infection, trauma [13]. Most lesions are due to HSV‐1.
recurrent HSV lesions are usually less severe, more local- The finger is the site most commonly affected, account-
ized and heal more rapidly. A prodrome including irrita- ing for 67% of lesions. HSV infection usually involves the
tion, tingling, pain, numbness and a burning sensation digital pulp space and lateral aspect of the fingers, with
occurs at the affected site, usually less than 6 hours before the lateral or proximal nailfold being affected only rarely.
a lesion appears. Some 60% of patients will experience a The thumb, palm and wrist are affected in order of
prodrome. Initially erythema is present, followed by decreasing frequency.
grouped papules and then vesicles. The vesicles rupture Children with a primary infection from exogenous
within 2–3 days, leaving an ulcer that becomes encrusted. inoculation have the most severe illness and are often
Healing is usually complete by 6–10 days. Constitutional febrile and have constitutional symptoms. Presentation is
symptoms including fever are uncommon but, with with sudden onset of pain, redness and swelling around
recurrent HSV lesions, mood changes in children are well the infected area. The infected site is initially erythema-
documented. Cranial nerve palsies, cluster headaches tous and swollen followed by vesiculation, development
and psychotic episodes have been associated with HSV of pustules and rupture of lesions. On heavily keratinized
infections in the past have been due to HSV‐2 rather than

HSV‐1. Although there is geographical variation, there is
now epidemiological evidence of a significant increase in
HSV‐1 genital disease [89]. A study in Scotland found
that the number of genital herpes cases due to HSV‐1 rose
from 33% to 56% over a period of approximately 10 years
[92]. Younger children may acquire HSV genital infection
due to autoinoculation from herpetic digital disease or
gingivostomatitis [90], exogenous inoculation from a
carer, usually a parent with recurrent herpetic digital
disease [93], close nonsexual physical contact and child
sexual abuse [94–96]. In the young child, careful judge-
ment is often needed when considering the route by
which herpetic genital disease has been acquired, and the
possibility of child sexual abuse must be considered
[94,95]. Genital HSV infection in neonates usually reflects
transmission from the birth canal during labour [97].
Primary HSV genital infection may be asymptomatic
but can be severe if there has been no previous HSV
exposure (HSV seronegative). A milder illness tends to
occur if antibodies to the heterologous HSV are present.
Symptoms tend to be more extensive in females than in
males because of a larger area of skin and greater mucous
membrane involvement. Multiple anatomical sites (labia
majora, labia minora, vagina and cervix) are usually
infected in women. Lesions in males tend to be located on
the penis, including the distal urethra and/or scrotum.
HSV infections are also being seen more frequently in
perianal, anorectal and extragenital sites such as the
upper thighs and suprapubic regions.
Fig. 50.3 HSV infection of the hand. Vesicles have coalesced to form
The incubation period is usually 2–7 days. Initially one
bullae.
or more small pruritic erythematous papules appear and
then progress rapidly to vesicles. After 3–5 days, the vesi-
areas such as the palm, vesicles may coalesce and, after cles develop into painful shallow ulcers that crust. New
pustulation, resolve slowly without breaking [9]. The crops can appear for up to 10 days. Associated symptoms
fluid from lesions is often clear, opalescent or serosan- include pain, itching, fever, dysuria, vaginal and/or ure-
guinous rather than pustular. The draining lymph nodes, thral discharge, malaise, headache, myalgia, paraesthesia,
including the epitrochlear and axillary, are often enlarged herpetic whitlow, an ulcerative/exudative pharyngitis
and tender. Lymphangitis may be prominent. Spontaneous (10–15% of cases) and, less commonly, self‐limited aseptic
resolution tends to occur in 18–20 days. Recurrences are meningitis. In males, urethritis and dysuria out of propor-
usually less severe, occur in approximately 20% of cases tion to the urethral discharge is suggestive of HSV infec-
and are of shorter duration than the initial infection, last- tion. The illness tends to last 2–3 weeks. Complications
INFECTIONS
ing 7–10 days. A prodrome of pain, tenderness, pruritus, include secondary bacterial infection, urinary retention
aching or burning is usually experienced and lasts a vari- and fibrinous adhesions leading to phimosis in males and
able time interval of a few hours to 3 days. Triggering fac- labial adhesions in females. When there are ulcerative
tors are the same as for recurrent herpes labialis. It is lesions in adolescents, then syphilis coexists with HSV in
important to distinguish HSV infection from bacterial 3–10% of cases and the risk of HIV infection is increased
infection of the hand to avoid unnecessary surgery [10,85]. significantly [89]. The ulcers of HSV are often smaller
Complications of HSV infection of the hand are rare but than isolated syphilitic ulcers [89].
include local hypoaesthesia, secondary ocular involve- Approximately 50–65% of patients suffer from recurrent
ment and genital disease. The most common complication genital herpetic infection but with gradually decreasing
is probably secondary bacterial infection. Herpetic whit- frequency [98]. HSV‐2 genital infections are more fre-
low is also often seen in adults who work with children quently recurrent than those due to HSV‐1 [38,99].
such as nursery staff and healthcare workers, especially Recurrences are of shorter duration than the initial genital
paediatricians and dental practitioners [86]. infection and are less intense and usually without systemic
manifestations. Long‐term complications of recurrent
Genital herpes simplex virus infection HSV genital infection include physical discomfort,
(herpes genitalis) psychological disturbances [100], transmission of HSV to
Most children with HSV genital infection [2,87–91] are neonates and an increased risk of HIV infection, probably
adolescents, after the onset of sexual activity [11]. Most due to the entrance of HIV into the ulcers [11].
Other cutaneous herpes simplex virus infections of an intense desire to compete, and exposed areas of
HSV infection may occur at any site on the body, particu- skin of fellow players are susceptible to HSV infection.
larly where the skin surface is abraded. Fig. 50.4 shows
HSV infection beneath the eye of a young child and Herpes simplex encephalitis
Fig. 50.5 shows primary HSV infection of the pinna of an HSV encephalitis [103–105] tends to present with non-
8‐year‐old boy. Epidemics may occur in sports involving specific symptoms and signs in children. It should be
close physical contact such as rugby (scrum pox) [101] suspected in a febrile child with focal seizures, focal
and wrestling (herpes gladiatorum) [102]. Young sport- neurological signs and progressive decrease in the level
speople often do not report their HSV infection because of consciousness. Skin lesions are usually not prominent.
Treatment with intravenous aciclovir, especially if started
early in the course of the illness, has significantly
decreased morbidity and mortality from HSV encephalitis.
There is increasing evidence that susceptibility to infec-
tions is genetically determined by abnormalities in various
pathways of immune defence. There is some evidence
that patients with genetic abnormalities in toll‐like
receptor 3 (TLR3) and production of interferon may be
predisposed to herpes simplex encephalitis [106,107].
Herpes keratitis
This is rare as a primary HSV infection in children or as an
extension of oral lesions [108,109]. It may occur due to
inoculation from HSV digital disease. Redness, watering,
discharge with gritty sensation in the eye, itching and
eyelid swelling may be present. Less common symptoms
include pain, photophobia, lid vesicles, ulcers and blurred
vision. Recurrences are not uncommon and iridocyclitis,
keratouveitis and corneal scarring are all recognized
complications without prompt treatment. Classically, in
acute infections, a dendritic corneal ulcer is seen with a
Fig. 50.4 HSV infection beneath the eye with erythema, vesicles and fluorescein stain viewed under ultraviolet light.
crusting.
Disseminated HSV infection
Disseminated HSV infection in otherwise healthy chil-
dren has been reported but is very uncommon [110].
Predisposing conditions include chronic protein malnu-
trition, concomitant infection such as measles, pertussis
or Haemophilus influenzae [111], immunocompromise in
children or neonates and dermatoses that predispose to
cutaneous HSV infection [112]. Predisposing dermatoses

include atopic dermatitis (eczema herpeticum), Darier
disease [113], Hailey–Hailey disease, Grover disease,
INFECTIONS
ichthyosis vulgaris [114], burns [115–117], congenital ich-
thyosiform erythroderma [118], incontinentia pigmenti
[119], pemphigus vulgaris and foliaceus [120,121] and
other bullous dermatoses [122]. Disseminated infection
may involve the liver, lungs, adrenals, pancreas, small or
large bowel, kidneys, bone marrow and central nervous
system and is usually associated with widespread cuta-
neous lesions [103,123,124]. Disseminated disease is
associated with a significant mortality rate.
Infection in immunocompromised children

Children with a primary immune deficiency [2,125]
mainly affecting cell‐mediated immunity are particularly
susceptible to HSV infection, unlike those with impaired
humoral immunity [9]. Similarly, children with an under-
lying malignancy on cytotoxic chemotherapy and those
with leukaemia or acquired immune deficiency syndrome
Fig. 50.5 HSV infection of the pinna. (AIDS) have an increased susceptibility to HSV. HSV
infection is usually due to reactivation of virus. There is a multiforme. The main differential diagnoses for herpetic
spectrum of disease ranging from lesions that are local- whitlow are bacterial infections of the hand such as bul-
ized, short‐lived and self‐limited with normal healing to lous impetigo and acute paronychia. When lesions occur
prolonged destructive lesions occurring with increased locally on other parts of the skin, herpes zoster should be
frequency. Lesions are usually in sites typically infected considered and the dermatomal distribution of the lesions
by HSV (oral mucous membranes, genital area, cutaneous tends to point towards a diagnosis of zoster. Disseminated
sites). Less commonly, HSV causing respiratory disease HSV infections in neonates and the immunocompromised
(tracheobronchitis, pneumonia) or oesophagitis, usually may mimic primary varicella or disseminated VZV infec-
due to an extension of oral lesions and HSV colitis, has tion and polymerase chain reaction (PCR) analysis of skin
been reported [126]. In addition, immunocompromised samples can be very useful in differentiating them [131].
patients suffer from increased severity, more frequent In addition, generalized immunobullous disorders such
episodes of reactivation, atypical presentations including as bullous pemphigoid and pemphigus vulgaris may
extensive ulceration, prolonged shedding, and a much occasionally fall into the differential diagnosis of dissemi-
greater risk for potential dissemination which may even nated disease.
prove fatal [127]. The differential diagnosis of genital ulceration induced
by HSV includes other sexually transmitted infections
Eczema herpeticum such as syphilis, chancroid, lymphogranuloma venereum
Eczema herpeticum, also known as Kaposi varicelliform and granuloma inguinale (donovanosis). Noninfectious
eruption, is a well‐recognized complication of atopic causes to consider include Behçet syndrome, trauma
dermatitis (see also Chapter 15). It usually results from (including factitial) and fixed drug eruption. If the ulcer
a primary HSV infection and results in extensive persists, especially despite antiviral treatment, malig-
facial, chest and occasionally more widespread lesions. nancy should be excluded with an appropriate biopsy. In
Widespread disease should be regarded as a medical addition, Epstein–Barr virus (EBV) may occasionally
emergency as occasional fatal cases have been reported. induce acute painful genital ulceration typically in young
The condition is usually associated with systemic symp- females (Lipschutz ulcer) [132].
toms such as fever and dehydration. It is important to
recognize that the most common clinical presentation is Laboratory/histology findings. As discussed in the
one of monomorphic ‘punched‐out’ superficial ulcers/ c orresponding section on VZV infections of the skin, the
erosions on a background of atopic dermatitis. The histological features of HSV and VZV infections are very
absence of characteristic herpetic vesiculation in typical similar [133]. Distinction between HSV‐1 and ‐2 and VZV
cases of eczema herpeticum is a common reason for the will depend on the clinical features and ultimately PCR
diagnosis not being considered [128]. Recurrent attacks of studies. The earliest histological features, which may pre-
eczema herpeticum may occur and are an indication for cede clinical disease by 2–3 days, are cytopathic changes
prophylactic antiviral therapy, especially if patients are within the nuclei of epidermal cells. These include
on immunosuppressive drugs. Recurrent lesions tend to nuclear enlargement, peripheral condensation of chroma-
be less severe, less extensive and of shorter duration. tin, ground glass homogenization and nuclear moulding.
Later changes include vacuolization of the cytoplasm,
Bell’s palsy followed by characteristic multinucleation and focal
Bell’s palsy is defined as an idiopathic peripheral facial eosinophilic nuclear and/or cytoplasmic inclusions. The
nerve paralysis. However, although still relatively contro- intranuclear inclusions with a surrounding artefactual
versial, there are some studies showing isolation of cleft are known as Cowdry type A inclusions. These
HSV‐1 or VZV from cerebrospinal fluid in some cases of changes start in the basal and suprabasal layers of the epi-
INFECTIONS
peripheral facial nerve paralysis [129,130]. Given the dermis and spread upwards. At the time of the biopsy
above association some physicians advocate antiviral there is usually an intraepidermal vesicle which results
therapy for Bell’s palsy. The Ramsay Hunt syndrome from ballooning and reticular degeneration. Ballooning
occurs when VZV reactivation affects the facial nerve. degeneration of the epidermis describes a phenomenon
particular to viral infections and results from increasing
Neonatal HSV infection oedema within keratinocytes. Reticular degeneration,
See Chapter 7. which is not specific to viral infections, results from
rupture of keratinocytes due to extreme balloon degener-
Erythema multiforme ation. The intraepidermal vesicle usually contains fluid,
See Chapter 66. cell debris and virally infected acantholytic and multinu-
cleate giant cells. The vesicle may appear subepidermal
Differential diagnosis. See also VZV differential diagnosis at a later stage when the vesicle expands and the full
(Chapter 51). thickness of the epidermis is affected
The differential diagnosis of HSV‐1 and ‐2 infections HSV infections, like VZV, commonly show cytopathic
will vary depending on the site and severity of clinical changes within adnexal structures. The hair follicle and
findings. For oral ulceration the differential diagnosis will sebaceous gland may show typical cytopathic changes
include aphthous ulcers, Behçet syndrome, herpangina associated with necrosis of the affected epithelium. Less
due to Coxsackie virus, pemphigus vulgaris and erythema commonly the eccrine apparatus may be affected. Indeed,
Nowadays, the diagnosis of HSV‐1 or ‐2 infection can

