An Update on Pediatric Atopic Dermatitis and Food Allergies Tuyet Ann Nguyen, BS1,2, Stephanie A. Leonard, MD2,3, and Lawrence F. Eichenfield, MD1,2
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n otherwise healthy 15-month-old female presented to Pediatric Dermatology for evaluation and management of moderate atopic dermatitis since 4 months of age. The patient had eczematous dermatitis with a waxing and waning course, with significant pruritus, sleep disturbance, and no symptom-free periods. The family had previously been instructed to use a combination of daily moisturizers with hydrocortisone 2.5% ointment during flares, but because of concerns about steroid side effects used only very small quantities of prescription medication. At 8 months and while exclusively being breastfed, the patient was evaluated by an allergist. Mother had noticed that when she ingested large amounts of egg, the infant’s eczema would flare. When she removed egg from her diet, the eczema improved but did not resolve. Skin testing was performed on the child and was positive to egg and negative to milk and peanut. Serum IgE food allergy (FA) testing at 14 months was positive to milk, wheat, and tree nuts; however, the child ingested wheat and tree nuts regularly without any noted symptoms. The family limited the patient’s dairy intake because of concerns that it exacerbated the dermatitis but did not see significant improvement. Physical examination was significant for diffuse eczematous plaques with lichenification and moderate thickening on the neck and upper and lower extremities favoring the antecubital and popliteal fossae. Scattered erythematous, edematous plaques, and excoriations were also present diffusely. Approximately 30% of the body surface area was involved. The diagnosis of atopic dermatitis was reviewed in detail including clinical course, treatment options, and possible triggers and trigger avoidance. The role of FAs and potential false positive food-specific IgE testing were discussed in detail, and the patient was started on a treatment plan to control her atopic dermatitis using triamcinolone ointment 1%, 30-40 g per week for the first 2 weeks, with a tapered-dosing schedule. No change in diet was recommended except for continued avoidance of egg. At her 1-month follow-up appointment, the patient’s skin symptoms were significantly improved. Physical examination revealed mild hypopigmentation with small focal areas of erythema and mild lichenification in the antecubital fossae and neck, with no exudation or excoriation. Importantly, the patient’s mother reported significantly improved quality of sleep and decreased pruritus. The mother was advised to
AIT DBPCFC FA FLG OIT
Allergy immunotherapy Double-blind placebo-controlled food challenge Food allergy Filaggrin Oral immunotherapy
continue the atopic dermatitis treatment as planned and continue to follow-up with her allergist to monitor for possible outgrowing of the egg allergy. Atopic dermatitis is the most common chronic, relapsing inflammatory skin condition in children worldwide, affecting 5%-20% of pediatric patients.1 It is a complex disease mediated by both genetic and environmental factors arising from dysregulation of the immune system, dysfunction of the epidermal barrier, and inflammation.2 It is characterized by pruritus and skin changes such as xerosis, erosions, and excoriations. Even mild cases can have a profound impact on patient quality of life. Although it has been known for many years that atopic dermatitis and FA are highly associated, the role of FA in the pathogenesis and severity of atopic dermatitis is still a subject of controversy. FAs affect approximately 4%-6% of children and 3%-4% of adults.3,4 The prevalence of FA is significantly higher in those with atopic dermatitis, affecting approximately 15% of these patients.5,6 The most common FAs in this population include egg, milk, peanut, soy, wheat, tree nuts, fish, and shellfish.3,4 FAs are more likely to play a factor in infants and young children with atopic dermatitis and are more common with moderate to severe atopic dermatitis that is refractory to skin care treatment.7 Some children with atopic dermatitis may have eczematous exacerbations with exposure to certain foods.8 Patients with a history of atopic dermatitis are also at higher risk for IgE-sensitization, which may not be associated with clinically relevant FAs, yielding false positive skin prick and specific IgE tests.9,10 These data suggest that although atopic dermatitis and FA are strongly associated, it is difficult to define their relationship.11
Pathogenesis and Risk Factors Several theories exist regarding the role of FAs in the pathogenesis and severity of atopic dermatitis. Major theories support an immune-mediated inflammatory reaction to food allergens causing exacerbation of atopic dermatitis. IgE may contribute to the characteristic inflammation seen in the skin of patients with atopic dermatitis.12 Many patients have elevated serum concentrations of total and foodspecific IgE.12 Studies in mice demonstrated an antigenspecific IgE-mediated activation of basophils, mast cells, and eosinophils in the skin.13 In a study by Sampson et al,
From the 1Department of Dermatology, University of California, San Diego, La Jolla; and Divisions of 2Dermatology and 3Allergy/Immunology, Rady Children’s Hospital, San Diego, CA The authors declare no conflicts of interest. 0022-3476/$ - see front matter. Copyright ª 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jpeds.2015.05.050
