Food protein-induced allergic proctocolitis (FPIAP) is a non-IgE-mediated allergic condition that presents with hematochezia in otherwise healthy infants. It is most commonly induced by cow\'s milk protein via breast milk or formula. The prognosis for FPIAP is generally considered favorable with most infants achieving symptomatic resolution after diet modification. Most infants go on to tolerate the offending foods by 1-3 years of age. Over 8 years at our institution, five patients were identified and noted to have FPIAP to cow\'s milk during infancy with subsequent development of IgE-mediated allergic reaction to cow\'s milk and other foods. All five cases developed other atopic disorders (atopic dermatitis in four cases). IgE-mediated cow\'s milk allergy has persisted beyond the preschool years in at least two patients (currently 8 and 16 years old). For three of the patients, the IgE-mediated reaction to cow\'s milk was severe with development of anaphylaxis or angioedema. In addition, three patients experienced anaphylaxis or angioedema to allergens other than milk. While FPIAP is a non-IgE-mediated process traditionally thought not to progress past the first year of life, some infants with FPIAP develop severe, persistent IgE-mediated cow\'s milk allergy. To our knowledge, this is the first detailed clinical description of such patients.

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.

There are conflicting associations reported between food allergies (FAs) and poor growth, with some indication that children with multiple FAs are at highest risk.
We analyzed longitudinal weight-for-length (WFL) trajectories from our healthy cohort to evaluate growth in children with IgE-mediated FAs and food protein-induced allergic proctocolitis (FPIAP), a non-IgE-mediated FA.
Our observational cohort of 903 healthy newborn infants was prospectively enrolled to evaluate the development of FAs. Longitudinal mixed effects modeling was used to compare differences in WFL among children with IgE-FA and FPIAP, compared with unaffected children, through age 2.
Among the 804 participants who met inclusion criteria, FPIAP cases had significantly lower WFL than unaffected controls during active disease, which resolved by 1 year of age. In contrast, children with IgE-FA had significantly lower WFL than unaffected controls after 1 year. We also found that children with IgE-FA to cow\'s milk had significantly lower WFL over the first 2 years of age. Children with multiple IgE-FAs had markedly lower WFL over the first 2 years of age.
Children with FPIAP have impaired growth during active disease in the first year of age which resolves, whereas children with IgE-FA, particularly those with multiple IgE-FA, have impaired growth more prominently after the first year of age. It may be appropriate to focus nutritional assessment and interventions accordingly during these higher risk periods in these patient populations.

Background: The majority of mixed-fed infants with non-IgE-mediated cow\'s milk protein allergy (CMPA) enteropathies are managed with an extensively hydrolysed cow\'s milk based infant formula (eHF). Given the high variability in peptide distribution of available eHFs, it is important to understand the suitability of a specific product in the management of distinct phenotypes. Objective: To assess the symptom resolution of various phenotypes of clinical manifestations of CMPA enteropathies and constipation managed by a casein-based eHF. Methods: The data of 20 full-term infants (n = 15 with non-IgE-mediated CMPA and n = 5 with constipation) attending a paediatric allergy clinic in Cyprus and managed with a casein-based eHF were retrospectively analysed. Results: Based on the clinical symptoms and history, infants were classified into the following phenotypes: (a) 11/15 (73.3%) FPIAP, (b) 3/15 (20%) FPIES, and (c) 1/15 (6.7%) severe diarrhoea. Overall, 14 (93.3%) patients were successfully managed with the casein-based eHF and 1 (6.7%) required an AAF. This formula was effective in 91% of patients with FPIAP, in 100% with FPIES and with diarrhoea. Three (60%) patients with constipation responded to the eHF. Conclusion: This case-series report supports the efficacy of a particular casein-based eHF for the nutritional management of non-IgE mediated CMPA enteropathies.

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

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.