A topic dermatitis, often called “eczema,” is one of the most common chronic conditions affecting children (see Figure 1). The associated itch, inflammation, and sleep loss have a profound effect on the quality of life of the child, as well as on family members. The pediatrician is usually the first to evaluate the condition. This makes familiarity with its features, and its management, essential. This article covers some of the recent findings and advances in the field to help practitioners stay current on issues related to this skin disorder.
Figure 1. Infant with atopic dermatitis showing typical inflamed plaques and xerosis. Source: Tom W. Reprinted with permission.
Defective Skin Barrier
The pathogenesis of atopic dermatitis (AD) is complex, but is now thought to stem from a genetically predisposed defective epidermal barrier that allows increased allergen, irritant, and microbial penetration; these ultimately elicit a dysregulated inflammatory response. The production of cytokines, recruitment of T-lymphocytes and other cells, and scratching in response to itch lead to further impairment of the skin barrier, ensuing in a vicious cycle.1,2
Multiple defects affecting both the structure and function of the epidermis are present in AD. These include a decrease in the quantity of ceramide lipids, an imbalance of protease enzymes over their inhibitors, and increased tran-sepidermal water loss.1,2 Genome-wide association and large-scale candidate gene studies have generated insight into some of the genes leading to skin barrier dysfunction. In particular, loss-of-function mutations in the filaggrin (FLG) gene have been a widely replicated major risk factor for AD. FLG is a structural protein involved in aggregating keratin filaments. These provide the template for assembly of the cornified envelope (the envelope that surrounds the outermost cells of the skin); its breakdown products play a role in the water-binding capacity of the stratum corneum. FLG mutations are associated with more severe AD, early onset of disease, enhanced systemic allergen sensitization, and an increased risk for asthma in those with a history of AD.3
However, there are certainly other factors involved in the pathogenesis of AD. Many with severe disease do not have FLG null mutations, and approximately 40% with null mutations in FLG do not have AD. Some of the other implicated factors include other members of the epidermal differentiation complex, and tight junction proteins in the stratum granulosum (eg, claudin), the layer directly below the stratum corneum.2,4 The genetics of atopic dermatitis and the influence on disease remain an evolving picture.
Emollients vs. Topical Barrier Repair Products
Proper skin care and treatment of xerosis are cornerstones of AD management. Mild, fragrance-free cleansers should be used and bubble baths avoided. Thicker emollients such as ointments and creams are better than lotions and should be used several times daily, particularly after bathing.
Besides traditional emollients, a newer class of topical products has been developed to address the defective skin barrier itself. Initial agents included pamitoylethanolamide cream, a 70% oil dispersed in 30% water hydrolipid cream, and a glycyrrhetinic acid-containing hydrolipid cream. These were followed by ceramide-based creams, including one with a 3:1:1 ratio of ceramide: cholesterol:free fatty acids that uses physiologic lipid components to optimize epidermal function and repair. There is evidence that these topicals can lessen the amount of topical corticosteroids (TCs) used, as well as help with itch and xerosis.5,6
The 3:1:1 ceramide:cholesterol:free fatty acids cream was tested in a randomized, investigator blind trial against fluticasone cream. The barrier repair agent was not as effective as the topical steroid in reducing disease severity in the first several weeks of use, but reached comparable effect by 4 weeks.6 However, these prescription barrier repair products are significantly more expensive than traditional emollient ointments and creams, plus there are few comparative data to demonstrate superiority.
One recent trial found equal efficacy among the glycyrrhetinic acid-containing hydrolipid cream, the 3:1:1 cer-amide:cholesterol:free fatty acids cream, and an over-the-counter (OTC) petroleum-based skin protectant moisturizer when used for 3 weeks in those with mild to moderate AD.7 In addition, these barrier therapies are approved under the FDA’s 510(k) registration as medical devices without active ingredients and have not had the same long-term efficacy and safety testing required of approved drugs. More recently, creams that contain ceramide and filaggrin breakdown products have been introduced to the OTC market. Their use shows improved hydration relative to not using any emollient, but they have not been compared with other OTC products.8 Thus, while barrier repair agents may be helpful adjuvant therapies to decrease AD symptoms, xerosis, and perhaps the need for topical anti-inflammatory medications, their role and benefit relative to traditional emollients remain unclear.
