Mary Aglipay1, Catherine S Birken2, Patricia C Parkin2, Mark B Loeb3, Kevin Thorpe4, Yang Chen5, Andreas Laupacis6, Muhammad Mamdani5, Colin Macarthur2, Jeffrey S Hoch7, Tony Mazzulli8, Jonathon L Maguire9. 1. Department of Pediatrics, St Michael's Hospital, Pediatric Research, Toronto, Ontario, Canada. 2. Pediatric Outcomes Research Team, Division of Pediatric Medicine, Department of Pediatrics, the Hospital for Sick Children, Toronto, Ontario, Canada3Department of Pediatrics, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada4Institute for Health Policy, Management and Evaluation, University of Toronto, Toronto, Ontario, Canada5Child Health Evaluative Sciences, Sick Kids Research Institute, Toronto, Ontario, Canada. 3. Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada7Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Ontario, Canada. 4. The La Ka Shing Knowledge Institute of St Michael's Hospital, University of Toronto, Toronto, Ontario, Canada9Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada. 5. The La Ka Shing Knowledge Institute of St Michael's Hospital, University of Toronto, Toronto, Ontario, Canada. 6. The La Ka Shing Knowledge Institute of St Michael's Hospital, University of Toronto, Toronto, Ontario, Canada10Institute for Clinical Evaluative Sciences, Toronto, Canada11Faculty of Medicine, University of Toronto, Toronto, Canada. 7. Institute for Health Policy, Management and Evaluation, University of Toronto, Toronto, Ontario, Canada8The La Ka Shing Knowledge Institute of St Michael's Hospital, University of Toronto, Toronto, Ontario, Canada12Department of Public Health Sciences, University of California, Davis, California. 8. Department of Microbiology, Mount Sinai Hospital, Toronto, Ontario, Canada14Department of Laboratory Medicine & Pathobiology, University of Toronto, Ontario, Canada. 9. Department of Pediatrics, St Michael's Hospital, Pediatric Research, Toronto, Ontario, Canada2Pediatric Outcomes Research Team, Division of Pediatric Medicine, Department of Pediatrics, the Hospital for Sick Children, Toronto, Ontario, Canada3Department of Pediatrics, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada4Institute for Health Policy, Management and Evaluation, University of Toronto, Toronto, Ontario, Canada8The La Ka Shing Knowledge Institute of St Michael's Hospital, University of Toronto, Toronto, Ontario, Canada.
Abstract
IMPORTANCE: Epidemiological studies support a link between low 25-hydroxyvitamin D levels and a higher risk of viral upper respiratory tract infections. However, whether winter supplementation of vitamin D reduces the risk among children is unknown. OBJECTIVE: To determine whether high-dose vs standard-dose vitamin D supplementation reduces the incidence of wintertime upper respiratory tract infections in young children. DESIGN, SETTING, AND PARTICIPANTS: A randomized clinical trial was conducted during the winter months between September 13, 2011, and June 30, 2015, among children aged 1 through 5 years enrolled in TARGet Kids!, a multisite primary care practice-based research network in Toronto, Ontario, Canada. INTERVENTIONS: Three hundred forty-nine participants were randomized to receive 2000 IU/d of vitamin D oral supplementation (high-dose group) vs 354 participants who were randomized to receive 400 IU/d (standard-dose group) for a minimum of 4 months between September and May. MAIN OUTCOME MEASURES: The primary outcome was the number of laboratory-confirmed viral upper respiratory tract infections based on parent-collected nasal swabs over the winter months. Secondary outcomes included the number of influenza infections, noninfluenza infections, parent-reported upper respiratory tract illnesses, time to first upper respiratory tract infection, and serum 25-hydroxyvitamin D levels at study termination. RESULTS: Among 703 participants who were randomized (mean age, 2.7 years, 57.7% boys), 699 (99.4%) completed the trial. The mean number of laboratory-confirmed upper respiratory tract infections per child was 1.05 (95% CI, 0.91-1.19) for the high-dose group and 1.03 (95% CI, 0.90-1.16) for the standard-dose group, for a between-group difference of 0.02 (95% CI, -0.17 to 0.21) per child. There was no statistically significant difference in number of laboratory-confirmed infections between groups (incidence rate ratio [RR], 0.97; 95% CI, 0.80-1.16). There was also no significant difference in the median time to the first laboratory-confirmed infection: 3.95 months (95% CI, 3.02-5.95 months) for the high-dose group vs 3.29 months (95% CI, 2.66-4.14 months) for the standard-dose group, or number of parent-reported upper respiratory tract illnesses between groups (625 for high-dose vs 600 for standard-dose groups, incidence RR, 1.01; 95% CI, 0.88-1.16). At study termination, serum 25-hydroxyvitamin D levels were 48.7 ng/mL (95% CI, 46.9-50.5 ng/mL) in the high-dose group and 36.8 ng/mL (95% CI, 35.4-38.2 ng/mL) in the standard-dose group. CONCLUSIONS AND RELEVANCE: Among healthy children aged 1 to 5 years, daily administration of 2000 IU compared with 400 IU of vitamin D supplementation did not reduce overall wintertime upper respiratory tract infections. These findings do not support the routine use of high-dose vitamin D supplementation in children for the prevention of viral upper respiratory tract infections. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01419262.
