Clinical characteristics, prognosis, and risk factors for tolerance development in food protein-induced allergic proctocolitis: a retrospective cohort study

Introduction

Food protein-induced allergic proctocolitis (FPIAP), characterized by bloody stools as its cardinal symptom, is a benign, non-IgE-mediated food allergy that predominantly affects infants with normal growth and development. FPIAP represents the most prevalent gastrointestinal manifestation of food allergy in neonates and infants and is among the most common non-IgE-mediated allergic disorders observed in exclusively breastfed infants (1-4).

Currently, the cornerstone of FPIAP management is an elimination diet. Considerable heterogeneity is observed among patients with food allergens, age at onset, platelet activation profiles, temporal patterns of symptom emergence, tolerance thresholds, comorbid allergic conditions, and rates of spontaneous remission, all of which substantially impact the timeline for attaining food tolerance (5-7). Although the prognosis of FPIAP is generally favorable, with approximately 70% of affected children achieving tolerance within the first year of life (3), a subset of patients persists with food intolerance and exhibits heightened susceptibility to multiple food allergies, functional gastrointestinal disorders, and other digestive pathologies (8,9). Given that FPIAP often manifests during this vulnerable period, the initial 1,000 days of life constitute a critical “window of opportunity” for optimizing physical and cognitive development in infants and young children (10). Nutritional status during early life not only significantly impacts growth and development but also plays a crucial role in shaping long-term health outcomes and quality of life, underscoring the need to delineate the factors influencing food protein tolerance.

Accordingly, this study sought to elucidate the clinical predictors of FPIAP prognosis, thereby informing the evidence-based selection of elimination dietary management strategies. We present this article in accordance with the STROBE reporting checklist (available at https://tp.amegroups.com/article/view/10.21037/tp-2025-1-909/rc).

Methods

Study design and population

This retrospective cohort study included pediatric patients aged 0–12 months who were diagnosed with FPIAP at the outpatient and inpatient departments of the Gastroenterology Department of Beijing Children’s Hospital, Capital Medical University between January 2024 and July 2024. A unified telephone follow-up was conducted in a concentrated manner in June 2025. The diagnosis of FPIAP in the study was made by the pediatrician caring for the infant. The research staff independently and comprehensively reviewed the charts of each child diagnosed with FPIAP.

Because the diagnostic criteria for FPIAP are debated, according to the European Society of Pediatrics Gastroenterology, Hepatology and Nutrition (ESPGHAN) position paper on cow’s milk allergy, World Allergy Organization (WAO) Diagnosis and Rationale for Action against Cow’s Milk Allergy (DRACMA) guidelines, and based on previous studies (1,2,11,12), the inclusion criteria were the treating physician’s clinical diagnosis of FPIAP. The diagnosis of FPIAP was established using a standardized clinical framework derived from the ESPGHAN position paper on cow’s milk allergy and the WAO DRACMA guidelines. All included patients were evaluated according to the same diagnostic approach.

A diagnosis of FPIAP required fulfillment of the following criteria:

• Compatible clinical presentation, primarily hematochezia in an otherwise well-appearing infant, with or without mild gastrointestinal symptoms;
• Exclusion of alternative causes of rectal bleeding, including infectious, anatomical, and coagulation disorders;
• Resolution of symptoms following elimination of the suspected trigger food, either through maternal dietary restriction in breastfed infants or use of extensively hydrolyzed or amino acid–based formula in formula-fed infants;
• Clinical reassessment within 2–4 weeks to confirm symptom improvement.

Reintroduction was performed on a case-by-case basis without standardized oral food challenges (OFC), in accordance with established guidelines in which standardized OFC is not required for mild cases (2). The decision to perform an OFC was made at the discretion of the pediatrician responsible for the infant’s care, based on clinical judgment. Reintroduction was conducted on a case-by-case basis after a symptom-free period. The exclusion criteria were failure to confirm an alternative cause of rectal bleeding and absent of information in the medical record. Management recommendations provided after clinical diagnosis were as follows:

• Exclusively breastfed infants: initial management consisted of maternal elimination of cow’s milk and eggs for 2–4 weeks. If symptoms did not improve, additional potential trigger foods could be removed from the maternal diet. Transition to an amino acid-based formula was considered under any of the following circumstances:
  • Persistent or severe symptoms despite maternal dietary avoidance;
  • Evidence of growth faltering or other nutritional deficiencies;
  • Substantial maternal weight loss or adverse health effects attributable to dietary restriction;
  • Significant psychological burden on the mother.
• Formula-fed infants: infants who were formula-fed were advised to switch to a hypoallergenic formula (extensively hydrolyzed or amino acid-based).
• Food reintroduction: reintroduction of the suspected trigger food(s) was generally attempted after an asymptomatic period of at least 1 month.
• Duration of elimination diet: the elimination diet was maintained for a minimum of 6 months or until the child reached 9–12 months of age, whichever occurred first.
• Individualized decision-making: adjustments to feeding and elimination strategies were made by the pediatrician on a case-by-case basis, considering clinical severity, breastfeeding status, and parental feeding preferences. Ultimately, the specific implementation of feeding and elimination practices was determined by the parents.

The study protocol was approved by the Medical Ethics Committee of Beijing Children’s Hospital, Capital Medical University (No. [2025]-E-054-R), and was conducted in accordance with the ethical guidelines of the 1975 Declaration of Helsinki (6th version, 2008). Given the retrospective nature of this study, informed consent was not required.

Data collection from medical records

We retrospectively extracted information on gender, age, birth weight, siblings, family/personal history of allergic comorbidities, mode of delivery, history of preterm birth or perinatal comorbidity, initial diet (extensive breastfeeding, formula, or mixed diet), clinical findings, and diagnosis of multiple food allergies from medical records. Information about initial laboratory tests [blood tests with white blood count, hemoglobin levels, platelet count (PLT), platelet crit (PCT), mean platelet volume (MPV), eosinophil count, and stool tests including screening for norovirus, rotavirus, and culture] and gastrointestinal ultrasound findings were also collected when these were performed. Multiple food allergies were defined as having two or more food allergies. These diagnoses were made by gastroenterologists and included not only cases in which multiple allergens triggered FPIAP, but also additional food allergies that emerged after the introduction of complementary foods.

Data collection from telephonic survey

All follow-up interviews were conducted using a structured questionnaire by trained research staff to enhance consistency and reduce reporting variability. The patients’ parents were telephonically surveyed about the timing and modality of the reintroduction of the trigger food, the success of the reintroduction attempt, and the future development of any atopic comorbidity (asthma, rhino conjunctivitis, atopic dermatitis, IgE-mediated food allergy). IgE-mediated food allergies were identified based on compatible clinical manifestations in conjunction with documented serum-specific IgE testing recorded in the medical charts. The diagnosis was made during routine clinical care by the treating physicians. Serum-specific IgE results were extracted retrospectively from the patients’ medical records when available.

Follow-up procedures and outcome assessment

Data on the elimination diet of the enrolled patients were retrieved. Three possible management approaches were adopted: (I) maternal trigger food elimination diet; (II) extensively hydrolyzed/amino acid formula (AAF); or (III) mixed feeding (maternal trigger food elimination diet combined with a hydrolyzed/AAF). The elimination diet lasted until the child was 9–12 months of age or at least 6 months in case the child accidentally consumed the trigger food and had no recurrence of symptoms.

Information on symptom progression, dietary practices, and any attempts at food reintroduction was obtained retrospectively through structured telephone interviews with parents and review of available medical records. As a result, the timing and extent of follow-up varied among participants and were largely dependent on parental recall.

During these retrospective interviews, some parents reported that they had independently introduced the suspected trigger food once symptoms had improved, typically as part of routine complementary feeding rather than under clinician guidance. When recurrent hematochezia or other compatible symptoms were described following such parent-initiated reintroduction, this was classified as a relapse.

Oral tolerance was defined as complete resolution of hematochezia and any accompanying gastrointestinal or cutaneous symptoms, followed by successful reintroduction of the suspected trigger food without recurrence of symptoms. Tolerance was considered achieved only when the infant was able to consume all forms of the trigger food without relapse after reintroduction.

Children with FPIAP were categorized into an early tolerance group (oral tolerance achieved by 12 months) and a late tolerance group (oral tolerance achieved after 12 months), according to the age at tolerance acquisition.

