The role of food allergy in atopic dermatitis

Matthew Greenhawt, M.D., M.B.A.

ABSTRACT

Atopic dermatitis (AD) affects 10% of children. Food allergy is a known provoking cause of AD in a subset of affectedchildren. A literature search of PubMed and Medline was conducted to review the epidemiology and pathophysiology of AD,with special focus on the role of food allergy in the development of AD, its management, and its long-term preventive strategies.A literature search of PubMed and Medline was conducted. Food allergens readily provoke AD in 35% of patients, as proventhrough double-blind placebo-controlled food challenge studies. Milk, egg, wheat, soy, and peanut account for 75% of the casesof food-induced AD. However, the positive predictive values of the parental history, skin-prick tests, or serum tests for detectingfood-specific IgE are low, making these unsuitable for use as single diagnostic modalities. Therefore, the use of a food challengetest is very helpful in objectively confirming the history or positive tests. Elimination diets are often helpful in challenge-provencases, but care must be taken to evaluate the nutritional status of the child. There are few effective long-term strategies toprevent the development of food allergeninduced AD. Early onset of AD has been shown to be a risk factor for the developmentof other allergic diseases, including other food allergy/sensitization, as part of the atopic march. Treatment of other causes ofAD, such as barrier dysfunction and cutaneous infection, are of equal importance to food allergen avoidance. Food allergy isan important provoking cause of AD, but it is only relevant in 35% of affected individuals.

(Allergy Asthma Proc 31:392397, 2010; doi: 10.2500/aap.2010.31.3393)

Atopic dermatitis (AD) is a chronic relapsing in-flammatory skin disease commonly associatedwith atopy. It affects up to 10% of children.1,2 Thecharacteristic rash in AD has a typical distribution,found in the antecubital and popliteal fossas, wristcreases, scalp, eyelids, and flexor surfaces. AD is fre-quently the initial manifestation of atopy and oftenaffects very young children early within the 1st year oflife. Many children who develop AD go on to developother allergic diseases such as food allergy, asthma, orallergic rhinitis (the atopic march).3 The clinical fea-tures of AD are well described and include, pruritus, arelapsing eczematous rash typically found over flexorsurfaces, and a personal history of atopy. Minor fea-tures include elevated serum IgE, cutaneous skin in-fection (Staphylococcus, Streptococcus, or fungus); Den-nie-Morgan lines, keratoconus, allergic shiners, whitedermatographism, ichthyosis, nonspecific hand/food

dermatitis, and cheilitis.2 The purpose of this article isto review the epidemiology, pathophysiology, and im-munobiology of AD and to discuss the specific role offood allergy in the development AD, its management,and long-term preventive strategies.

PREVALENCEMost studies suggest that the prevalence of AD is

high and the incidence is increasing, which may mirrorthe overall increase in atopy among the population. Alarge Danish twin concordance study found that therates increased from 3% between 1960 and 1964 to 7%between 1975 and 1979.4 A 1992 European cross-sec-tional study confirmed a prevalence rate of 15.6%.5 Asimilar study of U.S. children aged 59 years found arate of 17%.6 Two studies from Japan found an 11.2%point prevalence of AD in 1st graders and 6th gradersand a rate of 24% among children aged 56 years.7,8

Theories to explain the rise in AD include a decrease inthe amount of children who are exclusively breast-fed,an overall increased awareness of AD, increased expo-sure to air pollution, and increased exposure to aller-gens.9,10

THE ROLE OF IgE AND CYTOKINEIMMUNOBIOLOGY IN AD

Two distinct subtypes of AD have been identified.The extrinsic subtype is associated with elevated se-rum IgE levels in up to 80% of affected patients,whereas the intrinsic subtype lacks this and also is notassociated with allergen sensitization.9,11 Both sub-types are associated with peripheral eosinophilia.12

