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Vitamin D supplementation to prevent asthma exacerbations: a systematic review and meta-analysis of individual participant data.

Abstract

BACKGROUND

A previous aggregate data meta-analysis of randomised controlled trials showed that vitamin D supplementation reduces the rate of asthma exacerbations requiring treatment with systemic corticosteroids. Whether this effect is restricted to patients with low baseline vitamin D status is unknown.

METHODS

For this systematic review and one-step and two-step meta-analysis of individual participant data, we searched MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, and Web of Science for double-blind, placebo-controlled, randomised controlled trials of vitamin D3 or vitamin D2 supplementation in people with asthma that reported incidence of asthma exacerbation, published between database inception and Oct 26, 2016. We analysed individual participant data requested from the principal investigator for each eligible trial, adjusting for age and sex, and clustering by study. The primary outcome was the incidence of asthma exacerbation requiring treatment with systemic corticosteroids. Mixed-effects regression models were used to obtain the pooled intervention effect with a 95% CI. Subgroup analyses were done to determine whether effects of vitamin D on risk of asthma exacerbation varied according to baseline 25-hydroxyvitamin D (25[OH]D) concentration, age, ethnic or racial origin, body-mass index, vitamin D dosing regimen, use of inhaled corticosteroids, or end-study 25(OH)D levels; post-hoc subgroup analyses were done according to sex and study duration. This study was registered with PROSPERO, number CRD42014013953.

FINDINGS

Our search identified 483 unique studies, eight of which were eligible randomised controlled trials (total 1078 participants). We sought individual participant data for each and obtained it for seven studies (955 participants). Vitamin D supplementation reduced the rate of asthma exacerbation requiring treatment with systemic corticosteroids among all participants (adjusted incidence rate ratio [aIRR] 0·74, 95% CI 0·56-0·97; p=0·03; 955 participants in seven studies; high-quality evidence). There were no significant differences between vitamin D and placebo in the proportion of participants with at least one exacerbation or time to first exacerbation. Subgroup analyses of the rate of asthma exacerbations treated with systemic corticosteroids revealed that protective effects were seen in participants with baseline 25(OH)D of less than 25 nmol/L (aIRR 0·33, 0·11-0·98; p=0·046; 92 participants in three studies; moderate-quality evidence) but not in participants with higher baseline 25(OH)D levels (aIRR 0·77, 0·58-1·03; p=0·08; 764 participants in six studies; moderate-quality evidence; pinteraction=0·25). p values for interaction for all other subgroup analyses were also higher than 0·05; therefore, we did not show that the effects of this intervention are stronger in any one subgroup than in another. Six studies were assessed as being at low risk of bias, and one was assessed as being at unclear risk of bias. The two-step meta-analysis did not reveal evidence of heterogeneity of effect (I2=0·0, p=0·56).

INTERPRETATION

Vitamin D supplementation reduced the rate of asthma exacerbations requiring treatment with systemic corticosteroids overall. We did not find definitive evidence that effects of this intervention differed across subgroups of patients.

FUNDING

Health Technology Assessment Program, National Institute for Health Research (reference number 13/03/25).

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  • Authors+Show Affiliations

    ,

    Centre for Primary Care and Public Health, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.

    ,

    Centre for Primary Care and Public Health, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.

    ,

    Centre for Primary Care and Public Health, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.

    ,

    Centre for Primary Care and Public Health, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK; Asthma UK Centre for Applied Research, Blizard Institute, Queen Mary University of London, London, UK.

    ,

    Department of Emergency Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.

    ,

    Dublin City University, Glanevin, Dublin, Ireland.

    ,

    Priority Research Centre Grow Up Well, University of Newcastle, Newcastle, NSW, Australia.

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    Department of Statistics, The Pennsylvania State University, Hershey, PA, USA.

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    Department of Pediatrics and Allergy, Medical University of Lodz, Lodz, Poland.

    ,

    Division of Molecular Epidemiology, Jikei University School of Medicine, Tokyo, Japan.

    Centre for Primary Care and Public Health, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK; Asthma UK Centre for Applied Research, Blizard Institute, Queen Mary University of London, London, UK. Electronic address: a.martineau@qmul.ac.uk.

    Source

    The Lancet. Respiratory medicine 5:11 2017 11 pg 881-890

    MeSH

    Adolescent
    Adrenal Cortex Hormones
    Adult
    Aged
    Aged, 80 and over
    Anti-Asthmatic Agents
    Asthma
    Child
    Child, Preschool
    Dietary Supplements
    Disease Progression
    Female
    Humans
    Male
    Middle Aged
    Secondary Prevention
    Treatment Outcome
    Vitamin D
    Vitamins
    Young Adult

    Pub Type(s)

