Eosinophilic gastroenteritis is a rare disease characterized by striking tissue eosinophilia in any layer of the gut wall; however, many diseases can cause increased gut eosinophilia. Allergic reactions to food are an important cause of gut eosinophilia. Not all adverse reactions to food are IgE mediated, and most cases of IgE-mediated food allergy do not have eosinophilic gastroenteritis. Parasitic, bacterial, and viral pathogens as well as certain systemic diseases such as vasculitis can cause gut eosinophilia. These heterogeneous conditions are reviewed in this article.
Eosinophilic gastroenteritis is a rare disease characterized by striking tissue eosinophilia in any layer of the gut wall; however, many diseases can cause increased gut eosinophilia. Allergic reactions to food are an important cause of gut eosinophilia. Not all adverse reactions to food are IgE mediated, and most cases of IgE-mediated food allergy do not have eosinophilic gastroenteritis. Parasitic, bacterial, and viral pathogens as well as certain systemic diseases such as vasculitis can cause gut eosinophilia. These heterogeneous conditions are reviewed in this article.
The following search strategy was applied. Ovid MEDLINE and Pub Med (no time limit) on-line databases were searched to identify the published literature in the English language or translations when available. An initial search was performed using the terms eosinophilic gastroenteritis, gastrointestinal eosinophilia , and gut eosinophilia. These terms were then coupled with other secondary search terms, that is, food allergy , cow milk protein allergy , drugs/medications , parasites , bacteria , virus , transplant , graft versus host disease (GVHD) , polyps , hypereosinophilic syndrome , and specific types of vasculitis . Relevant published articles and, when important, abstracts were included and referenced herein. Due to the paucity of literature, case reports were also carefully considered and included if deemed appropriate. All levels of evidence were considered, but more emphasis was placed on randomized trials in this review. When evidence is lacking, this is stated explicitly.
Food Allergy
The presence of increased eosinophils in the gastrointestinal tract may occur as an allergic reaction to certain foods. Food allergy and food intolerance are the two major groups of adverse reactions. Food intolerances (non-allergic food hypersensitivities) are adverse responses caused by some unique physiologic characteristic of the host, such as metabolic disorders (eg, enzymatic or transport deficiencies), whereas food hypersensitivity/allergy is an adverse immunologic reaction that might be due to IgE- or non–IgE-mediated immune mechanisms.
Epidemiology of Food Allergy
Unfortunately, data on the prevalence of true allergic reactions to food are lacking, but probably no more than 1% to 2% of the population is affected. Food intolerance and several other disorders result in symptoms mimicking food allergy, which makes it particularly difficult to calculate the actual number of persons with true food allergies. Both food allergy and intolerance are reported more commonly in children than adults. The frequency of self-reported symptoms from food intolerance is estimated to range from 4.9% to 20% , the vast majority of which are non-immunogenic, with lactose intolerance being the most frequently reported . Peanut or tree nut and seafood and egg allergies are the best documented IgE-mediated food allergies in the United States. Studies have estimated that 1.3% of Americans are allergic to peanuts or tree nuts , and seafood allergies affect 3.5% to 4% of the population . Egg is another common allergen, especially in childhood, with an estimated cumulative prevalence of 2% to 6% by age 2 to 5 years . Altman and Chiaramonte reported on average 1.17 household members with food allergy in their survey of 5000 demographically representative American households. Milk, various fruits and vegetables, seafood, chocolate, eggs, and peanuts were the individual foods most frequently reported in this survey.
Pathologic Mechanisms
The gut-associated lymphoid system includes organized lymphoid tissue such as mesenteric lymph nodes, Peyer’s patches, and lymphoid follicles within the lamina propria. This system comes into direct contact with food antigens, which may explain why as many as 50% of food allergic disorders present with gastrointestinal manifestations. Even though 2% of ingested food antigens are absorbed, tolerance develops through a variety of mechanisms (eg, T-cell anergy or induction of regulatory T cells) that protect against the development of allergy. In a sensitized host, a food antigen can bind to IgE, activating and releasing several potent mediators and cytokines and leading to accumulation of interleukin-5 (IL-5), eosinophils, basophils, IgE, and mast cells in intestinal biopsy specimens of patients with food allergy . On the other hand, food protein–induced proctocolitis presents in the first few months of life. The eosinophils may have a critical role independent of the presence of IgE or immediate hypersensitivity. It has been suggested that maternal dietary protein is complexed in some fashion with breast milk immunoglobulin (IgA) or another immunologic component, initiating an inflammatory response .
