These fads are here to stay—clinicopathological patterns of food allergic diseases

Article Outline

• Comment
• Copyright

Latcham R, Francisca M, Lang A, Garvey J, Thomson M, Walker-Smith JA, Davies S, Phillips AD, Murch S (Centre for Paediatric Gastroenterology and Department of Dietetics and Histopathology, Royal Free and University College School of Medicine, London, England). A consistent pattern of minor immunodeficiency and subtle enteropathy in children with multiple food allergy. J Pediatr 2003;143:39–47.

Food allergic diseases (FADs) may present as classic immediate hypersensitivity (immunoglobulin [Ig] E-mediated) reactions such as peanut anaphylaxis, or as cell mediated (non-IgE) responses as in celiac disease. For these diseases, clinical symptoms and serological testing ultimately allow one to make a final diagnosis and institute prompt therapy. However, recently physicians have noted increasing numbers of adults and children presenting with vague abdominal complaints (abdominal pain, vomiting) and/or seemingly unrelated extraintestinal symptoms (eczema, rhinitis, wheezing) occurring long after ingestion of specific food products. While these atopic patients might have any common gastrointestinal disease such as lactose intolerance or food-borne infections, increasing clinical experience dictates that this clinical scenario also represents delayed onset of FADs. Despite detailed historical questioning, serological analysis, and even skin prick testing, the diagnosis often remains uncertain leading to procurement of mucosal biopsies. In the best of circumstances, experienced pathologists will recognize abnormal histological patterns that, when combined with appropriate clinical data, ultimately lead to a diagnosis, restriction of appropriate food product(s), and symptom resolution.

Two large impediments prevent this best-case scenario from evolving. First, abnormal patterns associated with FADs are not yet entirely clear. Second, lack of vital communication between pathologist and gastroenterologist often leads to misinterpretation and untoward outcomes. Latcham and colleagues attacked these barriers in their retrospective study of 121 children with delayed non-IgE-mediated food allergic reactions. The group of investigators included gastroenterologists and pathologists who sought to determine distinct immunological or histopathological features in these challenging patients. Clinical records and histological slides of children with multiple food allergies (MFAs), aged 1 to 93 months (mean age, 17.3 months), formed the database examined. Clinical history was obtained by chart review and subsequent administration of a parental questionnaire. Patients were divided into 2 groups based on onset of symptoms; Group 1 consisted of 44 patients who developed hypersensitivity responses within 1 hour after exposure to food products and group 2 consisted of 77 patients with delayed responses (>1 hour after food ingestion). Forty-one of the 44 patients in group 1 had both immediate and delayed symptoms.

All patients in whom it was deemed safe underwent food challenge. Immunological assessment included serum IgA, IgG, IgM, and total and specific IgE levels. T-cell subsets were measured by flow cytometry, and skin prick tests were performed using a variety of common antigens. Two pathologists blinded to clinical data made detailed histological analyses including measurements of villous height and crypt depth; interobserver variability was negligible.

Analysis of the clinical data revealed no statistically significant differences between immediate (group 1) and delayed (group 2) responders. Both groups developed symptoms during infancy and had a family history of atopy. At presentation, children in group 1 developed classic atopic symptoms such as urticaria, anaphylaxis, and wheezing more commonly than group 2. Delayed responders exhibited vomiting, failure to thrive, and colic and required amino acid-based formulas more frequently than immediate responders.

Upon challenge, several important observations were made. First, immediate responders developed classic atopic symptoms (hives, urticaria, anaphylaxis), whereas delayed responders manifested nondescript symptoms including eczema, diarrhea, and constipation. Interestingly, a diagnosis of Munchausen’s by proxy was considered in 5 children before referral, suggesting that the diagnosis of FADs was not considered or fully evaluated. Immunological assessment revealed that IgE levels were significantly higher in group 1 than 2. Both groups showed a pattern of lower IgA, increased IgG1, decreased IgG 2/4, increased percentage of CD4 and CD19 cells, and decreased CD8 and natural killer cells.

Three significant abnormal features were identified in the duodenal mucosae of patients with FADs included focal lymphocytic/eosinophilic infiltration, villous blunting, and reduced crypt-villous ratio. Importantly, many of these biopsy specimens had originally been reported as normal.

The authors conclude that there is a subtle enteropathy and pattern of immune deviation seen in children with multiple food allergies regardless of mode of onset of the allergic reaction.