From the University of Michigan Food Allergy Center, Division of Allergy andClinical Immunology, The University of Michigan Medical School, The University ofMichigan Health Systems, Ann Arbor, MichiganPresented at the Eastern Allergy Conference, Palm Beach Florida, May 7, 2010Received nonfinancial research support from the Food Allergy & Anaphylaxis NetworkDisclosures/Conflicts: The author had nothing pertinent to this reviewM. Greenhawt received speaking honorarium from Phadia, is a member of the medicaladvisory team for Kids With Food Allergies, and is a member of speakers bureau forNutricia and SepracorAddress correspondence and reprint requests to Matthew Greenhawt, M.D., M.B.A.,The University of Michigan Food Allergy Center, Division of Allergy and ClinicalImmunology, The University of Michigan Medical School, The University of Michi-gan Health Systems, 24 Frank Lloyd Wright Drive, Lobby H-2100, Box 442, AnnArbor, MI 48106E-mail address: mgreenha@med.umich.eduCopyright 2010, OceanSide Publications, Inc., U.S.A.

392

DO N

OT C

OPY

IgE-mediated responses in AD provoke pruritus, ery-thema, and mediator release from mast cells.9 Cyclicadenosine monophosphatephosphodiesterase expres-sion in leukocytes taken from patients afflicted withAD is overactive, which contributes to increased IgEproduction and increased IL-4 secretion.13 Similarly,increased CD86 expression on B cells of patients withAD compared with controls also promotes increasedIgE production.14 There is increased expression ofhigh-affinity IgE receptor (FcR-1) on Langerhans cellsand inflammatory dendritic epidermal cells, resultingfrom increased FcR-1 -chain synthesis.15 Both celltypes are highly effective at antigen presentation andare highly efficient at activating TH2 cells and inducingfurther T-cell proliferation specific to particular anti-gen.16 Inflammatory dendritic epidermal cell stimula-tion through FcR-1 promotes more TH1 cytokine re-lease, as opposed to FcR-1 stimulation on Langerhanscells.17

Although food allergy is usually a type I hypersen-sitivity, involving IgE, AD is a mixed IgE and cellular-mediated event, with a mechanism mediated throughT cells. However, the cytokine profile expressed bythese T cells in acute AD is characterized by IL-4,IL-5, and IL-13, a TH2 milieu similar to that seen inIgE-mediated reactions.1,18 T-cell cytokine expres-sion more characteristic of delayed-type hypersensi-tivity involves interferon and IL-2.19,20 Several stud-ies have shown a link between food ingestion,symptom development, and release of specific cellularmarkers that are elevated in patients with AD. Samp-son noted that children with AD and food-specific IgEundergoing challenge to that food had a detectableelevation of plasma histamine levels compared withcontrol patients.21 He later showed that chronic inges-tion of allergenic foods was associated with higherspontaneous basophil histamine release in cell culturesof patients with AD compared with controls.22 Suoma-lainen and Magnarin showed increased eosinophilgranule release in AD patients undergoing food chal-lenge and food-induced symptoms correlated toplasma eosinophil activation in these patients.23,24 Arecent Korean study suggested that elevated periph-eral eosinophil counts may aid as a predictive tool inthe evaluation of patients with AD triggered by foodallergy, and showed a significant decrease in the eo-sinophilia after following a milk elimination diet inpatients with milk-triggered AD.25 Several groupshave described food-specific T cells reactive to casein,ovalbumin, and peanut in serum of patient withfood-induced AD.26 29 Food-specific T cells havebeen cloned from both affected and normal skin ofpatients with AD. In addition, cutaneous lympho-cyte antigen bearing T cells have been found in highpercentages in milk-allergic patients with AD butnot in milk-allergic patients without milk-induced

AD.26,30 The role of cutaneous lymphocyte antigen isto interact with E-selectin to direct the homing of Tcells to skin, which highlights a part of the mecha-nism of how these food-specific T cells are directedto the skin, as well as how unknown or unrecognizedexposure may result in a specific T-cell sensitiza-tion.10,29,31,32 Barrier dysfunction, through loss-of-function mutations in the gene filaggrin (FLG), anepidermal structural protein that is part of the nat-ural moisturization factor, is an emerging risk factorassociated with early onset of severe AD and in-creased allergen sensitization, although no specificrole pertaining to food allergen sensitization hasbeen identified.33,34 FLG-deficient patients carry anodds ratio of 1.91 for the development of allergicsensitization.35