Risk Factors
Many food proteins have been identified as potential allergens ( Table 1 ). Certain allergens, such as peanuts, have been suggested to be associated with an increased risk of sensitization to other foods. Schafer and colleagues in their study reported that more than 70% individuals were sensitized to more than one allergen, with the highest concomitant sensitization being to hazelnuts, peanuts, and celery.
| Age group | Most common foods implicated in food allergy |
|---|---|
| Infants | Cow’s milk, soya proteins |
| Children | Cow’s milk, eggs, peanuts, soy, wheat, tree nuts, fish and shellfish |
| Adults | Peanuts, tree nuts, fish and shellfish, chocolate, eggs |
Food allergy is the result of exposure of a susceptible individual to an allergen, but the influence of various genetic and environmental factors may increase this risk. Over the years multiple studies have tried to identify a possible relationship between certain genes and manifestations of food allergy. One gene of particular interest is a polymorphism in the promoter region for CD14, which is the receptor for lipopolysaccharide. Woo and colleagues studied 175 asthmatic and 77 food-allergic patients of varying age and suggested a significant association between the -159T allele, one of the alleles in that region, and the presence of food allergy and non-atopic asthma. Similarly, in another study by Hand and colleagues , the relationship between HLAs and nut allergy was investigated in 84 individuals with a clinical history. The frequency of HLA-B ∗ 07 (28.57%) and DRB1 ∗ 11 (15.48%) was increased in the nut-allergic patients when compared with atopic controls (12.20% and 3.66%, respectively). Sicherer and colleagues studied 70 twin pairs with at least one member with peanut allergy. Among the monozygotic pairs (n = 14), nine were concordant for peanut allergy (pair-wise concordance, 64.3%); and among dizygotic pairs (n = 44), three were concordant for peanut allergy (pair-wise concordance, 6.8%; P < .0001). The heritability of peanut allergy was estimated at 81.6% (95% CI, 41.6–99.7). The significantly higher concordance rate of peanut allergy among monozygotic twins suggested a strong genetic influence on peanut allergy. Although statistically significant, these findings appear to be of limited clinical significance, and, to date, no gene has been linked conclusively to food allergy . The search for genes strongly associated with food allergy continues.
Maternal exposure to certain foods during pregnancy and lactation is a risk factor in the development of food allergy in children. Frank and colleagues reviewed 25 peanut-sensitized and 18 control children (allergy to milk but not to peanuts) and concluded that mothers who consumed peanuts more than once a week were more likely to have a peanut-allergic child than mothers who consumed peanuts less than once a week.
A connection between food allergy and natural rubber latex allergy has been recognized in the literature . Kim and Hussain reported 49 potential allergic reactions to foods in 29 of 115 (21.1%) patients with a confirmed type I latex allergy. Foods responsible for these reactions included bananas (18%), avocado (16%), shellfish (12%), fish (8%), kiwi (12%), and tomato (6%).
Clinical Presentation
As mentioned earlier, food allergy can broadly be classified into IgE- and non–IgE-mediated processes, and the symptoms range from minor impairments to life-threatening shock reactions. Each subclass is discussed individually in the following sections.
IgE-mediated reactions
In food-allergic individuals, IgE is produced against naturally occurring food components, primarily glycoprotein, that usually retain their allergenicity after heating or proteolysis. Adults tend to be allergic to fish, crustaceans, peanuts, and tree nuts, whereas children tend to be allergic to cow’s milk, egg white, wheat, and soy. These reactions are rapid in onset and comprise both intestinal and extraintestinal manifestations.