Anti-Inflammatory Use and Safety
The second major hallmark of AD is cutaneous inflammation. TCs remain the mainstay of therapy to control this aspect of disease. Prescribing methods vary greatly: with some using a short burst of mid- to high-potency agents to induce remission, followed by a quick tapering of potency; and others using the lowest potency thought to be needed, then adjusting upward if these fail. Newer formulations of TCs include nongreasy foams and hydrogels, which may be useful for hair-bearing sites such as the scalp. Topical calcineurin inhibitors (TCIs) are alternatives to TCs and are approved as second-line agents for the short-term and noncontinuous chronic treatment of moderate to severe AD in immunocompetent patients aged 2 years or older.9 Since 2006, they have carried a boxed warning stating that their long-term safety has not been established because rare post-market cases of malignancy (ie, skin cancer and lymphoma) have been reported with treatment.
Studies to address these concerns include one involving 293,253 patients, which found an increased risk for lymphoma that correlated with AD severity but not with TCI use.10 Interim analysis of an ongoing 10-year observational study at 4.3 years has also not found any evidence of increased malignancy risk with their use.11 Unlike topical steroids, TCIs do not carry a risk for skin atrophy, and therefore they can be helpful for sites of thinner skin (ie, face, eyelids, groin) or to decrease the use of topical steroids in those with recurrent disease.
The overall goals of AD therapy are: to obtain clearance/control of flares; to prolong the period until the next flare with a long-term maintenance phase; and to establish a rescue strategy in the event of disease relapse. Proactive therapy can be beneficial in the maintenance phase, in which a topical anti-inflammatory agent is used on a scheduled intermittent basis two to three times weekly rather than waiting until the disease recurs. Randomized controlled trials using TCs and TCIs in this manner noted a reduced risk of relapse, decreased number of exacerbations, and increased time to first recurrence without any adverse effects.12,13 Histologic and expression studies have found that non-lesional and previously involved but subsequently normal-appearing skin are not actually “normal,” but show some mild inflammatory changes and continued barrier defects.14,15 It is not unexpected that in some patients such sites could relapse relatively quickly; scheduled intermittent therapy may be appropriate for managing these cases.
Itch remains one of the most distressing features of AD and still lacks optimal therapy. Although widely used, there is little evidence that H1 antihistamines improve AD-associated pruritus. Sedating H1 blockers may be helpful at night due to their soporific effect. Other mediators of itch include cytokines, prostaglandins, proteases, and neuropeptides such as substance P, which binds to neurokinin receptor-1. A pilot study of an oral antagonist of this receptor found a reduction in itch in those with chronic pruritus and an atopic diathesis.16
Recent data have also shown upregulation of IL-31, a T-cell-derived cytokine, in animal models and in AD skin samples.17 The histamine H4 receptor, which is expressed on T cells, antigenpresenting cells, and keratinocytes, may also play a role in AD-associated itch.18 These are additional potential targets for the development of antipruritic therapy.
Although it is common to recommend limiting contact with potential triggers, such as astringents, harsh detergents, abrasive fabrics/wool, and excessive heat or low humidity in those with AD, these mainly stem from consensus and expert opinion, with few supportive studies. The role of aeroallergens, such as dust mites and animal dander, as triggers also remains unclear.9,19
Although commonly implicated by parents, foods are not necessarily causative of AD flares. Rather, those with AD are predisposed to have food allergy as a comorbid condition, but such allergies generally manifest on the skin as hives (urticaria) or angioedema. In 2010, the National Institute of Allergy and Infectious Diseases (NIAID) published guidelines stating that a positive specific IgE test or skin prick test alone does not constitute a food allergy. Instead, a reproducible adverse health effect must occur (ie, skin, gastrointestinal, or respiratory symptoms) with exposure. Regarding children with AD, testing is recommended for milk, egg, peanut, wheat, and soy only in those younger than 5 years of age with moderate to severe disease if they have either: persistent disease despite appropriate therapy; or a reliable history of an immediate reaction after ingestion of a specific food. If there is no documented or proven food allergy, it is not recommended to avoid potentially allergenic foods as a means of managing AD.20 Testing and dietary challenge or avoidance trials should be done under the supervision of an allergist.
