Atopic Dermatitis (Atopic Eczema)

Etiology

AD is a complex genetic disorder that results in a defective skin barrier, reduced skin innate immune responses, and polarized adaptive immune responses to environmental allergens and microbes that lead to chronic skin inflammation.

Pathology

Acute AD skin lesions are characterized by spongiosis , or marked intercellular edema, of the epidermis. In AD, dendritic antigen-presenting cells (APCs) in the epidermis, such as Langerhans cells, exhibit surface-bound IgE molecules with cell processes that reach into upper epidermis to sense allergens and pathogens. These APCs play an important role in cutaneous responses to type 2 immune responses (see Chapter 166 ). There is marked perivenular T-cell and inflammatory monocyte-macrophage infiltration in acute AD lesions. Chronic, lichenified AD is characterized by a hyperplastic epidermis with hyperkeratosis and minimal spongiosis. There are predominantly IgE-bearing Langerhans cells in the epidermis, and macrophages in the dermal mononuclear cell infiltrate. Mast cell and eosinophil numbers are increased, contributing to skin inflammation.

Pathogenesis

AD is associated with multiple phenotypes and endotypes that have overlapping clinical presentations. Atopic eczema is associated with IgE-mediated sensitization (at onset or during the course of eczema) and occurs in 70–80% of patients with AD. Nonatopic eczema is not associated with IgE-mediated sensitization and is seen in 20–30% of patients with AD. Both forms of AD are associated with eosinophilia. In atopic eczema, circulating T cells expressing the skin homing receptor cutaneous lymphocyte-associated antigen produce increased levels of T-helper type 2 (Th2) cytokines, including interleukin (IL)-4 and IL-13, which induce isotype switching to IgE synthesis. Another cytokine, IL-5, plays an important role in eosinophil development and survival. Nonatopic eczema is associated with lower IL-4 and IL-13 but increased IL-17 and IL-23 production than in atopic eczema. Age and race have also been found to affect the immune profile in AD.

Compared with the skin of healthy individuals, both unaffected skin and acute skin lesions of patients with AD have an increased number of cells expressing IL-4 and IL-13. Chronic AD skin lesions, by contrast, have fewer cells that express IL-4 and IL-13, but increased numbers of cells that express IL-5, granulocyte-macrophage colony-stimulating factor, IL-12, and interferon (IFN)-γ than acute AD lesions. Despite increased type 1 and type 17 immune responses in chronic AD, IL-4 and IL-13 as well as other type 2 cytokines (e.g. TSLP, IL-31, IL-33) predominate and reflect increased numbers of Type 2 innate lymphoid cells and Th2 cells. The infiltration of IL-22–expressing T cells correlates with severity of AD, blocks keratinocyte differentiation, and induces epidermal hyperplasia. The importance of IL-4 and IL-13 in driving severe persistent AD has been validated by multiple clinical trials now demonstrating that biologics blocking IL-4 and IL-13 action lead to clinical improvement in moderate to severe AD.

In healthy people the skin acts as a protective barrier against external irritants, moisture loss, and infection. Proper function of the skin depends on adequate moisture and lipid content, functional immune responses, and structural integrity. Severely dry skin is a hallmark of AD. This results from compromise of the epidermal barrier, which leads to excess transepidermal water loss, allergen penetration, and microbial colonization. Filaggrin , a structural protein in the epidermis, and its breakdown products are critical to skin barrier function, including moisturization of the skin. Genetic mutations in the filaggrin gene (FLG) family have been identified in patients with ichthyosis vulgaris (dry skin, palmar hyperlinearity) and in up to 50% of patients with severe AD. FLG mutation is strongly associated with development of food allergy and eczema herpeticum. Nonetheless, up to 60% of carriers of a FLG mutation do not develop atopic diseases. Cytokines found in allergic inflammation, such as IL-4, IL-13, IL-22, IL-25, and tumor necrosis factor, can also reduce filaggrin and other epidermal proteins and lipids. AD patients are at increased risk of bacterial, viral, and fungal infection related to impairment of innate immunity, disturbances in the microbiome, skin epithelial dysfunction, and overexpression of polarized immune pathways, which dampen host antimicrobial responses.

