Management of severe, refractory atopic dermatitis (eczema) in children.
1. Osmonova Gulnaz Zhenishbaevna
2. Adeel
3. Marif Ali
(1. Teacher, International Medical Faculty, Osh State University, Osh, Kyrgyz Republic.
2. Student, International Medical Faculty, Osh State University, Osh, Kyrgyz Republic.
3. Student, International Medical Faculty, Osh State University, Osh, Kyrgyz Republic.)
INTRODUCTION
Atopic dermatitis (AD) is a common, chronic, inflammatory skin disorder characterized by a pruritic eczematous skin eruption. In most children, the disorder is managed with careful skin care practices, barrier repair strategies, topical therapies for inflammation, and the elimination of exacerbating factors. Patients with severe disease that fails to improve with topical therapy may benefit from systemic medications or phototherapy.
This topic reviews the causes and treatment of severe, refractory AD in children. The standard management of AD, including maintenance of skin hydration, control of pruritus, topical anti-inflammatory therapies, and management of infection, is discussed separately. The clinical manifestations and diagnosis of AD and the role of allergy in AD are also discussed separately.
DEFINITION OF SEVERE ATOPIC DERMATITIS
Most patients with AD have mild to moderate disease. However, a subpopulation of patients develops severe symptoms. Severe AD may be loosely described as the presence of widespread eczematous lesions, unremitting itching, or physically or emotionally disabling disease that significantly compromises a patient's quality of life (picture 1). Patients with severe AD who do not respond to first-line topical therapies may be classified as having severe, refractory disease.
ASSESSMENT OF SEVERITY
Clinical studies have utilized scales for defining the severity of AD, such as the Investigator Global Assessment (IGA), the Scoring of Atopic Dermatitis (SCORAD) index, and the Eczema Area and Severity Index (EASI) [1]. Although such scales are useful for standardizing the results of research studies, they are not routinely used in clinical practice and may not reflect the disease severity as perceived by the individual patients.
An international study involving over 1000 patients or parents of children with AD from 34 countries found that the symptoms considered to be important by 80 percent of the participants included itch, pain/soreness, skin feeling hot or inflamed, bleeding, involvement of visible or sensitive body sites, cracks, sleep difficulties, amount of the body affected, and weeping/oozing [2].
Two validated severity assessment tools incorporate the patient's perception of severity and disease control associated with treatments and have been recommended by experts [3-5]:
●POEM – The Patient-Oriented Eczema Measure (POEM), a fully patient-derived and patient-assessed scale, has been proposed as a core instrument to complement the clinician-assessed scales in the evaluation of disease severity and response to treatment in patients with AD [4].
●ADCT – A similar tool called the Atopic Dermatitis Control Tool (ADCT) has been validated for patients 12 years of age and older [6]. This six-question scale is designed for clinical use and seeks to determine if the condition is under control, something perhaps more relevant than the disease severity from a patient perspective. A version for younger patients is being validated as well [7].
A practical guide to visual assessment of eczema severity that also includes the evaluation of disease impact on quality of life and psychosocial well-being has been proposed by the United Kingdom National Institute for Health and Care Excellence:
●Mild – Areas of dry skin, infrequent itching (with or without small areas of redness); little impact on everyday activities, sleep, and psychosocial well-being.
●Moderate – Areas of dry skin, frequent itching, redness (with or without excoriation and localized skin thickening); moderate impact on everyday activities and psychosocial well-being, frequently disturbed sleep.
●Severe – Widespread areas of dry skin, incessant itching, redness (with or without excoriation, extensive skin thickening, bleeding, oozing, cracking, and alteration of pigmentation); severe limitation of everyday activities and psychosocial functioning, nightly loss of sleep.
ASSESSMENT OF POTENTIAL CAUSES OF REFRACTORY DISEASE
Circumstances that may contribute to severe or refractory AD include financial considerations, poor adherence or incorrect use of medications, presence of environmental exacerbating factors, secondary infection, and hypersensitivity reactions to topical treatments or other allergens (table 1). Prior to initiating additional treatments for AD, clinicians should ensure that severe, refractory disease is not a result of the presence of an avoidable or treatable factor.
Poor adherence/incorrect medication use — For many patients, a lack of adherence to the treatment regimen and basic skin care techniques contributes to persistent disease. Over 50 percent of patients with AD do not administer treatment as recommended by their clinicians [8-10]. Specific reasons for inadequate application of treatment include financial considerations, concerns about medication side effects, patient dislike of topical preparations, and insufficient time for clinicians to educate patients about skin care [11].
