Introduction

Atopic dermatitis (AD) is a complex, chronic disorder that has been referred to as ‘the itch that rashes’. The origin of AD is multifactorial, including many commonly encountered triggers. In 1892 Besnier used the term ‘neurodermatitis’ to describe a chronic, pruritic skin condition seen in patients with a nervous disorder. In the early 1900s, Coca and Cooke noted the occurrence of a similar disorder with asthma and hay fever, and used the term ‘atopy’ to refer to the constellation of these allergic diseases. The term ‘atopic dermatitis’ was then coined by Wise and Sulzberger in 1933 to comprehensively describe this inheritable skin disorder. Since its earliest description, AD has had one primary feature: intense pruritus triggered by a variety of stimuli. In this chapter, we review how the ingestion of specific foods can trigger the condition of AD.

A strong correlation exists between AD and other atopic conditions, and AD is often the first manifestation of the ‘atopic march’. Approximately 50% of patients with AD develop it in the first year of life, and as many as 50% to 80% of children with AD will develop allergic respiratory disease later in life. Because of these early historical observations, investigators have explored the role of various allergens as triggers for the pathogenesis of AD ( Box 47-1 ).

Food allergy has been strongly correlated with the development and persistence of AD, especially during infancy and early childhood. The skin is the site that is most often involved in food hypersensitivity reactions. For most skin manifestations of food hypersensitivity, pruritus is a hallmark of the disease. As depicted in Figure 47-1 , the earlier the onset and the more severe the AD, the more likely it is that the child will develop food allergies.

The prevalence of infants allergic to foods (peanut, egg, sesame) is correlated with the age of diagnosis of eczema and treatment required for eczema. Infants diagnosed at a younger age and with increased severity of eczema had higher prevalence of food allergy.

(From Martin PE & The HealthNuts Study Investigators. Clin Exp Allergy 2015;45(1):255–64.

Pathophysiology

In the early 20th century, Schloss, Talbot and Blackfan published case reports of patients who had improvement in their AD after removing specific foods from their diets. Subsequent conflicting reports spurred controversy related to the role of specific food allergens in the pathogenesis of AD. This controversy has continued into the 21st century, although there is now significant laboratory and clinical evidence that would suggest the debate is no longer valid. Factors important in the pathophysiology of AD include barrier function, innate and adaptive immune responses and genetics, all of which have some relationship to allergen exposure. Studies have demonstrated that allergen-induced, IgE-mediated mast cell activation has, as its end product, hypersensitivity reactions characterized by tissue (i.e. skin) infiltration of eosinophils, monocytes and lymphocytes. The pattern of cytokine and chemokine expression found in lymphocytes infiltrating acute AD lesions is predominantly that of the T helper cell type 2 (Th2) (interleukin [IL]-4, IL-5, and IL-13). In addition, these cytokines promote influx of activated eosinophils and release of eosinophil products. Epidermal, myeloid-derived dendritic cells express high-affinity IgE receptors (FcεRI) that bind IgE and are noted in biopsy tissue from inflamed AD skin. These cells take up and present allergens to Th1, Th2 and T regulatory cells, all of which are important in AD. In addition, IgE-bearing Langerhans cells that are up-regulated by cytokines are highly efficient at presenting allergens to T cells, activating a combined Th1/Th2 profile in chronic lesions. Thus, it appears that IgE antibody and the Th2 cytokine/chemokine milieu combine to play a major role in AD.

Several articles have speculated on the role of food-specific T cells in the pathophysiology of AD and have used the atopic patch test (APT) to provide further information. In some patients who may have a delayed response to foods, authors hypothesize that the reactions may occur via high-affinity IgE receptors expressed on Langerhans and dendritic cells leading to allergen-specific T cell responses capable of promoting IgE production and delayed-type hypersensitivity reactions.

Genetic mutations resulting in clinical disease have provided additional insight into the potential relationship of AD and food allergy. Two disorders provide particularly compelling information. IPEX (immune dysregulation, polyendocrinopathy, enteropathy, X-linked) is a fatal disorder characterized by autoimmune enteropathy, endocrinopathy, severe dermatitis, elevated serum IgE and multiple food allergies. IPEX syndrome results from a mutation in FOXP3, a protein that plays a central role in the generation of regulatory T cells that are important for balance between oral tolerance and food allergy development. Similarly, mutations in the SPINK5 gene have been associated with Netherton syndrome, an autosomal recessive disorder characterized by an AD-like rash and associated Th2 skewing and increased IgE levels. Japanese investigators have also found an association of SPINK5 mutations in children with AD and food allergy. More recently, a significant association has been found between loss-of-function mutations of filaggrin, a key epidermal protein for maintaining the barrier function of the skin, and food allergy.

