Eczematous eruptions in childhood

Pathogenesis of atopic dermatitis

Our improved understanding of the basis for AD has led to new therapeutic interventions (see the Management section). AD involves genetic factors dictating immune response and skin barrier integrity, as well as environmental influences, including one’s microbiome. The “inside-out” concept of AD pathogenesis focuses on immune abnormalities as being primary, and the “outside-in” theory considers the epidermal barrier dysfunction (a form of innate immunity) as primary, but it is the interplay of these factors that leads to disease.

A role for genetic alterations is suggested by the concordance of 77% in monozygotic twins and the greater probability of having AD if one or, even more so, both parents have AD. By far the most common and influential genetic change is having uniallelic or biallelic loss-of-function mutations in profilaggrin (FLG). FLG mutations occur overall in approximately 10% of the population and are the cause of ichthyosis vulgaris, a genetic disorder characterized by climate-dependent dry, scaling skin and hyperlinear palms (see Chapter 5 ). Mutations in FLG occur in 10% to 30% of AD patients. In addition to the tight linkage of AD with genes of the epidermal differentiation complex (particularly encoding profilaggrin), genome-wide association (GWA) studies have shown numerous other associated loci, primarily related to epidermal barrier function and innate-adaptive immunity.

Heterozygous loss-of-function mutations in CARD11 (encoding caspase recruitment domain-containing protein 11) have also been associated ^, with moderate to severe AD. Many but not all patients have concurrently been affected by other forms of atopy, pneumonia, bronchiectasis, cutaneous viral infections, oral ulcerations, autoimmunity, neutropenia, hypogammaglobulinemia, or lymphoma. Affected individuals may have reduced T-cell responsiveness in vitro with increases in B lymphocytes and abnormal B-cell differentiation. Interestingly, homozygous null mutations in CARD11 cause a form of severe combined immunodeficiency (SCID), whereas heterozygous gain-of-function mutations lead to a form of B-cell lymphoproliferative disease. Loss-of-function mutations in CARD14 (vs. the gain-of-function mutations associated with the psoriasis–pityriasis rubra pilaris spectrum) may also underlie a severe variant of AD. Heterozygous gain-of-function mutations in JAK1 have recently been associated with severe AD with hypereosinophilia but not high levels of immunoglobulin E (IgE). Eosinophilic infiltration of the liver and gastrointestinal tract with hepatosplenomegaly, autoimmune disease, and failure to thrive or short stature are other features, and patients respond to Janus kinase (JAK) inhibition.

In the acute phase of AD, environmental triggers such as irritants, allergens, and microbes and mechanical injury (scratching or rubbing) activate the skin’s innate immune system, which includes epidermal Langerhans cells and keratinocytes. ^, Expression of cytokines, particularly alarmins interleukin-25 (IL-25), IL-33, and thymic stromal lymphopoietin (TSLP) activate group 2 innate lymphoid cells (ILC2s), leading to T helper 2 (Th2) cell activation. Th2 cells express IL-4, -5, and -13, which promote eosinophilia and IgE production but suppress the expression of epidermal barrier proteins as well as antimicrobial peptides such as β-defensins and cathelicidin. This reduction in antimicrobial peptide production may contribute to the propensity toward development of skin infection in AD patients. TSLP, IL-4/-13, and IL-31 are thought to mediate AD pruritus. ^,

Recent studies show that AD T cells also differentiate into Th22 cells, which produce IL-22 and thereby stimulate expression of keratinocyte S100As. ^, IL-22 has been implicated in the thickening of skin with lichenification. The role of Th17 cells in AD is not well understood, but increased levels of IL-17 are found in some patients (although not to the extent of Th2 cytokines and IL-22), particularly in young children with recent onset, patients with intrinsic (vs. extrinsic) AD, and people of Asian descent. Although adults with chronic AD also may have increases in Th1 cytokines, Th1 immunity and the Th1/Th2 ratio are very low in children with AD. The immune profile of AD is age dependent, with older children and adolescents having an intermediate profile between those of recent-onset AD in young children and in adults.