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patients with food hypersensitivity as demonstrated by double-blind placebo-controlled food challenge (DBPCFC) that frequently ingested the offending food allergens had higher rate of “spontaneous” basophil histamine release at baseline.14 When the offending food allergen was eliminated from the diet, significantly lower rates of spontaneous basophil histamine release were recorded, along with improvement of atopic dermatitis symptoms. Basophil-mediated inflammation may play a role in both sensitization to FAs and secondary worsening of atopic dermatitis. Other studies show that food allergen-specific T cells may play a role in the pathogenesis of FAs and atopic dermatitis. Systemic contact dermatitis is thought to be a form of delayed-onset, cell-mediated atopic dermatitis and occurs in persons who have been sensitized to a substance through skin contact. Re-exposure by ingestion then causes dermatitis. In fact, primary cutaneous exposure is more sensitizing than primary oral exposure through a distinct Th2 cellmediated immune reaction and may even prevent oral tolerance later in life, leading to the development of IgE-mediated FA.11,15,16 Once sensitized, re-exposure to environmental food allergens through oral ingestion can then worsen skin symptoms.11,17 Studies have also found food allergenspecific T cells in the skin of children with atopic dermatitis.18,19 Sicherer and Sampson showed that elevated levels of food-allergen specific T cells correlate with an increased homing of these T cells to the skin which may influence the pathogenesis of atopic dermatitis.5 There is evidence of a genetic component in the development of FA and atopic dermatitis. Filaggrin (FLG) mutations appear to play a role in the pathogenesis of the atopic march given their association with atopic dermatitis, allergic rhinitis, asthma, and FAs.20 FLG is a skin matrix protein present in the stratum corneum that promotes keratin aggregation and is essential in the regulation of epidermal homeostasis.21 Mutations in FLG can lead to epidermal barrier dysfunction, an increased risk for dry and irritated skin, and are the most recognized genetic risk factor for atopic dermatitis. Even in patients with atopic dermatitis without mutations in FLG, there is a downregulation in expression of this gene.21 Approximately 50% of moderate to severe cases and about 15% of mild to moderate atopic dermatitis are associated with some form of FLG mutation.21 Margolis et al22 performed a longitudinal cohort study on patients with atopic dermatitis with and without FLG mutations and found that those with FLG mutations do not respond to treatment as robustly. This suggests that patients with atopic dermatitis with FLG mutations should be evaluated and treated earlier and more aggressively than those without this mutation. FLG mutations have also been found in children with FAs. Studies by Asai et al23 and Brown et al24 showed that FLG loss of function mutations are associated with peanut allergy even after controlling for occurrence of atopic dermatitis (OR 3.8). FLG mutations are also independently associated with food sensitization without clinical symptoms of FA. FLG is not found in either the respiratory or gastrointestinal system 2
Vol. -, No. and, therefore, the risk for FA might not be attributed to sensitization through these routes. The presence of atopic dermatitis, particularly severe atopic dermatitis, during the first 6 months of life is associated with an increased risk of peanut allergy.11 It is suspected that the epidermal barrier dysfunction caused by FLG mutations allows increased exposure to environmental and food allergens through the skin leading to early sensitization.23 Low-dose cutaneous exposure to food allergens occurs frequently through household surfaces, dust, and hands.25 Repeat exposure to these allergens then causes an immune response that contributes to local inflammation and worsening of the skin barrier defect leading to a flare of atopic dermatitis symptoms.21
Diagnosis of FAs in Atopic Dermatitis The approach to diagnosis of FA in patients with atopic dermatitis consists of a detailed history, including dietary history (or maternal dietary history if breast-fed), tests for sensitization such as skin prick testing and serum food-specific IgE levels, and assessment of the clinical significance of positive tests.4,26 In 2010, the National Institutes of Health and National Institute of Allergy and Infectious Disease sponsored a panel of experts to publish clinical guidelines for diagnosis and management of FA.27 In these guidelines, a FA was defined as “an adverse health effect arising from a specific immune response that occurs reproducibly on exposure to a given food.” The guidelines recommend testing for FA in all children who have experienced an immediate reaction following ingestion of a specific food. Although FA is more prevalent in children with atopic dermatitis, routine screening of all children with atopic dermatitis is not recommended. The expert panel stated that, in individuals without documented or proven FA, avoiding potentially allergenic foods as a means of managing atopic dermatitis is not recommended. The expert panel did suggest that children less than 5 years of age with moderate-to-severe atopic dermatitis should be considered for FA evaluation for milk, egg, peanut, wheat, and soy if: (1) the child has persistent atopic dermatitis in spite of optimized management and topical therapy; and/or (2) the child has a reliable history of an immediate reaction after ingesting specific foods.26,27 Tests for sensitization, such as skin prick testing and serum food-specific IgE levels, are designed to detect the presence of food-specific IgE, a marker of food sensitization.28 Because over 90% of FAs in children are due to milk, egg, peanut, wheat, and soy, the initial approach recommended by the expert panel involves screening for reactions to these common food allergens.27,28 Many patients can have sensitization to a food allergen without development of clinical symptoms, leading to a high false-positive rate to either specific IgE testing or skin prick testing.10 For instance, consider testing for a cow’s milk allergy, where in 1 study skin prick test had a sensitivity of 0.85 and a specificity of 0.75.29 If we estimate the prevalence of milk allergy to be 5% (higher than in most studies, but useful for this exercise), 50 individuals would have true allergy in a population of 1000. With a Nguyen, Leonard, and Eichenfield
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In some studies, FA elimination diets led to improvement in atopic dermatitis skin findings for up to 4 years of follow-up
