Vitamin D supplementation to prevent acute respiratory infections: individual participant data meta-analysis

Adrian R Martineau; David A Jolliffe; Lauren Greenberg; John F Aloia; Peter Bergman; Gal Dubnov-Raz; Susanna Esposito; Davaasambuu Ganmaa; Adit A Ginde; Emma C Goodall; Cameron C Grant; Wim Janssens; Megan E Jensen; Conor P Kerley; Ilkka Laaksi; Semira Manaseki-Holland; David Mauger; David R Murdoch; Rachel Neale; Judy R Rees; Steve Simpson; Iwona Stelmach; Geeta Trilok Kumar; Mitsuyoshi Urashima; Carlos A Camargo; Christopher J Griffiths; Richard L Hooper

doi:10.3310/hta23020

Vitamin D supplementation to prevent acute respiratory infections: individual participant data meta-analysis

Adrian R Martineau, David A Jolliffe, Lauren Greenberg, John F Aloia, Peter Bergman, Gal Dubnov-Raz, Susanna Esposito, Davaasambuu Ganmaa, Adit A Ginde, Emma C Goodall, Cameron C Grant, Wim Janssens, Megan E Jensen, Conor P Kerley, Ilkka Laaksi, Semira Manaseki-Holland, David Mauger, David R Murdoch, Rachel Neale, Judy R ReesSteve Simpson, Iwona Stelmach, Geeta Trilok Kumar, Mitsuyoshi Urashima, Carlos A Camargo, Christopher J Griffiths, Richard L Hooper

Applied Health Research

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Abstract

BACKGROUND: Randomised controlled trials (RCTs) exploring the potential of vitamin D to prevent acute respiratory infections have yielded mixed results. Individual participant data (IPD) meta-analysis has the potential to identify factors that may explain this heterogeneity.

OBJECTIVES: To assess the overall effect of vitamin D supplementation on the risk of acute respiratory infections (ARIs) and to identify factors modifying this effect.

DATA SOURCES: MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials (CENTRAL), Web of Science, ClinicalTrials.gov and the International Standard Randomised Controlled Trials Number (ISRCTN) registry.

STUDY SELECTION: Randomised, double-blind, placebo-controlled trials of supplementation with vitamin D3 or vitamin D2 of any duration having incidence of acute respiratory infection as a prespecified efficacy outcome were selected.

STUDY APPRAISAL: Study quality was assessed using the Cochrane Collaboration Risk of Bias tool to assess sequence generation, allocation concealment, blinding of participants, personnel and outcome assessors, completeness of outcome data, evidence of selective outcome reporting and other potential threats to validity.

RESULTS: We identified 25 eligible RCTs (a total of 11,321 participants, aged from 0 to 95 years). IPD were obtained for 10,933 out of 11,321 (96.6%) participants. Vitamin D supplementation reduced the risk of ARI among all participants [adjusted odds ratio (aOR) 0.88, 95% confidence interval (CI) 0.81 to 0.96; heterogeneity p < 0.001]. Subgroup analysis revealed that protective effects were seen in individuals receiving daily or weekly vitamin D without additional bolus doses (aOR 0.81, 95% CI 0.72 to 0.91), but not in those receiving one or more bolus doses (aOR 0.97, 95% CI 0.86 to 1.10; p = 0.05). Among those receiving daily or weekly vitamin D, protective effects of vitamin D were stronger in individuals with a baseline 25-hydroxyvitamin D [25(OH)D] concentration of < 25 nmol/l (aOR 0.30, 95% CI 0.17 to 0.53) than in those with a baseline 25(OH)D concentration of ≥ 25 nmol/l (aOR 0.75, 95% CI 0.60 to 0.95; p = 0.006). Vitamin D did not influence the proportion of participants experiencing at least one serious adverse event (aOR 0.98, 95% CI 0.80 to 1.20; p = 0.83). The body of evidence contributing to these analyses was assessed as being of high quality.

LIMITATIONS: Our study had limited power to detect the effects of vitamin D supplementation on the risk of upper versus lower respiratory infection, analysed separately.

CONCLUSIONS: Vitamin D supplementation was safe, and it protected against ARIs overall. Very deficient individuals and those not receiving bolus doses experienced the benefit. Incorporation of additional IPD from ongoing trials in the field has the potential to increase statistical power for analyses of secondary outcomes.

STUDY REGISTRATION: This study is registered as PROSPERO CRD42014013953.

FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Original language	English
Pages (from-to)	1-44
Number of pages	44
Journal	Health Technology Assessment
Volume	23
Issue number	2
DOIs	https://doi.org/10.3310/hta23020
Publication status	Published - 1 Jan 2019

Bibliographical note

Martineau AR, Jolliffe DA, Greenberg L, Aloia JF, Bergman P, Dubnov-Raz G, et al. Vitamin D supplementation to prevent acute respiratory infections: individual participant data meta-analysis. Health Technol Assess 2019;23(2)

ASJC Scopus subject areas

Health Policy

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This output contributes to the following UN Sustainable Development Goals (SDGs)

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Martineau, A. R., Jolliffe, D. A., Greenberg, L., Aloia, J. F., Bergman, P., Dubnov-Raz, G., Esposito, S., Ganmaa, D., Ginde, A. A., Goodall, E. C., Grant, C. C., Janssens, W., Jensen, M. E., Kerley, C. P., Laaksi, I., Manaseki-Holland, S., Mauger, D., Murdoch, D. R., Neale, R., ... Hooper, R. L. (2019). Vitamin D supplementation to prevent acute respiratory infections: individual participant data meta-analysis. Health Technology Assessment, 23(2), 1-44. https://doi.org/10.3310/hta23020

@article{ebf5e3990df9406bb779dbaf6c3bba71,

title = "Vitamin D supplementation to prevent acute respiratory infections: individual participant data meta-analysis",

abstract = "BACKGROUND: Randomised controlled trials (RCTs) exploring the potential of vitamin D to prevent acute respiratory infections have yielded mixed results. Individual participant data (IPD) meta-analysis has the potential to identify factors that may explain this heterogeneity.OBJECTIVES: To assess the overall effect of vitamin D supplementation on the risk of acute respiratory infections (ARIs) and to identify factors modifying this effect.DATA SOURCES: MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials (CENTRAL), Web of Science, ClinicalTrials.gov and the International Standard Randomised Controlled Trials Number (ISRCTN) registry.STUDY SELECTION: Randomised, double-blind, placebo-controlled trials of supplementation with vitamin D3 or vitamin D2 of any duration having incidence of acute respiratory infection as a prespecified efficacy outcome were selected.STUDY APPRAISAL: Study quality was assessed using the Cochrane Collaboration Risk of Bias tool to assess sequence generation, allocation concealment, blinding of participants, personnel and outcome assessors, completeness of outcome data, evidence of selective outcome reporting and other potential threats to validity.RESULTS: We identified 25 eligible RCTs (a total of 11,321 participants, aged from 0 to 95 years). IPD were obtained for 10,933 out of 11,321 (96.6%) participants. Vitamin D supplementation reduced the risk of ARI among all participants [adjusted odds ratio (aOR) 0.88, 95% confidence interval (CI) 0.81 to 0.96; heterogeneity p < 0.001]. Subgroup analysis revealed that protective effects were seen in individuals receiving daily or weekly vitamin D without additional bolus doses (aOR 0.81, 95% CI 0.72 to 0.91), but not in those receiving one or more bolus doses (aOR 0.97, 95% CI 0.86 to 1.10; p = 0.05). Among those receiving daily or weekly vitamin D, protective effects of vitamin D were stronger in individuals with a baseline 25-hydroxyvitamin D [25(OH)D] concentration of < 25 nmol/l (aOR 0.30, 95% CI 0.17 to 0.53) than in those with a baseline 25(OH)D concentration of ≥ 25 nmol/l (aOR 0.75, 95% CI 0.60 to 0.95; p = 0.006). Vitamin D did not influence the proportion of participants experiencing at least one serious adverse event (aOR 0.98, 95% CI 0.80 to 1.20; p = 0.83). The body of evidence contributing to these analyses was assessed as being of high quality.LIMITATIONS: Our study had limited power to detect the effects of vitamin D supplementation on the risk of upper versus lower respiratory infection, analysed separately.CONCLUSIONS: Vitamin D supplementation was safe, and it protected against ARIs overall. Very deficient individuals and those not receiving bolus doses experienced the benefit. Incorporation of additional IPD from ongoing trials in the field has the potential to increase statistical power for analyses of secondary outcomes.STUDY REGISTRATION: This study is registered as PROSPERO CRD42014013953.FUNDING: The National Institute for Health Research Health Technology Assessment programme.",