The intact epidermis itself also plays a role in the skin’s innate immune system because it functions as a barrier against water loss (preventing dry skin) and activation of the innate immune system by high-molecular-weight allergens such as dust mite antigens, foods, and microbes. This barrier primarily is composed of tight junction proteins (particularly claudins, middle of the stratum granulosum) and stratum corneum structural proteins and lipids. Filaggrin is the major component of the stratum granulosum of epidermis and binds to keratin. ^, Its precursor, profilaggrin, contains 10 to 12 monomers of filaggrin, and fewer monomers within the profilaggrin gene (e.g., 10 vs. 12) have been linked to an increased risk of developing AD, which complements the known increased risk of developing AD with filaggrin insufficiency. ^, Filaggrin is also broken down into natural moisturizing factor (NMF), particularly urocanic acid, which promotes skin hydration, providing another explanation for the dry skin of AD and ichthyosis vulgaris. NMF has been shown to be low during the first year of life, especially on the cheeks. AD in association with mutations in FLG has been shown to be more severe and more persistent. ^,

The stratum corneum lipid matrix predominantly is composed of cholesterol, free fatty acids, and ceramides, densely stacked into a highly ordered, three-dimensional structure of lipid lamellae, which depends on lipid composition. These lipids are secreted by the lamellar bodies into the intercellular space of the stratum corneum. AD skin has a decreased content of very long chain ceramides ^, and free fatty acids, related to a deficiency of elongases that synthesize very long-chain fatty acids. The barrier can also be altered by the increased activity of proteases (especially kallikreins 5 and 7), which degrade barrier proteins and are more active at increased pH, as occurs in association with deficiency of filaggrin products (e.g., urocanic acid).

The skin (and perhaps gut) microbiome is another environmental influence on both the barrier and skin immunity. A meta-analysis of 95 studies showed that Staphylococcus aureus is found on lesional skin of 70% and nonlesional skin of 39% of patients with AD. Most of the S. aureus is methicillin-sensitive S. aureus (MSSA), although 7% of patients have methicillin-resistant S. aureus (MRSA). Flares of AD are associated with a shift in the microbiome toward a greater percentage of S. aureus (and S. epidermidis ) and reduced bacterial diversity, and the shift is greater in patients with MRSA than MSSA. Commensal organisms are recognized to play a key role in killing S. aureus and modulating immune responses. A recent birth cohort suggested that having commensal Staphylococcus spp. at day 2 could protect infants against the development of AD. Patients with AD not only have fewer commensals with active disease but also have fewer commensals that are able to kill S. aureus . Topical application of commensal organisms (e.g., Staphylococcus hominis or Roseomonas mucosa ) as treatment for AD is a new direction that in early studies appears to reduce AD severity and the use of topical corticosteroid.

Clinical features

The cardinal features of AD are pruritus, chronicity, and the age-specific morphology and distribution of lesions ( Box 3.1 ). Extent of involvement may range from mild and limited—for example, to flexural areas—to generalized and severe. The tremendous itch of AD can translate into issues with sleep, especially with wake after sleep onset, but also difficulty in falling asleep, because the pruritus tends to be worst at bedtime. Skin pain can also be a feature.

The morphology of AD and distribution of lesions is often age dependent, although there is considerable overlap (e.g., infants may show the typical distribution of adult AD). Infants with AD typically have intense itching, erythema, papules, vesicles, oozing, and crusting. In infants, AD often begins on the cheeks, forehead, or scalp ( Figs. 3.1 , 3.2 , and 3.3 ) and then may extend to the trunk ( Fig. 3.4 ) or particularly the extensor aspects of the extremities in scattered, ill-defined, often symmetric patches. Generalized xerosis is common. Exacerbation of facial dermatitis on the medial cheeks and chin is often seen concomitant with teething and initiating foods. This localization likely reflects exposure to irritating saliva and foods, although contact dermatitis or urticaria may contribute. By 8 to 10 months of age the extensor surfaces of the arms and legs often show dermatitis ( Fig. 3.5 ), perhaps because of the role of friction associated with crawling and the exposure of these sites to irritant and allergenic triggers such as those found in carpets. Although dermatitis of the antecubital and popliteal fossae, periorbital areas, and neck are more commonly involved in older children and adolescents, these sites may be affected in infants and young children as well ( Fig. 3.6 ). Typically, lesions of AD spare the groin and diaper area during infancy ( Fig. 3.7 ), which aids in the diagnosis. This sparing likely reflects the combination of increased hydration in the diaper area, protection from triggers by the diaper, and inaccessibility to scratching and rubbing. The “headlight sign” has been used to describe the typical sparing of the nose and medial cheeks in AD, even when there is extensive facial involvement elsewhere (see Fig. 3.1 ).