DEFINING FOOD ALLERGY IN ADFood allergy involves a combination of sensitization,

the presence of allergen-specific IgE (sIgE; positive skintest or serum test), and symptomatic reactivity attrib-utable to that particular food within 24 hours of in-gestion.36 Sensitization without a history of reactivityattributable to that particular food may be clinicallyirrelevant, and thus the diagnosis of food allergy cannot be made by just a positive skin or blood test alone.In patients with AD, nearly 80% will have positive food(or pollen) sIgE, often against multiple foods, althoughvery few are clinically relevant.3739 Therefore, cautionmust be taken before considering a positive test in thesetting of AD. Although negative skin tests confer up-ward of a 95% negative predictive value (NPV) for anallergy, positive tests have a positive predictive value(PPV) of only 60%.32,40,41 Serum tests (e.g., Immuno-CAP [Phadia US, Portage, MI], TurboRAST [AgilentTechnologies, Santa Clara, CA], and Immulite [Sie-mens Medical Solutions Diagnostics, Fort Madison,IA]) have similar NPVs and slightly less PPVs.32,40,41 Arecent, large meta-analysis commissioned by the Na-tional Institutes of Health highlighted the heterogenic-ity of how food allergy diagnoses are made and rec-ommended a combination approach involving sIgEand a history of clinical reactivity, confirmed throughfood challenge.42 Challenge may not be necessary incases with a strong supporting history of reaction,where the ImmunoCAP or skin test wheal exceeds acertain size (called the 95% cutoff diagnostic decisionpoint).36,41,4345

THE ROLE OF FOOD ALLERGY IN ADThe first documented report of food allergy as a

provoking factor in AD was by Schloss in 1915, de-scribing eczematous eruption in response to food, withimprovement on elimination.46 Since then numerouscase reports and double-blind, placebo-controlled food

Allergy and Asthma Proceedings 393

DO N

OT C

OPY

challenge (DBPCFC) studies have shown that AD issometimes closely associated with the development offood allergy.10,32 However, making an accurate diag-nosis can be difficult because one must exclude otherpotential confounding factors influencing the subjec-tive interpretation. The delayed onset of symptoms inAD (6 hours to as long as 48 hours after challenge) makesobservation difficult, although up to 25% will presentwithin 12 hours of ingestion.47,48 Moreover, results froma single challenge may be different compared to whatmay happen with chronic exposure.41 Studies show thatthe parental history of a particular food causing AD hasa low PPV.47,49 Similarly, there is a low correlation ofpositive skin and/or serum tests and challenge re-sults.38,47,50 Chronically eczematous skin is prone to non-specific irritation and false positive skin test results. Se-rum testing can be falsely positive in the setting of abaseline elevation of IgE, resulting in a nonspecific bind-ing.40 Therefore, caution must be taken in interpretingsuch diagnostic modalities in isolation in the patient withAD.32,41 As confirmed through several studies, cowsmilk, hens eggs, wheat, soy, and peanut are responsiblefor 75% of food-associated AD.51,52

Early challenge-based studies establishing the role offood allergens were plagued by poor design and ques-tionable effect of the food(s) involved.5355 There are anumber of later studies that provide good evidencethat a subset of children with AD are affected by foodallergy. Sampson and Scanlon, in a prospective 4-yearfollow-up study of 34 children that used DBPCFC-guided food elimination, found that 17/34 improvedon such a diet.56 Lever et al., using a dermatology-based referral population, showed that a randomizedcontrolled trial of egg elimination in egg-sensitizedchildren with AD led to improvement in the amount ofoverall affected skin and symptom scores versus con-trol patients without AD.57 Burks et al., in two studiesof patients with moderate-to-severe AD referred to anallergy clinic, found that 33 and 38.7% of childrenundergoing DBPCFC reacted to foods.51,52 Eigenmann

et al., in two very similar studies of university-baseddermatology patients, found that in patients pre-screened with ImmunoCAP and skin tests, 37 and33.8% (respectively) had a relevant food allergy deter-mined by challenge.39,58

More recently, Breuer found that in 64 children withAD selected from a university dermatology clinic, 46%reacted to selective foods on challenge, but, more im-portantly, the PPV for the presence of food-specific IgEor atopy patch test in determining a positive foodchallenge was only 64%.47 In contrast, however,Thompson showed that in 23 children with AD pre-senting to a university dermatology clinic with food-specific complaints, aggressive skin treatment despitepositive sensitizations significantly decreased parentalconcern for food allergy as measured by a pre- andposttreatment questionnaire.59 Table 1 summarizes theresults of several challenge-based studies determininga rate of AD affected by food allergy. The overall rateis best estimated that 3540% of food-sensitized ADwill have a relevant food allergy on challenge.

