Food Protein-induced Allergic Proctocolitis Research Articles

Assessment of intracellular zinc levels in infants with food protein–induced allergic proctocolitis

Food protein-induced allergic proctocolitis (FPIAP) is characterized by bloody stools in well-appearing infants. Zinc is a micronutrient that plays a crucial role in immune modulation and is essential for cellular function during immune response. Although there are studies on the assessment of intracellular zinc levels in allergic diseases, no data is available on erythrocyte zinc levels of patients with FPIAP. This study aimed to assess the erythrocyte zinc levels of children with allergic proctocolitis and compare zinc levels with clinical and demographic characteristics. This was a case-control study that prospectively compared 50 patients with FPIAP and 50 healthy children without malnutrition. The erythrocyte zinc levels of children were determined using atomic absorption spectrophotometry. Fifty patients with FPIAP, including 28 (51%) girls, with median age of 7.1 ± 2.9 (3-14) months and 50 healthy children, including 26 (53.1%) girls, with median age of 7.7 ± 2.8 (3-13) months were included in the study. Seventy percent (n = 35) of the patients with FPIAP started to have symptoms while they were exclusively breastfeeding. Offending allergen foods were cow's milk (78%), egg (40%), sesame (10%), hazelnut (8%), almond (6%), beef (6%), and peanuts (6%, n = 3). Intracellular (erythrocyte) zinc levels in patients with FPIAP were lower than in the healthy control group (495.5 ± 134 µg/dL, 567.3 ± 154.4 µg/dL, respectively, P = 0.01). Patients with FPIAP aged younger than 6 months had lower intracellular zinc levels compared with those aged above 6 months (457 ± 137 µg/dL; 548 ± 112 µg/dL, respectively, P = 0.01). There was no relationship between zinc levels and time of symptom onset, presence of concomitant disease, being allergic to multiple foods, and family history of atopy (P > 0.05). FPIAP is a food allergy with limited information on its pathogenesis. Considering the beneficial effects on gastrointestinal system epithelia, zinc may be involved in the pathogenesis of FPIAP. Future comprehensive prospective research on this subject is of importance.

NOVEL PLANT-BASED PEDIATRIC FORMULA ALTERNATIVE FOR MANAGEMENT OF NON-IGE-MEDIATED FOOD ALLERGIES: A CASE STUDY

<h3>Introduction</h3> Traditional management of food protein-induced allergic proctocolitis (FPIAP) includes use of extensively hydrolyzed or elemental formula and/or the removal of dairy and soy from maternal diet for breastmilk-fed infants. This case outlines use of a novel plant-based pediatric formula in an infant diagnosed with dairy and soy-protein FPIAP. <h3>Case Description</h3> At 2 weeks of age, P presented with a dusky, distended belly and stridor within 24 hours of initial exposure to a polymeric cow milk-based infant formula. Following standard protocol for suspected FPIAP, he was transitioned to an elemental formula and his mother was placed on an elimination diet. Breastmilk was re-introduced after 10 days of elimination diet with formula supplementation. He was transitioned to supplemental extensively-hydrolyzed casein formula at 6 months. At age 10 months, due to U.S. infant formula shortages, P transitioned successfully to a novel plant-based pediatric formula sourced from almonds and buckwheat that is free of soy, rice, and pea proteins. P failed cow's milk challenge and subsequently pea-protein milk challenge upon turning 12 months, which both induced repeated gastrointestinal distress. Symptoms resolved upon re-introduction of the novel plant-based formula. <h3>Discussion</h3> This case demonstrates that an alternative protein-sourced formula has the potential to serve as a safe alternative therapy strategy to address patients with FPIAP unable to exclusively breastfeed and/or tolerate traditional formulas. These findings justify the need for further development and demonstration in a clinical setting of an alternative protein-sourced infant formula to be used in the standard management of food allergy disorders.

Longitudinal disease-associated gut microbiome differences in infants with food protein-induced allergic proctocolitis

