Clinical Question:
54yof presents for evaluation of suspected viral sinusitis, reports she frequently and recurrently has viral respiratory infections. She states she heard from her PCP that vitamin D supplementation can help prevent colds.
PICO Question:
In the general adult population, does vitamin D supplementation prevent respiratory infections compared to placebo?
| P | I | C | O |
| adults | Vitamin D supplementation | control | Incidence of respiratory infection |
| D3 supplementation | placebo | Prevention of respiratory infection | |
| D2 supplementation | Rate of respiratory infection | ||
| Cholecalciferol supplementation | Frequency of respiratory infection | ||
Search Strategy:
In searching for my articles, my strategy had a few different components. First, I limited my search results to be for articles from the past 10 years; however, results were abundant enough that I prioritized articles from the last 7 years only. I came across a bit of an obstacle in that the majority of the results I found were specifically about COVID-19. This makes a lot of sense given the applicability of that data within the last five years; However, I was aiming to research viral infections on a broader lens, so I had to prioritize articles that did not include COVID-19 in the title. Furthermore, I wanted to ensure that my chosen articles were highest level, so I included “review” as either a keyword or a search filter – Not only because they provide the highest level of evidence, but also because I know that my search question is fairly broad and rigorously researched, so I expected reviews to be plentiful. From there, I browsed articles and chose ones that thoroughly vetted the articles they included and specifically had analyses dedicated to more than one viral URI.
- CUNY York OneSearch → vitamin D supplement respiratory infection systematic review → 2014-2024 → 87 results
- I scrolled through the first 25 results. I prioritized peer-reviewed level 1 evidence studies with open access. I looked for articles from American journals. I looked for titles that best matched my PICO keywords. I avoided articles that made mention of specific viral infections such as COVID-19 or influenza. I opened 5 articles total and opted to include 3 of them here.
- The Jolliffe et al. article was the second result
- The Martineau et al. article was the third result
- The Cho et al. article was the 23rd result
- I scrolled through the first 25 results. I prioritized peer-reviewed level 1 evidence studies with open access. I looked for articles from American journals. I looked for titles that best matched my PICO keywords. I avoided articles that made mention of specific viral infections such as COVID-19 or influenza. I opened 5 articles total and opted to include 3 of them here.
- NIH PMC → “vitamin D respiratory infection review” → 2014-2024 → 692 results
- I scrolled through the first 15 results. I looked for articles from American journals. I looked for titles that best matched my PICO keywords. I avoided articles that made mention of specific viral infections such as COVID-19 or influenza. I opened 4 articles but did not choose to include any of them. I strongly considered including a meta-analysis of the effect of vitamin D on various body systems, including respiratory amongst others, but I opted to keep looking for something more specific. I saw the 3 articles that I already selected amongst the results.
- Google Scholar
- Being familiar with it, I know the Google Scholar algorithm tends to generate many more results than other search engines do. I opted to include more keywords in my search and limit my publish date filter more strictly than I did on the other search engines, in hopes of making my results more selective and applicable to my PICO.
- vitamin d supplementation respiratory infection review → 2020-2024 → 16,700 results
- I scrolled through two pages of results, and seeing how abundant they were while also noting that the overwhelming majority of them were specifically about COVID-19, I opted to limit my search to studies from the last year only
- vitamin d supplementation respiratory infection prevention review → Since 2023 → 16,900 results
- I scrolled through the first page of results, but keeping my search strategy in mind, none felt worthy of including in my PICO
- vitamin d supplementation respiratory infection prevention review → Since 2023 → 16,900 results
- Given my equivocal findings amongst my articles so far, I really wanted something extremely recent. I broadened my study types but narrowed my years.
- vitamin d URI prevention review → since 2023 → 17,100 results
- The Jia et al. article was the first result
- vitamin d URI prevention review → since 2023 → 17,100 results
- Being familiar with it, I know the Google Scholar algorithm tends to generate many more results than other search engines do. I opted to include more keywords in my search and limit my publish date filter more strictly than I did on the other search engines, in hopes of making my results more selective and applicable to my PICO.
