To Diet or Not to Diet This Is the Question in Food-Protein-Induced Allergic Proctocolitis (FPIAP)-A Comprehensive Review of Current Recommendations.

Food-protein-induced allergic proctocolitis (FPIAP) is an increasingly reported transient and benign form of colitis that occurs commonly in the first weeks of life in healthy breastfed or formula-fed infants. Distal colon mucosal inflammation is caused by a non-IgE immune reaction to food allergens, more commonly to cow's milk protein. Rectal bleeding possibly associated with mucus and loose stools is the clinical hallmark of FPIAP. To date, no specific biomarker is available, and investigations are reserved for severe cases. Disappearance of blood in the stool may occur within days or weeks from starting the maternal or infant elimination diet, and tolerance to the food allergen is typically acquired before one year of life in most patients. In some infants, no relapse of bleeding occurs when the presumed offending food is reassumed after a few weeks of the elimination diet. Many guidelines and expert consensus on cow's milk allergy have recently been published. However, the role of diet is still debated, and recommendations on the appropriateness and duration of allergen elimination in FPIAP are heterogeneous. This review summarizes and compares the different proposed nutritional management of infants suffering from FPIAP, highlighting the pros and cons according to the most recent literature data.

Food protein-induced allergic proctocolitis in infants is associated with low serum levels of macrophage inflammatory protein-3a.

BACKGROUND: Food protein-induced allergic proctocolitis (FPIAP) is a nonimmunoglobulin (IgE)-mediated food hypersensitivity and the exact mechanisms that cause FPIAP are unknown. Chemokines play crucial roles in the development of allergic diseases. OBJECTIVE: To examine serum levels of a group of chemokines in infants with FPIAP. METHODS: In 67 infants with FPIAP and 65 healthy infants, we measured serum levels of mucosa-associated epithelial chemokine (MEC/CCL28), thymus-expressed chemokine (TECK/CCL25), CX3CL1 and macrophage inflammatory protein (MIP)-3a/CCL20. RESULTS: Infants with FPIAP had a lower median value of MIP3a/CCL20 than healthy infants [0.7 (0-222) vs. 4 (0-249) pg/mL, respectively] (p < 0.001). Infants with MIP3a/CCL20 levels ≤0.95 pg/mL have 13.93 times more risk of developing FPIAP than infants with MIP3a/CCL20 levels >0.95 pg/mL. Serum MEC/CCL28, TECK/CCL25, and CX3CL1 levels were similar between the infants with FPIAP and the control group. CONCLUSION: MIP3a/CCL20 serum levels were reduced in infants with FPIAP compared with healthy controls. Whether this finding has a role in pathogenesis remains to be determined.

Cow's Milk Protein Allergy.

Cow's milk allergy refers to an immunological reaction to milk protein. It is one of the commonest food protein allergies with an estimated prevalence of 0.5% to 3% at 1 y of life. The disease may be IgE or non-IgE mediated or mixed with a wide range of symptoms often involving multiple organ systems. Gastrointestinal manifestations are common in non-IgE disease and may consist of enteropathy, proctocolitis, colic, reflux-like symptoms, constipation, enterocolitis syndrome and eosinophilic esophagitis. The gold standard for diagnosis remains a double-blind placebo-controlled oral challenge. Specific IgE and skin prick tests may predict severe and persistent disease, and aid in deciding on reintroduction or oral immunotherapy; however, they do not contribute to a definitive diagnosis as they indicate only sensitization. In practice, an elimination diet followed by open challenge under medical supervision is often used for diagnosis except when symptoms are severe such as anaphylaxis. Management consists of the elimination of the allergen with resolution of symptoms between 1-4 wk later depending on the type of allergy. Extensively hydrolyzed and Amino acid formulas are used to substitute milk in infants. Soy-based formulas are often utilized in resource-limited settings. Tolerance to the protein develops over time and periodic reintroduction should be attempted every six months after the initial one year of elimination diet. Oral immunotherapy is a newer treatment technique for IgE-mediated disease. There is no firm evidence on prevention apart from recommending breast feeding in early life along with initiating complementary feeding between 4-6 mo age.

What is Known About Cow's Milk Protein Allergy in Preterm Infants?