BackgroundComplex interactions between the gut microbiome and immune cells in infancy are thought to be part of the pathogenesis for the marked rise in pediatric allergic diseases, particularly food allergies. Food protein-induced allergic proctocolitis (FPIAP) is commonly the earliest recognized non-immunoglobulin E (IgE)-mediated food allergy in infancy and is associated with atopic dermatitis and subsequent IgE-mediated food allergy later in childhood. Yet, a large prospective longitudinal study of the microbiome of infants with FPIAP, including samples prior to symptom onset, has not been done.ResultsHere, we analyzed 954 longitudinal samples from 160 infants in a nested case-control study (81 who developed FPIAP and 79 matched controls) from 1 week to 1 year of age by 16S rRNA ribosomal gene sequencing as part of the Gastrointestinal Microbiome and Allergic Proctocolitis (GMAP) study. We found key differences in the microbiome of infants with FPIAP, most strongly a higher abundance of a genus of Enterobacteriaceae and a lower abundance of a family of Clostridiales during the symptomatic period. We saw some of these significant taxonomic differences even prior to symptom onset. There were no consistent longitudinal differences in richness or stability diversity metrics between infants with FPIAP and healthy controls.ConclusionsThis study is the first to identify differences in the infant gut microbiome in children who develop FPIAP, some even before they develop symptoms, and provides a foundation for more mechanistic investigation into the pathogenesis of FPIAP and subsequent food allergic diseases in childhood.-xZ6ju8fWHHm1JuGutM5rmVideo abstract.

Practice Variations in the Management of Infants With Non-IgE-Mediated Cow's Milk Protein Allergy.

Infants with non-IgE-mediated food allergies are often referred to gastroenterologists or immunologists. We hypothesized that there are practice variations between these disciplines in the diagnosis and management of such infants. A computerized questionnaire was distributed between pediatric gastroenterologists and immunologists. The questions addressed diagnosis, management, and follow-up in 3 scenarios of infants with concern for food protein-induced allergic proctocolitis (FPIAP) due to non-IgE-mediated responses to cow's milk. Three cases of infants with suspected FPIAP were presented: milk-based formula-fed (case 1) or breast-fed (case 2) infants that are well appearing and thriving, and a breast-fed infant who is not growing appropriately along with a personal and family history of atopy (case 3). Fifty-eight pediatric gastroenterologists and 32 immunologists completed the questionnaire. Significant differences between gastroenterologists and immunologists were noted regarding the recommended dietary changes in these scenarios. Moreover, despite available guidelines generated by both societies, most physicians confirm the diagnosis based on resolution of symptoms after the dietary change, without re-exposure to the the suspected trigger. In addition, time for recommended re-exposure in infants with FPIAP was also different; most gastroenterologists recommended waiting until 12 months of age, while immunologists suggested reintroduction earlier, up to 6 months of age. We identified significant practice variations in diagnosis and management of FPIAP between pediatric gastroenterologists and immunologists, with lack of adherence to society guidelines. Joint task forces of primary care pediatricians, gastroenterologists, and immunologists should provide uniform guidelines to standardize care.

Effects of elimination diets and clinical findings on mothers' anxiety in infants with food allergy with non-life-threatening reactions.

Background. In food allergies (FA), the current treatment is eliminating the responsible food from the diet until tolerance develops. We aimed to determine the effects of the mother's elimination diets and clinical findings on the mothers' anxiety in infants with food allergy (FA) with non-life-threatening reactions. Methods. Our study included 100 infants with FA and 35 healthy infants as control. A data form was prepared to collect information about the infants' and their mothers' socio-demographic characteristics, clinical findings, features of the mother's elimination diet, and FA-related internet search. State-Trait Anxiety Inventory (STAI) was applied to all mothers. Results. The STAI (state anxiety and trait anxiety) scores of the mothers of the infants with FA were higher than the control group (p less than 0.001, p = 0.001, respectively). Of the infants with FA, 51% had food protein-induced allergic proctocolitis (FPIAP), 29% had atopic dermatitis (AD), 20% had urticaria-angioedema (U/AE). It was found that state anxiety scores were higher in mothers whose child had FPIAP, who had multiple food eliminations, who followed the allergy groups on social media, and who made the elimination diet herself (p = 0.008, p = 0.048, p less than 0.001, p = 0.001, respectively). Conclusions. The state anxiety and trait anxiety of the mothers of the infants with FA were higher than the control group, and the state anxiety scores were higher especially in the mothers of infants with FPIAP and multiple food elimination.

Food Protein-Induced Allergic Proctocolitis: The Effect of Maternal Diet During Pregnancy and Breastfeeding in a Mediterranean Population.