- Struggling to find a 5th article, I returned to NIH PMC and modified some keywords to broaden my search → vitamin d supplementation respiratory infection → 10 years → 10,405 results
- I scrolled through the first 15 results, and I opened 2 studies that had potential to be applicable to my PICO following my general search strategy above
- The Rejnmark et al. article was the second result
- I scrolled through the first 15 results, and I opened 2 studies that had potential to be applicable to my PICO following my general search strategy above
Articles Chosen for Inclusion:
Article 1
| Link | Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data |
| Citation | Martineau AR, Jolliffe DA, Hooper RL, et al. Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data. BMJ. 2017;356:i6583. Published 2017 Feb 15. doi:10.1136/bmj.i6583 |
| Abstract | ObjectivesTo assess the overall effect of vitamin D supplementation on risk of acute respiratory tractinfection, and to identify factors modifying this effect.DesignSystematic review and meta-analysis of individual participant data (IPD) from randomized controlled trials.Data sourcesMedline, Embase, the Cochrane Central Register of Controlled Trials, Web of Science, ClinicalTrials.gov, and the International Standard Randomised Controlled Trials Number registry from inception to December 2015. eligibility criteria for study selectionRandomized, double blind, placebo controlled trials of supplementation with vitamin D3 or vitamin D2 of any duration were eligible for inclusion if they had been approved by a research ethics committee and if data on incidence of acute respiratory tract infection were collected prospectively and prespecified as an efficacy outcome.Results25 eligible randomized controlled trials (total 11 321 participants, aged 0 to 95 years) were identified. IPD were obtained for 10 933 (96.6%) participants. Vitamin D supplementation reduced the risk of acute respiratory tract infection among all participants (adjusted odds ratio 0.88, 95% confidence interval 0.81 to 0.96; P for heterogeneity <0.001). In subgroupanalysis, protective effects were seen in those receiving daily or weekly vitamin D without additional bolus doses (adjusted odds ratio 0.81, 0.72 to 0.91) but not in those receiving one or more bolus doses (adjusted odds ratio 0.97, 0.86 to 1.10; P forinteraction=0.05). Among those receiving daily or weekly vitamin D, protective effects were stronger in those with baseline 25-hydroxyvitamin D levels <25 nmol/L (adjusted odds ratio 0.30, 0.17 to 0.53) than in those with baseline 25-hydroxyvitamin D levels ≥25 nmol/L (adjusted odds ratio 0.75, 0.60 to 0.95; P for interaction=0.006). Vitamin D did not influence the proportion of participants experiencing at least one serious adverse event (adjusted odds ratio 0.98, 0.80 to 1.20, P=0.83). The body of evidence contributing to these analyses was assessed as being of high quality.ConclusionsVitamin D supplementation was safe and it protected against acute respiratory tract infection overall. Patients who were very vitamin D deficient and those not receiving bolus doses experienced the most benefit |
Article 2
| Link | Vitamin D supplementation to prevent acute respiratory infections: a systematic review and meta-analysis of aggregate data from randomized controlled trials |
| Citation | Jolliffe DA, Camargo CA Jr, Sluyter JD, et al. Vitamin D supplementation to prevent acute respiratory infections: a systematic review and meta-analysis of aggregate data from randomized controlled trials. Lancet Diabetes Endocrinol. 2021;9(5):276-292. doi:10.1016/S2213-8587(21)00051-6 |