be confirmed by PCR or immunohistochemistry. The
current gold standard for diagnosis of HSV‐1 and ‐2 infec-
tions [2] is detection of viral DNA by PCR. Growth of the
virus by culture in a variety of cell lines is mainly restricted
to research purposes. PCR is able to distinguish quickly
and reliably between HSV‐1, HSV‐2 and VZV. There are
now specific commercial antibodies to HSV‐1 and ‐2;
although readily available and reliable, they generally
take longer to perform than PCR techniques. They are
most commonly performed on paraffin‐embedded sec-
tions using immunoperoxidase techniques. In addition,
commercially available antibodies to VZV are less readily
available in most cellular pathology laboratories, and as a
result, in routine practice, PCR techniques are usually
required to confirm a diagnosis of VZV infection. PCR is
Fig. 50.6 High‐power histological image demonstrating HSV infection also particularly useful in providing rapid diagnosis in
affecting a hair follicle. The infected hair follicle demonstrates disruption, life‐threatening situations such as from cerebrospinal
necrosis and characteristic cytopathic changes of herpes simplex infections. fluid in HSV encephalitis and skin lesions in disseminated
Note that identical histology is seen in varicella zoster virus infections. The
HSV infections in immunocompromised patients when
cytopathic changes of the infected nuclei include moulding, enlargement,
and peripheral condensation of nuclear chromatin giving rise to a ground
the clinical features may be atypical and/or resemble
glass appearance. Characteristic multinucleated giant cells are also seen. disseminated chickenpox or herpes zoster [138].
(haematoxylin–eosin stain; original magnification ×200).
herpes may occasionally present with follicular lesions Treatment and prevention

clinically mimicking a folliculitis [134]. It is important to Primary
note that if the overlying epidermis has very prominent Mild uncomplicated HSV infections require no treatment.
necrosis and secondary changes, typical cytopathic Supportive therapy. Supportive therapy includes effec-
changes of HSV are commonly found in the infundibular tive analgesia, local hygiene and antibiotics for secondary
portion of underlying hair follicles (Fig. 50.6). The under- bacterial infection. Oral fluids need to be encouraged
lying dermis usually contains a variably dense mixed when multiple mouth lesions are present. Patients with
inflammatory infiltrate containing lymphocytes, neutro- severe HSV gingivostomatitis should be monitored for
phils and eosinophils in varying percentages. As expected, dehydration and treated with intravenous fluids if this
the infiltrate commonly also shows a perineural distribu- becomes a problem.
tion which on rare occasions may show frank neuronal
necrosis. As with VZV it is important to be aware of Specific antiviral chemotherapy. Treatment with specific
‘herpes incognito’ from a histological point of view [135]. antiviral therapy depends on severity and site of infection
This describes the situation when a pathologist sees a [139–143]. In primary HSV, gingivostomatitis treatment is
lichenoid and/or vasculopathic tissue reaction in the usually needed only if infection is severe or if the patient
absence of the typical cytopathic changes of a herpes presents early in the course of disease. Patients late in

infection. Commonly, further serial sections on the same acute disease are unlikely to benefit from treatment.
specimen will reveal the diagnostic changes that allow a Treatment is required in disseminated infection including
INFECTIONS
confident diagnosis to be made. neonatal herpes simplex, an immunocompromised child,
Herpes infections are sometimes associated with a painful herpetic whitlows and most genital infections.
dense dermal lymphoid infiltrate which may raise the High‐dose intravenous aciclovir therapy has been
question of a lymphoma or pseudolymphoma, especially shown to reduce infant mortality from 85% to 29% in
if the typical cytopathic changes are not evident in the tis- disseminated neonatal HSV infections. In addition, the
sue sections examined. In addition, it is not uncommon for mortality associated with HSV encephalitis in neonatal
these dense lymphoid infiltrates to contain a significant infections was also reduced from 50% to 4% [144,145].
percentage of CD30+ cells, resulting in diagnostic confu- Topical antiviral therapy is used in the treatment of
sion with CD30+ lymphoproliferative disorders such as herpetic eye infections.
lymphomatoid papulosis [136,137]. Another important Nucleoside analogues were discovered in the 1970s and
point when assessing tissue sections histologically is that remain the mainstay of treatment for HSV‐1, HSV‐2 and
the features of late ulcerated lesions are not diagnostic VZV infections. Systemic aciclovir (acycloguanosine) is
unless the neighbouring epithelial tissue shows the typical the treatment of choice for primary HSV infections and
cytopathic changes. However, careful analysis of the ulcer is licensed for use in children. An oral syrup formulation
exudate may show necrotic and apoptotic epithelial cells is available. It exhibits both low toxicity and high selec-
containing ‘ghost outlines’ of viral inclusions. In such a tivity. Aciclovir is a synthetic purine (guanosine) nucleo-
situation, immunohistochemistry can be extremely useful side analogue that is converted by viral thymidine kinase
in helping to confirm the diagnosis. to aciclovir monophosphate and then by cellular enzymes
to the diphosphate and triphosphate form. Aciclovir such oral treatment could be an effective alternative to
triphosphate is a selective inhibitor of HSV and VZV intravenous aciclovir in resource‐limited situations [155].
DNA polymerase and inhibits viral DNA replication, In addition, oral valaciclovir has been used to treat
with resultant chain termination following its incorpora- encephalitis in a child who developed a severe localized
tion into the viral DNA [146]. It acts only during active skin reaction to aciclovir [156].
HSV replication, and treatment should be started as Famciclovir is the prodrug of penciclovir (penciclovir is
soon as possible. Therapy with aciclovir does not affect only available in topical form) and has 100‐fold higher
healing, the establishment of latency during primary levels than aciclovir in HSV‐infected cells. There are
infections or the subsequent frequency of recurrences. reports of its beneficial use in patients with aciclovir‐
It has a very low toxicity to uninfected host cells as the induced renal injury [157]. However, a relatively large
enzyme thymidine kinase of normal, uninfected cells retrospective community‐based study showed no signifi-
does not use aciclovir effectively as a substrate. Treatment cant difference in the incidence of acute kidney injury
with aciclovir is usually for 5 days but is adjusted depend- between aciclovir, valaciclovir or famciclovir [158]. Both
ing on patient response and immunocompetence. At least valaciclovir and famciclovir have the advantage of a
10 days of therapy is needed for HSV encephalitis, and twice‐daily dosage regimen and are recommended for the
longer courses of 2 weeks or more may prevent subse- treatment of adolescents with genital HSV infection [159].
quent relapse [147]. Weight‐adjusted dosing schedules are available for
Aciclovir is mainly excreted unchanged by the kidneys, younger children [160]. As the mode of action of these
with the metabolite 9‐carboxymethoxymethylguanine newer agents is similar to that of aciclovir, with phospho-
accounting for 10–15% of the dose excreted in the urine. rylation by HSV thymidine kinase in infected cells, pat-
It is important to maintain adequate hydration, and in terns of HSV resistance seen are similar to those of
renal failure the dose should be modified according to aciclovir. Other nucleoside analogues include vidarabine,
the degree of impairment [148]. Aciclovir is only partially idoxuridine, trifluridine, brivudine and cidofovir [161].
absorbed from the gut. The usual oral dose is 100 mg Brief mention is made of brivudine which is a thymi-
five times daily for children under 2 years and 200 mg dine analogue and has a similar mechanism of action to
five times daily for children over 2 years. In severe aciclovir. It is available in oral and topical preparations.
infections, those that are life‐threatening and neonatal Brivudine also inhibits viral DNA polymerase after phos-
infection, aciclovir should be given by intravenous phorylation by viral thymidine kinase. Interestingly, bri-
infusion over 1 hour, in an age‐appropriate dose, every vudine has selective inhibitory activity against HSV‐1 but
8 hours. Recommended doses are as follows: children not HSV‐2. It is also active against other herpesviruses
up to 3 months of age, 10 mg/kg 8 hourly; in those aged including EBV and VZV but not cytomegalovirus (CMV).
3 months to 12 years, 250 mg/m2 8 hourly; and 5 mg/kg Brivudine has potent activity against VZV in vitro com-
8 hourly in children over 12 years of age. The dose of aci- pared to aciclovir [162], and is licensed in Europe for the
clovir should be doubled when treating HSV encephalitis, treatment of herpes zoster and herpes simplex keratitis.
immunocompromised children and eczema herpeticum. Resistance to aciclovir is not a significant problem in
Prophylaxis is required in children with troublesome immunocompetent patients. The prevalence is low and
recurrent HSV infection, after neonatal HSV infection and has been stated at around 0.3–0.7%. The prevalence of
in the immunocompromised. resistance is higher in immunocompromised patients and
There have been few adverse side‐effects associated ranges between 2.5% and 25% depending on the underly-
with aciclovir [149,150]. Rapid intravenous injection
ing cause and degree of the immunosuppression [163]. It

has been associated with a transient rise in urea and has been described in immunocompromised children,
creatinine. Inflammation and phlebitis may occur at the early in the course of neonatal herpes [164] and in those
INFECTIONS
site of injection. treated with multiple courses of aciclovir or long‐term

Poor oral absorption of aciclovir led to the develop- prophylaxis [165,166]. Most aciclovir‐ and other nucleo-
ment of newer acyclic guanosine analogues, valaciclovir side‐resistant HSV strains have mutations in viral thymi-
and famciclovir, with better oral bioavailability than dine kinase, encoded by the UL23 gene in HSV [167].
aciclovir [151]. Both famciclovir and valaciclovir are used More rarely, they may also have alterations of the sub-
widely in adults including as prophylaxis after bone strate specificity of viral thymidine kinase or DNA poly-
marrow transplantation and to decrease the risk of trans- merase [139,152]. The emergence of resistant strains has
mitting genital HSV to heterosexual partners [152,153]. lead to the generation of other antiviral therapies which
They are not currently licensed for use in children, but are focus on inhibiting the viral DNA polymerase by other
being used with increased frequency, particularly in means. Foscarnet and cidofovir are two such agents most
children >12 years old. Valaciclovir is the l‐valyl ester of commonly used in clinical practice for resistant strains.
aciclovir and is indicated for treatment of both herpes They both act by inhibiting the catalytic subunit of viral
labialis and genitalis, including suppressive therapy. DNA polymerase, without requiring activation by viral
A paper in the New England Journal of Medicine showed thymidine kinase.
that it effectively reduces transmission of genital herpes Foscarnet, a phosphonic acid derivative, selectively
[154]. A small study in adults showed that oral valaciclovir inhibits HSV DNA polymerase by reversibly binding to
achieved acceptable levels of aciclovir within the cerebro- its pyrophosphate binding site, and is approved to treat
spinal fluid of patients with HSV encephalitis. Therefore, HSV strains that are resistant to aciclovir in the immuno-
compromised and neonates [140,168]. It has poor oral cathelicidins secreted by various epithelial tissues and
absorption and is given intravenously every 8–12 hours lactoferrin as well as plant abstracts [161].
[86–88,140–142]. Foscarnet has significant toxicity, with Other options that are occasionally used for orofacial
renal impairment being the most common serious toxic HSV infections include trifluridine and docosanol [177].
effect often necessitating discontinuation of therapy; Trifluridine is a nucleoside analogue and can also be used
resistance to foscarnet may also occur. Thymidine kinase topically to treat herpes keratitis. Docosanol is occasion-
mutants are thought to be less neurovirulent and less ally used topically to treat recurrent herpes labialis. Its
capable of establishing latency. After a herpetic episode is proposed mechanism of action is the prevention of viral
terminated, the next recurrence is often due to the original entry into the cell [178].
latent virus, which is sensitive to aciclovir [148]. Cross‐ Topical preparations are available for herpes simplex
resistance to foscarnet and aciclovir suggests either an infections but they are generally less effective than sys-
alteration in the DNA polymerase or a combination of temic medication. They may be useful for milder infec-
separate HSV drug‐resistant populations. tions or as an adjunct to systemic treatment. The one main
Cidofovir, a nucleoside analogue that targets viral DNA exception is in the treatment of eye disease. Topical prepa-
polymerase, is phosphorylated into an active form by cel- rations include aciclovir 5% ointment, docosanol 10%
lular kinases independently of viral participation and has cream, penciclovir 1% cream [179], idoxuridine 15% solu-
been used when both aciclovir and foscarnet resistance tion and cidofovir 1% gel. However, where possible, oral
have been present [143,169]. Cidofovir is active against a drug treatment should be generally advised, to prevent
wide range of double‐stranded DNA viruses including drug resistance emerging.
the human herpesviruses, polyomaviruses, poxviruses Artesunate is a semi‐synthetic derivative of artemisin,
and adenoviruses [170]. Cidofovir, like foscarnet, is also which is derived from the plant Artemisia annua. This
associated with significant renal toxicity, and as a result class of compounds has activity against falciparum
both treatments are only indicated for lesions with proven malaria, cancer cells and schistosomiasis. In addition,
resistant mutations or for patients who have failed first‐ they also have broader bioactivity and inhibit several
line treatment with aciclovir or one of its derivatives. viruses including members of the herpes family such as
Cidofovir is available in topical and intravenous prepara- CMV, EBV and HSV [180]. Artesunate at a dose of 100 mg
tions only. daily for 30 days has been used successfully to treat an
Brincidofovir (CMX001) is a potentially very useful oral immunosuppressed patient with severe multidrug‐resistant
drug which may gain more widespread usage against HSV‐2 infection [181]. The exact antiviral mechanisms
double‐stranded DNA viruses such as the herpesviruses. remain unclear but the targets may include host rather
It is a derivative of cidofovir, and is converted to cidofovir than viral targets. A study in mice also showed a synergistic
intracellularly by cellular phospholipases [171]. As a effect of adding artesunate to valaciclovir for the treat-
result of its predominantly intracellular activity, side‐ ment of herpes simplex encephalitis [182].
effects such as myelosuppression and nephrotoxicity HIV patients may develop genital herpetic lesions that
seen with cidofovir are significantly reduced [172]. become extensive and persist for long periods. These
Brincidofovir has the same broad‐spectrum activity lesions also frequently show resistance to aciclovir ther-
against double‐stranded DNA viruses as cidofovir. apy and may become very thickened resulting in a pseu-
Interestingly, brincidofovir has been shown to have at dotumourous appearance. A study of six patients showed
least a 100‐fold increased activity against HSV‐1 and ‐2, that the immunomodulators imiquimod and thalidomide