BackgroundThe aim of the current investigation was to explore the association of food protein-induced allergic proctocolitis (FPIAP) with the maternal diet during pregnancy and breastfeeding in Greek infants.MethodsA multicenter retrospective case-control study was conducted in 6 regions in Greece, with 96 mothers of infants with and 141 mothers of infants without a history of FPIAP. Maternal dietary habits during pregnancy and breastfeeding were evaluated with the following validated questionnaires: (a) The Mediterranean Diet Score and (b) The Mediterranean Oriented Culture-Specific Semi-Quantitative Food Frequency Questionnaire.ResultsFPIAP was associated with cow's milk (83.6%), egg (7.3%), wheat (6.4%), and beef (6.4%) in the maternal diet. Adherence to Mediterranean Diet was similar among the mothers. Mothers of FPIAP infants consumed more vegetables. Elastic net prediction models showed that, in this Mediterranean population, increased consumption during pregnancy and lactation of common allergens, whole grain products, homemade food, fish and shellfish, and fruits was associated with a decreased risk of FPIAP. Conversely, a high intake of vegetables, sugar and total fat, and non-stick/grilled cooking, were associated with increased risk of FPIAP, as was a high intake of salt and white flour during lactation only.ConclusionsComponents of a maternal Mediterranean Diet may protect against FPIAP when traditional cooking methods are adopted and fish, fruit, and whole wheat products are consumed frequently during pregnancy and breastfeeding.

Clinical Features and Clinical Course of Food Protein—Induced Allergic Proctocolitis: 10-Year Experience of a Tertiary Medical Center

Food protein-induced allergic proctocolitis (FPIAP) is a food allergy characterized by bloody stools in well-appearing breast-fed infants. To determine the clinical course of FPIAP and the factors affecting the development of tolerance. Over a 10-year period, patients with a diagnosis of FPIAP who were followed at the outpatient Allergy-Immunology clinic in a tertiary care children's hospital in Turkey were retrospectively analyzed. The frequency of FPIAP was 0.18% among 64,549 patients. The median age of symptom onset was 2 months (interquartile range, 1.0-3.5 months), and the median age of tolerance development was 12 months (interquartile range, 8.0-17.21 months). The occurrence of symptoms in the neonatal period was associated with a history of premature birth (odds ratio, 3.75; 95% CI, 1.33-10.59; P= .031) and neonatal intensive care unit hospitalization (odds ratio, 4.72; 95% CI, 1.78-12.53; P= .002). Use of a cow's milk-based formula was associated with a higher risk of the onset of symptoms after 1 month (odds ratio, 2.69; 95% CI, 1.19-6.07; P= .016). The use of an amino acid-based formula and the presence of diarrhea at admission were associated with later development of tolerance (P= .023 and P < .001, respectively). An IgE-mediated reaction was observed during oral food challenge testing in 6% of the patients. The manifestations of FPIAP appeared earlier in premature infants and later in infants using formula. The use of amino acid-based formula and having had diarrhea were associated with delayed tolerance.

Non-IgE mediated food allergy: food protein-induced allergic proctocolitis - An update

Non-IgE mediated food allergy: food protein-induced allergic proctocolitis - An update