| Abstract | BackgroundA 2017 meta-analysis of data from 25 randomized 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.Methods 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 D3, vitamin D2, 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 beenapproved 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. Usingthe 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 estimatewhether 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 enrollment (<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.Findings 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; I²=35·6%, pheterogeneity=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; I²=53·5%, pheterogeneity=0·003), at daily dose equivalents of 400–1000 IU (0·70 [0·55–0·89]; ten studies; I²=31·2%, pheterogeneity=0·16), for a duration of 12 months or less (0·82 [0·72–0·93]; 29 studies; I²=38·1%, pheterogeneity=0·021), and to participants aged 1·00–15·99 years at enrolment (0·71 [0·57–0·90]; 15 studies; I²=46·0%, pheterogeneity=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 eventin the vitamin supplementation group compared with the placebo group was observed (0·97 [0·86–1·07]; 36 studies; I²=0·0%, pheterogeneity=0·99). Risk of bias within individual studies was assessed as being low for all but three trials. InterpretationDespite 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. |
Article 3
| Link | Efficacy of Vitamin D Supplements in Prevention of Acute Respiratory Infection: A Meta-Analysis for Randomized Controlled Trials |
| Citation | Hae-Eun Cho, Seung-Kwon Myung, Cho H. Efficacy of Vitamin D Supplements in Prevention of Acute Respiratory Infection: A Meta-Analysis for Randomized Controlled Trials. Nutrients. 2022;14(4):818. doi:https://doi.org/10.3390/nu14040818 |
| Abstract | Background: Previous systematic reviews and meta-analyses of randomized controlledtrials (RCTs) have reported inconsistent results regarding the efficacy of vitamin D supplements in the prevention of acute respiratory infections (ARIs). Methods: We investigated these efficacy results by using a meta-analysis of RCTs. We searched PubMed, EMBASE, and the Cochrane Library in June 2021. Results: Out of 390 trials searched from the database, a total of 30 RCTs involving 30,263 participants were included in the final analysis. In the meta-analysis of all the trials, vitamin D supplementation showed no significant effect in the prevention of ARIs (relative risk (RR) 0.96, 95% confidence interval (CI) 0.91–1.01, I2 = 59.0%, n = 30). In the subgroup meta-analysis, vitamin D supplementation was effective in daily supplementation (RR 0.83, 95% CI, 0.73–0.95, I2 = 69.1%, n = 15) and short-term supplementation (RR 0.83, 95% CI, 0.71–0.97, I2 = 66.8%, n = 13). However, such beneficial effects disappeared in the subgroup meta-analysis of high-quality studies (RR 0.89, 95% CI, 0.78–1.02, I2 = 67.0%, n = 10 assessed by the Jadad scale; RR 0.87, 95% CI, 0.66–1.15, I2 = 51.0%, n = 4 assessed by the Cochrane’s risk of bias tool). Additionally, publication bias was observed.Conclusions: The current meta-analysis found that vitamin D supplementation has no clinical effect in the prevention of ARIs |
Article 4
| Link | Vitamin D supplementation for prevention of acute respiratory infections in older adults: A systematic review and meta-analysis |
| Citation | Jia H, Sheng F, Yan Y, Liu X, Zeng B. Vitamin D supplementation for prevention of acute respiratory infections in older adults: A systematic review and meta-analysis. PLoS One. 2024;19(5):e0303495. Published 2024 May 24. doi:10.1371/journal.pone.0303495 |
| Abstract | BackgroundAcute respiratory infections (ARIs) have a substantial impact on morbidity, healthcare utilization, and functional decline among older adults. Therefore, we systematically reviewed evidence from randomized controlled trials (RCTs) to evaluate the efficacy and safety of vitamin D supplementation in preventing ARIs in older adults. MethodsPubMed, Embase, the Cochrane Library, and ClinicalTrials.gov were searched until 1 February 2024. RCTs evaluating the use of vitamin D supplements to protect older adults from ARIs were included. Two reviewers independently screened papers, extracted the data and assessed the risk of bias. Data were summarized as relative risks (RRs) or odds ratios (ORs) with corresponding 95% confidence intervals (CIs). Random effects meta-analyses were used to synthesize the results. GRADE was used to evaluate the quality of evidence. All the analyses were performed with Stata version 17. ResultsTwelve trials (41552 participants) were included in the meta-analysis. It showed that vitamin D supplementation probably does not reduce the incidence of ARIs (RR, 0.99; 95% CI, 0.97–1.02, I2 = 0%; moderate certainty). No significant effect of vitamin