Allergic and Immunologic Diseases: A Practical Guide To The Evaluation, Diagnosis and Management of Allergic and Immunologic Christopher C Chang

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Allergic and Immunologic Diseases
A Practical Guide to the Evaluation, Diagnosis and Management
of Allergic and Immunologic Diseases
Allergic and
Immunologic Diseases
A Practical Guide to the Evaluation,
Diagnosis and Management of Allergic and
Immunologic Diseases
Edited by
Christopher Chang
Division of Pediatric Immunology, Allergy and Rheumatology,
Joe DiMaggio Children‘s Hospital, Memorial Healthcare System,
Hollywood, FL, United States; Division of Rheumatology, Allergy and
Clinical Immunology, University of California Davis School of Medicine,
Davis, CA, United States
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SET ISBN: 978-0-323-95061-9
Volume 1 ISBN: 978-0-12-820603-4
Volume 2 ISBN: 978-0-323-95322-1
For Information on all Academic Press publications

visit our website at https://www.elsevier.com/books-and-journals
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Typeset by MPS Limited, Chennai, India
Dedication
Dedicated to Laura, Francesca, Santiago, Michael,

Jennifer and the memory of my father, who passed away
during the COVID-19 pandemic
Contents
List of contributors xliii

Preface li
Volume 1
Section A
Background
1. Introduction 3
Christopher Chang
The origin of allergy and immunology as a specialty 4
The role of allergy and immunology in the world of medicine 5
The allergy and immunology workforce in the United States 6
Training of allergy and immunology specialists 8
Professional organizations 9
Allergy and immunology journals 9
Summary 16
References 16
2. A brief history of allergy and immunology 17

Kranthi Nomula, Kyndra Liburd, Xiang Ge, JinLyu Sun and
Christopher Chang
Introduction 18
An early history of immunology 18
The age of vaccines 18
Discovery of cellular and humoral components of immunity 19
Complement 21
Allergic diseases and early descriptions and treatment of
“hay fever” and food allergy 22
Blood typing, transfusions, and plasma proteins 23
Early studies on transplantation 25
A modern history of allergy and immunology 25
Molecular immunology and the biotechnology revolution 26
vii
viii Contents
Immortal cells and the ability to produce monoclonal antibodies 28

The 21st century—a brave new world 28
Checkpoint inhibitors and the modern treatment of cancer 39
COVID-19 39
Conclusion 40
References 41
3. Basic immunology 43
Christopher Chang
Introduction 44
Primary and secondary lymphoid organs 45
Innate and adaptive immunity 45
Characteristics and attributes of the human immune system 46
Rapidity of response 46
Diversity of response 46
Specificity of the response 49
Strength (amplification) of the response 49
Regulation of the response 50
Immunological concepts 51
Autoimmunity and immune tolerance 51
Protein phosphorylation 52
The ability to recall—immunological memory 53
Apoptosis and autophagy 53
Immunosenescence 54
Epigenetics 55
Immune paradigms 55
T helper cell paradigms 55
Th17 Treg paradigm 56
Stromal immunology 56
Cellular immunity—cells of the immune system 57
Granulocytes 57
Mononuclear cells 59
Lymphocytes 59
Natural killer cells 65
Monocytes and macrophages 65
Ontogeny of immune cells and antibodies 66
T cell dependent and T cell independent antigens 66
Humoral immunity—immunoglobulins and other molecules 67
Antigen recognition 67
Cytokines 72
Chemokines 72
Growth factors 78
Complement 78
Computational immunology 86
Summary and conclusions 86
References 86
Contents ix
4. The allergy and immunology history and physical 89

Hanadys Ale, Marlen Rodriguez and Wilfredo Cosme-Blanco
Introduction 90
The allergy and immunology chief complaint and its relevance 91
The main elements of history taking 91
The history of the present illness 92
The past medical history 92
Family history 92
Environmental history 92
Social history 93
Review of systems 93
Essentials of the clinical history and physical exam approach
in a patient with ocular complaints 94
Clinical history 94
Physical exam 96
in a patient with upper respiratory complaints 98
Clinical history 98
Physical examination 99
in a patient with lower respiratory complaints 101
Clinical history 101
Physical exam 101
in a patient with skin complaints 102
Physical exam 104
in a patient with gastrointestinal complaints 105
Physical exam 106
in a patient with recurrent infections 109
Physical exam 110
Conclusions 111
Acknowledgments 111
References 117
5. Basic genetics and epigenetics for the immunologist

and allergist 119
Meng Chen, Stéphanie Lejeune, Xiaoying Zhou and Kari Nadeau
Introduction 120
The human genome and the genetic code 120
Epigenetic modifications 121
x Contents
Types of genetic studies 121

Gene environment interactions 125
Ongoing research and future areas of research 127
Diagnostic tools 127
Genetic and epigenetic basis of allergic disease 127
Atopic dermatitis 127
Asthma 131
Allergic rhinitis 132
Food allergy 132
Drug allergy 133
Genetic and epigenetic basis of immunologic diseases 134
Primary immunodeficiency 134
Hereditary angioedema 135
Applications of genetics and epigenetics 135
Understanding endotypes 135
Predicting who will be affected 136
Predicting response to treatment 136
Challenges and limitations of genetic testing 138
Interpretation 138
Cost 138
Accessibility 138
Ethical considerations 138
Conclusions 139
References 139
6. Laboratory skills for immunologists: utility and

limitations with emphasis on allergy research 145
Rasika Patkar, Christine Y.Y. Wai, Nicki Y.H. Leung, Iris Nkamba,
Shang An Shu and Patrick S.C. Leung
Abbreviations 146
Introduction 148
Section 1: Western blotting 150
Overview 150
Preparation and procedure 150
Data analysis 152
Applications 152
Section 2: Enzyme-linked immunosorbent assay 154
Overview 154
Data analysis 157
Applications 157
Section 3: Flow cytometry 158
Overview 158
Data analysis 161
Applications 163
Contents xi
Section 4: Basophil activation test 165

Overview 165
Data analysis 167
Applications 168
Section 5: Microarray 169
Overview 169
Data analysis 170
Applications 171
Section 6: Animal models 172
Overview 172
Data analysis 175
Applications 175
Conclusion 176
Future directions and challenges 176
Western blotting 176
ELISA 177
Flow cytometry 177
BAT 177
Microarray 177
Animal models 179
References 179
7. Developments and emerging technologies in allergic

and immunologic disease management 187
Nicki Y.H. Leung, Christine Y.Y. Wai, Tihong Shao,
Ka Hou Chu and Patrick S.C. Leung
Abbreviations 187
Introduction 189
Section 1: Diagnosis of allergic diseases 190
Component-resolved diagnosis 190
Molecular microarray for the diagnosis of allergic diseases 192
Basophil activation test 193
Section 2: Latest development of allergen-specific immunotherapy 193
Novel routes of AIT 194
Novel adjuvants of AIT 197
Virus-like particles for AIT 198
DNA vaccines for AIT 198
Section 3: Omics in the management of allergic diseases 199
Multiomics approach on severe food-associated respiratory allergy 203
Multiomics approach on reaction severity in peanut allergy 203
Section 4: Artificial intelligence in the management of allergic diseases 204
AI in asthma research 204
AI in food allergy research 205
xii Contents
AI in atopic dermatitis research 206

Section 5: Omics and AI in the management of immunodeficiency
diseases and autoimmune diseases 206
Concluding remarks—implications of novel technologies in
allergy and immunology research and care 210
References 211
8. Genomics technologies and bioinformatics in allergy

and immunology 221
Satishkumar Ranganathan Ganakammal, Ke Huang, Magdalena
Walkiewicz and Sandhya Xirasagar
Introduction 222
Types of genetic diseases and variants 223
High throughput methods 224
Chromosomal microarray 224
Sanger sequencing 225
Next-generation sequencing 225
Application of high-throughput sequencing 232
Research variants 240
Downstream exploratory analysis 240
Data science and big data analytics 245
Importance of scalable infrastructure and data standardization 248
Conclusion 251
Acknowledgment 251
References 251
Section B
Diagnosis of allergic diseases
9. Epicutaneous and intradermal skin testing 263
Divya Seth and Pavadee Poowuttikul
Introduction 264
Mechanism of skin response 265
Indications of skin testing 266
Allergic rhinitis/conjunctivitis 266
Food allergy 266
Drug allergy 266
Insect sting allergy 266
Latex allergy 267
Allergic broncho-pulmonary aspergillosis 267
Factors affecting skin testing 267
Medications 267
Allergen extracts 272
Skin test sites 273
Contents xiii
Physiological characteristics 273

Number of skin test 275
Selection of allergens 275
Cross-reactivity 277
Methods of skin testing 279
Prick-puncture tests 280
Intradermal tests 287
False-positive and false-negative skin test results 291
The use of skin tests for nondiagnostic purposes 292
Standardization of allergens 292
Immunotherapy studies 293
Pharmacologic studies 293
Epidemiological studies 293
Correlation with other diagnostic tests for diagnosing allergic diseases 293
In vitro tests/serology 293
In vivo tests/allergen challenges 294
Conclusion 295
References 295
10. Skin prick testing for foods 303

Roxanne C. Oriel and Scott H. Sicherer
Introduction 304
Approach to food allergy diagnosis 304
Pathophysiology of immunoglobulin E-mediated food allergy and
rationale for skin prick testing to foods 308
Skin prick testing procedure 311
Skin prick test measurement 314
Skin prick test interpretation 314
Skin prick testing variability 316
Device type variability 316
Quantity of antigen 317
Limitations of skin prick testing 317
Safety 318
Conclusions 318
References 318
11. In vitro methods to assess allergy 323

Nicole Akar-Ghibril and Christopher Chang
Introduction 324
Total IgE levels 325
Allergen-specific IgE 326
In vitro testing for environmental allergens 334
In vitro testing for food allergens 334
In vitro testing for venom allergy 335
In vitro testing for latex 336
xiv Contents
In vitro testing for drugs 337

In vitro testing for occupational protein allergens 337
Tryptase 338
In vitro tests primarily used in research—basophil tests and
eosinophil cationic protein 338
Unvalidated in vitro tests 339
Conclusion 340
References 340
12. Oral food challenges 345

Christopher Chang, Nicole Akar-Ghibril and Kathleen Hathaway
Introduction 346
Epidemiology of food allergies 346
The heterogeneity of adverse food reactions 346
Oral food challenges 349
Selection of the patient for an oral food challenge 349
Setting up the site for conducting oral food challenges 351
Preparing the patient for an oral food challenge 355
Shared decision making 355
Informed consent 356
Oral food challenge procedure 358
Before the challenge 358
The day of the challenge 361
Terminating the challenge 361
Documentation of the challenge results 373
Postchallenge management 373
A “positive” challenge 373
A “negative” challenge 373
Discharge instructions 374
Special populations 374
Oral food challenges in the infant 374
Oral food challenges in the adult patient 375
Specific foods 375
Baked food challenges 375
Variations on oral food challenges 378
Food-dependent exercise-induced anaphylaxis 378
Oral food challenges for food protein induced enterocolitis syndrome 381
Frequently asked questions 383
Conclusions 384
References 384
13. Physical urticarias: diagnosis and testing 389

Karen M. Anstey and Iris M. Otani
Introduction 390
General recommendations for provocation testing 390
Contents xv
Symptomatic dermographism 391

Characteristics 391
Provocation testing 391
Delayed pressure induced urticaria 392
Characteristics 392
Provocation Testing 393
Cold-contact urticaria 393
Characteristics 393
Heat-contact urticaria 395
Characteristics 395
Solar urticaria 396
Characteristics 396
Testing 396
Vibratory urticaria 396
Characteristics 396
Conclusion 397
Conflict of interest 397
References 397
14. Techniques to evaluate asthma 401