Food Protein-Induced Allergic Proctocolitis May Have Distinct Phenotypes

To investigate the prevalence of immunoglobulin E (IgE) sensitization and transition to IgE-mediated allergy to the culprit food or other concomitant foods in infants with food protein-induced allergic proctocolitis (FPIAP).In this retrospective study, we included 204 infants with confirmed FPIAP, evaluated between January 2015 and December 2018 at Hacettepe University, in Ankara, Turkey.Infants were categorized into 3 groups on the basis of clinical history, serum immunoglobulin E (sIgE) levels, and skin-prick tests (SPTs). Group 1 was those with FPIAP with or without IgE-mediated food hypersensitivity to offending and “nonoffending” foods at the initial consultation (n = 180). Group 2 was those with FPIAP with IgE sensitization but no clinical hypersensitivity symptoms to offending foods at onset or during study follow-up (n = 17), and group 3 was those with FPIAP with no sensitization at onset but who had a later transition to IgE-mediated hypersensitivity at follow-up (n = 7).FPIAP onset occurred at a median age of 2 months (25% to 75%; interquartile range [IQR]: 1.0–3.0). Milk was the trigger for 62.7% (n = 128). In 36.7% (n = 75), the trigger was milk plus other foods, and 0.5% (n = 1) had a trigger that was not milk. Children developed tolerance at a median of 12 months (IQR: 10.0–14.0). Among 180 infants in group 1, 86% (n = 156) did not show IgE to any food, 7.7% (n = 14) had IgE sensitization to offending foods at the initial consultation, and 9 of these 14 patients had symptoms of both IgE-mediated allergy and FPIAP to cow’s milk (CM) and egg white at onset of FPIAP. The median age of tolerance in group 1 was 11 months (IQR: 10–14]. Group 2 had sensitization to FPIAP triggering foods but no symptoms of IgE-mediated allergy. Twelve had positive SPT or sIgE to CM, 3 were positive to egg, and 3 had positive test results to CM and egg (the median sIgE to CM was 0.5 kUA/L; the median IgE to egg was 2.1 kUA/L at FPIAP onset). The median age of tolerance to FPIAP trigger foods in group 2 was 11 months (IQR: 9.5–12). Group 3 developed IgE-mediated symptoms to trigger foods at a median age of 5 months (IQR: 5–6). The median age of tolerance to IgE-mediated FPIAP triggering foods was 19 months (IQR: 18.0–29.0). Children with multiple food FPIAP developed tolerance later than those with single-food FPIAP (the median age for multiple food FPIAP groups was 13 months [IQR: 11–16] versus that of single-food FPIAP, which was 11 months [IQR: 10–13]; P < .001).On the basis of this study, some infants with FPIAP may transition to different food allergy clinical phenotypes, including IgE-mediated hypersensitivity to FPIAP triggering foods. Although all infants in the study developed tolerance, there was a delay in tolerance development among infants who transitioned to IgE-mediated hypersensitivity, compared with that of other groups. Those with multiple food FPIAP also had delayed tolerance when compared with infants with single-food FPIAP.Because of the retrospective nature, the strength of the conclusions are limited by a lack of systematic timing of challenge to trigger foods in infants with FPIAP and IgE-mediated allergy. Nonetheless, this information can be useful in counseling families regarding the likely time to resolution when concomitant IgE-mediated symptoms occur in individuals initially diagnosed with FPIAP and those with multiple food FPIAP. Unfortunately, they were not able to determine risk factors for development of IgE-mediated allergy in these infants with FPIAP. Further prospective studies are needed.

Prospective Assessment of Pediatrician-Diagnosed Food Protein-Induced Allergic Proctocolitis by Gross or Occult Blood

To prospectively define the incidence of food protein–induced allergic proctocolitis (FPIAP) and identify risk factors.Newborn infants (n = 903) from a single suburban, private, primary pediatrics practice in Massachusetts from April 2014 to February 2017: Gastrointestinal Microbiome and Allergic Proctocolitis cohort.Infants were recruited at their initial newborn visit and managed prospectively at routine well-child checks and sick visits for a diagnosis of FPIAP. The primary outcome was pediatrician-diagnosed FPIAP, which was then confirmed by research staff by using prespecified inclusion criteria, including documentation of gross or occult blood in the stool.The recruited cohort was predominately male (54%), White (69%), term (89%), and delivered vaginally (68%). A cumulative incidence of 17% (n = 153) of infants met inclusion criteria for a FPIAP diagnosis. The median age at symptom onset was 26 days, and the median age at FPIAP diagnosis was 35 days. Of the FPIAP cases, 41% (n = 63) had gross blood, and 37% (n = 56) had mucus with microscopic blood in their stool. The median age of symptom resolution was 123 days. Risk factors for FPIAP included a first-degree relative with food allergy (odds ratio [OR]: 1.9; 95% confidence interval [CI]: 1.2 to 2.8; P = .005), eczema (OR: 1.5; 95% CI: 1.1 to 2.2; P = .02), and household pets at birth (OR: 1.5; 95% CI: 1.01 to 2.1; P = .043). Infants initially fed both breast milk and formula were 61% less likely to develop FPIAP, compared with infants exclusively formula fed (hazard ratio [HR]: 0.39; P = .005). Infants fed both breast milk and formula at any point during the first 4 months were 56% less likely than exclusively formula-fed infants and 38% less likely than exclusively breastfed infants to develop FPIAP (HR: 0.44 [P = .005]; HR: 0.62 [P =.0497].When diagnosed clinically by community pediatricians, without confirmatory oral challenge, the prospectively defined FPIAP incidence is markedly higher than previous published estimates.FPIAP is generally considered a mild, self-limited, non–immunoglobulin E–mediated food allergy (with cow’s milk protein the most common trigger) found in otherwise healthy infants. There is a lack of validated diagnostic criteria, but elimination diet and rechallenge have been proposed. Diagnosis based solely on occult blood is controversial. This prospective observational cohort study found an exceptionally high rate of diagnosis by using the criteria applied and is possibly biased by the single-center design. This is not a criticism! It raises many important questions about infants presenting with gross or occult fecal blood. Interestingly, many of the infants had associated gagging, vomiting, food refusal, reflux, and/or irritability. Are there alternative diagnoses among this cohort? Do we need firmer diagnostic criteria? These findings underscore the need for exploring this population with gross or occult blood in the stool to better understand diagnoses, causes, and treatments. A follow-up analysis of this cohort revealed that children with the FPIAP diagnosis had a twofold risk of developing immunoglobulin E–mediated food allergy, even when accounting for atopic dermatitis as a risk (Martin VM, Virkud YV, Phadke NA, et al. Increased IgE-mediated food allergy with food protein-induced allergic proctocolitis. Pediatrics. 2020;146[3]:e20200202). This could be explained by a shared pathophysiology, or the possibility that dietary elimination was a risk factor. Because symptoms of FPIAP are often not reproduced by reexposure, there may be an unnecessary risk imposed by presumptive dietary elimination. Although, in the study, the researchers raise fascinating questions, it is important to strongly consider confirming a food trigger. Earlier milk reintroduction attempts in infants with FPIAP are thus encouraged.