author = "Martineau, {Adrian R} and Jolliffe, {David A} and Lauren Greenberg and Aloia, {John F} and Peter Bergman and Gal Dubnov-Raz and Susanna Esposito and Davaasambuu Ganmaa and Ginde, {Adit A} and Goodall, {Emma C} and Grant, {Cameron C} and Wim Janssens and Jensen, {Megan E} and Kerley, {Conor P} and Ilkka Laaksi and Semira Manaseki-Holland and David Mauger and Murdoch, {David R} and Rachel Neale and Rees, {Judy R} and Steve Simpson and Iwona Stelmach and {Trilok Kumar}, Geeta and Mitsuyoshi Urashima and Camargo, {Carlos A} and Griffiths, {Christopher J} and Hooper, {Richard L}",

note = "Martineau AR, Jolliffe DA, Greenberg L, Aloia JF, Bergman P, Dubnov-Raz G, et al. Vitamin D supplementation to prevent acute respiratory infections: individual participant data meta-analysis. Health Technol Assess 2019;23(2)",

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doi = "10.3310/hta23020",

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Martineau, AR, Jolliffe, DA, Greenberg, L, Aloia, JF, Bergman, P, Dubnov-Raz, G, Esposito, S, Ganmaa, D, Ginde, AA, Goodall, EC, Grant, CC, Janssens, W, Jensen, ME, Kerley, CP, Laaksi, I, Manaseki-Holland, S, Mauger, D, Murdoch, DR, Neale, R, Rees, JR, Simpson, S, Stelmach, I, Trilok Kumar, G, Urashima, M, Camargo, CA, Griffiths, CJ & Hooper, RL 2019, 'Vitamin D supplementation to prevent acute respiratory infections: individual participant data meta-analysis', Health Technology Assessment, vol. 23, no. 2, pp. 1-44. https://doi.org/10.3310/hta23020

TY - JOUR

T1 - Vitamin D supplementation to prevent acute respiratory infections

T2 - individual participant data meta-analysis

AU - Martineau, Adrian R

AU - Jolliffe, David A

AU - Greenberg, Lauren

AU - Aloia, John F

AU - Bergman, Peter

AU - Dubnov-Raz, Gal

AU - Esposito, Susanna

AU - Ganmaa, Davaasambuu

AU - Ginde, Adit A

AU - Goodall, Emma C

AU - Grant, Cameron C

AU - Janssens, Wim

AU - Jensen, Megan E

AU - Kerley, Conor P

AU - Laaksi, Ilkka

AU - Manaseki-Holland, Semira

AU - Mauger, David

AU - Murdoch, David R

AU - Neale, Rachel

AU - Rees, Judy R

AU - Simpson, Steve

AU - Stelmach, Iwona

AU - Trilok Kumar, Geeta

AU - Urashima, Mitsuyoshi

AU - Camargo, Carlos A

AU - Griffiths, Christopher J

AU - Hooper, Richard L

N1 - Martineau AR, Jolliffe DA, Greenberg L, Aloia JF, Bergman P, Dubnov-Raz G, et al. Vitamin D supplementation to prevent acute respiratory infections: individual participant data meta-analysis. Health Technol Assess 2019;23(2)

PY - 2019/1/1

Y1 - 2019/1/1

N2 - BACKGROUND: Randomised controlled trials (RCTs) exploring the potential of vitamin D to prevent acute respiratory infections have yielded mixed results. Individual participant data (IPD) meta-analysis has the potential to identify factors that may explain this heterogeneity.OBJECTIVES: To assess the overall effect of vitamin D supplementation on the risk of acute respiratory infections (ARIs) and to identify factors modifying this effect.DATA SOURCES: MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials (CENTRAL), Web of Science, ClinicalTrials.gov and the International Standard Randomised Controlled Trials Number (ISRCTN) registry.STUDY SELECTION: Randomised, double-blind, placebo-controlled trials of supplementation with vitamin D3 or vitamin D2 of any duration having incidence of acute respiratory infection as a prespecified efficacy outcome were selected.STUDY APPRAISAL: Study quality was assessed using the Cochrane Collaboration Risk of Bias tool to assess sequence generation, allocation concealment, blinding of participants, personnel and outcome assessors, completeness of outcome data, evidence of selective outcome reporting and other potential threats to validity.RESULTS: We identified 25 eligible RCTs (a total of 11,321 participants, aged from 0 to 95 years). IPD were obtained for 10,933 out of 11,321 (96.6%) participants. Vitamin D supplementation reduced the risk of ARI among all participants [adjusted odds ratio (aOR) 0.88, 95% confidence interval (CI) 0.81 to 0.96; heterogeneity p < 0.001]. Subgroup analysis revealed that protective effects were seen in individuals receiving daily or weekly vitamin D without additional bolus doses (aOR 0.81, 95% CI 0.72 to 0.91), but not in those receiving one or more bolus doses (aOR 0.97, 95% CI 0.86 to 1.10; p = 0.05). Among those receiving daily or weekly vitamin D, protective effects of vitamin D were stronger in individuals with a baseline 25-hydroxyvitamin D [25(OH)D] concentration of < 25 nmol/l (aOR 0.30, 95% CI 0.17 to 0.53) than in those with a baseline 25(OH)D concentration of ≥ 25 nmol/l (aOR 0.75, 95% CI 0.60 to 0.95; p = 0.006). Vitamin D did not influence the proportion of participants experiencing at least one serious adverse event (aOR 0.98, 95% CI 0.80 to 1.20; p = 0.83). The body of evidence contributing to these analyses was assessed as being of high quality.LIMITATIONS: Our study had limited power to detect the effects of vitamin D supplementation on the risk of upper versus lower respiratory infection, analysed separately.CONCLUSIONS: Vitamin D supplementation was safe, and it protected against ARIs overall. Very deficient individuals and those not receiving bolus doses experienced the benefit. Incorporation of additional IPD from ongoing trials in the field has the potential to increase statistical power for analyses of secondary outcomes.STUDY REGISTRATION: This study is registered as PROSPERO CRD42014013953.FUNDING: The National Institute for Health Research Health Technology Assessment programme.