Gerald B. Lee and Katherine L. Tison
Introduction 402
Subjective evaluations 403
Physiologic evaluations 404
Pulmonary function testing 404
Peak flow monitoring 409
Impulse oscillometry 409
Bronchoprovocation with direct and indirect challenge testing 409
Mechanistic evaluations 412
Total and allergen-specific immunoglobulin E 413
Peripheral blood eosinophils 413
Sputum eosinophils 413
Fractional exhaled nitric oxide 413
Periostin 414
T2-low biomarkers 414
Conclusion 416
References 416
15. Drug allergy testing 419

Min J. Lee and Jeffrey M. Chambliss
Introduction 420
Types of adverse drug reactions 420
xvi Contents
Evaluation of immediate drug reactions 421

Skin testing other drug classes 423
Laboratory studies and in vitro testing 431
Direct oral challenge 432
Evaluation of delayed hypersensitivity reactions 433
Discussion/Conclusion 436
References 436
16. Diagnosis and management of rhinitis and

rhinosinusitis 441
Auddie M. Sweis and David W. Kennedy
Introduction 442
Definition 442
Epidemiology 443
Etiology and pathogenesis 443
Clinical presentation 444
Patient demographics/signs and symptoms 444
Diagnostics 445
Typical computed tomography radiographic features 450
Medical management and outcomes 452
Topical therapy 454
Systemic therapy 457
Surgical management and outcomes 459
Conclusion 461
References 462
17. Approach to the rash from an allergy and

immunology perspective 471
Sonam Sani and Luz Fonacier
Introduction 472
Eczematous rashes 473
Introduction 473
Pathophysiology 473
Clinical features 474
Diagnosis 474
Contact dermatitis 474
Introduction 474
Pathophysiology 475
Diagnosis 476
Seborrheic dermatitis 476
Introduction 476
Pathophysiology 477
Contents xvii
Diagnosis 478
Nummular eczema 478
Introduction 478
Pathophysiology 478
Diagnosis 478
Lichen simplex chronicus/prurigo nodularis 479
Introduction 479
Pathophysiology 479
Diagnosis 480
Mycosis fungoides 480
Introduction 480
Pathophysiology 480
Diagnosis 481
Urticarial rashes 481
Acute urticaria 481
Chronic urticaria 484
Introduction 484
Pathophysiology 484
Diagnosis 485
Physical urticaria 486
Dermatographism 486
Cholinergic 486
Cold induced 487
Aquagenic 487
Solar 487
Vibratory angioedema/urticaria 488
Delayed pressure 488
Urticarial vasculitis 488
Introduction 488
Pathophysiology 489
Diagnosis 490
Cutaneous mastocytosis 491
Introduction 491
Pathophysiology 491
Diagnosis 492
Papulosquamous disorders 492
Psoriasis 492
Pityriasis rosea 495
Lichen planus 496
Drug eruptions 497
Exanthematous/maculopapular drug eruption 497
xviii Contents
Stevens Johnson syndrome/toxic epidermal necrolysis 498

Introduction 498
Pathophysiology 498
Diagnosis 499
Drug reaction with eosinophilia and systemic symptoms 500
Introduction 500
Pathophysiology 500
Diagnosis 501
Acute generalized exanthematous pustulosis 501
Introduction 501
Pathophysiology 502
Diagnosis 502
Fixed drug eruption 502
Introduction 502
Pathophysiology 503
Diagnosis 503
Bullous disorders 503
Bullous pemphigoid 503
Pemphigus vulgaris 505
Introduction 505
Pathophysiology 505
Diagnosis 505
Conclusion 505
References 506
18. Patch testing and the evaluation of contact allergy 511

Stephanie L. Mawhirt and Luz Fonacier
Abbreviations 512
Introduction 513
Pathophysiology 514
Physical examination 518
Histologic findings 520
Site-specific considerations 520
Face and neck 520
Eyelid 520
Lip 521
Hand 521
Foot 521
Axillary 521
Ano-genital region 522
Contents xix
Other important considerations 522

Allergic contact dermatitis in children 522
Systemic contact dermatitis 524
Allergens causing allergic contact dermatitis 524
Nickel sulfate 527
Fragrances 528
Balsam of Peru 528
Preservatives 528
Methylchloroisothiazolinone/methylisothiazolinone and
methylisothiazolinone 529
Paraben 529
p-Phenylenediamine 529
Lanolin 530
Cocamidopropyl betaine 530
Rubber 530
Medications 530
Corticosteroids 531
Patch testing and patch test allergens 531
Patch testing technique 532
Patch test reading and interpretation 532
False-positive and false-negative patch testing results 534
Determining clinical relevance 534
Repeat open application test and use test 534
Management: allergen avoidance and treatment 535
Conclusion 536
References 536
19. Skin biopsies: their utility to allergists and

immunologists 543
Maxwell A. Fung, Smita Awasthi, Samuel T. Hwang and Joyce S. Lee
Introduction 550
Biopsy types 551
Direct immunofluorescence testing 552
Eczematous reactions 552
Atopic dermatitis (eczema) 552
Contact dermatitis 553
Dyshidrotic dermatitis (dyshidrosis, pompholyx) 554
Id reaction (autoeczematization) 554
Nummular dermatitis 554
Seborrheic dermatitis 554
Stasis dermatitis 554
Xerotic (asteatotic) dermatitis 555
Urticarial eruptions 555
Urticaria 555
Urticarial vasculitis 556
Neutrophilic urticarial dermatosis 556
xx Contents
Urticarial dermatitis 556

Papular urticaria 557
Other urticarial reactions 557
Autoinflammatory syndromes 557
ADAM17 deficiency 558
Aicardi-Goutières syndrome 558
AP1S3 and autoinflammatory psoriasis 558
Autoimmunity and PLCγ2-associated antibody deficiency and
immune dysregulation 558
Autoinflammatory periodic fever, immunodeficiency, and
thrombocytopenia 558
Behçet syndrome 559
Blau syndrome 559
CANDLE syndrome 559
CARD14-mediated psoriasis 559
Cryopyrin-associated periodic syndromes 560
Deficiency of adenosine deaminase 2 560
Deficiency of interleukin-1 receptor antagonist 560
Familial chilblain lupus 560
Familial Mediterranean fever 561
H syndrome 561
Majeed syndrome 561
NLRP1-associated disease 561
NLRP12-associated autoinflammatory disease 561
Pyogenic sterile arthritis, pyoderma gangrenosum, acne 561
PLCγ2-associated antibody deficiency and immune
dysregulation 562
Singleton Merton syndrome 562
Schnitzler syndrome 562
Spondyloenchondrodysplasia with immune dysregulation 562
STING-associated vasculopathy with onset in infancy 562
Synovitis, arthritis, pustulosis, hyperostosis, osteitis 563
Tumor necrosis factor receptor associated periodic syndrome 563
Immunodeficiency syndromes 563
Ataxia-telangiectasia 563
Chédiak Higashi syndrome 563
Chronic granulomatous disease (Bridges Good syndrome,
Quie syndrome) 564
Combined immunodeficiency 564
Common variable immunodeficiency 564
DiGeorge syndrome (22q11.2 deletion) 564
Griscelli syndrome 565
Good syndrome 565
Hemophagocytic lymphohistiocytosis 565
Hereditary angioedema 565
Hyper-IgE syndrome 565
Immunodysregulation polyendocrinopathy enteropathy X-linked
syndrome 566
Contents xxi
Leukocyte adhesion deficiency 566

Netherton syndrome 566
Nijmegen breakage syndrome 566
Severe combined immunodeficiency 566
Wiskott Aldrich syndrome 567
X-linked agammaglobulinemia (Bruton disease) 567
Other inflammatory disorders of the skin 567
Autoimmune diseases 567
Granulomatous dermatitis 568
Immunobullous disorders 568
Morbilliform eruptions 569
Acknowledgment 569
References 569
20. Evaluation and diagnosis of mast cell associated

disorders 579
Young Hwan Park and Jonathan J. Lyons
Introduction 580
Physiologic roles of mast cells 581
Evolution of mast cells 582
Host defense 583
Wound healing 583
Toxin clearance 584
Mast cell activation and mediator release 584
IgE FcεRI signaling 584
Mas-related G protein coupled receptor-X2 585
SCF KIT (CD117) signaling 585
IL-33 ST2 signaling 586
IL-6 IL-6R/GP130 signaling 586
Mast cell mediators 587
Defining mast cell associated disorders 589
Clonal disorders of mast cells 589
Nonclonal disorders associated with mast cell activation 593
Genetic disorders involving mast cells 596
Hereditary alpha-tryptasemia 596
PLCG2-associated antibody deficiency and immune dysregulation 598
Adhesion G protein coupled receptor E2 gain-of-function 599
Clinical testing modalities 600
Testing of mast cell mediators in blood and urine 600
Tryptase genotyping 605
KIT p.D816V variant detection by allele-specific and ddPCR 607
Next-generation sequencing panels 607
Bone marrow and tissue biopsy 608
Clinical evaluation for mast cell associated disorders 608
Evaluation of patients with suspected mast cell associated disorders 608
Conclusion 612
xxii Contents
Acknowledgments 614
Funding 614
References 614
21. The evaluation of a patient with urticaria

and angioedema 627
Omar Elsayed-Ali and Jennifer Shih
Urticaria 628
Clinical definition of urticaria and angioedema 628
Classification of urticaria 628
Differential diagnosis of urticaria 629
History and physical examination of urticaria 629
Workup of urticaria 630
Recurrent angioedema in the absence of wheals 632
Classification and differential diagnosis of recurrent angioedema
in the absence of wheals 632
History and physical examination of recurrent angioedema
in the absence of wheals 632
Workup of recurrent angioedema in the absence of wheals 634
Assessing disease activity/control 635
Discussion 636
References 636
22. Evaluation of a patient with anaphylaxis 639

Sehrish Viqar and Panida Sriaroon
Introduction 640
History taking 641
Differential diagnosis 644
Mechanisms of anaphylaxis 645
Causes of anaphylaxis 647
Foods 647
Drugs 649
Perioperative medications 650
Latex 651
Radiocontrast media 651
Hymenoptera sting 652
Exercise-induced anaphylaxis 653
Idiopathic anaphylaxis 654
Mast cell activation syndromes and mastocytosis 655
Workup 657
Laboratory assay 657
Skin testing 659
Graded challenge 660
Conclusions 660
References 661
Contents xxiii
23. Evaluating patients with eosinophilia and eosinophilic

disorders 665
Heather Stern, D.O. and Gisoo Ghaffari, M.D.
Introduction 666
Eosinophil biology 667
What is eosinophilia? 668
Severity classification of eosinophilia 668
Mechanisms of eosinophilia 669
Target organs 669
Causes of eosinophilia 669
“Secondary” eosinophilia 670
Allergic and atopic diseases 670
Drug-induced 670
Infection-related 672
Neoplastic/hematologic 673
Immune 674
Miscellaneous 675
Primary eosinophilia 675
Hypereosinophilic syndrome 675
Organ-specific eosinophilic disorders 678
Eosinophilic skin disease 679
Eosinophilic lung disease 680
Eosinophilic gastrointestinal disease 680
Eosinophilic cystitis 681
Approach to the patient with eosinophilia 681
Summary 684
References 684
24. Unproven and controversial tests and treatments

in allergy and immunology 687
Suqing Zhou, Haijing Wu, Christopher Chang and Qianjin Lu
Introduction 688
Unconventional diagnostic methods 689
Leukocytotoxic test 689
Provocation neutralization tests 690
Electrodermal testing 691
Applied kinesiology testing 692
Serum IgG or IgG4 testing 693
Unproven treatment methods 694
Rotary diversified diet 695
Nambudripad’s allergy elimination technique 695
Spiritual healing 696
Concluding remarks 700
References 700
xxiv Contents
Section C
Evaluation of immune function
25. Newborn screening for severe combined
immunodeficiency and related issues 705
Amandeep Sandhu and Jennifer Heimall
Introduction 706
Newborn screening for severe combined immunodeficiency and
other immunodeficiencies 707
Severe combined immunodeficiency diagnosis 712
Nonsevere combined immunodeficiency lymphopenia 715
Clinical evaluation 716
Laboratory evaluation 718
Genetic testing 718
Management 719
Treatment 721
Discussion/conclusion 722
Acknowledgment 722
References 723
26. Testing the innate immune system 725