Gastrointestinal anaphylaxis and oral allergy syndrome are the most important symptom complexes. Similar mechanisms have been suggested in 10% to 15% cases of infantile colic .
Gastrointestinal anaphylaxis
Gastrointestinal anaphylaxis is a common form of IgE-mediated food allergy. Yocum and colleagues reviewed the medical records of Olmsted County inhabitants and reported an annual incidence of food anaphylaxis of 7.6 cases per 100,000 person-years and a food anaphylaxis occurrence rate of 10.8 cases per 100,000 person-years. Its pathophysiology is well understood. The antigen cross-links with IgE antibody and activates immunoglobulin receptors on inflammatory cells. This activation causes a release of multiple inflammatory mediators that, in turn, increase vascular permeability and cause smooth muscle contractions . Gastrointestinal symptoms of nausea, a painful abdomen, edema of the lips and tongue, nausea, vomiting and diarrhea usually develop within minutes of ingesting the offending agent; however, the onset of diarrhea and colic may be delayed for up to 6 hours. Other organ systems are also involved, including the respiratory (shortness of breath, wheezing, laryngeal edema), skin (hives, pruritus, angioedema), and cardiovascular system (hypotension, tachycardia, and circulatory collapse). A biphasic anaphylactic reaction has been described in the literature with a recurrence of symptoms after a period of recovery. Its incidence is highly variable, ranging from a low of 1% to a high of 20% of episodes . The nature and severity of the symptoms, the time of onset after administration of antigen, and the history of a previous biphasic reaction have all been described as risk factors in various studies . The severity of the late-phase reaction is highly variable, and events have ranged from mild to severe with rare fatalities.
The diagnosis is mostly clinical, and a careful history of ingestion of any particular food is of great importance. Recurrences of symptoms after food re-challenge and evidence of food-specific IgE antibodies (high serum IgE levels and positive skin prick test) may increase the diagnostic yield , although the former is usually contraindicated in patients with a clear-cut history of anaphylaxis.
Anaphylaxis is a medical emergency. The treatment protocol should include the administration of epinephrine, intravenous fluids, antihistamines, bronchodilators, or corticosteroids . A 24-hour period of posttreatment observation is ideal for biphasic reactions.
Avoidance of offending agent is the best preventative strategy; however, accidental or contaminant exposure to the allergen is possible, and epinephrine self-administration injections should be prescribed to all patients at risk for anaphylaxis.
Oral allergy syndrome
Oral food allergy syndrome, also known as pollen food allergy syndrome, is a clinical term used for a form of contact hypersensitivity that occurs when a susceptible individual ingests a food that has cross-reactive antigens to pollens that they are sensitive to.
Schafer and colleagues surveyed 1537 patients with questionnaires and reported 659 (42.9%) patients with oral symptoms. The frequency varied with different types of food consumed, with fruits (72.3%) and nuts (68%) being the most common culprits. An association between pollen and oral allergy syndrome has been well recognized , and some patients have oral allergy syndrome symptoms only during the pollen season when anti–birch-specific IgE titers rise .
Symptoms usually occur within minutes after the offending agent comes in contact with oral mucosa. The most common symptoms are mild itching and swelling of the lips and mouth. Severe angioedema of the pharyngeal mucosa causing life-threatening emergencies has been reported .
Diagnosis is based on a careful history that should include details about seasonal patterns and pollen and specific food exposures. The development of symptoms with raw fruits and vegetables and not to cooked food strongly points toward the diagnosis. Physical examination is once again invaluable and should include a careful inspection of the oral cavity and pharynx for rash, urticaria, or angioedema. A positive skin prick test (prick-to-prick skin test) is the preferred method of testing in most cases. Prick-to-prick testing is performed by inserting the needle into the fruit, withdrawing it, and then immediately pricking the patient’s cleaned skin. Anhoej and colleagues compared the skin prick test and basophil histamine release tests of 36 patients with grass or birch allergies and 17 control subjects. All of the subjects were skin prick tested and had basophil histamine release tests done with fresh fruits and various extracts of hazelnut, apple, and melon. The diagnosis of oral allergy syndrome was confirmed by oral challenges. In addition, histamine release to recombinant Bet v 1 and Bet v 2 and recombinant Phl p 1, Phl p 2, and Phl p 5 was performed. The skin prick test showed an almost optimal diagnostic value, with a satisfactory sensitivity (>89%) and excellent negative predictive value with fresh fruits. Oral challenge did not result in severe systemic reactions, and no systemic reactions were observed with skin prick tests with fresh fruits. When the skin prick test with the culprit food item cannot be performed, histamine release is a diagnostic alternative, although it is still limited to tertiary research centers.