Clinical Manifestations

AD typically begins in infancy. Approximately 50% of patients experience symptoms in the 1st yr of life, and an additional 30% are diagnosed between 1 and 5 yr of age. Intense pruritus , especially at night, and cutaneous reactivity are the cardinal features of AD. Scratching and excoriation cause increased skin inflammation that contributes to the development of more pronounced eczematous skin lesions. Foods (cow's milk, egg, peanut, tree nuts, soy, wheat, fish, shellfish), aeroallergens (pollen, grass, animal dander, dust mites), infection ( Staphylococcus aureus , herpes simplex, coxsackievirus, molluscum), reduced humidity, excessive sweating, and irritants (wool, acrylic, soaps, toiletries, fragrances, detergents) can trigger pruritus and scratching.

Acute AD skin lesions are intensely pruritic with erythematous papules ( Figs. 170.1 and 170.2 ). Subacute dermatitis manifests as erythematous, excoriated, scaling papules. In contrast, chronic AD is characterized by lichenification ( Fig. 170.3 ), or thickening of the skin with accentuated surface markings, and fibrotic papules . In chronic AD, all 3 types of skin reactions may coexist in the same individual. Most patients with AD have dry, lackluster skin regardless of their stage of illness. Skin reaction pattern and distribution vary with the patient's age and disease activity. AD is generally more acute in infancy and involves the face, scalp, and extensor surfaces of the extremities. The diaper area is usually spared. Older children and children with chronic AD have lichenification and localization of the rash to the flexural folds of the extremities. AD can go into remission as the patient grows older, however, many children with AD have persistent eczema as an adult ( Fig. 170.1 C ).

Laboratory Findings

There are no specific laboratory tests to diagnose AD. Many patients have peripheral blood eosinophilia and increased serum IgE levels. Serum IgE measurement or skin-prick testing can identify the allergens (foods, inhalant/microbial allergens) to which patients are sensitized. The diagnosis of clinical allergy to these allergens requires confirmation by history and environmental challenges.

Diagnosis and Differential Diagnosis

AD is diagnosed on the basis of 3 major features: pruritus, an eczematous dermatitis that fits into a typical pattern of skin inflammation, and a chronic or chronically relapsing course ( Table 170.1 ). Associated features, such as a family history of asthma, hay fever, elevated IgE, and immediate skin test reactivity, reinforce the diagnosis of AD.

Many inflammatory skin diseases, immunodeficiencies, skin malignancies, genetic disorders, infectious diseases, and infestations share symptoms with AD and should be considered and excluded before a diagnosis of AD is established ( Tables 170.2 and 170.3 ). Severe combined immunodeficiency (see Chapter 152.1 ) should be considered for infants presenting in the first yr of life with diarrhea, failure to thrive, generalized scaling rash, and recurrent cutaneous and/or systemic infection. Histiocytosis should be excluded in any infant with AD and failure to thrive (see Chapter 534 ). Wiskott-Aldrich syndrome, an X-linked recessive disorder associated with thrombocytopenia, immune defects, and recurrent severe bacterial infections, is characterized by a rash almost indistinguishable from that in AD (see Chapter 152.2 ). One of the hyper-IgE syndromes is characterized by markedly elevated serum IgE values, recurrent deep-seated bacterial infections, chronic dermatitis, and refractory dermatophytosis. Many of these patients have disease as a result of autosomal dominant STAT3 mutations. In contrast, some patients with hyper-IgE syndrome present with increased susceptibility to viral infections and an autosomal recessive pattern of disease inheritance. These patients may have a DOCK8 (dedicator of cytokinesis 8 gene) mutation. This diagnosis should be considered in young children with severe eczema, food allergy, and disseminated skin viral infections.

Adolescents who present with an eczematous dermatitis but no history of childhood eczema, respiratory allergy, or atopic family history may have allergic contact dermatitis (see Chapter 674.1 ). A contact allergen may be the problem in any patient whose AD does not respond to appropriate therapy. Sensitizing chemicals, such as parabens and lanolin, can be irritants for patients with AD and are commonly found as vehicles in therapeutic topical agents. Topical glucocorticoid contact allergy has been reported in patients with chronic dermatitis receiving topical corticosteroid therapy. Eczematous dermatitis has also been reported with HIV infection as well as with a variety of infestations such as scabies. Other conditions that can be confused with AD include psoriasis, ichthyosis, and seborrheic dermatitis.

Treatment

The treatment of AD requires a systematic, multifaceted approach that incorporates skin moisturization, topical antiinflammatory therapy, identification and elimination of flare factors ( Table 170.4 ), and, if necessary, systemic therapy. Assessment of the severity also helps direct therapy ( Table 170.5 ).