Statistical analysis

Statistical analysis were conducted using IBM SPSS v.29. Statistical analysis were performed using SPSS software (version 29.0). For normally distributed measurement data, results are presented as mean ± standard deviation (SD), and comparisons between two groups were made using the t-test; comparisons among multiple groups were made using analysis of variance (ANOVA). For non-normally distributed measurement data, results are presented as median [interquartile range (IQR)] [M (P25, P75)]; comparisons between two groups were made using the Mann-Whitney U test, and comparisons among multiple groups were made using the Kruskal-Wallis H test. Categorical data are presented as cases (%), and comparisons between groups were performed using the χ² test. When the conditions for the χ² test were not met, the exact probability method was used. Binary logistic regression analysis was used to analyze the factors influencing oral tolerance to specific food proteins. In this study, the median follow-up time was obtained by directly calculating the median of the total follow-up duration of all patients, which was the duration from disease onset to centralized follow-up in June 2025. After sorting the follow-up durations of all patients, the median value was used as the median follow-up time. Statistical significance was set at P<0.05.

Results

A total of 163 children (84 males and 79 females) were enrolled in the study. The median age at symptom onset was 2 months (IQR: 1–4 months), with a median follow-up of 14 months. Vaginal delivery occurred in 94 (57.7%) cases, preterm birth in 11 (6.7%) cases, and low birth weight in seven (4.3%) cases within the entire cohort. Perinatal antibiotic exposure was noted in 15 cases (9.2%), and a positive family history of allergy was noted in 84 cases (51.5%). A singleton child was observed in 123 children (75.5%). In addition to hematochezia, the most prevalent clinical manifestations included diarrhea in 128 cases (78.5%), mucoid stools in 80 cases (49.1%), and skin symptoms (eczema or urticaria) in 65 cases (39.9%) (Figure 1). Six percent of patients presented with a single manifestation, 26% with two manifestations, 36% with three manifestations, 26% with four manifestations, and 7% with five or more manifestations (n=163). The distribution and proportions of the main clinical symptom types are shown in Figure 2. The predominant trigger food was cow’s milk protein in 161 cases (98.8%). Eggs and wheat each accounted for three cases (1.8%). Among all patients, two cases (1.2%) had two concomitant trigger foods. The initial feeding pattern was exclusive breastfeeding in 85 children (52.1%), mixed feeding in 60 (36.8%), and formula feeding in 18 (11.0%). Of the patients, 66.3% (108 out of 163) achieved oral tolerance by 12 months of age. No significant intergroup differences were observed between the early and late tolerance groups regarding sex, delivery mode, gestation, birth weight, perinatal antibiotic exposure, and sibling status (all P>0.05). The rate of positive family history of allergy was significantly higher in the late tolerance group than in the early tolerance group (P<0.05), as detailed in Table 1. In terms of the initial examination, the PLTs and PCT values were significantly higher in the late tolerant group than in the early tolerant group (both P<0.05). No significant differences were observed between the groups in terms of white blood cell counts, hemoglobin levels, eosinophil counts, or the presence of pneumatosis intestinalis and/or portal venous gas (all P>0.05), as summarized in Table 2.

Figure 1 Frequency of clinical manifestations in children with FPIAP. FPIAP, food protein-induced allergic proctocolitis.

Figure 2 Distribution of concurrent clinical manifestations in children with FPIAP. The stacked bars represent the percentage distribution of patients with single, two, three, four, and five or more concurrent manifestations within each symptom category. Overall, 6% of patients presented with a single manifestation, 26% with two manifestations, 36% with three manifestations, 26% with four manifestations, and 7% with five or more manifestations (n=163). FPIAP, food protein-induced allergic proctocolitis.

