What About Diet? the Complex Relationship Between Food and Atopic Dermatitis

>>CLINICAL FOCUS What About Diet? The Complex Relationship between Food and Atopic Dermatitis

Exploring the clinical implications of our current understanding of diet and eczema. BY SARA N. BILIMORIA AND PETER A. LIO, MD

In the past decade, prodigious the causation and treatment of the lat- unreasonable notion, as about one >> leaps in the understanding of ter...”4 In a more contemporary take, third of moderate to severe AD atopic dermatitis (AD) have begun the National Institute of Allergy and patients have verifiable food allergies: to flesh out the picture of a complex Infectious Diseases (NIAID) stated that type I hypersensitivity reactions with and multifactorial disease.1 While skin it, “does not mean to imply that atopic hives, angioedema, or anaphylaxis.11 barrier dysfunction may well be the dermatitis results from food allergy,” Such a reaction constitutes bona fide primary or “root cause” in some or and that “... the role of food allergy in food allergy and remains a critically perhaps even most patients,2 it has also the pathogenesis and severity of this important consideration for patients. been conclusively demonstrated that condition remains controversial.”5 Although correlation most certainly barrier damage can occur as a second- It continues to be a contentious does not equal causation, it can be ary phenomenon in the presence of area, with many families and health hard to ignore the power of their inflammation.3 This underscores the care practitioners promoting the allergenicity: a single bite is often fact that barrier impairment is always idea that food is an important driver enough to trigger an impressive an important aspect of AD, regardless of eczema.6 In a recent study of 211 immediate reaction. While this of its primacy. Thus, the stage is set for patients with AD, more than half reaction could secondarily trigger an a deeper exploration of the complex (57 percent) reported discussing AD flare, it is fundamentally different relationship between AD and diet. In diet with a health care provider, but from a primary eczematous response, this brief review we will explore some over one third (38 percent) felt the and assuredly not what people are of the key studies that have shaped the discussion was unhelpful.7 In the same talking about when searching for thinking about this contentious rela- report, 68 percent of children were causative foods. tionship, culminating in a very current reported to have excluded foods Several studies have sought to sepa- viewpoint that suggests that the skin from the diet. Another study found rate these concepts of food allergy and barrier dysfunction of AD may actually that the perceived prevalence of food what might be called ‘‘food-induced drive the development of food allergy, intolerance is more than 10 times atopic dermatitis.” In a carefully con- and not the other way around. higher than the true prevalence,8 and trolled environment, 19 children with others confirm the fairly widespread severe, unremitting atopic dermati- CONNECTIONS practice of untested and unsupervised tis were challenged with test foods Diet has long been implicated in the dietary modification in an attempt and observed for a worsening of AD pathogenesis of AD, and this relation- to control AD, with up to 71 percent rather than an urticarial response. ship has been fraught. A paper in the of patients having made a dietary Remarkably, only one patient had British Medical Journal from 1830 sum- change.9,10 It is abundantly clear that worsening AD after food challenge.12 marized it by saying: “There is probably there are clinical gaps in this area that Another study by Hill, et al. sought no subject in which more deeply rooted require addressing. delayed eczematous reactions several convictions have been held…as regards Food driving AD is not an days after a cow’s milk challenge, and

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©istockphoto Optimizing topical care takes on “ new importance, as an impaired barrier may be a gateway to transcutaneous sensitization and actually developing allergies if left unchecked. At the same time, it is difficult to argue against recommending a healthy diet, as there is little doubt that eating well promotes health in every organ system, including the skin.”