Increased IgE-Mediated Food Allergy With Food Protein-Induced Allergic Proctocolitis

To examine the relationship between food protein-induced allergic proctocolitis (FPIAP) and the risk of developing immunoglobulin E–mediated food allergy (IgE-FA) in infants.In the study, the researchers included 903 infants who were enrolled in the Gastrointestinal Microbiome and Allergic Proctocolitis (GMAP) cohort, an observational healthy-infant cohort study in which researchers characterized the epidemiology of FPIAP in the primary care setting.Infants diagnosed with FPIAP with presence of documented blood in the stool were included. IgE-FA was determined by 2 allergists independently reviewing clinical and sensitization data from children whose parents reported suspect reactions and included if both reviewers agreed the diagnosis was “confirmed” or probable.” The rate of IgE-FA was compared between healthy infants and those with FPIAP. Additional variables, including the presence of eczema, were evaluated by using univariable and multivariable logistic regression.More children with FPIAP developed IgE-FA (11%), compared with healthy children (5%). Adjusting for eczema, children with FPIAP had twice the odds of developing IgE-FA to any food. FPIAP was most strongly associated with IgE-FA to milk, although the study was not powered to detect relationships to individual foods.Children with FPIAP were at an increased risk for having IgE-FA. This may be multifactorial, including shared pathogenesis in the development of FPIAP and IgE-FA and/or an effect of antigen elimination diet used to treat FPIAP.FPIAP is a common diagnosis early in infancy that is benign and self-resolved. However, a diagnosis of FPIAP often leads to prolonged dietary restriction from cow’s milk (the most common cause) and potentially soy protein as well. Although conventional teaching is to wait until 12 months of age to reintroduce dairy to infants with FPIAP, it can likely be introduced much earlier. In this study, researchers found an association between a diagnosis of FPIAP with increased risk for IgE-FA, although diagnosis was not confirmed through oral food challenges. Although the authors report some potential common immunologic pathways between FPIAP (a non–immunoglobulin E–mediated food reaction) and IgE-FA, a true causative effect has not been established. Now that current evidence-based guidelines recommend early introduction of allergenic foods to all infants (beginning ∼4-6 months of age) and ongoing inclusion in the diet as the best path toward food allergy prevention, with this study, the authors reinforce the need for pediatricians to discuss these guidelines with parents. This is especially true in infants at a higher risk to develop food allergy, including those with severe or persistent atopic dermatitis and now, potentially, other forms of non–immunoglobulin–mediated food allergy. Now, more than ever, we need to let the infants eat!

Rectal Bleeding and Cow’s Milk Protein-induced Allergic Proctocolitis: A Prospective Study