and at least a 10‐fold increased activity against VZV com- allowed five patients to achieve a complete response [183].
pared with cidofovir [173]. Like cidofovir and foscarnet, There have also been a few further case reports docu-
brincidofovir has been shown to be very useful for resist- menting the effectiveness of thalidomide for recalcitrant
INFECTIONS
ant CMV and HSV infections [174]. The most common anogenital HSV‐2 infections [184].
side‐effect of treatment with brincidofovir is diarrhoea.
It has also shown synergistic acitivity when added to aci- Surgery. Although surgery is usually contraindicated,
clovir therapy for the treatment of HSV infections [175]. occasionally removal of part of a nail overlying a herpetic
Two relatively new drugs, amenamevir and pritelivir, whitlow or perforation of the nail by electrocautery may
belonging to the class of so‐called helicase–primase be needed for pain relief [85]. Aspiration of tense vesicles
inhibitors, have so far shown promising results in phase II may also decrease pain.
clinical trials [176]. The viral helicase–primase complex is
essential for synthesis of primers and unwinding DNA Recurrent attacks
during viral replication. This complex represents an Many recurrences are mild and require no treatment.
attractive target as there is no eukaryotic equivalent and Topical aciclovir cream, applied to affected areas five
it is essential for viral replication. In addition, the actions times daily, is useful for troublesome recurrences if
of helicase–primase inhibitors are independent of viral started early in the prodromal phase. It is for external
thymidine kinase and can therefore protect infected and use only and not recommended for application to
uninfected cells from infection. Current antiviral research mucous membranes or the eye. Penciclovir cream is also
in HSV infections is focused on better oral availability of licensed for use in patients >12 years and in vitro pene-
synthetic drugs and natural compounds with different trates deeper into the epidermal cells than aciclovir, but
modes of action, e.g. antimicrobial peptides including needs to be applied every 2 hours for 4 days [185,186].
Topical idoxuridine in adults has also been used to 5 Chang T‐W. Herpes simplex. Clin Dermatol 1984;2:5–7.
6 Snavely SR, Liu C. Clinical spectrum of herpes simplex virus infec-
decrease pain and duration of recurrences [187] and
tions. Clin Dermatol 1984;2:8–22.
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INFECTIONS
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612
CHA PTER 5 1
Varicella Zoster Virus Infections

Manuraj Singh1 & Judith Breuer2
St George’s University Hospitals, London, UK
1
Great Ormond Street Hospital, UCL Division of Infection and Immunity, London, UK
2
Abstract spread in skin is dependent on replication within differentiating

keratinocytes. Knowledge of the pathogenesis of VZV infections
and latency has improved with in vitro models and xenograft
Varicella zoster virus (VZV) is characterized by its tropism for
studies in the severe combined immunodeficiency (SCID) mouse
epithelial tissue and persistence following primary infection

model. However, the exact mechanisms responsible for latency
in neuronal tissue. Primary infection with VZV causes varicella
and reactivation currently remain unresolved. Therapy for VZV
(chickenpox), a common childhood infection manifesting as a
infections, such as aciclovir, is not indicated in uncomplicated
vesicular rash on the face and trunk. Following primary infection
infections in childhood but can be lifesaving in patients with sig-
the virus infects sensory nerve endings to establish latency in
nificant immunosuppression. The development of effective live
dorsal root or cranial nerve ganglia. Reactivation of the virus
attenuated vaccines has been successful in reducing the incidence
causes a painful unilateral dermatomal rash known as herpes
and complications of VZV. However, the vaccine is not currently
zoster or ‘shingles’. Epithelial replication is central to the natural
recommended for widespread use in the childhood immunization
history of VZV infection. Following reactivation, VZV initially
programme within the UK.
infects the richly innervated isthmus of the hair follicle. Further
Key points features within the nucleus are nuclear enlargement, peripheral
condensation of chromatin, eosinophilic inclusions and
multinucleation.
• Varicella zoster virus (VZV) is an α‐herpesvirus, like herpes
• Definitive diagnosis of VZV infections is usually achieved by
simplex virus. VZV causes primary varicella (chickenpox) and,
polymerase chain reaction (PCR) or immunohistochemistry using
after reactivation from latency, herpes zoster (shingles).
specific VZV antibodies.
• Primary varicella is a common exanthema of childhood. Herpes
• Treatment of uncomplicated primary varicella in healthy children
zoster is less common in children but may be increased with
is generally not required. However patients with a history of
underlying immunodeficiency, such as human immunodeficiency
chronic skin disease such as moderate‐to‐severe eczema should
virus (HIV).
receive systemic treatment. Rapid initiation of intravenous
• The histological features of VZV infections are very similar
aciclovir can significantly reduce mortality in disseminated VZV
to those of HSV. They are characterized by varying degrees
infections in immunocompromised patients.
of epidermal blistering and necrosis. The typical cytopathic
globe [2–4]. It is unclear whether the strain distribution is

Brief introduction/history. Varicella zoster virus (VZV) is
actually driven by climate or other factors such as immi-
characterized by its tropism for epithelial tissue and per-
gration patterns. The most current genotypic classification

sistence following primary infection in neuronal tissue.
divides the virus into six different clades. Although clades
Primary infection with VZV causes varicella (chicken-
1 and 3 are predominant in Europe and North America,
INFECTIONS
pox), an infection manifesting as a vesicular rash on the

and clade 2 is predominant in Japan, there are no strict
face, trunk and proximal limbs. Following primary infec-
geographical implications in this naming nomenclature.
tion the virus infects sensory nerve endings to establish
Recent studies have also shown intra‐ and inter‐clade
latency in the dorsal root or cranial nerve ganglia.
recombination of the VZV genome [5–9].
Reactivation of the virus causes a painful unilateral der-
matomal rash known as herpes zoster or ‘shingles’.
Epithelial replication is central to the natural history of Epidemiology. Primary varicella (chickenpox) demon-
VZV infection [1]. strates a prominent seasonal pattern in temperate cli-
VZV is an α‐herpesvirus, which includes viruses such as mates, compared to herpes zoster which tends to occur
herpes simplex virus (HSV) 1 and 2, pseudorabies virus sporadically throughout the year. In temperate climates,
and Marek disease virus. Only VZV and HSV can infect chickenpox is most common in the winter and spring [10],
humans. Several studies have demonstrated a d istinctive but a later peak in June occurs in France and the UK [11].
geographical distribution of the major VZV genotypes Chickenpox also demonstrates periodic epidemics,
aligning with cool versus warm climate regions of the followed by years of lower incidence [12]. Chickenpox is
Chapter 51 Varicella Zoster Virus Infections 613
highly infectious with secondary attack rates in households vaccination has caused some controversy. There are some
ranging between 60% and 80% [13]. Chickenpox is a dis- models that predict an increase rather than a decrease
ease of childhood in temperate climates, with approxi- incidence due to the loss of exogenous immune boosting
mately 90% of cases occurring by the age of 10–14 years from the presence of reduced varicella circulation [28].
(mean, 6.7–10.6 years) [14]. The peak incidence of approx-
imately 90 cases/1000 tends to occur in the 1–4 age group Pathogenesis. All herpesvirus infections of the skin,
[15]. Although the incidence rate is much lower after the including HSV and VZV, result in epidermal cell lysis
age of 14, the case fatality rate rises from <5 to over 15 and clinical blistering. The model of primary varicella
deaths/100 000 cases in adults [16]. These figures are infection was first put together from the mouse pox
derived from the pre‐vaccination era, and the introduc- model described by Fenner in 1948 and clinical observa-
tion of widespread varicella vaccination is predicted tions [29,30]. This model describes two viraemic phases,
to decrease the incidence by at least 57%, and related but this has been superseded by studies from human
complications by 76% over time [17]. The case fatality rate skin xenografts explanted on the severe combined
is also higher in infants, pregnant women and immuno- immunodeficiency (SCID) mouse model which suggest
suppressed patients, compared to healthy young children. that the long 14‐ to 15‐day incubation period is due to
Within tropical climates (e.g. India and the West Indies) innate immunity in the skin [31]. VZV induces an antivi-
the epidemiology of varicella is remarkably different, ral response in neighbouring uninfected keratinocytes.
with a higher proportion of cases occurring in the adult This includes upregulation of interferons, particularly
population. The reasons for this difference still remain interferon (IFN)‐α, and signal transducer and activator
unclear; earlier studies suggested that rural living condi- of transcription 1 (STAT1) which activates other innate
tions within these tropical countries reduce transmission cytokines and important antiviral defence proteins such
rates [18,19], but more recent data have shown lower as promyelocytic leukaemia (PML) protein. Using the
infectivity of the virus in tropical climates [9]. SCID model it has been shown that antibodies blocking
The overall incidence of herpes zoster ranges from 1.2 the action of IFN‐α cause increased viral titres and blis-
to 3.4 per 1000 person‐years, and in contrast to chicken- ter formation in human skin xenografts. In addition,
pox has a much higher incidence in the elderly popula- VZV triggers particular cellular responses in infected
tion [20]. For example, in one study, incidence rates as cells that are distinct from the antiviral response of
high as 11.8 cases per 1000 person‐years in the 65–75+ age neighbouring uninfected cells. These include the upreg-
group have been reported [21]. The complications of zos- ulation of signal transducer and activator of transcrip-
ter include acute and chronic pain, neurological compli- tion 3 (STAT3) and subsequent induction of the
cations, ocular disease, secondary infection and visceral antiapoptotic protein survivin. In contrast to uninfected
involvement. Zoster complications occur much more fre- cells there is also inhibition of IFN‐α and STAT1 [32].
quently in the elderly and immunosuppressed [22]. In the Using the SCID mouse model, several viral proteins
elderly the complication of post‐herpetic neuralgia (pain (e.g. IE62, gB, gC, ORF47, ORF61) have been shown to be
persisting for more than 1 month after the onset of the very important for replication in these three‐dimensional
rash) has an increased prevalence [23]. The pathogenesis skin grafts but some, like gC and OR47, are not essential
of this disorder is poorly understood. It is very debilitat- in monolayer cultures [33–37]. This finding highlights the
ing and commonly resistant to standard painkillers. importance of the interaction between VZV infection and
Herpes zoster does occur in children, although its age‐ epidermal differentiation. A separate study that analysed
the host and viral transcriptome keratinocytes confirmed