Not uncommonly, infants initially show signs of seborrheic dermatitis, particularly during the first month or two of life. The associated pruritus and the dry (rather than greasier) scale suggest the combination of both disorders (see Fig. 3.3 ); the seborrheic component usually clears by 6 to 12 months, whereas the AD features persist. Alopecia may accompany the scalp involvement because of inflammation and chronic rubbing.

By about 2 years of age, children with AD are less likely to have exudative and crusted lesions and have a greater tendency toward chronicity and lichenification ( Fig. 3.8 ). Eruptions are characteristically drier and more papular and often occur as circumscribed scaly patches. The classic areas of involvement in this group are the wrists, ankles, hands, feet, neck, and antecubital and popliteal regions ( Figs. 3.9 and 3.10 ). Facial involvement switches from cheeks and chin to periorbital ( Figs. 3.11 and 3.12 ) and perioral, the latter sometimes manifesting as “lip-licker’s dermatitis” (see Fig. 3.56 ). Dermatitis of the nipples ( Fig. 3.13 ) occurs in some infants and children and can be exacerbated by rubbing on clothing. Pruritus is often severe. Some children with AD show nummular or coin-shaped lesions with sharply defined oval scaly plaques on the face, trunk, and extremities (see Nummular Dermatitis section). In Black children, the lesions of AD are often more papular and follicular ( Fig. 3.14 ). Although localization at flexural areas is more common, some children show an inverse pattern with involvement primarily of extensor areas. Lymphadenopathy may be a prominent feature in affected children ( Fig. 3.15 ), reflecting the role of lymph nodes in handling local infection and inflammation. Nail dystrophy may be seen when fingers are affected, indicating involvement of the nail matrix; children may show secondary staphylococcal or pseudomonal paronychia.

By later childhood and adolescence, predominant areas of involvement include the flexural folds ( Fig. 3.16 ), the face and neck, the upper arms and back, and the dorsal aspect of the hands, feet, fingers, and toes. The eruption is characterized by dry, scaling erythematous papules and plaques and by the formation of large lichenified plaques from lesional chronicity. Weeping, crusting, and exudation may occur from the AD itself but usually is the result of superimposed staphylococcal infection or allergic contact dermatitis. Prurigo nodularis, characterized by well-circumscribed, usually hyperpigmented thickened papules, most commonly on the lower extremities, is most often seen during adolescence ( Fig. 3.17 ).

Postinflammatory reduction of pigmentation may occur at any age, especially in individuals with darker skin. Although postinflammatory hypopigmentation is more common (see Figs. 3.16 and 3.18 ), pigment reduction may be severe enough to be depigmented, resembling vitiligo ( Fig. 3.19 ), especially on distal extremities. The pigmentary changes are transient and are reversible when the underlying inflammation is controlled; however, 6 months or more may be required for repigmentation (and years if vitiliginous), and sun exposure may accentuate the differences between uninvolved and hypopigmented skin areas. In contrast, hyperpigmentation is predominantly noted at sites of lichenification ( Figs. 3.12 , 3.15 , 3.17 , and 3.20 .), because the thickened epidermis accumulates epidermal melanin pigment, especially in darker skinned individuals. Children with lichenification show accentuation of skin ( Fig. 3.21 ). Parents may mistake the postinflammatory pigment change seen in some children for scarring or a toxicity of topically applied medications and need reassurance. AD lesions are not usually scarring, but secondary infection and deep gouging of lesions can leave residual scarring and long-term pigmentary change.

Other clinical signs

Several other clinical signs are seen with increased incidence in children with AD, although they may appear in children without AD as well. Dermographism, a manifestation of the triple response of Lewis that occurs in approximately 5% of the normal population, is characterized by a red line, flare, and wheal reaction. A red line develops within 15 seconds at the exact site of stroking, followed within 15 to 45 seconds by an erythematous flare (because of an axon-reflex vasodilation of arterioles). The response finally eventuates in a wheal (because of transudation of fluid from the injured capillaries in the original stroke line) 1 to 3 minutes later. Individuals with AD often demonstrate a paradoxical blanching of the skin termed white dermographism ( Fig. 3.22 ). The initial red line is replaced, generally within 10 seconds, by a white line without an associated wheal. Patients with AD may also show circumoral pallor, thought to relate to local edema and vasoconstriction.