found evidence of such in only 28 out at play—regardless of the mechanism is more severe and undertreated, of 135 children, or about 20 percent or any test results, the patients simply certain factors may be more likely to of these highly-selected patients with seemed to be able to tolerate foods trigger a flare than when things are a history strongly suggestive of cow’s that they previously had suspected as better controlled. This is particularly milk allergy.13 Importantly, 12 of the being triggers. relevant when invoking non-allergic 28 positive cases (43 percent) had This draws two possibilities into the mechanisms for potential food-related negative skin prick tests to cow’s milk light: the first is the idea that much exacerbations. This area remains allergen, suggesting an alternative of the concern about foods is emo- somewhat murky, but is important to pathogenesis than type I allergy. Finally, tional and/or psychological. There is consider, as some foods may simply all of the patients with eczematous significant literature that highlights be pro-inflammatory, working to exacerbations, save one, showed associ- the power of placebo in dietary exacerbate the disease outside of a ated gastrointestinal and/or respiratory change across several disease states, specific allergic mechanism.20,21 manifestations, making an isolated and it would not be surprising if this While these studies certainly do not eczema flare an extremely rare occur- at least partially explained some of disprove true food-induced AD, and rence. these cases.15–18 This is magnified in in fact validate its existence to some A striking study by Thompson and the context of a waxing and waning degree, they underscore how rare it Hanifin demonstrated another poten- disease like AD, in which it has been is, even in carefully selected high-risk tial facet of this relationship. They convincingly argued that misattribu- patients. Moreover, they confirm that found that in 80 percent of cases in tion is common and presumably works such an eczematous reaction does not which patients were convinced that in both directions: that food can cause correlate with skin prick or serologic food was a significant factor contribut- AD as well as that excluding foods can testing in a reliable way, calling their ing to their AD, such concerns became improve it.19 use into question for this specific negligible once better control of the The second possibility, admittedly clinical scenario. The Hill, et al. study eczema was achieved.14 Importantly, very speculative, is that there may underscores the rarity of an isolated such a finding helps to dismiss the idea be something of a threshold effect eczematous response, with nearly that non-allergic mechanisms could be at play. That is to say, when eczema all of the patients having associated

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gastrointestinal or respiratory symptoms as well. Finally, more closely to gain insight into the subtleties therein. the Thompson and Hanifin study raises the specter of non- In 1978, Atherton, et al. performed a 12-week double- specific inflammatory effects playing a small role, possibly blind, controlled, crossover trial of an egg and cow’s milk modulated by background disease severity. exclusion diet in 36 children with AD. They found that 14 This may be a good point to outline at least provisional patients responded better to the exclusion diet than to definitions for some of the terminology discussed: the control diet, whereas only one responded better to the • Sensitization or Sensitivity can be defined as having control diet.23 Notably, there was no correlation between a positive IgE blood testing or skin prick testing to a food positive skin prick test and response to the exclusion diet, regardless of clinical applicability. suggesting that this was not type-I allergy mediated. • IgE-mediated food allergy refers to a clinical response to Businco, et al. placed 59 children on a four-week elimina- a food, including urticaria, angioedema, or anaphylaxis tion diet of cow’s milk, eggs, or both (depending on their in someone who is sensitized. diet), and reported an almost unbelievable 80 percent clini- • Food intolerance is a broader category including non- cal improvement.24 Critically, the mean age of those who immunologic issues such as inability to digest lactose responded was significantly younger than those who did not (“lactose intolerance”), but may also include irritable respond (3.5 vs 4.7 yrs) (p < 0.01). The authors attempted bowel syndrome, reactions to sulfites, and even the to justify this by positing that the foods were more likely to immune-mediated disease celiac sprue in some taxono- be part of the younger children’s diet. Here again, they con- mies. cluded that skin prick tests and serum IgE tests would not • Less-specific “inflammatory” foods and “anti-inflam- be helpful for predicting benefit. matory” foods that may indirectly contribute to or Other studies have been less convincing. What do we modulate against some degree of inflammation in the make of the double-blind randomized controlled trial of body either directly or indirectly through better overall egg and cow’s milk exclusion diet completed in 40 patients health, weight loss, and even through the powerful pla- over six weeks by Neild, et al.?25 They found no statistically cebo effect of feeling better about one’s health and diet. significant differences in skin area affected, itching, or topical steroid use between the groups. And what about the IS THE PROOF IN ELIMINATING THE PUDDING? study of 29 children with AD on a two-week elimination We have thus far looked at scenarios that utilize food diet? It showed significant improvement in itch and body challenge, but do exclusionary diets improve AD? While surface area affected by eczema, challenging the conclusions the notion of simply removing troublesome foods remains of the Neild, et al. study. Notably, the elimination diet did appealing, a recent comprehensive review of the literature not improve sleep disturbance or clinical severity scores.26 has concluded that, “current evidence suggests that strict diet Concerningly, only 13 of the 29 children completed the management is not effective in the treatment of AD in the trial, and only two of the children were ultimately able to vast majority of patients.”22 It is worth examining a few studies identify relevant foods. Worse, they reported similar clinical improvement in three of eight children who had stopped the elimination diet during the study, yet again raising the possibility that other factors may be at work. Thus far, these studies have employed general or unselected elimination diets that focus on presumably high-risk foods, specifically cow’s milk and egg. A tailored elimina- DID YOU KNOW? tion diet is one in which foods are chosen based on testing. Eliminating only specific foods with cause may be a more Staphylococcus aureus colonization has increasingly strategic approach. A study of 100 children with AD demonstrated encourag- been found to play an important pathogenic role in AD ing results with an elimination diet based on positive dou- and, in turn, may also directly impact food sensitization. ble-blind placebo-controlled food challenges (DBPCFCs). This tailored diet not only improved disease severity, but In a recent study, Staphylococcus aureus colonization also decreased topical corticosteroid use by 85 percent com- was found to be, independent of atopic dermatitis pared to control.27 The food allergy breakdown in this study severity, associated with food sensitization and allergy. was notable for being similar to the most common IgE- mediated allergens: egg (67 percent), peanut (54 percent), and milk (30 percent), to name a few. Another study placed