There is no recommended treatment protocol for oral allergy syndrome. Generally, avoidance of the offending food is recommended. Patient education about early recognition of the symptoms in the event of accidental ingestion and epinephrine self-administration training are advised in patients who have rare severe systemic reactions. Therapies of unproven benefit for pollen food allergy syndrome include prophylactic administration of H 1 antihistamines, immunotherapy for pollinosis, and anti-IgE therapy .
Infantile colic
Infantile colic is an ill-defined condition of infancy characterized by paroxysmal fussing and excessive crying. The most commonly used definition of colic was coined in 1954 by Wessel and colleagues who described it by using a “rule of three”: crying for more than 3 hours per day, for more than 3 days per week, and for more than 3 weeks in an infant that is well fed and otherwise healthy. During this time, infants cry an average of 2.2 hours per day, peaking at 6 weeks of age and gradually decreasing . Various studies have reported the incidence of infantile colic to be 5% to 25% of infants . Gastrointestinal, psychosocial, and neurodevelopmental disorders have been suggested as the cause of colic . IgE-mediated hypersensitivity has been proposed as a pathogenic factor, possibly in 10% to 15% of colicky infants .
The child is usually brought to the physician by concerned parents seeking advice, and a careful history and physical examination are imperative to determine whether there is an organic cause for the crying or to relieve parental fears and allow for a diagnosis of colic. Documentation of the frequency and quantity of spitting up is necessary to satisfy the diagnostic criteria of infantile colic and to rule out gastroesophageal reflux or pyloric stenosis .
Colic usually resolves in 60% of infants by 3 months of age and in 90% of infants by 4 months of age . Multiple strategies have been employed in management of the infant with prolonged or excessive crying , including hypoallergenic (protein hydrolysate) formula (for formula fed infants), a low-allergen maternal diet (for breastfeeding mothers), a dicyclomine trial, and reduced environmental stress on the child.
Five trials have studied the effect of eliminating cow’s milk protein on excessive crying . Two reports studying hypoallergenic (protein hydrolysate) formula in nearly 130 infants found an effect size of 0.22 (95% CI, 0.10–0.34). A comparison of breast milk with standard cow’s milk in infants who were already weaned showed no significant differences.
The anticholinergic drugs dicyclomine and dicycloverine showed a clear benefit in the treatment of excessive crying. The pooled results showed a clinically significant improvement (effect size of 0.46 [95%CI, 0.33–0.60]) . Dicyclomine is effective in treating infantile colic, but 5% of the treated infants had side effects. The manufacturer reports breathing difficulties, seizures, syncope, asphyxia, muscular hypotonia, and coma as side effects . Taubman found that increasing parental responsiveness decreased crying significantly from 2.09 ± 1.07 h/d to 1.19 ± 0.60 h/d.
Non–IgE-mediated reactions
Non–IgE-mediated hypersensitivities are believed to be the result of abnormal antigen processing or cell-mediated mechanisms and include dietary protein-induced eosinophilic proctocolitis, dietary protein-induced enterocolitis, dietary protein-induced enteropathy, and celiac disease and gliadin-sensitive enteropathy.
Celiac disease and gliadin-sensitive enteropathy leading to malabsorption with associated dermatitis herpetiformis, a chronic blistering skin disorder, is a classic gastrointestinal food allergy that is not IgE mediated and believed to be the result of various cell-mediated mechanisms. Celiac disease is reviewed elsewhere in this issue.