Topical corticosteroid phobia, defined as a concern or fear about using topical corticosteroids, is common, with a prevalence among patients and caregivers ranging from 20 to over 80 percent worldwide [12-14]. Corticosteroid phobia is likely a contributing cause of poor adherence to treatment and treatment failure among patients with AD.
Exacerbating factors/environmental triggers — Circumstances that may contribute to severe or refractory AD include noncompliance with conventional therapy, secondary infection, hypersensitivity reactions to topical treatments, and persistent exposure to triggers of disease flares.
Exacerbating factors for AD may include low humidity environments; xerosis (dry skin); sweat and overheating of skin; emotional or physiologic stress; and exposure to irritating substances, such as harsh chemicals or soaps. Avoiding these factors is helpful for avoiding acute flares as well as for long-term management, although this is not always possible. (See "Treatment of atopic dermatitis (eczema)".)
Infection — Patients with AD are at an increased risk for secondary cutaneous bacterial, viral, and dermatophyte infections. The possibility of secondary infection should be considered in patients with skin lesions that appear refractory to conventional therapy. In particular, clinicians should be aware of the possibility of Staphylococcus aureus and herpes simplex virus (HSV) infections.
Colonization with S. aureus occurs more frequently in individuals with AD than in the general population, and S. aureus is a common cause of secondary infection in these patients. The presence of purulence or honey-colored crusts suggests S. aureus infection. Even in the absence of overt infection, colonization by S. aureus may be an exacerbating factor for AD. (See "Treatment of atopic dermatitis (eczema)", section on 'Staphylococcus aureus'.)
Secondary HSV infection (eczema herpeticum) may also occur and, rarely, may lead to life-threatening dissemination of HSV in patients with AD. Punched-out erosions, hemorrhagic crusts, and vesicles are indicators of this infection. Rarely, coxsackie virus and vaccinia virus (in smallpox vaccine) can give a similar clinical picture [15,16]. (See "Treatment of atopic dermatitis (eczema)", section on 'Viral infections'.)
Hypersensitivity reactions to treatment — Delayed hypersensitivity reactions to contact allergens in topical emollients or medications are another cause of an apparent lack of response to treatment.
Allergic contact dermatitis can be caused by vehicle or active ingredients in products being used on the skin, including emollients (eg, lanolin, propylene glycol, fragrances, preservatives), cleansers/washes, wipes, and topical antibiotics (eg, bacitracin, neomycin) [17-23]. (See "Common allergens in allergic contact dermatitis".)
Contact allergy to a topical emollient, medication, or other allergen (eg, nickel, preservatives) present in wipes or cosmetic products should also be considered when patients present with AD that fails to respond to or appears to worsen with topical therapies [23,24].
Allergic contact dermatitis to topical corticosteroids is uncommon. It has been reported in 0.3 to 5 percent of patients undergoing patch testing with standard series that included several corticosteroids [25,26]. Allergic contact dermatitis to topical calcineurin inhibitors is rare and has been reported in a few case reports [27,28].
The identification and elimination of a contact allergen can lead to rapid clinical improvement in affected individuals. If a contact allergy is suspected, patch testing should be performed to identify the responsible allergen. (See "Overview of dermatitis (eczematous dermatoses)", section on 'Allergic contact dermatitis' and "Allergic contact dermatitis in children".)
Food and environmental allergies — In some cases, patients with refractory AD may have undiagnosed food or environmental allergies that may worsen the symptoms of their disease, although food allergy is not the trigger of the eczematous flares in most cases. It is important to exclude immediate and delayed hypersensitivity through allergy testing (eg, skin prick testing, specific immunoglobulin E [IgE] measurement, patch testing).
However, clinicians should be cognizant that evidence of allergen sensitization is not proof of clinically relevant allergy. Moreover, even a clinically relevant food allergy is often not the trigger of the persistent eczema, as food allergies most often present with urticaria and angioedema and not dermatitis.
Confirming clinical reactivity is especially important when food allergies are suspected in young children, since avoidance of food allergens can result in less-than-optimal nutritional intake [29]. Additionally, there is some evidence that food avoidance may actually induce sensitization, including an increased risk of developing anaphylaxis [30,31].
The role of allergy in AD is discussed in detail separately. (See "Role of food and environmental allergies in atopic dermatitis (eczema)", section on 'Food allergies' and "Role of food and environmental allergies in atopic dermatitis (eczema)", section on 'Environmental allergies'.)
Incorrect diagnosis — An incorrect diagnosis may account for a failure to respond to conventional therapy. The possibility of other disorders that may present with clinical features that resemble AD should be considered. These may include conditions such as scabies, psoriasis, inherited ichthyosis, cutaneous T cell lymphoma, autoimmune disorders, and nutritional or immune system deficiencies (table 2).