Background: Cow's milk protein allergy (CMPA) is well described in term infants, as opposed to preterm infants. In preterm infants, CMPA shares many gastrointestinal symptoms with necrotizing enterocolitis (NEC). Objectives: To evaluate the presentation of CMPA in preterm infants and to investigate the different diagnostic and therapeutic options. Materials and Methods: We searched for the relevant literature using the medical databases PubMed, Web of Science, and the Cochrane Library. We performed a post hoc analysis on the 25 case reports included in this study. Results: Literature was scarce and heterogeneous. The majority of preterm infants with CMPA were exposed to bovine-based milk proteins before the development of symptoms. The most common clinical manifestations were bloody stools, vomiting, and abdominal distension. Of the 25 cases, only 7 (28%) retained human milk in their diet after diagnosis. In the larger studies, no study has human milk as primary feeding choice after diagnosis. Conclusions: Preterm infants exposed to a type of cow's milk-based formula in their first days of life have a higher risk of developing CMPA. Most of the preterm infants are no longer fed with human milk after the diagnosis of CMPA is made, which is in contrast with current nutrition guidelines in preterm infants. We strongly advocate that human milk with mothers on a cow's milk-free diet is the first choice of feed after the diagnosis of CMPA. Prospective studies are necessary to obtain more information regarding clinical presentation, diagnostic tools, and therapeutic approaches.

Allergic Proctocolitis: Literature Review and Proposal of a Diagnostic-Therapeutic Algorithm.

Allergic proctocolitis (AP) is a benign condition, frequent in childhood, that is classified as a non-IgE-mediated food allergy. The prevalence is unknown; however, its frequency appears to be increasing, especially in exclusively breastfed infants. Clinical manifestations typically begin in the first few months of life with the appearance of bright red blood (hematochezia), with or without mucus, in the stool of apparently healthy, thriving infants. Most cases of AP are caused by cow's milk proteins; however, other allergens, such as soy, egg, corn, and wheat, may be potential triggers. Diagnosis is based on the patient's clinical history and on the resolution of signs and symptoms with the elimination of the suspected food antigen from the diet and their reappearance when the food is reintroduced into the diet. The treatment of AP is based on an elimination diet of the trigger food, with resolution of the symptoms within 72-96 h from the beginning of the diet. The prognosis of AP is good; it is a self-limiting condition, because most children can tolerate the trigger food within one year of life, with an excellent long-term prognosis. The purpose of this review is to provide an update on the current knowledge and recommendations in epidemiological, diagnostic, and therapeutic terms to the pediatricians, allergists, and gastroenterologists who may find themselves managing a patient with AP.

A different starting line for allergic march: food protein-induced allergic proctocolitis.

OBJECTIVE: The aim of this study is to investigate the long-term prognosis of food protein--induced allergic proctocolitis (FPIAP) patients, the risk of developing both allergic and gastrointestinal diseases, and to evaluate whether it leads to allergic march. METHODS: A total of 149 children who were diagnosed with FPIAP and developed tolerance at least 5 years prior to the study and 41 children (with no history of food allergy) as a control group were enrolled. Both groups were re-evaluated for allergic diseases as well as gastrointestinal disorders. RESULTS: The mean age of diagnosis for the FPIAP group was 4.2 ± 3.0 months, while the mean age of tolerance was 13.9 ± 7.7 months. The mean age of both FPIAP and control groups at the last visit was 101.6 ± 24.4 and 96.3 ± 24.1 months, respectively (P = 0.213). At the final evaluation of both groups, the comorbid allergic disease was significantly higher in the FPIAP group (P < 0.001). There was no significant difference between the two groups in terms of functional gastrointestinal disorders (FGIDs), eosinophilic gastrointestinal diseases, and inflammatory bowel disease (P = 0.198, 0.579, and 0.579, respectively).In the FPIAP group, the allergic disease was significantly higher at the final visit in patients with comorbid allergic disease at diagnosis (P < 0.001). In the FPIAP group, FGID was significantly higher in the group that developed allergic diseases in the future, compared to the group that did not develop allergic diseases in the future (P = 0.034). The proportion of both FGID and allergic diseases was significantly higher in subjects that developed tolerance at >18 months, compared to subjects that developed tolerance at >18 months (P < 0.001 and <0.001, respectively). CONCLUSIONS: Patients with FPIAP may develop allergic diseases as well as FGID in the long term.

Perspectives on Non-IgE-Mediated Gastrointestinal Food Allergy in Pediatrics: A Review of Current Evidence and Guidelines.