Laboratory Investigation

Several studies support a role for food-specific IgE antibodies in the pathogenesis of AD. Many patients have elevated concentrations of total IgE and food-specific IgE antibodies. More than 50 years ago, Wilson and Walzer demonstrated that the ingestion of foods would allow antigens to penetrate the gastrointestinal barrier and then be transported in the circulation to IgE-bearing mast cells in the skin. Additional investigations have shown that in children with food-specific IgE antibodies undergoing oral food challenges, positive challenges are accompanied by increases in plasma histamine concentration, elaboration of eosinophil products and activation of plasma eosinophils ( Box 47-2 ).

Children with AD who were chronically ingesting foods to which they were allergic were found to have increased ‘spontaneous’ basophil histamine release (SBHR) from peripheral blood basophils in vitro compared with children without food allergy or normal subjects. After placement on the appropriate elimination diet, food-allergic children experienced significant clearing of their skin and a significant fall in their SBHR. Other studies have shown that peripheral blood mononuclear cells from food-allergic patients with high SBHR elaborate specific cytokines termed histamine-releasing factors (HRFs) that activate basophils from food-sensitive, but not food-insensitive, patients. Furthermore, passive sensitization experiments in vitro with basophils from nonatopic donors and IgE from patients allergic to specific foods showed that basophils could be rendered sensitive to HRFs.

Food allergen-specific T cells have been cloned from normal skin and active skin lesions in patients with AD. There has been some disagreement in the literature about the validity of in vitro lymphocyte proliferation responses to specific foods in this disorder. There appears to be an increase in antigen-specific lymphocyte proliferation, but there is considerable overlap in individual responses with that seen in normal individuals. Cutaneous lymphocyte associated antigen (CLA) is a homing molecule that interacts with E-selectin and directs T cells to the skin. A study compared patients with milk-induced AD to control subjects with milk-induced gastrointestinal reactions without AD and with nonatopic control subjects. Casein-reactive T cells from children with milk-induced AD had a significantly higher expression of CLA than Candida albicans reactive T cells from the same patients and either casein or C. albicans reactive T cells from the control groups.

An alternative and emerging paradigm has been championed by several investigators: that sensitization to food allergens occurs due to cutaneous exposure to antigen, e.g. peanut protein in house dust, due to poor barrier function in the skin of AD patients. Lack and colleagues found an association between peanut allergy in preschool children with AD and increased exposure to peanut-based skin oils. Subsequent studies from the same group noted a dose-response effect between environmental peanut exposure and the development of peanut allergy. These observations have led to the hypothesis that environmental exposure to allergens through skin of infants with AD is responsible for allergen sensitivity and allergic disease. Results using a murine model of filaggrin (FLG) deficiency support the theory that skin barrier dysfunction and inflammation can lead to epicutaneous sensitization to food proteins, e.g. ovalbumin and peanut. Further research should elucidate the role of filaggrin in AD and food allergies as well as identify additional factors involved in skin barrier function since more than 50% of patients with moderate to severe AD do not have FLG mutations and 60% of all carriers of FLG -null alleles do not have AD.

Clinical Studies

Multiple clinical studies have addressed the role of food allergy in AD. Investigators have shown that elimination of the relevant food allergen can lead to improvement in skin symptoms and that repeat challenges can lead to recurrence of symptoms.

A number of studies have addressed the therapeutic effect of dietary elimination in the treatment of AD. Atherton and colleagues reported that two thirds of children with AD between the ages of 2 and 8 years showed marked improvement during a double-blind, cross-over trial of milk and egg exclusion. However, there were problems in this study, including high dropout and exclusion rates, as well as confounding variables such as environmental factors and other triggers of AD. Another trial by Neild and colleagues was able to demonstrate improvement in some patients during the milk and egg exclusion phase, but no significant difference was seen in 40 patients completing the cross-over trial. Juto and colleagues reported that approximately one third of AD patients had resolution of their rash and that one half improved on a highly restricted diet. The cumulative results of these studies support the role for food allergy in the exacerbation of AD. Notably, most of the trials failed to control for confounding factors such as other trigger factors, as well as the placebo effect or observer bias.