To assess time to resolution of food protein–induced allergic proctocolitis (FPIAP).In this study, researchers evaluated 76 infants aged <4 months with rectal bleeding (RB) referred to the pediatric gastrointestinal department at Trousseau Hospital in Paris, France, between May 2014 and December 2017. Only infants whose RB responded to a cow’s milk elimination diet were included in the study.This was a prospective cohort of infants with concern for cow’s milk protein (CMP) allergy who had resolution of RB with CMP elimination. Exclusion criteria included RB because of another etiology and exclusively breastfed infants. A total of 2 to 8 weeks after resolution of RB, CMP oral food challenge (OFC) was completed. If FPIAP was confirmed, OFC was repeated every 2 months after the age of 4 months to assess the time to tolerance of CMP. Ongoing FPIAP CMP was defined as RB, behavioral change, diarrhea, and vomiting. Tolerance was defined as CMP daily without symptoms.Only 31% of the cohort failed OFC at initial diagnostic challenge, meaning that over two-thirds of infants who initially responded to CMP exclusion did not have return of symptoms on rechallenge just weeks later. Of the patients confirmed to have FPIAP CMP, the median age of tolerance was determined to be 6.8 months, with >75% of the cohort tolerant by 10 months. Infants with a first-degree family history of atopic disease developed tolerance later (8.9 months versus 5.1 months).In this work, it was confirmed that the majority of RB in infants is likely not related to FPIAP CMP. This study also revealed that the time to resolution might be earlier than previously thought.Although there are no solid guidelines on introduction of CMP in presumed FPIAP CMP, the majority of patients exclude CMP until approximately 1 year. In this study, it was found that only one-third of RB before 4 months was due to FPIAP. Of those with FPIAP, CMP could be challenged earlier and at more frequent intervals depending on family wishes. A major limitation of this study is that exclusively breastfed infants were excluded and the lack of information on maternal diet in those who were nursing.

A Synopsis of the Synopses, 2020–2021

A Synopsis of the Synopses, 2020–2021

Pathophysiology of Non-IgE-Mediated Food Allergy.

Non-IgE-mediated food allergies are a group of disorders characterized by subacute or chronic inflammatory processes in the gut. Unlike IgE mediated food allergies that may result in multi-organ system anaphylaxis, the non-IgE mediated food allergies primarily affect the gastrointestinal tract. This review outlines the clinical manifestations, epidemiology, pathophysiology, and management of non-IgE-mediated food allergies. An updated literature search of selected non-IgE-mediated food allergies was conducted for this review using PubMed database to the current year (2021). Reviewed disorders include food protein-induced enterocolitis syndrome (FPIES), food-protein enteropathy (FPE), food protein-induced allergic proctocolitis (FPIAP), and eosinophilic gastrointestinal disorders (EGIDs) such as eosinophilic esophagitis (EoE). While extensive gains have been made in understanding FPIES, FPIAP, FPE, and EoE, more information is needed on the pathophysiology of these food allergies. Similarities among them include involvement of innate immunity, T-lymphocyte processes, alteration of the intestinal lumen at the cellular level with the appearance of inflammatory cells and associated histologic changes, and specific cytokine profiles suggesting food-specific, T-cell, and immune-mediated responses. While FPIES and FPIAP typically resolve in early childhood, EGIDs typically do not. Emerging new therapies for EoE offer promise of additional treatment options. Further studies identifying the immunopathogenesis, associated biomarkers, and mechanisms of tolerance are needed to inform prevention, diagnosis and management.

Risk Factors Influencing Tolerance and Clinical Features of Food Protein-Induced Allergic Proctocolitis

To examine the clinical course and risk factors of food protein-induced allergic proctocolitis (FPIAP).A total of 257 infants who presented to 5 outpatient pediatric allergy or gastroenterology clinics with rectal bleeding and were given a diagnosis of FPIAP were included in the study.After enrollment, infants had serum immunoglobulin E testing, skin-prick testing (SPT), and complete blood cell count. Clinical characteristics were prospectively managed. Patients with other known gastrointestinal illnesses were excluded. Cow’s milk elimination was trialed first in both the infant’s diet as well as the mother’s diet if breastfeeding, and, if no improvement, egg was eliminated next. Combined elimination of wheat, nuts, and soy followed, if no improvement. Eliminated foods were then reintroduced after 2 to 4 weeks, and a worsening of symptoms confirmed diagnosis.There was no sex predominance, with 50.2% being female (n = 129). The vast majority were breastfed at diagnosis (97.2%), with 66.5% exclusively breastfed. Blood in stool was present in every case, and other common complaints were mucous in stool (n = 224) and loose stool (n = 168). Cow’s milk was the most common causative food, accounting for 99.2% of cases. Comparing those with only 1 food allergy (75.9%) versus those with multiple food allergies, children with a single-food allergy more often were exclusively breastfeeding at diagnosis, had a longer duration of breastfeeding, had less antibiotic use in the first 6 months, and had higher tolerance development (P = .003, < 0.001, < 0.001, and < 0.001, respectively). Immunoglobulin E (IgE) sensitization was assessed in 239 patients, and 55 (23%) had positive test results. Sensitized children less often developed tolerance to the offending allergen compared with nonsensitized children (52.4% versus 81.2%). Only 16 patients underwent endoscopy and were continued to be treated as having FPIAP.Most patients with FPIAP resolve within a year. Infants with colic, IgE sensitization, and multiple food allergies may be at risk for delayed tolerance. Cow’s milk should be the first excluded food in infants and breastfeeding mothers, and elimination should resolve symptoms in most patients. Breastfeeding and lower antibiotic use was associated with a decrease in the development of multiple food allergies. The role of SPT and IgE testing is still unclear and may not add benefit to most cases. Endoscopy did not change management, even in severe cases.This is an important study that characterizes a common condition. The prospective nature of this study is a strength, along with high retention of subjects throughout the study. The involvement of multiple centers and specialties introduced some variability in practice. More severe cases of FPIAP are likely represented in this study because subjects had referral to allergy or gastroenterology specialists. Also, the high prevalence of breastfeeding in this cohort may limit its generalizability to other communities; regional food preferences and breastfeeding prevalence may have a large effect on the development of allergies and food sensitization.