Jacqueline D. Squire and Jennifer W. Leiding
Background 726
Testing techniques 726
Immunoassays 726
Flow cytometry 727
Testing components of the innate immune system 728
Polymorphonuclear leukocytes (neutrophils) 728
Natural killer cells 729
Complement system 729
Interferon-gamma and interleukin-12/23 pathway 730
Toll-like receptor and NF-κB pathway 732
Immune dysregulatory disorders 733
Conclusions 734
References 734
27. Testing the adaptive immune system 737

Jacqueline D. Squire and Jennifer W. Leiding
Background 738
Testing components of the adaptive immune system 738
Immunoglobulin levels 739
Vaccine titers and isohemagglutinins 740
Lymphocyte subsets 741
Lymphocyte function 742
Contents xxv
T-cell receptor excision circle 743

Discussion and conclusion 744
References 744
28. Infections in primary immunodeficiency 747

Ahnika Kline and Christa Zerbe
Immunodeficiencies affecting cellular and humoral immunity 748
Introduction 748
Infections in severe combined immune deficiency 748
Combined immune deficiencies less profound than severe combined
immune deficiency 752
Combined immunodeficiencies with syndromic features 756
Wiskott-Aldrich syndrome and related deficiencies 756
DNA repair defects with syndromic features 757
Thymic defects with additional congenital anomalies 758
Immune-osseous dysplasias 758
Hyper-IGE syndromes 759
Dyskeratosis congenita 759
Defects of vitamin B12 and folate metabolism 760
Anhidrotic ectodermodysplasia with immunodeficiency 760
Calcium channel defects 760
Other defects 761
Predominantly antibody deficiencies 761
Introduction 761
Diseases of immune dysregulation 764
Introduction 764
Congenital defects of phagocyte number or function 767
Introduction 767
Defects in intrinsic and innate immunity 768
Introduction 768
Autoinflammatory disorders 773
Complement deficiencies 773
Introduction 773
Phenocopies and therapies 775
Conclusion 776
Acknowledgments 776
References 777
29. Periodic fever syndromes and autoinflammatory

diseases 791
Angel A. Herrera Guerra and Victoria R. Dimitriades
Introduction 792
xxvi Contents

Background 793
Epidemiology 793
Pathophysiology 793
Clinical manifestations 794
Laboratory features 795
Diagnosis 795
Treatment 796
Prognosis 796
Mevalonate kinase deficiency 797
Background 797
Epidemiology 797
Pathophysiology 797
Diagnosis 798
Treatment 798
Prognosis 799
Tumor necrosis factor receptor-associated periodic syndrome 799
Background 799
Epidemiology 799
Pathophysiology 800
Diagnosis 800
Treatment 801
Prognosis 801
Cryopyrin associated autoinflammatory syndrome 802
Background 802
Epidemiology 802
Pathophysiology 802
Diagnosis 804
Treatment 804
Prognosis 805
Periodic fever with adenitis, pharyngitis, and aphthous stomatitis 805
Background 805
Epidemiology 805
Pathophysiology 806
Diagnosis 807
Treatment 807
Prognosis 808
Other autoinflammatory conditions 808
Conclusion 816
References 816
Contents xxvii
30. Primary immune regulatory disorders 829

Maria Chitty-Lopez and Jolan E. Walter
Background 830
ALPS/ALPS-like disorders 833
IPEX and IPEX-related disorders 835
CVID, CVID-like, and profound/late-onset combined immune
deficiency disorders 836
Immune phenotype and genetic testing in PIRD 837
Hyperinflammatory disorders and immune dysregulation 838
Discussion and conclusion 840
References 840
31. The history, diagnosis, and pathophysiology of

human immunodeficiency virus and acquired
immunodeficiency syndrome 845
Kelly Valentini, Eric McGrath, Divya Seth and Elizabeth Secord
Introduction 846
Human immunodeficiency virus and acquired immunodeficiency
syndrome 846
Background and history 846
Pathophysiology and immune dysfunction 849
Atopy and human immunodeficiency virus 851
Diagnosis 852
Retroviral conversion syndrome 853
Diagnosis in asymptomatic persons and treatment as prevention 853
Human immunodeficiency virus testing 854
Human immunodeficiency virus testing in infants and children 854
Human immunodeficiency virus testing in breastfed infants 856
Missed opportunities and postexposure prophylaxis 856
Diagnosis of acquired immunodeficiency syndrome 856
Conclusion 857
References 857
32. The evaluation and treatment of autoimmune diseases 863

Kristina Wiers-Shamir, Jessica Simpson and Christopher Chang
Introduction 864
The history of present illness and physical examination in the
evaluation of the rheumatologic patient 864
Laboratory testing for autoimmune diseases 865
What to consider when using a test 865
Specific antibodies 866
Antinuclear antibodies 866
Antidouble-stranded DNA antibodies 868
Extractable nuclear antigens 868
xxviii Contents
Inflammatory markers 871

Human leukocyte antigen associations in autoimmune diseases 875
Imaging in autoimmune diseases 875
Treatment of autoimmune diseases 876
Disease-modifying antirheumatic drugs 876
Corticosteroids 878
Cytotoxic agents 878
T cell targets 879
Antiinflammatory agents 879
Monoclonal antibodies 880
Conclusions 881
References 881
33. Neurologic autoimmune diseases 887

Yhojan Rodrı́guez, Lucas Restrepo, Christopher Chang and
Juan-Manuel Anaya
Introduction 888
Multiple sclerosis 889
Epidemiology 889
Environmental factors 889
Genetic factors 890
Immunopathology 890
Diagnosis 895
Treatment 896
Neuromyelitis optica 898
Epidemiology 898
Genetic factors 898
Immunopathology 899
Diagnosis 900
Treatment 903
Guillain Barré syndrome 905
Epidemiology 905
Genetic factors 905
Immunopathology 907
Clinical features and diagnosis 912
Treatment 912
Chronic inflammatory demyelinating polyneuropathy 913
Epidemiology 913
Genetic factors 913
Immunopathology 913
Contents xxix
Treatment 925
Myasthenia gravis 925
Epidemiology 925
Genetic and environmental factors 926
Immunopathology 926
Treatment 930
Autoimmune encephalitis 934
Epidemiology 934
Genetic factors 934
Immunopathology 935
Diagnosis 938
Treatment 940
Paraneoplastic neurological disorder 941
Epidemiology 941
Immunopathology 942
Treatment 945
Summary 945
References 945
Volume 2
Section D
Treatment of allergic diseases
34. Immunotherapy to environmental allergens 979
Kristine Vanijcharoenkarn and Merin Kuruvilla
Background 980
Patient selection 980
Formulation of allergen immunotherapy extract 982
Injection schedules 985
Duration of immunotherapy 985
Monitoring of treatment 988
Reactions to allergen immunotherapy 989
Local reactions 989
Systemic reactions 989
Pretreatment 990
Subcutaneous immunotherapy versus sublingual immunotherapy 990
Clinical efficacy 990
Asthma 990
xxx Contents
Rhinoconjunctivitis 991
Efficacy of fungal extracts 992
Efficacy of multiallergen immunotherapy 993
Other administration routes 998
New technologies 999
Conclusion 999
References 1000
35. Drug desensitization 1005

Lourdes Ramirez, Faina Shenderov and Christopher Chang
Introduction 1006
Mechanisms of drug hypersensitivity 1006
Type I hypersensitivity reactions: IgE mediated and non-IgE mediated 1007
Type II hypersensitivity reactions 1008
Type III hypersensitivity reactions 1008
Type IV hypersensitivity reactions 1009
Drug desensitization 1009
Mechanisms of drug desensitization 1009
Indications 1010
Choosing desensitization protocols 1010
Premedication 1011
Route and dosing 1012
Desensitization protocols 1012
Desensitization to vaccines 1012
Desensitization to antibiotics 1013
Desensitization to nonsteroidal anti-inflammatory drugs 1018
Desensitization to monoclonal and chemotherapeutic agents 1022
Optimization of the desensitization procedure—pharmacy
considerations 1028
Conclusion 1034
References 1035
36. Oral, sublingual, and dermatologic immunotherapy

for food allergy 1039
Mary Grace Baker and Julie Wang
Introduction 1040
Oral immunotherapy 1040
Background/mechanism 1040
Studies 1041
In combination with other therapies: allergen oral
immunotherapy 1 omalizumab or probiotics 1058
Pros/cons 1060
How to incorporate oral immunotherapy into clinical practice 1061
Future directions 1061
Epicutaneous immunotherapy 1061
Contents xxxi
Background 1061
Mechanism 1062
Studies 1062
Pros/cons 1064
Sublingual immunotherapy 1065
Background 1065
Mechanism 1065
Studies 1066
Pros/cons 1069
Summary 1069
References 1070
37. Conventional medications for the treatment of

allergic rhinitis and conjunctivitis 1077
Elizabeth J. Feuille, Wanda Phipatanakul and Perdita Permaul
Introduction 1078
Medications used for allergic rhinitis and allergic conjunctivitis 1079
Overview 1079
Nasal saline 1090
Antihistamines 1090
Glucocorticoids 1095
Mast cell-stabilizing agents 1097
Anticholinergics 1099
Leukotriene receptor antagonists 1099
Decongestants 1100
Future directions/conclusion 1101
Disclosure statement 1103
References 1103
38. New biologics in allergy 1111

Heather K. Lehman and Colleen M. Sabella
Introduction 1112
Currently available biologics for allergic diseases 1112
Anti-IgE monoclonal antibodies 1112
Anti-IL-5 monoclonal antibodies 1119
Biologics currently in development 1127
Anti-IL-13 monoclonal antibody 1127
Anti-thymic stromal lymphopoietin monoclonal antibody 1129
CRTH2 antagonists 1130
Non-Th2 biologics in atopic disease 1132
Anti-IL-17 monoclonal antibodies 1132
xxxii Contents

Anti-kallikrein monoclonal antibody 1133
Additional considerations when utilizing biological therapies 1134
Conclusion 1135
References 1135
39. Action plans and quality of life evaluations 1147

Pavadee Poowuttikul and Divya Seth
Abbreviations 1148
Introduction 1149
Objectives of asthma action plans 1150
Structure of asthma action plans 1151
Asthma action plans and asthma outcome 1156
Asthma action plans and quality of life of asthma patients and
parents 1158
Asthma action plans and adherence to medications 1159
Barriers and facilitators of using asthma action plans 1159
Quality of life measurement of asthma patients and caregivers 1162
Tools to measure quality of life for adults with asthma 1162
Tools to measure quality of life for children with asthma and
their caregivers 1162
Food allergy action plans 1169
Quality of life tools for food allergy 1175
Conclusion 1176
References 1182
40. Treatment of atopic dermatitis 1191