compared with controls.39 However, the National Institutes of Health expert panel did not recommend avoidance of potentially allergenic foods as a means of managing atopic dermatitis.27 Individuals with atopic dermatitis who appear to have eczematous exacerbations with specific food should undergo allergy testing. With documented FA and atopic dermatitis, it is reasonable to avoid the specific food allergens. As with all individuals with FA, nutritional counseling and regular growth monitoring may be an important part of management. Researchers have examined the role of maternal diet during pregnancy and lactation on the development of atopic disease and food hypersensitivity. Sicherer et al42 showed that maternal consumption of peanuts during pregnancy might increase risk of sensitization in children. Studies examining the use of food elimination diets in mothers during pregnancy and lactation have shown inconsistent results. Although infants of mothers who excluded food allergens such as eggs or milk from their diet had significantly decreased incidence of atopic dermatitis and FA in early life, there was no difference at follow-up at 4 years of age.43-45 Conversely, there has been evidence that maternal peanut exposure during pregnancy may reduce the risk of peanut allergy in children.46,47 Some studies also suggest that maternal food elimination diets have also been associated with lower mean gestational weight gain, lower mean birth weight, and an increased risk for preterm birth.48 The expert panel does not recommend restricting maternal diet during pregnancy or lactation as a strategy for preventing atopic dermatitis or FA at this time.27,49 Even though recommendations in the past included delaying allergenic foods until 1-3 years of age in order to delay or prevent the development of atopic dermatitis and FA, there has been little evidence to support this.50 In fact, there is evolving evidence that early introduction of food allergens, such as peanuts, may increase oral tolerance and prevent the development of FAs in children at high risk for atopic conditions.51,52 Du Toit et al52 demonstrated significantly decreased prevalence of peanut allergy in high-risk infants (those with severe atopic dermatitis or egg allergy) who had early introduction of peanuts in the diet compared with those who avoided peanuts. Early peanut feeding showed an 11%-25% absolute risk reduction of developing peanut allergy with a relative risk reduction of 80%.52 However, it is still unknown how the early introduction of foods influences the onset or course of atopic dermatitis in infants at risk.51,52 Together these data imply that sensitization vs tolerance response occurs at a young age, possibly through both oral and cutaneous paths. Immunotherapy has become a major topic of interest in the last decades for treatment of IgE-mediated diseases. The goal of allergy immunotherapy (AIT) is to induce desensitization through immune tolerance to specific antigens. It is believed that continuous exposure to a specific allergen can lead to eventual desensitization, decreased IgE, and decreased severity of symptoms in affected individuals.53 Currently, oral, sublingual, and epicutaneous routes of immunotherapy
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sensitivity of 0.85, 8 individuals would have false negatives. More significantly, with a specificity of 0.75, testing would lead to 238 false positives, and a potential for false diagnoses of cow’s milk allergy. Thus, the interpretation of FA tests can be quite difficult, limiting its utility as a screening tool for FA in atopic dermatitis. A positive test may be useful but should be interpreted with caution as misdiagnosis of FA based on tests for sensitization can easily occur.30 Negative results, on the other hand, are much more useful in ruling out FAs.31,32 The gold standard diagnostic test for FA is the DBPCFC.4 Sampson et al5,33 performed hundreds of DBPCFCs to identify causal food allergens in children with atopic dermatitis, finding approximately 40% of the challenges resulting in allergic reactions. Although DBPCFCs are highly effective in identifying true FAs in patients with atopic dermatitis, they can be very tedious and are not easily performed, limiting their utility in clinical practice. More typical are open oral food challenges done in the office that are performed if risk of reaction is assessed to be low; emergency medications must still be available in case of reaction.34 Testing for late reactions to food is less straightforward because symptoms may be delayed and can appear hours after the food challenge has ended. Food diaries may be useful in some cases to identify foods in the diet that may be affecting atopic dermatitis, but families’ abilities to predict FAs are limited.27
Prognosis and Long-Term Outcome Atopic dermatitis is usually thought of as a disease of childhood, and symptoms typically improve with age.35 Rystedt36 performed a long-term follow-up study (minimum 24 years) and found that approximately 60% of patients with childhood atopic dermatitis were free from symptoms by adolescence, although recurrences or flares did occur. Individuals with FLG mutations are more likely to have persistence of disease.22 Similarly, FAs in children can resolve with age. Most children tolerate milk, egg, soy, and wheat by adolescence.37 In 1 study, those with atopic dermatitis as their sole FA symptom were among the most likely to outgrow their FA with time.38 Sampson and Scanlon performed a study on children with atopic dermatitis and FA placed on food elimination diets. On food re-challenge, 25% of the patients lost all signs of clinical food hypersensitivity after 1 year, and an additional 11% were no longer hypersensitive after 2 years.39 In another study, approximately one-half of children with atopic dermatitis and FA no longer exhibited clinical symptoms in response to a food challenge after 12 years.40 Therefore, patients on food elimination diets should be intermittently re-challenged to determine whether a food hypersensitivity is still present, unless there is a history of a severe food-induced anaphylaxis or a reaction within the past year.5,41
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exist. Studies have shown that oral immunotherapy (OIT) can desensitize children to food allergens such as peanut, egg, and milk. However, side effects including gastrointestinal symptoms, lack of standardization, and its time consuming nature have limited its practical application.54 Also, rare, severe reactions including anaphylaxis have occurred with OIT as well. Sublingual and epicutaneous immunotherapy have improved safety profiles compared to OIT and are able to induce desensitization in affected children. However, data suggests that these methods of immunotherapy may not be as efficacious as OIT.54 There is some evidence that AIT has the potential to improve atopic dermatitis severity compared with placebo or pharmacotherapy in regards to environmental allergens.55,56 Unfortunately, no studies exist to date on the use of AIT for FA-associated atopic flares. More research needs to be performed on the use of AIT for treatment of FA-related atopic dermatitis, but this could be a useful treatment alternative in a subset of patients with atopic dermatitis. n Submitted for publication Mar 12, 2015; last revision received Apr 13, 2015; accepted May 26, 2015. Reprint requests: Lawrence F. Eichenfield, MD, Division of Dermatology, Rady Children’s Hospital, Suite 602, 8010 Frost St, San Diego, CA 92123-4204. E-mail: [email protected]
