Search Results (14)

Background: Food protein-induced allergic proctocolitis (FPIAP) is generally considered a benign and self-limited condition; however, both its natural course and the impact of management strategies on prognosis remain controversial. Data on modifiable factors influencing tolerance acquisition are limited. Methods: We conducted a retrospective cohort study including 180 infants with cow’s milk-induced FPIAP. Clinical characteristics, management strategies, and outcomes were analysed. Logistic regression was used to identify factors associated with delayed tolerance, and Kaplan–Meier and Cox regression analyses were performed to evaluate time to tolerance. Results: Tolerance was achieved in 91.2% of infants, with a median time from diagnosis to tolerance of 31.1 weeks. In multivariable logistic regression, multi-food elimination at presentation (OR, 2.58; 95% CI, 1.02–6.54; p = 0.046) and a longer interval from diagnosis to reintroduction (OR per week, 1.08; 95% CI, 1.02–1.14; p = 0.022) were independently associated with delayed tolerance. Exclusive breastfeeding was associated with lower odds of delayed tolerance in univariable analysis but not after adjustment. In unadjusted time-to-event analyses, observation-first management was associated with earlier tolerance acquisition (HR, 0.37; 95% CI, 0.22–0.62; p < 0.001), whereas multiple food allergy was associated with a lower probability of tolerance acquisition over time (HR, 0.60; 95% CI, 0.41–0.88; p = 0.009). Feeding modality also showed an unadjusted temporal association with tolerance acquisition, with exclusively breastfed infants demonstrating a more favorable pattern than formula-fed infants. Conclusions: The course of FPIAP appears to be influenced not only by clinical characteristics but also by management strategies. Delayed reintroduction and multi-food elimination were associated with later tolerance, while observation-first management was associated with earlier tolerance acquisition. These findings suggest that commonly used strategies such as prolonged elimination or delayed reintroduction may warrant reconsideration in selected infants and support a more individualized and less restrictive approach to management. Full article

Background/Objectives: Food protein-induced allergic proctocolitis (FPIAP) is a non-IgE-mediated gastrointestinal food allergy. Although tolerance to the culprit food is usually achieved within the first year of life, late acquisition occurs and remains poorly predictable. This study aimed to analyze clinical characteristics and explore factors that may potentially function as predictors of late tolerance acquisition to cow’s milk (CM). Methods: We conducted a cross-sectional study at two Italian pediatric clinics (2020–2024), including infants diagnosed with FPIAP. Clinical, dietary, and immunological variables; onset and duration of rectal bleeding (visible blood in the stools); and time to CM tolerance were analyzed. Late tolerance was defined as acquisition after 19 months according to the distribution of tolerance achievement in our population. Statistical analyses included χ², Mann–Whitney U, Spearman’s correlation, and logistic regression. Results: Ninety-four infants were included (median age at onset 2.9 months [IQR 1.9–4.7]); 58 (62%) were exclusively breastfed and 18 (19%) were born preterm (<37 completed weeks of gestation). CM was the culprit food in all cases; tolerance was achieved in all infants at a median age of 12 months. Family history of atopy and atopic dermatitis were reported in 44% and 19% of infants, respectively. Late CM tolerance was associated with preterm birth, fortification of human milk, early antibiotic exposure, growth faltering, and recurrent infections. Logistic regression identified family history of atopy (OR 5.4 [95% CI 1.2–25.4]; p = 0.031), atopic dermatitis (OR 8.2 [1.7–40.7]; p = 0.010), rectal bleeding >18 days before elimination diet (OR 5.9 [1.3–27.7]; p = 0.023), and IgE sensitization (OR 6.4 [1.2–35.0]; p = 0.034) as factors that may potentially function as predictors of late tolerance acquisition to CM. Conclusions: Identification of factors that may potentially function as predictors of late tolerance acquisition to CM in infants with FPIAP may help providing a personalized clinical management for these patients. Full article