specific incidence is less, and development of primary
varicella as an infant increases the risk. The risk of herpes that VZV gene and protein expression were significantly
zoster in patients with acute lymphoblastic leukaemia is increased with calcium‐induced epidermal differentia-
INFECTIONS
approximately 120 times greater than in patients without tion, as was viral replication [38].
an underlying malignancy [24]. Patients with suppressed In addition, certain proteins are more important for
cell‐mediated immune mechanisms are at increased risk replication in certain tissues. For example, mutations
of herpes zoster and its complications. Mortality is associ- causing deletions in the tegument protein ORF10 cause
ated with cutaneous dissemination and widespread vis- reduced infection in skin but have no effect on replication
ceral involvement. Patients with HIV/AIDS or certain in T cells [39]. Other examples of important viral proteins
cancers and transplant recipients fall into this high‐risk involved in skin replication include ORF61, which is cru-
group. Patients with haematological malignancies, par- cial for causing dispersal of antiviral promyelocytic leu-
ticularly Hodgkin lymphoma, and bone marrow trans- kaemia nuclear bodies (PML‐NBs) [40]. VZV glycoprotein
plant recipients are particularly at risk for the development E (gE) is essential for viral replication and also plays a role
of zoster. Untreated, the mortality rate is approximately in spread of the virus from cell to cell, secondary envelop-
20–40% in allogeneic bone marrow transplant recipients ment and viral entry [41,42]. The other glycoproteins
[25]. In Africa, herpes zoster is the commonest presenta- involved in similar processes to gE and also important for
tion of HIV [26]. The incidence rates of herpes zoster infection in skin are gB, gH and gI [43,44].
within the HIV population are 15–25 times higher than The SCID mouse model has also been used very pro-
the general population, and 3–7 times greater than the ductively to study the tropism of VZV in T cells and
elderly population [27]. The effect on herpes zoster neurons in fetal human thymus–liver and dorsal root
incidence after the introduction of widespread varicella ganglia (DRG) xenografts respectively [45,46]. The skin
xenografts are implanted beneath the mouse skin and induces a humoral response with production of IgA, IgM
the thymus–liver and DRG xenografts are placed and IgG anti‐VZV antibodies [58]. The last of these anti-
beneath the kidney capsule. This model allows the skin bodies tends to persist; it is a marker of previous infection
to fully differentiate into an epidermis with a stratum and serves to protect against reinfection. Infected patients
corneum and underlying dermis. As a result the interac- are generally considered contagious during the prodrome
tion of VZV, including vaccine and mutant strains, with and up until all the lesions are dry and crusted. VZV has
epidermal differentiation can be studied in more detail the ability to interfere with the expression of major histo-
[47]. Xenograft tissue infected with VZV can be har- compatibility complex (MHC) class I and class II proteins
vested at different time points and analysed using vari- required for CD8 and CD4 T‐cell recognition respectively,
ous techniques to look at gene and protein expression of leading to delayed clearance of virus‐infected cells
viral and epidermal proteins. This model also allows [59–62]. Open reading frame 66 (ORF66) of VZV encodes
assessment of the effect of interfering with cellular or a protein kinase that modulates apoptosis and interferon
viral proteins by treating the mice with various antibod- pathways, downregulates MHC class I protein expression
ies or inhibitors. In addition, novel antiviral therapies on cell membranes, and facilitates tropism of VZV for T
can be assessed using this model [48]. cells [63].
The method of transmission is primarily via the aerosol As stated previously, it is known that several VZV pro-
route from close contacts. The virus is thought to replicate teins, although dispensable for growth in tissue culture
first in the adenoids and tonsils [49], then the regional monolayers, are essential for skin infection in vivo. This dis-
lymph nodes, followed by a viraemia [50]. Viral transfer to crepancy is thought to relate to the interaction of VZV
migrating T cells in the tonsils may facilitate cell‐associated and epidermal differentiation. Using a calcium‐induced
viraemia, and preferential infection of CD4 T cells that keratinocyte differentiation model and RNA‐seq analysis
express skin homing markers may enhance VZV transport we showed that VZV infection specifically alters epidermal
to cutaneous sites of replication [51]. The precise mecha- differentiation, driving a specific pattern of changes that
nisms for virus transfer to skin are still not known, but T are characteristic of blistering and skin‐shedding diseases
cells may migrate out of capillaries to directly infect skin [38]. In particular VZV specifically reduces expression of
compartments, or transfer VZV directly to endothelial specific suprabasal cytokeratins such as keratin 1 (KRT1)
cells, from which the virus then spreads to epithelial com- and keratin 10 (KRT10) and desmosomal proteins, particu-
partments. The tropism of VZV for the melanocyte in tis- larly desmoglein 1 (DSG1) and desmocollin 1 (DSC1), lead-
sue culture may suggest the melanocyte as a putative skin ing to disruption of epidermal structure and function.
target in vivo [52]. A predominant mechanism by which These changes, together with upregulation of kallikreins
VZV enters cells is a process known as virus–cell fusion. and serine proteases, are also observed in genetic disorders
VZV receptors found to date include heparan sulphate of skin barrier function such as Netherton syndrome. These
proteoglycans [53], cation‐independent mannose findings taken together strongly suggest that VZV infec-
6‐phosphate receptor (MPRci) [54] and insulin degrading tion promotes blistering and desquamation of the epider-
enzyme (IDE) [55]. VZV binds to these receptors via its mis, both of which are essential for viral spread.
glycoproteins, which include gB, gH, gE and gI. Binding In summary, studies such as these highlight the inti-
to these receptors triggers fusion between the viral and mate host–pathogen interaction following VZV infection
host envelope, releasing the viral tegument proteins and of skin and show that VZV is dependent on epidermal
nucleocapsid into the host cell cytoplasm. The tegument differentiation and remodels the epidermal environment
proteins then migrate to and enter the host cell nucleus,
to promote its own replication and spread.

while the naked viral nucleocapsid fuses with the nuclear Histological examination of newly formed vesicles
membrane and releases the viral genome into the nucleus demonstrates prominent involvement of endothelial cells
INFECTIONS
[56]. The tegument contains key proteins such as IE62 and at an early stage. Epidermal alterations caused by the
IE63 that are key facilitators of viral gene transcription. virus are characterized by swelling of the cytoplasm and
Four VZV envelope glycoproteins contain mannose‐6‐ nucleus, followed by nuclear inclusions, cell fusion and
phosphate (Man 6‐P), and Man 6‐P blocks infection of cells balloon degeneration. Cell fusion results in the character-
by cell‐free VZV. A nice study showed that cell lines defi- istic multinucleated giant cell (MNC), a pathological hall-
cient in MPRci are resistant to infection by cell‐free virus mark of cutaneous herpes infections [64]. However,
but are readily infected by cell‐associated virus [54]. In histology alone cannot distinguish between HSV and
addition, these MPRci‐deficient cell lines produced higher VZV infections, and this must be confirmed using specific
titres of cell‐free virus when infected by cell‐associated immunohistochemical antibodies or molecular tech-
virus. This result suggests that intracellular MPRci appear niques. The vesicles are formed by the exudation of clear
to divert newly enveloped VZV to late endosomes for fluid from infected degenerating epithelial cells, and
destruction. Further work by the same group showed that contain numerous virions. The fluid turns turbid after
staining of VZV‐infected skin lesions demonstrates a migration of inflammatory cells into the vesicle. The floor
reduction in MPRci expression with keratinocyte differen- of the vesicle is formed by MNCs of the basal layer, and
tiation and provides an explanation for increased cell‐free the roof by the stratum spinosum of the epidermis. The
virus within the suprabasal layers of the epidermis [54,57]. vesicle roof eventually breaks down, releasing infective
The production of this cell‐free virus within the epider- virions into the atmosphere for further transmission to
mis facilitates person‐to‐person spread. Primary infection nonimmune hosts.
There are two modes of viral spread to the dorsal root and no production of infectious virus. However, deep
ganglia, where the virus lies dormant for the remaining sequencing using a technique called RNA‐seq detected
lifetime of the host. The first is the haematogenous route multiple viral mRNAs at low levels, the functional sig-
via infected T cells, which takes place during the viraemic nificance of which was considered unclear. This study
phase of primary varicella [65], and the second is the also showed that latently infected neurons treated with
retrograde neuronal transport of virions from mucocuta- antibodies to nerve growth factor (anti‐NGF Ab), simi-
neous lesions [66]. The mechanisms controlling latency lar to HSV, resulted in reactivation and production of
and reactivation of VZV are incompletely understood, infectious virus.
largely due to a lack of in vitro or in vivo models that This same study also compared a vaccine strain
reproduce both latency and reactivation. VZV latency and (vOka) with its parental wild type, designated pOka.
reactivation differ in several ways from HSV (see vOka is used as live attenuated vaccine and is effective
Chapter 50), as VZV is known to reactivate much less at preventing both primary varicella and herpes zoster.
frequently than HSV, and reactivation is more common in It was originally derived from pOka by serial propaga-
older individuals. tion in cultured cell lines [77,78]. vOka is a mixture of
Studies of sensory ganglia at autopsy have shown that genotypes and differs from pOka by mutations in multi-
about 4% of neurons contain low copy numbers (2–9/cell) ple different regions of the genome. This genetic differ-
of VZV genomes [67]. Latent viral DNA exists in a state ence is likely to account for its attenuation [7,47,79–82].
where the genome of the virus is joined ‘end to end’ vOka was equivalent to pOka in establishing latency
to form structures consistent with unit length episomes/ but was impaired for reactivation after neurons were
concatemers and from which viral gene transcription is treated with anti‐NGF Ab. vOka also showed lower
restricted. There is increasing evidence that this restriction levels of viral transcription by RNA‐seq analysis during
is epigenetically regulated. One proposed mechanism for latency compared to pOka.
α‐herpesvirus reactivation, including HSV and VZV, The result of continued VZV reactivation is the pain-
involves a three‐stage process of latency, generalized ful vesicular rash herpes zoster, which usually involves
deregulation (animation) and progression through DNA the dermatomal distribution of a single sensory nerve.
replication. Models looking at explants of VZV‐infected The infectious virus is carried in an antegrade direction
human trigeminal ganglia taken post mortem show gener- towards the skin. Occasionally patients may present
alized deregulation, characterized by transcription of with the characteristic pain in a dermatomal distribution
multiple viral genes. This is followed by reactivation char- without the rash [83]. Infection is then restricted by
acterized by coordinated VZV DNA replication, but the innate cutaneous responses in addition to VZV‐specific
exact mechanisms that trigger this transition are not fully T cells. The increased frequency and risk of severe zoster
understood to date [67]. in the elderly and immunosuppressed populations is
There has been controversy regarding the expression related to a deficiency in VZV cell‐mediated immunity.
and translation of viral VZV genes within neurons of sen- IFN‐γ‐secreting VZV‐specific CD4+ T cells in the blood
sory and cranial nerve ganglia. Many studies have found are significantly reduced in the elderly. In addition, a
low‐level transcription of ORF63, which encodes the pro- relatively recent study has found that the number of
tein IE63, to be the most abundantly expressed gene VZV‐specific CD4+ T cells is equivalent in the skin of the
and protein respectively in human ganglia post mortem young and elderly. However, in the elderly there is an
[68–70]. IE63 has antiapoptotic functions that might facili- increased number of inhibitory T cells, such as Foxp3+

tate the transition to latency [71,72]. However, the pres- regulatory T cells, in the skin [84]. The increased risk of
ence of IE63 is yet to be confirmed in human ganglia in herpes zoster in HIV‐infected patients would suggest
vivo, and may be confounded by cross‐reacting antibodies that VZV‐specific T cells also limit reactivation in ganglia,
INFECTIONS
[73,74]. The expression that is seen immediately post mor- however this is still not currently proven. It is interesting
tem may reflect very early reactivation. Only ORF63 to note that the histological features of primary varicella
mRNA could be detected by reverse transcriptase‐ and herpes zoster are very similar. However, herpes
quantitative polymerase chain reaction (RT‐qPCR), in zoster lesions tend to show more folliculo‐sebaceous and
ganglia obtained less than 9 hours post mortem. However, endothelial inflammation [85]. This may reflect the high
increased levels of ORF63 mRNA and multiple other VZV density of cutaneous nerves around these structures. The
mRNAs were detected when ganglia were obtained more histopathological examination of ganglia during VZV
than 9 hours post mortem. This later finding suggests that reactivation shows inflammation, necrosis and cellular
the detection of multiple VZV mRNAs reflects reactiva- disruption of neuronal and non‐neuronal cells [86]. This
tion rather than true latency [75]. inflammation may extend to the anterior horn of the
A recent study by Sadaoka et al. has shown that viral spinal cord, resulting in motor dysfunction [87,88].
gene expression may be even more restricted than this
during latency [76]. Using an in vitro system of neurons Clinical features and differential diagnosis
derived from human embryonic stem cells (hESCs), Chickenpox
they were able to produce selective axonal infection Primary varicella (chickenpox) is a highly contagious
and maintenance of latent VZV using cell‐free virus. exanthema which is most common in childhood with a
This latent infection model was characterized by an peak incidence between 5 and 9 years of age [89]. The
inability to detect viral gene expression by RT‐qPCR infection is transmitted by aerosol droplets from the
respiratory tract and is initially characterized by a viral usage of salicylates in children has been abandoned [95].
prodrome consisting of fevers, malaise, myalgia, headache Certain patient groups such as adults, pregnant women
and arthralgia. This prodrome typically lasts 2–3 days and the immunocompromised have a higher risk of these
before onset of the characteristic vesicular eruption. The complications. Up to half the deaths from chickenpox
incubation period ranges from 10 to 21 days with a mean occur in adults [11]. In immunocompromised hosts the
of 14–17 days. The eruption typically occurs in crops giv- mortality risk is higher and lesions may become large and
ing rise to lesions at different stages of evolution. The ulcerated (varicella gangrenosa) or even chronic and ver-
time to crusting and noninfectivity varies between 2 and rucous in nature [96]. The mortality rate ranges from
12 days. The initial eruption consists of erythematous approximately 10% to 30% in immunosuppressed patients
macules 2–4 mm in diameter, followed by tear drop such as those suffering from leukaemia, HIV or congeni-
vesicles (likened to ‘dew drops on rose petals’) that subse- tal immunodeficiency and organ transplant recipients
quently become pustular and crusted (Fig. 51.1). The rash [97]. Among the congenital immunodeficiencies, those
is most prominent on the trunk followed by the scalp and associated with natural killer (NK) or natural killer T
proximal limbs. Mucosal involvement is relatively com- (NKT) cell deficiency are particularly associated with
mon although palm and sole involvement is a rare event. severe and potentially life‐threatening primary varicella
The eruption is usually pruritic but this symptom varies [98]. Patients with primary immunodeficiencies associ-
from mild to severe. Systemic symptoms tend to be mild ated with reduced interferon levels are also at risk of
in children but are frequently severe in neonates, adults severe primary varicella [31,99]. Other much rarer
and immunocompromised patients [90]. complications include nephritis, hepatitis, myocarditis,

Common complications of varicella include skin and arthritis, orchitis, uveitis, glomerulonephritis, rhabdomy-
soft tissue infections, usually due to Group A Streptococcus olysis, haemorrhagic disease and thrombocytopenia.
and Staphylococcus aureus [91,92]. This occurs in approxi- Purpura fulminans is a recognized, albeit rare complica-
mately 5–10% of cases. Rare reports of necrotizing fasciitis tion of primary varicella in children due to acquired
post primary varicella have been reported [93]. Although deficiencies in protein S and/or protein C [100–103].

rare, pulmonary and neurological syndromes are the next Blood tests commonly show features of disseminated
most common [94]. In children, pneumonia is usually due intravascular coagulation. Another important complica-
to secondary bacterial infection compared to direct viral tion of primary varicella is the increased risk of stroke in
pneumonitis in adults. The rare neurological complica- the immediate months after infection. A study by Thomas
tions include aseptic meningitis, encephalitis, cerebellar et al. showed that there was a fourfold increased risk of
ataxia, Guillain–Barré syndrome (GBS), transverse myeli- stroke in children up to 6 months after chickenpox
tis and Reye syndrome, which is now uncommon because compared to a twofold increased risk in adults [104].