Increasingly recognized in children, including those with worsening or recalcitrant AD, is the high prevalence of allergic contact dermatitis. Unlike urticaria, this is a delayed hypersensitivity reaction. The most common allergens in children include nickel, cobalt, neomycin/antibiotics, fragrance, and rubber chemicals.21 Diagnosis is made by patch testing, whereby suspected allergens are placed on unaffected skin for 24 to 48 hours. The reaction is noted at patch removal, and again at a later delayed reading. Patch testing should be considered in cases in which there is an unusual and atypical distribution of lesions for AD; if there is later onset of disease or new significant worsening; if there is no family history of atopy; if the disease is aggravated by topical medications or emollients; and in those not responding to standard therapies for AD.21,22
Cutaneous Immune System and Secondary Infections
Skin affected with AD is particularly prone to bacterial and viral infections. This is due to the defective physical barrier, combined with an immune response to microbes that is impaired on several levels. AD skin has decreased expression of antimicrobial peptides (eg, cathelicidin, beta-defensin), inadequate pathogen recognition by innate immune receptors, and diminished recruitment of cells such as neutrophils and natural killer cells to combat infectious agents after their entry.1,2
Exacerbation of AD related to colonization and infection by Staphylococcus aureus is well-recognized, and oral antibiotic use and occasional dilute bleach bath therapy (once to twice weekly) can be of benefit in those with repeated infection.23S. aureus may secrete exotoxins that act as superantigens to activate T lymphocytes and drive excessive inflammation. Of interest are data from several centers that suggest that children with AD may actually have lower rates of methicillin-resistant S. auerus (MRSA) skin infection than those without AD, but further affirmation is needed.24
Secondary infection by herpes simplex virus, called eczema herpeticum (EH, Figure 2, see page e2), tends to occur in those with more severe manifestations of AD, earlier age of disease onset, or with additional associated allergic disorders and/or high serum IgE levels. Recent studies have shown that those with a history of EH have additional defects relative to those who do not get secondary herpes infection, with further suppression of antimicrobial peptide production and even lower expression of skin barrier proteins and enzymes producing natural moisturizing factor.25,26
Figure 2. Eczema herpeticum is a secondary infection with the herpes simplex virus and can be severe, as seen in this 16-year-old patient. Typically, the lesions erode quickly and intact vesicles may not be seen. Source: Tom W. Reprinted with permission.
Primary prevention of AD is highly desired, but little has shown consistent positive effect. Probiotic use in pregnant mothers and infants has yielded conflicting results, with dosing, timing, and the type of probiotic used varying greatly among studies. Maternal avoidance of cow’s milk, eggs, and peanuts during pregnancy does not appear to affect risk.
Studies assessing the association of breast-feeding and the development of AD have been limited by methodologic differences and flaws in study design and blinding; results have ranged from demonstration of a protective effect in those with a family history of atopy to suggestion of a higher risk for AD with longer duration of breast-feeding. There is a modest but inconsistent benefit with low-allergen maternal diets during lactation and with the use of hydrolyzed protein formulas compared with cow’s milk formulas. Soy formulas do not appear to be helpful.27,28 Currently, exclusive breast-feeding for at least 4 months is recommended for infants at high risk for developing AD, but delaying the introduction of solids (including possible allergenic foods) beyond the first 4 to 6 months of life is not advocated for any infant.9,29
More recently, focus has turned to skin barrier protection in the newborn period to prevent AD. An open-label, prospective study of at least daily use of OTC emollient and petrolatum in high-risk newborns found three of 20 (15%) developed disease during the follow-up period. The researchers said that similar high-risk cohorts have a 30% to 50% rate of AD by the age of 2 years, but their time of follow-up (ranging from 90 to 773 days) was not adequate to make comparison; additionally, the small sample size is limiting.30 Nevertheless, early barrier protection for the primary prevention of AD is an intriguing concept needing further investigation. Additional studies under way include a comparison of commonly used OTC emollients with topical application of natural/plant oils (eg, sunflower seed oil, coconut oil) for prevention.