Food allergy is an immune-mediated disease that can result in considerable morbidity and even mortality, with a significant negative impact on patients' quality of life. It is characterized by allergic symptoms that can occur shortly after a relevant food allergen ingestion, or can be delayed or chronic, which make it more difficult for diagnosis. The symptoms of this disease can range from mild to severe, and rarely can cause anaphylaxis, a life-threatening allergic reaction. The prevalence of non-immunoglobulin E (IgE)-mediated food allergy is poorly established outside of cow's milk allergy, with an adjusted incidence ranging between 0.13% and 0.72%. Several disorders are classified as non-immunoglobulin E (IgE)-mediated food allergies that predominantly affect the gastrointestinal tract including food protein-induced enterocolitis syndrome (FPIES), food protein-induced allergic proctocolitis (FPIAP), food protein-induced allergic enteropathy (FPE), and food protein-induced dysmotility disorders (GORD and constipation). Eosinophilic esophagitis (EoE) is listed in this group, even though it considered by some authorities to be mixed reaction with both IgE and cell-mediated immune response to be involved in the reaction. The most common types of non-IgE-mediated food allergy are food protein-induced enterocolitis syndrome (FPIES) and food protein-induced allergic proctocolitis (FPIAP). These disorders typically present in infancy and are often triggered by cow's milk protein. Patients with FPIES present with profuse emesis and dehydration, while FPIAP patients present with hematochezia in otherwise healthy infants. Since there are no specific confirmatory non-invasive diagnostic laboratory tests, the diagnosis is usually made clinically when typical symptoms improve upon the removal of the culprit food. Food reintroduction should be attempted, when possible, with documentation of symptoms of relapse to confirm the diagnosis. The management includes dietary avoidance, supportive treatment in the case of accidental exposure, and nutritional counseling. This review focuses on the clinical manifestations, epidemiology, management, and recent guidelines of the most common non-IgE-mediated food hypersensitivity disorders (FPIES, FPIAP, and FPE).

Outcomes reported in randomized controlled trials for mixed and non-IgE-mediated food allergy: Systematic review.

BACKGROUND: Mixed and non-IgE-mediated food allergy is a subset of immune-mediated adverse food reactions that can impose a major burden on the quality of life of affected patients and their families. Clinical trials to study these diseases are reliant upon consistent and valid outcome measures that are relevant to both patients and clinicians, but the degree to which such stringent outcome reporting takes place is poorly studied. OBJECTIVE: As part of the Core Outcome Measures for Food Allergy (COMFA) project, we identified outcomes reported in randomized clinical trials (RCT) of treatments for mixed or non-IgE-mediated food allergy. DESIGN: In this systematic review, we searched the Ovid, MEDLINE and Embase databases for RCTs in children or adults investigating treatments for food protein-induced enterocolitis syndrome, food protein-induced allergic proctocolitis, food protein-induced enteropathy and eosinophilic gastrointestinal disorders including eosinophilic esophagitis [EoE], eosinophilic gastritis and eosinophilic colitis published until 14 October 2022. RESULTS: Twenty-six eligible studies were identified, with 23 focused on EoE (88%). Most interventions were corticosteroids or monoclonal antibodies. All EoE studies assessed patient-reported dysphagia, usually using a non-validated questionnaire. Twenty-two of 23 EoE studies used peak tissue eosinophil count as the primary outcome, usually using a non-validated assessment method, and other immunological markers were only exploratory. Thirteen (57%) EoE studies reported endoscopic outcomes of which six used a validated scoring tool recently recommended as a core outcome for EoE trials. Funding source was not obviously associated with likelihood of an RCT reporting mechanistic versus patient-reported outcomes. Only 3 (12%) RCTs concerned forms of food allergy other than EoE, and they reported on fecal immunological markers and patient-reported outcomes. CONCLUSIONS: Outcomes measured in clinical trials of EoE and non-IgE-mediated food allergy are heterogeneous and largely non-validated. Core outcomes for EoE have been developed and need to be used in future trials. For other forms of mixed or non-IgE-mediated food allergies, core outcome development is needed to support the development of effective treatments. SYSTEMATIC REVIEW REGISTRATION: OSF public registry DOI:10.17605/OSF.IO/AZX8S.

Dietary Factors May Delay Tolerance Acquisition in Food Protein-Induced Allergic Proctocolitis.