Back to Article Outline

Comment 

Increasing clinical experience and emerging basic data document the mounting burden of FADs. Precise reasons for this rise escape our present understanding, but speculations include the hygiene hypothesis, increasing use of anti-acid medications (J Allergy Clin Immunol 2003;112:616–623), and intestinal sensitization to aeroallergens (J Clin Invest. 2001;107:83–90). As is often the case with new diseases like FADs, practical aspects of caring for patients far outpace development of widely applicable diagnostic techniques and our understanding of the pathogenesis. For instance, gastroenterologists are faced with patients with vague abdominal complaints who also have a history of atopic diseases such as asthma. Although the gastrointestinal tract is seemingly removed from the world of atopy, these atopic clues are beginning to give us insights into mucosal mysteries associated with FADs. Our allergy colleagues have not needed endoscopy to make the association of eczema and FADs, and they successfully treat the skin with dietary restriction in select patients.

These clinical scenarios provide the perfect backdrop for the intriguing recent study by Latcham and colleagues in which they shed insight on clinicopathological aspects regarding children with multiple food allergies (MFAs) and open new doors to thinking about pathogenetic mechanisms. First, clinical findings demonstrate that children with MFAs present with wide ranging complaints, some of which provide a clear road map to the diagnosis (early responders), whereas others lead to confusion, as was likely the case in 5 children in whom a diagnosis of Munchausen’s by proxy was considered. Importantly, children affected with MFAs developed initial symptoms during infancy, suggesting that one should raise a diagnostic eyebrow in this age group especially if there is a maternal history of autoimmunity. Although it appeared that late responders developed rectal bleeding and failure to thrive more frequently, no features significantly differentiated early or late responders. Food antigens included common proteins such as milk, egg, wheat, soy, and nuts, suggesting that these patients are not unique in exhibiting novel hypersensitivity to unusual foods.

This study also highlights immunopathological assessments leading to interesting insights regarding potential FAD mechanisms. Latcham et al. noted low IgA levels in patients from both the immediate and delayed response group. Importantly, intestinal flora induce transforming growth factor (TGF)-β, a cytokine known to shift B cell production of IgA; recent work by this same group demonstrated that TGF-β is reduced in the mucosa of food allergic patients (Eur J Immunol 2003;33:2307–2315). In combination, these studies suggest that reduced TGF-β leads to decreased IgA production and potentially altered innate immune response. Interestingly, IgG4 was absent in 40% of children. Studies to date have not confirmed a role for IgG testing in the evaluation of patients with FADs, but this provides an interesting clue as the authors suggest a possible defect in innate immunity.

The most practical aspect of this study lay in the histopathological results. Careful analysis by the investigators determined that endoscopic biopsy specimens from affected patients contained increased mucosal lymphocytes and eosinophils and a pattern of subtle villous blunting and crypt lengthening similar to patients with cow’s milk-sensitive enteropathy. These pathological determinations suggest ongoing activation of the mucosal immune system and elaboration of proinflammatory mediators. These findings emphasize the importance of thorough analysis of mucosal biopsies because many biopsies were initially reported as normal. In day-to-day clinical practice, mucosal pinch biopsy specimens are sent to the pathologist with little more than a single line on a requisition sheet. For emerging diseases such as FADs, this degree of communication between pathologist and clinician is unsatisfactory. For example, mucosal biopsy specimens obtained from patients with GERD-like symptoms that were unresponsive to acid blockade often received the “final impression” of severe reflux esophagitis. On the basis of this report, patients were referred for fundoplication. A number of investigations have since determined that large numbers of eosinophils in the squamous epithelium from such patients likely represent eosinophilic esophagitis, an allergic disease of the esophagus, rather than recalcitrant peptic disease. Communication between pathologist and clinician has been critical to making this connection, and the findings of Latcham et al. serve to reinforce this assertion in patients with FADs.

It would have been interesting to see how the clinical symptoms of children with early and late MFAs compared to another control group, e.g., children with a single food allergen such as celiac disease or milk protein colitis of infancy. Do the clues of maternal autoimmunity still hold true and are there other clinical features that might allow distinctions to be made? Is there a gender predilection for children with MFAs like the male predilection in eosinophilic esophagitis? Figures of the immunopathology would have been instructive since this will serve as a launching point for other investigations and potential applications to diagnostic testing.

Despite these issues, this article serves both clinician and scientist alike. MFAs can be medically and socially devastating spawning parental anxiety, school and work absence, reliance on tube feeding, and increased health care costs. Latcham and colleagues have expanded the many faces of FADs and enhanced the journey toward improving our understanding of their pathogenesis.

Still the only certain thing for sure is what I do not know.

—Lyle Lovett