Matching the pathophysiology, the management of AD is multimodal and must include improving the skin barrier, controlling inflammation, reducing itch, treating and preventing infections, and addressing and/or avoiding triggers. Figure 3 (see page e3) illustrates an approach to management of a child with AD. Much work is ongoing to understand better the factors at play and to improve therapeutic options, both for those affected as well as for those at risk for disease.
Figure 3. Management approach for atopic dermatitis. Source: Tom W. Reprinted with permission.
- Elias PM, Schmuth M. Abnormal skin barrier in the etiopathogenesis of atopic dermatitis. Curr Opin Allergy Clin Immunol. 2009; 9(5):437–446. doi:10.1097/ACI.0b013e32832e7d36 [CrossRef]
- Boguniewicz M, Leung DY. Atopic dermatitis: a disease of altered skin barrier and immune dysregulation. Immunol Rev. 2011; 242(1):233–246. doi:10.1111/j.1600-065X.2011.01027.x [CrossRef]
- Kawasaki H, Kubo A, Sasaki T, Amagai M. Loss-of-function mutations within the filaggrin gene and atopic dermatitis. Curr Probl Dermatol. 2011;41:35–46. doi:10.1159/000323291 [CrossRef]
- O’Regan GM, Sandilands A, McLean WH, Irvine AD. Filaggrin in atopic dermatitis. J Allergy Clin Immunol. 2009; 124(3 Suppl 2):R2–R6.
- Eberlein B, Eicke C, Reinhardt HW, Ring J. Adjuvant treatment of atopic eczema: assessment of an emollient containing N-palmitoylethanol-amine (ATOPA study). J Eur Acad Dermatol Venereol. 2008; 22(1):73–82.
- Sugarman JL, Parish LC. Efficacy of a lipid-based barrier repair formulation in moderate-to-severe pediatric atopic dermatitis. J Drugs Dermatol. 2009; 8(12):1106–1111.
- Miller DW, Koch SB, Yentzer BA, et al. An over-the-counter moisturizer is as clinically effective as, and more cost-effective than, prescription barrier creams in the treatment of children with mild-to-moderate atopic dermatitis: a randomized, controlled trial. J Drugs Dermatol. 2011;10(5):531–537.
- Simpson E, Dutronc Y. A new body moisturizer increases skin hydration and improves atopic dermatitis symptoms among children and adults. J Drugs Dermatol. 2011; 10(7):744–749.
- Krakowski AC, Eichenfield LF, Dohil MA. Management of atopic dermatitis in the pediatric population. Pediatrics. 2008; 122(4):812–824. doi:10.1542/peds.2007-2232 [CrossRef]
- Arellano FM, Wentworth CE, Arana A, Fernández C, Paul CF. Risk of lymphoma following exposure to calcineurin inhibitors and topical steroids in patients with atopic dermatitis. J Invest Dermatol. 2007; 127(4):808–816. doi:10.1038/sj.jid.5700622 [CrossRef]
- Paller AS, Michaels MA, Bieber T. Assessing the long-term safety of tacrolimus ointment for the treatment of atopic dermatitis: An update on a prospective pediatric longitudinal evaluation study (APPLES). J Am Acad Dermatol. 2010; 62(3),Suppl.1: AB10. doi:10.1016/j.jaad.2009.11.076 [CrossRef]
- Wollenberg A, Frank R, Kroth J, Ruzicka T. Proactive therapy of atopic eczema — an evidence-based concept with a behavioral background. J Dtsch Dermatol Ges. 2009; 7(2):117–121. doi:10.1111/j.1610-0387.2008.06772.x [CrossRef]
- Schmitt J, von Kobyletzki L, Svensson A, Apfelbacher C. Efficacy and tolerability of proactive treatment with topical corticosteroids and calcineurin inhibitors for atopic eczema: systematic review and meta-analysis of randomized controlled trials. Br J Dermatol. 2011;164(2):415–428. doi:10.1111/j.1365-2133.2010.10030.x [CrossRef]
- Wollenberg A, Bieber T. Proactive therapy of atopic dermatitis — an emerging concept. Allergy. 2009; 64(2):276–278. doi:10.1111/j.1398-9995.2008.01803.x [CrossRef]
- Suárez-Fariñas M, Tintle SJ, Shemer A, et al. Nonlesional atopic dermatitis skin is characterized by broad terminal differentiation defects and variable immune abnormalities. J Allergy Clin Immunol. 2011; 127(4):954–964.e1–e4. doi:10.1016/j.jaci.2010.12.1124 [CrossRef]
- Ständer S, Siepmann D, Herrgott I, Sunderkötter C, Luger TA. Targeting the neurokinin receptor 1 with aprepitant: a novel antipruritic strategy. PLoS One. 2010;5(6):e10968. doi:10.1371/journal.pone.0010968 [CrossRef]
- Lee CH, Yu HS. Biomarkers for itch and disease severity in atopic dermatitis. Curr Probl Dermatol. 2011; 41:136–148. doi:10.1159/000323307 [CrossRef]
- Ständer S, Luger TA. Itch in atopic dermatitis — pathophysiology and treatment. Acta Dermatovenerol Croat. 2010; 18(4):289–296.