EVALUATION OF THE AD PATIENT WITHSUSPECTED FOOD ALLERGY

One should start by taking a thorough history, whichincludes specific delineation of which suspected foodexposures actually are attributed to directly causing aflare within hours after ingestion, the extent that par-ticular food is consumed in the present diet, and theextent that elimination of that food has helped, as wellas the extent of skin treatment that has been used tohelp treat the AD. The history, despite a low PPV, isstill a helpful guide to understand the familys con-cerns, treatments already tried, and to rule in likelyfood allergens. It is recommended to skin/serum testonly to relevant exposures supported by the history,because of high false positive rates and low PPVs ofthese tests. The use of screening panels that includeitems unlikely to be contributing factors should bediscouraged.

Table 1 Prevalence of food allergy confirmed by double-blind placebo-controlled food challenge in patientswith known atopic dermatitis

Authors Year n Allergy (%) Selected for Presence ofPotential Food Allergy

Country

Sampson73 1985 113 56 Yes United StatesBurks51 1988 46 33 Yes United StatesEigenmann39 1998 63 37 No United StatesBurks52 1998 165 39 Yes United StatesNiggemann49 1999 107 51 Yes GermanyEigenmann58 2000 74 34 No SwitzerlandBreuer47 2004 64 46 Yes Germany

Source: Adapted and modified from Ref. 50.

394

DO N

OT C

OPY

In managing positive test results, consider a trial ofshort-term elimination of relevant triggers if this hasnot been tried already, with a plan for a time-limitedinterval assessment of the effect. Nutritional referralis strongly recommended to support caloric needsduring allergen avoidance, and it should be clearlyunderstood that dietary removal is not withoutstrong consequences to both the nutrition of thechild and the quality of life of the family.60 Despitereports of successful resolution of AD with foodelimination, a challenge is still recommended to ruleout a placebo effect or influence of another con-founding variable. Evidence-based decision pointsindicating 95% diagnostic cutoff values are availablefor selected foods and can serve as a guide in decid-ing if challenge is appropriate.36 Caution should betaken, however, in universally applying such cutoffvalues to ones own patient population without fullyunderstanding the study population and its charac-teristics that helped determine these decisionpoints.61 Most importantly, practitioners should si-multaneously be maximizing other treatment op-tions besides dietary intervention, because AD ismultifocal in influence.62

APPROACH TO THE ORAL FOOD CHALLENGEIN AD

It is generally recommended that the patient un-dergo a prolonged period of strict avoidance of thesuspected food (2 weeks), while at the same timeaggressive and intense skin therapy should be initi-ated to clear the skin as best possible in preparationfor the challenge. It is acceptable to continue a low-potency topical corticosteroid during the challengebut only if necessary. However, antihistamine andUV light therapy must be discontinued. Publishedchallenge protocols are available.50,63 One must beable to observe the skin closely over the ensuing 48hours, and, very often, patients are admitted to thehospital so such observation is possible. It is highlyrecommended to use a standardized skin scoringsystem (e.g., SCORAD).64 Although any type of chal-lenge can be used, the DBPCFC protocol is recom-mended to most objectively confirm the out-come.50,63

RISKS FROM EARLY ONSET AD AND FOODALLERGY PROGNOSIS

The atopic march is well described and is dis-cussed in detail elsewhere.3 It is worth noting that inpatients with AD, up to 50% may develop otheratopic diseases by the age of 1 year (80% eventually);35% with milk sIgE develop other food sensitizationby age the of 3 years; and 70% with egg white sIgE inthe setting of a positive family history of atopy de-

velop recurring wheezing by age the of 5 years.3,10,32

Unfortunately, a subset of children will develop non-eczematous food allergy. However, 33% will out-grow selected foods over 13 years with strict elimi-nation (milk and egg, as opposed to peanut).56,65 68 Ithas been observed that very often skin tests willremain positive even in children who tolerate inges-tion of that food, but the ImmunoCAP value gener-ally does decrease in proportion to tolerance.32,69 Todate, no good preventative strategy exists despitenumerous suggested approaches.70 These includethe use of probiotic supplements, use of extensivelyhydrolyzed casein formula in high-risk infants,breast-feeding with selected maternal allergenavoidance, and delayed introduction of solids.62,70 72