Richika Makol and Peck Y. Ong
Introduction 1192
Diagnosis and assessment of atopic dermatitis severity 1192
Atopic dermatitis triggers 1194
Current atopic dermatitis therapy 1196
Routine skincare 1196
Topical corticosteroids 1197
Wet-wrap therapy 1198
Topical calcineurin inhibitors 1200
Topical phosphodiesterase 4 inhibitor 1201
Topical Janus kinase inhibitor 1201
Systemic therapy 1202
Medications for itch and infections in atopic dermatitis 1203
Summary and new treatments on the horizon 1204
References 1205
Further reading 1211
Contents xxxiii
41. Recognition and treatment of anaphylaxis 1213

Sehrish Viqar and Panida Sriaroon
Introduction 1214
Recognition of anaphylaxis 1215
Definition of anaphylaxis 1215
Grading system of anaphylaxis 1217
Management of anaphylaxis 1217
Epinephrine 1217
Acute management following epinephrine administration 1220
Other medications 1222
Length of observation 1223
Fatal anaphylaxis 1225
Biphasic reactions 1225
Epinephrine autoinjector 1226
Prevention of anaphylaxis 1228
Education and trigger avoidance 1228
Anaphylaxis emergency action plan 1229
Outpatient management of anaphylaxis 1229
Underuse of epinephrine for the treatment of anaphylaxis 1231
Conclusion 1232
References 1233
42. Venom allergy evaluation, diagnosis, and treatment 1237

Amy Dowden
Epidemiology 1238
Etiology 1238
Reactions 1242
Diagnosis 1244
Treatment 1247
Prevention 1252
Risk factors 1252
Biting insect allergy 1253
Conclusions 1253
References 1254
43. Treatment of itch in atopic dermatitis 1259

Zoe Morgan Lipman, Rachel Shireen Golpanian and
Gil Yosipovitch
Introduction 1260
Pathophysiology of itch in atopic dermatitis 1260
Current treatment options for the atopic itch 1262
Topical treatments 1262
xxxiv Contents
Systemic treatments 1266

Emerging treatment options for atopic itch 1272
Topical treatments 1272
Systemic treatments 1272
Conclusion 1273
Conflicts of interest 1273
References 1274
44. Treatment of eosinophilic and hypereosinophilic

disorders 1281
Aparna Daley and Gisoo Ghaffari
General principles of management 1283
Key definitions and concepts 1283
Eosinopenia 1284
Severity of hypereosinophilia 1284
Excluding secondary causes 1284
Deciding the focus of treatment—the underlying condition,
eosinophilia, or both? 1287
Risk assessment 1287
Deciding when to treat 1288
Hypereosinophilia of undetermined significance
(asymptomatic hypereosinophilia) 1289
General management of hypereosinophilic syndrome,
complications of treatment, and acute life-threatening
presentations 1289
Treatment approach to myeloproliferative variants 1289
Treatment approach to lymphocytic variants 1291
Treatment approach to FGFR1-, JAK2-, and FLT3-rearranged
neoplasms 1292
Treatment approach to idiopathic HES 1292
Medications 1293
Systemic Glucocorticoids 1293
Hydroxyurea 1295
Interferon-α 1296
Imatinib mesylate 1296
Biologic agents 1298
Alemtuzumab 1298
Mepolizumab 1299
Reslizumab 1299
Omalizumab 1300
Dupilumab 1300
Tezepelumab 1300
Transplantation 1300
Biologic drugs and other medications with potential for
future use 1302
Contents xxxv
Benralizumab 1302
Anti-Siglec-8 1303
Dexpramipexole 1303
Anti-EMR1 1303
Tyrosine kinase inhibitors 1303
Ruxolitinib and tofacitinib 1303
Therapies that are not efficacious in the management of
hypereosinophilic syndrome 1304
Supportive care and surgery 1304
Conclusion 1305
References 1305
Further reading 1308
45. Treatment of urticaria and angioedema 1309

Jennifer Xu and Jennifer Shih
Introduction 1310
Urticaria 1310
Definition of urticaria 1310
Treatment of urticaria 1310
Angioedema 1315
Mast cell mediator-induced angioedema therapy 1315
Bradykinin-induced angioedema 1315
Summary 1322
References 1323
46. Integrative medicine in allergy and immunology 1325

Lidan Linda Zhong, Wai Ching Lam, Hei Lam Helena Cheung
and Aiping Lyu
Philosophy of integrative medicine in allergy and immunology 1326
Approaches of integrative medicine in allergy and immunology 1327
Evaluation of integrative medicine in allergy and immunology 1328
Allergic rhinitis 1328
Definition in Chinese medicine and integrative medicine 1328
Pathophysiology 1329
Integrative therapy 1330
Preventive approach in Chinese medicine and integrative medicine 1331
Recommendations according to the grade of current practice
evidence 1332
Systemic lupus erythematosus 1332
Definition 1332
xxxvi Contents
Preventive approach 1337

Level of evidence and recommendations 1338
Rheumatoid arthritis 1338
Definition in Chinese medicine and integrative medicine 1338
Preventive approach in Chinese medicine and integrative
medicine 1342
Recommendations according to the grade of current practice
evidence 1343
Inflammatory bowel disease 1344
Definition 1344
Preventive approach 1347
Level of evidence and recommendations 1348
Overall summary 1348
References 1350
Section E
Treatment of immunological disorders
47. Treatment of primary immunodeficiencies and
inborn errors of immunity 1363
Lisa J. Kobrynski
Introduction 1364
Nutrition 1364
Treatment of antibody deficiencies 1365
Immunoglobulin replacement 1365
Prophylaxis 1370
Complications of antibody deficiencies 1372
Treatment of combined immune deficiencies 1374
Precautions 1374
Prophylaxis 1375
Autoimmunity associated with primary immune deficiencies 1377
Treatment of phagocytic disorders 1379
Prophylaxis 1379
Other considerations 1382
Treatment of asplenia or hyposplenia 1383
Complement deficiencies 1384
Vaccination in PIDD 1385
Vaccination in B cell defects 1386
Vaccination in combined immune deficiency 1389
Vaccination in innate immune deficiency 1390
Contents xxxvii
Conclusion 1390
References 1390
48. Management of autoinflammatory syndromes and

periodic fevers 1399
Claire J. Peet and Helen J. Lachmann
Introduction 1400
Management of autoinflammatory diseases by condition 1401
Cryopyrin-associated periodic syndrome 1405
Tumor necrosis factor receptor-associated periodic syndrome 1407
Mevalonate kinase deficiency 1408
Pharmacological aspects of management 1410
Putative pathophysiological mechanisms in autoinflammatory
diseases 1410
Colchicine 1410
Anti-interleukin-1 agents 1411
Agents targeting other inflammatory pathways 1415
Nonpharmacological aspects of management 1416
Setting of care 1416
Monitoring in autoinflammatory syndromes 1416
Vaccinations in patients with systemic autoinflammatory
diseases 1419
Family planning and systemic autoinflammatory conditions 1420
Conclusions and future directions 1421
References 1421
49. Immunomodulatory pharmaceuticals for the

treatment of immune dysfunction 1431
Maria Chitty-Lopez and Jolan E. Walter
Background 1432
Immune modulation in primary immune deficiency disorder 1432
Immune modulators safety profile 1433
Infusion-related reactions 1433
Infections and organ damage 1440
Cytopenias 1440
Hypogammaglobulinemia 1440
Immunomodulators and immunodeficiencies: special
considerations 1440
Rituximab and common variable immunodeficiency 1440
Immunomodulation in hemophagocytic lymphohistiocytosis 1441
Immunomodulatory drugs and severe Coronavirus
disease of 2019 1441
xxxviii Contents
Discussion 1442
References 1443
50. Management and prophylaxis of infections in

primary immunodeficiency 1447
Renata Medina and Christa Zerbe
Introduction 1448
Immunizations 1449
Antimicrobial prophylaxis 1451
Antibacterial prophylaxis 1451
Antiviral prophylaxis 1453
Antifungal prophylaxis 1454
Adjunctive therapies 1454
Bacterial infections 1458
Gram-positive infections 1458
Gram-negative infections 1458
Mycobacterial infections 1459
Viral infections 1461
Respiratory viruses 1461
Enteric viral infections 1461
Herpesviruses 1462
Human papillomavirus 1465
Poxviruses 1465
Polyoma viruses 1466
Fungal infections 1466
Candida 1466
Aspergillus 1467
Cryptococcus 1468
Endemic mycoses 1469
Pneumocystis jirovecii 1470
Toxoplasma 1470
Protozoal infections 1471
Treatment 1471
Conclusion 1471
Acknowledgment 1471
References 1472
51. Bone marrow transplant for the patient with

primary immune deficiency disorder 1479
Gary Kleiner, Siena Vadakal, Erini Nessim Kostandy, Nia Rush,
Nevenda Velikova Rose, Nina Hein and Jennifer Gebbia
History and indications 1480
The early days 1480
Contents xxxix
Indications for transplant 1483

Special considerations in bone marrow transplantation for primary
immunodeficiency 1484
Transplant process 1485
Transplant complications 1489
Timeline to infections 1491
Preengraftment period 1491
Early postengraftment period 1492
Late postengraftment period 1493
Graft versus host disease 1493
Graft versus host disease severity 1494
Graft versus host disease prophylaxis 1494
Graft versus host disease treatment 1494
Chronic Graft versus host disease 1497
Long-term concerns in primary immune deficiency 1497
Conclusion 1498
References 1499
52. An immunologist’s guide to solid-organ

transplantation 1505
Maryanne Chrisant
Introduction 1506
The journey of clinical transplantation 1507
Evaluation 1508
Listing 1511
Transplant 1512
Post-transplant 1513
Routine transplant maintenance therapy 1514
Rejection and treatment 1520
Tolerance and ABO-incompatible transplant 1522
References 1523
53. The use of therapeutic apheresis in allergic and

immunological diseases 1527
Rachel K. Horton, Daniel D. Summerfield and Jeffrey L. Winters
Introduction 1528
Brief history of apheresis 1528
Role of apheresis in immunological disorders 1530
Definitions 1531
American Society for Apheresis guidelines 1531
Overview 1531
Indication categories 1532
American Society for Apheresis Grade Recommendations 1533
xl Contents
Therapeutic plasma exchange 1561