Dietary (food) protein-induced enteropathy
Dietary protein-induced enteropathy is a symptom complex characterized by malabsorption, failure to thrive, diarrhea, emesis, and hypoproteinemia . Although it is predominantly a disease of infancy, residual symptoms may persist to school age . It is usually related to an immunologic reaction to cow’s milk protein but has also been associated with sensitivities to soy, egg, wheat, rice, chicken, and fish. Damage to the intestinal mucosa by allergic inflammation leads to villous architectural distortion and mild eosinophilic infiltration causing malabsorption and osmotic diarrhea . Beyer and colleagues demonstrated milk-specific lymphocytes in duodenal biopsies of 60% of infants with milk protein–induced enteropathy. Clinical and histologic features share similarities with celiac disease, which should be considered as the main differential diagnosis; however, unlike in celiac disease, loss of protein sensitivity occurs by the age of 6 to 18 months. Colitis features such as mucus and gross or microscopic hematochezia are usually absent .
For an accurate clinical diagnosis, challenge with the offending food after a demonstrated response to cow’s milk elimination is critical. When available, serial small intestinal bowel biopsies related to elimination and challenge are also important .
Dietary protein-induced enterocolitis
Food protein-induced enterocolitis syndrome (FPIES) is a gastrointestinal allergic inflammation of the small intestine and colon in young infants aged 1 week to 3 months. Although cow’s milk and soy are considered the main causative allergens, other solid foods, including vegetables, cereals, fish, and poultry meats, have been reported as allergens . FPIES usually presents with profuse diarrhea, vomiting, dehydration, acidosis, transient methemoglobinemia, and failure to thrive. Anemia, occult positive stools, and gastrointestinal hemorrhage may be the presenting symptoms . The pathophysiology of this disorder remains unclear. Chung and colleagues performed immunohistochemical staining for TGF-β1, type 1 and 2 TGF-β receptors, and TNF-α on duodenal biopsy specimens of 28 infants diagnosed with FPIES by means of clinical criteria and challenge test results. Duodenal villous atrophy was associated with increased tissue staining for TNF-α, whereas expression of duodenal TGF-β was reduced in patients with FPIES.
Stools contain occult blood and leukocytes, predominantly neutrophils and eosinophils. Jejunal biopsies classically reveal flattened villi, edema, and increased numbers of lymphocytes, eosinophils, and mast cell infiltration . Complete resolution of symptoms within 72 hours with elimination of the causative allergen and recurrence with oral challenge is diagnostic .
Dietary protein-induced eosinophilic proctocolitis
Food-induced eosinophilic proctocolitis appears in the first 2 months of life with blood-tinged stools. Initially reported in the literature as a disorder of breast-fed infants , it has increasingly been reported in infants receiving cow’s milk, soy, and hydrolysate formula . It is unclear why the allergic inflammation is limited only to the lower colon, and the role of eosinophils in this process has not been clearly defined.
The infants typically have blood-streaked, normal-to-soft stools at 2 to 8 weeks of age. The age of the infant can range from 2 days to 3 months . Weight gain and growth are normal. Endoscopic biopsies reveal increased eosinophils and T-cell infiltration of the colonic mucosa . Stool cultures are negative for bacteria or Clostridium difficile by definition.
Complete resolution of symptoms occurs with 3 to 4 days of elimination of the offending protein from the diet . Bleeding and fecal leukocytes may clear within days; the endoscopic and histologic healing can take several weeks. Re-challenge with the offending protein usually provokes a recurrence of bleeding; however, the infant can tolerate an unrestricted diet after 9 months of age.
Diagnostic Evaluation
Laboratory tests
Food-specific serum IgE antibody testing is now commercially available. Levels above the clinical cut-off indicate a more than 95% likelihood of experiencing an allergic reaction and can be used to compliment skin prick testing . The positive predictive values for the three major food allergens (ie, egg, milk, and peanut) are 95% or greater ; however, a definitive diagnosis of gastrointestinal food allergy still relies on standard double-blind, placebo-controlled food challenges .
