Allergy Pediatric Reference: Epidemiology, Immunopathogenesis and Management Dermatitis Atopy

Clinical concept of atopic dermatitis (AD) evolves from the better understanding of all the immunologic aberrations expressed by the polygenic combinations and permutations associated with the atopic diathesis. Recognizing the immunopathologic features of AD readily underscores that AD without “atopy” is an oxymoron. Appreciating “pruritus” as the impetus to scratch, which isomorphically gives rise to the “eczema,” shifts the goal of management from suppressing inflammation to avoiding the triggers of pruritus. Recognizing the full spectrum of dermatologic findings in AD endorses the preferred label as a dermatitis , rather than the inferred restrictive label, atopic eczema . As our knowledge of immunology evolves, our criteria for the diagnosis and management of the atopic diathesis are sure to change.

Atopic dermatitis (AD) is a chronic inflammatory skin disease that frequently predates the development of allergic rhinitis or asthma. It is an important skin condition with significant costs and morbidity to patients and their families; the disease affects more than 10% of children. Recent studies have demonstrated the complex interrelationship of genetic, environmental, skin barrier, pharmacologic, psychologic, and immunologic factors that contribute to the development and severity of AD. The current review will examine the cellular and molecular mechanisms that contribute to AD as well as the immunologic triggers involved in its pathogenesis. These insights provide new opportunities for therapeutic intervention in this common skin condition.

Atopic dermatitis (AD) is a chronic, relapsing, highly pruritic, inflammatory skin disease that frequently predates the development of allergic rhinitis or asthma. It is an important skin condition with significant costs and morbidity to the patient, their families, and society overall. Quality of life can be severely impaired because of disruption of school, family, and social interactions as well as sleep deprivation from the intense pruritus, which is exacerbated at night. Population studies suggest that the prevalence of AD has been steadily increasing since World War II, and in most countries it now affects more than 10% of children at some point during childhood. Interestingly, there are wide variations in prevalence both within and between countries inhabited by similar ethnic groups, suggesting that environmental factors are critical in determining disease expression.

In 1980 Hanifin and Rajka published diagnostic criteria for atopic dermatitis (AD) that have become universally accepted as the standard for the diagnosis of that clinical entity. Since then, significant progress in our understanding of AD, both on the clinical level and immunopathogenetic level compels us to consider a reexamination of those original criteria.

Whether clinicians are aware of the diagnostic criteria or not, few have difficulty in identifying the patient with typical AD, although prescribing the appropriate management for these patients can be a perplexing challenge. The quandary is partially the result of the implication that AD, being part of the atopic triad, must be an allergic disease. Yet, its obvious cutaneous manifestations place it in the realm of dermatology. Thus, depending on one’s personal bias, AD is usually regarded to be predominantly allergic or dermatologic, and only casually are both factors fully evaluated.

Clinical features in children with AD

Associated disorder

Manifestations

Keratosis pilaris Follicular-based keratotic papules; lateral aspects of face, extensor aspects of arms, and anterior thighs
Lichen spinulosus Round collections of numerous, tiny, skin-colored to hypopigmented dry spiny papules
Pityriasis alba ≥ 1 cm hypopigmented patches, sometimes with fine scale; especially on face, upper arms
Hyperlinear palms Accentuated markings on the palms and soles; distinguish from ichthyosis vulgaris
Atopic pleats Groove of the lower eyelid; often present from infancy
Allergic shiners Slate-gray to violaceous infraorbital discoloration with or without swelling

The diagnosis of AD can only be made by the presence of 3 essential criteria (each of which are included in the Hanifin and Rajka major and minor features of AD): personal or (first-degree) family history of atopy, pruritus, and eczema.

Immunopathogenesis

The histopathologic changes in atopic dermatitis are nonspecific and contribute little to understanding the pathogenesis of the disease. Acute lesions show epidermal spongiosis and dermal perivascular inflammatory cell infiltration. Chronic atopic dermatitis lesions show thickening of the epidermis with elongation of the rete ridges and fibrosis around the rete ridges. Langerhans’ cells and mast cells may be increased in number, and endothelial cells are enlarged. Most lymphocytes in biopsy specimens are T cells possessing the CD4 phenotype. Langerhans’ cells and macrophages infiltrating atopic dermatitis skin lesions show surface-bound IgE molecules.