Newborns with Bloody Stools-At the Crossroad between Efficient Management of Necrotizing Enterocolitis and Antibiotic Stewardship.

The onset of bloody stools in neonates often results in antibiotic treatment for suspected necrotizing enterocolitis (NEC). Food protein-induced allergic proctocolitis (FPIAP) is an often-neglected differential diagnosis. We performed a retrospective analysis of antibiotic exposure at our tertiary center from 2011 to 2020 that included three time periods of differing antimicrobial stewardship goals. We compared these data with the conventional treatment guidelines (modified Bell’s criteria). In our cohort of 102 neonates with bloody stools, the length of antibiotic exposure was significantly reduced from a median of 4 to 2 days. The proportion of treated neonates decreased from 100% to 55% without an increase in negative outcomes. There were 434 antibiotic days. Following a management strategy according to modified Bell’s criteria would have led to at least 780 antibiotic days. The delayed initiation of antibiotic treatment was observed in 7 of 102 cases (6.9%). No proven NEC case was missed. Mortality was 3.9%. In conclusion, with FPIAP as a differential diagnosis of NEC, an observational management strategy in neonates with bloody stools that present in a good clinical condition seems to be justified. This may lead to a significant reduction of antibiotic exposure. Further prospective, randomized trials are needed to prove the safety of this observational approach.

A Prospective Assessment of Clinical Characteristics and Responses to Dietary Elimination in Food Protein–Induced Allergic Proctocolitis

Some aspects of diagnostic elimination/challenge diets in food protein-induced allergic proctocolitis (FPIAP) are still poorly defined. This study investigated the symptom spectrum, time required for resolution of each symptom, triggering foods, and risk factors for multiple food allergies (MFA) in FPIAP. Infants referred with visible blood in stool were enrolled after etiologies other than FPIAP had been excluded. Laboratory evaluation, clinical features, and elimination/challenge steps were performed prospectively during diagnostic management. Ninety-one of 102 infants (53 boys) were diagnosed with FPIAP. Eleven children did not bleed during challenges. Visible blood in stool began before 2 months of age in 63.6% of the infants not diagnosed with FPIAP, compared with 18.9% of the patients with FPIAP (P= .003). Offending foods were identified as cow's milk (94.5%), egg (37.4%), beef (10.9%), wheat (5.5%), and nuts (3.3%). MFA was determined in 42.9% of patients. Multivariate logistic regression analysis identified atopic dermatitis (AD) (odds ratio [OR]: 2.98, 95% confidence interval [CI]: 1.18-7.55, P= .021) and an eosinophil count ≥300 cells/μL (OR: 2.72, 95% CI: 1.09-6.80, P= .032) as independent risk factors for MFA. Blood and mucus in stool disappeared in a median 3 days (interquartile range [IQR]: 1-14.5 days) and 30 days (IQR: 8-75 days), respectively. A tendency to transient bleeding occurs in infants who present with bloody stool before 2 months of age. A 2-week duration of elimination for blood in stool is sufficient to reach a judgment of suspected foods for FPIAP. Mucus in stool is the last symptom to disappear. Concurrent AD suggests a high probability of MFA in FPIAP.

Non-IgE-Mediated Gastrointestinal Food Protein-Induced Allergic Disorders. Clinical Perspectives and Analytical Approaches

Non-IgE-mediated gastrointestinal food allergy (non-IgE-GI-FA) is the name given to a series of pathologies whose main entities are food protein-induced allergic proctocolitis (FPIAP), food protein-induced enteropathy (FPE), and food protein-induced enterocolitis syndrome (FPIES). These are more uncommon than IgE-mediated food allergies, their mechanisms remain largely unknown, and their diagnosis is mainly done by clinical history, due to the lack of specific biomarkers. In this review, we present the latest advances found in the literature about clinical aspects, the current diagnosis, and treatment options of non-IgE-GI-FAs. We discuss the use of animal models, the analysis of gut microbiota, omics techniques, and fecal proteins with a focus on understanding the pathophysiological mechanisms of these pathologies and obtaining possible diagnostic and/or prognostic biomarkers. Finally, we discuss the unmet needs that researchers should tackle to advance in the knowledge of these barely explored pathologies.

