BIOMARKERS FOR THE DIAGNOSIS OF FOOD PROTEIN-INDUCED ENTEROCOLITIS SYNDROME: A SYSTEMATIC REVIEW AND META-ANALYSIS

Abstract

Background: Food protein-induced enterocolitis syndrome (FPIES) is still diagnosed mainly on clinical grounds because no laboratory biomarker has been
sufficiently validated for routine practice. This study systematically reviewed and quantitatively synthesized candidate biomarkers for FPIES diagnosis, differential
diagnosis, severity assessment, and short-term prognosis.
Methods: A systematic search was conducted from database inception to 19 March 2026 across PubMed/MEDLINE, Embase, Scopus, Web of Science Core
Collection, PsycINFO, Cochrane CENTRAL, ClinicalTrials.gov, WHO ICTRP, and grey-literature sources. Two reviewers independently screened studies,
extracted data, and assessed risk of bias, with disagreements resolved by a third reviewer. Eligible studies included patients with clinically diagnosed or oral food
challenge-confirmed FPIES and reported blood, cellular, tissue, or omics-based biomarkers.
Results: Seventeen studies were included in the qualitative review. Among these, only two case-control studies provided sufficiently comparable data for metaanalysis, both evaluating acute thymus and activation-regulated chemokine (TARC/CCL17) levels in Japan. These studies showed that acute-phase TARC
concentrations were higher in FPIES than in infectious gastroenteritis or IgE-mediated food allergy. Random-effects meta-analysis demonstrated a large effect size
favoring higher TARC levels in FPIES (Hedges’ g = 1.64; 95% CI: 1.12–2.16; I² = 0%; τ² = 0). Other biomarkers, including procalcitonin, acute cytokine surges,
neutrophilia, thrombocytosis, and proteomic/metabolomic signatures, were reported in small observational studies, but heterogeneity in sampling time, assay
methods, comparator groups, and outcomes prevented meaningful pooling. Routine inflammatory markers such as C-reactive protein and leukocyte indices
appeared biologically relevant but lacked diagnostic specificity.
Conclusion: Current evidence suggests that TARC/CCL17 is the most promising acute diagnostic biomarker for FPIES, while procalcitonin and cytokine signatures
require further prospective validation. At present, no biomarker can replace established clinical criteria or supervised oral food challenge in diagnosing FPIES.