BACKGROUND: Dietary and environmental factors may influence tolerance acquisition in food protein-induced allergic proctocolitis (FPIAP). This retrospective observational study explored the role of maternal diet during pregnancy and breastfeeding in tolerance acquisition in infantile FPIAP. METHODS: Breastfed infants with FPIAP from six diverse regions in Greece were divided into two groups, based on development of tolerance to the trigger food: Group A (n = 43), before, and Group B (n = 53), after, the 6th month of age. Maternal diet during pregnancy and breastfeeding was elicited using the Mediterranean Diet Score Questionnaire and the Mediterranean Oriented Culture Specific Semi-Quantitative Food Frequency Questionnaire. RESULTS: Mean age at diagnosis of FPIAP (1.5 months) and weaning (5.5 months) were the same in both groups. The main trigger was cow's milk. Group A received infant milk formula earlier than Group B. Group B had a higher incidence of asthma/wheeze, siblings with milk allergy, maternal smoking and rural residence. On multivariate analysis, earlier resolution of FPIAP was associated with higher maternal education and with salt intake and consumption of goat/sheep cheese during pregnancy and olive oil during breastfeeding. Consumption of multivitamins during pregnancy and meat, winter fruits, green vegetables, butter, salt, "ready-to-eat" meals and pastries during breastfeeding were correlated with longer duration of symptoms. CONCLUSIONS: Mothers of children with FPIAP to cow's milk protein can be advised to eat more yogurt, cheese and olive oil during subsequent pregnancies, and avoid multivitamins, grilled food, "ready-to-eat" meals, pastries, meat and alcohol during breastfeeding, to reduce the duration of FPIAP presenting in future infants.

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

BACKGROUND: 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. OBJECTIVE: This study aimed to assess the erythrocyte zinc levels of children with allergic proctocolitis and compare zinc levels with clinical and demographic characteristics. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.

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

Background: 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. Objective: This study aimed to assess the erythrocyte zinc levels of children with allergic proctocolitis and compare zinc levels with clinical and demographic characteristics. Methods: 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. Results: 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). Conclusions: FPIAP is a food allergy with limited information on its pathogenesis (AU)

[Classification of food allergy: generalities]. / Clasificación de la alergia alimentaria: generalidades.

The prevalence of food allergy has increased in some regions of the world, and with it the incidence, according to geographical variability, in the phenotype and clinical manifestations. Food allergy arises from the specific immune response induced by exposure to the proteins of a certain food. Food intolerance refers to non-immune reactions, caused by unique physiological characteristics of the individual, including metabolic, toxic, pharmacological and undefined mechanisms. Adverse reactions to foods are classified as: IgE-mediated: Type I Hypersensitivity, non-IgE-mediated: Type IV Hypersensitivity, mixed: Types I and IV Hypersensitivity Non-Allergic; toxic, pharmacological, metabolic, intolerances. These types of alterations are rare but have increased in recent years; These include protein-induced enterocolitis syndrome, which can cause emesis, diarrhea and hypotension, and shock, which begins two hours after ingestion of the allergen. Protein-induced allergic proctocolitis is a condition that includes allergy to cow's milk protein. Delayed reactions usually affect the digestive system, are more insidious in their onset and are not immediately controlled, even with the suspension of food. There are eight foods responsible for 90% of food allergies: milk, eggs, soy, wheat, peanuts, walnuts, fish, and shellfish.

La prevalencia de alergia alimentaria se ha incrementado en algunas regiones del mundo, y con ello la incidencia, según la variabilidad geográfica, en el fenotipo y manifestaciones clínicas. La alergia alimentaria surge de la respuesta inmune específica inducida por la exposición a las proteínas de cierto alimento. La intolerancia alimentaria se refiere a reacciones no inmunitarias, causadas por características fisiológicas únicas del individuo, que incluyen mecanismos metabólicos, tóxicos, farmacológicos e indefinidos. Las reacciones adversas a los alimentos se clasifican en: mediada por IgE: Hipersensibilidad Tipo I, no mediada por IgE: Hipersensibilidad Tipo IV, mixtas: Hipersensibilidad Tipos I y IV No Alérgicas; tóxicas, farmacológicas, metabólicas, intolerancias. Este tipo de alteraciones son poco frecuentes, pero se ha incrementado en los últimos años; entre estas se encuentra el síndrome de enterocolitis inducida por proteínas, que puede producir emesis, diarrea e hipotensión, y estado de shock, que inicia dos horas después de la ingestión del alergeno. La proctocolitis alérgica inducida por proteínas es una afectación que incluye la alergia a la proteína de leche de vaca. Las reacciones retardadas suelen afectar el aparato digestivo, son más insidiosas en su inicio y no se controlan inmediatamente, aún con la suspensión del alimento. Existen ocho alimentos responsables del 90% de alergia alimentaria: leche, huevo, soya, trigo, cacahuate, nuez, pescados y mariscos.