The Low Maternal Consumption of Homemade Fermented Foods in Pregnancy Is an Additional Risk Factor for Food Protein-Induced Allergic Proctocolitis: A Case-Control Study

Introduction: Food protein-induced allergic proctocolitis (FPIAP) is the most common non-IgE-mediated food allergy and it varies between 4% and 8% in infants. The aim of the study was to evaluate the potential association between FPIAP in infants and maternal daily consumption of homemade fermented foods (FFs) during pregnancy. Methods: Two hundred and seven infants were included in this case-control study, 106 with physician-diagnosed FPIAP (FPIAP group) and 101 age- and gender-matched healthy infants (control group), together with their mothers. The frequency and diversity of the 8 most consumed homemade FFs in traditional Turkish cuisine and daily maternal consumption of these during pregnancy were evaluated retrospectively using a structured questionnaire. Results: Rates of vaginal delivery, maternal smoking during pregnancy, educational status, and monthly household income were higher in the FPIAP group than the control group (p = 0.046, p = 0.014, p < 0.001, and p = 0.009, respectively). The 3 most common daily-consumed FFs during pregnancy were, in order, yogurt, cheese, and tarhana. The diversity of daily-consumed FFs during pregnancy (p = 0.004) and the consumption of the 3 most common FFs (p = 0.011) were lower in the FPIAP group than in the control group. Maternal smoking during pregnancy (odds ratio [OR]: 2.97, 95% confidence interval [CI]: 1.19–7.41, p = 0.019) and a higher maternal educational status (OR: 3.34, 95% CI: 1.63–6.84, p = 0.001) increased the risk of FPIAP at multivariate logistic regression, while the diversity of maternal FF consumption was protective against FPIAP (OR: 0.75, 95% CI: 0.58–0.96, p = 0.025). Conclusion: Daily maternal consumption of yogurt, cheese, and tarhana during pregnancy was less common in FPIAP. The diversity of traditional Turkish homemade FFs may reduce the risk of FPIAP, whereas maternal smoking and a higher maternal educational status were associated with an increased risk of FPIAP.

Influences of non-IgE-mediated cow's milk protein allergy-associated gut microbial dysbiosis on regulatory T cell-mediated intestinal immune tolerance and homeostasis

Gut microbial dysbiosis is closely associated with cow's milk protein allergy (CMPA) during infancy. Recent research has highlighted the crucial role of the commensal microbiota-induced intestinal regulatory T (Treg) cell response in the development of oral tolerance and protection against IgE-mediated food allergies. However, the influences of CMPA (particularly non-IgE-mediated CMPA)-associated microbial dysbiosis on Treg cell-mediated intestinal immune tolerance and homeostasis remain poorly characterized. To investigate this issue, fecal microbiota from infant donors with food protein-induced allergic proctocolitis (FPIAP) associated with cow's milk, which is the most frequent clinical type of non-IgE-mediated gastrointestinal CMPA, and from age-matched healthy controls were transplanted into germ-free mice in this study. Two weeks post fecal microbiota transplantation, the gut microbiome of the recipient mice was analyzed by 16S rRNA gene sequencing, and the intestinal immunological alterations associated with the Treg cell compartment and intestinal immune homeostasis were detected. The specific gut microbial phylotypes that were potentially responsible for the disruption of intestinal immune homeostasis were also analyzed. We observed that the main characteristics of the gut microbiome in infant donors could be stably maintained in recipient mice. We also found that mice colonized with the gut microbiome from infants with cow's milk-induced FPIAP showed significant deficiencies in the accumulation and function of intestinal Treg cells. Furthermore, these mice showed disrupted intestinal immune homeostasis, which was characterized by an overactivated Th2 biased immune response. We further identified two potentially pathogenic genera that contribute to this disruption. Overall, our results highlight a destructive effect of non-IgE-mediated CMPA-associated microbial dysbiosis on intestinal immune tolerance and homeostasis. We believe these findings will help improve our understanding of the gut microbiota-mediated pathogenesis of non-IgE-mediated CMPA in the future.