Food-protein-induced enterocolitis syndrome caused by fish

IntroductionFood protein-induced enterocolitis syndrome (FPIES) occurs in infants. Typical symptoms include profuse vomiting and/or diarrhea several hours after ingestion of a given food. The disorder is a non-IgE mediated food hypersensitivity. The most frequently involved foods are milk and soy, but some cases of FPIES induced by solid foods have been described. We report 14 patients with FPIES due to fish protein.Material and methodsHistory and physical examination, skin prick test (SPT) with fish allergens and Anisakis simplex, prick-by-prick test with implicated fish and determination of specific IgE antibodies against fish were performed. In eight children atopy patch test (APT) were also performed. In nine patients an open oral food challenge with the implicated fish was carried out.ResultsThere were six boys and eight girls, aged from 9 to 12 months at diagnosis, with between two and six reactions to the offending fish proteins before the diagnosis was established. Four patients had a previous history of atopy. Presenting symptoms included diarrhea in two patients, profuse vomiting in six patients, and recurrent vomiting and subsequent diarrhea in three patients. In addition to these symptoms, associated septic appearance, apathy and lethargy were present in the remaining three patients. Onset of symptoms occurred a few minutes after fish ingestion in two patients and from 60 minutes to 6 hours in the 12 remaining patients. SPT to fish were negative in all patients. Serum food-specific IgE antibodies were negative in all patients except one. APT was positive in three patients. Open oral challenge (OC) was performed in nine infants and was positive in all. The patients were followed-up for between 1 and 7 years after diagnosis, and follow-up OC tests were performed after fish had been eliminated from the patients’ diet for 3-4 years. Four patients became clinically tolerant to the causal food. Three patients currently tolerate only one type of fish (swordfish).ConclusionsWe report 14 patients with FPIES caused by fish protein. The symptoms suggest a form of cell-mediated, non-IgE mediated food hypersensitivity. The gold standard for diagnosis is OC, although caution should be exercised in infants with several reactions or a recent diagnosis. After a period of elimination of the causal food from the diet, tolerance can develop.     

Effect of extensively hydrolyzed milk formula on growth and resistance to bronchitis and atopic dermatitis in infants and toddlers.

OBJECTIVE: This study aimed to evaluate the adverse effects of extensively hydrolyzed milk formula on growth in infants and toddlers. METHODS: Prospectively, 45 infants and toddlers with a positive history of cow's milk allergy confirmed by positive skin prick test and high IgE levels for either alpha-lactalbumin, beta-lactoglobulin, or casein and positive single-blind food challenge received extensively hydrolyzed milk formulas for 1 year. Sex-normalized percentiles of heights and weights of infants and toddlers before their enrollment in the study were compared to those at the end of the study. The contribution of breastfeeding, early use of bottle feeding and intake of adapted or special milk formulas, and history of bronchitis and atopic dermatitis on toddlers' growth were also evaluated by multivariate analysis. RESULTS: Similar percentiles of the children's weight and height were observed at the beginning of the study and 1 year later. According to the multivariate analysis, sex, breastfeeding, early bottle feeding, ingestion of adapted or special milk formulas, atopic dermatitis, and bronchitis were not correlated with either the children's weight or height at diagnosis of the allergy or at 1 year of follow-up (P > .10). Weights and heights were not different between toddlers who had atopic dermatitis or bronchitis during the study period and those who did not. CONCLUSIONS: Growth of infants and toddlers with cow's milk allergy was not affected by the intake of extensively hydrolyzed milk for 1 year. Atopic dermatitis and bronchitis did not appear to have any deleterious effect on these children's growth.     

Casein hydrolysate formula-induced liver dysfunction in a neonate with non-immunoglobulin E-mediated cow's milk allergy.