Much attention at present is being focused on therole of reduced epidermal barrier (loss of functionfillagrin mutation) and how this may affect earlyfood allergy sensitization.35

CONCLUSIONA subset of children with AD have food allergy, but

a larger percentage have clinically irrelevant food sen-sitization. Care and caution must be undertaken whenevaluating the patient with AD suspected of havingfood allergy, given poor PPV of both food sensitiza-tion, and parental histories. Food challenge is highlyrecommended to confirm sensitization and to ensurethat a particular dietary avoidance is necessary. Atten-tion must be paid to other confounding factors, such asthe role of cutaneous infection or genetically conferredbarrier dysfunction, and treatment options beyond di-etary intervention should be maximized. In cases ofchildren allergic to eggs, wheat, and milk, the naturalhistory is to outgrow these sensitivities (as opposed topeanut), although many children who develop AD at ayoung age may develop other food sensitivities ordevelop worsening food allergy with more classicsymptoms. Preventive strategies have not been wellestablished.

ACKNOWLEDGMENTSThe author thanks James Baldwin, M.D., and Georgiana Sanders,

M.D., M.S., of the Division of Allergy and Clinical Immunology, TheUniversity of Michigan Health Systems, for their assistance in re-viewing this article.

REFERENCES1. Hamid Q, Boguniewicz M, and Leung DY. Differential in situ

cytokine gene expression in acute versus chronic atopic derma-titis. J Clin Invest 94:870876, 1994.

2. Hanifin JM, and Rajka G. Diagnostic features of atopic derma-titis. Acta Derm Venereol (Stockh) 92:4447, 1980.

3. Hahn EL, and Bacharier LB. The atopic march: The pattern ofallergic disease development in childhood. Immunol AllergyClin North Am 25:231246, 2005.

Allergy and Asthma Proceedings 395

DO N

OT C

OPY

4. Schultz Larsen F. Atopic dermatitis: A genetic-epidemiologicstudy in a population-based twin sample. J Am Acad Dermatol28:719723, 1993.

5. Schultz Larsen F, Diepgen T, and Svensson A. The occurrence ofatopic dermatitis in north Europe: An international question-naire study. J Am Acad Dermatol 34:760764, 1996.

6. Laughter D, Istvan JA, Tofte SJ, and Hanifin JM. The prevalenceof atopic dermatitis in Oregon schoolchildren. J Am Acad Der-matol 43:649655, 2000.

7. Sugiura H, Umemoto N, Deguchi H, et al. Prevalence of child-hood and adolescent atopic dermatitis in a Japanese population:Comparison with the disease frequency examined 20 years ago.Acta Derm Venereol 78:293294, 1998.

8. Saeki H, Iizuka H, Mori Y, et al. Prevalence of atopic dermatitisin Japanese elementary schoolchildren. Br J Dermatol 152:110114, 2005.

9. Akdis CA, Akdis M, Bieber T, et al. Diagnosis and treatment ofatopic dermatitis in children and adults: European Academy ofAllergology and Clinical Immunology/American Academy of Al-lergy, Asthma and Immunology/PRACTALL Consensus Report. JAllergy Clin Immunol 118:152169, 2006.

10. Leung DY, and Boguniewicz M. Atopic dermatitis. In Middle-tons Allergy Principles and Practice, 7th ed. Chap. 62. Adkin-son NF, Bochner BS, Busse WW, et al. (Eds). St. Louis, MO:Mosby, 10831099, 2009.