References 1. Williams H, Robertson C, Stewart A, Ait-Khaled N, Anabwani G, Anderson R, et al. Worldwide variations in the prevalence of symptoms of atopic eczema in the International Study of Asthma and Allergies in Childhood. J Allergy Clin Immunol 1999;103:125-38. 2. Mao W, Mao J, Zhang J, Wang L, Cao D, Qu Y. Atopic eczema: a disease modulated by gene and environment. Front Biosci (Landmark Ed) 2014; 19:707-17. 3. Sicherer SH, Sampson HA. Food allergy: epidemiology, pathogenesis, diagnosis, and treatment. J Allergy Clin Immunol 2014;133:291-307. quiz 8. 4. Forbes LR, Saltzman RW, Spergel JM. Food allergies and atopic dermatitis: differentiating myth from reality. Pediatr Ann 2009;38:84-90. 5. Sicherer SH, Sampson HA. Food hypersensitivity and atopic dermatitis: pathophysiology, epidemiology, diagnosis, and management. J Allergy Clin Immunol 1999;104:S114-22. 6. Silverberg JI, Simpson EL. Association between severe eczema in children and multiple comorbid conditions and increased healthcare utilization. Pediatr Allergy Immunol 2013;24:476-86. 7. Zheng T, Yu J, Oh MH, Zhu Z. The atopic march: progression from atopic dermatitis to allergic rhinitis and asthma. Allergy Asthma Immunol Res 2011;3:67-73. 8. Werfel T, Breuer K. Role of food allergy in atopic dermatitis. Curr Opin Allergy Clin Immunol 2004;4:379-85. 9. Shaker M. New insights into the allergic march. Curr Opin Pediatr 2014; 26:516-20. 10. Bird JA, Crain M, Varshney P. Food allergen panel testing often results in misdiagnosis of food allergy. J Pediatr 2015;166:97-100. 11. Lack G. Epidemiologic risks for food allergy. J Allergy Clin Immunol 2008;121:1331-6. 12. Johnson EE, Irons JS, Patterson R, Roberts M. Serum IgE concentration in atopic dermatitis. Relationship to severity of disease and presence of atopic respiratory disease. J Allergy Clin Immunol 1974;54: 94-9. 13. Liu FT, Goodarzi H, Chen HY. IgE, mast cells, and eosinophils in atopic dermatitis. Clin Rev Allergy Immunol 2011;41:298-310. 4
Vol. -, No. 14. Sampson HA, Broadbent KR, Bernhisel-Broadbent J. Spontaneous release of histamine from basophils and histamine-releasing factor in patients with atopic dermatitis and food hypersensitivity. N Engl J Med 1989;321:228-32. 15. Noti M, Kim BS, Siracusa MC, Rak GD, Kubo M, Moghaddam AE, et al. Exposure to food allergens through inflamed skin promotes intestinal food allergy through the thymic stromal lymphopoietin-basophil axis. J Allergy Clin Immunol 2014;133:1390-9. 9.e1-6. 16. Strid J, Hourihane J, Kimber I, Callard R, Strobel S. Epicutaneous exposure to peanut protein prevents oral tolerance and enhances allergic sensitization. Clin Exp Allergy 2005;35:757-66. 17. Tordesillas L, Goswami R, Benede S, Grishina G, Dunkin D, Jarvinen KM, et al. Skin exposure promotes a Th2-dependent sensitization to peanut allergens. J Clin Invest 2014;124:4965-75. 18. Reekers R, Beyer K, Niggemann B, Wahn U, Freihorst J, Kapp A, et al. The role of circulating food antigen-specific lymphocytes in food allergic children with atopic dermatitis. Br J Dermatol 1996;135:935-41. 19. van Reijsen FC, Bruijnzeel-Koomen CA, Kalthoff FS, Maggi E, Romagnani S, Westland JK, et al. Skin-derived aeroallergen-specific Tcell clones of Th2 phenotype in patients with atopic dermatitis. J Allergy Clin Immunol 1992;90:184-93. 20. Barnes KC. An update on the genetics of atopic dermatitis: scratching the surface in 2009. J Allergy Clin Immunol 2010;125:16-29.e1-11. quiz 30-1. 21. McAleer MA, Irvine AD. The multifunctional role of filaggrin in allergic skin disease. J Allergy Clin Immunol 2013;131:280-91. 22. Margolis DJ, Apter AJ, Gupta J, Hoffstad O, Papadopoulos M, Campbell LE, et al. The persistence of atopic dermatitis and filaggrin (FLG) mutations in a US longitudinal cohort. J Allergy Clin Immunol 2012;130:912-7. 23. Asai Y, Greenwood C, Hull PR, Alizadehfar R, Ben-Shoshan M, Brown SJ, et al. Filaggrin gene mutation associations with peanut allergy persist despite variations in peanut allergy diagnostic criteria or asthma status. J Allergy Clin Immunol 2013;132:239-42. 24. Brown SJ, Sandilands A, Zhao Y, Liao H, Relton CL, Meggitt SJ, et al. Prevalent and low-frequency null mutations in the filaggrin gene are associated with early-onset and persistent atopic eczema. J Invest Dermatol 2008;128:1591-4. 25. Brough HA, Makinson K, Penagos M, Maleki SJ, Cheng H, Douiri A, et al. Distribution of peanut protein in the home environment. J Allergy Clin Immunol 2013;132:623-9. 26. Sidbury R, Tom WL, Bergman JN, Cooper KD, Silverman RA, Berger TG, et al. Guidelines of care for the management of atopic dermatitis: section 4. Prevention of disease flares and use of adjunctive therapies and approaches. J Am Acad Dermatol 2014;71:1218-33. 27. Boyce JA, Assa’ad A, Burks AW, Jones SM, Sampson HA, Wood RA, et al. Guidelines for the diagnosis and management of food allergy in the United States: summary of the NIAID-Sponsored Expert Panel report. J Am Acad Dermatol 2011;64:175-92. 28. Du Toit G, Santos A, Roberts G, Fox AT, Smith P, Lack G. The diagnosis of IgE-mediated food allergy in childhood. Pediatr Allergy Immunol 2009;20:309-19. 29. Mehl A, Rolinck-Werninghaus C, Staden U, Verstege A, Wahn U, Beyer K, et al. The atopy patch test in the diagnostic workup of suspected food-related symptoms in children. J Allergy Clin Immunol 2006;118: 923-9. 30. Fleischer DM, Burks AW. Pitfalls in food allergy diagnosis: serum IgE testing. J Pediatr 2015;166:8-10. 31. Sampson HA, Albergo R. Comparison of results of skin tests, RAST, and double-blind, placebo-controlled food challenges in children with atopic dermatitis. J Allergy Clin Immunol 1984;74:26-33. 32. Bock SA, Buckley J, Holst A, May CD. Proper use of skin tests with food extracts in diagnosis of hypersensitivity to food in children. Clin Allergy 1977;7:375-83. 33. Sampson HA, McCaskill CC. Food hypersensitivity and atopic dermatitis: evaluation of 113 patients. J Pediatr 1985;107:669-75. 34. Fleischer DM, Bock SA, Spears GC, Wilson CG, Miyazawa NK, Gleason MC, et al. Oral food challenges in children with a diagnosis of food allergy. J Pediatr 2011;158:578-83.e1.
