Werfel T, Spergel JM, Kiess W (eds): Atopic Dermatitis in Childhood and Adolescence.

Pediatr Adolesc Med. Basel, Karger, 2011, vol 15, pp 110

Classification, Clinical Features

and Differential Diagnostics of
Atopic Dermatitis
Thomas Werfel
Medizinische Hochschule Hannover, Klinik fr Dermatologie, Allergologie und Venerologie,
Abteilung Immundermatologie und experimentelle Allergologie, Hannover, Germany

Classification of Atopic Dermatitis

Classification by Means of Allergic Sensitization

Atopic dermatitis (AD) is characterized by severe pruritus, a chronically relapsing
course, a distinctive distribution of eczematous skin lesions, and a personal or family history of atopic diseases. It often begins in early infancy and follows a course
of remissions and exacerbations. The role of exogenous and endogenous factors in
the pathophysiology of AD has been intensively discussed in recent years. There
is increasing evidence that T cell responses to environmental or food allergens are
important for the pathogenesis of AD. In patients with AD, the skin disease is most
often associated with the existence of environmental or food allergen-specific IgE.
This variant of the disease, which is also associated with environmental allergenspecific IgE, is usually called the extrinsic form of AD. The intrinsic variant is
found in 20% of diseases with the typical clinical appearance of AD but without
specific IgE [1].
In this respect, AD resembles bronchial asthma: Indeed, this dichotomy of extrinsic versus intrinsic was first used for asthma. The terminology of extrinsic or allergic
asthma was first introduced by Rackeman in 1947 and referred to the triggering role
of allergens in asthma. As intrinsic asthmatic patients appeared not to be improved
by conventional treatments, Rackeman considered intrinsic asthma to be caused by a
nonallergic, unknown phenomenon [2].
The concept of extrinsic and intrinsic types was adopted by Brunello Wthrich,
Zrich, Switerland in the 1980s [3]. Authors from The Netherlands denominate the
intrinsic variant also atopiform dermatitis [4]. According to an EAACI nomenclature

Table 1. Characteristics of intrinsic AD (summarized by Tokura [18])

Serological findings
Normal total serum IgE values (mean total serum IgE, 22.2134 kU/l)
Absence of specific IgE for environmental allergens and food allergens
Female predominance (collectively 7080%)
Clinical features
No ichthyosis vulgris or palmar hyperlinearity
No nonspecific hand or foot eczema
Lower colonization of S. aureus
Relatively late onset
Milder severity
Skin barrier
Normal barrier function
No filaggrin mutation
Immunological features
Lower expression of IL-4, IL-5, and IL-13
Higher expression of IFN-
High prevalence of metal allergy

task force, the term atopic eczema/dermatitis syndrome (AEDS) was proposed to
be used to cover the different subtypes of AD. In this nomenclature, the intrinsic
type was termed nonallergic AEDS, which shows normal IgE levels, no specific IgE,
no association with respiratory diseases (bronchial asthma or allergic rhinitis), and
negative skin-prick tests to common aeroallergens or food allergens [5]. However, the
classification into extrinsic AD and intrinsic AD has been most widely used during
the last years. Perhaps the old term neurodermatitis should be reintroduced to differentiate the intrinsic form from AD associated with specific IgE to food or inhalant
allergens (table 1).
Classification of Atopic Dermatitis by Genetic Factors and Phenotypes
It appears that more different disease mechanisms than IgE-mediated sensitizations
are important for different subgroups of patients suffering from AD. This is reflected
by the fact that a multifactorial trait involving numerous gene loci on different chromosomes (3, 5 and 11) have been observed. Described genetic polymorphisms in AD
involve mediators of atopic inflammation on different chromosomes, some of these
may also play a role in respiratory atopy [6]. By means of genetic differences, different
classification schemes may be developed.
One group of involved genes with mutations or polymorphism detected in subgroups of patients with AD is related to skin barrier: high associations have been

Werfel

shown with mutations in the filaggrin gene also associated with ichthyosis vulgaris,
highlighting the predisposing barrier defect in AD patients. That means that for a
substantial part of patients abnormal skin barrier function (dry skin) due to abnormal lipid metabolism and/or epidermal structural protein formation (e.g. filaggrin
loss-of-function mutations, protease inhibitor deficiency) may be relevant for the initiation of the disease. On the other hand, there may be a smaller subgroup of patients
with AD not suffering from dry skin [7, 8].
Other pathologic factors of innate immunity may lead to abnormal microbial
colonization with pathogenic organisms such as Staphylococcus aureus or Malassezia
furfur (compared to Staphylococcus epidermidis in normal individuals) and subsequent increased susceptibility to skin infection [9]. Some of the innate immune
defects observed in AD are primary defects such as defects in signaling or expression
of innate receptors (e.g. TLR2, NOD2). Others may be secondary to the effects of
the adaptive immune response. For example, deficiencies in antimicrobial peptides
may be due to the overexpression of Th2 cytokines such as IL-4 and IL-13 in acute
eczema.
A number of immune deviations in the adaptive immune system have been
described these may in part be associated rather with the so-called extrinsic variant
of AD: Like in other atopic diseases there is a general overexpression of Th2 cytokines
in many patients with AD. Polymorphisms in IL-4, IL-5, IL-13 and the IL-4R have
been described for patients with AD in numerous publications [6].
Th2-associated molecules are closely linked to the regulation of IgE which is higher
than normal in 80% of all patients. Specific IgE is commonly associated with food or
environmental allergens. Antigen-bearing dendritic cells, binding IgE mainly via the
high-affinity Fc receptor FcRI, are present in the epidermis and mainly in the dermis
in AD. Polymorphisms of this receptor have been described as well for subgroups of
AD patients. Binding of allergens to Fc receptors of those cells is thought to facilitate
antigen presentation to specific T cells [8].
T cells, many of them expressing the skin homing molecule cutaneous lymphocyte
antigen, have been identified in the circulation and in the skin in AD. More recent
studies point to the fact that specific immune responses including T lymphocytes and
specific IgE are directed against autoantigens and microbial antigens as well [9, 10].
Those antigens/allergens may be directly involved in the eczematous skin reaction
and may lead to chronic courses (autoantigens) or clinical phenotypes (e.g. head and
neck dermatitis and malasezia antigens).
Eczematous patch-test reactions to house dust mites, pollen, animal dander,
or foods are frequently observed in sensitized patients. These tests have helped to
understand the pathophysiological role of different hematopoietic cell populations in
the early eczematous reaction. In the acute phase of eczema, the majority of T cells
express Th2 cytokines (IL-4, IL-13, and the novel itch-inducing Th2 cytokine IL-31).
During chronification, the Th1 cytokine IFN-y is increased in the skin. More recently,
it became clear that IL-17 and IL-22, two T cell cytokines acting on constitutive