In one of the original prospective follow-up studies, Sampson and Scanlon studied 34 patients with AD, of whom 17 had food allergy diagnosed by double-blind, placebo-controlled food challenges (DBPCFCs). These patients were placed on appropriate allergen elimination and experienced significant improvement in their clinical symptoms. At 1- to 2-year and 3- to 4-year follow-ups, the subjects were compared with control subjects who did not have food allergy and to children with food allergy who were not compliant with their diet. Food-allergic patients with appropriate dietary restriction demonstrated highly significant improvement in their AD compared with the control groups.

Lever and colleagues performed a randomized controlled trial of egg elimination in young children with AD and a positive radioallergosorbent test (RAST) to eggs who presented to their dermatology clinic. At the end of this study, egg allergy was confirmed by oral challenge, and 55 children who were allergic to egg were ultimately identified. There was a significant decrease in the skin area affected in the children avoiding eggs compared with the control subjects (percent involvement, 19.6% to 10.9% vs 21.9% to 18.9%). There was also a significant improvement in symptom score ( P = .04) for the children avoiding eggs.

Oral food challenges have been used to demonstrate that food allergens can induce symptoms of rash and pruritus in children with food allergy-related AD. Sampson and colleagues and Eigenmann and colleagues published a number of articles using DBPCFCs to identify causal food proteins that are involved as trigger factors of AD. In studies during the past 25 years, Sampson and colleagues have conducted more than 4,000 oral food challenges with greater than 40% of the challenges resulting in reaction (personal communication). These studies showed that cutaneous reactions occurred in 75% of the positive challenges, generally consisting of pruritic, morbilliform or macular eruptions in the predilection sites for AD. Isolated skin symptoms were seen in only 30% of the reactions; gastrointestinal (50%) and respiratory (45%) reactions also occurred. Almost all reactions occurred within the first hour of beginning the oral challenges. Clinical reactions to egg, milk, wheat and soy accounted for almost 75% of the reactions. Some patients had repeated reactions during a series of daily challenges and had increasingly severe AD, further showing that ingestion of the causal food protein can trigger pruritus and scratching with recrudescence of typical lesions of AD.

Subsequent studies confirmed that a limited number of foods cause clinical symptoms in younger patients with AD. Milk, eggs and peanuts generally cause more than 75% of the IgE-mediated reactions. If soy, wheat, fish and tree nuts were added to this list of foods, more than 98% of the foods that cause clinical symptoms would be identified.

Prevention

Longitudinal studies have been conducted in general population birth cohorts and cohorts of high-risk infants to determine the role of breastfeeding, maternal diet restriction during pregnancy and lactation, the use of hydrolyzed formulas and delayed food introduction on development of AD and other atopic diseases. These studies led to new recommendations for early nutritional interventions by the American Academy of Pediatrics in 2008. A meta-analysis determined that exclusive breastfeeding during the first 3 months of life is associated with lower incidence rates of AD during childhood in children with a family history of atopy. The authors concluded that breastfeeding should be strongly recommended to mothers of infants with a family history of atopy as a possible means of preventing AD.

In two series, infants from atopic families whose mothers excluded eggs, milk and fish from their diets during lactation (prophylaxis group) had significantly less AD and food allergy compared at 18 months with those infants whose mothers’ diets were unrestricted. Follow-up at 4 years showed that the prophylaxis group had less AD, but there was no difference in food allergy or respiratory allergy. In a 2006 Cochrane review, the authors concluded that dietary avoidance of allergenic foods by lactating mothers of infants with AD may reduce the severity of the eczema, however larger trials are needed to confirm this.