Background/Objectives: Food protein-induced allergic proctocolitis (FPIAP) is a non-immunoglobulin-E-mediated allergic colitis. Most cases resolve after 1 year of age, but delayed resolution and growth retardation may occur in some refractory cases. We aimed to explore the clinical characteristics, treatment approaches, and outcomes of such pediatric patients. Methods: We retrospectively analyzed 35 patients with refractory FPIAP at our center between January 2015 and January 2025. Patients were categorized into early- and non-early-onset groups according to timing of symptom onset; various clinical data were collected and treatment regimens were monitored. Results: The proportion of patients with growth retardation was significantly higher in the non-early onset group than in the early-onset group (73.3% vs. 35.0%, p = 0.041), whereas hemoglobin levels were higher in the early-onset group (118.95 ± 11.26 g/L vs. 107.93 ± 14.61 g/L, p = 0.017).The proportion of corticosteroid use was significantly lower in the early-onset group (15.0% vs. 60.0%; p = 0.011). During follow-up, among 35 patients, 14 (40%) could not tolerate certain foods, including cow’s milk (100%), eggs (42.9%), and wheat (35.7%). Conclusions: Refractory FPIAP was protracted, with a higher incidence of growth retardation, lower hemoglobin levels, and higher corticosteroid use in the non-early onset group. The optimal treatment approach should be explored. Full article

Background: The pathophysiology of non-IgE-mediated cow’s milk allergy is mostly unknown. Previous studies suggested a mechanism mediated by T cells, but this was not confirmed in subsequent studies. The aim of this study was to investigate the immunological mechanisms, especially the role of regulatory T cells (Tregs), in the pathophysiology of allergic proctocolitis (FPIAP). Methods: A prospective observational study was conducted on infants with FPIAP and a control group of healthy infants with similar ages. The main variables were lymphocyte populations, included Tregs, which were extracted from peripheral blood and processed immediately by flow cytometry at two time points: in the acute phase (“T0”) and after clinical resolution (“Tres”). Results: A total of 32 patients with FPIAP and 10 healthy infants were enrolled. There was a higher T-CD4 memory cell count, increased numbers of regulatory B cells and a higher percentage of Tregs (p < 0.01) in patients with acute FPIAP in contrast to the healthy group. The levels of granulocytes (mainly eosinophils), dendritic cells (mDC2) and NK16+56- cells were also significantly higher in the FPIAP group. NK16+56- cells and the number of granulocytes appeared to be the best markers for distinguishing between the healthy and FPIAP infants based on the ROC curves. Conclusions: FPIAP does not appear to have an immune mechanism mediated by T cells, but it may be associated with innate immunity responses characterized by an increase in NK16+56- cells, eosinophils and dendritic cells. These cells could be evaluated in future studies as possible markers of non-IgE-mediated cow’s milk protein allergy. Full article

Background/Objectives: Pediatric patients with non-IgE-mediated gastrointestinal food allergies (non-IgE-GIFAs) may experience alterations of nutritional status. This non-randomized, prospective intervention study investigated the impact of dietary counseling on nutritional status in pediatric patients with non-IgE-GIFAs. Methods: Patients of both sexes aged 0–14 years newly diagnosed with non-IgE-GIFAs received dietary counseling provided by certified pediatric dietitians immediately after diagnosis. Nutritional status parameters were assessed to identify nutritional status alterations at baseline and after 12 months of intervention (T12). Results: The study included 100 patients (58% male, mean age 8.5 ± 8.8 months). Non-IgE-GIFAs phenotypes included food protein-induced enteropathy (FPE, 44%), food protein-induced enterocolitis syndrome (FPIES, 11%), food protein-induced allergic proctocolitis (FPIAP, 17%), and food protein-induced motility disorders (FPIMD, 28%). At diagnosis, 1% was affected by obesity (1 FPIAP), 5% were affected by overweight (2 FPE, 1 FPIAP, and 2 FPIMD), 7% were moderately underweight (5 FPE and 2 FPIMD), 1% was severely underweight (1 FPE), 7% were moderately stunted (4 FPE, 1 FPIAP, and 2 FPIMD), 16% were moderately wasted (11 FPE, 1 FPIES, 1 FPIAP, and 3 FPIMD), and 4% were severely wasted (2 FPE and 2 FPIMD). At T12, improvements in anthropometric parameters were observed, along with a reduction in the prevalence of malnutrition by excess (6% at diagnosis vs. 2% at T12) and a reduction in the undernutrition subtypes rate, including underweight, stunting, and wasting (26% at diagnosis vs. 3% at T12, p < 0.001). Conclusions: Non-IgE-GIFAs can negatively impact the nutritional status of pediatric patients. Thus, dietary counseling could be an effective strategy for preventing and managing nutritional alterations in these patients. Full article