A 10-day-old male neonate was admitted with bilious vomiting and gross hematochezia. Peripheral eosinophilia, delayed positive skin prick test to artificial milk, and elevated eosinophil cationic protein levels suggested cow's milk allergy. Fluid infusion with prohibition of oral intake improved the digestive symptoms. Breast-feeding was resumed on hospital day 3 and only casein hydrolysate formula was fed from day 7 onward. Nevertheless, eosinophilia and elevated transaminase levels developed on day 14. Liver dysfunction associated with casein hydrolysate formula was suspected and the infant was transferred to soy formula. Eosinophil counts decreased and transaminase levels were normalized on day 19. A cow's milk protein-specific lymphocyte proliferation test was positive for alpha-casein, beta-lactoglobulin, and bovine serum albumin, indicating sensitization of T cells to cow's milk proteins. These observations suggest that careful attention should be paid to liver dysfunction in non-immunoglobulin E-mediated cow's milk allergy, even when hypoallergenic formula is used.     

Milk- and soy protein-induced enterocolitis: evidence for lymphocyte sensitization to specific food proteins

Stimulation ( [3H]thymidine incorporation) of blood lymphocytes cultured with food proteins was evaluated in infants with food protein-induced enterocolitis and correlated with the results of oral diagnostic challenges with the same foods (soy, cow's milk, and egg white). The geometric mean stimulation index for lymphocytes from patients with positive oral soy protein challenge that were cultured with soy protein was 8.5, and for patients with positive cow's milk challenge the stimulation index was 6.0 when casein was used in the cultures. Both values are significantly different from the values obtained from patients with negative oral challenges (p less than 0.01). The enhanced lymphocyte responses were specific for the food proteins responsible for clinical symptoms. It is not clear whether these lymphocyte responses are due to systemic immunization secondary to macromolecular absorption, or to an abnormality in immune regulation such as a delay in the development of oral tolerance mechanisms. They suggest, however, that circulating lymphocytes sensitive to the food antigens that produce the clinical symptoms are frequent in infants with this discrete form of food protein hypersensitivity.     

Eosinophilia in infants with food protein-induced enterocolitis syndrome in Japan

Background

Many Japanese infants with food protein-induced enterocolitis syndrome (FPIES) show eosinophilia, which has been thought to be a characteristic of food protein-induced proctocolitis (FPIP).

Food Protein-Induced Enterocolitis Syndrome (FPIES): Review of Recent Guidelines

Purpose of Review

To increase understanding of food protein-induced enterocolitis syndrome (FPIES), a non-immunoglobulin E (IgE)-mediated reaction to food, by reviewing a growing body of literature, including recently published international consensus guidelines.

Recent Findings

FPIES primarily affects infants and young children and is characterized by the delayed onset of gastrointestinal symptoms, predominantly repetitive vomiting, in response to a trigger food. Symptoms are often severe and can lead to shock. Diagnosis can be challenging due to a wide differential diagnoses and lack of disease biomarkers. FPIES is a clinical diagnosis, with allergy testing playing a very limited role, if any. Medically supervised oral food challenges are used to monitor resolution of disease, which generally occurs in early childhood.

Summary

FPIES is an important condition presenting to clinicians in a variety of settings. Recent international consensus guidelines and a growing body of literature can better equip practitioners to care for these often-challenging patients.

     

Non-breast milk feeding in developing countries: challenge from microbial and chemical contaminants

Complementary foods based on cow's milk or gruels consumed by children in developing countries are often contaminated by bacteria during preparation, and ambient temperature rapidly increases microbial load. Thus infant formula or other weaning foods may cause diarrhea in young infants accounting for 25-33% of all deaths <5 years globally. Environmental chemicals such as metals (As, Pb, Cu) and nitrates can cause vomiting/diarrhea. Polychlorinated biphenyls derived from plastics, present in formula and/or breast milk, are endocrine disruptors (the potential threats are not fully quantifiable). The prevailing view is that benefits from breastfeeding outweigh potential risks.     

Immunogenicity of hydrolysate formulas in children (part 1). Analysis of 202 reactions.