11. Novak N, and Bieber T. Allergic and nonallergic forms of atopicdiseases. J Allergy Clin Immunol 112:252262, 2003.

12. Tokura Y. Extrinsic and intrinsic types of atopic dermatitis. JDermatol Sci 58:17.

13. Hanifin JM, Chan SC, Cheng JB, et al. Type 4 phosphodiesteraseinhibitors have clinical and in vitro anti-inflammatory effects inatopic dermatitis. J Invest Dermatol 107:5156, 1996.

14. Jirapongsananuruk O, Hofer MF, Trumble AE, et al. Enhancedexpression of B7.2 (CD86) in patients with atopic dermatitis: Apotential role in the modulation of IgE synthesis. J Immunol160:46224627, 1998.

15. Novak N, Tepel C, Koch S, et al. Evidence for a differentialexpression of the FcepsilonRIgamma chain in dendritic cells ofatopic and nonatopic donors. J Clin Invest 111:10471056, 2003.

16. Mudde GC, Bheekha R, and Bruijnzeel-Koomen CA. Conse-quences of IgE/CD23-mediated antigen presentation in allergy.Immunol Today 16:380383, 1995.

17. Novak N, Valenta R, Bohle B, et al. FcepsilonRI engagement ofLangerhans cell-like dendritic cells and inflammatory dendriticepidermal cell-like dendritic cells induces chemotactic signalsand different T-cell phenotypes in vitro. J Allergy Clin Immunol113:949957, 2004.

18. Hamid Q, Naseer T, Minshall EM, et al. In vivo expression ofIL-12 and IL-13 in atopic dermatitis. J Allergy Clin Immunol98:225231, 1996.

19. Tsicopoulos A, Hamid Q, Varney V, et al. Preferential messen-ger RNA expression of Th1-type cells (IFN-gamma, IL-2) inclassical delayed-type (tuberculin) hypersensitivity reactions inhuman skin. J Immunol 148:20582061, 1992.

20. Sampson HA. Food allergy. Part 1: Immunopathogenesis andclinical disorders. J Allergy Clin Immunol 103:717728, 1999.

21. Sampson HA, and Jolie PL. Increased plasma histamine con-centrations after food challenges in children with atopic derma-titis. N Engl J Med 311:372376, 1984.

22. Sampson HA, Broadbent KR, and Bernhisel-Broadbent J. Spon-taneous release of histamine from basophils and histamine-releasing factor in patients with atopic dermatitis and foodhypersensitivity. N Engl J Med 321:228232, 1989.

23. Suomalainen H, Soppi E, and Isolauri E. Evidence for eosino-phil activation in cows milk allergy. Pediatr Allergy Immunol5:2731, 1994.

24. Magnarin M, Knowles A, Ventura A, et al. A role for eosino-phils in the pathogenesis of skin lesions in patients with food-sensitive atopic dermatitis. J Allergy Clin Immunol 96:200208,1995.

25. Noh G, Jin H, Lee J, et al. Eosinophilia as a predictor of foodallergy in atopic dermatitis. Allergy Asthma Proc 31:e18e24.

26. Abernathy-Carver KJ, Sampson HA, Picker LJ, and Leung DY.Milk-induced eczema is associated with the expansion of T cellsexpressing cutaneous lymphocyte antigen. J Clin Invest 95:913918, 1995.

27. Reekers R, Beyer K, Niggemann B, et al. The role of circulatingfood antigen-specific lymphocytes in food allergic children withatopic dermatitis. Br J Dermatol 135:935941, 1996.

28. van Reijsen FC, Bruijnzeel-Koomen CA, Kalthoff FS, et al. Skin-derived aeroallergen-specific T-cell clones of Th2 phenotype inpatients with atopic dermatitis. J Allergy Clin Immunol 90:184193, 1992.

29. van Reijsen FC, Felius A, Wauters EA, et al. T-cell reactivity fora peanut-derived epitope in the skin of a young infant withatopic dermatitis. J Allergy Clin Immunol 101:207209, 1998.

30. Beyer K, Castro R, Feidel C, and Sampson HA. Milk-inducedurticaria is associated with the expansion of T cells expressingcutaneous lymphocyte antigen. J Allergy Clin Immunol 109:688693, 2002.

31. Lee LA. Atopic dermatitis and allergy in children: A dynamicrelationship. Food Chem Toxicol 46(suppl 10):S6S11, 2008.