General overview 1561
Proposed mechanism of action of therapeutic plasma exchange 1561
Filtration versus centrifugation 1561
Plasma volume treated 1563
Vascular access 1564
Anticoagulation 1565
Replacement fluids 1565
Intraprocedural patient management 1566
Therapeutic plasma exchange nonselective reduction and
recovery of plasma constituents 1566
Immunoabsorption 1570
Available columns 1571
Extracorporeal photopheresis 1575
Proposed mechanism of extracorporeal photophereis 1576
Treatment schedule 1577
Determining response to therapy 1578
Adsorptive cytapheresis general overview 1579
Proposed mechanism 1580
Treatment schedule 1580
Conclusion 1581
References 1581
54. Management and treatment of human

immunodeficiency virus 1585
Eric McGrath, Joudeh B. Freij, Kelly Valentini and
Elizabeth Secord
Introduction 1586
Rationale for treatment 1586
Principles of treatment 1586
Pharmacotherapy 1587
Introduction to the antiretroviral drug classes 1587
Infants and pregnancy 1589
Children 1594
Adolescents and adults 1595
Prevention 1597
Postexposure prophylaxis 1597
Preferred regimens for postexposure prophylaxis 1601
Contents xli
Preexposure prophylaxis and human immunodeficiency virus

prevention 1601
Antiretroviral adherence and support 1605
References 1606
55. Gene therapy in the treatment of primary

immune deficiency diseases 1611
Saul O. Lugo Reyes and Armando Partida Gaytán
Introduction 1612
A history of gene therapy 1613
The mechanism 1615
Viral vectors 1616
Nonviral vectors 1617
Applications 1618
Setbacks and pitfalls for gene therapy 1622
Overexpression 1622
Theoretical concerns 1623
Leukemic transformation 1623
Gene editing 1623
CRISPR in immune deficiencies 1625
Future perspectives and ethics of gene editing 1625
From healing to enhancing 1626
COVID-19 vaccines as gene therapies 1627
References 1627
Section F
Supplements
Appendix A: Abbreviations 1631
Appendix B: Ordering allergen extracts for skin testing and
immunotherapy 1636
Appendix C: Oral and parenteral steroid dosing chart 1639
Appendix D: Topical corticosteroid potency chart 1640
Appendix E: Nonirritating concentrations of drugs for
purposes of skin testing 1641
Appendix F: Normal values of immune function tests 1644
Appendix G: Pneumococcal serotypes in vaccines and testing 1651
Appendix H: CD molecules and their function 1654
Appendix I: T-cell subsets and ontogeny 1674
Appendix J: Immunological check point inhibitors 1676
Appendix K: B-cell subsets and ontogeny 1679
Appendix L: Monoclonal antibodies and fusion proteins
currently in use in allergy and immunology 1680
Index 1685
List of contributors
Nicole Akar-Ghibril Division of Immunology, Allergy and Rheumatology,

Memorial Healthcare System, Hollywood, FL, United States
Hanadys Ale Joe DiMaggio Children’s Hospital, Memorial Healthcare System,
Hollywood, FL, United States; Herbert Wertheim College of Medicine, Florida
International University, Miami, FL, United States
Juan-Manuel Anaya Center for Autoimmune Diseases Research (CREA), School of
Medicine and Health Sciences, Universidad del Rosario, Bogota, Colombia
Karen M. Anstey Division of Pulmonary, Allergy, and Critical Care Medicine,
Oregon Health & Science University, Portland, OR, United States
Smita Awasthi Dermatology and Pediatrics, UC Davis Pediatric Dermatology
Service, University of California Davis School of Medicine, Davis, CA, United
States
Mary Grace Baker Division of Pediatric Allergy & Immunology, Department of
Pediatrics, Elliot and Roslyn Jaffe Food Allergy Institute, Icahn School of
Medicine at Mount Sinai, New York, NY, United States
Jeffrey M. Chambliss University of Texas Southwestern Medical Center, Dallas,
TX, United States
Christopher Chang Division of Pediatric Immunology, Allergy and Rheumatology,
Joe DiMaggio Children’s Hospital, Memorial Healthcare System, Hollywood, FL,
United States; Division of Rheumatology, Allergy and Clinical Immunology,
University of California Davis School of Medicine, Davis, CA, United States
Meng Chen Sean N. Parker Center for Allergy and Asthma Research, Stanford
University, Stanford, CA, United States
Hei Lam Helena Cheung School of Chinese Medicine, Hong Kong Baptist
University, Hong Kong
Maria Chitty-Lopez Division of Allergy/Immunology, Department of Pediatrics,
University of South Florida, Tampa, FL, United States; Division of Allergy/
Immunology, Department of Pediatrics, Johns Hopkins All Children’s Hospital,
St. Petersburg, FL, United States
Maryanne Chrisant Pediatric Cardiac Transplant, Heart Failure & Cardiomyopathy,
The Heart Institute, Joe DiMaggio Children’s Hospital, Hollywood, FL, United
States
Ka Hou Chu School of Life Sciences, The Chinese University of Hong Kong, Hong
Kong S.A.R, P.R. China
xliii
xliv List of contributors
Wilfredo Cosme-Blanco Veteran Affairs Caribbean Healthcare System, San Juan,

Puerto Rico
Aparna Daley Division of Pulmonary, Allergy and Critical Care Medicine, Penn
State College of Medicine, Hershey, PA, United States
Victoria R. Dimitriades Division of Pediatric Allergy, Immunology &
Rheumatology, University of California Davis Health, Sacramento, CA, United
States
Amy Dowden University of Iowa Hospitals and Clinics, Carver College of
Medicine, Iowa City, IA, United States
Omar Elsayed-Ali Department of Pediatrics, Washington University in St. Louis, St.
Louis, MO, United States
Elizabeth J. Feuille New York-Presbyterian Hospital/Weill Cornell Medicine,
Division of Pediatric Pulmonology, Allergy and Immunology, New York, NY,
United States; Weill Cornell Medical College, New York, NY, United States
Luz Fonacier NYU Langone Hospital, Long Island, NY, United States
Joudeh B. Freij Wayne State University School of Medicine, Detroit, MI, United
States
Maxwell A. Fung UC Davis Dermatopathology Service, Department of
Dermatology, University of California Davis School of Medicine, Sacramento,
CA, United States
Armando Partida Gaytán Mexican Foundation for Children With Primary
Immunodeficiencies (FUMENI), Mexico City, Mexico
Xiang Ge Laboratory of Allergy and Precision Medicine, Chengdu Institute of
Respiratory Health, The Third People’s Hospital of Chengdu, Chengdu, P.R. China
Jennifer Gebba Miller School of Medicine, University of Miami, Miami, FL,
United States
Gisoo Ghaffari Allergy and Immunology, Department of Medicine, Penn State
Milton S. Hershey Medical Center, Hershey, PA, United States
Rachel Shireen Golpanian Department of Dermatology and Cutaneous Surgery, and
Itch Center University of Miami Miller School of Medicine, Miami, FL, United
States
Kathleen Hathaway Division of Immunology, Allergy and Rheumatology,
Jennifer Heimall Division of Allergy and Immunology, Children’s Hospital of
Philadelphia, Philadelphia, PA, United States; Department of Pediatrics, Perelman
School of Medicine at University of Pennsylvania, Philadelphia, PA, United
States
Nina Hein Miller School of Medicine, University of Miami, FL, United States
Angel A. Herrera Guerra Division of Pediatric Allergy, Immunology &
Rheumatology, University of California Davis Health, Sacramento, CA, United
States
List of contributors xlv
Rachel K Horton Department of Laboratory Medicine and Pathology, Mayo Clinic,

Rochester, MN, United States
Ke Huang Bioinformatics and Computational Biosciences Branch, Office of Cyber
Infrastructure & Computational Biology, National Institute of Allergy and
Infectious Diseases, National Institutes of Health, Bethesda, MD, United States
Samuel T. Hwang Department of Dermatology, University of California Davis
School of Medicine, Davis, CA, United States
David W. Kennedy Perelman School of Medicine, University of Pennsylvania,
Philadelphia, PA, United States
Gary Kleiner Miller School of Medicine, University of Miami, FL, United States
Ahnika Kline National Institutes of Health, Department of Laboratory Medicine,
Bethesda, MD, United States
Lisa J. Kobrynski Department of Immunology, Pediatrics Institute of Emory and
Children’s Healthcare of Atlanta, Atlanta, GA, United States
Erini Nessim Kostandy Miller School of Medicine, University of Miami, Miami,
FL, United States
Merin Kuruvilla Emory University School of Medicine, Children’s Healthcare of
Atlanta, Atlanta, GA, United States
Helen J. Lachmann National Amyloidosis Centre, Royal Free Hospital London
NHS Foundation Trust, London, United Kingdom; Centre for Amyloidosis &
Acute Phase Proteins, Division of Medicine (Royal Free Campus), University
College London, London, United Kingdom
Wai Ching Lam School of Chinese Medicine, Hong Kong Baptist University, Hong
Kong
Gerald B. Lee Section of Allergy/Immunology, Department of Pediatrics, Emory
University School of Medicine, Atlanta, GA, United States
Joyce S. Lee Dermatopathology and Laboratories Division, National Skin Centre,
Singapore
Min J. Lee Hoag Medical Group, Dallas, TX, United States
Heather K. Lehman Division of Allergy, Clinical Immunology and Rheumatology,
Department of Pediatrics, Jacobs School of Medicine and Biomedical Sciences,
University of Buffalo, Buffalo, NY, United States
Jennifer W. Leiding Division of Allergy and Immunology, Department of
Pediatrics, Johns Hopkins University, St. Petersburg, FL, United States
Stéphanie Lejeune Sean N. Parker Center for Allergy and Asthma Research,
Stanford University, Stanford, CA, United States
Nicki Y.H. Leung Department of Paediatrics, Prince of Wales Hospital, The Chinese
University of Hong Kong, Hong Kong S.A.R, P.R. China
Patrick S.C. Leung Division of Rheumatology/Allergy and Clinical Immunology,
University of California, Davis, CA, United States
Kyndra Liburd Division of Immunology, Allergy and Rheumatology, Joe DiMaggio
Children’s Hospital, Memorial Healthcare System, Hollywood, FL, United States
xlvi List of contributors
Zoe Morgan Lipman Department of Dermatology and Cutaneous Surgery, and

Itch Center University of Miami Miller School of Medicine, Miami, FL, United
States
Qianjin Lu Department of Dermatology, Second Xiangya Hospital, Central South
University, Hunan Key Laboratory of Medical Epigenomics, Changsha, Hunan,
P.R. China
Saul O. Lugo Reyes Immune Deficiencies Lab, National Institute of Pediatrics,
Mexico City, Mexico
Jonathan J. Lyons Translational Allergic Immunopathology Unit, Laboratory of
Allergic Diseases, Bethesda, MD, United States
Aiping Lyu School of Chinese Medicine, Hong Kong Baptist University, Hong
Kong
Richika Makol Division of General Pediatrics, Children’s Hospital Los Angeles,
Los Angeles, CA, United States
Stephanie L. Mawhirt NYU Long Island School of Medicine, Long Island, NY,
United States; Allergy and Immunology Fellowship, NYU Langone Hospital,
Long Island, NY, United States; Division of Allergy and Immunology, NYU
Langone Hospital, Long Island, NY, United States
Eric McGrath Wayne State University School of Medicine, Detroit, MI, United
States
Renata Medina National Institutes of Health, Bethesda, MD, United States
Kari Nadeau Sean N. Parker Center for Allergy and Asthma Research, Stanford
University, Stanford, CA, United States
Iris Nkamba Division of Rheumatology/Allergy and Clinical Immunology,
Kranthi Nomula Division of Immunology, Allergy and Rheumatology, Joe
DiMaggio Children’s Hospital, Memorial Healthcare System, Hollywood, FL,
United States
Peck Y. Ong Division of Clinical Immunology and Allergy, Children’s Hospital Los
Angeles, Department of Pediatrics, Keck School of Medicine, University of
Southern California, Los Angeles, CA, United States
Roxanne C. Oriel The Elliot and Roslyn Jaffe Food Allergy Institute, Department of
Pediatrics, Division of Allergy and Immunology, Icahn School of Medicine at
Mount Sinai, New York, NY, United States
Iris M. Otani Division of Pulmonary, Critical Care, Allergy and Sleep, Department
of Medicine, UCSF, San Francisco, CA, United States
Young Hwan Park Translational Allergic Immunopathology Unit, Laboratory of
Allergic Diseases, National Institutes of Health, Bethesda, MD, United States
Rasika Patkar Division of Biological Sciences, University of California, San Diego,
CA, United States; Division of Rheumatology/Allergy and Clinical Immunology,
List of contributors xlvii
Claire J. Peet National Amyloidosis Centre, Royal Free Hospital London NHS
Foundation Trust, United Kingdom; Department of Medical and Molecular
Genetics, School of Basic & Medical Biosciences, King’s College London,
United Kingdom
Perdita Permaul New York-Presbyterian Hospital/Weill Cornell Medicine, Division
of Pediatric Pulmonology, Allergy and Immunology, Weill Cornell Medical
College, New York, NY, United States
Wanda Phipatanakul Boston Children’s Hospital, Division of Allergy and
Immunology, Harvard Medical School, Boston, MA, United States
Pavadee Poowuttikul Children’s Hospital of Michigan, Central Michigan
University, Detroit, MI, United States
Lourdes Ramirez Department of Pediatrics, Joe DiMaggio Children’s Hospital,
Hollywood, FL, United States
S. Ranganathan Ganakammal Office of Cyber Infrastructure & Computational
Biology, National Institute of Allergy and Infectious Disease, National Institutes
of Health, Bethesda, MD, United States
Lucas Restrepo David Geffen School of Medicine, Department of Neurology,
University of California, Los Angeles, CA, United States
Marlen Rodriguez Pediatric Associates Florida, Miami, FL, United States; Baptist
Health South Florida, Miami, FL, United States
Yhojan Rodrı́guez Center for Autoimmune Diseases Research (CREA), School of
Medicine and Health Sciences, Universidad del Rosario, Bogota, Colombia;
Clinica Del Occidente, Bogota, Colombia
Nevenda Velikova Rose Miller School of Medicine, University of Miami, Miami,
FL, United States
Nia Rush Miller School of Medicine, University of Miami, Miami, FL, United
States
Colleen M. Sabella Division of Allergy, Clinical Immunology and Rheumatology,
Department of Pediatrics, Jacobs School of Medicine and Biomedical Sciences,
University of Buffalo, Buffalo, NY, United States
Amandeep Sandhu Division of Allergy and Immunology, Children’s Hospital of
Philadelphia, Philadelphia, PA, United States
Sonam Sani NYU Langone Long Island, NY, United States
Elizabeth Secord Wayne State University School of Medicine, Detroit, MI, United
States
Divya Seth Children’s Hospital of Michigan, Central Michigan University, Detroit,
MI, United States
Tihong Shao Division of Rheumatology/Allergy and Clinical Immunology,
University of California, Davis, CA, United States; Department of Rheumatology
and Immunology, The First Affiliated Hospital of Anhui Medical University,
Hefei, P.R. China
xlviii List of contributors
Faina Shenderov Department of Pharmacy, Joe DiMaggio Children’s Hospital,