The elimination diet consisted of maternal trigger food elimination in 26 cases (16.0%), mixed feeding in 111 cases (68.1%), and extensively hydrolyzed formula (EHF)/AAF feeding in 26 cases (16.0%). Significant differences in the elimination diet were observed between the early and late tolerance groups (χ²=12.887, P=0.002). Pairwise comparisons revealed a significant distinction between maternal trigger food elimination and mixed feeding (χ²=9.552, P=0.002), whereas no significant differences were noted between maternal trigger food elimination and exclusive use of EHF/AAF or between mixed feeding and exclusive use of EHF/AAF (both P>0.02). The rate of exclusive breastfeeding during the first 6 months was significantly higher in the early tolerance group than in the late tolerance group (χ²=9.390, P=0.002). During follow-up, multiple food allergies—including cases in which multiple allergens triggered FPIAP and additional allergies emerging after the introduction of complementary foods—were observed in 12 cases (7.4%), mild malnutrition in 2 cases (1.2%), and comorbid allergic diseases in 20 cases (12.3%). Among these, 2 patients exhibited both eczema and allergic rhinitis, while the remaining 18 had eczema (n=16) or allergic rhinitis (n=2). The rates of comorbid allergic diseases and multiple food allergies were significantly higher in the late tolerance group than in the early tolerance group (both P<0.05). No significant intergroup differences were detected in the timing of complementary food introduction or breastfeeding duration (both P>0.05), as detailed in Table 3.

Univariate logistic regression identified variables with P<0.05, which were subsequently incorporated as independent predictors into a multivariate binary logistic regression model. The dependent variable was the status of oral tolerance at the age of 12 months. Forward stepwise selection was employed at an α=0.05 threshold and adjusted for potential confounders. Multivariate logistic regression analysis demonstrated that a family history of allergy [odds ratio (OR) =2.656, 95% confidence interval (CI): 1.189–5.935, P=0.02] and multiple food allergies (OR =10.760, 95% CI: 1.793–64.560, P=0.009) were significant risk factors for failure to achieve oral tolerance by 12 months of age. In contrast, exclusive breastfeeding within the first 6 months of life was associated with a substantially increased likelihood of tolerance development before 12 months (OR =0.051, 95% CI: 0.006–0.431, P=0.006), as presented in Table 4.

Discussion

This study investigated the real-world characteristics and management of FPIAP in the Chinese population. This study aimed to describe the demographic and clinical features, elimination diet, and prognosis of Chinese children affected by FPIAP, which are missing data in the literature.

In this retrospective observational cohort study of FPIAP infants, we found that the median age at symptom onset was 2 months (IQR: 1–4 months). Beyond hematochezia, the most prevalent clinical manifestations included diarrhea in 128 patients (78.5%), mucoid stools in 80 patients (49.1%), and cutaneous symptoms (eczema or urticaria) in 65 patients (39.9%). FPIAP infants is characterized by intermittent, mild-to-moderate hematochezia in healthy infants, often presenting as mucoid stools. Other gastrointestinal symptoms such as diarrhea and vomiting may also occur. Additionally, a subset of cases may present with cutaneous manifestations, such as eczema (11,13). Cow’s milk protein emerged as the predominant causative allergen in 161 cases (98.8%), followed by eggs in 3 cases (1.8%), wheat in 3 cases (1.8%). Among all patients, two cases (1.2%) had two concomitant trigger foods. Cow’s milk protein is the predominant allergen implicated in FPIAP, but other food proteins, such as those in eggs and wheat, can also be involved. Food allergens such as soy have been reported in other research but were not identified in our study, and concurrent multiple food allergies may occur (14-17).