Cow's milk protein hydrolyzed formulas appeared in the 1940s with the aim of decreasing or eliminating the allergenicity of cow's milk proteins, in addition to reducing the risk of sensitization. In recent years, the so-called "hypoallergenic" formulas have been developed. The use of such hydrolyzed formulas is based on the premise that predigested proteins, when fed as amino acids and peptides, provide nutrients in a nonantigenic form. Thus, protein hydrolyzed formulas have been classified as hypoallergenic. These formulas are processed by heat and enzymatic hydrolysis, and the conformational and sequential structures are more or less changed. The formulas contain peptides of lower molecular weight than the native protein source, which are thought to be less immunogenic. Hydrolyzed formulas appear to be nutritionally adequate and infants generally gain weight until they refuse the formula because of its bad taste. However, caution should be taken when such formulas are given for prolonged periods since no data are available on nutritional assessment of infants exclusively fed hydrolyzed formulas for several months. In this paper we report and discuss more than 202 reactions to different hydrolyzed formulas, including cases of anaphylactic shock and apparent life-threatening events. The cross-reactivity between different hydrolyzed formulas and cow's milk proteins, and the potential immunogenicity of such formulas are discussed. We conclude that none of the hydrolyzed formulas are nonallergenic, both for allergic children and for high-risk babies. Moreover, we suggest that double-blind placebo-controlled food challenge studies in larger cohorts of babies evaluated with well-defined and well-validated diagnostic methods may establish a more reliable prevalence of allergy to hydrolyzed formulas.     

Cytokine profile after oral food challenge in infants with food protein-induced enterocolitis syndrome

BackgroundAlthough food protein-induced enterocolitis syndrome (FPIES) is supposed to be caused by inflammation, the role of cytokines has not yet been clarified.MethodsTo elucidate the role of cytokines in the development of symptoms and abnormal laboratory findings at an oral food challenge (OFC), changes in serum cytokine levels were analyzed for 6 OFCs in 4 patients with FPIES. The result of OFC was judged positive if any gastrointestinal (GI) symptoms (vomiting, diarrhea, or bloody stool) were induced.ResultsAmong 11 cytokines profiled, serum levels of interleukin (IL)-2, IL-5, and IL-8 were clearly increased in all 4 positive OFCs in which elevations of the serum level of C-reactive protein (CRP) and peripheral blood neutrophilia were also seen. The level of serum IL-10 also rose in 2 positive OFCs. Remarkable increases in the serum level of interferon-gamma (IFN-γ), tumor necrosis factor-alpha (TNF-α), IL-6, and IL-12 were observed in a positive OFC where the serum level of CRP rose markedly (6.75 mg/dL). The serum levels of IL-5 were also elevated in 2 negative OFCs. No apparent specific correlations were found between cytokines and GI symptoms.ConclusionsThese results suggest that IL-2 and IL-8 are involved in the antigen-specific immune responses in most patients with FPIES. Further studies are needed to elucidate the significance of these cytokine in the pathogenesis of FPIES.     

Hypereosinophilia, hyper-IgE syndrome, and atopic dermatitis in a toddler with food hypersensitivity.

We describe a 20-month-old girl with hypereosinophilia, hyper-immunoglobulin (Ig) E syndrome, and atopic dermatitis. Her peripheral eosinophil count and IgE plasma levels were 2.65 x 10(9)/L and 6702 IU/mL, respectively. Specific IgE levels for a variety of foods and inhalants were high and single-blind food challenges were positive for cow's milk, hen's egg, oat, wheat, and soy. When the patient received an extensively hydrolyzed milk formula, an exclusion diet, and 2 mg/kg of prednisone daily, the atopic dermatitis partially improved. Further improvement was observed with 1 mg/kg of azathioprine daily. Long-term clinical response was satisfactory.We suggest that food hypersensitivity should be ruled out in patients with hypereosinophilia, hyper-IgE syndrome, and atopic dermatitis. Azathioprine may be a good therapeutic alternative for treatment in such cases.     

Use of an amino-acid-based formula in the treatment of cow's milk protein allergy and multiple food allergy syndrome