Skin puncture test
Skin prick or puncture testing is performed by introducing the food allergen to cutaneous mast cells. If food-specific IgE antibody is present on the surface of the patient’s mast cells, the cells will degranulate, releasing histamine and other mediators that cause localized cutaneous swelling (ie, a wheal). Vasodilatation also develops as a result of an axonal reflex (ie, a flare). Commercial extracts from foods with stable proteins, such as peanuts, milk, egg, tree nuts, fish, and shellfish, are generally better in terms of specific IgE antibody production. Extracts from fruits, vegetables, and other foods containing labile proteins may be altered during processing and can produce variable results .
The general sensitivity and specificity of skin prick testing for the diagnosis of food allergy are often estimated to be greater than 90% and approximately 50%, respectively . This test provides rapid detection of sensitization, and negative responses essentially confirm the absence of IgE-mediated allergy (negative predictive value over 95%); however, a positive test response does not indicate that the particular food is involved . The utility of the skin prick test can be greatly enhanced if it is used under correct clinical settings (ie, with a high pretest probability), and it should not be used as a screening test due to low specificity. Case series have shown that infants with milk or soy enterocolitis have negative skin prick tests, serum food-specific IgE tests, or both .
Endoscopic biopsies
Upper or lower gastrointestinal tract biopsies are not diagnostic. The small intestinal mucosa may show chronic villous atrophy similar to celiac disease; however, eosinophilic infiltrates in the rectal biopsy strongly suggest dietary protein-induced eosinophilic proctocolitis.
Bischoff and colleagues developed a new approach to improve the diagnostic yield of endoscopy called colonoscopic allergen provocation (COLAP). During this test, cecal mucosa of 70 adult patients with abdominal symptoms suspected to be related to food allergy and of five healthy volunteers were challenged endoscopically with three food antigen extracts, a buffer control, and a positive control (histamine). The mucosal weal and flare reaction was registered semiquantitatively 20 minutes after challenge, and tissue biopsy specimens were examined for mast cell and eosinophilic activation. The COLAP test was positive to at least one food antigen in 54 of 70 patients (77%), whereas no reaction in response to antigen was found in healthy volunteers.
Management
Diet
Avoiding the identified food allergen is the cornerstone of treatment in the management of food allergy and may improve the likelihood that tolerance will develop with time, especially to cow’s milk, egg, and soy . This avoidance is particularly important in peanut allergy, in which even tiny traces of allergens can initiate anaphylaxis. Nevertheless, the practicality of such elimination diets is limited. They necessitate well-trained counselors, time, and a great deal of motivation on the part of the affected persons. The response to an elimination diet is variable in adults, and relapses are common, which are more likely due to an accidental ingestion of a previously identified but hidden common food allergen (eg, milk, egg) rather than a reaction to a new food. An elimination diet can lead to malnutrition, especially in children if large numbers of food items are involved for prolonged periods of time .
Several studies have shown that milk and peanut protein are secreted into the breast milk of lactating women after maternal ingestion of these foods . On the basis of this observation, the American Academy of Pediatrics, the European Society for Pediatric Allergology and Clinical Immunology, and the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition all recommend exclusion of identified causal protein from the maternal diet if the infant is affected .
Newly implemented food labeling laws clearly indicate major food allergens, and patients should learn to understand these labels to avoid accidental exposure to allergens and foods with cross-reacting antigens. The Food Allergy Network is a useful source of information on food allergies and anaphylaxis ( http://www.foodallergy.org ).
If the patient fails to respond to diet elimination or if all of the provocative foods are not clearly identifiable, pharmacologic therapy may be required.
