193
C HA PTER 15
Clinical Features and Diagnostic Criteria
of Atopic Dermatitis
Sinéad M. Langan1 & Hywel C. Williams2
1
Faculty of Epidemiology and Population Health, London, School of Hygiene and Tropical Medicine, London, UK
2
The Centre of Evidence Based Dermatology, University of Nottingham, Nottingham, UK
Clinical features of atopic dermatitis, 194
Abstract
This chapter is divided into two sections: the first lists the common
and less common clinical features of atopic dermatitis (AD) with
the aim of helping those less familiar with diagnosing atopic der-
matitis in a clinical setting. The second part deals with diagnostic
criteria for atopic dermatitis that may be used in research studies.
The two sections are set apart deliberately since the requirements
of a disease definition for making a clinical diagnosis in an individual
may be somewhat different from making a group definition for
research participants. A clinical sign such as thinning of the lateral
eyebrows may be associated with AD, and possibly useful in the
context of tipping a clinician to make a diagnosis of AD in a child
with indeterminate skin inflammation. Yet it is too difficult to
Key points
Clinical features of atopic dermatitis
• Although atopic dermatitis (AD) can affect any part of the body, it has
a predilection for the skinfolds, the reason for which is still unclear.
• The distribution of eczema changes from involvement of the face,
scalp and extensor surfaces in infancy to flexural involvement in
childhood and later life.
• The morphological appearance of AD can vary greatly from acute
red vesicular eczema to chronic thickened purple/grey lichenified
patches.
• AD can be associated with serious complications including
secondary infections and exfoliative dermatitis.
• Other differential diagnoses should be considered when infants
present with a severe eczematous rash with failure to thrive,
recurrent infections or petechiae.
Diagnostic criteria for atopic dermatitis
• AD is a difficult disease to define since it is variable in morphology
and distribution according to age, skin type and whether the
skin is acutely or chronically affected.
• Although the term ‘atopic dermatitis’ is used throughout this
book, most cases of ‘atopic’ dermatitis are not atopic when
tested in populations. As a consequence there is debate as to
whether the term ‘atopic dermatitis’ should be reserved for
cases with evidence of IgE reactivity.
• The positive predictive value of diagnostic criteria will fall with
low disease prevalence even though sensitivity and specificity
might appear to be high.
Harper’s Textbook of Pediatric Dermatology, Fourth Edition. Edited by Peter Hoeger, Veronica Kinsler and Albert Yan.
© 2020 John Wiley & Sons Ltd. Published 2020 by John Wiley & Sons Ltd.
ATOPIC DERMATITIS
Diagnostic criteria for atopic dermatitis, 203
SECTION 3:
define reliably and too infrequent to be of use when examining
groups of individuals, especially when it adds very little to the
predictive ability of existing cardinal features such as flexural
involvement and dry skin. Likewise, diagnostic criteria that may
produce acceptable results for estimating the prevalence of AD in
a country may not be suitable when trying to diagnose AD in an
individual, since every set of diagnostic criteria will have limita-
tions in sensitivity (proportion of true cases correctly identified)
and specificity (proportion of non‐cases correctly identified). All
current diagnostic criteria will therefore misclassify some
individuals who have AD as not having AD, and some who do not
have AD as having AD. Such misclassification may be acceptable
in research studies, providing the degree of misclassification is
understood in relation to the objective of the study.
• Previous definitions of an incident case of AD have paradoxically
included chronicity.
• What is recognized as AD today may turn out to be four or five
different phenotypes (subtypes) in years to come. Any proposals
for new subtypes of AD should be based on strong evidence that
they increase predictive ability in terms of prognosis, disease
associations or response to treatments.
• While a clinical diagnosis is appropriate in clinical practice,
standardized diagnostic criteria for AD are essential when
comparing groups of people in clinical studies.
• A good disease definition should be valid, reliable, acceptable
to the population, coherent with prevailing clinical concepts and
comprehensive in its application.
• The Hanifin and Rajka list of diagnostic features was an important
landmark in suggesting major and minor criteria for AD.
• A systematic review suggested that the most extensively tested
criteria (the UK Working Party’s refinement of the Hanifin and
Rajka criteria) should be used in future intervention studies,
although there is room for improvement.
• Ideally, diagnostic criteria should be tested beforehand
for validity in the setting where they are to be used. If
translation or transcultural interpretation becomes a
problem, then question‐free methods of assessing visible
flexural dermatitis in a standardized way are an option for
comparative research.
• It is crucial to consider the type of clinical study before deciding
which diagnostic criteria can be used. Surveys will need a trade‐
off between sensitivity and specificity whereas clinical trials will
require specific criteria.
 194 Section 3 Atopic Dermatitis and Related Disorders

Clinical features of atopic dermatitis

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

morphology described here aid clinical diagnosis in the

absence of a specific laboratory test for AD.
SECTION 3:

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

(a)

Fig. 15.3 Symmetrical eczema involving the trunk and extensor surfaces
in atopic dermatitis in a child. Source: Courtesy of Professor Hywel C. Williams.

In childhood, AD distribution is seen most commonly in

a flexural pattern. The tendency for skin inflammation and
the effects of chronic rubbing (lichenification) to become
accentuated in the flexures is one of the classical hallmarks
of AD (Fig. 15.4) [3]. Flexures refer to bends in the articular
(b) skeleton where skin apposes skin. What exactly consti-
Fig. 15.1 Scalp involvement in atopic dermatitis in an infant. Source: tutes a flexure varies from text to text, but most agree that
Courtesy of Dr Paula E. Beattie. the fronts of the elbows, backs of the knees, around the
 Chapter 15 Clinical Features and Diagnostic Criteria of Atopic Dermatitis
neck and in front of the ankles are the commonly affected
flexures. All of the flexure is not always involved –
lichenification as a result of prolonged rubbing typically
occurs most prominently behind the knees along the most
prominent tendons (semimembranosus and semitendino-
sus) and likewise overlying the brachioradialis muscle
group on the antecubital fossae (Fig. 15.5a and b).
Other affected areas include the wrists and folds
beneath the buttocks (infragluteal folds). Why the most
flexural sites of the body, i.e. inguinal folds and apex
of the axillae, are infrequently involved is unclear.
Eczematous inflammation at these sites may be more
likely to be a marker of seborrhoeic dermatitis of infancy
or early‐onset psoriasis. Two points are worthy of note
with regards to flexural involvement; the first is that AD
Fig. 15.4 Thickened lichenified atopic dermatitis on the lower leg and
dorsal foot in darkly pigmented skin. Source: Courtesy of Professor Hywel
C. Williams.
(a)
Fig. 15.5 (a and b) Flexural subacute atopic dermatitis involving the antecubital and popliteal fossae with erythema and excoriations. Source: Courtesy of
Professor Hywel C. Williams.
195
can affect any part of the body. The fact that a child
presents with an itchy scalp and diffuse patches of skin
inflammation on extensor parts of the limbs should not
put one off diagnosing AD since it is the most common
inflamed itchy chronic skin eruption in children in
developed countries.
From puberty onwards, AD tends to affect the face,
hands, back, wrists and dorsal feet. The hands and fin-
gers are frequently involved, probably as a result of con-
stant irritant exposure, which may result in oedema
and fissures overlying the finger joints (Fig. 15.6) and
scaling on the palms adjoining the fingers (apron sign).
Adults may only have persisting hand or facial eczema
ATOPIC DERMATITIS
SECTION 3:
Fig. 15.6 Chronic hand eczema with loss of cuticles, nail dystrophy,
fissuring and scaling. Source: © Diepgen TL, Yihune G et al. Dermatology
Online Atlas (www.dermis.net). Reprinted with permission.
(b)
 196 Section 3 Atopic Dermatitis and Related Disorders
ATOPIC DERMATITIS
Fig. 15.7 Acute cheilitis in a child with atopic dermatitis with erythema
and swelling of the vermillion border and perioral region and fissuring of
SECTION 3:
the commissures. Source: © Diepgen TL, Yihune G et al. Dermatology
Online Atlas (www.dermis.net). Reprinted with permission.
Fig. 15.8 Fissures of the infra‐auricular region in childhood atopic
dermatitis. Source: © Diepgen TL, Yihune G et al. Dermatology Online
Atlas (www.dermis.net). Reprinted with permission.
(a) (b)
Fig. 15.10 (a) Acute nipple eczema with erythema, erosions, oozing and secondary impetiginization. Source: © Diepgen TL, Yihune G et al. Dermatology
Online Atlas (www.dermis.net). Reprinted with permission. (b) Chronic nipple eczema with lichenification and swelling. Source: Courtesy of Dr Diana Purvis.
and skin that is sensitive to irritant exposure, or they may
have persistent chronic AD.
Specific sites that are frequently involved by AD are as
follows: lips with cheilitis in childhood (Fig. 15.7), which
can lead to secondary ‘lip‐lick cheilitis’ or exfoliating
cheilitis with perlèche (single or multiple fissures and
cracks at the labial commissures) and involvement of the
vermillion border in adult AD. The infra‐auricular,
supra‐auricular and retroauricular region is frequently
affected by fissures (rhagades) in children (Fig. 15.8)
while eyelids and periorbital skin are frequently
involved in adolescents and adults, resulting in promi-
nent infraorbital creases from skin oedema and postin-
flammatory pigmentation resulting in the affected
individual appearing fatigued. Some sites of predilec-
tion of AD such as around the eyes, mouth or nose
(Fig. 15.9) or under the ear also occur probably as a result
of influences other than skin‐to‐skin contact such as air-
borne allergens and irritants, or irritant contact dermati-
tis around the mouth from saliva and wet foods in early
age. Nipple eczema is frequently seen from puberty
onwards, but is also seen in infants and can present with
nipple swelling (Fig. 15.10a and b).
Fig. 15.9 Subacute eczema with fissuring and oedema. Source: ©
Diepgen TL, Yihune G et al. Dermatology Online Atlas (www.dermis.net).
Reprinted with permission.
 Chapter 15 Clinical Features and Diagnostic Criteria of Atopic Dermatitis 197

ATOPIC DERMATITIS
SECTION 3:
(a) (b)

(c)
Fig. 15.11 (a) Acute, (b) subacute and (c) chronic eczema. Source: Courtesy of Professor Hywel C. Williams.

