title: Safety and predictors of adverse events during oral immunotherapy for milk allergy: severity of reaction at oral challenge, specific IgE and prick test.
abstract: BACKGROUND
  Strict avoidance is the only accepted management for cow's milk (CM) allergy. CM oral immunotherapy (CM-OIT) is under investigation.
  
  
  OBJECTIVE
  To evaluate long-term safety of CM-OIT. To identify clinical/immunological predictors of adverse events.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Allergy and Clinical Immunology Department, Hospital Sant Joan de Déu, Universitat de Barcelona, Barcelona, Spain. marta.vazquez.ortiz@gmail.com
authors.forename: M
authors.initials: M
authors.lastname: Vázquez-Ortiz
authors.forename: M
authors.initials: M
authors.lastname: Alvaro-Lozano
authors.forename: L
authors.initials: L
authors.lastname: Alsina
authors.forename: M B
authors.initials: MB
authors.lastname: Garcia-Paba
authors.forename: M
authors.initials: M
authors.lastname: Piquer-Gibert
authors.forename: M T
authors.initials: MT
authors.lastname: Giner-Muñoz
authors.forename: J
authors.initials: J
authors.lastname: Lozano
authors.forename: O
authors.initials: O
authors.lastname: Domínguez-Sánchez
authors.forename: R
authors.initials: R
authors.lastname: Jiménez
authors.forename: M
authors.initials: M
authors.lastname: Días
authors.forename: M A
authors.initials: MA
authors.lastname: Martín-Mateos
authors.forename: A M
authors.initials: AM
authors.lastname: Plaza-Martín
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000818:Animals; D002417:Cattle; D002648:Child; D002675:Child, Preschool; D003888:Desensitization, Immunologic / Q000009:adverse effects* / Q000379:methods; D005260:Female; D006801:Humans; D008297:Male; D016269:Milk Hypersensitivity / Q000517:prevention & control*; D012882:Skin Tests