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WHAT COULD GO WRONG? If the bar is so high for testing, why not just pick a food and try an elimination diet? What could go wrong? Several things, actually. The first is that heavily restricted diets that are unsupervised can be harmful. Practices such as taking unpasteurized goat’s milk can expose children to dangerous DID YOU KNOW? infections, while feeding them exclusively rice milk can lead to severe malnutrition and hypoalbuminemia.9,30 There have been multiple reports of children More insidiously, perhaps, is that there have been multiple with AD on elimination diets worsening into more reports of children with AD on elimination diets that wors- ened into more severe IgE-mediated reactions (including severe IgE-mediated reactions (including fatal fatal anaphylaxis) to the excluded foods.31,32 A recent paper anaphylaxis) to the excluded foods. A recent paper found that 19 percent of patients with a history of food- found that 19 percent of patients with a history of triggered AD and no prior immediate reactions developed new immediate food reactions after starting an elimination food-triggered AD and no prior immediate reactions diet. Most were cutaneous reactions only, but a sobering 30 developed new immediate food reactions after percent were anaphylaxis, with cow’s milk and egg being the most common offenders.33 starting an elimination diet. Dietary restrictions can be difficult for adults, perhaps even more so for children. They may thus add additional 44 children with AD on a tailored elimination diet. This stress, a known triggering factor for AD itself.34 Lastly, dietary study was less rigorous than the previous one, unfortunately, modifications can be a tremendous distraction to basic ther- and was based on an open oral provocation test. Here the apy, delaying treatment for someone who is suffering from elimination diet found moderate to marked improvement itch, poor sleep, and sometimes even infections and pain in an impressive 40 of 44 patients.28 The lack of a placebo while searching for a proverbial needle in a haystack—one control group and a blinding method are significant limi- that might not even be there. tations of this study, despite the high success rate. Unlike those in the prior study, the most common offending foods LEAKY SKIN here were chocolate, cheese, and yogurt, which were found Which brings us back to the beginning. We began with the to be generally negative on serum IgE testing. notion that skin barrier dysfunction was a primary cause in at Our wariness toward elimination diets as a method least some cases of AD. In 2015, the landmark Learning Early of controlling AD makes sense, as elimination diets are About Peanut Allergy (LEAP) study demonstrated that infants being challenged in the allergy world, as well. The concept significantly reduced the risk of developing peanut allergy of strict allergen avoidance as a method of food allergy with early introduction of peanuts into the diet.35 Researchers control has been undermined by the recent success of oral concluded that, “…early environmental exposure (through immunotherapy (OIT), in which patients are systematically the skin) to peanut may account for early sensitization, given the allergen in an attempt to build up their tolerance. whereas early oral exposure may lead to immune tolerance.” Numerous studies of OIT to foods commonly associated This idea that a deficient skin barrier could lead to with AD flares (cow’s milk, egg, and wheat) shed light on the developing food allergies represents a total reversal from complex relationship between food allergies and AD. A review where the discussion started: instead of looking for foods that by Eigenmann, et al. comparing such studies concluded that cause the eczema, it appears that treating the eczema (and its “skin rashes and AD flares were reported [during OIT trials], associated leaky skin) could prevent food allergy. This model but worsening of AD seemed to be mostly marginal.”29 of transcutaneous sensitization has been nicely demonstrated This all culminates in a very complex place: general, in animals,36 and likely bears out in people, as well.37,38 In unselected exclusion diets seem to be somewhat hit or the meantime, we have witnessed a significant shift in terms miss and may have other non-immunologic mechanisms of clinical guidelines based on this new understanding: at work. Tailored exclusion diets appear more favorable, while previous guidance suggested delaying introduction of but they come with a cost: the more accessible serum or allergenic foods into the diet of high-risk children, current skin prick testing does not appear to be helpful in selecting guidelines encourage those four to six months of age with AD these foods, making the much more onerous and expensive to eat peanuts in order to reduce the risk of peanut allergy. DBPCFC necessary to select the proper foods to exclude. It is crucial, however, to test those with severe AD and/or