Follicular hyperkeratosis, or chicken-skin appearance, particularly on the lateral aspects of the face, buttocks, and outer aspects of the upper arms and thighs, is termed keratosis pilaris (see Figs. 7.24 and 7.25 ). Keratosis pilaris is not seen at birth but is common from early childhood onward and often persists into adulthood. Each lesion represents a large cornified plug in the upper part of the hair follicles, often with surrounding inflammation and vasodilation. Keratosis pilaris is more commonly associated with AD in children who have ichthyosis vulgaris. Moisturizers alone tend to be insufficient as therapy for keratosis pilaris. Keratolytic agents such as urea or α-hydroxy acids may be helpful. Their use is limited, however, by the increased potential for irritation in children with AD. Treatment should be discouraged unless of significant cosmetic importance, because keratosis pilaris is almost always asymptomatic.

Lichen spinulosus manifests as round collections of numerous tiny, skin-colored to hypopigmented dry spiny papules ( Fig. 3.23 ). More common in Black children, lichen spinulosus usually occurs on the trunk or extremities. Lesions tend to be asymptomatic and may respond to application of emollients and mild topical corticosteroids. Children with AD also show an increased incidence of pityriasis alba, nummular dermatitis, dyshidrotic eczema, and juvenile plantar dermatosis (see related sections).

Individuals with atopic disorders have a distinct tendency toward an extra line or groove of the lower eyelid, the so-called “atopic pleat” ( Fig. 3.24 ). Seen just below the lower lid of both eyes, the atopic pleat may be present at birth or shortly thereafter and is often retained throughout life. This groove (commonly referred to as a Dennie–Morgan fold ) may result from edema of the lower eyelids and skin thickening; it represents a feature of the atopic diathesis rather than a pathognomonic marker of AD. The atopic pleat has been found with increased incidence in Black children. Slate-gray to violaceous infraorbital discolorations (“allergic shiners”), with or without swelling, are also seen in patients with allergies and in patients with AD. Allergic shiners are thought to be a manifestation of vascular stasis induced by pressure on underlying venous plexuses by edema of the nasal and paranasal cavities; the swelling and discoloration become more prominent as a result of repeated rubbing of the eyes and postinflammatory pigment darkening. Another clinical feature, an exaggerated linear nasal crease, is caused by rubbing of the nasal tip (the so-called “allergic salute”) and occurs in 7% of schoolchildren. Milia (tiny inclusion cysts; see Chapter 9 ) of the periorbital area are common in preadolescents ( Fig. 3.25 ), may resemble acne, and are thought to result from the recurrent rubbing. Milia tend to resolve spontaneously, although years may be required; extraction may be performed but is rarely necessary.

Many patients with atopic conditions exhibit an increased number of fine lines and accentuated markings of the palms ( Fig. 3.26 ). These accentuated palmar markings often are a clue to the concurrent diagnosis of ichthyosis vulgaris (see the previous discussion of the pathomechanism and also Chapter 5 ), a relatively common condition seen with increased incidence in children with AD. Ichthyosis vulgaris is considered a “semi-dominant” disorder because heterozygotes show manifestations (especially in drier, colder climates), but homozygotes tend to have greater severity. Most individuals with ichthyosis vulgaris merely think they have dry skin until the diagnosis is made when they are seen for AD. Diagnosis is based on the accentuated markings on the palms and soles, the characteristic generalized scaling with larger and more severe scaling on the lower extremities, worsening during winter months, and often positive family history.