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- 2015 35. Rudikoff D, Lebwohl M. Atopic dermatitis. Lancet 1998;351:1715-21. 36. Rystedt I. Long term follow-up in atopic dermatitis. Acta Derm Venereol Suppl (Stockh) 1985;114:117-20. 37. Eigenmann PA. Mechanisms of food allergy. Pediatr Allergy Immunol 2009;20:5-11. 38. Gupta RS, Lau CH, Sita EE, Smith B, Greenhawt MJ. Factors associated with reported food allergy tolerance among US children. Ann Allergy Asthma Immunol 2013;111:194-8.e4. 39. Sampson HA, Scanlon SM. Natural history of food hypersensitivity in children with atopic dermatitis. J Pediatr 1989;115:23-7. 40. Sampson HA. The immunopathogenic role of food hypersensitivity in atopic dermatitis. Acta Derm Venereol Suppl (Stockh) 1992;176:34-7. 41. Sampson HA. Utility of food-specific IgE concentrations in predicting symptomatic food allergy. J Allergy Clin Immunol 2001;107:891-6. 42. Sicherer SH, Wood RA, Stablein D, Lindblad R, Burks AW, Liu AH, et al. Maternal consumption of peanut during pregnancy is associated with peanut sensitization in atopic infants. J Allergy Clin Immunol 2010;126:1191-7. 43. Hattevig G, Kjellman B, Sigurs N, Bjorksten B, Kjellman NI. Effect of maternal avoidance of eggs, cow’s milk and fish during lactation upon allergic manifestations in infants. Clin Exp Allergy 1989;19:27-32. 44. Jirapinyo P, Densupsoontorn N, Kangwanpornsiri C, Limlikhit T. Lower prevalence of atopic dermatitis in breast-fed infants whose allergic mothers restrict dairy products. J Med Assoc Thai 2013;96:192-5. 45. Sigurs N, Hattevig G, Kjellman B. Maternal avoidance of eggs, cow’s milk, and fish during lactation: effect on allergic manifestations, skinprick tests, and specific IgE antibodies in children at age 4 years. Pediatrics 1992;89:735-9. 46. Lopez-Exposito I, Song Y, Jarvinen KM, Srivastava K, Li XM. Maternal peanut exposure during pregnancy and lactation reduces peanut allergy risk in offspring. J Allergy Clin Immunol 2009;124:1039-46. 47. Lopez-Exposito I, Jarvinen KM, Castillo A, Seppo AE, Song Y, Li XM. Maternal peanut consumption provides protection in offspring against
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48. 49. 50. 51. 52. 53.
54. 55. 56.
peanut sensitization that is further enhanced when co-administered with bacterial mucosal adjuvant. Food Res Int 2011;44:1649-56. Kramer MS, Kakuma R. Maternal dietary antigen avoidance during pregnancy or lactation, or both, for preventing or treating atopic disease in the child. Evid Based Child Health 2014;9:447-83. Fleischer DM, Spergel JM, Assa’ad AH, Pongracic JA. Primary prevention of allergic disease through nutritional interventions. J Allergy Clin Immunol Pract 2013;1:29-36. Thygarajan A, Burks AW. American Academy of Pediatrics recommendations on the effects of early nutritional interventions on the development of atopic disease. Curr Opin Pediatr 2008;20:698-702. Du Toit G, Katz Y, Sasieni P, Mesher D, Maleki SJ, Fisher HR, et al. Early consumption of peanuts in infancy is associated with a low prevalence of peanut allergy. J Allergy Clin Immunol 2008;122:984-91. Du Toit G, Roberts G, Sayre PH, Bahnson HT, Radulovic S, Santos AF, et al. Randomized trial of peanut consumption in infants at risk for peanut allergy. N Engl J Med 2015;372:803-13. Burks AW, Calderon MA, Casale T, Cox L, Demoly P, Jutel M, et al. Update on allergy immunotherapy: American Academy of Allergy, Asthma and Immunology/European Academy of Allergy and Clinical Immunology/PRACTALL consensus report. J Allergy Clin Immunol 2013; 131:1288-96.e3. Jones SM, Burks AW, Dupont C. State of the art on food allergen immunotherapy: oral, sublingual, and epicutaneous. J Allergy Clin Immunol 2014;133:318-23. Compalati E, Rogkakou A, Passalacqua G, Canonica GW. Evidences of efficacy of allergen immunotherapy in atopic dermatitis: an updated review. Curr Opin Allergy Clin Immunol 2012;12:427-33. Bae JM, Choi YY, Park CO, Chung KY, Lee KH. Efficacy of allergenspecific immunotherapy for atopic dermatitis: a systematic review and meta-analysis of randomized controlled trials. J Allergy Clin Immunol 2013;132:110-7.