The late phase of the IgE-mediated reaction has been proposed as a model for chronic allergic inflammation, including that seen in atopic dermatitis. Immediate hypersensitivity reactions in the skin are characterized by the development of a wheal-and-flare that peaks in 10 to 20 minutes. This may be followed by a late inflammatory reaction at the same site. Pathologic examination of the cutaneous late-phase reaction (LPR) has shown infiltration with mononuclear cells, neutrophils, basophils, and eosinophils, along with edema and mast cell degranulation. Studies have shown extracellular deposition of eosinophil and neutrophil granule proteins in the LPR beginning 1 hour after antigen challenge and persisting up to 56 hours. Electron microscopy has also shown evidence for eosinophil disruption in the LPR with fragments of eosinophils and free granules in interstitial spaces. Studies from allergen-induced pulmonary late-phase inflammation have shown increased IL-5 levels in concert with increased levels of leukotriene C4 and increased release of eosinophil granule proteins. Other studies of the cutaneous LPR have shown increased messenger RNA expression of the cytokine gene cluster, IL-3, IL-4, IL-5, and granulocyte-macrophage colony-stimulating factor. IL-3 and granulocyte-macrophage colony-stimulating factor, in addition to IL-5, strikingly enhance eosinophil degranulation in vitro.

To determine whether the pathologic changes in atopic dermatitis resembled those of the cutaneous LPR, the lesional atopic dermatitis specimens in which eosinophil granule proteins had been localized were also studied for neutrophil degranulation by indirect immunofluorescence of neutrophil elastase and lactoferrin. Neutrophil elastase is present in azurophilic granules and lactoferrin is present in specific granules of neutrophils. Immunoassays of serum were also performed for neutrophil elastase. Minimal or no neutrophil elastase or lactoferrin deposition was found in the atopic dermatitis specimens, and no patient had elevated levels of neutrophil elastase in the serum.

Therefore, in atopic dermatitis lesions, prominent dermal extracellular eosinophil granule protein deposition is present but dermal neutrophil granule protein deposition is not, which is in contrast to the IgE-mediated LPR in which both eosinophil granule protein and neutrophil elastase deposits are prominent in the dermis. Overall, the results indicate that eosinophils actively participate in the pathogenesis of atopic dermatitis but, unlike the IgE-mediated LPR, neutrophils do not appear to play a role in established lesions of atopic dermatitis.

Several observations suggest that IgE and allergens contribute to the pathogenesis of atopic dermatitis. Serum IgE levels are elevated in approximately 80% of patients with atopic dermatitis and are highest in patients with coexisting respiratory allergies. A correlation between serum IgE level and extent of skin involvement has been reported.

When prick or intradermal skin tests are performed, patients with atopic dermatitis often show wheal-and-flare responses to multiple allergens, and they frequently have elevated serum IgE antibody levels to multiple allergens. Controlled studies have shown that ingestion of foods by sensitive children with atopic dermatitis provoked cutaneous pruritus and erythema, which led to scratching and subsequent eczematoid lesions

Furthermore, these exacerbations were associated with significant increases in plasma histamine concentrations after food challenges, which suggests that at least in a subset of patients, repeated ingestion of food and the reactions that result from such exposure contributes to the development of atopic dermatitis skin lesions. Interest in the potential role of inhalant allergens in atopic dermatitis has long existed. Several decades  described several patients who experienced flaring of atopic dermatitis after exposure to horse dander or ragweed pollen.

The observed that patients with atopic dermatitis had pruritus and eczematoid skin lesions after inhalation of mold or ragweed pollen. Additional studies have focused on the role of direct contact by inhalant allergens in provoking atopic dermatitis lesions. Induced cutaneous eczematoid lesions in patients with atopic dermatitis by applying aqueous allergens to superficially abraded skin.

Subsequently demonstrated eczematous reactions to a variety of inhalant allergens on nonabraded skin of patients with atopic dermatitis. Avoidance of aeroallergens that elicit eczematous reactions at patch test sites or cause immediate hypersensitivity reactions results in improvement of atopic dermatitis.

The increasing evidence that the incidence of all atopic diseases has increased worldwide over the last few decades compels us to re-evaluate our data regarding its immunopathologic features, diagnostic criteria, and management. The recent knowledge explosion regarding the immunologic aberrations of atopy has given us better insight to the clinical manifestations and management of AD.

It seems obvious that the universal requirements for the diagnosis of AD must be atopy, pruritus and eczema. The unique inherent atopic skin findings are amply discussed in other papers of this supplement. The pruritus, which can be considered the “primary lesion” of AD, must be appreciated, because no therapeutic modality can be fully appreciated without the avoidance of all recognizable pruritogenic stimuli. The eczematous response of the atopic scratching can be seen in localized areas (eg, eyelids, nipples) or in hot sweaty areas (eg, the fossae and folds) or at times can be generalized. Its polymorphic (eg, acute, subacute, and/or chronic) presentation can be a diagnostic challenge for the most astute clinician. Fortunately, the common course and natural history of AD facilitates its recognition. Atypical presentations and lack of response to appropriate therapy should suggest an alternative diagnosis.

Allergy Pediatric Reference: Epidemiology, Immunopathogenesis and Management Dermatitis Atopy

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