    Journal Article
    Meta-Analysis
    Review
    Systematic Review

    Language

    eng

    PubMed ID

    28986128

    Citation

    Jolliffe, David A., et al. "Vitamin D Supplementation to Prevent Asthma Exacerbations: a Systematic Review and Meta-analysis of Individual Participant Data." The Lancet. Respiratory Medicine, vol. 5, no. 11, 2017, pp. 881-890.
    Jolliffe DA, Greenberg L, Hooper RL, et al. Vitamin D supplementation to prevent asthma exacerbations: a systematic review and meta-analysis of individual participant data. Lancet Respir Med. 2017;5(11):881-890.
    Jolliffe, D. A., Greenberg, L., Hooper, R. L., Griffiths, C. J., Camargo, C. A., Kerley, C. P., ... Martineau, A. R. (2017). Vitamin D supplementation to prevent asthma exacerbations: a systematic review and meta-analysis of individual participant data. The Lancet. Respiratory Medicine, 5(11), pp. 881-890. doi:10.1016/S2213-2600(17)30306-5.
    Jolliffe DA, et al. Vitamin D Supplementation to Prevent Asthma Exacerbations: a Systematic Review and Meta-analysis of Individual Participant Data. Lancet Respir Med. 2017;5(11):881-890. PubMed PMID: 28986128.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Vitamin D supplementation to prevent asthma exacerbations: a systematic review and meta-analysis of individual participant data. AU - Jolliffe,David A, AU - Greenberg,Lauren, AU - Hooper,Richard L, AU - Griffiths,Christopher J, AU - Camargo,Carlos A,Jr AU - Kerley,Conor P, AU - Jensen,Megan E, AU - Mauger,David, AU - Stelmach,Iwona, AU - Urashima,Mitsuyoshi, AU - Martineau,Adrian R, Y1 - 2017/10/03/ PY - 2017/05/23/received PY - 2017/07/21/revised PY - 2017/07/24/accepted PY - 2017/10/8/pubmed PY - 2018/6/26/medline PY - 2017/10/8/entrez SP - 881 EP - 890 JF - The Lancet. Respiratory medicine JO - Lancet Respir Med VL - 5 IS - 11 N2 - BACKGROUND: A previous aggregate data meta-analysis of randomised controlled trials showed that vitamin D supplementation reduces the rate of asthma exacerbations requiring treatment with systemic corticosteroids. Whether this effect is restricted to patients with low baseline vitamin D status is unknown. METHODS: For this systematic review and one-step and two-step meta-analysis of individual participant data, we searched MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, and Web of Science for double-blind, placebo-controlled, randomised controlled trials of vitamin D3 or vitamin D2 supplementation in people with asthma that reported incidence of asthma exacerbation, published between database inception and Oct 26, 2016. We analysed individual participant data requested from the principal investigator for each eligible trial, adjusting for age and sex, and clustering by study. The primary outcome was the incidence of asthma exacerbation requiring treatment with systemic corticosteroids. Mixed-effects regression models were used to obtain the pooled intervention effect with a 95% CI. Subgroup analyses were done to determine whether effects of vitamin D on risk of asthma exacerbation varied according to baseline 25-hydroxyvitamin D (25[OH]D) concentration, age, ethnic or racial origin, body-mass index, vitamin D dosing regimen, use of inhaled corticosteroids, or end-study 25(OH)D levels; post-hoc subgroup analyses were done according to sex and study duration. This study was registered with PROSPERO, number CRD42014013953. FINDINGS: Our search identified 483 unique studies, eight of which were eligible randomised controlled trials (total 1078 participants). We sought individual participant data for each and obtained it for seven studies (955 participants). Vitamin D supplementation reduced the rate of asthma exacerbation requiring treatment with systemic corticosteroids among all participants (adjusted incidence rate ratio [aIRR] 0·74, 95% CI 0·56-0·97; p=0·03; 955 participants in seven studies; high-quality evidence). There were no significant differences between vitamin D and placebo in the proportion of participants with at least one exacerbation or time to first exacerbation. Subgroup analyses of the rate of asthma exacerbations treated with systemic corticosteroids revealed that protective effects were seen in participants with baseline 25(OH)D of less than 25 nmol/L (aIRR 0·33, 0·11-0·98; p=0·046; 92 participants in three studies; moderate-quality evidence) but not in participants with higher baseline 25(OH)D levels (aIRR 0·77, 0·58-1·03; p=0·08; 764 participants in six studies; moderate-quality evidence; pinteraction=0·25). p values for interaction for all other subgroup analyses were also higher than 0·05; therefore, we did not show that the effects of this intervention are stronger in any one subgroup than in another. Six studies were assessed as being at low risk of bias, and one was assessed as being at unclear risk of bias. The two-step meta-analysis did not reveal evidence of heterogeneity of effect (I2=0·0, p=0·56). INTERPRETATION: Vitamin D supplementation reduced the rate of asthma exacerbations requiring treatment with systemic corticosteroids overall. We did not find definitive evidence that effects of this intervention differed across subgroups of patients. FUNDING: Health Technology Assessment Program, National Institute for Health Research (reference number 13/03/25). SN - 2213-2619 UR - https://www.unboundmedicine.com/medline/citation/28986128/Vitamin_D_supplementation_to_prevent_asthma_exacerbations:_a_systematic_review_and_meta_analysis_of_individual_participant_data_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S2213-2600(17)30306-5 DB - PRIME DP - Unbound Medicine ER -