Allergic keratoconjunctivitis (AKC) is a chronic noninfectious inflammatory condition and is one of the most severe ophthalmic complications associated with atopic dermatitis. AKC has been described in up to 30% of children with AD. It typically begins during late teenage years but has been described as early as 7 years of age. Patients experience chronic itching and pain of the eyes, as well as tearing, redness, and blurred vision. It requires prompt and effective treatment to prevent permanent vision loss; moderate to severe eye irritation, increased redness, discharge, and any visual symptoms are features that require more urgent referral to an ophthalmologist. Complications of AKC include cataracts, keratoconus, infectious keratitis, blepharitis, tear dysfunction, and steroid-induced glaucoma. Treatment options include a combination of mast cell inhibitors, antihistamines, corticosteroids, and calcineurin inhibitors.

Posterior subcapsular cataracts have been described in up to 13% of adult patients with severe AD. Rarely seen in children, these cataracts are usually asymptomatic. Keratoconus (elongation and thinning of the corneal surface) has been reported in about 1% of patients with AD and seems to develop independently of cataracts. Keratoconus is exacerbated by continuous rubbing of the eyes and may require corneal transplantation.

Effect on quality of life

The quality of life in infants, children, and adolescents with moderate to severe dermatitis is significantly reduced, and having severe AD during childhood can have a great impact on psychosocial development. Infants with AD have been shown to be excessively dependent and fearful. Sleep disturbance affects up to 60% of children with AD overall and 83% of children during flares. Impaired sleep quality occurs in children with mild AD and even inactive AD but is particularly problematic in children with more severe disease, especially wake after sleep onset. Neurocognitive function is impaired in children with sleep problems. Even in clinical remission, children with AD show more sleep disturbance than healthy children, including increased nocturnal wakefulness and a longer latency to rapid-eye-movement (REM) sleep.

Disfigurement associated with moderate to severe AD, coupled with the reduction in sleep, restlessness, and fatigue at school, as well as limitations in participation in sports, isolates the affected child and strains relationships with peers and with teachers.

As a chronic disorder that requires frequent attention, the family of a child with AD carries a high financial burden of parental missed days from work for doctor visits and home care; lost wages owing to interruption of employment; expensive medications; and the costs of special or additional bedding, clothes, and food. The socioeconomic impact of AD in the United States alone is estimated to be $364 million to $3.8 billion annually. The demonstrated average reduction by 1 to 2 hours of parental sleep nightly also translates into increased parental stress and the tendency of affected children to cosleep with parents affects family dynamics. These stressful psychological factors often exacerbate the AD, as may concurrent infectious illness or the stress of assignments at school.

Comorbidities of atopic dermatitis

Infectious complications

In contrast to a prevalence of a carrier state in 5% to 20% of individuals who have no atopic condition, S. aureus is recovered in up to 90% of patients from lesions of AD—up to 76% from uninvolved (normal) skin and 50% to 60% from the anterior nares. The increased adherence of S. aureus to the epidermal cells of individuals with AD and a failure to produce endogenous antimicrobial peptides in the inflamed skin of patients with AD may account for the high rate of S. aureus colonization and infection. Although secondary infection in AD is usually from S. aureus (72%), 16% of cultures in infected patients with AD yield S. pyogenes, and 14% are mixed cultures. Patients infected with group A Streptococcus were more likely to be febrile, have facial and periorbital involvement, have bacteremia and cellulitis, and be hospitalized compared with those infected with S. aureus alone.

The pyoderma associated with AD is usually manifested by erythema with exudation and crusting ( Fig. 3.27 , A and B ), particularly at sites of scratching, and occasionally by small pustules at sites of dermatitis ( Fig. 3.28 ). This complication must be considered whenever a flare of chronic AD develops or fails to respond to appropriate therapy. S. aureus exacerbates the AD through (1) release of super-antigen toxins, which enhance T-cell activation; (2) activation of superantigen-specific and allergen-specific T cells ; (3) expression of IgE antistaphylococcal antibodies ^, ; and (4) increased expression of Th2 cytokines (including IL-31 and TSLP, which are known to cause pruritus directly) and increased expression of IL-22, which is associated with epidermal thickening. Superantigen production also increases the expression of an alternative glucocorticoid receptor that does not bind to topical corticosteroids, leading to resistance. Other factors produced by S. aureus are likely to exacerbate AD as well. These observations emphasize the role of S. aureus as an important trigger of AD and endorse therapies that decrease the numbers of bacteria on the skin.