AB - BACKGROUND: Randomised controlled trials (RCTs) exploring the potential of vitamin D to prevent acute respiratory infections have yielded mixed results. Individual participant data (IPD) meta-analysis has the potential to identify factors that may explain this heterogeneity.OBJECTIVES: To assess the overall effect of vitamin D supplementation on the risk of acute respiratory infections (ARIs) and to identify factors modifying this effect.DATA SOURCES: MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials (CENTRAL), Web of Science, ClinicalTrials.gov and the International Standard Randomised Controlled Trials Number (ISRCTN) registry.STUDY SELECTION: Randomised, double-blind, placebo-controlled trials of supplementation with vitamin D3 or vitamin D2 of any duration having incidence of acute respiratory infection as a prespecified efficacy outcome were selected.STUDY APPRAISAL: Study quality was assessed using the Cochrane Collaboration Risk of Bias tool to assess sequence generation, allocation concealment, blinding of participants, personnel and outcome assessors, completeness of outcome data, evidence of selective outcome reporting and other potential threats to validity.RESULTS: We identified 25 eligible RCTs (a total of 11,321 participants, aged from 0 to 95 years). IPD were obtained for 10,933 out of 11,321 (96.6%) participants. Vitamin D supplementation reduced the risk of ARI among all participants [adjusted odds ratio (aOR) 0.88, 95% confidence interval (CI) 0.81 to 0.96; heterogeneity p < 0.001]. Subgroup analysis revealed that protective effects were seen in individuals receiving daily or weekly vitamin D without additional bolus doses (aOR 0.81, 95% CI 0.72 to 0.91), but not in those receiving one or more bolus doses (aOR 0.97, 95% CI 0.86 to 1.10; p = 0.05). Among those receiving daily or weekly vitamin D, protective effects of vitamin D were stronger in individuals with a baseline 25-hydroxyvitamin D [25(OH)D] concentration of < 25 nmol/l (aOR 0.30, 95% CI 0.17 to 0.53) than in those with a baseline 25(OH)D concentration of ≥ 25 nmol/l (aOR 0.75, 95% CI 0.60 to 0.95; p = 0.006). Vitamin D did not influence the proportion of participants experiencing at least one serious adverse event (aOR 0.98, 95% CI 0.80 to 1.20; p = 0.83). The body of evidence contributing to these analyses was assessed as being of high quality.LIMITATIONS: Our study had limited power to detect the effects of vitamin D supplementation on the risk of upper versus lower respiratory infection, analysed separately.CONCLUSIONS: Vitamin D supplementation was safe, and it protected against ARIs overall. Very deficient individuals and those not receiving bolus doses experienced the benefit. Incorporation of additional IPD from ongoing trials in the field has the potential to increase statistical power for analyses of secondary outcomes.STUDY REGISTRATION: This study is registered as PROSPERO CRD42014013953.FUNDING: The National Institute for Health Research Health Technology Assessment programme.

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U2 - 10.3310/hta23020

DO - 10.3310/hta23020

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SN - 1366-5278

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SP - 1

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JO - Health Technology Assessment

JF - Health Technology Assessment

IS - 2

ER -

Vitamin D supplementation to prevent acute respiratory infections: individual participant data meta-analysis

Abstract

Bibliographical note

ASJC Scopus subject areas

UN SDGs

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