Sodium cromoglycate
This drug prevents the release of toxic mast cell mediators. It also alters the mucosal permeability of the gastrointestinal tract by reducing direct absorption of antigens . In a clinical trial conducted in the early 1970s, Freier and Berger used oral sodium cromoglycate in a dose of 50 mg every 6 hours in four infants with milk protein intolerance. All four were re-challenged with milk and remained asymptomatic. Symptoms recurred in one child after cessation of treatment. Subsequently, Kocoshis and Gryboski in a double-blind, clinical, placebo-controlled trial involving 14 children with milk allergy and concomitant allergies to one or more foods evaluated the efficacy of orally given cromolyn sodium versus placebo. Treatment was begun while the children were receiving elimination diets; they were then challenged with specific antigen after 48 hours of drug administration. Crossover took place if the initial agent was ineffective. Cromolyn was effective in 11 of 13 children compared with three of nine in the placebo group. In a case-control study, Patriarca and colleagues used oral desensitization treatment over a period of 6 to 8 months in combination with sodium cromoglycate (250–500 mg before each meal) in 47 patients with a clinical or biochemical diagnosis of allergies to various food products (positive prick-by-prick test and high IgE levels plus urticaria/angioedema, erythema with pruritus, rhinitis, rhinorrhea, vomiting or diarrhea with abdominal pain or general malaise, collapse or loss of consciousness). Desensitization was successful (based on a negative skin prick test, decrease in specific IgE, and clinical improvement) in 45 of the 54 treatments (83%). Although oral desensitization treatment in combination with oral cromoglycate may be an alternate approach in a patient with food allergy when avoidance has failed, this is not the standard of care.
Molkhou and Dupont treated 16 children and four adults suffering from food allergy or food intolerance with a 1-mg daily dose of ketotifen, another mast cell stabilizer. Gastrointestinal permeability was measured in 5 of 20 patients using mannitol and lactulose. In five individuals, food ingestion resulted in a significant rise of the lactulose to mannitol urinary ratio, and the administration of ketotifen resulted in a normalization of the mannitol to lactulose urinary ratio. Patients with urticaria with or without angioedema, gastrointestinal symptoms, asthma, and oropharynx pruritus with edema of the lips appeared to be protected from food allergy in this study. Suzuki and colleagues successfully treated a 10-year-old boy with ketotifen and oral disodium cromoglycate who was suffering from protein-losing enteropathy, eosinophilic gastroenteritis, and increased allergen-specific IgE antibodies to some food items.
Corticosteroids
Systemic corticosteroids remain the first-line therapy for management of eosinophilic gastroenteritis in acutely symptomatic patients or those who fail or cannot tolerate dietary restrictions because they provide rapid and effective relief of symptoms within a few days to weeks. Most experts recommend doses similar to those used in inflammatory bowel disease (1–2 mg/kg/d) orally for 8 weeks and tapered over 6 to 8 weeks to induce remission .
Although topical corticosteroids have been proven effective in eosinophilic esophagitis , there is no evidence in the literature to establish their usefulness in gastrointestinal food allergy.
Leukotriene receptor antagonists
Due to various side effects associated with the prolonged use of corticosteroid therapy, multiple steroid-sparing modalities have been tried with variable results. The cysteinyl leukotrienes (LTC 4 , LTD 4 , LTE 4 ) are potent inflammatory eicosanoids released from various cells, including mast cells and eosinophils, that bind to cysteinyl leukotriene receptors (CysLT) found in the human airway and cause a number of airway actions, including bronchoconstriction, mucous secretion, vascular permeability, and eosinophil recruitment. Montelukast binds selectively, competitively, and with high affinity to these receptors (CysLT1), blocking the eosinophilic chemotactic and other proinflammatory actions.
There have been anecdotal case reports of successful treatment of food allergy with montelukast. Vanderhoof and colleagues observed marked improvement in the symptoms of eight children ranging in age from 2 to 17 years with gastrointestinal eosinophilia unresponsive to standard therapies, including diet and cow’s milk protein restriction. The optimal dose is not documented in the literature. Despite its use for weeks to months with gradual tapering of the steroids, tissue eosinophilia may persist .