In the German Infant Nutritional Intervention Study (GINI), 2,252 healthy term infants were randomized to receive one of four blinded formulas during the first 4 months of life when breastfeeding was insufficient: partially (PHW) or extensively hydrolyzed whey (EHW), extensively hydrolyzed casein (EHC) or cow’s milk (CM). These infants were followed for 6 years for allergic manifestations. The study showed a long-term preventive effect of hydrolyzed infant formulas for AD until age 6 years with the relative risk of a physician diagnosis of AD compared with CM of 0.79 (95% CI, 0.64–0.97) for PHW and 0.71 (95% CI, 0.58–0.88) for EHC. No preventive effect was seen for EHW. Similar findings were noted in a high-risk birth cohort of 120 infants from the Isle of Wight followed for 8 years. In the prophylactic group, infants were either breastfed with the mother maintaining a low allergen diet or given extensively hydrolyzed formula and placed on an allergen elimination diet (egg, milk, soy, wheat, nuts, fish) and dust mite avoidance through age 12 months, and compared to control infants in routine care. Those in the intervention group were noted to have reduced asthma (OR 0.24), AD (OR 0.23), allergic rhinitis (OR 0.42) and atopy (OR 0.13) compared to the controls ( P < .001).

Timing of solid food introduction and its influence on AD has been examined as well. A study by Saarinen and Kajosaari found that while exclusive breastfeeding for the first 6 months of life led to decreased AD at 1 year of age compared to early introduction of solids (at 3 months), no difference in the prevalence of AD was observed during follow-up at 5 years. Fergusson and Horwood also noted an increased risk for AD with early introduction of a diverse number of solid foods in the first 4 months of life using a birth cohort of 1,265 children followed to the age of 10 years. In contrast, delayed introduction of solid foods has not been shown to have a protective effect against AD. Thus, current recommendations encourage exclusive breastfeeding until 4–6 months of age as well as introduction of solid foods at 4–6 months of age.

Vitamin D is another factor recently implicated in atopy, therefore several studies have explored its potential role in AD. In a study examining cord blood vitamin D levels in 231 high-risk infants from an Australian prospective birth cohort, reduced maternal vitamin D levels during pregnancy were noted to be significantly associated with eczema in the first year of life. In addition, Peroni et al reported an association between vitamin D deficiency and increased severity of AD in children. Vitamin D deficiency has also been noted to correlate with IgE-mediated food sensitization as well as food allergy. Recently, Baek et al have suggested that severity of AD is independently associated with vitamin D status and allergic sensitization to foods.

Gut microbiota is hypothesized to have an immune regulatory role in protecting from allergic disorders. Thus, there has been interest in exploring the possibility of probiotic supplementation for the primary prevention of allergies in children at high risk for allergy (defined as those with a biological parent or sibling with current or history of allergic rhinitis, asthma, eczema or food allergy). In a double-blind placebo-controlled trial of 241 mother-infant pairs, a significant reduction of risk for developing eczema during the first 24 months of life was seen in infants whose mothers received probiotics 2 months before delivery and during the first 2 months of breastfeeding. Recent systematic reviews concluded that probiotic supplementation in pregnancy and early life moderately reduces the incidence and severity of atopic dermatitis. Thus, World Allergy Organization (WAO) guidelines suggest that probiotics be used in pregnant women at high risk for allergy in their children, in women who are breastfeeding infants at high risk for allergy, and in infants at high risk for allergy because studies have shown a benefit for the prevention of eczema.

Epidemiology of Food Allergy in Atopic Dermatitis

The prevalence of food allergy in patients with AD varies with the age of the patient and severity of AD. In a study of 2,184 Australian infants, investigators found that the earlier the age of onset of AD and the greater the severity of disease, the greater the frequency of associated high levels of food-specific IgE. Lowe and colleagues also noted that, in some infants, sensitization precedes and predicts the development of AD, while in others AD precedes and predicts the development of sensitization. In a study of children with AD, Burks and colleagues diagnosed food allergy in approximately 35% of 165 patients with AD referred to both university allergy and university dermatology clinics. Many of the patients were referred to an allergist, which might lead to an ascertainment bias favoring food-allergic subjects, so Eigenmann and colleagues addressed this potential bias by studying 63 unselected children with moderate to severe AD who were referred to a university dermatologist. After an evaluation including oral food challenges, 37% of these patients were diagnosed with food allergy. In another study that evaluated more than 250 children with AD, investigators noted that increased severity of AD in the younger patients was directly correlated with the presence of food allergy. Additional studies in adults with severe AD are relatively limited and have not shown a significant role for food allergy or success in reducing symptoms during trials of elimination diets.