Morphology
The morphology of AD can be variable and depends on
the stage of the lesion. Acute lesions are characterized by
ill‐defined erythema, papules, papulovesicles, erosions,
oedema and weeping (Fig. 15.11a). Subacute lesions are
erythematous scaly excoriated plaques and papules
(Fig. 15.11b) while thickened purple/grey lichenified
plaques and fibrotic papules (prurigo) are seen in chronic
lesions (Fig. 15.11c). During infancy, AD tends to be acute
and exudative with chronic forms of AD developing later
in childhood. In longstanding AD, individuals may mani-
fest all three stages of AD concurrently or at different
times depending on the level of disease activity, reflecting
the relapsing and remitting nature of eczema.
Fig. 15.12 Symmetrical infraorbital Morgan–Dennie folds. Source:
© Diepgen TL, Yihune G et al. Dermatology Online Atlas (www.dermis.net).
Associated physical signs Reprinted with permission.
A number of clinical signs frequently accompany AD and
these may be clues to the diagnosis when the distribu-
tion and morphology are not classical, although they 50–60% of cases of AD. However, this sign appears to
may not be pathognomonic of AD. A number of these will vary depending on ethnicity, being more common in
be briefly discussed here. darkly pigmented ethnic groups regardless of AD, and
shows significant variability even within individuals [4]
Periocular and ocular signs (Fig. 15.12). Periorbital pigmentation, ‘atopic shiners’,
Infraorbital folds (Dennie–Morgan lines) are frequently describes a periorbital brown to grey discolouration [5].
seen in AD, with most studies reporting their presence in As previously discussed, thinning or absence of the outer
 198 Section 3 Atopic Dermatitis and Related Disorders

(blanching of the skin at the site of stroking with a blunt

instrument rather than developing a partial or full triple
response of Lewis with reflex erythema), are frequently
described in AD and are thought to represent abnormal
vascular responses (Fig. 15.15).
Dry skin (xerosis) is seen in all age groups with AD and
is considered a hallmark of AD (Fig. 15.16). Atopic xerosis
ATOPIC DERMATITIS

Fig. 15.13 Thinning of the outer eyebrows (Hertoghe’s sign) with extensive
scaling and lichenification of the forehead. Source: © Diepgen TL, Yihune G
SECTION 3:

et al. Dermatology Online Atlas (www.dermis.net). Reprinted with permission.

eyebrows (Hertoghe’s sign), a sign originally described in

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

Other cutaneous ‘minor’ signs

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

Fig. 15.14 Rippled hyperpigmentation of the lateral neck (atopic ‘dirty

neck’). Source: © Diepgen TL, Yihune G et al. Dermatology Online Atlas Fig. 15.16 Xerosis in infantile atopic dermatitis. Source: Courtesy of
(www.dermis.net). Reprinted with permission. Dr Paula E. Beattie.
 Chapter 15 Clinical Features and Diagnostic Criteria of Atopic Dermatitis 199

ATOPIC DERMATITIS
SECTION 3:
(a)

Fig. 15.17 Hyperlinear palms with exaggerated wrinkling of the palms.

Source: Courtesy of Professor Alan Irvine.

may be generalized and is frequently most noticeable on

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

Clinical features of specific subtypes Diffuse ‘dry type’ AD

of atopic dermatitis This type of AD was first described in Japan and refers to
Specific subtypes of childhood AD deserve a mention as a diffuse dry type AD, sometimes called patchy pityriasi-
their morphology and distribution have not been previously form lichenoid eczema, which is slightly irritating and
discussed in this chapter. clinically consists of confluent scaly nonhyperkeratotic
 200 Section 3 Atopic Dermatitis and Related Disorders
ATOPIC DERMATITIS
SECTION 3:
Fig. 15.19 Postinflammatory hypo‐ and hyperpigmentation in darkly
pigmented skin. Source: Courtesy of Professor Hywel C. Williams.
skin‐coloured papules or ‘chicken‐skin spots’, mainly on
the trunk region [14]. Seasonal variations are described,
with worsening in winter.
Eczema subtypes/phenotypes
There is increasing evidence supporting the existence of
discrete clinical phenotypes of eczema. This encom-
passes heterogeneity in the clinical disease course, asso-
ciations with specific infections, disease distribution
and responses to treatment. Usual phenotypic group-
ings are based on disease trajectories, atopy status and
associated comorbidities with different groupings in
published papers. For example Leung et al. describe
eight categories: onset in infancy and (1) transient or (2)
persistent; onset in adolescence and (3) mild to moder-
ate or (4) persistent and severe; (5) associated with high
IgE level and sensitization; (6) non‐IgE associated; (7)
associated with Staphylococcus aureus infections; and (8)
associated with disseminated viral infections [15].
Garmhausen et al. report the existence of five pheno-
typic groups based on disease trajectories and associa-
tions with IgE. Most studies concur that persistent AD
is frequently associated with early‐onset eczema with
associated rhinitis and childhood hand eczema [16].
Recent advances in our understanding of the genetic
basis for AD are likely to lead to other subtypes of AD.
Specific emerging subtypes include eczema associated
with null filaggrin mutations. These mutations appear to
be associated with severe early‐onset extrinsic (­elevated
Fig. 15.20 Nummular atopic dermatitis affecting the torso in a young
child. Source: Courtesy of Professor Hywel C. Williams.
IgE levels) eczema with palmar hyperlinearity and ker-
atosis pilaris [13,17]; however, filaggrin null mutations
are absent in >50% of individuals with eczema [18–22].
Population‐based studies from Denmark and Sweden
have reported associations between the presence of
filaggrin mutations and persistent hand dermatitis in
adults, with a further Danish study suggesting addi-
tional associations with self‐reported foot dermatitis
[22,23].
AD with eczema herpeticum is another proposed
clinical phenotype, reported to be associated with a
greater risk of atopic diseases and associated bacterial
infections [24].
Complications
Bacterial infections
Staph. aureus colonization can be demonstrated in 90% of
eczema lesions and its density is associated with disease
severity [25]. Clinically infected AD is characterized by
honey‐coloured crusted impetigo, folliculitis and pyo-
derma or as worsening of AD with increased erythema,
oozing and pain (Fig. 15.21). Infections are usually caused
by Staph. aureus but β‐haemolytic streptococci may also
be isolated from infected AD. There is increasing research
into the mechanisms of increased cutaneous infection
risk in individuals with AD. This research has focused on
the roles of the defective skin barrier (genetic and
acquired) and staphylococcal colonization, and the role
of staphylococcal superantigens acting in concert with
defects in adaptive and innate immunity, the latter high-
lighted by the reduced capacity to upregulate cutaneous
antimicrobial peptides including cathelicidin and
defensins [26].
 Chapter 15 Clinical Features and Diagnostic Criteria of Atopic Dermatitis
Fig. 15.21 Clinically infected infantile atopic dermatitis affecting the
extensor aspects of the limbs and trunk. Source: Courtesy of Professor
Hywel C. Williams
Fig. 15.22 Perioral eczema herpeticum displaying grouped punched‐out
erosions with secondary impetiginization. Source: Courtesy of Professor
Hywel C. Williams.
Viral infections
Infections with herpes simplex virus (HSV) are more
common in individuals with AD and can result in
eczema herpeticum (also known as Kaposi varicelliform
eruption). This is a serious but infrequent complication
occurring in 3% of AD patients. It is characterized by
disseminated HSV infection and associated with sig-
nificant morbidity, including multiorgan involvement,
and rarely mortality. Clinically this presents with
grouped or widespread umbilicated vesicopustules and
eroded vesicles (Fig. 15.22). This complication is usu-
ally secondary to HSV‐1 infection and recent studies
suggest that there may be an association with filaggrin
201
ATOPIC DERMATITIS
SECTION 3:
Fig. 15.23 Molluscum contagiosum presenting as infraorbital umbilicated
and crusted papules. Source: © Diepgen TL, Yihune G et al. Dermatology
Online Atlas (www.dermis.net). Reprinted with permission.
mutations [27]. A clinically similar eruption (eczema
vaccinatum) can be seen following smallpox vaccina-
tion in susceptible individuals, hence AD or house-
hold AD contacts is a contraindication for smallpox
vaccination.
Molluscum contagiosum (MC) is a common childhood
cutaneous poxvirus infection that presents with single or
grouped skin‐coloured papules and is frequently seen in
children with AD (Fig. 15.23). Studies have reported an
increased incidence of MC with AD, with a recent cross‐
sectional study showing that 24% of children with MC
from a tertiary centre had AD [28].
Genetic variants involved in regulation of the immune
response in combination with genetic and acquired skin
barrier defects may increase the risk of viral infections;
staphylococcal toxins may also play a role in the dissemi-
nation of viral infections in AD [26].
Exfoliative dermatitis
Exfoliative dermatitis is a life‐threatening dermatosis that
rarely develops in AD (<1% of cases). In this condition,
intense erythema and peeling of more than 90% of the
skin surface is accompanied by fever, systemic malaise
and lymphadenopathy. This usually develops secondary
to either a bacterial infection (e.g. Staph. aureus) or eczema
herpeticum.
Differential diagnosis
Although AD is one of the most common causes of an
itchy rash in childhood, and in the vast majority of indi-
viduals the diagnosis is straightforward, it is important
to consider other differential diagnoses. Table 15.1 lists
diagnoses that can present in a similar manner to AD.
A specific situation in which other differential diagnoses
should be considered is when infants present with a
 202 Section 3 Atopic Dermatitis and Related Disorders