32. Jones SM, and Burks AW. Atopic dermatitis and food hyper-sensitivity. In Pediatric Allergy: Principles and Practice. LeungDYM, Sampson HA, Geha RS, and Szefler SJ (Eds). Chap. 51.St. Louis, MO: Mosby, 538545, 2003.

33. Baurecht H, Irvine AD, Novak N, et al. Toward a major riskfactor for atopic eczema: Meta-analysis of filaggrin polymor-phism data. J Allergy Clin Immunol 120:14061412, 2007.

34. Rodriguez E, Baurecht H, Herberich E, et al. Meta-analysis offilaggrin polymorphisms in eczema and asthma: Robust riskfactors in atopic disease. J Allergy Clin Immunol 123:13611370,e7, 2009.

35. van den Oord RA, and Sheikh A. Filaggrin gene defects and riskof developing allergic sensitisation and allergic disorders: Sys-tematic review and meta-analysis. BMJ 339:b2433, 2009.

36. Sicherer SH, and Sampson HA. Food allergy. J Allergy ClinImmunol 125:S116S125.

37. Hill DJ, Sporik R, Thorburn J, and Hosking CS. The associationof atopic dermatitis in infancy with immunoglobulin E foodsensitization. J Pediatr 137:475479, 2000.

38. Hill DJ, Heine RG, Hosking CS, et al. IgE food sensitization ininfants with eczema attending a dermatology department. J Pe-diatr 151:359363, 2007.

39. Eigenmann PA, Sicherer SH, Borkowski TA, et al. Prevalence ofIgE-mediated food allergy among children with atopic derma-titis. Pediatrics 101:E8, 1998.

40. Bernstein IL, Li JT, Bernstein DI, et al. Allergy diagnostic test-ing: An updated practice parameter. Ann Allergy Asthma Im-munol 100:S1S148, 2008.

41. Sicherer SH, and Sampson HA. Food hypersensitivity andatopic dermatitis: Pathophysiology, epidemiology, diagnosis,and management. J Allergy Clin Immunol 104:S114S122, 1999.

42. Chafen JJ, Newberry SJ, Riedl MA, et al. Diagnosing and man-aging common food allergies: A systematic review. JAMA 303:18481856.

43. Sampson HA, and Ho DG. Relationship between food-specificIgE concentrations and the risk of positive food challenges inchildren and adolescents. J Allergy Clin Immunol 100:444451,1997.

44. Sampson HA. Utility of food-specific IgE concentrations inpredicting symptomatic food allergy. J Allergy Clin Immunol107:891896, 2001.

396

DO N

OT C

OPY

45. Perry TT, Matsui EC, Kay Conover-Walker M, and Wood RA.The relationship of allergen-specific IgE levels and oral foodchallenge outcome. J Allergy Clin Immunol 114:144149, 2004.

46. Scholoss OM. Allergy to common foods. Trans Am Pediatr Soc27:6268, 1915.

47. Breuer K, Heratizadeh A, Wulf A, et al. Late eczematous reac-tions to food in children with atopic dermatitis. Clin Exp Al-lergy 34:817824, 2004.

48. Celik-Bilgili S, Mehl A, Verstege A, et al. The predictive value ofspecific immunoglobulin E levels in serum for the outcome oforal food challenges. Clin Exp Allergy 35:268273, 2005.

49. Niggemann B, Sielaff B, Beyer K, et al. Outcome of double-blind, placebo-controlled food challenge tests in 107 childrenwith atopic dermatitis. Clin Exp Allergy 29:9196, 1999.

50. Werfel T, Erdmann S, Fuchs T, et al. Approach to suspectedfood allergy in atopic dermatitis. Guideline of the Task Force onFood Allergy of the German Society of Allergology and ClinicalImmunology (DGAKI) and the Medical Association of GermanAllergologists (ADA) and the German Society of Pediatric Al-lergology (GPA). J Dtsch Dermatol Ges 7:265271, 2009.

51. Burks AW, Mallory SB, Williams LW, and Shirrell MA. Atopicdermatitis: Clinical relevance of food hypersensitivity reactions.J Pediatr 113:447451, 1988.

52. Burks AW, James JM, Hiegel A, et al. Atopic dermatitis andfood hypersensitivity reactions. J Pediatr 132:132136, 1998.

