Etiology

AD is a complex genetic disorder that results in a defective skin barrier, reduced skin innate immune responses, and exaggerated T-cell 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 (LCs), exhibit surface-bound immunoglobulin (Ig) E molecules. These APCs play an important role in cutaneous allergen presentation to T helper type 2 (Th2) cells (Chapter 134). There is a marked perivenular T-cell infiltrate with occasional monocyte-macrophages in acute AD lesions. Mast cells are found in normal numbers but in different stages of degranulation. Chronic, lichenified AD is characterized by a hyperplastic epidermis with hyperkeratosis, and minimal spongiosis. There are predominantly IgE-bearing LCs in the epidermis, and macrophages in the dermal mononuclear cell infiltrate. Mast cell and eosinophil numbers are increased. Eosinophils contribute to allergic inflammation by secreting cytokines and mediators that augment inflammatory responses and induce tissue injury in AD through the production of reactive oxygen intermediates and release of toxic granule proteins.

Pathogenesis

Two forms of AD have been identified. 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 (CLA) produce increased levels of Th2 cytokines, including interleukin-4 (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. These CLA+ T cells also produce abnormally low levels of interferon-γ (IFN-γ), a Th1 cytokine known to inhibit Th2 cell function. Nonatopic eczema is associated with lower IL-4 and IL-13 production than is atopic eczema. Another Th2 cytokine, IL-31, induces marked pruritus in experimental animals.

Compared with the skin of healthy subjects, both unaffected skin and acute skin lesions of patients with AD have an increased number of cells expressing IL-4 and IL-13; however, acute AD does not involve significant numbers of cells that express IFN-γ or IL-12. Chronic AD skin lesions, by contrast, have significantly fewer cells that express IL-4 and IL-13 but increased numbers of cells that express IL-5, granulocyte-macrophage colony-stimulating factor (GM-CSF), IL-12, and IFN-γ than acute AD lesions. Thus, chronic AD, unlike acute AD, is characterized by a shift from a Th2-dominant to a Th1-dominant profile. The increased expression of IL-12 in eosinophils, inflammatory dendritic epidermal cells, and macrophages in chronic AD skin lesions may play a role in initiating this switch to Th1 cell development. Persistent skin inflammation may be associated with a relative lack of T-regulatory cells in the skin of AD subjects and increased expression of IL-17.

The development of AD skin lesions is orchestrated by local tissue expression of proinflammatory cytokines and chemokines. Cytokines, such as tumor necrosis factor-α (TNF-α) and IL-1 from keratinocytes, mast cells, and dendritic cells, bind to receptors on vascular endothelium. The ligand-receptor pair activates cellular signaling, including the NF-κB pathway, and induces expression of vascular endothelial cell adhesion molecules (VCAM). These events proceed from tethering, activation, and adhesion to the endothelium, followed by extravasation of inflammatory cells. Once the inflammatory cells infiltrate the tissue, they respond to chemotactic gradients established by chemokines, which are released at sites of injury or infection. Chemokines play a central role in defining the nature of the inflammatory infiltrate in AD. The chemotactic protein, CCL27, is highly upregulated in AD and preferentially attracts CLA+ T cells to the skin. Other C-C chemokines, RANTES (“regulated on activation, normal T expressed and secreted”), monocyte chemotactic protein-4 (MCP-4), and eotaxin are increased in AD skin lesions, resulting in chemotaxis of eosinophils, macrophages, and Th2 lymphocytes expressing their receptor (CCR3). Selective recruitment of CCR4-expressing Th2 cells into skin affected by AD may also be mediated by macrophage-derived chemokine (MDC) and TARC (expand), which are increased in AD. Elevated IL-5 and GM-CSF in chronic AD may lead to enhanced survival of eosinophils and monocyte-macrophages as well as LCs.

Research has identified the mechanisms leading to barrier dysfunction in 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 is a result of compromise of the physical and chemical structures of the epidermal barrier, which leads to excess transepidermal water loss. Filaggrin, a component of the cytoskeleton, and its breakdown products are critical to skin barrier function. Genetic mutations in the filaggrin gene family have been identified in up to 50% of severe patients with AD. Such patients have increased risk of bacterial, viral, and fungal infection related to impairment of innate immunity, including a loss of barrier function and impaired generation of antimicrobial peptides.

Clinical Manifestations

AD typically begins in infancy. Approximately 50% of patients experience symptoms in the 1st year 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 milk, egg, peanut, tree nuts, soy, wheat, fish, shellfish), inhalant allergens, bacterial infection, reduced humidity, excessive sweating, and irritants (wool, acrylic, soaps, toiletries, fragrances, detergents) can exacerbate (trigger) pruritus and scratching.

Acute AD skin lesions are intensely pruritic with erythematous papules (Figs. 139-1 and 139-2). Subacute dermatitis manifests as erythematous, excoriated, scaling papules. In contrast, chronic AD is characterized by lichenification (Fig. 139-3), or thickening of the skin with accentuated surface markings, and fibrotic papules (prurigo nodularis). In chronic AD, all three types of skin reactions may coexist in the same individual. Most patients with AD have dry, lackluster skin irrespective 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 often goes into remission as the patient grows older, leaving an adolescent or adult with skin prone to itching and inflammation when exposed to exogenous irritants.

Figure 139-1 Atopic dermatitis, typical cheek involvement.

(From Eichenfield LF, Friedan IJ, Esterly NB: Textbook of neonatal dermatology, Philadelphia, 2001, WB Saunders, p 242.)

Figure 139-2 Crusted lesions of atopic dermatitis on the face.

(From Eichenfield LF, Friedan IJ, Esterly NB: Textbook of neonatal dermatology, Philadelphia, 2001, WB Saunders, p 242.)

Figure 139-3 Lichenification of the popliteal fossa from chronic rubbing of the skin in atopic dermatitis.

(From Weston WL, Lane AT, Morelli JG: Color textbook of pediatric dermatology, ed 2, St Louis, 1996, Mosby, p 33.)

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 prick skin testing can identify the 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 presentation, and a chronic or chronically relapsing course (Table 139-1). Associated features, such as a family history of asthma, hay fever, elevated IgE, and immediate skin test reactivity, are variably present.

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 (Table 139-2). Severe combined immunodeficiency syndrome (Chapter 120.1) should be considered for infants presenting in the 1st year of life with diarrhea, failure to thrive, generalized scaling rash, and recurrent cutaneous and/or systemic infection. Histiocytosis (Chapter 501) should be excluded in any infant with AD and failure to thrive. Wiskott-Aldrich syndrome (Chapter 120.2), 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. Hyper-IgE syndrome (Chapter 120.2) is characterized by markedly elevated serum IgE values, recurrent deep-seated bacterial infections, chronic dermatitis, and refractory dermatophytosis.