Interestingly, there was no significant risk of stroke
7–12 months after chickenpox in either adults or children
[105]. The post‐varicella arteriopathy predominantly pre-
sents with acute arterial ischaemic stroke or transient
ischaemic attack and is associated with vascular stenosis
that tends to subsequently regress [106]. There is also
some evidence that VZV vasculopathy may occasionally
lead to the development of intracerebral aneurysms, with
or without haemorrhage. In addition, there has been a

link between VZV vasculopathy and giant cell arteritis
[107]. VZV vasculopathy is diagnosed by the presence of
INFECTIONS
either VZV DNA or anti‐VZV IgG antibody in cerebrospi-

nal fluid [108,109].
The development of primary varicella in pregnancy can
affect both the mother and the fetus. Although rare, vari-
cella pneumonia may lead to maternal death. Intrauterine
infection carries the risk of congenital varicella syndrome
(CVS), which is approximately 1.2–2.2%. The greatest risk
of this complication occurs in mothers who contract
primary varicella within the first two trimesters. The man-
ifestations include low birthweight and skin lesions that
typically manifest as scar‐like lesions in a dermatomal dis-
tribution and/or aplasia cutis. Other well‐recognized
features include cataracts, microphthalmia, chorioretini-
tis, skeletal hypoplasia and neurological abnormalities.
The last complication is typified by mental retardation,
microcephaly and dysfunction of urinary and rectal
Fig. 51.1 Varicella/chickenpox. Source: Courtesy of Dr Friedlander and sphincters [110]. Prenatal diagnosis is now aided by
Dr Tom. various tests including serial ultrasound examination,
virus‐specific IgM estimation and amniocentesis to confirm pustular and crusted, as in primary varicella. They may
viral transmission by PCR techniques [111–113]. After also coalesce to form large bullae and may take on a
20 weeks’ gestation the risk of CVS is negligible although haemorrhagic appearance.
there is an increased risk of herpes zoster in early life. In Common complications include secondary bacterial
addition, a large study found no cases of CVS in mothers infection, scarring and keloid formation. Rarely necrotiz-
who developed herpes zoster in pregnancy [110]. ing fasciitis may complicate an episode of herpes zoster,
The development of primary varicella less than 7 days as in primary varicella. Post‐herpetic neuralgia, defined
before birth in the mother carries a very high risk of as pain persisting many months after the acute episode, is
neonatal varicella, due to a lack of protective maternal a relatively common complication in the elderly but is less
antibodies in the newborn [114]. This is a serious compli- common in childhood cases [122]. It is important to recog-
cation with a 30% mortality rate if left untreated, mostly nize involvement of the ophthalmic branch of the trigemi-
due to hepatitis and pneumonitis. The risk is said to be nal nerve which may produce serious eye complications.
highest for mothers who contract the disease from 5 days The Ramsay Hunt syndrome is due to involvement of the
before delivery to 2 days after. With prompt treatment in seventh cranial nerve and is characterized by facial nerve
the form of varicella zoster immune globulin (VZIG) and paralysis, palatal and external auditory canal lesions, and
intravenous aciclovir the mortality rate drops to approxi- auditory and vestibular symptoms [123].
mately 5% [115]. The VZV vaccine is a live attenuated vaccine and there
is a risk of herpes zoster in children who receive
Herpes zoster the vaccine. Another very important complication is the
Herpes zoster or shingles is due to reactivation of VZV high risk of more severe disease and potentially fatal
from dorsal root ganglia of sensory nerves. This is analo- disseminated herpes zoster in immunocompromised
gous to reactivation of herpes simplex virus but reactiva- patients. This is especially pertinent to those who have
tion typically occurs less frequently with VZV. Herpes significant cell‐mediated immunodeficiency such as leu-
zoster in children is not uncommon but if recurrent or kaemia patients and bone marrow and organ transplant
multidermatomal should prompt investigation to exclude recipients [124]. The presentation in such patients also
an underlying immunodeficiency such as HIV [116]. The tends to be more atypical, with lesions tending to be
introduction of widespread varicella vaccine, as in the more bullous, haemorrhagic and ulcerative. The lungs,
USA, has reduced the incidence of herpes zoster by liver, gastrointestinal tract and brain tend to be sites of
65–79% in vaccinated individuals. However, there are preferential involvement in disseminated disease [125].
data showing an increased incidence of herpes zoster The most common brain manifestation is a progressive
among children with varicella infection aged ≥2 years in leukoencephalitis.
the post varicella vaccination era [117,118]. This may Verrucous VZV, characterized by persistent hyperkera-
reflect loss of exogenous immune boosting due to reduced totic lesions resembling viral warts, is an unusual but
varicella circulation. It is important to realize that herpes well‐recognized presentation in patients with immunode-
zoster is a common presentation of HIV in Africa. Herpes ficiency and is most commonly seen in patients with AIDS
zoster typically presents as a painful and vesicular rash in [126]. Similar lesions have occasionally been reported in
a unilateral and dermatomal distribution. Rarely, noncon- transplant patients and rarely as a consequence of intrau-
tiguous multidermatomal cutaneous involvement may terine infection. Interestingly a study showed reduced
occur. Although less common in childhood, herpes zoster expression of the envelope proteins gE and gB in chronic

is a common disorder in the elderly and immunocompro- verrucous lesions [127]. In addition, herpes zoster may
mised host, and affects 10–20% of people during their life- complicate the immune reconstitution inflammatory syn-
time. The disorder can affect any dermatome but the most drome (IRIS) in HIV patients treated with antiretroviral
INFECTIONS
common are thoracic, lumbar and trigeminal nerve therapy [128].
involvement resulting in facial lesions. The risk of child- Another interesting but under‐recognized phenom-
hood zoster is greatly increased in patients with immuno- enon is the occurrence of Wolf’s isotopic response in
compromise or malignancies [119]. Childhood‐onset the scars of resolved herpes zoster [129]. Wolf’s iso-
systemic lupus erythematosus (SLE), commonly associ- topic response is the name given to a separate and new
ated with lymphopenia and immunosuppressive treat- skin disorder occurring at the site of a healed and
ment, is also a significant risk factor for herpes zoster, unrelated condition. There have been many conditions
although most patients had a benign outcome in a large associated with this phenomenon occurring at the site
study [120]. In addition, herpes zoster can develop in of herpes zoster scars, including granuloma annulare,
immunocompetent children as a consequence of intrau- sarcoid, granulomatous vasculitis, lichen sclerosus,
terine infection or postnatal exposure at an early age lymphoma, pseudolymphoma, leukaemia cutis and
[121]. In adults and the elderly, herpes zoster is usually a skin cancers.
febrile illness preceded by paraesthesia or pain in the Herpes zoster may also be complicated by acute, suba-
affected dermatome. However, these prodromal features cute and chronic neurological complications, even occa-
are typically lacking in childhood cases. If there is a sionally in the absence of a clinical rash [95,130].
prodrome, the rash typically occurs after 2–4 days and is Neurological complications include cranial nerve palsies,
characterized by grouped vesicles on an erythematous motor paresis, ocular disorders and vasculopathy. Due
and oedematous plaque. These vesicles rapidly become to this vasculopathy, and similar to primary varicella,
herpes zoster is associated with a subsequent increased

risk of stroke and myocardial infarction (approximately
twofold for both). Again the risk is mainly within the first
6 months after the zoster episode and zoster vaccination
does not seem to modify the risk [131]. This increased risk
of acute cardiovascular events following an episode of
zoster is seen particularly below the age of 40 [132]. The
pathogenesis is similar to the VZV vasculopathy follow-
ing primary varicella described previously.
The differential diagnosis of VZV primarily involves
HSV infections, particularly when VZV infections are
localized such as in herpes zoster, and the ulcerative or
verrucous lesions occurring in immunocompromised
patients. Although primary and recurrent HSV‐1 and
‐2 infections are usually localized, they can produce a
more widespread systemic infection in neonates and
immunocompromised patients mimicking primary vari- (a)
cella. PCR studies can readily distinguish between the
viruses HSV‐1, HSV‐2 and VZV [133]. Other considera-
tions for primary varicella, depending on the clinical set-
ting, may include immunobullous disorders, severe drug
reactions such as Stevens–Johnson syndrome, bacterial
folliculitis or disseminated bacterial or fungal infections
in immunosuppressed patients.
Laboratory/histology findings. The histological features

of the cutaneous lesions of VZV in the form of primary
varicella or herpes zoster are very similar to those of
HSV‐1 or ‐2. Isolated or prominent follicular involvement
is said to be a pointer in favour of VZV infections, particu-
larly herpes zoster, when compared to HSV [134]. In fully
developed lesions there are varying degrees of epidermal
necrosis and blister formation within the epidermis
(Fig. 51.2a and b). The two main mechanisms involved in (b)
the formation of these intraepidermal vesicles/blisters are Fig. 51.2 (a) Low‐power histology of a case of herpes zoster showing an
known as balloon and reticular cell degeneration. However, intraepidermal blister filled with eosinophilic fluid and containing
the pathognomonic changes are evident within the nucleus. acantholytic cells. Similar findings would be seen in primary varicella
These consist of nuclear enlargement with peripheral con- and herpes simplex infections. (Haematoxylin–eosin stain; original
magnification ×40.) (b) High‐power histology of same case as (a)
densation of chromatin giving rise to a ground glass
demonstrating characteristic cytopathic changes of varicella zoster virus
appearance of the nucleus. The earliest abnormality within infections. The infected cells near the base of the blister demonstrate
the cytoplasm is vacuolization. In addition, there are moulding, enlargement and peripheral condensation of nuclear chromatin
usually varying degrees of multinucleation of infected
giving rise to a ground glass appearance. Characteristic multinucleated
INFECTIONS
keratinocytes and intranuclear eosinophilic inclusions. giant cells are also seen. In addition intranuclear and intracytoplasmic
There is commonly a fibrinopurulent exudate associated eosinophilic inclusions are seen focally, the former are known as Cowdry
with a dermal infiltrate that varies from mild to dense. This type A inclusions. (Haematoxylin–eosin stain; original magnification ×400.)
infiltrate is typically composed of perivascular, periad-

nexal and interstitial lymphocytes with variable numbers which typically terminates under the epidermis via
of neutrophils, and occasionally eosinophils may be promi- nonmyelinated nerve fibres.
nent. A lichenoid and/or vasculitic reaction pattern in the Rare histological presentations of VZV are more com-
absence of typical cytopathic changes has been termed monly seen in immunosuppressed patients. They include
‘herpes incognito’ [135]. When faced with this combination vasculitis and adnexal involvement, including folliculo‐
of reaction patterns in a histological section, it would be sebaceous and/or eccrine involvement, in the absence of
prudent to perform serial sections to look for diagnostic typical epidermal changes (Fig. 51.3a and b) [138,139].
nuclear cytopathic changes. The verrucous or wart‐like lesions that are typically
Early biopsies from herpes zoster typically show encountered in immunosuppressed patients such as those
cytopathic changes within the follicular epithelium with HIV demonstrate hyperkeratosis and acanthosis
[136]. This reflects the neural pathway of viral spread with viral cytopathic changes and less vesiculation [126].
from the dorsal root ganglia via myelinated nerve fibres Clinical features usually allow the distinction between
that terminate at the level of the isthmus of the hair fol- HSV and VZV but there are many situations in which this
licle [137]. This is in contrast to the reactivation of HSV may be difficult or impossible. This is especially the case
techniques that can be used to diagnose cutaneous herpes

infections include electron microscopy, immunofluores-
cence of blister contents, growth in tissue culture and
in situ hybridization. However, the most common tech-
niques employed in routine diagnostic practice are immu-
nohistochemistry and PCR [141].
Treatment and prevention. Treatment of chickenpox in

previously healthy children is primarily symptomatic.
Prevention of secondary bacterial infection and allevia-
tion of pruritus and/or pain are the main goals. Oral
paracetamol and ibuprofen may be used for fever and/or
pain and oral antihistamines can be prescribed for pruri-
tus. Topical therapies such as calamine lotion may p rovide
symptomatic relief from pruritus.
VZV infections may be treated by administration of
(a) one of the following licensed drugs: aciclovir (and its
prodrug valaciclovir), penciclovir (and its prodrug fam-
ciclovir), ganciclovir, cidofovir, brincidofovir, brivudine
and foscarnet [142]. By far the most commonly used
drug is aciclovir and its related compounds. All these
drugs work by inhibiting DNA replication. Aciclovir,
ganciclovir and penciclovir are nucleoside analogues
that must be phosphorylated to the monophosphate
form by virus‐encoded thymidine kinases (TKs) and
then further phosphorylated to triphosphate forms by
cellular kinases before they become competitive inhibi-
tors of DNA polymerase by competing with the binding
of natural deoxyguanine triphosphate. The other drugs
inhibit viral DNA synthesis independent of viral TKs
[143]. See herpes simplex infections (Chapter 50,
Treatment and prevention) for more details of cidofovir,
brincidofovir, brivudine and foscarnet.
(b) Generally, systemic antiviral therapy should be
Fig. 51.3 (a) Low‐power histology of a renal transplant patient who reserved for complicated varicella and infections occur-
presented with a painful purpuric rash down one leg. This case ring in children with significant risk factors for moderate
demonstrates a rare presentation of herpes zoster without epidermal or life‐threatening disease. These include patients with
involvement. The histology shows a mild upper dermal infiltrate associated immunocompromise, moderate‐to‐severe chronic skin
with prominent red cell extravasation and a multinucleated cell within the
disorders such as eczema, those over 12 years of age and
hair follicle. (Haematoxylin–eosin stain; original magnification ×100.)