Probiotics
Probiotics are microbial cell preparations or components of microbial cells that have a beneficial effect on the health and well-being of the host . Most of these agents belong to the genera lactobacilli or bifidobacteria, appear safe for human use, and can bind to and colonize human intestine . The concept of replenishing gut flora is not new. The Russian scientist Eli Metchnikoff at the beginning of the twentieth century first suggested that it would be possible to modify the gut flora and to replace harmful microbes by useful microbes .
Loskutova in 1985 reported the improvement of food allergy symptoms with the administration of a mixture containing propionibacteria and Lactobacillus acidophilus . Multiple studies since then have yielded variable results. Wheeler and colleagues in a randomized crossover study compared the immune parameters of participants who received 16 oz of yogurt fermented with Lactobacillus bulgaricus and Streptococcus thermophilus versus 16 oz of milk per day and reported no significant improvements in any parameter. In contrast, Majamaa and Isolauri in a prospective trial showed a clinical and biologic response of atopic eczema and cow’s milk protein allergy by using cow’s milk elimination without (n = 14) and with (n = 13) the addition of lactobacillus GG (5 × 10 8 colony-forming units/g formula) in an extensively hydrolyzed whey formula. A significant drop was noted in stool inflammatory markers in infants treated with the extensively hydrolyzed whey formula fortified with lactobacillus GG when compared with the extensively hydrolyzed whey formula alone.
Currently, clinical data supporting the efficacy of probiotic therapy in the management of food allergy are limited, and rigorous scientific effort is required to elucidate the characteristics of distinct probiotic strains and to determine their safety and efficacy in food allergy.
Infections
Parasites
Due to improved hygiene conditions in developed countries, human worm infestations have almost been eradicated, except in travelers, exotic food adventurers, and immigrants from underdeveloped countries. Although eosinophils kill and phagocytose bacteria, they are unable to clear a bacterial infection in the absence of neutrophils. Their primary function is considered to be defensive against organisms that are too large to be phagocytosed, particularly parasitic helminthes . Eosinophilia induced by helminthic infection is mainly dependent on IL-5 generated by TH2 lymphocytes. Carbohydrate ligands expressed on the parasite surface attract and activate eosinophils that, in turn, release their toxic granules on the parasite surface. The killed parasite is eventually phagocytosed by macrophages. Studies showing how eosinophils protect against schistosomiasis support this concept .
Helminthic infections characteristically are associated with peripheral eosinophilia reflecting an immunologic response to tissue migration. Gastrointestinal eosinophilia has been associated with Ancylostoma , Strongyloides ( Figs. 1 and 2 ) , Enterobius vermicularis , Eustoma rotundatum , Trichuris trichiura , Gnathostoma spinigerum , Anisakis simplex , Trichinella spiralis , Ascaris suum , Schistosoma , Necator americanus , Isospora belli , and Toxocara canis ( Table 2 ) . Treatment with anthelmentic drugs results in resolution of symptoms and tissue eosinophilia in most cases.
| Site of eosinophilia | Parasite | Reference |
|---|---|---|
| Esophagitis | Gnathostoma spinigerum | |
| Gastroenteritis | Anisakis simplex | |
| Enterobius vermicularis | ||
| Trichuris trichiura | ||
| Toxocara canis | ||
| Enteritis | Anisakis simplex | |
| Trichinella spiralis (rat) | ||
| Schistosoma mansoni (rat) | ||
| Necator americanus | ||
| Sarcocystis hominis | ||
| Isospora belli | ||
| Strongyloides stercoralis | ||
| Terminal ileitis | Enterobius vermicularis | |
| Eustoma rotundatum | ||
| Anisakis simplex | ||
| Colitis/proctitis | Enterobius vermicularis | |
| Ascaris suum | ||
| Trichuris trichiura | ||
| Strongyloides stercoralis | ||
| Ancylostoma duodenale |
Related posts:
Eosinophilic Esophagitis in Children: Clinical Manifestations
Functional Gastrointestinal Disorders and the Potential Role of Eosinophils
Pediatric Anorectal Disorders
Autoimmune Pancreatitis
Diagnosis and Treatment of Autoimmune Hepatitis
Antimitochondrial Antibody–Negative Primary Biliary Cirrhosis
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