Table 15.1 Differential diagnosis of atopic dermatitis (AD)

Other forms of dermatitis

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

Allergic contact A hypersensitivity reaction to specific substances to which individuals have been sensitized, such as nickel (jewellery), rubber
dermatitis (gloves) or glues (some shoes). Linear cut‐off and distribution may suggest diagnosis, but patch tests are needed to establish
SECTION 3:

diagnosis. May coexist with AD

Frictional lichenoid Shiny papules occurring in sites of repeated frictional trauma such as outer forearms in children. Probably quite common
dermatitis
Hyper‐IgE syndrome Features of AD within a few weeks of birth accompanied by staphylococcal infections of the skin, sinuses and lungs,
characteristic facies and abnormal dentition. Laboratory findings include high IgE and eosinophils
Wiskott–Aldrich The rash of Wiskott–Aldrich is identical to AD. It occurs usually in male infants in the first month of life and is accompanied by
syndrome petechiae, purpura and bloody diarrhoea
Other immunological A range of other immunological disorders may have eczematous features, including severe combined immunodeficiency,
disorders OMENN and IPEX syndromes
Inherited ichthyosis Inherited ichthyotic disorders may be associated with eczema and dry skin, including ichthyosis vulgaris, Netherton syndrome,
autosomal recessive congenital ichthyosis and X‐linked ichthyosis
Other inflammatory and Diverse inflammatory and bullous skin diseases including psoriasis, dermatitis herpetiformis, graft‐versus‐host disease, urticaria
bullous dermatoses pigmentosa and pityriasis alba may display features that might mimic eczema and the last may be associated with eczema
Other exogenous skin conditions
Scabies May produce nonspecific eczematous changes on the entire body. Burrows and pustules on palms, soles, genitalia and between
fingers help to establish diagnosis
Onchocercarial dermatitis In its chronic phase, may produce a widespread lichenification of the skin similar to that seen in chronic AD
Insect bites May often develop secondary eczematization and be confused with AD, especially on the limbs of children in tropical countries
Nutritional deficiencies A range of nutritional deficiencies can be associated with eczematous features, including zinc, pyridoxine, biotin, niacin,
phenylketonuria, lipid storage disease and cystic fibrosis
Tinea corporis May resemble eczema, particularly in acute florid phase where vesicles are present. Usually asymmetrical