53. Atherton DJ, Sewell M, Soothill JF, et al. A double-blind con-trolled crossover trial of an antigen-avoidance diet in atopiceczema. Lancet 1:401403, 1978.

54. Juto P, Engberg S, and Winberg J. Treatment of infantile atopicdermatitis with a strict elimination diet. Clin Allergy 8:493500,1978.

55. Neild VS, Marsden RA, Bailes JA, and Bland JM. Egg and milkexclusion diets in atopic eczema. Br J Dermatol 114:117123,1986.

56. Sampson HA, and Scanlon SM. Natural history of food hyper-sensitivity in children with atopic dermatitis. J Pediatr 115:2327, 1989.

57. Lever R, MacDonald C, Waugh P, and Aitchison T. Randomisedcontrolled trial of advice on an egg exclusion diet in youngchildren with atopic eczema and sensitivity to eggs. PediatrAllergy Immunol 9:1319, 1998.

58. Eigenmann PA, and Calza AM. Diagnosis of IgE-mediated foodallergy among Swiss children with atopic dermatitis. PediatrAllergy Immunol 11:95100, 2000.

59. Thompson MM, and Hanifin JM. Effective therapy of childhoodatopic dermatitis allays food allergy concerns. J Am Acad Der-matol 53:S214S219, 2005.

60. Teufel M, Biedermann T, Rapps N, et al. Psychological burdenof food allergy. World J Gastroenterol 13:34563465, 2007.

61. Bahna SL. Reflections on current food allergy controversies:Specific IgE test application, patch testing, eosinophilic esoph-agitis, and probiotics. Allergy Asthma Proc 29:447452, 2008.

62. Boguniewicz M, and Leung DY. Recent insights into atopicdermatitis and implications for management of infectious com-plications. J Allergy Clin Immunol 125:413, 2010.

63. Nowak-Wegrzyn A, Assaad AH, Bahna SL, et al. Work Groupreport: Oral food challenge testing. J Allergy Clin Immunol123:S365S383, 2009.

64. Oranje AP, Glazenburg EJ, Wolkerstorfer A, and de Waard-vander Spek FB. Practical issues on interpretation of scoring atopicdermatitis: The SCORAD index, objective SCORAD and thethree-item severity score. Br J Dermatol 157:645648, 2007.

65. Bock SA. The natural history of food sensitivity. J Allergy ClinImmunol 69:173177, 1982.

66. Fleischer DM, Conover-Walker MK, Matsui EC, and Wood RA.The natural history of tree nut allergy. J Allergy Clin Immunol116:10871093, 2005.

67. Skripak JM, Matsui EC, Mudd K, and Wood RA. The naturalhistory of IgE-mediated cows milk allergy. J Allergy Clin Im-munol 120:11721177, 2007.

68. Savage JH, Matsui EC, Skripak JM, and Wood RA. The naturalhistory of egg allergy. J Allergy Clin Immunol 120:14131417,2007.

69. Shek LP, Soderstrom L, Ahlstedt S, et al. Determination of foodspecific IgE levels over time can predict the development oftolerance in cows milk and hens egg allergy. J Allergy ClinImmunol 114:387391, 2004.

70. Greer FR, Sicherer SH, and Burks AW. Effects of early nutri-tional interventions on the development of atopic disease ininfants and children: The role of maternal dietary restriction,breastfeeding, timing of introduction of complementary foods,and hydrolyzed formulas. Pediatrics 121:183191, 2008.

71. Taylor AL, Dunstan JA, and Prescott SL. Probiotic supplemen-tation for the first 6 months of life fails to reduce the risk ofatopic dermatitis and increases the risk of allergen sensitizationin high-risk children: A randomized controlled trial. J AllergyClin Immunol 119:184191, 2007.

72. Ozdemir O. Any benefits of probiotics in allergic disorders?Allergy Asthma Proc 31:103111, 2010.

73. Sampson HA, and McCaskill CC. Food hypersensitivity andatopic dermatitis: Evaluation of 113 patients. J Pediatr 107:669675, 1985. e

Allergy and Asthma Proceedings 397

DO N

OT C

OPY

Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.