IMPORTANCE: Epidemiological studies support a link between low 25-hydroxyvitamin D levels and a higher risk of viral upper respiratory tract infections. However, whether winter supplementation of vitamin D reduces the risk among children is unknown. OBJECTIVE: To determine whether high-dose vs standard-dose vitamin D supplementation reduces the incidence of wintertime upper respiratory tract infections in young children. DESIGN, SETTING, AND PARTICIPANTS: A randomized clinical trial was conducted during the winter months between September 13, 2011, and June 30, 2015, among children aged 1 through 5 years enrolled in TARGet Kids!, a multisite primary care practice-based research network in Toronto, Ontario, Canada. INTERVENTIONS: Three hundred forty-nine participants were randomized to receive 2000 IU/d of vitamin D oral supplementation (high-dose group) vs 354 participants who were randomized to receive 400 IU/d (standard-dose group) for a minimum of 4 months between September and May. MAIN OUTCOME MEASURES: The primary outcome was the number of laboratory-confirmed viral upper respiratory tract infections based on parent-collected nasal swabs over the winter months. Secondary outcomes included the number of influenza infections, noninfluenza infections, parent-reported upper respiratory tract illnesses, time to first upper respiratory tract infection, and serum 25-hydroxyvitamin D levels at study termination. RESULTS: Among 703 participants who were randomized (mean age, 2.7 years, 57.7% boys), 699 (99.4%) completed the trial. The mean number of laboratory-confirmed upper respiratory tract infections per child was 1.05 (95% CI, 0.91-1.19) for the high-dose group and 1.03 (95% CI, 0.90-1.16) for the standard-dose group, for a between-group difference of 0.02 (95% CI, -0.17 to 0.21) per child. There was no statistically significant difference in number of laboratory-confirmed infections between groups (incidence rate ratio [RR], 0.97; 95% CI, 0.80-1.16). There was also no significant difference in the median time to the first laboratory-confirmed infection: 3.95 months (95% CI, 3.02-5.95 months) for the high-dose group vs 3.29 months (95% CI, 2.66-4.14 months) for the standard-dose group, or number of parent-reported upper respiratory tract illnesses between groups (625 for high-dose vs 600 for standard-dose groups, incidence RR, 1.01; 95% CI, 0.88-1.16). At study termination, serum 25-hydroxyvitamin D levels were 48.7 ng/mL (95% CI, 46.9-50.5 ng/mL) in the high-dose group and 36.8 ng/mL (95% CI, 35.4-38.2 ng/mL) in the standard-dose group. CONCLUSIONS AND RELEVANCE: Among healthy children aged 1 to 5 years, daily administration of 2000 IU compared with 400 IU of vitamin D supplementation did not reduce overall wintertime upper respiratory tract infections. These findings do not support the routine use of high-dose vitamin D supplementation in children for the prevention of viral upper respiratory tract infections. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01419262.
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