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known egg allergy prior to introduction, Optimizing topical care takes on dietary vasoactive amines in migraine. Arch Dis Child. 1987;62(5):458-460. 16. Staudacher HM, Irving PM, Lomer MCE, Whelan K. The challenges of control since they have the highest risk of new importance, as an impaired barrier groups, placebos and blinding in clinical trials of dietary interventions. Proc Nutr already being peanut allergic.39 may be a gateway to transcutaneous Soc. 2017;76(3):203-212. 17. Masi A, Lampit A, Glozier N, Hickie IB, Guastella AJ. Predictors of placebo Taking this a step further is the idea sensitization and actually developing response in pharmacological and dietary supplement treatment trials in pediatric that skin barrier dysfunction is so cen- allergies if left unchecked. At the same autism spectrum disorder: a meta-analysis. Transl Psychiatry. 2015;5:e640. 18. Hurst P, Foad A, Coleman D, Beedie C. Athletes Intending to Use Sports tral to AD that enhancing the barrier time, it is difficult to argue against Supplements Are More Likely to Respond to a Placebo. Med Sci Sports Exerc. with moisturizers to “seal up the leaky recommending a healthy diet, as 2017;49(9):1877-1883. 19. Knibb RC. Why Do People Misdiagnose Themselves with Food skin” may actually prevent the very there is little doubt that eating well Hypersensitivity? An Exploration of the Role of Biopsychosocial Factors. Emerg development of AD, and consequently, promotes health in every organ system, Med J. 2019;4(1):30-37. 20. Fuglsang G, Madsen G, Halken S, Jørgensen S, Ostergaard PA, Osterballe O. secondary diseases such as food allergy. including the skin. But to do so while Adverse reactions to food additives in children with atopic symptoms. Allergy. Studies have already demonstrated cut- maintaining a focus on the skin, where 1994;49(1):31-37. 21. Ehlers I, Worm M, Sterry W, Zuberbier T. Sugar is not an aggravating factor in ting the development of AD in high-risk we can rapidly and much more reliably atopic dermatitis. Acta Derm Venereol. 2001;81(4):282-284. patients by up to 50 percent with mois- make a difference, may represent the 22. Lim NR, Lohman ME, Lio PA. The Role of Elimination Diets in Atopic Dermatitis-A Comprehensive Review. Pediatr Dermatol. 2017;34(5):516-527. turization alone, and larger studies are middle path. n 23. Atherton DJ, Sewell M, Soothill JF, Wells RS, Chilvers CE. A double-blind planned to confirm these findings.40–42 controlled crossover trial of an antigen-avoidance diet in atopic eczema. Lancet. 1978;1(8061):401-403. There is a remarkable convergence Peter A. Lio, MD is a Clinical Assistant 24. Businco L, Businco E, Cantani A, Galli E, Infussi R, Benincori N. Results of a milk with another developing line of thought: Professor of Dermatology and Pediatrics at and/or egg free diet in children with atopic dermatitis. Allergol Immunopathol . 1982;10(4):283-288. Staphylococcus aureus colonization Northwestern University Feinberg School 25. Neild VS, Marsden RA, Bailes JA, Bland JM. Egg and milk exclusion diets in has increasingly been found to play of Medicine and a partner at Medical atopic eczema. Br J Dermatol. 1986;114(1):117-123. 26. Van Asperen PP, Lewis M, Rogers M, Kemp AS, Thompson S. Experience 43 an important pathogenic role in AD Dermatology Associates of Chicago. with an elimination diet in children with atopic dermatitis. Clin Allergy. and, in turn, may also directly impact Sara N Bilimoria is a second-year 1983;13(5):479-485. 27. Marie-Helene G, Anyfantakis V, Guillet G. Food allergen-free diet in severe food sensitization. In a recent study, medical student at Northwestern atopic dermatitis related to food allergy. Indian J Dermatol Venereol Leprol. Staphylococcus aureus colonization was University Feinberg School of Medicine 2011;77(3):332-333. 28. 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Association of Staphylococcus aureus colonization mechanisms of exacerbation leaves allays food allergy concerns. J Am Acad Dermatol. 2005;53(2 Suppl 2):S214-S219. with food allergy occurs independently of eczema severity. J Allergy Clin Immunol. many unanswered questions. 15. Salfield SA, Wardley BL, Houlsby WT, et al. Controlled study of exclusion of 2019;In Press. doi:10.1016/j.jaci.2019.04.025

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