severe eczematous rash with failure to thrive, recurrent
infections or petechiae [29]. In this scenario, it is impor-
tant to exclude immunodeficiency states. For example,
Omenn, IPEX (immune dysregulation, polyendo-
crinopathy, enteropathy, X‐linked), Wiskott–Aldrich and
Job syndromes are associated with eczema. In children
from the Caribbean and Africa, severe infected AD may
be a manifestation of human T‐lymphotropic virus‐1
(HTLV1) infection [30–32].
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7 Merdler I, Hassidim A, Sorkin N et al. Keratoconus and allergic
­diseases among Israeli adolescents between 2005 and 2013. Cornea
2015;34:525–9.
8 Borkar DS, Gonzales JA, Tham VM et al. Association between atopy
and herpetic eye disease: results from the pacific ocular inflammation
study. JAMA Ophthalmol 2014;132:326–31.
9 Wells R. Ichthyosis. Br Med J 1966;2:1504–6.
10 Smith F, Irvine A, Terron‐Kwiatkowski A et al. Loss‐of‐function
mutations in the gene encoding filaggrin cause ichthyosis vulgaris.
Nat Genet 2006;38:337–42.
11 Fartasch M, Diepgen T, Hornstein O. Atopic dermatitis – ichthyosis
vulgaris – hyperlinear palms – an ultrastructural study. Dermatologica
1989;178:202–5.
12 Brenninkmeijer E, Spuls P, Legierse C et al. Clinical differences
between atopic and atopiform dermatitis. J Am Acad Dermatol
2008;58:407–14.
13 Brown SJ, Relton CL, Liao H et al. Filaggrin haploinsufficiency is
highly penetrant and is associated with increased severity of eczema:
Further delineation of the skin phenotype in a prospective epidemio-
logical study of 792 school children. Br J Dermatol 2009;161:884–9.
14 Wuthrich B. Minimal variants of atopic eczema. In: Ring JPB, Ruzicka T
(eds) Handbook of Atopic Eczema. Berlin: Springer, 2006:74–86.
15 Leung DY, Guttman‐Yassky E. Deciphering the complexities of
atopic dermatitis: shifting paradigms in treatment approaches.
J Allergy Clin Immunol 2014;134:769–79.
16 Garmhausen D, Hagemann T, Bieber T et al. Characterization of
different courses of atopic dermatitis in adolescent and adult patients.
Allergy 2013;68:498–506.
17 Weidinger S, Rodríguez E, Stahl C et al. Filaggrin mutations strongly
predispose to early‐onset and extrinsic atopic dermatitis. J Invest
Dermatol 2007;127:724–6.
18 Flohr C, England K, Radulovic S et al. Filaggrin loss‐of‐function
mutations are associated with early‐onset eczema, eczema severity
and transepidermal water loss at 3 months of age. Br J Dermatol
2010;163:1333–6.
 Chapter 15 Clinical Features and Diagnostic Criteria of Atopic Dermatitis
19 Brown SJ, Asai Y, Cordell HJ et al. Loss‐of‐function variants in the
filaggrin gene are a significant risk factor for peanut allergy. J Allergy
Clin Immunol 2011;127:661–7.
20 van den Oord RA, Sheikh A. Filaggrin gene defects and risk of
developing allergic sensitisation and allergic disorders: systematic
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21 Henderson J, Northstone K, Lee S et al. The burden of disease associ-
ated with filaggrin mutations: a population‐based, longitudinal
birth cohort study. J Allergy Clin Immunol 2008;121:872–7.
22 Heede NG, Thyssen JP, Thuesen BH et al. Anatomical patterns of
dermatitis in adult filaggrin mutation carriers. J Am Acad Dermatol
2015;72:440–8.
23 Thyssen JP, Carlsen BC, Menné T et al. Filaggrin null mutations
increase the risk and persistence of hand eczema in subjects with atopic
dermatitis: results from a general population study. Br J Dermatol
2010;163:115–20.
24 Beck LA, Boguniewicz M, Hata T et al. Phenotype of atopic dermatitis
subjects with a history of eczema herpeticum. J Allergy Clin Immunol
2009;124:260–9, 269.
25 Lever R, Hadley K, Downey D, Mackie R. Staphylococcal colonization
in atopic dermatitis and the effect of topical mupirocin therapy. Br J
Dermatol 1988;119:189–98.
26 Ong PY, Leung DY. Bacterial and viral infections in atopic dermatitis:
a comprehensive review. Clin Rev Allergy Immunol 2016;51:329–37.
27 Gao P, Rafaels N, Hand T et al. Filaggrin mutations that confer risk of
atopic dermatitis confer greater risk for eczema herpeticum. J Allergy
Clin Immunol 2009;124:507–13.
28 Dohil M, Lin P, Lee J et al. The epidemiology of molluscum contagio-
sum in children. J Am Acad Dermatol 2006;54:47–54.
29 Hochreutener H, Wüthrich B, Huwyler T et al. Variant of hyper‐IgE
syndrome: the differentiation from atopic dermatitis is important
because of treatment and prognosis. Dermatologica 1991;182:7–11.
30 La Grenade L, Manns A, Fletcher V et al. Clinical, pathologic, and
immunologic features of human T‐lymphotrophic virus type I‐associ-
ated infective dermatitis in children. Arch Dermatol 1998;134:439–44.
31 Purvis D. Guidelines for the diagnosis and assessment of eczema.
DermNet NZ 2014. http://www.dermnetnz.org/topics/guidelines‐
for‐the‐diagnosis‐and‐assessment‐of‐eczema/ (accessed 20 October
2018).
32 Eichenfield LF, Tom WL, Chamlin SL et al. Guidelines of care for
the management of atopic dermatitis: section 1. Diagnosis and
assessment of atopic dermatitis. J Am Acad Dermatol 2014;
70:338–51.
Diagnostic criteria for atopic
dermatitis
Although disease definition may sound a potentially
boring topic, it is a fundamental aspect of all compara-
tive knowledge that was summarized perfectly by
Kendell [1]:
It is probably more exciting for an architect to design para-
bolic canopies or baroque façades than it is to calculate the
size and shape of the concrete slab on which his building will
rest. But theories of causation and therapeutic claims have no
more chance of surviving than buildings if they are not built on
secure foundations. Developing reliable diagnostic criteria
may be as tedious as filling in muddy holes with concrete but
both provide the foundation on which all else depends.
Kendell 1975 [1]. Reproduced with
permission of John Wiley & Sons
Much of the evidence discussed in this section has
arisen from work that one of the authors (HW) led, that
culminated in the UK refinement of Hanifin and Rajka’s
diagnostic criteria [2–4]. Because other criteria for AD
have also been proposed, more emphasis has been
placed in this chapter on an independent and thorough
203
systematic review of diagnostic criteria for AD conducted
by Brenninkmeijer and colleagues [5].
References
1 Kendell RE. The Role of Diagnosis in Psychiatry. Oxford: Blackwell
Scientific, 1975;5.
2 Williams HC, Burney PGJ, Hay RJ et al. The UK Working Party’s diag-
nostic criteria for atopic dermatitis I: Derivation of a minimum set of
discriminators for atopic dermatitis. Br J Dermatol 1994;131:383–96.
3 Williams HC, Burney PGJ, Strachan D, Hay RJ. The UK Working
Party’s diagnostic criteria for atopic dermatitis II: Observer variation
of clinical diagnosis and signs of atopic dermatitis. Br J Dermatol
1994;131:397–405.
4 Williams HC, Burney PGJ, Pembroke AC, Hay RJ. The UK Working
Party’s diagnostic criteria for atopic dermatitis III: Independent
ATOPIC DERMATITIS
hospital validation. Br J Dermatol 1994;131:406–16.
5 Brenninkmeijer EEA, Schram M, Leeflang MMG et al. Diagnostic
criteria for atopic dermatitis: a systematic review. Br J Dermatol
SECTION 3:
2008;158:754–65.
Nomenclature
Strictly speaking, the term ‘atopic dermatitis’ or its syn-
onymous term ‘atopic eczema’ should only be used to
denote those with the phenotype of eczema who also
have evidence of allergen‐specific circulating IgE anti-
bodies as demonstrated by high serum levels and/or
positive skin prick tests [1]. Yet evidence from the
International Study of Asthma and Allergies in Childhood
(ISAAC) Phase Two – the largest sample of AD cases,
defined according to physical examination, in the
world – suggests that around 50% of AD cases in devel-
oped countries are in fact not atopic, and an even greater
proportion in developing countries are not atopic [2]. The
study concluded that any association between atopy and
examined flexural eczema is weak and more variable than
previously suggested, and that the strength of this asso-
ciation is positively linked to gross national income. Some
researchers have suggested that there are two types of
AD – atopic (or extrinsic) and nonatopic (intrinsic or
atopiform) [3,4] – but this division may have arisen in
part by the fact that atopy is more common in people with
more severe disease, who typically make up the hospital‐
based populations featured in studies trying to separate
atopic from nonatopic eczema. Indeed, some have even
argued that raised IgE could be an epiphenomenon of
disease severity [5]. It is not surprising therefore that
those who have mainly studied individuals with severe
disease have a firm belief that AD is atopic, whereas the
reality is that nonatopic eczema can sometimes form the
majority of cases in population surveys. It is also worth
pointing out that nonatopic and atopic dermatitis are still
not clearly distinguishable without recourse to skinprick
tests or estimation of circulating IgE antibodies to com-
mon and relevant environmental allergens.
In order to overcome confusion about the correct use
of the term ‘atopy’ and different synonyms for AD, the
World Allergy Organization (WAO) nomenclature com-
mittee recommended that the term ‘eczema’ be used to
denote what we typically refer to as the phenotype of AD,
and that the prefix atopy only be used when defining a
subset that is truly atopic as indicated in Fig. 15.24 [1]. The
term eczema in the WAO scheme is quite specific to the
AD phenotype, and clearly separated from other types of
 204 Section 3 Atopic Dermatitis and Related Disorders
Dermatitis
Other forms Contact
Eczema
of dermatitis dermatitis
Atopic Nonatopic Allergic Nonallergic
ATOPIC DERMATITIS
eczema eczema CD CD
Fig. 15.24 World Allergy Organization revised classification for atopic
SECTION 3:
dermatitis showing that the term eczema is now the agreed term to
replace the transitional term atopic eczema/dermatitis syndrome (AEDS).
Atopic eczema is eczema in a person of the atopic constitution. Source:
Johansson et al. 2004 [1]. Reproduced with permission of Elsevier.
dermatitis such as seborrhoeic, asteatotic, venous, num-
mular and photosensitive (classified under ‘other forms
of dermatitis’) and the two forms of contact dermatitis as
in Fig. 15.24. The WAO proposition makes good sense
and it obviates the need for yet more sets of diagnostic
criteria such as the millennium criteria [6], which look
very similar to the original Hanifin and Rajka criteria [7]
with IgE reactivity added as a necessary criterion.
Geographical variations in the use of names for AD
occur. ‘Atopic dermatitis’ is the most frequently used
term used by clinicians in the USA, yet the term ‘eczema’
is used by the National Eczema Association (https://
nationaleczema.org/eczema/) and in large population‐
based surveys in the USA [8]. AD is also the most widely
used term in Japan and other Far Eastern countries such
as Korea and Taiwan, whereas the phrase ‘atopic eczema’
is used more commonly in Europe and just ‘eczema’ in
the UK to denote AD. A review of AD nomenclature by
Kantor et al. found that of 33 060 relevant publications,
64.4% used the term ‘atopic dermatitis’ and 46.9% used
the term ‘eczema’, with many papers using both terms
[9]. The authors (all of whom lived in countries where the
standard term was AD) strongly concluded that the term
AD should be used in future studies. They claimed that
the term eczema is a nonspecific one that denotes several
forms of skin inflammation, but this statement is simply
not the case when the term eczema is used scientifically as
per the WAO classification in Fig. 15.24. It is worth point-
ing out that the purpose of a name is to increase commu-
nication and understanding – whether this is with patients
and the public or in scientific communications. Insisting
that the phrase ‘atopic dermatitis’ should be used hence-
forth in the UK (for example) for what is widely under-
stood by the public as ‘eczema’ is likely to result in more
misunderstanding and possible harm, especially as the
UK public’s understanding of the term ‘dermatitis’ has
connotations of occupationally acquired hand eczema.
Much scientific energy has been wasted debating whether
the term eczema or dermatitis should be used. The key
is to use the term that is most likely to result in clear
communication. The author uses the term ‘eczema’ in his
own publications and clinics as it is based on the most
scientific rationale to date, whereas he is comfortable
using the term ‘atopic dermatitis’ or ‘atopic eczema’ when
talking to US or other European audiences respectively, as
in this chapter. The author is not aware of any evidence
of harm caused by using these terms synonymously.
In future, better classification of dermatitis into various
subtypes may result in a scientific advancement beyond
the WAO classification. Trying to force the whole world to
adopt the term ‘atopic dermatitis’ (which may be neither
atopic nor dermatitis) is unlikely to help and may hinder
harmonious international scientific endeavour to improve
outcomes for patients with AD.
Just for consistency with the rest of this chapter, we will
use the term atopic dermatitis (AD) to refer to the clinical
phenotype without implying that such people are truly
atopic as per the more scientific rationale developed by
the WAO.
References
1 Johansson SGO, Bieber T, Dahl R et al. Revised nomenclature for
allergy for global use. Report of the Nomenclature Review Committee
of the World Allergy Organization, October 2003. J Allergy Clin
Immunol 2004;113:832–6.
2 Flohr C, Weiland SK, Weinmayr G et al.: the ISAAC Phase Two
Study Group. The role of atopic sensitization in flexural eczema:
findings from the International Study of Asthma and Allergies in
Childhood Phase Two. J Allergy Clin Immunol 2008;121:141–7.
3 Eedy DJ, Graham‐Brown RA. Atopiform dermatitis: what’s in a name?
Br J Dermatol 2002;147:415–17.
4 Tokura Y. Extrinsic and intrinsic types of atopic dermatitis. J Dermatol
Sci 2010;58:1–7.
5 Flohr C, Johansson SGO, Wahlgren CF, Williams H. How ‘atopic’ is
atopic dermatitis? J Allergy Clin Immunol 2004;114:150–8.
6 Bos JD, Van Leent EJ, Sillevis Smitt JH. The millennium criteria for
the diagnosis of atopic dermatitis. Exp Dermatol 1998;7:132–8.
7 Hanifin JM, Rajka G. Diagnostic features of atopic eczema. Acta
Dermatol Venereol (Stockh) 1980;92:44–7.
8 Kathuria P, Silverberg JI. Association of pollution and climate with
atopic eczema in US children. Pediatr Allergy Immunol 2016;27:478–85.
9 Kantor R, Thyssen JP, Paller AS, Silverberg JI. Atopic dermatitis, atopic
eczema, or eczema? A systematic review, meta‐analysis, and recommen-
dation for uniform use of ’atopic dermatitis’. Allergy 2016;71:1480–5.
Relative importance of sensitive versus
specific criteria in different study types
It is easy to dive into the topic of diagnostic criteria for AD
in the belief that there may be a universal ‘one size fits all’
definition, yet it is critical to think about the purpose of
the criteria before choosing which set of criteria or which
version of the criteria to use. The need for a disease defini-
tion usually arises in the context of research or clinical
audit when groups of people need to be described and
compared. In a population survey, for example, where the
main purpose is to estimate the true prevalence of AD,
some individuals with AD will always be misclassified as
not having AD and vice versa. Whatever criteria are used,
no single set of criteria can be perfect with 100% sensitivity
and specificity. When undertaking a prevalence survey
therefore, the ideal criteria represent a trade‐off between
sensitivity (the proportion with true disease that is cor-
rectly classified) and specificity (the proportion without
AD that is correctly identified). Some misclassification is
 Chapter 15 Clinical Features and Diagnostic Criteria of Atopic Dermatitis 205