(b) Immunofluorescence microscopy of same case as (a), using a polyclonal
those on long‐term oral corticosteroids. Several large
antibody against IE63 (an immediate early varicella zoster virus protein). randomized controlled studies have shown that oral

There is positive red staining within the hair follicle confirming a diagnosis aciclovir treatment for chickenpox is most effective when
INFECTIONS
of herpes zoster presenting with purpura and absent epidermal given within the first 24 hours [144,145]. This early treat-
involvement (note lack of red staining within the epidermis). ment was also associated with reduced viral shedding
(Original magnification ×40.) and a quicker resolution of the rash and associated consti-
tutional symptoms. A 5‐day course of aciclovir was also
in disseminated infections and those occurring with atyp- found to be sufficient, as treatment continued for 7 days
ical presentations in immunocompromised patients. Since provided no additional benefit [146]. If the patient is
the histological findings of HSV and VZV are very simi- severely immunocompromised, intravenous aciclovir
lar, a definitive diagnosis is usually made either via therapy should be started as soon as possible. The recom-
specific immunohistochemistry or by PCR/molecular
mended dose in this situation is 10 mg/kg every 8 hours
methods on viral swabs. HSV‐1 and ‐2 antibodies are rou- or 500 mg/m2 per dose three times daily for 7–10 days,
tinely available in most diagnostic cellular pathology and should be given as soon as possible and ideally
laboratories. Although there are sensitive and specific within 48–72 hours. Studies have shown that intravenous
VZV antibodies commercially available, they tend not to aciclovir prevents potentially fatal dissemination and vis-
be so readily available in routine diagnostic practice [140]. ceral disease, in both primary varicella and herpes zoster,
PCR is a very sensitive technique that can readily distin- in immunosuppressed patients [147]. VZIG is a high‐titre
guish HSV‐1, HSV‐2 and VZV infections. In addition, preparation of VZV IgG immunoglobulin. VZIG
PCR tests have yielded positive results from the oral should be strongly considered in immunocompromised
cavity even after lesions have apparently resolved. Other patients or non-immune pregnant women with a known
exposure to VZV. The earlier it can be given the better, but given 2 months apart by intramuscular injection. It has
it can be given up to 96 hours post exposure. Other indi- been shown to reduce the risk of herpes zoster by 97% in
cations for VZIG include infants born to mothers at risk of those aged 50 years and older, and by 91% in those aged
neonatal varicella, adult patients, and infants born before 70 years and older [154,155]. Another study has shown
28 weeks and exposed to chickenpox in the first 3 months that the gE‐specific cellular and humoral immunogenic-
of gestation. The therapeutic effect of VZIG lasts approxi- ity persists for at least 6 years after two doses of the
mately 3–4 weeks [148,149]. vaccine [156]. The vaccine also holds great promise for
Treatment of herpes zoster includes the above sympto- vaccinating immunocompromised patients as in these
matic measures in addition to specific antiviral therapy. In patients live vaccines are contraindicated [157,158]. A
clinical trials, systemic therapy decreases the duration of study looking at the long‐term effectiveness of the vari-
the disease and reduces the risk of post‐herpetic neuralgia cella vaccine showed that it reduced the incidence of
if given within 72 hours of onset [150]. As for chickenpox, varicella by up to 10‐fold and showed no significant loss
intravenous aciclovir therapy should be instituted as soon of efficacy over time [159].
as possible in severely immunosuppressed patients to
prevent dissemination and life‐threatening disease.
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1539–44.

INFECTIONS
624
CHA PTER 5 2
Poxvirus Infections
Susan Lewis‐Jones1 & Jane C. Sterling2
Ninewells Hospital & Medical School, Dundee, UK
1
Department of Dermatology, Cambridge University Hospitals NHS Foundation Trust, Addenbrooke’s Hospital, Cambridge, UK
2
Introduction, 624 Parapoxvirus infection, 643

Orthopoxvirus infection, 626 Yatapoxvirus infection, 647
Abstract with an infected animal, the lesion(s) develop at the site(s) of c ontact
and may be associated with systemic features. Over the course of a
few days, the initial macule evolves to a papule, a vesicle and then an
Poxvirus infections are most commonly acquired from animals
ulcer, which will heal spontaneously over days to weeks. The geo-
and are therefore relatively uncommon and usually occupational
graphical distribution depends on the reservoir hosts of the virus.
hazards, although childhood infections often occur. After contact
Key points • Recovery and healing occur without specific treatment, but
supportive therapy may be necessary in severe cases, although
fatality is very rare.
• Orthopoxvirus and parapoxvirus infections in humans are
• Smallpox has been eradicated worldwide and routine vaccination
zoonotic.
with vaccinia virus is no longer performed.
• Lesions develop as papules, which quickly progress to vesicles
and then ulcers.
infections are caused by the viruses of sheep/goatpox

Introduction (capripoxvirus), swinepox (suipoxvirus), myxomatosis
Poxviruses of vertebrates are classified into two subfami- (leporipoxvirus), crocodile pox (crocodylidpoxvirus) or
lies: Chordopoxvirinae and Entomopoxvirinae. All human avianpox (avipoxvirus).
poxvirus infections are caused by viruses in genera within Poxviruses are large complex DNA viruses that
the Chordopoxvirinae and, although closely related, have replicate in the cytoplasm of infected cells using virus‐
distinct genetic and antigenic features [1]. The causative associated, DNA‐dependent polymerase and are charac-
agents of molluscum contagiosum (see Chapter 48) and terized by the production of skin lesions. All poxviruses
smallpox are the only poxviruses exclusive to humans. encode cytokine and cytokine receptor analogues that
Smallpox was eradicated by 1980 and therefore, apart allow them to modulate the immune response and
from molluscum contagiosum, naturally occurring perpetuate their existence. They are not only cytopathic,
human poxvirus infections are acquired solely from causing host tissue damage, but also encode an array of
animal reservoirs [2]. immunomodulatory molecules that affect the severity
INFECTIONS
The viruses concerned belong to three genera, and of disease [3]. They are generally brick shaped or ovoid,
knowledge of the geographical distribution of the viruses varying in size from 240 × 300 nm (orthopoxvirus) to
and the potential animal sources is of considerable value 160 × 250 nm (parapoxvirus) [1,4].
in differential clinical diagnosis [2]. Poxvirus zoonoses Electron microscopy can be of considerable value in
range worldwide from trivial occupational hazards rapid diagnosis [5,6] (Fig. 52.1). Their size and the pres-
caused by parapoxviruses, which are less likely to cause ence of conspicuous surface tubules enable poxviruses to
paediatric infections, to rare and geographically be differentiated from herpesviruses. Furthermore, the
restricted infections such as monkeypox, which causes characteristic long, spirally wound, surface tubule of the
considerable mortality in children (Table 52.1). There are parapoxviruses enables them to be differentiated from
occasional reports of zoonotic parapoxvirus infections orthopoxviruses and tanapoxviruses. The epidemiologi-
in those working with New Zealand red deer and seals, cal history, clinical features and electron microscopy
but there is at present no good evidence that human will in many instances indicate a certain diagnosis but if
Table 52.1 Poxviruses causing human disease
Genus Virus (species) Distribution Sources of human Comment

infection (less
important sources
in parentheses)
Molluscipoxvirus Molluscum contagiosum Worldwide Human

virus
Orthopoxvirus Camelpox Africa, Middle East, Asia, Camels Occupational hazard, papulovesicular
southern Russia lesions progressing to ulcer, usually on
hands or arms
Cowpox Europe, including some Cats (cows) (rodents [R]) Painful haemorrhagic ulcer; relatively more
states of the former USSR common in young girls
Monkeypox West Africa, Congo basin Squirrels (R) (monkeys) Severe generalized infection; >400 cases
since 1970, c. 90% in children with c.
15% mortality; limited case‐to‐case
spread. USA outbreak from infected
imported rodents
Buffalopox India Buffalo (R?) Occupational hazard, painful skin lesion;
virus is subspecies of vaccinia
Taterapox Vaccinia infection only after vaccination
Occupational. Resembles cowpox.
Not endemic Araçatuba and Cantagalo viruses
Vaccinia, bovine vaccinia Brazil and South America No reservoir host (subspecies of vaccinia)
Cattle (R?)
Variola (smallpox) Eradicated Not naturally occurring
Parapoxvirus Orf Worldwide Sheep (R), goats (R), Relatively painless granulomatous skin
cattle (R) lesions; occupational hazard of those in
contact with reservoir hosts
Pseudocowpox (milker’s Worldwide Sheep (R), cattle (R) Occupational hazard of those in contact
nodes) with reservoir hosts; clinically similar
to orf
Sealpox Europe and USA (and Seals (R?) Resembles orf
regions frequented by Confirmed by PCR as human zoonosis in
seals) seal handlers
Yatapox Tanapox Congo basin, Kenya Monkeys (R) Nodular skin lesions usually singular, with
pyrexia
R, reservoir hosts.

INFECTIONS
(a) (b) (c)

Fig. 52.1 Electron micrographs of (a) cowpoxviruses showing the common ‘mulberry’ (M) form with conspicuous short, randomly arranged surface tubules
and the less common ‘capsule’ (C) form with deeper stain penetration; (b) whole M and C forms of parapoxvirus, showing the characteristic long spiralling
of the surface tubule of the former; (c) whole herpesviruses showing one particle with intact nucleocapsid and one broken, allowing stain penetration
(phosphotungstic acid, ×120 000). Source: Reproduced with permission of Springer Nature.
necessary the viruses may be isolated and identified [3,5]. Orthopoxvirus infection
Rapid identification by orthopoxvirus‐specific polymer-
ase chain reaction (PCR) is quicker and more specific than Smallpox
culture and is of growing availability [7–10]. Specialized
laboratories are available for the diagnosis of smallpox Introduction and history. Smallpox (variola major) has
should the need arise. altered the course of world history [1,2]. For centuries an
Parapoxviruses are not routinely isolated by the diag- endemic disease throughout the world, it caused millions
nostic laboratory. A differential diagnosis of orf or milk- of deaths and frequently left survivors with damaged
er’s nodules may be suspected based on animal contact health, unsightly pock‐marked skin and blindness. In
if known; if there is no known contact with infected mediaeval times, the overall mortality ranged from 10%
animals, a diagnosis of orf/milker’s nodules is often to 60%, with an average of about 25–30%. By the twenti-
suspected, based on the clinical appearance. Poxviruses eth century, mortality had fallen to between 5% and 25%,
are resistant to environmental conditions and will sur- although the childhood mortality rate remained as high
vive sufficiently in dried scabs or in vesicle fluid dried as 40% [2,3].
on a microscope slide to enable them to be transported The origins of smallpox are uncertain but from sequence
by post or courier to the laboratory. However, if a dif- analysis it has been suggested that the original animal
ferential laboratory diagnosis is required, virus trans- source was a wild rodent in Africa [4]. During the first
port medium should be used to preserve more labile millennium ad, the disease spread through Asia into
viruses. Zoonotic poxviruses will grow well in human Europe and, around 700 ad, into North Africa [1–3]. The
cell cultures and in cells from their reservoir hosts; Spanish Conquistadors carried it to the New World in the
orthopoxviruses grow well on chick chorioallantois 1500s, where it spread rapidly in the ‘virgin population’.
[5,6]. Preliminary identification is by suitable biological It is estimated that over 3.5 million native South Americans
markers, but increasing use is being made of DNA anal- died in smallpox epidemics. A similar epidemic occurred
ysis, which enables individual strains within a species to in North America when smallpox wiped out millions of
be recognized [11,12]. Reviews of human zoonotic pox- the members of native tribes [1–3,5]. The annual smallpox
virus infections include details of other hosts and poten- mortality rate in Europe in the eighteenth century was
tial therapeutic agents [2,13]. estimated at about 200 000–600 000, making up 7–12% of
all deaths. The majority of these mortalities occurred in
children, especially infants, and the disease accounted for
one third of all childhood deaths [1]. The succession of the
References
1 Esposito JJ, Baxby D, Black DN et al. Poxviridae. In: Murphy FA, European monarchy was considerably altered by small-
Faquet CM, Bishop DHL (eds) Virus Taxonomy: Classification and pox deaths [1].
Nomenclature of Viruses. Vienna: Springer‐Verlag, 1995:79–91. In the early twentieth century, a minor form of smallpox,
2 Essbauer S, Pfeffer M, Meyer H. Zoonotic poxviruses. Vet Microbiol
2010;140:229–36.
alastrim, with a mortality of 1% or less, appeared in Africa
3 Stanford MM, McFadden G, Karupiah G, Chaudhri G. and spread throughout the USA and Europe [3,5–7].
Immunopathogenesis of poxvirus infections: forecasting the impend- Vaccination alone was unsuccessful in eradicating
ing storm. Immunol Cell Biol 2007;85:93–102. smallpox and in 1967, when the estimated world preva-
4 Smith GL. Poxviruses. In: Mahy BWJ, ter Meulen V (eds) Topley and
Wilson’s Microbiology and Microbial Infections, Virology, 10th edn. lence was 10–15 million, the World Health Organization
London: Wiley, 2007:578–93. (WHO) commenced a global programme of identifica-
5 Nakano JH, Esposito JJ. Poxviruses. In: Schmidt NJ, Emmons RW tion, isolation and containment of cases and contacts [2,3].
(eds) Diagnostic Procedures for Viral, Rickettsial and Chlamydial

