Safety and predictors of adverse events during oral immunotherapy for milk allergy: severity of reaction at oral challenge, specific IgE and prick test

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Strict avoidance is the only accepted management for cow's milk (CM) allergy. CM oral immunotherapy (CM-OIT) is under investigation.


To evaluate long-term safety of CM-OIT. To identify clinical/immunological predictors of adverse events.


Prospective longitudinal epidemiological intervention study. CM-allergic children aged 5–18 underwent a Spanish-approved CM-OIT protocol without premedication. Clinical data, skin prick test (SPT) and specific IgE (sIgE) at baseline and 1 year after OIT were registered. All dose-related reactions, treatments needed and cofactors involved were recorded. Through survival analysis, we studied the cumulative probability of reactions resolution over time and clinical/immunological risk factors of reactions persistence.


81 children were recruited. Mean follow-up was 25 months. 95% of children suffered reactions, 91% of which affected a single organ. Reactions were heterogeneously distributed: (a) 60 children (75%) had occasional symptoms which ceased over time. 86% of them reached complete desensitization (200 mL). (b) 20 children (25%) suffered frequent (78% of total reactions), more severe and unpredictable reactions, which persisted during follow-up or led to withdrawal (6 cases). Reactions persistence was associated with a higher frequency and severity. Kaplan–Meier estimate revealed a cumulative probability of reactions resolution of 25% at 3 months (95% CI: 1.9–4.1) and 50% (95% CI: 6.1–9.9) at 8 months based on all patients. Cox proportional hazards multivariate regression model identified 3 variables (CM-sIgE ≥ 50 KU L−1, CM-SPT ≥ 9 mm and Sampson's severity grades 2, 3 and 4 at baseline food challenge) as independent risk factors of reactions persistence. The combination of 2 or 3 of these factors involved hazard ratios to develop persistent reactions of 2.26 (95% CI: 1.14–4.46; P = 0.019) and 6.06 (95% CI: 2.7–13.7; P < 0.001), respectively.

Clinical implications

CM-OIT was insufficiently safe in 25% of children. The above-mentioned clinical and immunological parameters would help clinicians to identify highly reactive patients before CM-OIT. In them, individualized schedules and premedication should be considered.

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