Although MRSA colonization and superinfection of AD is increasing, the majority of children with AD harbor MSSA. ^, MRSA infection may manifest as pustules ( Fig. 3.29 , A ), abscesses (see Fig. 3.29 , B ), or crusting that is indistinguishable clinically from MSSA infection but much more difficult to eradicate; suppression of MRSA often requires that the entire family (including pets, who can harbor MRSA) be treated initially or even on an intermittent basis to reduce colonization, such as with intranasal mupirocin ointment and once to twice weekly bleach baths or use of sodium hypochlorite–containing cleansers.

Greater cutaneous dissemination of certain viral infections has also been noted in children with AD and has been attributed to defects in the generation of antimicrobial peptide and the relative deficiency of Thl cytokine generation and cytotoxic T-cell function. Molluscum contagiosum is a cutaneous viral infection of childhood that most commonly affects the trunk, axillae, antecubital, popliteal fossae, and crural areas (see Chapter 15 ). Lesions are usually small, dome-shaped papules that often show central umbilication. The often-extensive molluscum lesions tend to be most numerous at sites of active dermatitis and can induce pruritus as well as dermatitis around the molluscum papules (“molluscum dermatitis”).

Eczema herpeticum (EH, also termed Kaposi varicelliform eruption ) describes the explosive development of a vesiculopustular eruption caused by herpes simplex virus (HSV) in an individual with an atopic condition. Children with more severe AD and other atopic conditions are at greatest risk. The tendency toward eczema herpeticum is associated with an elevated Th2 and reduced Th1 T-cell immune response to HSV1. ^, The clustering and often umbilication of the vesicles is characteristic ( Figs. 3.30 and 3.31 ; see Fig. 8.15 ), with sites of the dermatitis most commonly affected. Nevertheless, with a confluence of vesicles and crusting, eczema herpeticum can be mistaken for bacterial infection ( Fig. 3.32 ). The diagnosis can be verified by polymerase chain reaction (PCR) and viral culture. If these tests are not available, a Tzanck test can be performed by scraping the floor of vesicles and, after staining the smear with Giemsa or Wright stain, searching for multinuclear virus “giant cells” or balloon cells.

Hospitalization may be necessary, especially in infants younger than 1 year and in association with fever or other systemic symptoms. Early administration of acyclovir has been shown to lead to better outcomes for EH, and use of topical corticosteroids or calcineurin inhibitors has not been associated with poorer outcomes in children hospitalized with EH. Systemic antibiotics should be administered if secondary bacterial infection is strongly suspected but should not be used empirically.

Eczema vaccinatum was a problem when smallpox vaccinations were compulsory, most commonly contracted by accidental contact with a recently vaccinated individual. The global threat of bioterrorism and consideration of smallpox vaccinations has again brought to attention the risk of eczema vaccinatum for patients, particularly children, with AD. Eczema vaccinatum is characterized by the widespread cutaneous dissemination of vaccinia viral lesions that manifest as firm, deep-seated vesicles or pustules that are all in the same stage of development (see Chapter 15 ). Lesions may become umbilicated or confluent.

Eczema coxsackium (see Chapter 16 ) is a recently coined term to describe the unusual cutaneous concentration in sites of previous or current AD of vesicles and erosions from coxsackievirus A6 and, less commonly, coxsackievirus A16 infection, which could be confused with EH ( Fig. 3.33 ). ^, Fever, oral erosions or ulcerations, and sore throat or mouth are among the most common associated symptoms. Lesions clear spontaneously in an average of 12 days but may persist for a month.

Reactivity to Malassezia has been blamed for recalcitrant AD of the head and neck in adolescents. Although there are no documented differences in Malassezia species colonization, patients with head and neck AD are more likely to have positive skin prick test results and Malassezia -specific IgE compared with healthy control subjects and patients with atopy without head and neck dermatitis. These patients may benefit from a 1- to 2-month course of daily itraconazole or fluconazole followed by long-term weekly treatment.

Differential diagnosis

AD is a chronic fluctuating disease. The distribution and morphology of lesions vary with age, but itching is the cardinal symptom of this disorder. Although many skin conditions may occasionally resemble AD, certain characteristics assist in their differentiation. Three common forms of dermatitis that are seen often with AD are contact dermatitis (both irritant and allergic), seborrheic dermatitis, and nummular dermatitis. Each of these disorders is discussed in detail later in the chapters and, as such, is mentioned only briefly here as relevant to AD.