Hollywood, FL, United States
Jennifer Shih Department of Medicine, Emory University School of Medicine,
Atlanta, GA, United States
Shang An Shu Division of Rheumatology/Allergy and Clinical Immunology,
Scott H. Sicherer The Elliot and Roslyn Jaffe Food Allergy Institute, Department of
Pediatrics, Division of Allergy and Immunology, Icahn School of Medicine at
Mount Sinai, New York, NY, United States
Jessica Simpson Department of Pediatrics, Joe DiMaggio Children’s Hospital,
Jacqueline D. Squire Division of Pulmonary, Allergy and Sleep Medicine, Mayo
Clinic, Jacksonville, FL, United States
Panida Sriaroon Johns Hopkins All Children’s Hospital, Department of Pediatrics,
St. Petersburg, FL, United States; University of South Florida Morsani College of
Medicine, Department of Pediatrics, Division of Allergy/Immunology, Tampa,
FL, United States
Heather Stern, D.O. Division of Allergy and Immunology, Department of
Pediatrics, Penn State Children’s Hospital, Hershey, PA, United States
Daniel D. Summerfield Division of Transfusion Medicine, Department of
Laboratory Medicine and Pathology, Mayo Clinic Rochester, MN, United States
JinLyu Sun Allergy Department, State Key Laboratory of Complex Severe and Rare
Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical
Sciences and Peking Union Medical College, Beijing, P.R. China
Auddie M. Sweis Division of Otolaryngology-Head and Neck Surgery, NorthShore
University HealthSystem, Pritzker School of Medicine, University of Chicago,
Evanston, IL, United States
Katherine L. Tison Section of Allergy/Immunology, Department of Pediatrics, Emory
University School of Medicine, Atlanta, GA, United States
Siena Vadakal Miller School of Medicine, University of Miami, Miami, FL, United
States
Kelly Valentini Wayne State University School of Medicine, Detroit, MI, United States
Kristine Vanijcharoenkarn Emory University School of Medicine, Children’s
Healthcare of Atlanta, Atlanta, GA, United States
Sehrish Viqar Johns Hopkins All Children’s Hospital, Department of Pediatrics, St.
Petersburg, FL, United States
Christine Y.Y. Wai Department of Paediatrics, Prince of Wales Hospital, The
Chinese University of Hong Kong, Hong Kong S.A.R, P.R. China
M. Walkiewicz Centralized Sequencing Program, Division of Intramural Research,
National Institute of Allergy and Infectious Diseases, National Institutes of
Health, Bethesda, MD, United States
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I'll send McFrazer post haste to Nyaruma and get my friend
Wynyard, the District Commissioner, to send reliable native trackers.
These blighters are unholy frauds."
And signing to the natives to get out of the way, the Colonel urged
his horse into a hand-gallop, his companions following his example.
But his physical powers were unequal to the demand of his moral
strength and resolution; for upon arriving at Kilembonga he fell
forward in his saddle in a swoon. Van der Wyck was only just in time
to save him from a dangerous tumble.
So far the search for the missing lads had not only been
unsuccessful, but other misfortunes had descended upon this little
outpost of civilisation in the wilds of East Africa.
CHAPTER XXVII
THE RAVING OF THE WITCH-DOCTOR
On Piet Van der Wyck, the Colonel's guest, descended the mantle
of responsibility. With the exception of the dour Scot, McFrazer, he
was the only active white man on the estate, and in spite of his years
he rose nobly to the occasion.
The first step was to have the injured man carried to his bed. Here
the Afrikander, skilled in veldt surgery and medicine, deftly removed
Colonel Narfield's boots and leggings. Already the sprained ankle
had swollen badly, and once the compression of the foot gear was
removed, the foot enlarged to greatly abnormal dimensions.
With the aid of embrocation and hot water Van der Wyck dressed
the injury and then proceeded to restore the patient to
consciousness.
Colonel Narfield's first act upon opening his eyes was to attempt to
get out of bed, protesting that happen what may he was not going to
lie there while his two young charges were still missing.
The old farmer firmly exercised his authority.
"You'll have to stay there for a few days," he declared. "By getting
up you will not only injure yourself, but no doubt hamper the work of
the searchers. I am sending McFrazer as you ordered, and until the
native trackers arrive I will patrol the road with the Haussas."
The injured man saw the force of Van der Wyck's contentions. He
simply had to give up, although the state of his active mind can well
be imagined.
McFrazer, booted and spurred, was ready for his long ride when
the Afrikander left the patient's room.
"Would you be thinking it was an aeroplane?" he asked, for he had

already heard from the Haussas how far the spoor of the missing
youths had been tracked.
Van der Wyck shook his head.
"Impossible," he replied. "There were trees meeting overhead."
McFrazer accepted the denial with characteristic brevity.
"Oh, ay," he replied. "Then I'm just awa'," as if a 150-mile ride were
an everyday occurrence.
As a matter of fact the journey to Nyaruma took him exactly fifteen

hours, for at twelve miles from Kilembonga the rough track joined a
well-constructed post-road from Tabora to Ujiji, where there were
relay-horses at convenient distances.
Meanwhile Van der Wyck rode over to Sibenga's Kraal and saw
Logula again. Most of the natives had recovered from their feast, and
several of them, with a view to a reward, offered to search for the
missing white men. Selecting two trackers, Van der Wyck set them
on the spoor, which to a European would be by this time utterly lost.
The natives did almost exactly what their fellow tribesmen had
done the previous day, coming to a halt in precisely the same spot
and declaring that the lost men had "gone up."
Van der Wyck, who spoke most of the Kaffir dialects fluently, had
little difficulty in making himself understood in the tongue of
Sibenga's people; but he found it impossible to get the natives to
climb the trees and make further investigations. They professed
ignorance of the command, shaking their heads and uttering the
word "Maquishi" (finished).
So the Afrikander had to leave it at that as far as these fellows were

concerned, but he determined to carry out further investigations in
that direction, although he himself was too old and too inexperienced
in woodcraft to be able to climb trees.
At four o'clock on the day next following two motor-cars dashed up

to the gate of Kilembonga.
In the first was Wynyard, the District Commissioner, his secretary,

and McFrazer. The second contained a native sergeant, two police,
and two black trackers from Lilwana's country, men known for miles
as the craftiest and most highly-skilled human sleuthhounds in East
Africa.
Wynyard meant to do his task thoroughly. Apart from the fact that
two Englishmen had disappeared, Colin and Desmond were, like
himself, Stockmere Old Boys.
He had accomplished the journey in the record time of seven

hours, the cars attaining a speed of nearly fifty miles an hour over
the post-road, and rarely falling below twenty over the rest of the
way.
McFrazer had already related all he knew of the case. During a

hasty meal Wynyard elicited further information from Van der Wyck,
and also had a brief but business-like interview with the invalid,
Colonel Narfield.
"Right-o!" he declared, cheerfully. "We'll find them. S'pose they're

not playing a practical joke, by any chance?"
"Not with serious work on hand," replied Colonel Narfield. "They

were keeping an eye on the niggers carrying the ivory, and they
knew the importance of that. Yet, curiously enough, the blacks didn't
notice the lads' disappearance, otherwise some, if not all, of the ivory
would have been missing. It wasn't."
Within forty minutes of his arrival Wynyard was on the road again.
With him went Van der Wyck, none too readily, for he mistrusted
mechanical cars. He would have preferred his trusty horse, but that
animal had been worked hard of late, and, as time was a great
consideration, the Afrikander took courage and rather nervously sat
beside Wynyard in the car.
In the rear were crowded Tenpenny Nail, Blue Fly, and the native
sergeant, while the second car was packed with native trackers,
police, and a huge dog, partly bloodhound and partly wolfhound.
"We are nearing the place where the Sibenga Kraal trackers lost
the spoor," cautioned Van der Wyck, as the leading car jolted and
bumped through the dense avenue.
"Oh," ejaculated Wynyard, "is that so? But I think I'll start at the
beginning. There's nothing like independent clues."
The cars pulled up outside the hut of Logula, Sibenga's successor

came out to do "Konza," accompanied by almost every man, woman
and child in the village.
There was a sneer on the Chief's face as he watched the
preparations. He rather resented the employment of trackers from
another tribe, but he said nothing and thought the more.
Meanwhile Wynyard was holding one of Colin's sun-helmets to the

hound's nose. The animal, quickly picking up the scent, trotted off
with his tail erect and his nose close to the ground.
Twenty yards or so behind followed the car containing the District

Commissioner and Van der Wyck, with the Haussas riding on the
running-board. The other car came close behind, with four of the
more daring natives of Sibenga's Kraal augmenting the numbers of
the already closely-packed occupants.
Van der Wyck was not in the least surprised that the hound came to
a standstill at the very spot which the two pairs of trackers had
already indicated as the end of the spoor. The animal, showing a
decided disinclination to proceed, was led back to the second car,
and the Nyaruma trackers were told to carry on the good work.
In five minutes they delivered their verdict. The missing white men
had "gone up." They were positive about that, but, like the Sibenga
Kraal trackers, they resolutely declined to continue their
investigations in the overhanging branches of the trees.
"Dashed if I'll be done!" exclaimed Wynyard. Then turning to the

native sergeant, he bade him bring a rope from the second car and
make it fast to one of the branches.
Assisted by Tenpenny Nail and Blue Fly, the sergeant carried out
his instructions. Thereupon Wynyard swarmed up the rope and
gained the leafy branch. But there was nothing that afforded him a
clue, or, if there were, he failed to detect it. The leaves and young
twigs showed no sign of having been disturbed; the resinous wood
bore no trace of the contact of the studded sole of a boot.
"Were they carrying rifles?" he inquired, calling down to Van der