Food allergy to cow's milk proteins (APLV) is frequently found in young infants. Treatment is by starting an elimination diet. Different substitution products have been proposed: soya milk, partial hydrolysate of the proteins of lactoserum, powdered casein hydrolysate, hydrolysed soya and pork collagen. Allergic reactions to soya milk, hydrolysates of lactoserum proteins, powdered casein hydrolysates and hydrolysates of soya have been described. The study that we present evaluates the effect on the natural development of these allergies of a formula based on amino-acids (Neocate) in 26 patients who presented a syndrome of multiple allergies one of which was a food allergy to milk. Twenty-five of them had a severe atopic dermatitis, isolated (14 cases), or associated with gastro-intestinal troubles (6) break in the growth curve (5), anaphylactic reactions (2), one asthma (1). One child had a chronic diarrhoea associated with a weight plateau. Evaluation 2 or 3 months later showed a significant improvement of the atopic dermatitis. Return of the stature-weight growth was noted in 4 children from 5, the check in one was reported as due to a initially unrecognised allergy to gluten. The recovery of the APLV was shown by double-blind oral provocation test in 20/23 children between 11 and 37 months (22 +/- 9). Duration of administration of Neonate was between 6 to 19 months (12 + 5) months. This study confirmed the beneficial effect of the amino-acid formula on weight gain, gastro-intestinal troubles and development of atopic dermatitis. The level of recovery of APLV of 86% at the age of 2 years is better than that reported in the syndrome of multiple food allergies of 22%. The influence of this diet on the development of other food allergies remains to be evaluated.     

Egg and milk allergy in asthmatic children: assessment by immulite allergy food panel, skin prick tests and double-blind placebo-controlled food challenges

There is a perception that asthmatic symptoms may be worsoned by ingestion of certain foods. This study aimed to investigate whether ingestion of cow's milk or egg might induce respiratory symptoms in asthmatic children. Fifty asthmatic children aged 1.5 to 6 years old, with positive Immulite Food Panel FP5 test results were included in the study. Fifty healthy children within the same age group were accepted as control group. Total serum IgE levels were measured and skin prick tests for food allergens including milk and egg were performed. All of the subjects underwent oral, double-blind, placebo-controlled challenge with fresh egg and cow's milk powder. Two medical histories were confirmed by double-blind, placebo-controlled challenge in 9 patients (22.2%). Skin prick tests were positive in 9 patients (18%) with milk and 18 patients (36%) with egg antigen. Two children experienced wheezing, one after ingesting milk and the other after egg challenge (4%). In the control group no positive reactions were seen with egg or milk challenges. Our findings confirm that food allergy can elicit asthma in children, but its incidence is low, even with major allergens such as egg and milk. History, specific IgE determinations and skin prick tests are not reliable in diagnosing food reactions. Since any diet can cause rapid deficiencies in infancy, diet restrictions must not be applied, without performing double-blind, placebo-controlled challenge.     

Palatability of hydrolysates and Other substitution formulas for cow's milk-allergic children: a comparative study of taste, smell, and texture evaluated by healthy volunteers.

BACKGROUND: Hydrolyzed formulas used to feed infants with cow's milk-allergy can be classified as soy based, extensively hydrolyzed (casein, whey and mixed), and amino-acid based. Their unsatisfactory taste is reported by parents and physicians. OBJECTIVE: The aim of this study was to ascertain the palatability of these formulas in a double-blind taste test. MATERIALS AND METHODS: Fifty healthy volunteers performed a randomized-order double-blind test with 12 different milks. The taste, smell, smell, and texture of each formula were evaluated o n scales ranging from 1 (worst) t o 5 (best). The Pearson correlation coefficient between the peptide weight of each formula and the score obtained for each evaluated attribute was calculated. RESULTS: The soy formulas and rice formula had the best taste scores, followed by the whey hydrolysates; the mixed hydrolysates and the casein hydrolysates had the lowest taste scores. Individually the most palatable formula was mixed hydrolysate 1, by total score. We found a statistically significant correlation between peptide weight, reflecting the degree of hydrolysis of each formula, and the scores obtained for taste, texture, and overall palatability. CONCLUSION: The palatability of formulas is determined by the amount of bitter peptides obtained through hydrolysis. Flavorings and sweeteners may also contribute to palatability. Further studies are needed in order to determine how to modify the organoleptic properties of these products with the purpose of improving their palatability.     