Seborrheic dermatitis is characterized by a greasy yellow or salmon-colored scaly eruption that may involve the scalp, cheeks, trunk, extremities, and diaper area. The major differentiating features include a tendency toward earlier onset, characteristic greasy yellowish or salmon-colored lesions with a predisposition for intertriginous areas, a generally well-circumscribed eruption, and a relative absence of pruritus (see later). Infants may show both atopic and seborrheic dermatitis (see Fig. 3.3 ), with progression or persistence of the atopic lesions as the seborrheic dermatitis subsides.

Irritant and allergic forms of contact dermatitis are common comorbidities of AD (see related section). Primary irritant dermatitis is commonly seen in infants and young children on the cheeks and the chin (owing in part to the irritation of saliva), the extensor surfaces of the extremities (as a result of harsh soaps, detergents, or rough fabrics), and the diaper area (usually spared in AD; primarily from feces and vigorous cleansing). Irritant dermatitis may also result from bubble baths, personal care products, and handled materials such as modeling clays. Primary irritant dermatitis is generally milder, less pruritic to asymptomatic, and not as eczematous and oozing as the eruptions seen in association with AD. Irritant contact dermatitis to saliva and to exposure to harsh soaps and fabrics occurs more often in children with concomitant AD.

Allergic contact dermatitis (ACD), although relatively uncommon in the first few months of life, can mimic almost any type of eczematous eruption and is characterized by a well-circumscribed pruritic, erythematous, papular, and vesicular eruption. Although such eruptions involute spontaneously on identification and removal of the cause, this disorder often requires a carefully detailed history and prolonged observation before the true causative agent is identified. ACD to nickel occurs often in children with AD and may be misdiagnosed as recalcitrant periumbilical AD. Patients with recalcitrant AD may have concomitant allergic contact reactions, particularly to nickel and less often to topically applied medications and emollients, suggesting the role for patch testing. Positive patch tests for potential allergens other than nickel have been described in up to 45% of children with AD, ^{, ,} and more than half of these are reactions to components in their emollients (lanolin, neomycin, formaldehyde, sesquiterpene lactone mix [including parthenolide], compositae mix, and fragrances) or foaming products (cocamidopropyl betaine). Topical corticosteroids are unusual contact allergens but can be tested based on structural class with tixocortol-21-pivalate, budesonide, and hydrocortisone 17-butyrate. ^{, ,}

Nummular dermatitis is a distinctive disorder characterized by coin-shaped lesions. Measuring 1 cm or more in diameter, lesions of nummular dermatitis develop on dry skin and are more often seen during dry winter months. The eruption is characterized by discrete erythematous round plaques formed by the confluence of papules and vesicles ( Figs. 3.34 and 3.35 ). Nummular lesions tend to be secondarily infected and often more recalcitrant to topical therapy. If the combination of medium-strength to potent topical steroid plus topical antibiotic does not suffice, a course of systemic antibiotic may be required. Dilute sodium hypochlorite baths should also be considered.

The lesions of psoriasis, another common skin disease of children, are bright red and topped with loosely adherent silvery micaceous scale (see Chapter 4 ). Psoriatic lesions usually show a sharply delineated edge and have a predilection for the extensor surfaces (particularly the elbows and knees), the scalp, the buttock, and the genital regions. Approximately 5% of children with psoriasis also show dermatitis, either as typical psoriasis and AD lesions or a psoriasiform dermatitis; these children often have a family history of both atopy and psoriasis.

Scabies in infants and children is commonly complicated by eczematous changes because of scratching and rubbing of involved areas or the application of harsh topical therapeutic agents. The diagnosis of scabies is best made by the history of itching, a characteristic distribution of lesions, the recognition of primary lesions (particularly the pathognomonic burrow when present), positive identification of the mite on microscopic examination of skin scrapings, and the presence of infestation among the patient’s family or associates (see Chapter 18 ).

Langerhans cell histiocytosis (LCH) most commonly occurs before 3 years of age (see Chapter 10 ). In affected neonates, reddish-brown, purpuric, crusted papules or vesiculopapules are typically present. In infants this skin eruption is often characterized as a scaly, erythematous seborrheic eruption on the scalp, behind the ears, and in the intertriginous regions. On close inspection the presence of reddish-brown, petechial or purpuric lichenoid papules or vesicular or crusted papules in infants is typical. Cutaneous biopsy and identification of CD1a ⁺ Langerhans cells by immunostaining confirms the diagnosis of LCH.