Systematic

y
T or

ey e
r ic
Screening for

T t ic

r v nc
review of all

ho s t
RC nat

RC m a
c o gno

s u ale
Case-control possible

Pr t
a
possible

ag

ev
pl

o
study inclusion in study

Ex

Pr

Pr
studies of AD

Fig. 15.25 Schematic illustration of the different

requirements of the trade‐off between sensitivity
and specificity of diagnostic criteria for atopic
dermatitis in relation to different study designs.
AD, atopic dermatitis; RCT, randomized More specific More sensitive
controlled trial.

ATOPIC DERMATITIS
tolerable at a group level for the purpose of the study. The the positive predictive values (proportion of those who

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

Table 15.2 The effect of prevalence of atopic eczema (AE) on predictive values of the UK Diagnostic Criteria for Atopic Dermatitis, assuming a sensitivity
of 80% and specificity of 97%

True prevalence of AE Prevalence of AE by criteria Positive predictive value Negative predictive value

25% 22.2% 90.1 93.6

20% 18.4% 87.0 95.1
15% 14.5% 82.8 96.5
12% 12.2% 78.7 97.3
10% 10.7% 74.8 97.8
9% 9.9% 72.7 98.0
8% 9.2% 69.6 98.2
7% 8.4% 66.7 98.5
6% 7.6% 63.2 98.7
5% 6.8% 58.8 98.9
4% 6.1% 52.5 99.1
3% 5.3% 45.3 99.4
2% 4.5% 35.6 99.6
1% 3.8% 21.1 99.8
 206 Section 3 Atopic Dermatitis and Related Disorders
Applying diagnostic criteria in the clinic
There is a dilemma to be met when diagnostic criteria are
applied to individuals in a clinical setting as these criteria
were not developed for this purpose. It is important that
those who use the criteria in a clinical setting as a diag-
nostic aid realize that the criteria refer to probability of
disease, and that they should be used as a guide and not
a rigid rule. Thus it is possible to quote exceptional indi-
viduals such as a child who has an itchy skin condition
that began at 3 years of age, who also has a history of
flexural involvement and visible flexural dermatitis, but
no history of dry skin or other atopic disease, who,
although not fulfilling the UK diagnostic criteria or some
ATOPIC DERMATITIS
other criteria, might well have true AD. However, when
applied to a population of children where AD affects 12%
SECTION 3:
of children, the probability that a child does not have AD if
he/she does not fulfil the criteria is over 97%.
Defining new cases
Definition of an incident case is also a tricky area, because
many definitions of AD incorporate having a chronically
relapsing course as a component [4]. A systematic review
of 102 prevention studies found that no definition of an
incident case was given in 27 studies, and that the Hanifin
and Rajka criteria (which include disease chronicity as a
major criterion) had been used in 75 studies [5]. With the
advent of more birth cohort studies [6] and randomized
controlled trials of disease prevention starting at birth [7],
there is a clear need for a uniform definition for an inci-
dent case of AD that provides a good trade‐off between
not including all transient irritant eczematous eruptions
in infancy and not excluding more transient forms of true
AD [8]. Such a definition has been proposed in a system-
atic review on this topic [5].
References
1 Williams HC, Flohr C. So How Do I Define Atopic Eczema? A Practical
Manual for Researchers Wishing to Define Atopic Eczema. University
of Nottingham, 1995 (https://www.nottingham.ac.uk/research/groups/
cebd/resources/uk‐diagnostic‐criteria‐for‐atopic‐dermatitis.aspx).
2 Saeki H, Oiso N, Honma M et al. Prevalence of atopic dermatitis in
Japanese adults and community validation of the U.K. diagnostic cri-
teria. J Dermatol Sci 2009;55:140–1.
3 Odhiambo JA, Williams HC, Clayton TO et al.; ISAAC Phase Three Study
Group. Global variations in prevalence of eczema symptoms in children
from ISAAC Phase Three. J Allergy Clin Immunol 2009;124:1251–8.
4 Hanifin JM, Rajka G. Diagnostic features of atopic eczema. Acta
Dermatol Venereol (Stockh) 1980;92:44–7.
5 Simpson EL, Keck LE, Chalmers JR, Williams HC. How should an inci-
dent case of atopic dermatitis be defined? A systematic review of primary
prevention studies. J Allergy Clin Immunol 2012;130:137–44.
6 Yang YW, Tsai CL, Lu CY. Exclusive breastfeeding and incident atopic
dermatitis in childhood: a systematic review and meta‐analysis of pro-
spective cohort studies. Br J Dermatol 2009;161:373–83.
7 Simpson EL, Chalmers JR, Hanifin JM et al. Emollient enhancement of
the skin barrier from birth offers effective atopic dermatitis prevention.
J Allergy Clin Immunol 2014;134:818–23.
8 Yates VM, Kerr RE, MacKie RM. Early diagnosis of infantile sebor-
rhoeic dermatitis and atopic dermatitis – clinical features. Br J Dermatol
1983;108:633–8.
Approaches to disease definition
Binary versus continuous definitions
Pickering et al. suggested as long ago as 1960 that essen-
tial hypertension was a graded characteristic that shaded
insensibly into normality [1], but many clinicians and
researchers still have difficulties in viewing diseases as
continuous processes. Yet in a population setting, even for
diseases like scalp ringworm, which might at first appear
to conform well to a dichotomous disease definition of
diseased or not diseased, one sees a gradation of sickness
ranging from those who are apparently healthy (many of
whom are carriers of the responsible fungus or have sub-
clinical infection) to those who have isolated patches of
hair loss and some who are quite ill with severe inflam-
matory reactions affecting the entire scalp. Perhaps the
most appropriate question therefore is not ‘Has he/she
got this disease: yes/no?’ but rather ‘How much of this
disease does he/she have?’. Measuring the total amount
of disease in a population on a quantitative scale may
sound attractive in that it provides information on all of
the individuals in that population, but it also presents
some serious difficulties in interpretation. It is important
to return to the main purpose of disease definition, i.e. to
aid communication and increase our predictive abilities.
Whereas a log odds score of AD of 4.321 might mean
something to a researcher trying to predict the degree to
which a hairdressing apprentice is likely to be incapaci-
tated by irritant hand dermatitis [2], such a score might
have little utility to clinicians who wish to describe the
disease pattern in their population. Continuous scoring
methods for assessing the degree of AD are probably non-
linear, i.e. double the score does not mean twice as much
AD, like doubling height and weight. In addition, the
weights applied to individual disease features derived
from regression models are highly dependent upon the
population that was selected to derive the criteria, and 10
different studies could produce 10 different sets of weight-
ing, leading to international disputes on which weighting
was ‘correct’. Others have expressed enthusiasm for
revisiting quantitative methods for assessing AD [3].
Dichotomous or categorical disease definitions, on the
other hand, require a line to be drawn between disease
and non‐disease. Indeed the word ‘diagnosis’, which is
derived from the Greek words διá (the number two) and
γιγνώσκειν (to perceive), implies a dichotomous outcome.
Such dichotomous definitions are far more widely used
and easily understood in public health settings, and are
therefore logical choices for promoting international com-
munication. Their main drawback is that the imposition
of boundaries between those who are sick and those who
are apparently healthy almost always results in the mis-
classification of some people. Unless the disease in ques-
tion has an abrupt natural cut‐off between normal and
abnormal, the imposition of an arbitrary dividing line
will always be subject to a trade‐off between sensitivity
and specificity. On balance, a clinical approach of sum-
marizing a constellation of symptoms and signs seems to
be the most clinically relevant to the study of AD, as other
groups have concluded [4].
Progressive nosology
It is worth noting that new discoveries about disease
aetiology can lead to changes in disease classification.
The aetiology of AD is not yet fully understood, and
 Chapter 15 Clinical Features and Diagnostic Criteria of Atopic Dermatitis
because the pursuit of an objective test has been fruitless
to date, a clinical syndrome based on a constellation of
symptoms and signs remains the most appropriate start-
ing point currently. This statement does not imply that
this clinical syndrome could not be redefined in genetic
or aetiological terms in the future consistent with the
concept of progressive nosology, such as the division of
‘pemphigus’, which formerly referred to several diseases
in which blistering was a feature, into pemphigoid, pem-
phigus and linear IgA disease on the basis of immuno-
logical discoveries. Changes of this sort are not a problem
providing they are explicit, and that they confer benefits
to patients. By analogy, what is recognized as a clinical
syndrome of AD today may in time be shown to be com-
posed of three or four different diseases such as a diffuse
dry type of AD associated with filaggrin gene defects, a
nummular form associated with defective Staph. aureus
handling, an early‐onset more severe form and an eczema/
respiratory form, based on genetic, immunological or
aetiological discoveries [5,6]. This does not imply that the