Diseases, 6th edn. Washington, DC: American Public Health
As a result, the last naturally occurring case of smallpox
Association, 1989:224–65. was recorded in Somalia in 1977, although a small UK
INFECTIONS
6 Baxby D, Bennett M, Getty B. Human cowpox 1969–93: a review laboratory outbreak did occur in 1978 [3]. In 1980, the
based on 54 cases. Br J Dermatol 1994;131:598–607. WHO declared the world to be free from smallpox, the
7 Ropp SL, Jin Q, Knight JC et al. PCR strategy for identification and
differentiation of smallpox and other orthopoxviruses. J Clin first and to date the only virus infection to have been suc-
Microbiol 1995;33:2069–76. cessfully eradicated [2,3]. After this, all stocks of smallpox
8 Naidoo J, Baxby D, Bennett M et al. Characterisation of orthopoxvi- virus were destroyed except for those held in specialized
ruses isolated from feline infections in Britain. Arch Virol
laboratories in the USA and the former USSR for research
1992;125:261–72.
9 Abrahão JS, Drumond BP, Trindade G de S et al. Rapid detection of purposes [5].
Orthopoxvirus by semi‐nested PCR directly from clinical specimens:
a useful alternative for routine laboratories. J Med Virol
2010;82:692–9.
Epidemiology and pathogenesis. The smallpox virus is a
10 Ryabinin VA, Shundrin LA, Kostina EB et al. Microarray assay for large brick‐shaped orthopoxvirus measuring 240 × 300 nm
detection and discrimination of Orthopoxvirus species. J Med Virol (Fig. 52.1a). The virus is very stable and in the past
2006;78:1325–40. attempts to attenuate it proved largely unsuccessful [3,8].
11 Inoshima Y, Morooka A, Sentsui H. Detection and diagnosis of para-
poxvirus by the polymerase chain reaction. J Virol Methods Epidemics were most common in winter and spring,
2002;84:201–8. transmission occurring by inhalation of infected droplets
12 Abrahão JS, Lima LS, Assis FL et al. Nested‐multiplex PCR detec- in aerosolized form or indirectly from fomites in clothes
tion of Orthopoxvirus and Parapoxvirus directly from exanthematic
and bedding [2,3,5–7]. The infectious dose is unknown
clinical samples. Virol J 2009;6:140.
13 Lewis‐Jones MS. Zoonotic pox virus infections in man: review article. but is likely to be very small [5,9]. There are no known
Curr Opin Infect Dis 2004;17:81–9. animal or insect vectors [2,3,5].
Chapter 52 Poxvirus Infections 627
The virus enters through the mucosal surfaces of the Table 52.2 A classification of clinical types of variola major
nasopharyngeal tract and is transmitted to the local
lymph nodes, where it replicates. After 3 or 4 days, an Type Features
asymptomatic viraemia occurs, transmitting the small-
Ordinary type Raised pustular skin lesions
pox virus to the rest of the reticuloendothelial system.
• Confluent: confluent rash on face and forearms
Further replication occurs in the spleen, bone marrow • Semi‐confluent: confluent rash on face, discrete
and lymph nodes. Between 8 and 10 days after exposure, elsewhere
infected lymphocytes cause a second symptomatic virae- • Discrete: areas of normal skin between
mia, homing particularly to the vessels in the papillary pustules, even on face
dermis and infecting local epidermal cells to produce Modified type Like ordinary type but with an accelerated course
cutaneous lesions. Persons incubating the disease Variola sine Fever without rash caused by variola virus;
eruptione serological confirmation
become infectious only at this point. Their saliva is most
Flat type Pustules remained flat; usually confluent or
infectious during the first week of illness and especially semi‐confluent; usually fatal
when oral lesions rupture. Ruptured pustules are also Haemorrhagic Widespread haemorrhages in skin and mucous
very infectious, but scabs much less so [2,3,5]. The virus type membranes
is not as contagious as chickenpox or influenza and the • Early: purpuric rash; always fatal
secondary attack rate among unvaccinated contacts • Late: haemorrhages into base of pustules;
ranges from 37% to 88% [3]. Transmission usually occurs usually fatal
among close contacts, but occasionally there are more
Source: Fenner F, Henderson DA, Arita I et al. Smallpox and its Eradication.
extensive outbreaks [9].
Geneva: World Health Organization, 1988 (based on Rao 1972 [10]).
Reproduced with permission of the World Health Organization.
Clinical features. The most recent illustrated accounts of
the clinical features of smallpox are found in publications
by Dixon in 1962 [7], Rao in 1972 [10] and Fenner et al. in 5 In variola sine eruptione, fever occurred without rash in
1988 [3]. Rao [10] studied 3544 cases in India and reclassi- previously vaccinated persons or in infants with mater-
fied smallpox into five types (Table 52.2). This classifica- nal antibodies. This form of smallpox could only be
tion was later adopted by the WHO [3]. confirmed by serological testing. This last type may not
1 ‘Ordinary’ smallpox accounted for the majority of cases: cause transmissible smallpox.
88.8% of unvaccinated patients and 70% of vaccinated The incubation period for ‘ordinary’ smallpox is around
patients. There are three subtypes. The confluent sub- 10–14 days (range 7–17 days) [2,3,5–7]. Patients are
type was the most serious, with a mortality of 62% in largely asymptomatic and remain noninfectious until the
the unvaccinated, and was characterized by lesions that end of the second week, when there is an abrupt onset of
were confluent on the face and forearms but discrete a high prodromal fever associated with severe malaise
elsewhere. Patients with the semi‐confluent subtype had and ‘flu‐like’ symptoms. Most have severe headache,
confluent lesions only on the face (37% mortality), usually frontal, and backache is common. Vomiting
while those with the discrete form, the most common occurs in about half of patients, sometimes with severe
type, had no confluent lesions (9.3% mortality). abdominal pain. About 10% of patients, especially
2 A milder, modified type, rarely fatal and with an acceler- infants, develop diarrhoea. Very rarely, infants develop
ated course, occurred in 2% of unvaccinated persons acute dilation of the stomach, which is usually fatal.
and 25% of those previously vaccinated.

Some adults become delirious and convulsions may
3 The rare purpuric or haemorrhagic‐type smallpox (3%, occur in children. The fever falls by the second or third
usually adults), with widespread haemorrhage into day and erythematous mucosal lesions (enanthema)
INFECTIONS
skin and mucous membranes, caused early death from appear in the mouth and pharynx, often associated with
septicaemia. Subconjunctival haemorrhages and bleed- pharyngitis. The exanthema develops the following day
ing from any orifice could occur. Characteristically, the and consists of small cutaneous erythematous macules
incubation period was short and the prodromal illness [3,5–7,10].
was severe and accompanied by abdominal pain. The The eruption is characteristically centrifugal, develop-
‘early type’ was always fatal and the ‘later’, with haem- ing initially on the face, hands and palms and then spread-
orrhage into pustules, usually fatal. It occurred more ing distally to the trunk and limbs and the soles
commonly in pregnancy. (Figs 52.2–52.4). The lesions evolve more slowly than in
4 The flat type (7%), fatal in 66% of cases, occurred chickenpox, developing over a period of 4–7 days. The
mainly in children (72%). A short incubation period lesions begin as small ‘papules’, in reality early vesicles,
and severe prostrating illness was followed by conflu- which are firm and hard. They evolve briefly into 2–4 mm
ent or semi‐confluent, slowly developing lesions. vesicles and then into deep, firm, circular pustules
These lesions never formed pustules but remained (4–6 mm). In severe cases, these lesions become confluent.
soft and flattened with an erythematous and velvety At any one time, unlike chickenpox, all lesions are in the
appearance. The distribution was not always centrifu- same stage of evolution. By the seventh or eighth day of
gal. In survivors, the skin healed without scab forma- the rash, the pustules start to flatten and become umbili-
tion and widespread epidermal peeling sometimes cated (Fig. 52.3) and then gradually crust by the end of the
occurred. second week, lasting longest on the palms and soles. Final
(a) (b) (c)
Fig. 52.2 (a–c) ‘Ordinary’ smallpox, discrete type, demonstrating the centrifugal distribution of lesions, particularly on the face and distal limbs, hands and
feet with fewer lesions on the trunk. Source: Reproduced with permission from the World Health Organization.
(a)
INFECTIONS
Fig. 52.4 ‘Ordinary’ smallpox in a child at the umbilicated/crusted stage.

Note the confluent lesions on the face. Source: CDC/James Hicks [Public
domain], via Wikimedia Commons.
resolution of lesions occurs at about the end of the

third week of the rash, leaving postinflammatory hyper‐
(b) and/or hypopigmentation initially. Although this gradu-
Fig. 52.3 Close‐up of typical lesions on the hands and feet showing ally fades, a proportion develop fibrosis, causing deeply
involvement of the palms and soles with early umbilication of lesions in (a). pitted scars or ‘pock’ marks of 2 mm or more. Destruction
Source: Reproduced with permission from the World Health Organization. of sebaceous glands causes the face to be particularly
deformities may occur [3]. As variola is cytocidal, most

pregnant women miscarry in the early stages of smallpox;
however, if the fetus survives to term it has temporary
immunity from maternal antibodies [3]. Congenital small-
pox is usually fatal [3,10].
In a few vaccinated patients, there may be a fleeting
erythematous rash during the prodromal stage, particu-
larly around the vaccination scar and in the axillae, groins
and popliteal fossae [3,4]. The more toxic forms of small-
pox, apart from the haemorrhagic type, are less common
in vaccinated individuals [3].
‘Modified‐type’ smallpox sometimes occurs in previ-
ously vaccinated individuals and is hardly ever fatal. The
prodrome may still be severe but the course of the disease
is accelerated, the lesions often being smaller and fewer
and the secondary eruptive fever absent [3,10].
Differential diagnosis. Early lesions or milder forms of

smallpox could be confused with many eruptive exan-
thems, especially chickenpox, but a full‐blown case of
ordinary‐type smallpox is unlikely to be missed. Children
are usually extremely toxic and display the typical cen-
trifugal distribution of lesions [3,5–7,10,11]. In chicken-
pox, the rash is centripetal, seen mainly on the trunk and
Fig. 52.5 Granulomatous smallpox lesions of the face causing destruction rarely on the palms and soles. Unlike smallpox, there is a
of the sebaceous glands. rapid evolution and healing of lesions in recurrent crops,
so that many lesions are in different phases in the same
body site. Monkeypox is almost identical to smallpox,
affected in 65–80% of cases (Fig. 52.5) [3,5,6]. Involvement with the same acral distribution, but with more marked
of organs other than the skin, mucous membranes and adenopathy. Lesions of eczema herpeticum may all be at
reticuloendothelial system is uncommon and most deaths the same stage of development (Fig. 52.6) but are smaller
(usually between days 10 and 16) result from toxaemia and more superficial, rupturing easily and crusting within
and hypotension, probably caused by circulating immune the first week. Scanning electron microscopy or PCR will
complexes and soluble variola antigens [3,5]. Smallpox rapidly differentiate between herpes‐ and poxviruses.
infection confers lifelong immunity in most cases, but Other acral blistering disorders, such as hand, foot
occasional subclinical smallpox was reported in patients and mouth disease, are sufficiently distinctive to make
who had previously had smallpox [3]. confusion unlikely. In bullous erythema multiforme
The fever of ordinary‐type smallpox is bimodal. In the major, the lesions are not uniform in size or shape. The
prodromal stage, there is a peak of around 40 °C, followed lesions on the palms and soles of secondary syphilis are
of varying sizes and do not progress to form blisters.

