Threshold heterogeneity and dose-related clinical reaction profiles in infantile food protein-induced enterocolitis syndrome.

BACKGROUND: Oral food challenge (OFC) protocols in food protein-induced enterocolitis syndrome (FPIES) often select starting doses with consideration of prior reaction severity, implying that dose may influence reaction intensity; however, patient-level evidence linking antigen dose to reaction profiles remains limited. OBJECTIVE: To characterize threshold heterogeneity and compare clinical reaction profiles between diagnostic and reactive threshold OFCs within individual patients. METHODS: In this prospective study, 54 infants with OFC-confirmed FPIES (egg yolk, 36; cow's milk, 18) underwent threshold characterization at 0.001 g/kg (ultra-low) and 0.01 g/kg (low); all had previously reacted at a diagnostic OFC (median 0.38 g/kg). For the 30 reacting at a threshold challenge, the primary endpoint was objective reaction intensity (vomiting, examination signs); treatment intensity and a composite burden category were supporting measures. RESULTS: Of 54 patients, 12 (22%) reacted at 0.001 g/kg, 18 (33%) at 0.01 g/kg, and 24 (44%) tolerated both. Among the 30 threshold reactors, reactions were objectively milder than at the diagnostic OFC: median vomiting 2 (IQR 2-3) versus 4 (4-6) (p < .001), pallor 27% versus 63% (p = .019), decreased activity 43% versus 80% (p = .007). No ICG-defined severe features (hypotension/shock, severe lethargy) occurred at either OFC. Treatment intensity was also lower (intravenous fluid and prolonged observation each 27% versus 67%; both p < .001). CONCLUSION: Reactions at ultra-low and low threshold doses were objectively milder than at diagnostic doses within patients, while clinically meaningful reactions still occurred. These findings support systematic threshold assessment beginning at 0.001 g/kg, independent of diagnostic OFC clinical burden.