Previous investigations have demonstrated that rectal biopsies in children with FPIAP frequently exhibit eosinophilic infiltration within the lamina propria and muscularis mucosae (15); nonetheless, endoscopy and biopsy are no longer routine in clinical practice, and no specific laboratory assays or biomarkers for FPIAP are currently available (1,18). Therefore, the diagnosis of FPIAP is challenging. We found increased PLT and PCT in the late tolerance group (both P<0.05), without a corresponding increase in platelet volume (MPV) (P=0.92). Multivariate analysis further indicated that neither PLT nor PCT was an independent risk factor, potentially due to confounding variables. Platelet activation, induced by agonists [e.g., adenosine diphosphate (ADP), thromboxane A₂ (TXA₂), and platelet-activating factor (PAF)] and proinflammatory cytokines [e.g., interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α)], results in elevated PLTs, aggregation at sites of injury, and morphological changes, including pseudopodia formation, localized degranulation, and participation in fibrotic and inflammatory cascades (19-21). Platelets are increasingly recognized as active participants in allergic inflammation rather than passive bystanders. Upon activation, platelets release proinflammatory mediators such as PAF, TXA₂, and various cytokines, which may contribute to mucosal inflammatory amplification. In addition, platelet interactions with eosinophils and T lymphocytes have been shown to enhance Th2-skewed immune responses, potentially sustaining intestinal immune activation. A study by Nacaroglu et al. (22) reported significantly higher mean MPV and PCT levels in FPIAP cases, with elevations particularly pronounced in those with late tolerance. Although PLT and PCT differed significantly between groups in univariate comparisons, they did not emerge as independent predictors in multivariable analysis. This discrepancy may reflect confounding by broader atopic or inflammatory background factors or limited statistical power. Consequently, platelet indices may serve as adjunctive markers for the differential diagnosis and monitoring of FPIAP. Therefore, the prognostic utility of platelet indices should be interpreted cautiously and warrants validation in larger prospective cohorts.

In our study, 66.3% of FPIAP infants achieved tolerance within the first year. Mild malnutrition was observed in only 2 cases (1.2%). FPIAP is generally associated with a favorable prognosis, with approximately 70% of patients attaining oral tolerance within the first year of life, and the rate escalating to 90% by the second year (3,13). Furthermore, this condition typically exerts no substantial impact on growth and development (23,24). The “dual allergen exposure hypothesis” posits that impaired cutaneous barriers contribute to food sensitization, wherein low-dose percutaneous allergen exposure predisposes individuals to allergic responses, and disrupted barriers exacerbate inflammatory processes (25). Emerging evidence indicates that eczema is a risk factor for FPIAP development and may undermine the efficacy of maternal allergen elimination diets in breastfed infants (11,26). Research has found that eczema is a risk factor for the development of FPIAP and is also a risk factor for the ineffectiveness of maternal dietary elimination of allergenic foods in breastfed infants. In our study, comorbid allergic diseases were observed in 20 children (12.3%) with FPIAP, predominantly eczema and allergic rhinitis. The rate of these comorbidities was significantly higher in the late tolerance group (P<0.05). Notably, although allergic rhinitis is rare in infancy and only a small number of children develop allergy-related symptoms before 3 years of age (27), our cohort included such cases, with diagnoses rigorously confirmed by attending pediatricians rather than relying solely on parental reports. Furthermore, multiple food allergies were identified in 7.4% of cases, consistent with previously reported incidences ranging from 5% to 42.9% (7,14,17,28-30). Multiple food allergies were associated with increased odds of belonging to the late-tolerance group (OR =10.760, 95% CI: 1.793–64.560, P=0.009). However, only 12 patients in our cohort had multiple food allergies, and the wide confidence interval reflects substantial statistical uncertainty and limited precision of the effect estimate. The relatively small number of events may have reduced statistical power and affected the stability of the regression model. Therefore, this association should be interpreted cautiously and regarded as exploratory rather than definitive evidence of an independent causal relationship. The existing literature indicates that children with multiple food allergies frequently exhibit increased peripheral eosinophilia and atopic dermatitis (5,17,28). Multiple food allergies may require the avoidance of multiple food proteins, complicating the management of FPIAP. Population-based cohort studies have established eczema as a significant risk factor for IgE-mediated food allergies (31). FPIAP may represent an early manifestation within the spectrum of the “allergic march”. Although traditionally classified as a non-IgE-mediated food allergy, the coexistence of eczema and later allergic symptoms in some patients suggests potential immunologic continuity across allergic phenotypes. Shared mechanisms, including epithelial barrier dysfunction and Th2-skewed immune responses, may contribute to this trajectory. However, our findings do not establish a causal progression from FPIAP to IgE-mediated allergic disease. Rather, they indicate that FPIAP in certain infants may occur within a broader atopic context that could influence the timing of clinical tolerance development. Longitudinal studies are needed to further clarify this relationship.

