When a previously healthy infant presents to an emergency department with profuse vomiting, lethargy, and signs of circulatory collapse, the working diagnosis is rarely a food allergy — yet that misclassification may be costing young children appropriate care. Food protein-induced enterocolitis syndrome (FPIES) sits in a diagnostic blind spot precisely because it defies the conventional allergy playbook.
Unlike IgE-mediated food allergies, FPIES leaves no immunological fingerprints on standard testing: skin prick tests are negative, serum IgE is unremarkable, and there is no urticaria, wheezing, or anaphylaxis. Instead, acute FPIES erupts one to four hours after ingestion of trigger foods — most commonly rice, oats, cow's milk, and soy — producing repetitive vomiting severe enough to drive hypovolemic shock. Chronic FPIES, typically affecting infants under three months on cow's milk or soy formula, unfolds more insidiously over days to weeks with episodic vomiting, watery diarrhea, and faltering growth. The 2017 international consensus guidelines represented the first formal diagnostic framework, yet prevalence data remain poorly characterized and pathophysiology is still debated — T-cell mediated mechanisms and innate immune dysregulation are leading hypotheses, but causal clarity is lacking.
The clinical significance of this review lies in what it reveals about systemic underrecognition. Because FPIES mimics sepsis and viral gastroenteritis, affected infants frequently undergo unnecessary septic workups, antibiotic exposure, and prolonged hospitalizations before the correct diagnosis is reached. Most cases self-resolve by ages three to five, but cow's milk and soy allergies carry a higher risk of persistence into adulthood — a population largely invisible in current research. The therapeutic toolkit remains essentially empty beyond food avoidance and supportive hydration. This is an area where even incremental mechanistic advances could meaningfully shorten the diagnostic odyssey families currently face. As a review, this article synthesizes existing evidence rather than generating new data, so its primary value is clinical education rather than paradigm shift.