- Boguniewicz M, Nicol N, Kelsay K, Leung DY. A multidisciplinary approach to evaluation and treatment of atopic dermatitis. Semin Cutan Med Surg. 2008; 27(2):115–127. doi:10.1016/j.sder.2008.05.001 [CrossRef]
- Boyce JA, Assa’ad A, Burks AW, et al. Guidelines for the Diagnosis and Management of Food Allergy in the United States: Summary of the NIAID-Sponsored Expert Panel Report. J Allergy Clin Immunol. 2010; 126(6):1105–1118. doi:10.1016/j.jaci.2010.10.008 [CrossRef]
- Matiz C, Hsu JW, Paz Castanedo-Tardan M, Jacob SE. Allergic contact dermatitis in children: a review of international studies. G Ital Dermatol Venereol. 2009; 144(5):541–556.
- Castanedo-Tardan MP, Matiz C, Jacob SE. Contact dermatitis in children — a review of current opinions. Actas Dermosifiliogr. 2011; 102(1):8–18. doi:10.1016/j.ad.2009.12.028 [CrossRef]
- Schnopp C, Ring J, Mempel M. The role of antibacterial therapy in atopic eczema. Expert Opin Pharmacother. 2010;11(6):929–936. doi:10.1517/14656561003659992 [CrossRef]
- Matiz C, Tom WL, Eichenfield LF, Pong A, Friedlander SF. Children with atopic dermatitis appear less likely to be infected with community acquired methicillin-resistant Staphylococcus aureus: the San Diego experience. Pediatr Dermatol. 2011; 28(1):6–11. doi:10.1111/j.1525-1470.2010.01293.x [CrossRef]
- Hata TR, Kotol P, Boguniewicz M, et al. History of eczema herpeticum is associated with the inability to induce human β-defensin (HBD)-2, HBD-3 and cathelicidin in the skin of patients with atopic dermatitis. Br J Dermatol. 2010;163(3):659–661. doi:10.1111/j.1365-2133.2010.09892.x [CrossRef]
- Broccardo CJ, Mahaffey S, Schwarz J, et al. Comparative proteomic profiling of patients with atopic dermatitis based on history of eczema herpeticum infection and Staphylococcus aureus colonization. J Allergy Clin Immunol. 2011; 127(1):186–193, 193.e1–e11. doi:10.1016/j.jaci.2010.10.033 [CrossRef]
- Batchelor JM, Grindlay DJ, Williams HC. What’s new in atopic eczema? An analysis of systematic reviews published in 2008 and 2009. Clin Exp Dermatol. 2010; 35(8):823–827. doi:10.1111/j.1365-2230.2010.03901.x [CrossRef]
- Vandenplas Y. Infant formula with partial protein hydrolysates: evidence and remaining questions. J Pediatr Gastroenterol Nutr. 2010; 50(4):356–358.
- Filipiak B, Zutavern A, Koletzko S, et al. Solid food introduction in relation to eczema: results from a four-year prospective birth cohort study. J Pediatr. 2007; 151(4):352–358. doi:10.1016/j.jpeds.2007.05.018 [CrossRef]
- Simpson EL, Berry TM, Brown PA, Hanifin JM.A pilot study of emollient therapy for the primary prevention of atopic dermatitis. J Am Acad Dermatol. 2010; 63(4):587–593. doi:10.1016/j.jaad.2009.11.011 [CrossRef]