Among FPIAP children, the proportion exhibiting a parental allergic disease history exceeded that in the general population, positioning it as a plausible risk factor, although the extant literature exhibits inconsistencies regarding this association (32). In our study, the rate of family history of allergy among FPIAP infants was 51.5%, aligning with prior literature reports ranging from 25% to 42.3% (6,12,17,33), which corroborates the genetic predisposition noted in earlier studies. Notably, a family history of allergy was associated with increased odds of delayed tolerance (OR =2.656, 95% CI: 1.189–5.935, P=0.02), suggesting a potential genetic influence on tolerance development. Food allergies are modulated by a complex interplay of genetic, environmental, and gene-environment interactions. Established or putative risk factors encompass non-modifiable elements such as sex and race/ethnicity, alongside modifiable contributors, including atopic dermatitis, hygiene practices improvement, and microbiome (34). A seminal report from the U.S. The National Academies of Sciences, Engineering, and Medicine (NAS) (35) underscored, in accordance with the hygiene hypothesis, that diminished microbial exposure may attenuate immunoregulatory mechanisms; accordingly, cesarean delivery and antibiotic exposure were identified as risk factors for food allergies, whereas pet or animal exposure conferred protective effects. Environmental influences, such as parental tobacco use, have also been linked in select studies to an increased risk of pediatric food allergies (36,37). For other allergic disorders, evidence suggests associations between maternal and infant dietary patterns, family sibship size, and a reduced incidence of childhood asthma (38). In our study, variables including sex, mode of delivery, gestational age, birth weight, perinatal antibiotic exposure, sibship status, and direct tobacco exposure were evaluated in children with FPIAP, revealing no significant intergroup differences between the early and late tolerant groups (all P>0.05). These may predispose individuals to food allergy onset but are unlikely to influence tolerance development.

Food antigens transmitted via breast milk can elicit sensitization in exclusively breastfed infants, precipitating a T cell-mediated, allergen-specific immune response that culminates in the onset of FPIAP (39-41). Breastfeeding predominated among in our study (61.8%), aligning with prior reports of rates ranging from 56.8% to 83.3% (7,11,28-30,42). Moreover, exclusive breastfeeding within 6 months was associated with an increased likelihood of oral tolerance development by 12 months of age (OR =0.051, 95% CI: 0.006–0.431, P=0.006). Regarding the management approach, cases in which allergen elimination was achieved solely by modifying the maternal diet might represent milder forms of FPIAP, as these infants often responded rapidly without requiring EHF or AAF. In such cases, the early tolerance observed might be a result of the milder disease severity rather than a direct effect of exclusive breastfeeding. Therefore, the conclusion that exclusive breastfeeding promotes early tolerance development in infants with FPIAP should be interpreted with caution, as it may be influenced by potential selection bias or confounding factors related to disease severity. Furthermore, because feeding practices were retrospectively reported by parents, residual recall bias may have contributed to the observed association. Contemporary systematic reviews and meta-analyses indicate that breastfeeding neither prevents nor elevates the risk of food allergies (43). However, in real-world studies, when comparing breastfeeding with other feeding patterns, it is impossible to randomly assign participants to a non-breastfeeding group, which introduces analytical complexities. The hygiene hypothesis, first articulated in 1989, posits a link between microbial exposure and allergic diathesis. Contemporary research has emphasized the interplay between infant gut microbiota and food allergies, with accumulating evidence associating dysbiosis with allergic phenotypes (44,45). Moreover, the maternal-infant microbiome dyad exerts a pivotal influence on allergy susceptibility (46). In addition to essential nutrients, breast milk contains immunomodulatory components, vitamins, human milk oligosaccharides, and a diverse microbial consortium, the latter of which plays a critical role in infant immune maturation (47-49). These microbes, transferred to the infant gut via breastfeeding, facilitate microbial colonization, modulate immune responses, and bolster intestinal barrier integrity (50-52). Enhanced microbial diversity in breast milk fosters a balanced infant gut microbiome, promoting oral tolerance and mitigating the risk of food allergies (53-57). The richness of oligosaccharides, secretory IgA, cytokines, and probiotics in breast milk further attenuates allergy susceptibility (58). Thus, breast milk exerts protective effects by augmenting gut barrier function and enhancing pathogen tolerance. In accordance with the World Health Organization guidelines on infant and young child feeding, exclusive or predominant breastfeeding for the first 6 months is advocated as an optimal target. In our cohort, exclusive breastfeeding within the first 6 months was associated with earlier oral tolerance. Breast milk contains immunomodulatory components and influences early-life gut microbiota, both of which may support mucosal immune maturation and tolerance development. However, this association should be interpreted cautiously. Infants with milder disease may have been more likely to continue exclusive breastfeeding, introducing potential confounding by disease severity, and feeding practices were retrospectively reported, allowing for residual recall bias. Therefore, our findings do not establish a causal protective effect of breastfeeding. Exclusive breastfeeding is generally recommended for infants with FPIAP, with the gradual introduction of complementary foods while maintaining breastfeeding when feasible. Nonetheless, feeding decisions should be individualized based on disease severity, allergen control, and clinical guidance, as multiple factors may influence the development of oral tolerance. Prospective studies are needed to further clarify the role of breastfeeding in tolerance outcomes.