Acrodermatitis enteropathica is an autosomal recessive disorder characterized by vesiculobullous eczematoid lesions of the acral and periorificial areas, failure to thrive, diarrhea, alopecia, nail dystrophy, and frequent secondary bacterial or candidal infection (see Chapters 2 and 24 ). The characteristic distribution of lesions accompanied by listlessness, diarrhea, failure to thrive, and low serum zinc levels differentiate lesions of acrodermatitis enteropathica from those of AD. Usually a disorder in formula-fed babies with the hereditary form, acrodermatitis enteropathica may also occur in breastfed babies as a result of deficient zinc secretion into maternal breast milk.

Dermatitis during the neonatal or infantile periods is also seen in immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome, which manifests with early onset intractable diarrhea and type 1 diabetes mellitus. The disorder is often fatal during the first year of life. The cutaneous manifestations are seen in 70% of affected babies and tend to be the first sign. Although an atopic-like dermatitis is most common, the eruption has also been described as psoriasiform or resembling ichthyosiform erythroderma. Lesions are often pruritic, secondarily infected by S. aureus , and resistant to treatment with topical corticosteroids. Other common cutaneous manifestations include severe cheilitis, onychodystrophy, and alopecia. Infections of the upper and lower airways and gastrointestinal (GI) tract are common, and affected patients may succumb to sepsis. Food allergies and high levels of IgE and eosinophils are also associated. The autoimmune enteropathy is characterized by persistent, watery, and sometime mucoid or bloody diarrhea during the neonatal period, resulting in malabsorption and failure to thrive. Type 1 diabetes is difficult to control and results from lymphocytic infiltration of the pancreas. Other autoimmune symptoms, such as hypothyroidism, cytopenia, hepatitis, nephropathy, and arthritis can develop in patients who survive the initial acute phase. IPEX syndrome results from mutations in FOXP3, leading to absent or dysfunctional regulatory T cells and self-reactive T-cell activation and proliferation. Detection of enterocyte autoantibodies helps make the diagnosis. Treatment generally includes supportive care and systemic immunosuppressive therapy (steroids, methotrexate, tacrolimus), although rapamycin has shown promise. Stem-cell transplantation is the curative treatment if a suitable donor can be found.

Generalized erythroderma in association with atopic features can be seen in other disorders with barrier abnormalities, notably Netherton syndrome (biallelic mutations in SPINK5 ) and SAM syndrome ( s evere skin dermatitis, multiple a llergies and m etabolic wasting; biallelic mutations in DSG1 ) ; failure to thrive, recurrent infections, and hypotrichosis are associated with both of these ichthyotic disorders (see Chapter 5 ).

Typical AD may be a feature of several forms of immunodeficiency, most notably in Wiskott–Aldrich syndrome (WAS) and the hyperimmunoglobulinemia E syndrome (HIES) (see related sections). These disorders are distinguished from AD by their recurrent noncutaneous infections and other characteristic features (e.g., thrombocytopenic purpura, bloody diarrhea, and purpuric lesions in WAS and facial and intertriginous staphylococcal abscesses in HIES).

Management

The overall goals of therapy are to reduce itch and maintain sufficient control to minimize any adverse effects of the AD on quality of life. In general, a multistep approach is taken toward management that includes patient and parent education, avoidance of irritants and allergic triggers, good moisturization, normalization of dysbiosis, and use of antiinflammatory medications ( Table 3.1 ). Patient compliance is the main reason for poor outcome and is fueled by concerns about the use of topical corticosteroids and calcineurin inhibitors (see later). Aggressively but safely managing AD flares is important in preventing the exacerbation of disease by delayed or inadequate treatment. The National Eczema Association (NEA) offers a website for education and patient support ( www.nationaleczema.org ). Age-specific structured educational programs have improved objective and subjective severity scores, and educational videos may improve severity beyond direct education. Written action plans have been shown to improve adherence to therapy. ^{, , ,} Several guidelines for AD management in children have been published.