Wyck, twenty-five or thirty feet below.
"Yes," replied the old farmer. "They had when we left the kraal."
"And these haven't been found?"
"No; we found nothing."
Wynyard knotted his brow in perplexity. Presumably, Sinclair and

Desmond were either carrying their rifles in their left hands or else
had the weapons slung across their backs.
Assuming the native trackers' assertions to be correct, what

happened to the rifles? Either they would have fallen to the ground
or else they would have caught and torn away some of the foliage.
"Well, I consider this the limit—the absolute limit," declared

Wynyard, as he prepared to descend.
Arriving upon terra firma, the District Commissioner consulted a

map of the district. It was based upon a German survey, and,
therefore, remarkably accurate, for the Hun, painstaking and
methodical and convinced that he had come to stay, had triangulated
and mapped out his largest colony with Teutonic thoroughness.
From it he discovered that the forest extended a good twenty miles

in a north-easterly direction, and was about half that distance across
its widest part. The furthermost limits extended to the base of a lofty
ridge of mountains forming part of that mighty system that early
nineteenth century cartographers vaguely indicated as the
Mountains of the Moon.
Wynyard was still engaged in scanning the map when his attention
was distracted by the sounds of shouting and yelling. Four hundred
yards down the road came Logula and his warriors, all armed in
characteristic fashion with spears, shields, and kerries, and rigged
out in feathers, paint, and other native insignia.
"By Jove!" he ejaculated. "I hope those beggars aren't up to

mischief," and he found himself wishing that he had a full company
of armed police with him in place of the three or four men at his
disposal.
But Logula's intentions were friendly, even though they appeared

the opposite. By his side capered a tall fellow in the full panoply of a
witch-doctor.
"Great Chief," began Logula, "you have failed, even as my snake

told me you would. Therefore I bring you aid."
"We are in no need of the black man's magic, Logula," declared

Wynyard sternly.
"You can but try," protested the Chief.
"And waste time," rejoined the District Commissioner. "Begone!"
Logula stuck to his guns.
"Hearken, Great One," he continued. "I have twenty good oxen. If

my witch-doctor fails to give you the knowledge you seek, then they
are yours."
Wynyard was on the point of contemptuously declining the offer

when Van der Wyck interposed.
"Let him try, Mr. Wynyard," advised the old man. "Times before I
have both heard and seen these wizards at work in the Transvaal
and Zululand. I have no faith in their methods, but their results are
sometimes very wonderful. Out of darkness we may find light."
"Very well," agreed Wynyard grumblingly, "Let the jolly old

jamboree proceed."
The witch-doctor needed no second bidding. With many weird and

unintelligible incantations he lighted a fire on the very spot that had
so frequently been pointed out during the last three days. Then he
began dancing and capering violently, at times literally treading in the
midst of the flames with his bare feet.
After about ten minutes of this sort of thing he suddenly collapsed
in a heap, his head resting on his knees, at the same time emitting
mournful howls.
"O Talula!" exclaimed Logula, addressing the semi-conscious

wizard. "Tell me, have you smelt out the White Man-who-wears-the-
Sacred-Amulet?"
"I have, O Chief."
"What do you see—blood?"
"I see no blood."
"Hau!" exclaimed Logula. "The White Man-who-wears-the-Sacred-

Amulet still lives."
The witch-doctor raised himself to a sitting position and pointed to

the north-east.
"Warriors not of our nation. Spears in hundreds. A great hole in the

earth .... I see two white men ... at present they are not spirits."
"Ask him," exclaimed Wynyard, addressing Logula, "ask him if he

will be able to rescue them?"
"They might be restored to their own people," announced the witch-

doctor, without waiting for the question to be put to him. "More, I
cannot say, save that the Great One from Nyaruma will not succeed
in the attempt .... I have it ...."
With a convulsive effort he sprang to his feet, clutched at the empty

air, and uttered one word:
"Makoh'lenga."
CHAPTER XXVIII
KIDNAPPED
"Good night's work that, Tiny, old bird," remarked Colin.
"Yes, you lucky beggar," agreed his chum enviously. "Of course, it's
jolly sporting of you to divide your share, and I'm grateful. At the
same time, 'tisn't the same, if you can understand. S'posing, for
instance, it had been my lucky shot, you'd understand then."
"It was a jolly good thing I picked up those explosive cartridges by

accident," conceded Sinclair. "It was a fluke—absolutely."
"Colonel Narfield would have been snuffed out if you hadn't," said
Tiny. "The ordinary .303's had no more effect than tickling a wild cat
with a straw. By Jove! I am sleepy ... aren't those niggers kicking up
an infernal row?"
"Let's slow down a bit and miss most of the dust and noise,"
suggested Colin. "We can keep an eye on the bearers just as well, if
not better."
Checking their horses, the two chums allowed the bearers to draw
on ahead. It was a case of distance lending enchantment to the
scene, as the early sunlight glinted on the muscular, copper skins of
the wildly-excited natives.
"Ugh! The flies!" exclaimed Tiny. "That one nearly jumped down my
throat. 'Tain't all jam being in the rear of a procession—eh, what?"
"I'm going to have the best piece of the ivory sawn off," declared
Colin, ignoring his companion's complaint and reverting to the
subject of the spoils of the chase. "Then I'll send it home to my
people. And a chunk for Dr. Narfield, too. Probably the head will
shove it in the school museum with a notice on it, 'Shot by an Old
Boy,' sort of thing. My word, I'm jolly glad I came out here, aren't
you?"
"Better'n fooling round in an office, any old day," declared Tiny.

"More than likely I'd have been under the turf now if I'd stopped at
home."
"And now you're quite fit," remarked his chum.
"Hope so," said Desmond. "There's one thing, I've lost that rotten
cough .... Hullo! We're nearly into the forest. Hadn't we better hurry
along a bit. If those niggers took it into their heads to do a bunk,
you'd lose your ivory for a dead cert., old son."
"Half a mo!" exclaimed Colin. "My girth's slipping a bit. Hang on, old
man."
Throwing his reins to his chum, Sinclair dismounted and deftly

readjusted the slack girth. Then, climbing into the saddle, he urged
his horse onwards.
By this time the rear of the column was nearly three hundred yards
ahead and already in the shade of the dense foliage. The bearers,
probably with the idea of keeping up their courage in the gloom,
redoubled their shouts.
"What a contrast!" remarked Desmond as the two lads entered the

forest. "After the glare I can hardly see a yard——"
His remarks were cut short in a totally unexpected manner. From a

stout branch of a tree immediately overhead two hide ropes,
terminating in running nooses, were dexterously dropped over the
shoulders of the astonished lads.
Before they could utter a sound—even if they had, the din made by
the native bearers would have deadened it—they were jerked out of
the saddles and hauled aloft.
At the sudden tightening of the noose, Colin immediately relaxed

his grip of the reins and instinctively made a frantic ineffectual grab
at his slung rifle. The noose, pinning his arms tightly against his
sides, rendered the attempt futile.
Like a shoulder of mutton hanging from a roasting-jack, Colin found

himself being hoisted upwards, spinning round and round, and more
than once colliding with his companion in misfortune.
The coup had been neatly planned and dexterously executed.

Strong, lithe, brown hands emerging from the leafy cover gripped the
two lads, stifling their unheard shouts for aid. Other hands grasped
their rifles, cutting the leather slings in order to disarm the kidnapped
youths.
Then, bound hand and foot and effectually gagged, Colin and Tiny
were laid at full length upon a broad branch thirty feet above the
ground, with a dozen or more sinewy, active men keeping guard over
the captives and others in the higher branches watching with much
approval the deft work of their companions.
Then someone spoke in a tongue that neither Colin nor Tiny

recognised, although by this time they had a useful smattering of the
native dialects in use around Kilembonga.
There was no doubt about it—the man in charge of the kidnappers

knew how to handle them. The discipline was perfect. Unlike most
African natives, who can hardly ever carry out any work silently,
these men maintained absolute quiet, moving with the precision and
smoothness of a well-regulated machine.
Each captive was carefully lifted from branch to branch until they
were at least eighty feet above the ground. During the operation the
men took particular pains not to break off any of the foliage,
methodically bending the twigs that hampered their progress, and
not allowing any part of the captives' bodies or clothing to come in
contact with the bark.
The next step was to pass the prisoners literally from hand to hand
and from tree to tree, the close formation of the massive branches
forming an almost continuous arboreal highway.
As fast as each native passed on his load he dropped to a lower

branch and made his way to the front of the long line of bearers
ready to renew his part in the endless human chain, so that at the
end of an hour Colin and Desmond were at least two miles from the
scene of their capture.
Here the party—captors and captives—descended to the ground.

More natives were waiting with two hammock-like litters of woven
grass. Into these Colin and Desmond were placed, no attempt being
made to remove either their gags or their bonds.
Then at a rapid pace, but with the same orderly silence that
characterised the opening stages of the operations, the natives
moved off, the two litters being borne in the centre of the long double
file.
At the end of a tedious journey, in which Colin calculated they had

covered from ten to twelve miles, the cortège halted in an open
space, bounded on three sides by the forest, and on the fourth by a
cliff rising sheer to a height of two thousand feet.
The gags were then removed and the prisoners' ankles freed,
although their arms were still securely bound as before. Then into a
vast circle of armed warriors Colin and his chum were led, to find
themselves confronted by a gigantic man holding a gleaming axe of
yellow metal. By his side was a pillar of wood, somewhat resembling
the mediaeval executioner's block.
"If they've brought us all this way for the purpose of cutting off our
heads," thought Colin, "all I can say is they've gone to a lot of
unnecessary trouble. Tiny, old man," he added aloud, "for goodness'
sake don't let them see we've got the wind up. Let them see we're
Englishmen."
CHAPTER XXIX
IN THE HANDS OF THE MAKOH'LENGA
Colin Sinclair had been curious concerning the mysterious