Limitations

This retrospective cohort study was inherently susceptible to selection bias and incomplete data ascertainment, so this study has several limitations. First, the reliance on clinical judgment without routine OFC introduces potential misclassification bias, as some cases might have been over- or under-diagnosed without confirmatory challenges. Second, key outcome variables—including dietary intervention details, the timing and success of food reintroduction, and feeding practices—were obtained through structured telephone follow-up and parental recall. Although interviews were conducted using a standardized questionnaire by trained investigators, and efforts were made to cross-check information with available medical records when possible, recall bias and information bias cannot be entirely excluded. Parents’ recollections of feeding patterns and reintroduction timing may have varied in accuracy, particularly across families with different socioeconomic and educational backgrounds, potentially leading to non-differential or differential misclassification. Moreover, heterogeneous feeding strategies observed in this cohort may reflect real-world clinical practice; however, such variability could also confound the observed associations and should be considered when interpreting the results. Additionally, although the overall sample size was acceptable for a single-center retrospective study, the limited number of events in certain subgroups—particularly patients with multiple food allergies (12 out of 163)—may have reduced statistical power and compromised the precision and stability of regression estimates. Consequently, effect sizes for these variables should be interpreted with caution and warrant confirmation in larger multicenter cohorts. Furthermore, although the dichotomous classification of tolerance using a 12-month cutoff is consistent with previous studies, it remains an inherently arbitrary threshold. Alternative analytical approaches—such as using Kaplan-Meier survival curves to model time to tolerance as a continuous variable—could provide a more nuanced understanding of tolerance trajectories. However, these methods were not feasible in the present study due to its retrospective design and modest sample size. We therefore recommend that future prospective studies with larger cohorts consider incorporating such time-to-event analyses. Notably, although PLTs and plateletcrit were significantly elevated in the late-tolerance group, they did not emerge as independent predictors in the multivariate analysis, warranting further mechanistic investigations to determine their potential utility as prognostic biomarkers.

Conclusions

In conclusion, FPIAP has a favorable prognosis, with 66.3% of infants achieving oral tolerance within the first year of life. Children with a family history of allergy and those with multiple food allergies were less likely to achieve oral tolerance by 12 months of age. Exclusive breastfeeding within the first 6 months of life was associated with a higher probability of tolerance acquisition before 12 months. These findings indicate that a family history of allergic diseases and multiple food allergies may prolong tolerance development; however, this relationship should be interpreted with caution given the potential influence of disease severity and residual confounding. Children with a family history of allergy or multiple food allergies require close monitoring and individualized management. Promoting breastfeeding and personalized elimination diets may optimize clinical outcomes in this population.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tp.amegroups.com/article/view/10.21037/tp-2025-1-909/rc

Data Sharing Statement: Available at https://tp.amegroups.com/article/view/10.21037/tp-2025-1-909/dss

Peer Review File: Available at https://tp.amegroups.com/article/view/10.21037/tp-2025-1-909/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tp.amegroups.com/article/view/10.21037/tp-2025-1-909/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.The study protocol was approved by the Medical Ethics Committee of Beijing Children’s Hospital, Capital Medical University (No. [2025]-E-054-R), and was conducted in accordance with the ethical guidelines of the 1975 Declaration of Helsinki (6th version, 2008). Given the retrospective nature of this study, informed consent was not required.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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