title: Neonatal BCG vaccination has no effect on recurrent wheeze in the first year of life: A randomized clinical trial.
abstract: BACKGROUND
  Recurrent wheeze (RW) is frequent in childhood. Studies have suggested that BCG vaccination can have nonspecific effects, reducing general nontuberculosis morbidity, including respiratory tract infections and atopic diseases. The mechanisms behind these nonspecific effects of BCG are not fully understood, but a shift from a TH2 to a TH1 response has been suggested as a possible explanation.
  
  
  OBJECTIVE
  We hypothesized that BCG at birth would reduce the cumulative incidence of RW during the first year of life.
  
  
  METHODS
  The Danish Calmette Study is a multicenter randomized trial conducted from 2012-2015 at 3 Danish hospitals. The 4262 newborns of 4184 included mothers were randomized 1:1 to BCG (SSI strain 1331) or to a no-intervention control group within 7 days of birth; siblings were randomized together as one randomization unit. Exclusion criteria were gestational age of less than 32 weeks, birth weight of less than 1000 g, known immunodeficiency, or no Danish-speaking parent. Information was collected through telephone interviews and clinical examinations at 3 and 13 months of age; data collectors were blind to randomization group. RW was defined in several ways, with the main definition being physician-diagnosed and medically treated RW up to 13 months of age.
  
  
  RESULTS
  By 13 months, 211 (10.0%) of 2100 children in the BCG group and 195 (9.4%) of 2071 children in the control group had received a diagnosis of RW from a medical doctor and received antiasthma treatment (relative risk, 1.07; 95% CI, 0.89-1.28). Supplementary analyses were made, including an analysis of baseline risk factors for development of RW.
  
  
  CONCLUSIONS
  Neonatal BCG had no effect on the development of RW before 13 months of age.
authors.affiliation: Department of Pediatrics, Kolding Hospital, and the Institute of Regional Health Research, University of Southern Denmark, Kolding, Denmark. Electronic address: lmje@dadlnet.dk.
authors.forename: Lisbeth Marianne
authors.initials: LM
authors.lastname: Thøstesen
authors.affiliation: Department of Paediatrics and Adolescent Medicine, Juliane Marie Centret, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
authors.forename: Lone Graff
authors.initials: LG
authors.lastname: Stensballe
authors.affiliation: Department of Pediatrics, Kolding Hospital, and the Institute of Regional Health Research, University of Southern Denmark, Kolding, Denmark.
authors.forename: Gitte Thybo
authors.initials: GT
authors.lastname: Pihl
authors.affiliation: Research Unit for Women's and Childrens' Health, Department of Paediatrics and Adolescent Medicine, Juliane Marie Centret, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
authors.forename: Jesper
authors.initials: J
authors.lastname: Kjærgaard
authors.affiliation: Department of Pediatrics, Copenhagen University Hospital, Hvidovre, Denmark.
authors.forename: Nina Marie
authors.initials: NM
authors.lastname: Birk
authors.affiliation: Department of Pediatrics, Copenhagen University Hospital, Hvidovre, Denmark.
authors.forename: Thomas Nørrelykke
authors.initials: TN
authors.lastname: Nissen
authors.affiliation: Research Center for Vitamins and Vaccines (CVIVA), Bandim Health Project, Statens Serum Institut, and the Section of Biostatistics, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Aksel Karl Georg
authors.initials: AKG
authors.lastname: Jensen
authors.affiliation: Bandim Health Project, Statens Serum Institut, Copenhagen, Denmark.
authors.forename: Peter
authors.initials: P
authors.lastname: Aaby
authors.affiliation: Department of Obstetrics and Gynecology, Odense University Hospital, Odense, Denmark.
authors.forename: Annette Wind
authors.initials: AW
authors.lastname: Olesen
authors.affiliation: Department of Pediatrics, Copenhagen University Hospital, Hvidovre, Denmark.
authors.forename: Dorthe Lisbeth
authors.initials: DL
authors.lastname: Jeppesen
authors.affiliation: Research Center for Vitamins and Vaccines (CVIVA), Statens Serum Institut, Copenhagen, and OPEN, Institute of Clinical Research, University of Southern Denmark/Odense University Hospital, Odense, Denmark.
authors.forename: Christine Stabell
authors.initials: CS
authors.lastname: Benn
authors.affiliation: Department of Pediatrics, Kolding Hospital, and the Institute of Regional Health Research, University of Southern Denmark, Kolding, Denmark.
authors.forename: Poul-Erik
authors.initials: PE
authors.lastname: Kofoed
mesh_terms: D018927:Anti-Asthmatic Agents / Q000627:therapeutic use; D001249:Asthma / Q000276:immunology* / Q000517:prevention & control; D001500:BCG Vaccine / Q000276:immunology*; D003718:Denmark; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D012008:Recurrence; D012135:Respiratory Sounds / Q000276:immunology*; D058408:Th1-Th2 Balance; D016896:Treatment Outcome; D014611:Vaccination
chemical_list: D018927:Anti-Asthmatic Agents; D001500:BCG Vaccine
keywords: BCG; heterologous immunity; infant; nonspecific effects; recurrent wheeze; vaccination