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n otherwise healthy 15-month-old female presented to Pediatric Dermatology for evaluation and management of moderate atopic dermatitis since 4 months of age. The patient had eczematous dermatitis with a waxing and waning course, with significant pruritus, sleep disturbance, and no symptom-free periods. The family had previously been instructed to use a combination of daily moisturizers with hydrocortisone 2.5% ointment during flares, but because of concerns about steroid side effects used only very small quantities of prescription medication. At 8 months and while exclusively being breastfed, the patient was evaluated by an allergist. Mother had noticed that when she ingested large amounts of egg, the infant’s eczema would flare. When she removed egg from her diet, the eczema improved but did not resolve. Skin testing was performed on the child and was positive to egg and negative to milk and peanut. Serum IgE food allergy (FA) testing at 14 months was positive to milk, wheat, and tree nuts; however, the child ingested wheat and tree nuts regularly without any noted symptoms. The family limited the patient’s dairy intake because of concerns that it exacerbated the dermatitis but did not see significant improvement. Physical examination was significant for diffuse eczematous plaques with lichenification and moderate thickening on the neck and upper and lower extremities favoring the antecubital and popliteal fossae. Scattered erythematous, edematous plaques, and excoriations were also present diffusely. Approximately 30% of the body surface area was involved. The diagnosis of atopic dermatitis was reviewed in detail including clinical course, treatment options, and possible triggers and trigger avoidance. The role of FAs and potential false positive food-specific IgE testing were discussed in detail, and the patient was started on a treatment plan to control her atopic dermatitis using triamcinolone ointment 1%, 30-40 g per week for the first 2 weeks, with a tapered-dosing schedule. No change in diet was recommended except for continued avoidance of egg. At her 1-month follow-up appointment, the patient’s skin symptoms were significantly improved. Physical examination revealed mild hypopigmentation with small focal areas of erythema and mild lichenification in the antecubital fossae and neck, with no exudation or excoriation. Importantly, the patient’s mother reported significantly improved quality of sleep and decreased pruritus. The mother was advised to
AIT DBPCFC FA FLG OIT
Allergy immunotherapy Double-blind placebo-controlled food challenge Food allergy Filaggrin Oral immunotherapy
continue the atopic dermatitis treatment as planned and continue to follow-up with her allergist to monitor for possible outgrowing of the egg allergy. Atopic dermatitis is the most common chronic, relapsing inflammatory skin condition in children worldwide, affecting 5%-20% of pediatric patients.1 It is a complex disease mediated by both genetic and environmental factors arising from dysregulation of the immune system, dysfunction of the epidermal barrier, and inflammation.2 It is characterized by pruritus and skin changes such as xerosis, erosions, and excoriations. Even mild cases can have a profound impact on patient quality of life. Although it has been known for many years that atopic dermatitis and FA are highly associated, the role of FA in the pathogenesis and severity of atopic dermatitis is still a subject of controversy. FAs affect approximately 4%-6% of children and 3%-4% of adults.3,4 The prevalence of FA is significantly higher in those with atopic dermatitis, affecting approximately 15% of these patients.5,6 The most common FAs in this population include egg, milk, peanut, soy, wheat, tree nuts, fish, and shellfish.3,4 FAs are more likely to play a factor in infants and young children with atopic dermatitis and are more common with moderate to severe atopic dermatitis that is refractory to skin care treatment.7 Some children with atopic dermatitis may have eczematous exacerbations with exposure to certain foods.8 Patients with a history of atopic dermatitis are also at higher risk for IgE-sensitization, which may not be associated with clinically relevant FAs, yielding false positive skin prick and specific IgE tests.9,10 These data suggest that although atopic dermatitis and FA are strongly associated, it is difficult to define their relationship.11
Pathogenesis and Risk Factors Several theories exist regarding the role of FAs in the pathogenesis and severity of atopic dermatitis. Major theories support an immune-mediated inflammatory reaction to food allergens causing exacerbation of atopic dermatitis. IgE may contribute to the characteristic inflammation seen in the skin of patients with atopic dermatitis.12 Many patients have elevated serum concentrations of total and foodspecific IgE.12 Studies in mice demonstrated an antigenspecific IgE-mediated activation of basophils, mast cells, and eosinophils in the skin.13 In a study by Sampson et al,
From the 1Department of Dermatology, University of California, San Diego, La Jolla; and Divisions of 2Dermatology and 3Allergy/Immunology, Rady Children’s Hospital, San Diego, CA The authors declare no conflicts of interest. 0022-3476/$ - see front matter. Copyright ª 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jpeds.2015.05.050
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patients with food hypersensitivity as demonstrated by double-blind placebo-controlled food challenge (DBPCFC) that frequently ingested the offending food allergens had higher rate of “spontaneous” basophil histamine release at baseline.14 When the offending food allergen was eliminated from the diet, significantly lower rates of spontaneous basophil histamine release were recorded, along with improvement of atopic dermatitis symptoms. Basophil-mediated inflammation may play a role in both sensitization to FAs and secondary worsening of atopic dermatitis. Other studies show that food allergen-specific T cells may play a role in the pathogenesis of FAs and atopic dermatitis. Systemic contact dermatitis is thought to be a form of delayed-onset, cell-mediated atopic dermatitis and occurs in persons who have been sensitized to a substance through skin contact. Re-exposure by ingestion then causes dermatitis. In fact, primary cutaneous exposure is more sensitizing than primary oral exposure through a distinct Th2 cellmediated immune reaction and may even prevent oral tolerance later in life, leading to the development of IgE-mediated