original older criteria were ‘wrong’ at the time, provided
they measured something useful or were instrumental
in stimulating further research into the aetiology of that
syndrome.
References
1 Oldham PD, Pickering G, Fraser Roberts JA, Sowry GSC. The nature of
essential hypertension. Lancet 1960;i:1085–93.
2 Fartasch M, Diepgen TL. Atopic diathesis and occupational derma-
toses. J Invest Dermatol 1994;102:620–1.
3 Andersen RM, Thyssen JP, Maibach HI. Qualitative vs. quantitative
atopic dermatitis criteria – in historical and present perspectives. J Eur
Acad Dermatol Venereol 2016;30:604–18.
4 Darsow U, Wollenberg A, Simon D et al. for the European Task Force
on Atopic Dermatitis/EADV Eczema Task Force. ETFAD/EADV
Eczema Task Force 2009 position paper on diagnosis and treatment of
atopic dermatitis. J Eur Acad Dermatol Venereol 2010;24:317–28.
5 Rodríguez E, Baurecht H, Herberich E et al. Meta‐analysis of filaggrin
polymorphisms in eczema and asthma: robust risk factors in atopic
disease. J Allergy Clin Immunol 2009;123:1361–70.
6 Mortz CG, Andersen KE, Dellgren C et al. Atopic dermatitis from
adolescence to adulthood in the TOACS cohort: prevalence, persistence
and comorbidities. Allergy 2015;70:836–45.
Key requirements of a disease definition
for atopic dermatitis
Validity
Validity refers to the ability of a diagnostic test or set of
criteria to measure what it purports to measure. Validity,
in the context of defining a case with a skin disease, has
two components:
• sensitivity, i.e. the definition should catch as many
cases as possible
• specificity, i.e. the definition should exclude as many
non‐cases as possible.
Sensitivity and specificity are measured in relation to a
­reference or ‘gold’ standard. Choosing a gold standard is
relatively easy for some skin diseases such as malignant
melanoma where histology is used, but for many skin
diseases (including AD) no such objective test is available.
In these circumstances, diagnosis by dermatologist may
serve as a clinical gold standard, providing dermatologists
can be shown to agree on what constitutes a typical case [1].
207
Table 15.3 Between‐observer agreement for 18 signs in atopic dermatitis
from a specially designed repeatability study of UK consultant dermatologists
Substantial (kappa Truncal dermatitis
>0.61)
Moderate Flexural dermatitis, hand/foot dermatitis, facial
(kappa 0.41–0.60) dermatitis, hypopigmented patches, orbital fold,
periorbital dermatitis, ear fissure, hyperlinear
palms
Fair (kappa Follicular accentuation, periaural dermatitis,
0.21–0.40) cheilitis
Slight (kappa Keratosis pilaris, fine hair, periorbital pigmentation,
0.01–0.20) dry skin, extensor dermatitis (visible dermatitis)
ATOPIC DERMATITIS
Repeatability
SECTION 3:
Between‐observer and within‐observer variation in
recording the diagnostic criteria should be kept to a mini-
mum. Agreement over dichotomous features, such as the
presence or absence of periorbital pigmentation, is usu-
ally expressed in terms of a chance corrected measure
known as the kappa statistic, which usually varies from 0
(no better than chance) to 1 (perfect agreement), with val-
ues of 0.6 or more indicating substantial agreement. As
can be seen from the data on signs of AD recorded by UK
dermatologists in Table 15.3, even experienced physicians
may exhibit poor agreement over classical features of a
skin disease [1]. Many minor signs, such as infraorbital
crease, can vary according to a number of factors, such
as the time of day (Fig. 15.26) or ethnic group [2].
Repeatability can be improved by keeping the number of
criteria small, and by clear instructions and training of
field workers. Although it is true that good validity usu-
ally implies good repeatability, the converse is not always
true; for example, two clocks that are both 10 minutes
slow may well agree with each other, but neither is telling
the correct time.
Acceptability to the population
Although it may be possible and appropriate for phy-
sicians to perform quite invasive tests on patients in a
hospital setting, even relatively noninvasive procedures
such as examining the skin in covered areas or taking
nail clippings may result in a low response rate when
attempted in a population setting. The criteria should
also be easy and rapid to apply. Complicated and time‐
consuming procedures will lead to observer fatigue,
errors and lower response rates if conducted as part of a
large study.
Coherence with prevailing clinical concepts
Criteria should demonstrate a degree of face validity, i.e.
they should contain features that clinicians identify as
key elements for the disease syndrome. It is here that the
seminal work of Hanifin and Rajka excels [3]. They sug-
gested a list of major features and a long list of minor
features that characterize the clinical syndrome of AD
based on clinical experience. Although the long list is too
cumbersome and imprecisely defined to be used as a
research instrument, the features listed have formed a
good basis for subsequent scientific refinements such as
 208 Section 3 Atopic Dermatitis and Related Disorders
ATOPIC DERMATITIS
SECTION 3:
the UK Working Party’s minimum list of reliable criteria [4].
It is also worth pointing out that diagnostic criteria for
AD should also reflect some degree of morbidity; for
example, it may be possible to develop criteria that
measure very minor degrees of eczematous inflamma-
tion, but if those identified by such criteria are not itchy
or bothered by those features, then it is questionable
whether such a disease is worth studying. This is the
main reason for making ‘an itchy skin condition’ a neces-
sary criterion for the UK diagnostic criteria.
Comprehensiveness
Criteria need to be applicable to a wide range of groups
such as children and adults, those with dark skins (where
erythema may be less obvious) and different ethnic
groups who may have a different cultural understanding
of terms like ‘itching’, especially when compounded by
difficulties in translation [5].
References
1 Williams HC, Burney PGJ, Strachan D, Hay RJ. The UK Working
Party’s diagnostic criteria for atopic dermatitis II: Observer variation
of clinical diagnosis and signs of atopic dermatitis. Br J Dermatol
1994;131:397–405.
2 Williams HC, Forsdyke H, Pembroke AC. Infraorbital crease, ethnic
group and atopic dermatitis. Arch Dermatol 1996;132:51–4.
3 Hanifin JM, Rajka G. Diagnostic features of atopic eczema. Acta
Dermatol Venereol (Stockh) 1980;92:44–7.
4 Williams HC, Burney PGJ, Pembroke AC, Hay RJ. The UK working
party’s diagnostic criteria for atopic dermatitis III: Independent
hospital validation. Br J Dermatol 1994;131:406–16.
5 Chalmers DA, Todd G, Saxe N et al. Validation of the U.K. Working
Party diagnostic criteria for atopic eczema in a Xhosa‐speaking African
population. Br J Dermatol 2007;156:111–16.
A systematic review of diagnostic criteria
for AD
The last section highlighted the need for a short list of
reliable and valid criteria that can be used widely. Very
few studies have developed and tested diagnostic criteria
Fig. 15.26 Images of the same atopic person
taken 12 hours apart. Although signs such as
infraorbital crease (defined as one or more
prominent creases that extend beyond the midline
when the pupil gazes forward) may sound
straightforward to ascertain, these images show
how unreliable such a sign can be.
scientifically. Many groups have suggested diagnostic
criteria based on a hunch or consensus but the validity of
many diagnostic criteria remains untested. It is also worth
noting that instead of focusing on the really important
questions about the diagnostic criteria for AD, i.e. which
criteria are the best discriminators and which can be lost
in order to make a minimum list of reliable ones, lots of
studies have focused on the long list of minor features
and whether or not they apply to a particular study popu-
lation [1–3]. Although these studies are helpful in show-
ing some possible variation in the minor phenotypic
features that may be more or less prevalent in some coun-
tries and ethnic groups, they add little to the main quest
for a minimum list of reliable and valid major criteria that
permit international comparisons.
At least 10 different sets of diagnostic criteria for
AD had been proposed by 2007 [4–13], prompting
Brenninkmeijer and colleagues to undertake a system-
atic review of the validity of such studies [14]. Following
an extensive search of three databases and citations from
retrieved papers, they identified 27 validation studies
that were then quality‐assessed by two independent
data extractors using the Quality Assessment of
Diagnostic Accuracy (QUADAS) tool, which assesses
the risk of bias by means of 14 different items [15]. The
authors also compared sensitivity and specificity param-
eters and optimum cut‐offs for different criteria using
receiver‐operator curves. They found that some of the
proposed diagnostic criteria such as those of the Japanese
Dermatological Association, the Danish Allergy Research
Centre criteria and the Lillehammer criteria had not
undergone any form of validation at all. The original
Hanifin and Rajka criteria had only been validated in
two hospital studies, those of Schultz Larsen in two
studies, those of Diepgen et al. and those of Kang and
Tian in one study each, and the UK refinement of Hanifin
and Rajka’s criteria in 19 studies.