REFERRAL
Patients with severe, refractory AD should be seen by a specialist (eg, pediatric dermatologist, pediatric allergist) familiar with updated treatment guidelines and use of second-line treatments, such as biologics, other systemic agents, and phototherapy. Because of the paucity of randomized trials addressing the management of refractory AD in the pediatric age group, there is a wide variability among clinicians in the use of second-line therapies for children with severe disease [32,33].
MANAGEMENT
A number of systemic treatments are available for the treatment of refractory AD in children and adolescents. However, it is important to note that AD is a lifelong disease, and initiation of systemic therapy should be carefully considered.
Optimizing topical therapy
Basic principles — After excluding the factors potentially associated with recalcitrant disease (see 'Assessment of potential causes of refractory disease'above), our initial approach is to attempt to optimize topical treatment for several weeks (algorithm 1). This will help identify those children who are candidates for second-line therapies. To optimize topical treatment:
●Ensure that the appropriate strength topical medication expected to clear the flare in approximately 5 to 14 days is being used
●Initiate treatment at the first sign of a flare
●Continue treatment until there is complete or almost complete clearance of skin lesions
Wet wraps and proactive therapy are additional techniques that help to optimize topical treatments and, in many situations, can prolong the interval between flares.
Wet wrap therapy — For children with persistent, severe AD despite optimal treatment with topical corticosteroids and/or topical calcineurin inhibitors and for children with an acute, generalized exacerbation of AD, we suggest wet wrap therapy with low- to medium-potency topical corticosteroids (table 3) once to twice daily for 3 to 5 days and up to 14 days. Wet wraps can be maintained for two or more hours, as tolerated, and even overnight if patients feel comfortable. Wet wraps can also be applied for a shorter time (eg, 15 to 30 minutes) two or three times per day.
●Application – Wet wraps consist of a bottom wet layer and top dry layer. They are generally applied on top of emollients and/or topical corticosteroids and left in place for up to 24 hours [34]. Cotton clothing in two layers may be sufficient for some cases, but elasticated cotton tubular bandages of appropriate size, which can be cut to cover any part of the body, may be more convenient in some situations [35]. Special bodysuits for wet wrap therapy for infants and toddlers are also commercially available.
Because of the increased systemic absorption of topical corticosteroids with wet wraps, some experts suggested that diluting low- to mid-potency topical corticosteroids in emollients (eg, 1:20 for the face and body in infants and young children) and limiting the duration of treatment to a few days may reduce the risk of hypothalamic-pituitary-adrenal axis suppression [36,37]. Measurement of early morning fasting serum cortisol before and after treatment may be used to assess systemic absorption, although it is not generally performed for short-term use.
●Efficacy – Data on the efficacy of wet wraps are sparse and inconsistent due to a wide variability across studies in the treatment modality (eg, type of bandage used, frequency of application, treatment duration) and patient characteristics (eg, AD severity, body area involved) [38]. While several observational studies and a few small randomized trials support their efficacy as a short-term treatment (2 to 14 days) to induce a rapid remission in children with severe disease, other studies suggest that wet wraps are as effective as conventional treatment with topical corticosteroids and emollients [34,39,40].
●Adverse effects – Adverse effects include increased systemic absorption of topical corticosteroids, general discomfort, chills, and folliculitis. Temporary decreases in early morning serum cortisol levels have been reported, although short courses (<2 weeks) of use of diluted low- to mid-potency corticosteroids have not been associated with prolonged adrenal suppression [34].
Proactive (maintenance) topical therapy — Once the flare has subsided, patients can continue using topical therapy with a medium-potency topical corticosteroid (table 3) or topical calcineurin inhibitor (tacrolimus 0.03% or 0.1% or pimecrolimus 1%) intermittently in the area of previously flared skin to prevent exacerbations and prolong the interval in-between flares [29,41]. The frequency of application of proactive therapy varies from two to three days per week (eg, every other day or "weekend therapy").
In a 2022 systematic review, the pooled analysis of seven trials that compared weekend (proactive) topical corticosteroid therapy versus no topical corticosteroids showed that proactive therapy lasting 16 to 20 weeks decreased the likelihood of relapse from 58 to 25 percent (relative risk 0.43, 95% CI 0.32-0.57, moderate-certainty evidence) [42].
Emollients should be liberally used multiple times per day. (See "Treatment of atopic dermatitis (eczema)", section on 'Maintenance and prevention of relapses'.)
References:
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