Causative effect of cow''s milk protein and soy protein on progressive small bowel mucosal damage

Some infants intolerant to cow's milk protein (CMP) are often also intolerant to other food proteins including soy protein (SP). The effect of CMP and SP in infants recovering from diarrhoeal disease was studied in 22 infants who were maintained on an hypo-allergenic formula for 4-6 weeks. The infants were then challenged successively, initially with SP, followed 24 h later with CMP and then rechallenged with SP 24 h after CMP provocation. Three groups were recognized on the basis of clinical symptoms and mucosal changes following SP challenge. Group 1 comprised four infants who developed clinical and histological reactions on SP challenge. The subsequent CMP challenge, 24 h after the initial SP challenge, resulted in clinical symptoms in three of the four infants, and they developed increased mucosal injury. Rechallenge with SP in the three infants caused development of severe clinical symptoms. Group 2 comprised 12 infants who developed histological reaction but had no clinical symptoms to initial SP challenge. The subsequent CMP challenge caused further progression in mucosal pathology in 11 of the 12 infants and six also had associated clinical symptoms. Rechallenge with SP in the latter six infants resulted in development of clinical symptoms in three and tolerance to SP in three infants. Group 3 comprised six infants who tolerated SP and CMP but one of these infants developed mild histological changes to CMP. The progression of mucosal injury following SP and CMP challenge was associated with a significant decrease in mucosal disaccharidases, alkaline phosphatase levels and presence of reducing sugar in the stools. The 1 h blood xylose level continued to decrease significantly following the pre-SP, post-SP, and post-CMP challenge. It appears that the small bowel mucosa of young infants recovering from diarrhoeal disease remains sensitive not only to CMP but also to SP. The feeding of these proteins in rapid successive sequence to infants with mucosal damage might result in further progression of the mucosal injury. Thus, the exclusion for a variable period of time of antigenic food proteins like CMP and SP from the diet of young infants recovering from diarrhoea might reduce the risk of inducing mucosal sensitivity to these proteins in susceptible infants.     

Iron deficiency anemia and hypoproteinemia induced by fresh cow's milk]

We reported two patients who developed severe iron deficiency anemia and hypoproteinemia which were induced by excessive drinking cow's milk. Case 1, a 23-month-old girl, had started drinking 800-1,000ml of cow's milk everyday since the age of 9 months. She developed generalized edema at the age of 23 months and visited Saga Medical School for Treatment. Case 2, a 14-month-old girl began to drink cow's milk at the age of 6 months. She drank 1,500ml cow's milk every day at the age of 14 months. She was, referred to our hospital by her physician because of severe anemia. Hypoproteinemia and severe iron deficiency anemia in both of these patients were improved by oral iron intake and prohibiting of cow's milk. Although many children at their age usually drink more than 500ml cow's milk every day, manifestations of symptoms such as iron deficiency anemia and hypoproteinemia do not occur frequently. Thus some investigations suggest that genetic defects as well as other factors related to this disease may be important factors.     

Cow's milk provocation induces an immune response to unrelated dietary antigens.

The activation of immune mechanisms was evaluated by the solid phase enzyme linked immunoassay of immunoglobulin and specific antibody secreting cells in 27 patients (aged from nine to 69 months), subjected to a diagnostic cow's milk challenge or a rechallenge. A significant rise in the total number of immunoglobulin secreting cells was associated with clinically positive (n = 17), but not a negative (n = 10) cow's milk challenge in all immunoglobulin isotypes. The number of specific antibody secreting cells against beta lactoglobulin, mean (95% confidence interval), increased from 4.8 (1.4, 15.8) to 16.9 (5.5, 52.7) specific antibody secreting cells/10(6) cells, p = 0.02, and against casein from 2.2 (0.8, 6.1) to 7.5 (2.5, 22.5) specific antibody secreting cells/10(6) cells, p = 0.01, in patients positive to challenge in the IgM class only, indicating defective immune elimination of milk antigens. In addition to the specific immune response to cow's milk antigens, an increase in IgM specific antibody secreting cells against an unrelated dietary antigen, gliadin, from 8.2 (2.1, 31.1) to 31.0 (14.2, 67.6) specific antibody secreting cells/10(6) cells, p = 0.01, was observed. These results indicate that cow's milk challenge, in patients who have cow's milk allergy, induces a strong non-antigen specific immune response that includes a response against unrelated antigens concomitantly present in the intestinal lumen. Activation of such immune mechanisms may hence reflect increased antigenic load caused by the immune mediated lesion in the gut mucosa.     