[Non-IgE-mediated food allergy]. / Alergia alimentaria no mediada por IgE.

Food allergy is an immune response to proteins in food. It usually affects 8% of children and 2% of adults in Western countries. Non-IgE-mediated food allergy mainly affects the gastrointestinal tract. Gastrointestinal food allergies are classified, by their underlying pathogenesis, as: IgE-mediated, non-IgE-mediated, or mixed. The symptoms of patients with food protein-induced allergic proctocolitis originate from local inflammation of the distal colon, which causes hematochezia in neonates. It can affect the entire gastrointestinal tract and cause symptoms of intractable emesis, with subsequent metabolic disorders and hypovolemic shock. Food protein-induced enterocolitis syndrome is a non-IgE-mediated allergy that usually appears in childhood, with prolonged repetitive vomiting, starting 1 to 4 hours after ingestion of food. The manifestation in adults is usually triggered by the consumption of shellfish. Atopic diseases affect 40-60% of patients with food protein- induced enterocolitis syndrome, including 40-50% of those with food protein-induced enteropathy and proctocolitis. Probiotics (Lactobacillus GG) can alleviate the symptoms of allergic proctocolitis induced by food proteins, by altering the composition of the intestinal microbiota. Fecal microbiota transplantation (FMT) can change intestinal microecology efficiently compared to food or probiotics.

La alergia alimentaria es una respuesta inmunitaria a las proteínas de los alimentos. Suele afectar al 8% de los niños y al 2% de los adultos en países occidentales. La alergia alimentaria no mediada por IgE afecta, principalmente, el aparato gastrointestinal. Las alergias alimentarias gastrointestinales se clasifican, por su patogenia subyacente, en: mediadas por IgE, no mediadas por IgE, o mixtas. Los síntomas de pacientes con proctocolitis alérgica inducida por proteínas alimentarias se originan por la inflamación local del colon distal, que causa hematoquecia en neonatos. Puede afectar todo el conducto gastrointestinal y provocar síntomas de emesis intratable, con subsiguientes trastornos metabólicos y choque hipovolémico. El síndrome de enterocolitis inducida por proteínas alimentarias es una alergia no mediada por IgE que suele aparecer en la infancia, con vómito prolongado repetitivo, que inicia entre 1 a 4 horas después de la ingestión de alimentos. La manifestación en adultos suele desencadenarse por el consumo de mariscos. Las enfermedades atópicas afectan del 40-60% de los pacientes con síndrome de enterocolitis inducida por proteínas alimentarias, incluso al 40-50% de quienes padecen enteropatía y proctocolitis inducidas por proteínas alimentarias. Los probióticos (Lactobacillus GG) pueden aliviar los síntomas de proctocolitis alérgica inducida por proteínas alimentarias, al alterar la composición de la microbiota intestinal. El trasplante de microbiota fecal (TMF) puede cambiar la microecología intestinal de manera eficiente comparada con los alimentos o probióticos.

A different starting line for allergic march: food protein-induced allergic proctocolitis

Objective: The aim of this study is to investigate the long-term prognosis of food protein--induced allergic proctocolitis (FPIAP) patients, the risk of developing both allergic and gastrointestinal diseases, and to evaluate whether it leads to allergic march. Methods: A total of 149 children who were diagnosed with FPIAP and developed tolerance at least 5 years prior to the study and 41 children (with no history of food allergy) as a control group were enrolled. Both groups were re-evaluated for allergic diseases as well as gastrointestinal disorders. Results: The mean age of diagnosis for the FPIAP group was 4.2 ± 3.0 months, while the mean age of tolerance was 13.9 ± 7.7 months. The mean age of both FPIAP and control groups at the last visit was 101.6 ± 24.4 and 96.3 ± 24.1 months, respectively (P = 0.213). At the final evaluation of both groups, the comorbid allergic disease was significantly higher in the FPIAP group (P < 0.001). There was no significant difference between the two groups in terms of functional gastrointestinal disorders (FGIDs), eosinophilic gastrointestinal diseases, and inflammatory bowel disease (P = 0.198, 0.579, and 0.579, respectively). In the FPIAP group, the allergic disease was significantly higher at the final visit in patients with comorbid allergic disease at diagnosis (P < 0.001). In the FPIAP group, FGID was significantly higher in the group that developed allergic diseases in the future, compared to the group that did not develop allergic diseases in the future (P = 0.034). The proportion of both FGID and allergic diseases was significantly higher in subjects that developed tolerance at >18 months, compared to subjects that developed tolerance at >18 months (P < 0.001 and <0.001, respectively). Conclusions: Patients with FPIAP may develop allergic diseases as well as FGID in the long term (AU)