Background/Objectives: Food protein-induced allergic proctocolitis (FPIAP) is a non-IgE-mediated food allergy, usually presenting as bloody stools in breastfed, well-appearing, and regularly growing infants. The aim of our study was to describe the clinical features of Italian infants affected by FPIAP and their management and natural history in a real-life setting. Methods: A retrospective, observational study was performed at two tertiary pediatric hospitals (Florence and Trieste), including FPIAP-diagnosed infants between 2012 and 2022. Results: Most of the 100 enrolled patients were breastfed (68.0%), and the majority of those who underwent diagnostic tests (n = 51) showed normal hemoglobin and total IgE levels. A maternal elimination diet was performed in 69.0%, mostly for milk only, but 40.6% underwent multiple elimination diets. The remission rate was high both in breastfed infants (76.8%) and in those who received extensively hydrolyzed formula (81.8%). Nine subjects were left on a free diet, but six were lost at follow-up. The median time of complete remission was 30 days (IQR 14–60). Culprit food reintroduction was tolerated at a median age of 8 months (IQR 6–11), in ladder modality (for hen’s egg and cow’s milk) in 61.7%. Nine patients relapsed (14.3%) upon reintroduction with no associated variables identified at the regression analysis. The relapse rate was slightly higher when trigger food reintroduction was attempted > 12 months (16.7%) versus <12 months (13.0%). Conclusions: In our population, FPIAP had, as expected, a benign evolution. The early reintroduction of the suspect food in a gradual manner for cow’s milk and hen’s egg leads to good tolerance within the first year in most patients, avoiding unnecessary elimination diets. Full article

The bloody stools of newborns may be a clue for several clinical entities of varying severity, ranging from idiopathic neonatal transient colitis to food-protein-induced allergic proctocolitis (FPIAP) or necrotizing enterocolitis (NEC). Distinguishing among them at an early stage is challenging but crucial, as the treatments and prognoses are different. We conducted a monocentric retrospective study including all pre-term infants with bloody stools admitted to the Neonatal Intensive Care Unit (NICU) of the Vittore Buzzi Children’s Hospital (Milan) from December 2022 to May 2024. Patients diagnosed with NEC exhibited significantly lower eosinophil counts and higher procalcitonin levels than both patients with FPIAP and patients with idiopathic neonatal transient colitis, as well as a statistically significant increase in pathological features from abdomen ultrasounds and abdominal X-rays. In contrast, no lab markers or imaging techniques have been demonstrated to be useful in distinguishing between idiopathic neonatal transient colitis and FPIAP. Thus, after excluding a diagnosis of NEC, the only way to confirm FPIAP is through the oral food challenge, which can be performed in premature newborns presenting with bloody stools who are otherwise healthy and under medical supervision, in order to identify infants who may benefit from a cow’s-milk-free diet. Full article

