ReviewFood protein–induced enterocolitis syndrome: Dynamic relationship among gastrointestinal symptoms, immune response, and the autonomic nervous system
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.
Section snippets
Role of Clinical Assessment of Symptoms
FPIES is considered a heterogeneous disorder with a spectrum of clinical phenotypes. Diagnosis is based on a thorough history including recognition of key characteristic clinical symptoms, as defined by international consensus guidelines.2 Laboratory tests, imaging, and histologic findings on endoscopic biopsy are suggestive but nonspecific and are therefore not recommended for diagnostic purposes. The gold standard to confirm FPIES diagnosis is provocative testing with an oral food challenge.
FPIES and the ANS
The exaggerated cardiovascular response with associated GI symptoms observed in FPIES suggests potential involvement of the ANS. Whether ANS dysregulation is a cause or consequence of the cascade of events in FPIES is not clear. The ANS functions to maintain homeostasis and coordinate adaptive responses to external or internal stimuli.21 As an involuntary motor-effect system, outflow occurs either independently or by integration within a central autonomic network.22 The ANS is composed of the
Immune Response
It is well established that the immune system and ANS are tightly integrated and function to maintain physiological homeostasis when challenged by a foreign antigen. Coordinated responses and crosstalk between immune cells and neurons occur through inflammatory mediators, neurotransmitters, and neuropeptides.25 The GI tract specifically is an immunologically and neurologically rich barrier to the external environment. Downstream effects of the immune response in FPIES, specifically the ANS
Neuroimmune Interactions in FPIES
The ANS plays a role in modulating immune function in response to inflammation.46 All 3 divisions of the ANS—sympathetic, parasympathetic, and enteric nervous systems—receive input from immune cells and release neurotransmitters that regulate the immune response.24 The intestinal neuroimmune barrier consists of constant interactions among immune cells, enteric neurons, enteric glia, enteroendocrine cells, and microbiota. Inflammatory signals reach the central nervous system by humoral
Conclusion
FPIES is a disorder of immune intolerance to specific food antigens, primarily affecting infants but found to occur across all ages. It is characterized by immune dysregulation leading to profound GI symptoms and an exaggerated hemodynamic response that is not found in other allergic GI disorders. The ANS functions to regulate compensatory mechanisms to maintain organ perfusion and function and may play a critical role in the symptomatology of FPIES. Whether there is a dysregulated ANS response
Acknowledgment
The authors recognize Ms Elizabeth Ramirez for her efforts and attention to detail in assisting with the graphical design of the figures for this article.
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Disclosures: The authors have no conflicts of interest to report.
Funding: The authors have no funding sources to report.