 Chapter 15 Clinical Features and Diagnostic Criteria of Atopic Dermatitis
Overall, sensitivity and specificity of the various criteria
ranged from 10% to 95% and from 77.6% to 100%, respec-
tively, in hospital‐based studies, and from 42.8% to 100%
and from 44.7% to 96.6%, respectively, in population
studies. The two hospital‐based studies that evaluated
the Hanifin and Rajka criteria showed a sensitivity of
87.9% and 96.0% respectively, and specificity of 77.6% and
93.8%. The eight hospital‐based studies validating the UK
refinement of the Hanifin and Rajka criteria showed a
sensitivity ranging from 10% to 95.5% and specificity
from 90.4% to 98.3%. The 13 population‐based validation
studies showed a sensitivity ranging from 42.8% to 100%
and specificity from 89.3% to 99.1%. No meta‐analytic
summary estimates could be given due to the major
differences between studies in terms of participants,
setting and study design. Validity was particularly poor
in one community validation study of the UK criteria that
had been translated into the Xhosa language [16],
although other studies of translated versions in China,
Italy and Romania seemed to show good results [17–19],
suggesting that cultural factors rather than just translation
issues are important. One study from Ethiopia showed
that the questionnaire used in the ISAAC showed a posi-
tive predictive value of 48.8% and a negative predictive
value of 91.1% [20].
The methodological quality of the validation studies
varied considerably, making comparisons difficult.
Common methodological problems included an inap-
propriate reference standard, lack of blinding of those
determining the index test results from the reference test
results, lack of reporting of intermediate or uninterpreta-
ble results, and failure to provide details on participant
withdrawals. The authors of the systematic review also
point to problems such as the reference standard of
clinical diagnosis residing with just one clinician whose
perception of what constitutes AD might be very different
from others [21,22]. Another problem when validating
criteria that refer to symptoms over the course of a year
(to overcome seasonal variations when making compar-
isons) was that they were often validated by clinical
examination at just one point in time, a procedure that
will always underestimate genuine cases that are not
active at the time of examination. The authors concluded
that the UK diagnostic criteria are the most extensively
validated in hospital and community settings, and that
this set of criteria for AD should be recommended in
future intervention studies. They pointed out that the
ideal set of diagnostic criteria still has to be established,
and there is considerable scope for improvement of meth-
odological design for validation studies.
Guidance on how to design a good validation study for
diagnostic criteria for AD is summarized in Box 15.1 [22]
although it has rarely been followed. Guidance on what
makes a good prevalence study has been suggested by
Radalescu et al. [23]. An interactive website is available in
the public domain for those interested in finding out more
about using the UK Working Party’s diagnostic refine-
ment of the Hanifin and Rajka criteria, including transla-
tions, detailed field instructions, training images and a
quality control test [24].
209
Box 15.1 Attributes of a good validation study for diagnostic
criteria
1. Use the criteria questions and examination protocol exactly as
recommended.
2. Ensure that translation follows a strict format.
3. Test the criteria in the setting in which they are intended to be used.
4. Ensure that those acting as assessors or as the clinical criterion
standard are blinded to the criteria being tested.
5. Ensure that the clinician who is the clinical criterion standard is
comparable to other clinicians through interobserver repeatability
testing.
ATOPIC DERMATITIS
Source: Williams 1999 [22]. Reproduced with permission of the American
Medical Association.
SECTION 3:
References
1 Mevorah B, Frenk E, Wietlisbach V et al. Minor clinical features
of atopic dermatitis. Evaluation of their diagnostic significance.
Dermatologica 1988;177:360–4.
2 Nagaraja, Kanwar AJ, Dhar S et al. Frequency and significance of
minor clinical features in various age‐related subgroups of atopic
dermatitis in children. Pediatr Dermatol 1996;13:10–13.
3 Hiletework M. Evaluation of Hanifin and Rajka atopic eczema
diagnostic guidelines for reduced minor criteria. Ethiop Med J
­
2009;47:39–47.
4 Asher MI, Keil U, Anderson HR et al. International Study of Asthma
and Allergies in Childhood (ISAAC): rationale and methods. Eur
Respir J 1995;8:483–91.
5 Bos JD, Van Leent EJ, Sillevis Smitt JH. The millennium criteria for the
diagnosis of atopic dermatitis. Exp Dermatol 1998;7:132–8.
6 Diepgen TL, Sauerbrei W, Fartasch M. Development and validation of
diagnostic scores for atopic dermatitis incorporating criteria of data
quality and practical usefulness. J Clin Epidemiol 1996;49:1031–8.
7 Hanifin JM, Rajka G. Diagnostic features of atopic dermatitis. Acta
Derm Venereol Suppl (Stockh) 1980;92:44–7.
8 Johnke H, Vach W, Norberg LA et al. A comparison between criteria for
diagnosing atopic eczema in infants. Br J Dermatol 2005;153:352–8.
9 Schultz Larsen F, Hanifin JM. Secular change in the occurrence of
atopic dermatitis. Acta Derm Venereol Suppl (Stockh) 1992;176:7–12.
10 Schultz Larsen F, Diepgen T, Svensson A. Clinical criteria in diagnos-
ing atopic dermatitis: the Lillehammer criteria 1994. Acta Derm
Venereol Suppl (Stockh) 1996;96:115–19.
11 Williams HC, Burney PG, Hay RJ et al. The U.K. Working Party’s
Diagnostic Criteria for Atopic Dermatitis. I. Derivation of a mini-
mum set of discriminators for atopic dermatitis. Br J Dermatol
1994;131:383–96.
12 Kang KF, Tian RM. Criteria for atopic dermatitis in a Chinese popula-
tion. Acta Derm Venereol Suppl (Stockh) 1989;144:26–7.
13 Tagami H. Japanese Dermatology Association criteria for the diagno-
sis of atopic dermatitis. J Dermatol 1995;22:966–7.
14 Brenninkmeijer EEA, Schram M, Leeflang MMG et al. Diagnostic
criteria for atopic dermatitis: a systematic review. Br J Dermatol
2008;158:754–65.
15 Whiting P, Rutjes AW, Reitsma JB et al. The development of QUADAS:
a tool for the quality assessment of studies of diagnostic accuracy
included in systematic reviews. BMC Med Res Methodol 2003;3:25.
16 Chalmers DA, Todd G, Saxe N et al. Validation of the U.K. Working
Party diagnostic criteria for atopic eczema in a Xhosa‐speaking
African population. Br J Dermatol 2007;156:111–16.
17 Gu H, Chen XS, Chen K et al. Evaluation of diagnostic criteria for
atopic dermatitis: validity of the criteria of Williams et al. in a hospital‐
based setting. Br J Dermatol 2001;145:428–33.
18 Girolomoni G, Abeni D, Masini C et al. The epidemiology of atopic
dermatitis in Italian schoolchildren. Allergy 2003;58:420–5.
19 Popescu CM, Popescu R, Williams H et al. Community validation of
the United Kingdom diagnostic criteria for atopic dermatitis in
Romanian school children. Br J Dermatol 1998;138:436–42.
20 Haileamlak A, Lewis SA, Britton J et al. Validation of the International
Study of Asthma and Allergies in Children (ISAAC) and U.K. criteria
for atopic eczema in Ethiopian children. Br J Dermatol 2005;
152:735–41.
 210 Section 3 Atopic Dermatitis and Related Disorders
21 Firooz A, Davoudi SM, Farahmand AN et al. Validation of the diag-
nostic criteria for atopic dermatitis. Arch Dermatol 1999;135:514–16.
22 Williams HC. Defining atopic dermatitis – where do we go from
here? Arch Dermatol 1999;135:583–6.
23 Radalescu M, Diepgen T, Williams H. What makes a good prevalence
survey? In: Williams HC, Bigby M, Diepgen T et al. (eds) Evidence‐
Based Dermatology, 2nd edn. Oxford: Blackwell Publishing and BMJ
Publishing Group, 2008:61–7.
24 Williams HC, Flohr C. So How Do I Define Atopic Eczema? A Practical
Manual for Researchers Wishing to Define Atopic Eczema. University of
Nottingham, 1995 (https://www.nottingham.ac.uk/research/groups/
cebd/resources/uk‐diagnostic‐criteria‐for‐atopic‐dermatitis.aspx).
Other studies that have emerged since
the systematic review
ATOPIC DERMATITIS
A few other relevant validation studies have emerged
since the systematic review by Brenninkmeijer et al. [1].
SECTION 3:
The first is a study of validation of the UK diagnostic cri-
teria in adults in Japan [2] – a useful study as nearly all
work to date has involved children. Saeki et al. compared
the validity of the UK criteria with clinical examination
[2]. Such a comparison will always underestimate the true
validity of the criteria because a 1‐year period prevalence
is being compared against point prevalence. In other
words, many of those who were ‘positive’ for the UK
criteria in the last year may not have had active eczema at
the time of examination. Nevertheless, the study found
that the UK criteria showed a sensitivity of 68.8% (88/128)
and specificity of 93.5% (1863/1992) in an adult Japanese
population attending college and university. In an earlier
study of community validation of diagnostic criteria for
AD in schoolchildren, Saeki and colleagues illustrated
how validity of the UK criteria can appear to improve if
the time period for assessing symptoms is restricted to the
last week to make them more like a point prevalence
measure, which could then be more realistically com-