Atopic Dermatitis

epithelial cells are also secreted into the skin of AD patients. It may be envisioned that
a polymorphism in the regulation of these cytokines may lead to novel classifications
and therapeutic approaches to AD in the future [11, 12].
Clinical Features of Atopic Dermatitis
The highest incidence of AD is found within the first 2 years of life although the disease can begin virtually at any age [13]. A small proportion of patients present with
AD before the age of 6 months and, in this situation, it is important to exclude the
common dermatologic problem of infantile seborrheic dermatitis usually involving
the napkin area (in contrast to AD). In the young infant the trunk, cheeks, and the
extensor sites of the extremities are frequently involved and as the infant develops the
limbs also become affected.
Many infants with AD have erythematous oozing lesions, predominantly on the
cheeks. As the child grows, the affected sites tend to be the hands, the neck area, and
the feet. The older child has predominant involvement behind the knees, in the elbow
folds, and frequently also on the face. The adult patient has a more generalized distribution, commonly with diffuse involvement on the trunk and upper thigh area.
Many patients present subacute eczema in clinical practice (fig. 1a) and with continual rubbing and excoriation, the skin becomes lichenified and develops a thickened, coarse appearance (fig. 1b). A clinical variant found in adolescents and adults is
the pruriginous form of AD, which is probably caused by repeated localized scratching (fig. 1c).
The facial appearance of a patient with chronic AD is characteristic, with premature small wrinkles underneath both eyes Dennie-Morgan folds and, frequently,
the loss of the outer third of the eyebrow through rubbing the face on the pillow while
sleeping. This is referred to as Hertoghes sign. The characteristic white dermographism of the atopic patient gives rise to an unhealthy pallor.
Young women with AD may develop persistent and, at times, severe dermatitis
around the nipple and periareolar area.
In a proportion of patients with hand dermatitis their condition is associated with
atopy. This should be considered particularly with regard to hairdressers, nurses, and
others whose work involves persistent exposure of the skin to detergents, soaps and
other degreasing materials. A large proportion of patients with chronic AD have an
associated dry skin, which is frequently hypersensitive and mildly pruritic, and its
control may help to alleviate the pruritus of AD.
Some patients with AD do not develop their first lesions until later childhood,
adolescence, or even adulthood.
The diagnosis of AD is usually made by evaluation of anamnestic data and
clinical presentation. According to Hanifin and Rajka [14], three of their major
and three of their minor criteria (table 2) must be fulfilled to classify a skin disease as AD. Since this list is too long to be evaluated in daily practice, easier diagnostic criteria have been subsequently defined. The UK working group on AD

Werfel

b
c

Fig. 1. Different features of atopic dermatitis.

a Subacute dermatitis. b Chronic dermatitis with
lichenification. c Pruriginous nodules in AD.
d Acute oozing dermatitis.

Atopic Dermatitis

Table 2. Diagnostic criteria of AD according to Hanin and Rajka [14]: guidelines for the diagnosis of
AD
Major features (at least three must be fullled)
Pruritus
Typical morphology and distribution: flexural lichenication or linearity in adults, facial and
extensor involvement in infants and children
Chronic or chronically relapsing dermatitis
Personal or family history of atopy (asthma, allergic rhinitis, AD)

Table 3. Diagnostic criteria of AD according to the UK Working Partys diagnostic criteria for AD
Itchy skin condition (obligatory)
Plus three of more of the following
History of flexural involvement
History of asthma/hay fever
History of generalized dry skin
Onset of rash under the age of 2 years
Visible flexural dermatitis
According to Williams et al. [15].

displayed a simplified proposal, which was evaluated by a multicenter study group

later (table 3) [15].
Laboratory data may sometimes be helpful in the diagnosis and classification of
AD. Patients with AD frequently have eosinophilia and approximately 80% of patients
have abnormally high serum levels of IgE, the highest levels being recorded in those
patients with additional respiratory symptoms and in those with apparently associated food allergy. However, up to 15% of the normal population have serum IgE levels
above the normal range and a number of other diseases (e.g. helminthic infestations,
cutaneous T cell lymphoma) are also associated with high serum IgE levels. Thus,
total serum IgE levels are not specific markers of the AD patient.
In vitro or skin prick tests to identify IgE levels specific to allergens have a higher
specificity in the diagnosis of atopy than total serum IgE. In the young child, the bulk
of IgE is directed against ingested foodstuffs; however, later in life, a large proportion
of IgE appears to be directed against inhalant allergens. It is important to note that
these tests show a sensitization but often do not prove that the patient has a clinically
relevant allergy [16].
Patients with AD are unusually susceptible to cutaneous viral infections: patients
with AD have a higher than expected incidence of warts caused by human papilloma

Werfel