Hidden presence of cow's milk proteins in foods.

Cow's milk is one of the first foreign proteins ingested by infants and is one of the most common and potent food allergens. The presence of cow's milk is widespread due also to its unlabelled inclusion as an ingredient, or to errors in cooking, processing and preparation, and in restaurant food. As several foods may contain cow's milk in a hidden form, foods for allergic babies should be prepared at home or with food items with all their ingredients listed on the label. Parents should be provided with appropriate material and instructed how to detect potential sources of hidden cow's milk by judiciously reading food labels to avoid possible untoward reactions. A study on products with potential hidden forms of cow's milk or its proteins is reported herein.     

Disaccharidase deficiency in infants with cow's milk protein intolerance. Response to treatment

7 infants, aged 5 weeks to 11 months, with clinically documented intolerance to cow's milk protein, chronic diarrhea, and failure to thrive, underwent small intestinal (peroal, suction) biopsy before and after withdrawal of milk proteins. Mucosal specimens were examined by light microscopy and assayed for disaccharidase activities. In all patients, moderate to severe mucosal changes were presented, associated with marked inflammation of lamina propria and damages to the brushborder. Disaccharidase activities (lactase, sucrase, maltase and palatinase) were markedly depressed in all. Follow-up biopsies were obtained in 6 infants, after 3-5 months on a milk-protein-free diet. At the time of the second biopsy, the disaccharidase activities had risen significantly and histologic improvement had occurred in each instance. In infancy, intestinal mucosal lesions due to intolerance to cow's milk protein are histologically indistinguishable from those seen in gluten-sensitive enteropathy and are associated with marked secondary disaccharidase deficiencies. Following therapy, the activity of the disaccharidases become normal or near normal prior to the complete morphologic recovery of the small intestinal mucosa.     

Serum antibodies to cow's milk proteins in ulcerative colitis and Crohn's disease

Serum antibodies of immunoglobulin G, immunoglobulin M, and immunoglobulin A isotypes to five major proteins of cow's milk, casein, bovine serum albumin, alpha-lactalbumin, beta-lactoglobulin A, and beta-lactoglobulin B, were measured using enzyme-linked immunosorbent assay in 51 patients with ulcerative colitis, 49 with Crohn's disease, and 20 age-matched controls. Immunoglobulin G and immunoglobulin M antibodies to cow's milk proteins were significantly elevated in patients with inflammatory bowel disease as compared to controls. In contrast, no significant increase in immunoglobulin A antibodies to 3 of 5 proteins was noted. The increased titers of antibodies to milk proteins seem to be specific and not due to a polyclonal immunoglobulin activation, as naturally occurring blood group antibodies were not elevated in patients with ulcerative colitis and Crohn's disease. A good correlation of disease activity, as measured by serum alpha 1-acid glycoprotein concentrations, and immunoglobulin G and immunoglobulin A antibody titers against certain cow's milk proteins could be demonstrated in Crohn's disease, but not ulcerative colitis. These findings suggest that production of antibodies to cow's milk proteins reflects specific immunization with these antigens. The study of antibody isotypes and correlation with disease activity may provide better insight into the immune response to dietary antigens and its possible role in the pathogenesis of inflammatory bowel diseases.     

Clinical observations on 3,009 cases of ciguatera (fish poisoning) in the South Pacific

Clinical observations on ciguatera were collected between 1964 and 1977 on 3,009 patients from several South Pacific island groups. Patients generally presented with neurologic symptoms such as parasthesia, vertigo, and ataxia, in addition to gastrointestinal symptoms such as diarrhea, abdominal pain, nausea, and vomiting. Patients with this illness usually became symptomatic less than 24 hours after ingestion of the fish and most patients (76.8%) developed symptoms in less than 12 hours. Significant differences in certain symptoms were noted between Melanesian and Polynesian ethnic groups, suggesting a susceptibility difference, or a difference in the nature of the toxin found in different areas of the Pacific. Being poisoned multiple times appeared to result in a clinically more severe illness than disease observed in patients experiencing ciguatera for the first time.