pared with a clinical examination at one point in time [3].
They found in 2002 that when the UK diagnostic criteria
were used as a 1‐year prevalence measure, sensitivity and
specificity were 71.8% and 89.3%, respectively, with a
positive predictive value of 44.7%. When used as a point
prevalence estimate in 2004/5 in a different sample,
sensitivity had dropped slightly to 58.9% but specificity
had increased to 95.4%, which led to an increase in the
positive predictive value to 59.9% [3].
A further validation study concerning adults was
conducted on 1131 nursing staff in a Taiwanese teaching
hospital; this achieved a good 93% response rate [4]. The
Taiwanese study compared the validity of the UK criteria
and the ISAAC criteria in the last year against a derma-
tologist’s opinion of whether the person had AD in the
last year (using guidance that broadly followed the
Hanifin and Rajka list). They found that sensitivity and
specificity of the UK criteria were 42.2% and 99.6%,
respectively, and for the ISAAC criteria they calculated a
sensitivity and specificity of 36.7% and 92.9%, respec-
tively. Further analysis by means of receiver‐operator
curves indicated that dropping the criterion of ‘onset
under the age of 2 years’ resulted in better discrimination
for the UK criteria (sensitivity and specificity of 82.2%
and 94.2%, respectively). It should be pointed out,
however, that the original instructions on the use of the
UK diagnostic criteria in adults in the online manual
clearly state ‘Recall of onset of eczema under the age of 2
is likely to be inaccurate in adults’, and should be replaced
by ‘Did your eczema start when you were a child?’ as few
adults will know what happened in the first 2 years of
their life [5]. Another study of 518 children in Spain found
that the UK criteria administered in a telephone interview
agreed with physician diagnosis in 75.3% of cases [6].
Within Phase Two of the ISAAC, 30 358 schoolchildren
aged 8–12 years from 18 countries were examined for
flexural eczema and their parents completed the ISAAC
eczema symptom questionnaire [7]. As might be expected,
the point prevalence for flexural eczema based on a single
examination was lower than the questionnaire‐based 12‐
month period prevalence (mean centre prevalence 3.9%
vs. 9.4%), yet both were highly correlated (r = 0.77,
P <0.001). When analysed at an individual level, ques-
tionnaire‐derived symptoms of ‘persistent flexural
eczema in the past 12 months’ missed less than 10% of
cases of flexural eczema detected on physical examina-
tion, although between 33% and 100% of questionnaire‐
based symptoms of ‘persistent flexural eczema in the past
12 months’ were not confirmed on examination. The
authors concluded that prevalences derived using the
ISAAC questionnaires were sufficiently robust for com-
paring disease prevalence between populations. They
went on to say that when diagnostic precision at the indi-
vidual level is important, questionnaires should always
be validated first, or a standardized skin examination
protocol should be used such as that used by the UK
working party (see Fig. 13.1) [8].
One study has tried to see whether there are differences
in diagnostic features in children with AD (i.e. truly atopic
with IgE antibodies) versus those who look similar but
who do not have evidence of IgE reactivity (called ‘atopi-
form’ by some). The authors found that the atopiform
children had later disease onset, an absence of other atopic
diseases, fewer Dennie–Morgan creases, less hand/foot
eczema and a variety of other features, yet some of these
differences could be due to the fact that the atopiform
cases were milder, an important confounder that was not
taken into account in the selection of cases or analysis [9].
Schram and colleagues in 2011 revisited the millennium
criteria for AD for which allergen‐specific IgE is a manda-
tory criterion, accompanied by three additional criteria,
two of which need to be positive [10]. They removed the
requirement for allergen‐specific IgE and derived a set of
clinical predictors for AD based on a sample of 210 clinic
patients with a clinical diagnosis of AD. They then applied
these criteria to the same patients from which they were
derived and reintroduced specific IgE testing to further
subdivide them into truly atopic dermatitis and those
who had the AD phenotype but who were not atopic
(which they called atopiform dermatitis). They found that
the refined millennium criteria (without IgE requirement)
had a sensitivity and specificity of 81.8% and 98.8% respec-
tively, compared with corresponding values of 97.7% and
72.9% for the UK refinement of the Hanifin and Rajka
 Chapter 15 Clinical Features and Diagnostic Criteria of Atopic Dermatitis
criteria, and 100% and 48.8% for the original Hanifin and
Rajka criteria. Relative value (sensitivity plus specificity
minus 100) was 0.7 for the revised millennium criteria,
0.72 for the UK criteria and 0.51 for the Hanifin and
Rajka criteria for phenotypic AD. The study was well
reported, yet it tested the criteria on the same popula-
tion from which they were derived, a procedure that
may overestimate test performance. Further independent
studies are awaited.
Silverberg and colleagues in a US study in 2015 found
that self‐ and caregiver‐reported diagnosis of eczema in a
hospital clinic setting was good when compared with
physician diagnosis of AD, with positive predictive val-
ues of 0.87 and 0.76 for caregiver 1‐year reported history
of childhood eczema and self‐report of eczema in the last
year by adults, respectively [11]. The report is well‐­written
but their use of the term ‘eczema’ is at odds with a call
from the same group not to use such a term [12].
Yet another set of criteria has been suggested by the
Korean Atopic Dermatitis Association’s atopic dermati-
tis diagnostic criteria group. This set is composed of 11
questions (two major and nine minor), many of which
are remarkably similar to those used in the UK criteria
[13]. They derived their criteria from a training sample
(n = 1129) and tested them on an independent commu-
nity sample of children (n = 1191) and found a sensitivity
and specificity of 75.2% and 96.1% respectively when
compared with dermatologist examination performed
twice over the course of a year. These values were better
than corresponding values for the simple questions used
in the ISAAC (sensitivity of 68.8 and specificity of
92.9%), although it is unclear if these values were statis-
tically different. The Korean criteria were not compared
against the UK or millennium or Hanifin and Rajka cri-
teria in this study and further independent studies are
awaited.
211
References
1 Brenninkmeijer EEA, Schram M, Leeflang MMG et al. Diagnostic
criteria for atopic dermatitis: a systematic review. Br J Dermatol
2008;158:754–65.
2 Saeki H, Oiso N, Honma M et al. Prevalence of atopic dermatitis in
Japanese adults and community validation of the U.K. diagnostic
criteria. J Dermatol Sci 2009;55:140–1.
3 Saeki H, Iizuka H, Mori Y et al. Community validation of the UK
diagnostic criteria for atopic dermatitis in Japanese elementary
schoolchildren. J Dermatol Sci 2007;47:227–31.
4 Lan CC, Lee CH, Lu YW et al. Prevalence of adult atopic dermatitis
among nursing staff in a Taiwanese medical center: a pilot study
on validation of diagnostic questionnaires. J Am Acad Dermatol
2009;61:806–12.
5 Williams HC, Flohr C. So How Do I Define Atopic Eczema? A Practical
Manual for Researchers Wishing to Define Atopic Eczema. University
ATOPIC DERMATITIS
of Nottingham, 1995 (https://www.nottingham.ac.uk/research/groups/
cebd/resources/uk‐diagnostic‐criteria‐for‐atopic‐dermatitis.aspx);
Section 5‐3.
SECTION 3:
6 García‐Díez A, Puig L, Ortiz J, Blanco A. [Validity of a telephone
survey for determining the prevalence of atopic dermatitis and its
seasonal variation in Spain]. Actas Dermosifiliogr 2009;100:298–306.
7 Flohr C, Weinmayr G, Weiland SK et al. and the ISAAC Phase Two
Study Group. How well do questionnaires perform compared with
physical examination in detecting flexural eczema? Findings from
the International Study of Asthma and Allergies in Childhood
(ISAAC) Phase Two. Br J Dermatol 2009;161:846–53.
8 Williams HC, Forsdyke H, Boodoo G et al. A protocol for recording
the sign of visible flexural dermatitis. Br J Dermatol 1995;133:941–9.
9 Brenninkmeijer EE, Spuls PI, Legierse CM et al. Clinical differences
between atopic and atopiform dermatitis. J Am Acad Dermatol 2008;
58:407–14.
10 Schram ME, Leeflang MM, DEN Ottolander JP et al. Validation
and refinement of the Millennium Criteria for atopic dermatitis.
J Dermatol 2011;38:850–8.
11 Silverberg JI, Patel N, Immaneni S, Rusniak B et al. Assessment of
atopic dermatitis using self‐report and caregiver report: a multicentre
validation study. Br J Dermatol 2015;173:1400–4.
12 Kantor R, Thyssen JP, Paller AS, Silverberg JI. Atopic dermatitis,
atopic eczema, or eczema? A systematic review, meta‐analysis, and
recommendation for uniform use of ’atopic dermatitis’. Allergy
2016;71:1480–5.
13 Lee SC, Bae JM, Lee HJ et al.; Korean Atopic Dermatitis Association’s
Atopic Dermatitis Criteria Group. Introduction of the reliable estimation
of atopic dermatitis in childhood: novel, diagnostic criteria for childhood
atopic dermatitis. Allergy Asthma Immunol Res 2016;8:230–8.