Barts and The London School of Medicine and Dentistry, and Asthma UK Centre for Applied Research, Queen Mary University of London, London, UK.
Department of Emergency Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
Lancet Diabetes Endocrinol. 2021 May;9(5):276-292. doi: 10.1016/S2213-8587(21)00051-6. Epub 2021 Mar 30.
A 2017 meta-analysis of data from 25 randomised controlled trials (RCTs) of vitamin D supplementation for the prevention of acute respiratory infections (ARIs) revealed a protective effect of this intervention. We aimed to examine the link between vitamin D supplementation and prevention of ARIs in an updated meta-analysis.
For this systematic review and meta-analysis, we searched MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, Web of Science, and the ClinicalTrials.gov registry for studies listed from database inception to May 1, 2020. Double-blind RCTs of vitamin D, vitamin D, or 25-hydroxyvitamin D (25[OH]D) supplementation for any duration, with a placebo or low-dose vitamin D control, were eligible if they had been approved by a research ethics committee, and if ARI incidence was collected prospectively and prespecified as an efficacy outcome. Studies reporting results of long-term follow-up of primary RCTs were excluded. Aggregated study-level data, stratified by baseline 25(OH)D concentration and age, were obtained from study authors. Using the proportion of participants in each trial who had one or more ARIs, we did a random-effects meta-analysis to obtain pooled odds ratios (ORs) and 95% CIs to estimate the effect of vitamin D supplementation on the risk of having one or more ARIs (primary outcome) compared with placebo. Subgroup analyses were done to estimate whether the effects of vitamin D supplementation on the risk of ARI varied according to baseline 25(OH)D concentration (<25 nmol/L vs 25·0-49·9 nmol/L vs 50·0-74·9 nmol/L vs >75·0 nmol/L), vitamin D dose (daily equivalent of <400 international units [IU] vs 400-1000 IU vs 1001-2000 IU vs >2000 IU), dosing frequency (daily vs weekly vs once per month to once every 3 months), trial duration (≤12 months vs >12 months), age at enrolment (<1·00 years vs 1·00-15·99 years vs 16·00-64·99 years vs ≥65·00 years), and presence versus absence of airway disease (ie, asthma only, COPD only, or unrestricted). Risk of bias was assessed with the Cochrane Collaboration Risk of Bias Tool. The study was registered with PROSPERO, CRD42020190633.
We identified 1528 articles, of which 46 RCTs (75 541 participants) were eligible. Data for the primary outcome were obtained for 48 488 (98·1%) of 49 419 participants (aged 0-95 years) in 43 studies. A significantly lower proportion of participants in the vitamin D supplementation group had one or more ARIs (14 332 [61·3%] of 23 364 participants) than in the placebo group (14 217 [62·3%] of 22 802 participants), with an OR of 0·92 (95% CI 0·86-0·99; 37 studies; I=35·6%, p=0·018). No significant effect of vitamin D supplementation on the risk of having one or more ARIs was observed for any of the subgroups defined by baseline 25(OH)D concentration. However, protective effects of supplementation were observed in trials in which vitamin D was given in a daily dosing regimen (OR 0·78 [95% CI 0·65-0·94]; 19 studies; I=53·5%, p=0·003), at daily dose equivalents of 400-1000 IU (0·70 [0·55-0·89]; ten studies; I=31·2%, p=0·16), for a duration of 12 months or less (0·82 [0·72-0·93]; 29 studies; I=38·1%, p=0·021), and to participants aged 1·00-15·99 years at enrolment (0·71 [0·57-0·90]; 15 studies; I=46·0%, p=0·027). No significant interaction between allocation to the vitamin D supplementation group versus the placebo group and dose, dose frequency, study duration, or age was observed. In addition, no significant difference in the proportion of participants who had at least one serious adverse event in the vitamin supplementation group compared with the placebo group was observed (0·97 [0·86-1·07]; 36 studies; I=0·0%, p=0·99). Risk of bias within individual studies was assessed as being low for all but three trials.
Despite evidence of significant heterogeneity across trials, vitamin D supplementation was safe and overall reduced the risk of ARI compared with placebo, although the risk reduction was small. Protection was associated with administration of daily doses of 400-1000 IU for up to 12 months, and age at enrolment of 1·00-15·99 years. The relevance of these findings to COVID-19 is not known and requires further investigation.