FA.11,15,16 Once sensitized, re-exposure to environmental food allergens through oral ingestion can then worsen skin symptoms.11,17 Studies have also found food allergenspecific T cells in the skin of children with atopic dermatitis.18,19 Sicherer and Sampson showed that elevated levels of food-allergen specific T cells correlate with an increased homing of these T cells to the skin which may influence the pathogenesis of atopic dermatitis.5 There is evidence of a genetic component in the development of FA and atopic dermatitis. Filaggrin (FLG) mutations appear to play a role in the pathogenesis of the atopic march given their association with atopic dermatitis, allergic rhinitis, asthma, and FAs.20 FLG is a skin matrix protein present in the stratum corneum that promotes keratin aggregation and is essential in the regulation of epidermal homeostasis.21 Mutations in FLG can lead to epidermal barrier dysfunction, an increased risk for dry and irritated skin, and are the most recognized genetic risk factor for atopic dermatitis. Even in patients with atopic dermatitis without mutations in FLG, there is a downregulation in expression of this gene.21 Approximately 50% of moderate to severe cases and about 15% of mild to moderate atopic dermatitis are associated with some form of FLG mutation.21 Margolis et al22 performed a longitudinal cohort study on patients with atopic dermatitis with and without FLG mutations and found that those with FLG mutations do not respond to treatment as robustly. This suggests that patients with atopic dermatitis with FLG mutations should be evaluated and treated earlier and more aggressively than those without this mutation. FLG mutations have also been found in children with FAs. Studies by Asai et al23 and Brown et al24 showed that FLG loss of function mutations are associated with peanut allergy even after controlling for occurrence of atopic dermatitis (OR 3.8). FLG mutations are also independently associated with food sensitization without clinical symptoms of FA. FLG is not found in either the respiratory or gastrointestinal system 2
Vol. -, No. and, therefore, the risk for FA might not be attributed to sensitization through these routes. The presence of atopic dermatitis, particularly severe atopic dermatitis, during the first 6 months of life is associated with an increased risk of peanut allergy.11 It is suspected that the epidermal barrier dysfunction caused by FLG mutations allows increased exposure to environmental and food allergens through the skin leading to early sensitization.23 Low-dose cutaneous exposure to food allergens occurs frequently through household surfaces, dust, and hands.25 Repeat exposure to these allergens then causes an immune response that contributes to local inflammation and worsening of the skin barrier defect leading to a flare of atopic dermatitis symptoms.21
Diagnosis of FAs in Atopic Dermatitis The approach to diagnosis of FA in patients with atopic dermatitis consists of a detailed history, including dietary history (or maternal dietary history if breast-fed), tests for sensitization such as skin prick testing and serum food-specific IgE levels, and assessment of the clinical significance of positive tests.4,26 In 2010, the National Institutes of Health and National Institute of Allergy and Infectious Disease sponsored a panel of experts to publish clinical guidelines for diagnosis and management of FA.27 In these guidelines, a FA was defined as “an adverse health effect arising from a specific immune response that occurs reproducibly on exposure to a given food.” The guidelines recommend testing for FA in all children who have experienced an immediate reaction following ingestion of a specific food. Although FA is more prevalent in children with atopic dermatitis, routine screening of all children with atopic dermatitis is not recommended. The expert panel stated that, in individuals without documented or proven FA, avoiding potentially allergenic foods as a means of managing atopic dermatitis is not recommended. The expert panel did suggest that children less than 5 years of age with moderate-to-severe atopic dermatitis should be considered for FA evaluation for milk, egg, peanut, wheat, and soy if: (1) the child has persistent atopic dermatitis in spite of optimized management and topical therapy; and/or (2) the child has a reliable history of an immediate reaction after ingesting specific foods.26,27 Tests for sensitization, such as skin prick testing and serum food-specific IgE levels, are designed to detect the presence of food-specific IgE, a marker of food sensitization.28 Because over 90% of FAs in children are due to milk, egg, peanut, wheat, and soy, the initial approach recommended by the expert panel involves screening for reactions to these common food allergens.27,28 Many patients can have sensitization to a food allergen without development of clinical symptoms, leading to a high false-positive rate to either specific IgE testing or skin prick testing.10 For instance, consider testing for a cow’s milk allergy, where in 1 study skin prick test had a sensitivity of 0.85 and a specificity of 0.75.29 If we estimate the prevalence of milk allergy to be 5% (higher than in most studies, but useful for this exercise), 50 individuals would have true allergy in a population of 1000. With a Nguyen, Leonard, and Eichenfield
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In some studies, FA elimination diets led to improvement in atopic dermatitis skin findings for up to 4 years of follow-up
compared with controls.39 However, the National Institutes of Health expert panel did not recommend avoidance of potentially allergenic foods as a means of managing atopic dermatitis.27 Individuals with atopic dermatitis who appear to have eczematous exacerbations with specific food should undergo allergy testing. With documented FA and atopic dermatitis, it is reasonable to avoid the specific food allergens. As with all individuals with FA, nutritional counseling and regular growth monitoring may be an important part of management. Researchers have examined the role of maternal diet during pregnancy and lactation on the development of atopic disease and food hypersensitivity. Sicherer et al42 showed that maternal consumption of peanuts during pregnancy might increase risk of sensitization in children. Studies examining the use of food elimination diets in mothers during pregnancy and lactation have shown inconsistent results. Although infants of mothers who excluded food allergens such as eggs or milk from their diet had significantly