Proctocolite induzida por proteína alimentar - teste de provocação oral deve ser realizado para confirmar o diagnóstico de alergia ao leite de vaca em neonatos? / Induced proctocolitis - oral food challenge should be done to confirm the diagnosis of cow's milk allergy in neonates?

ABSTRACT Background: Suspicion of food protein-induced proctocolitis based on empirical understanding of rectal bleeding can lead to misdiagnosis. Objective: to verify clinical and evaluative characteristics of patients who presented neonatal rectal bleeding and were on a restricted cow's milk diet. Methods: A cross-sectional retrospective study included patients followed up in a tertiary care center, who presented rectal bleeding in the neonatal period. The analyzed data included gender, gestational age, type of delivery, use of antibiotics during the last trimester of pregnancy, use of parenteral nutrition before the first manifestation, use of mechanical ventilation, initial clinical manifestations associated with rectal bleeding, diet before the first manifestation, period of elimination diet, oral food challenge (OFC) results and symptoms presented in cases of positive OFC. Fisher's exact test and Mann-Whitney test were used to analyze the data. The level of significance was set to 5%. Results: Forty-two patients were selected: 30 preterm infants, 34 cesarean deliveries, 10 exclusively breastfed patients before rectal bleeding. Median age at OFC was 6.3 months old. Median of length of the elimination period before OFC was 5.9 months. OFC was negative in 33/42 (79%) patients and positive in 9/42 (21%). There was no association between OFC results and the evaluated data. The main symptom observed in patients with positive OFC was blood in stools. Conclusion: OFC was negative in most cases of suspected cow's milk allergy due to rectal bleeding in neonates, most of them with a history of prematurity.

RESUMO Contexto: A suspeita de proctocolite induzida por proteína alimentar (PCIPA) com base na compreensão empírica de sangramento retal pode levar a diagnósticos equivocados. Objetivo Verificar as características clínicas e evolutivas de pacientes que apresentavam sangramento retal neonatal e faziam uso de dieta restrita com leite de vaca. Métodos: Estudo transversal retrospectivo com pacientes acompanhados em um centro terciário, que apresentaram sangramento retal no período neonatal. Os dados analisados incluíram: sexo, idade gestacional, tipo de parto, uso de antibióticos no último trimestre da gravidez, uso de nutrição parenteral antes da primeira manifestação, uso de ventilação mecânica, manifestações clínicas iniciais associadas ao sangramento retal, dieta antes da primeira manifestação, período de dieta de eliminação, resultados do teste de provocação oral (TPO) e sintomas apresentados em casos de TPO positivo. O teste exato de Fisher e o teste de Mann-Whitney foram usados para analisar os dados. O nível de significância adotado foi de 5%. Resultados: Quarenta e dois pacientes foram selecionados: 30 prematuros, 34 partos cesáreos, 10 pacientes amamentadas exclusivamente antes do sangramento retal. A idade média na ocasião do TPO foi de 6,3 meses. A mediana da duração do período da dieta de eliminação antes do TPO foi de 5,9 meses. O TPO foi negativo em 33/42 (79%) pacientes e positivo em 9/42 (21%). Não houve associação entre os resultados do TPO e os dados avaliados. O principal sintoma observado em pacientes com TPO positivo foi sangue nas fezes. Conclusão: O TPO foi negativo na maioria dos casos de suspeita de alergia ao leite de vaca devido a sangramento retal em neonatos, a maioria deles com história de prematuridade.

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

Background: The 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. Methods: A 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. Results: FPIAP 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. Conclusions: Components 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.

BACKGROUND: Food protein-induced allergic proctocolitis (FPIAP) is a food allergy characterized by bloody stools in well-appearing breast-fed infants. OBJECTIVE: To determine the clinical course of FPIAP and the factors affecting the development of tolerance. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

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

BACKGROUND: Some aspects of diagnostic elimination/challenge diets in food protein-induced allergic proctocolitis (FPIAP) are still poorly defined. OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

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.

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.