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2017 年对 25 项随机对照试验（RCT）的数据分析进行的荟萃分析显示，维生素 D 补充剂可预防急性呼吸道感染（ARI）。我们旨在通过更新的荟萃分析来检验维生素 D 补充剂与预防 ARI 之间的联系。
本系统评价和荟萃分析，我们检索了 MEDLINE、Embase、Cochrane 中心对照试验注册中心、Web of Science 和 ClinicalTrials.gov 登记处，检索了截至 2020 年 5 月 1 日数据库成立以来的研究。如果研究已通过研究伦理委员会批准，并且前瞻性收集了 ARI 发病率并将其作为疗效结局进行了预先规定，则维生素 D、维生素 D 或 25-羟维生素 D（25[OH]D）补充剂的双盲 RCT 符合纳入标准，补充剂持续时间不限，且使用安慰剂或低剂量维生素 D 作为对照。报告主要 RCT 长期随访结果的研究被排除在外。从研究作者处获得汇总的研究水平数据，按基线 25（OH）D 浓度和年龄分层。我们采用每个试验中发生 1 次或多次 ARI 的参与者比例进行随机效应荟萃分析，以获得汇总优势比（OR）和 95%置信区间（CI），从而评估与安慰剂相比，维生素 D 补充剂对发生 1 次或多次 ARI 的风险的影响（主要结局）。进行亚组分析，以评估维生素 D 补充剂对 ARI 风险的影响是否因基线 25（OH）D 浓度（<25 nmol/L 与 25.0-49.9 nmol/L 与 50.0-74.9 nmol/L 与>75.0 nmol/L）、维生素 D 剂量（<400 国际单位 [IU] 与 400-1000 IU 与 1001-2000 IU 与>2000 IU）、给药频率（每日与每周与每月一次至每三个月一次）、试验持续时间（≤12 个月与>12 个月）、入组时年龄（<1.00 岁与 1.00-15.99 岁与 16.00-64.99 岁与≥65.00 岁）以及气道疾病的存在与否（即仅哮喘、仅 COPD 或不限）而有所不同。使用 Cochrane 协作风险偏倚工具评估风险偏倚。该研究在 PROSPERO 注册，注册号为 CRD42020190633。
我们确定了 1528 篇文章，其中 46 项 RCT（75541 名参与者）符合纳入标准。在 43 项研究中，48488 名（0-95 岁）参与者（49419 名参与者中的 98.1%）的数据可用于主要结局。与安慰剂组（22802 名参与者中的 14217 名[62.3%]）相比，维生素 D 补充组中有一个或多个 ARI（23364 名参与者中的 14332 名[61.3%]）的参与者比例明显较低，OR 为 0.92（95%CI 0.86-0.99；37 项研究；I=35.6%，p=0.018）。按基线 25（OH）D 浓度分层，未观察到维生素 D 补充对发生一个或多个 ARI 的风险有任何显著影响。然而，在维生素 D 每日给药方案（OR 0.78 [95%CI 0.65-0.94]；19 项研究；I=53.5%，p=0.003）、400-1000 IU 日剂量等效（OR 0.70 [0.55-0.89]；10 项研究；I=31.2%，p=0.16）、持续时间 12 个月或更短（OR 0.82 [0.72-0.93]；29 项研究；I=38.1%，p=0.021）和入组时年龄为 1.00-15.99 岁（OR 0.71 [0.57-0.90]；15 项研究；I=46.0%，p=0.027）的试验中观察到保护作用。未观察到维生素 D 补充组与安慰剂组之间的分配与剂量、剂量频率、试验持续时间或年龄之间存在显著的相互作用。此外，与安慰剂组相比，维生素补充组中至少有一次严重不良事件的参与者比例无显著差异（0.97 [0.86-1.07]；36 项研究；I=0.0%，p=0.99）。除了三项试验外，所有试验的个体研究风险偏倚均被评估为低。
尽管试验之间存在显著的异质性，但与安慰剂相比，维生素 D 补充剂是安全的，总体上降低了 ARI 的风险，尽管风险降低幅度较小。保护作用与每日 400-1000 IU 剂量的给药相关，入组时年龄为 1.00-15.99 岁。这些发现与 COVID-19 的相关性尚不清楚，需要进一步研究。
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