Objective: The aim of our study was to investigate whether a 1-month-long milk-free diet results in a reduction in faecal calprotectin (FC) and faecal-zonulin-related proteins (FZRP) in children with milk-protein-induced allergic proctocolitis (MPIAP). Materials and methods: This is a single-centre, prospective, observational cohort study involving 86 infants with MPIAP, aged 1–3 months, and 30 healthy controls of the same age. The FC and FZRP were marked using the ELISA method (IDK^® Calprotectin or Zonulin ELISA Kit, Immunodiagnostik AG, Bensheim, Germany). The diagnosis of MPIAP was confirmed with an open milk challenge test. Results: FFC and FZRP proved useful in evaluating MPIAP treatment with a milk-free diet, and the resolution of allergic symptoms and a significant (p = 0.0000) decrease in the concentrations of both biomarkers were observed after 4 weeks on the diet. The FC and FZRP concentrations were still higher than in the control group. A high variability of FC concentrations was found in all the study groups. An important limitation is the phenomenon of FZRP not being produced in all individuals, affecting one in five infants. Conclusions: FC and FZRP can be used to monitor the resolution of colitis in infants with MPIAP treated with a milk-free diet, indicating a slower resolution of allergic inflammation than of allergic symptoms. The diagnosis of MPIAP on the basis of FC concentrations is subject to considerable error, due to the high individual variability of this indicator. FZRP is a better parameter, but this needs further research, as these are the first determinations in infants with MPIAP. Full article

Non-IgE immune-mediated gastrointestinal disorders constitute a heterogeneous group of enigmatic conditions that are on the rise. This category encompasses entities like food protein-induced enterocolitis syndrome (FPIES), food protein-induced allergic proctocolitis (FPIAP), and food protein-induced enteropathy (FPE). These are immune-mediated reactions to certain foods without the involvement of allergen-specific IgE in their pathogenesis. Eosinophilic esophagitis (EoE) is also included in this group, acknowledged for its mixed IgE and non-IgE-mediated characteristics. The diagnostic landscape is fraught with challenges, given the poorly understood nature of these disorders and their propensity to manifest with varying and overlapping clinical presentations, typically emerging in infancy with common potential triggers such as cow’s milk and soy. Presently, confirmatory testing for most of these conditions is limited and invasive, emphasizing the pivotal role of a thorough history and physical examination in reaching a diagnosis. Notably, there are limited guidelines for diagnosis and management for most of these disorders. This article elucidates the key distinctions among these disorders, provides an overview of existing diagnostic and therapeutic approaches, and addresses existing knowledge and research gaps. The considerable impact on the quality of life of non-IgE immune-mediated allergic disorders of the gastrointestinal tract, which can result in debilitating complications such as nutritional deficiencies, mental health disorders, and eating disorders, underscores the urgency for comprehensive exploration and management strategies. Full article

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. Full article

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. Full article

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. Full article

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. Full article

Non-immunoglobulin E-mediated gastrointestinal food allergic disorders (non-IgE-GI-FA) include food protein-induced enterocolitis syndrome (FPIES), food protein-induced enteropathy (FPE) and food protein-induced allergic proctocolitis (FPIAP), which present with symptoms of variable severity, affecting the gastrointestinal tract in response to specific dietary antigens. The diagnosis of non-IgE-GI-FA is made clinically, and relies on a constellation of typical symptoms that improve upon removal of the culprit food. When possible, food reintroduction should be attempted, with the documentation of symptoms relapse to establish a conclusive diagnosis. Management includes dietary avoidance, nutritional counselling, and supportive measures in the case of accidental exposure. The prognosis is generally favorable, with the majority of cases resolved before school age. Serial follow-up to establish whether the acquisition of tolerance has occurred is therefore essential in order to avoid unnecessary food restriction and potential consequent nutritional deficiencies. The purpose of this review is to delineate the distinctive clinical features of non-IgE-mediated food allergies presenting with gastrointestinal symptomatology, to summarize our current understanding of the pathogenesis driving these diseases, to discuss recent findings, and to address currents gaps in the knowledge, to guide future management opportunities. Full article