Food protein–induced enterocolitis syndrome

Abstract

Objective

To explore the relationship among gastrointestinal (GI) symptoms, immune response, and autonomic nervous system (ANS) in food protein–induced enterocolitis syndrome (FPIES) in relation to the current understanding of disease phenotype and pathogenesis.

Data Sources

Relevant studies related to FPIES, GI symptomatology, and ANS were reviewed. Literature search was performed using PubMed, with keyword combinations including but not limited to FPIES, allergic GI disorders, ANS, autonomic dysfunction, dysautonomia, GI, diarrhea, vomiting, neuroimmune, and clinical phenotyping tools.

Study Selections

Peer-reviewed case-control studies, observational studies, reviews and guidelines, and systematic reviews related to FPIES and ANS were selected for review.

Results

There is limited research directly relating GI symptoms and FPIES to the ANS and immunologic response. To support the proposed mechanisms of action related to patient symptoms, studies relevant to coexisting GI-autonomic processes and FPIES immunologic triggers were examined. These related disease processes were extrapolated to FPIES based on the current knowledge of FPIES phenotype and pathogenesis.

Conclusion

The etiology of FPIES and the underlying mechanisms triggering symptoms are not well understood. On the basis of the exaggerated GI symptoms and hemodynamic response observed, the ANS likely plays an important role in FPIES, possibly as a compensatory response. The trigger for this cascade of symptoms may be related to the disruption of immunologic homeostasis that typically contributes to immune tolerance. To more accurately evaluate FPIES pathophysiology necessitates understanding the diverse spectrum of presenting symptoms. A consistent and comprehensive symptom assessment tool may improve our understanding of this dynamic relationship.

Introduction

FPIES is a non–IgE-mediated allergic disorder in which an apparent food antigen triggers an inflammatory cascade. This can result in profound gastrointestinal (GI) symptoms and hemodynamic instability.^1,2 Its etiology is not well understood, and the mechanisms precipitating symptoms are not defined. Cumulative incidence in infants ranges from 0.015% to 0.7%, whereas prevalence in US infants is estimated at 0.51%.3, 4, 5 Although the age of presentation varies, FPIES typically manifests in previously healthy infants,² which can make assessment of symptom progression challenging. Practitioners must therefore be attentive toward recognizing early symptoms after ingestion along with a high index of suspicion for a food trigger. Diagnosis requires a thorough history including recognition of key characteristic clinical symptoms.² Furthermore, recognition of a wide and diverse spectrum of presentations has raised the possibility that FPIES may extend to led to the now well-described entity of FPIES in older children and adults.⁶ To better understand the potential associations among the multiple symptoms in FPIES necessitates a consistent and comprehensive method of defining symptoms and identifying potential underlying comorbidities.

The severity of symptoms in FPIES includes rapid decompensation and potential multisystem involvement. GI symptoms in FPIES can progress rapidly to include cardiovascular decompensation and mental status changes. The inciting event is the breakdown of immunologic tolerance to a food antigen.^1,2,7 To date, no risk factors have been identified to anticipate the development of symptoms. Although it is difficult to predict the timing of symptom development, FPIES has been associated with history of atopy, FPIES to another food, and family history of allergic disease.^8,9 Laboratory abnormalities during an acute episode may include leukocytosis with neutrophilia, thrombocytosis, metabolic acidosis, and methemoglobinemia.² Although supportive of FPIES, laboratory markers remain nondiagnostic. Radiologic studies and histologic analysis of endoscopic biopsies have similarly proven to be nonspecific,² resulting in an absence of effective diagnostic biomarkers. FPIES, thus, remains a clinical diagnosis. Despite this, prognosis is excellent, as most children develop immune tolerance to their specific food antigen trigger by 3 years of age.²

The inflammatory cascade from the presumptive food exposure can be accompanied by systemic symptoms of vomiting, diarrhea, hypotension, lethargy, and pallor. These symptoms can be associated with autonomic dysregulation¹⁰ and raise the question of a role of the autonomic nervous system (ANS) in FPIES. The symptom profile of FPIES, specifically the hemodynamic response, may be driven in part by the ANS. This may be related to the need to maintain homeostasis in the face of an immune response to a food antigen trigger. In this review, we aim to discuss the GI symptoms in FPIES as they relate to the immune response and ANS. We will explore how inflammatory triggers mechanistically affect the GI tract and ANS resulting in the cascade of symptoms described in FPIES. Toward this end, we will emphasize the need for a comprehensive clinical assessment tool in FPIES revealing the value of transdiagnostic questionnaires used for other difficult-to-define clinical conditions.