by low‐grade pyrexia for a few days. The second peak of
around 39 °C occurs during the maximum evolutional or Haemorrhagic smallpox, however, could easily be mis-
pustular stage in the second week of the rash and gradu- taken for leukaemia or other purpuric conditions such as
INFECTIONS
ally subsides, often in a swinging pattern [3,5–7]. meningococcal meningitis (Waterhouse–Friderichsen
Persistence of fever after scab formation is a poor prog- syndrome), purpura fulminans, vasculitis or even drug
nostic indicator [3]. Respiratory involvement and cough, reactions. Breman and Henderson [11] gave a clear
with death from pneumonia, is more likely to occur in account of the differential diagnosis and management of
severe cases. Blindness was reported as common in the smallpox. In addition, public health websites such as
older literature but occurred in only about 1% of patients those of the WHO [12] or the USA Centers for Disease
in the twentieth century [3,7,11]. It was usually as a result Control and Prevention (CDC) [6] have excellent photo-
of keratitis, corneal ulceration and scarring, and rarely graphic images and an algorithm for the differential
secondary infection or panophthalmitis. Encephalitis was diagnosis of smallpox.
reported in 1 in 500 cases of variola major and 1 in 2000 of
variola minor [3]. It usually resolved slowly without com- Laboratory findings and histology. The variola virus can
plications, but very rarely (1%) a typical perivascular sometimes be detected in swabs from the nasopharynx as
demyelination developed, similar to that occurring with early as 5–6 days before the development of rash. The
vaccinia, measles or varicella [7]. Arthritis and osteomy- patient is not infectious at this time [4]. In addition,
elitis developed in about 2% of children, possibly as a lesional swabs, blister fluid, scabs, blood and urine
result of viral involvement of the metaphyses [3,11]. Signs should be taken, using the precautions and equipment
may be missed in the acute stages, but later sequelae of supplied by regional smallpox teams. These should
limb shortening, flail joints, subluxations and gross be transported by special arrangements to a designated
filled with large numbers of neutrophils. Destruction

occurs mainly in the epidermis and superficial dermis, so
that hair follicles and eccrine glands can recover. However,
the more superficial sebaceous glands are destroyed. In
the later stages, granulation tissue is seen around the
necrotic areas and causes deeply pitted scars. Electron
microscopy demonstrates two forms, the encapsulated or
‘C’ form (the most infectious) and the nonencapsulated or
mulberry ‘M’ form, which is more common (approxi-
mately 80%) (Fig. 52.1a).
Treatment. Smallpox is a hazard group 4 organism and

suspected cases should be treated as an international
health emergency [5,6,11], with immediate isolation at the
(a)
place of diagnosis and notification to locally designated
smallpox teams.
In response to the potential threat of the use of smallpox
in a terrorist attack, protocols were developed in most coun-
tries for the management of suspected cases of smallpox,
with designated regional teams for isolation, assessment,
treatment, decontamination and vaccination of contacts.
Detailed descriptions are beyond the scope of this chapter
and readers are referred to the appropriate public health
authority guidelines or website in their own country.
Hospital patients should be nursed in an environment
of high‐efficiency particulate air (HEPA) filtration by pre-
viously vaccinated staff [5]. Vaccination of all contacts
and their contacts, a process known as ring vaccination,
should be undertaken [3,5,11]. Fluid replacement and
attention to skin and eye care are essential. Although its
effect in smallpox is unproven, topical idoxuridine could
(b)
be used for corneal lesions [3,11]. Patients should be
Fig. 52.6 Eczema herpeticum of the distal arm and hand. (a) The
observed for signs of septicaemia, hypotension or pur-
distribution mimics smallpox in this case. (b) A close‐up shows the typical
lesion of herpes, some of which are at the same stage of evolution, but
pura and treated appropriately with general supportive
there is already early crusting at day 4 and the lesions are smaller and less measures. Secondary infection and pneumonia require
firm than smallpox. Source: Courtesy of Dr Susan Lewis‐Jones. antibiotic therapy. Vaccinia immune globulin (VIG),
which was used in the treatment of smallpox and compli-
cations of vaccination in the 1970s [3], is not currently
reference laboratory. Electron microscopy will quickly recommended during either the incubation period or
identify the presence of an orthopoxvirus, but PCR will
clinical stages of smallpox and should be reserved for the

be required for rapid diagnosis of variola virus [13,14]. complications of vaccination [5,6]. In the 1960s, semithi-
Isolation of virus on live cell cultures or growth on egg ocarbazone (marboran) derivatives were used to treat
INFECTIONS
chorioallantoic membrane is slow and outdated and smallpox, but their benefit was not substantiated [5]. The
nucleic acid identification is still required to distinguish DNA polymerase inhibitor cidofovir given intravenously
between different orthopoxviruses. At present, serologi- in the first days after exposure has been shown to be
cal testing does not differentiate between orthopox spe- effective against most poxviruses in the laboratory and in
cies or between recent infection and past vaccination, an animal model [16,17] and in theory could be used to
although in the future newer IgM detection methods may treat smallpox. However, this medication has significant
help to do so [11]. renal toxicity and should be administered with probene-
cid and hydration. It is not known to be more effective
Pathology. Multiplication of virions within the cellular than vaccination in the immediate postexposure phase in
cytoplasm of the basal and lower spinous keratinocytes humans [5]. Patients who die from smallpox should be
produces the typical cytoplasmic eosinophilic inclusion cremated as soon as possible and mortuary workers vac-
bodies common to all orthopox infections [15]. In variola, cinated [5].
they are small and located close to the nucleus, sur-
rounded by a clear halo (Guarnieri bodies) [15]. Similar References
bodies occur in vaccinia. Severe intracellular oedema, bal- 1 Hopkins DR. Princes and Peasants. Smallpox in History. Chicago:
University of Chicago Press, 1983.
looning and cell necrosis occur, producing microscopic 2 Kennedy RB, Lane JM, Henderson DA, Poland GA. Smallpox and vac-
vesicles that enlarge and coalesce to form large unilocular cinia. In: Plotkin SA, Orenstein WA, Offit PA (eds) Vaccines, 6th edn.
vesicles. During the pustular phase, the vesicles become Elsevier, Saunders, 2012:718–45.
3 World Health Organization. The Smallpox Eradication Programme – SEP stylets or stored in quills [1–3]. Supplies of vaccine were
(1996–1980). http://www.who.int/features/2010/smallpox/en/ (accessed
later assured by growth on calf skin, a practice that resulted
5 January 2019).
4 Hughes AL, Irausquin S, Friedman R. The evolutionary biology of in particular outrage from the antivaccination lobby [2].
poxviruses. Infect Genet Evol 2010;10:50. Secondary infection was common and reduced the vac-
5 Henderson DA, Inglesby TV, Bartlett JG et al. Smallpox as a biological cines’ effectiveness. In order to counteract this phenome-
weapon. JAMA 1999;281:2127–37.
6 Centers for Disease Control and Prevention. Smallpox home page
non, vaccination was often performed at multiple sites
website: http://www.cdc.gov/smallpox/ (accessed 5 January 2019). until the 1930s. The introduction of glycerated calf serum
7 Dixon CW. Smallpox. London: Churchill, 1962. Available at: www. considerably reduced the risk of infection and in the twen-
nlm.nih.gov/nichsr/esmallpox/esmallpox.html (accessed 5 January tieth century mass vaccination with stable freeze‐dried
2019).
8 Baxby D. Jenner’s Smallpox Vaccine: the Riddle of Vaccinia Virus and vaccines using vaccinia virus was both more effective and
its Origin. London: Heinemann Educational Books, 1981. less dangerous. This replaced the older vaccines [1–4].
9 Wehrle PF, Posch J, Richter KH et al. An airborne outbreak of small- Routine vaccination ceased in the early 1970s as the risk
pox in a German hospital and its significance with respect to other
recent outbreaks in Europe. Bull World Health Organ 1970;43:669–79.
of smallpox infection disappeared. For some years after
10 Rao AR. Smallpox. Bombay: Kothari Book Depot, 1972. Available that, medical and military personnel and scientists work-
at: www.nlm.nih.gov/nichsr/esmallpox/esmallpox.html (accessed ing with wild‐type or recombinant vaccinia virus were
5 January 2019). vaccinated. The recommendations now are that only
11 Breman JG, Henderson DA. The diagnosis and management of small-
pox. N Engl J Med 2002;346:1300–8. those with high‐risk work involving contact with replica-
12 WHO Slide Set on Diagnosis of Smallpox. www.who.int/entity/csr/ tion‐competent, fully infective strains of vaccinia, should
disease/smallpox/Smallpox‐English.ppt (accessed 5 January 2019). receive vaccination every 10 years [5]. Since 2002, the
13 Espy MJ, Cockerill FR III, Meyer RF et al. Detection of smallpox virus
threat of smallpox as a terrorist weapon (see The implica-
DNA by LightCycler PCR. J Clin Microbiol 2002;40:1985–8.
14 Ropp SL, Jin Q, Knight JC et al. PCR strategy for identification and tions of the use of smallpox as a bioterrorist weapon) has
differentiation of smallpox and other orthopoxviruses. J Clin again produced a rise in vaccinated personnel, including
Microbiol 1995;33:2069–76. those in the military and smallpox response teams.
15 Grayson W. Infectious diseases of the skin. In: Calonje JE, Brenn T,
Lazar A, McKee PH (eds). Pathology of the Skin: With Clinical
Correlations, 4th edn. Elsevier, Saunders, 2011:760–895. Vaccinia and modern vaccination. Vaccinia is an ortho-
16 Andrei G, Snoeck R. Cidofovir activity against poxvirus infections. poxvirus 300–400 nm in diameter, currently classified as a
Viruses 2010;2:2803–30.
species distinct from taterapoxvirus [6]. Its origins are
17 Israely T, Paran N, Lustig S et al. A single cidofovir treatment rescues
animals at progressive stages of lethal orthopoxvirus disease. Virol J unknown but it possibly originated from an extinct form
2012;9:119.

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Set in 9.5/11.5 pt Palatino by SPi Global, Pondicherry, India

List of Contributors, xi 10 Differential Diagnosis of Neonatal Erythroderma, 121

Section 3 Atopic Dermatitis and Related

Section 1 Development, Structure and 13 Epidemiology of Atopic Dermatitis, 167

17 Atopic Dermatitis and Related Disorders:

5 Neonatal Skin Care, 63 18 Atopic Dermatitis: Complications, 245

6 Transient Skin Disorders in the Neonate 19 Management of Atopic Dermatitis, 253

7 Congenital and Acquired Infections in the Neonate, 84

9 Developmental Anomalies, 101 21 Adolescent Seborrhoeic Dermatitis, 279

22 Irritant Contact Dermatitis, 287 39 Pitted Keratolysis, Erythrasma and Erysipeloid, 456

23 Allergic Contact Dermatitis, 300 40 Lyme Borreliosis, 463

24 Hypereosinophilic Disorders, 316 41 Bartonella Infections, 475

25 Juvenile Plantar Dermatosis, 335 42 Mycobacterial Skin Infections, 485

26 Perioral Dermatitis, 338 43 Rickettsial Disease, 503

44 Endemic Treponematoses: Yaws, Pinta and Endemic

45 Tropical Ulcer, 523

28 Psoriasis: Aetiology and Pathogenesis, 350

Section 9 Viral Skin Infections and Opportunistic

38 Cutaneous Manifestations of Gram‐negative 56 Cutaneous Infections in Immunocompromised

Section 10 Parasitic Skin Infestations Section 14 Blistering Disorders

61 Noxious and Venomous Creatures, 733

78 The Porphyrias, 957

66 Erythema Multiforme, Stevens–Johnson Syndrome Section 16 Granulomatous Diseases

67 Hypersensitivity Reactions to Drugs, 785 82 Granuloma Annulare, 1006

83 Orofacial Granulomatosis, 1017

Section 13 Nutritional Disorders

88 Primary Cutaneous Lymphoma, 1044 102 Panniculitis in Children, 1207

89 Childhood Leukaemias and Lymphomas, 1063 103 Lipodystrophies, 1221

Section 19 Histiocytic Disorders Section 23 Mosaic Disorders, Naevi and

106 Epidermal Naevi, 1260

Section 25 Vascular Tumours and Malformations

101 Lipoma and Lipomatosis, 1195 119 Infantile Haemangiomas, 1425

121 Disorders of Lymphatics, 1452 136 Incontinentia Pigmenti, 1718

137 Premature Ageing Syndromes, 1725

122 Inherited and Acquired Hyperpigmentation, 1463

125 Disorders of Hypopigmentation, 1492 140 Rothmund–Thomson Syndrome, Bloom Syndrome,

Section 27 Disorders of Keratin and

129 Mendelian Disorders of Cornification 144 Other RASopathies, 1857

130 Keratosis Pilaris and Darier Disease, 1599

131 The Erythrokeratodermas, 1608 145 Cutaneous Vasculitis, 1865

151 Erythromelalgia, 1961 Section 37 Psychological Aspects of Skin

165 Assessing and Scoring Life Quality, 2241

154 Cutaneous Manifestations of Endocrine Disease, 1993

155 Autoinflammatory Diseases and Amyloidosis, 2010 168 Topical Therapy, 2275

171 Surgical Therapy, 2310

173 Sedation and Anaesthesia, 2330

159 Hair Disorders, 2103

176 The Role of Histopathology and Molecular Techniques

Maria Eugenia Abad, MD Ali Alikhan Rosalia A. Ballona

Carol M. Black, DBE, MD, FRCP, Ralph P. Braun, MD Jane C. Burns, MD

Clinical Assistant Professor of Dermatology

Despina Eleftheriou, MBBS, Gayle O. Fischer, MBBS, FACD, Pamela Gangar, MD

FRCP, FRCPCH, MD, MMEd, MA

Research Fellow Warren R. Heymann, MD

Department of Dermatology and Division of

Gregor Holzer, MD Arun C. Inamadar, MD, FRCP Ayşen Karaduman, MD

Melanie Makhija, MD, MSc Jemima E. Mellerio, MD, FRDP Dermatology

Maria L. Marino, MD MRCP Derm Medical Director

Christian R. Millett, MD Iria Neri

Section 10 Parasitic Skin Infestations Section 14 Blistering Disorders

Section 19 Histiocytic Disorders Section 23 Mosaic Disorders, Naevi and

Section 27 Disorders of Keratin and

151 Erythromelalgia, 1961 Section 37 Psychological Aspects of Skin

Introduction in a continuum of events that modifies the skin. It is

iochemical or immunohistocytochemical assays for the

document these regional differences consistently through

e vidence for these interactions in the development of