decreased incidence of atopic dermatitis and FA in early life, there was no difference at follow-up at 4 years of age.43-45 Conversely, there has been evidence that maternal peanut exposure during pregnancy may reduce the risk of peanut allergy in children.46,47 Some studies also suggest that maternal food elimination diets have also been associated with lower mean gestational weight gain, lower mean birth weight, and an increased risk for preterm birth.48 The expert panel does not recommend restricting maternal diet during pregnancy or lactation as a strategy for preventing atopic dermatitis or FA at this time.27,49 Even though recommendations in the past included delaying allergenic foods until 1-3 years of age in order to delay or prevent the development of atopic dermatitis and FA, there has been little evidence to support this.50 In fact, there is evolving evidence that early introduction of food allergens, such as peanuts, may increase oral tolerance and prevent the development of FAs in children at high risk for atopic conditions.51,52 Du Toit et al52 demonstrated significantly decreased prevalence of peanut allergy in high-risk infants (those with severe atopic dermatitis or egg allergy) who had early introduction of peanuts in the diet compared with those who avoided peanuts. Early peanut feeding showed an 11%-25% absolute risk reduction of developing peanut allergy with a relative risk reduction of 80%.52 However, it is still unknown how the early introduction of foods influences the onset or course of atopic dermatitis in infants at risk.51,52 Together these data imply that sensitization vs tolerance response occurs at a young age, possibly through both oral and cutaneous paths. Immunotherapy has become a major topic of interest in the last decades for treatment of IgE-mediated diseases. The goal of allergy immunotherapy (AIT) is to induce desensitization through immune tolerance to specific antigens. It is believed that continuous exposure to a specific allergen can lead to eventual desensitization, decreased IgE, and decreased severity of symptoms in affected individuals.53 Currently, oral, sublingual, and epicutaneous routes of immunotherapy
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sensitivity of 0.85, 8 individuals would have false negatives. More significantly, with a specificity of 0.75, testing would lead to 238 false positives, and a potential for false diagnoses of cow’s milk allergy. Thus, the interpretation of FA tests can be quite difficult, limiting its utility as a screening tool for FA in atopic dermatitis. A positive test may be useful but should be interpreted with caution as misdiagnosis of FA based on tests for sensitization can easily occur.30 Negative results, on the other hand, are much more useful in ruling out FAs.31,32 The gold standard diagnostic test for FA is the DBPCFC.4 Sampson et al5,33 performed hundreds of DBPCFCs to identify causal food allergens in children with atopic dermatitis, finding approximately 40% of the challenges resulting in allergic reactions. Although DBPCFCs are highly effective in identifying true FAs in patients with atopic dermatitis, they can be very tedious and are not easily performed, limiting their utility in clinical practice. More typical are open oral food challenges done in the office that are performed if risk of reaction is assessed to be low; emergency medications must still be available in case of reaction.34 Testing for late reactions to food is less straightforward because symptoms may be delayed and can appear hours after the food challenge has ended. Food diaries may be useful in some cases to identify foods in the diet that may be affecting atopic dermatitis, but families’ abilities to predict FAs are limited.27
Prognosis and Long-Term Outcome Atopic dermatitis is usually thought of as a disease of childhood, and symptoms typically improve with age.35 Rystedt36 performed a long-term follow-up study (minimum 24 years) and found that approximately 60% of patients with childhood atopic dermatitis were free from symptoms by adolescence, although recurrences or flares did occur. Individuals with FLG mutations are more likely to have persistence of disease.22 Similarly, FAs in children can resolve with age. Most children tolerate milk, egg, soy, and wheat by adolescence.37 In 1 study, those with atopic dermatitis as their sole FA symptom were among the most likely to outgrow their FA with time.38 Sampson and Scanlon performed a study on children with atopic dermatitis and FA placed on food elimination diets. On food re-challenge, 25% of the patients lost all signs of clinical food hypersensitivity after 1 year, and an additional 11% were no longer hypersensitive after 2 years.39 In another study, approximately one-half of children with atopic dermatitis and FA no longer exhibited clinical symptoms in response to a food challenge after 12 years.40 Therefore, patients on food elimination diets should be intermittently re-challenged to determine whether a food hypersensitivity is still present, unless there is a history of a severe food-induced anaphylaxis or a reaction within the past year.5,41
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exist. Studies have shown that oral immunotherapy (OIT) can desensitize children to food allergens such as peanut, egg, and milk. However, side effects including gastrointestinal symptoms, lack of standardization, and its time consuming nature have limited its practical application.54 Also, rare, severe reactions including anaphylaxis have occurred with OIT as well. Sublingual and epicutaneous immunotherapy have improved safety profiles compared to OIT and are able to induce desensitization in affected children. However, data suggests that these methods of immunotherapy may not be as efficacious as OIT.54 There is some evidence that AIT has the potential to improve atopic dermatitis severity compared with placebo or pharmacotherapy in regards to environmental allergens.55,56 Unfortunately, no studies exist to date on the use of AIT for FA-associated atopic flares. More research needs to be performed on the use of AIT for treatment of FA-related atopic dermatitis, but this could be a useful treatment alternative in a subset of patients with atopic dermatitis. n Submitted for publication Mar 12, 2015; last revision received Apr 13, 2015; accepted May 26, 2015. Reprint requests: Lawrence F. Eichenfield, MD, Division of Dermatology, Rady Children’s Hospital, Suite 602, 8010 Frost St, San Diego, CA 92123-4204. E-mail: [email protected]
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