Makoh'lenga. Now he was finding out more about them than he
wished.
His captors were without exception tall and muscular and well-
proportioned. Their garb consisted solely of a white loin cloth. Their
bodies were "unadorned" with chalk and ochre after the fashion of
the majority of African tribes, nor were there any evidences of
voluntary mutilation so frequently to be met with amongst savages.
The only ornaments they wore were armlets of gold just above the
left elbow. Every male lenga over the age of sixteen wore one.
They were noticeably clean in their habits and persons, orderly and
well-disciplined, and, in short, seemed far in advance in the
principles of hygiene above even the doyen of the Kaffir races—the
pure-blooded Zulu.
But even these qualifications were no excuse for present

conditions. The possibility of making a touching acquaintance with
the golden axe rather blunted Sinclair's interest in his new and
undesirable acquaintances.
There was no denying one fact—he felt "scared stiff." It was only by
a determined effort that he kept his well-schooled and steady nerves
under control. Perhaps if his arms had not been so securely bound
he might have precipitated matters by planting a blow with his fist
between the eyes of the copper-hued giant who was watching him
so covertly.
The Makoh'lenga seemed in no hurry to commence the next phase

of the operations. In a two-deep circle they stood motionless as
statues, each warrior grasping the haft of a seven-foot, broad-bladed
spear, while on his right arm he wore a small circular shield with a
convex boss.
On the inside of each shield was a small sheath holding a short

double-edged knife. The weapons were plain and serviceable, no
attempt being made to engrave the metalwork or to embellish the
hafts with paint and feathers. Simplicity of equipment seemed to be
the keynote of these mysterious men.
At length, in reply to an invitation from the chief, two warriors

stepped forward and solemnly presented the trophies—the captives'
rifles. These were accepted without any hesitation, the chief
apparently knowing the principles of modern firearm construction;
but, strangely enough, he carefully examined the stocks as if to find
some inscription.
Discovering none, a shade of disappointment flitted over his

features, and without a word he handed them back to the men from
whom he had received them.
Although the giant was obviously a person of rank, even if he were

not the supreme head of the tribe, there was a total lack of servile
abasement noticeable in the case of the Zulu, Matabele, and other
Kaffir tribes.
The men tendering the rifles simply saluted by bringing the right
hand in a horizontal position up to the chin. This was the recognised
form of salutation. Equals greeted one another by bringing the right
hand only breast high.
Several times Colin bethought him of the amulet, but, his arms
being bound, he was unable to produce it. Perhaps, after all, it was a
trump card. On the other hand, it might fail to produce the same
effect upon these mysterious men as it had once upon the obviously
less intellectual natives around Kilembonga.
Presently four warriors, laying aside their spears and shields,

strode forward and grasped Desmond by the arms and legs, and
held him in a horizontal position. Tiny did not utter a sound, nor did
he offer any resistance, but he craned his neck and looked at the
executioner's block with ill-concealed dismay.
It was a moment when the rattle of a machine-gun would have

been most welcome. Even a stampeding of wild elephants or a
death-dealing thunderstorm would have been a pleasurable
diversion, but nothing of the sort happened.
At a word from the chief, Tiny's captors searched his pockets and
tore open his shirt. Every article they took—knife, cartridges,
handkerchief, matches, purse, and notebook they examined and
then placed in a row on to the ground. They expressed no delight at
the various objects which are highly prized by savages; indeed, their
looks betrayed disappointment.
The examination over, Tiny was set upon his feet and left alone.
The four warriors next directed their attention towards Colin, and he,
too, was placed in a horizontal position and searched.
Suddenly one of the men gave a shout of delight; it was the first
sound uttered by any one during the searching process. He had
discovered the swastika.
Cutting away the cord that held it, the finder reverently presented it
to the chief.
The latter, displaying considerable emotion, minutely examined the

gold and copper amulet, then, holding it aloft, he shouted:
"Ad idda ver h'lenga soya."
Although utterly ignorant of the language, Colin realised its import.

The chief had announced to his people that the much-sought-for
amulet had been found.
A roar of exultation greeted the words. Almost before the volume of

sound had abated a weird-looking contrivance was carried into the
centre of the ring by a dozen huge men. It resembled a gigantic
ram's horn, the bell mouth rising a good ten feet from the ground. At
the other end was a hollow cylinder with a disc of goat's skin
stretched tightly over the outer part.
Armed with a club-shaped stick, one of the natives began banging

upon the drum portion of the instrument, keeping up the performance
for the space of about a minute, the beats resembling the tapping of
a morse code buzzer.
The volume of sound emitted from the bell-mouthed horn was

stupendous. It seemed loud enough to deafen everyone within fifty
yards. Even the ground shook perceptibly under the roar of the
deep-pitched instrument.
The last long-drawn reverberations died away, and utter silence fell
upon the close ranks of the Makoh'lenga warriors. Then, after a
lapse of nearly five minutes, came a low, bass roar from a distant
source. Somewhere, far up in the rugged mountains, an alert
sentinel was replying to the sonorous message of the ram's horn.
The message was short and obviously satisfactory and to the point,
for the moment the sound ceased the chief issued an order.
With the alertness and methodical precision of a crack British

regiment, the circle of warriors dissolved, and the men reformed into
a close column. Up doubled a party of men with the two litters in
which Colin and Tiny had been carried through the forest.
With his own hands the Chief unknotted the bonds that secured the
lads' arms. Then he signed to them to retake possession of their
scanty belongings except their rifles. The amulet was retained by the
Chief, who motioned to the two chums to seat themselves in the
litters.
"This is going to be a bit of a picnic, after all, Tiny, old son,"

remarked Colin.
"Hope so," replied Desmond. "Only isn't it a bit too early to talk
about picnics and joy rides? That chap seems jolly pleased to be
able to bag your amulet. Now he's got that, what does he want us
for? That's what I want to know."
At a sign from the Chief, Colin and Tiny climbed into the litters.
Their previous acquaintance with this mode of conveyance had been
in a state of being bound hand and foot. Now their limbs were freed
and they were able to sit up and look about them, while an awning
had been provided to shelter them from the glare of the sun.
The chums were in the middle of a long column of men marching

four abreast, the warriors keeping step but taking much longer paces
than is the case with European troops. They moved almost silently,
their bare feet treading lightly upon the ground. Except when a
command was given, not a word was spoken.
Following the base of the line of cliffs the Makoh'lenga marched for
nearly two miles until they arrived at a shallow stream running
through a deep gorge. Here the warriors turned sharp to the left, in
file, and began ascending the stream, which varied from ankle to
knee-deep.
Although the rivulet was not less than ten feet in width the walls of
the gorge, which averaged two hundred feet in height, almost met at
the top, so that the inclosed space was deep in gloom. It was a weird
experience to the two chums, as they watched the symmetrical lines
of dark figures making their way up-stream.
At length, above the swish of the water as hundreds of feet forced
their way against the steady current, came the dull roar of a
waterfall. Louder and louder grew the sound, until Colin could see an
apparently unbroken sheet of water falling from a height of quite a
hundred and fifty feet and breaking into a cloud of foam as it came in
contact with the bed of the gorge.
Into this waterfall the Makoh'lenga plunged unhesitatingly. They,

evidently, did not share the dislike, amounting almost to fear, of Zulu
tribes for running water, yet it puzzled Colin to know where the men
went. They seemed to be swallowed up in the clouds of spray as file
after file disappeared. Beyond the waterfall was solid rock, and yet
the column held on without a check.
Then came Colin's turn to pass through the sheet of descending

water. To a great extent the canopy overhead prevented him from a
thorough soaking, although the spray invaded the open side of the
litter.
It was an ordeal quickly over. For a brief instant, as the water

poured unhindered upon the canopy, it seemed as if the covering
would collapse under the pressure. The bearers staggered under the
weight of the falling water, but quickly recovering themselves, they
bore Colin inside the fall.
Here was a clear space of about three yards between the wall of
rock that formed a barrier and the gulley and the curtain-like
waterfall, and on the right of this space was a natural tunnel driven
obliquely through the wall of the chasm.
This, then, was the secret gateway to Makoh'lenga Land.

CHAPTER XXX
TO WHAT END?
The tunnel was of large dimensions, averaging twenty-five feet in

height, and—when once clear of the gulley—fifteen feet in width, the
floor was remarkably even, with a stiff gradient. In remote ages the
tunnel had evidently been the outlet for an enormous quantity of
water—possibly a mountain lake—but the supply had long since
diminished and had found a new outlet.
Just within the entrance to the tunnel a guard of warriors was

drawn up in a recess, in one corner of which a fire was burning.
As the returning Makoh'lengas passed, every tenth man was given

a lighted torch, in order to illuminate the otherwise dark approach,
and soon the tunnel was brilliantly lit up, while the flambeaux gave
off very little smoke and emitted pleasant odours.
The bearers of the two litters were evidently anxious not to cause
their passengers any further inconvenience, for the two men in front
held the poles in their hands with the arms drooping to the full extent.
The men behind raised their ends of the poles upon their shoulders,
so that the litters were kept in practically a horizontal position.
During the passage of the tunnel the same silence on the part of
the warriors was observed, the only sounds being the pattering of
hundreds of bare feet upon the smooth rock and the hiss of the
flaring torches.
The subterranean march occupied about five minutes, then into the
blazing sunlight the long procession emerged.
Colin was frankly interested. He felt that as the threatened danger

had passed away, thanks to the amulet, there was little possibility of
its recurrence, especially as the lads' captors were now treating
them with consideration. True, Sinclair no longer had the swastika in
his possession, but whether that would influence further proceedings
remained a matter for speculation.
It was a strange sight that greeted Colin's gaze as the litter came to
a standstill on the Makoh'lenga terrace. Although this was by no
means the summit of the mountain it was several miles in length and
about one and a half in breadth.
On the side nearer the mountain were hundreds of stone and

plaster-built houses with thatched roofs. Each house had large
glazeless windows shaded by wide porches, while every door was
open.
Subsequently Sinclair discovered that the doorways were open for

the simple reason that there were no outside doors. It was a custom
of the Makoh'lenga to keep "open house," the natives being so
scrupulously honest that there was no necessity for anyone to bolt
and bar his household goods and chattels.
Each house was surrounded by a small, highly-cultivated garden,

while outside the village were common fields, both under cultivation
and for grazing purposes, the grass being particularly rich and
capable of supporting large herds of domestic cattle and flocks of
sheep and goats, the latter bearing a strong resemblance to the
Angoras.
At some distance from the houses were buildings given over to the
manufacture of metal, woodwork, pottery, and cotton and worsted
goods, the Makoh'lenga being skilled artisans. There were several
ingenious machines used in connection with the various industries,
many of these being driven by water-power.
Gold, copper, and iron were worked into manufactured goods to a

large extent, but the Makoh'lenga seemed ignorant of how to
produce steel or even cast-iron.
Colin soon discovered that the warriors who had escorted Tiny and
himself were only a small portion of the Makoh'lenga fighting men.

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Allergic and immunologic diseases : a

practical guide to the evaluation,

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For Information on all Academic Press publications

Publisher: Stacy Masucci

Dedicated to Laura, Francesca, Santiago, Michael,

List of contributors xliii

2. A brief history of allergy and immunology 17

Immortal cells and the ability to produce monoclonal antibodies 28

4. The allergy and immunology history and physical 89

5. Basic genetics and epigenetics for the immunologist

Types of genetic studies 121

6. Laboratory skills for immunologists: utility and

Section 4: Basophil activation test 165

7. Developments and emerging technologies in allergic

AI in atopic dermatitis research 206

8. Genomics technologies and bioinformatics in allergy

Physiological characteristics 273

10. Skin prick testing for foods 303

11. In vitro methods to assess allergy 323

In vitro testing for drugs 337

12. Oral food challenges 345

13. Physical urticarias: diagnosis and testing 389

Symptomatic dermographism 391

14. Techniques to evaluate asthma 401

15. Drug allergy testing 419

Evaluation of immediate drug reactions 421

16. Diagnosis and management of rhinitis and

17. Approach to the rash from an allergy and

Stevens Johnson syndrome/toxic epidermal necrolysis 498

18. Patch testing and the evaluation of contact allergy 511

Other important considerations 522

19. Skin biopsies: their utility to allergists and

Urticarial dermatitis 556

Leukocyte adhesion deficiency 566

20. Evaluation and diagnosis of mast cell associated

21. The evaluation of a patient with urticaria

22. Evaluation of a patient with anaphylaxis 639

23. Evaluating patients with eosinophilia and eosinophilic

24. Unproven and controversial tests and treatments

26. Testing the innate immune system 725

27. Testing the adaptive immune system 737

T-cell receptor excision circle 743

28. Infections in primary immunodeficiency 747

29. Periodic fever syndromes and autoinflammatory

Familial Mediterranean fever 793

30. Primary immune regulatory disorders 829

31. The history, diagnosis, and pathophysiology of

32. The evaluation and treatment of autoimmune diseases 863

Inflammatory markers 871

33. Neurologic autoimmune diseases 887