D supplementation on the risk of ARI was observed for any of the subgroups defined by baseline 25(OH)D concentration, control treatments, dose frequency, study duration, and participants’ condition. However, there was a possibility, although not statistically significant, that vitamin D may reduce the risk of ARI in patients with a baseline 25(OH)D concentration <50 nmol/L (OR, 0.90; 95% CI, 0.79–1.04, I2 = 14.7%). Additionally, vitamin D supplements might result in little to no difference in death due to any cause, any adverse event, hypercalcinemia, and kidney stones. ConclusionsVitamin D supplementation among older adults probably results in little to no difference in the incidence of ARIs. However, further evidence is needed, particularly for individuals with vitamin D deficiency and populations residing in low and middle income countries. |
Article 5
| Link | Non-skeletal health effects of vitamin D supplementation: A systematic review on findings from meta-analyses summarizing trial data |
| Citation | Rejnmark L, Bislev LS, Cashman KD, et al. Non-skeletal health effects of vitamin D supplementation: A systematic review on findings from meta-analyses summarizing trial data. PLoS One. 2017;12(7):e0180512. Published 2017 Jul 7. doi:10.1371/journal.pone.0180512 |
| Abstract | BackgroundA large number of observational studies have reported harmful effects of low 25-hydroxyvitamin D (25OHD) levels on non-skeletal outcomes. We performed a systematic quantitative review on characteristics of randomized clinical trials (RCTs) included in meta-analyses (MAs) on non-skeletal effects of vitamin D supplementation. Methods and findingsWe identified systematic reviews (SR) reporting summary data in terms of MAs of RCTs on selected non-skeletal outcomes. For each outcome, we summarized the results from available SRs and scrutinized included RCTs for a number of predefined characteristics. We identified 54 SRs including data from 210 RCTs. Most MAs as well as the individual RCTs reported null-findings on risk of cardiovascular diseases, type 2 diabetes, weight-loss, and malignant diseases. Beneficial effects of vitamin D supplementation was reported in 1 of 4 MAs on depression, 2 of 9 MAs on blood pressure, 3 of 7 MAs on respiratory tract infections, and 8 of 12 MAs on mortality. Most RCTs have primarily been performed to determine skeletal outcomes, whereas non-skeletal effects have been assessed as secondary outcomes. Only one-third of the RCTs had low level of 25OHD as a criterion for inclusion and a mean baseline 25OHD level below 50 nmol/L was only present in less than half of the analyses. ConclusionsPublished RCTs have mostly been performed in populations without low 25OHD levels. The fact that most MAs on results from RCTs did not show a beneficial effect does not disprove the hypothesis suggested by observational findings on adverse health outcomes of low 25OHD levels. |
Summary of the Evidence:
| Author (Date) | Level of Evidence | Sample/Setting(# of subjects/ studies, cohort definition etc. ) | Outcome(s) studied | Key Findings | Limitations and Biases |
| Martineau et al., 2017 | 1 – systematic review and meta-analysis | -Randomized, double blind, RCTs of supplementation with vitamin D3 or vitamin D2 of any duration-approved by a research ethics committee -data on incidence of acute respiratory tract infection were collected prospectively and prespecified as an efficacy outcome-Through December, 2015===-25 eligible randomized controlled trials-11,321 participants aged 0 to 95 years | Variable within individual included studies This SR primarily extracted and analyzed Incidence of respiratory tract infection amongst included RCTs | Vitamin D supplementation reduced the risk of acute respiratory tract infection among all participants Subgroup Analysis: protective effects were seen in those receiving daily or weekly vitamin D without additional bolus doses, but not in those receiving one or more bolus doses protective effects were stronger in those with baseline vitamin D levels <25 nmol/L than in those with baseline D levels ≥25 nmol/L | -Power to detect effects of vitamin D supplementation was limited for individuals with baseline 25-hydroxyvitamin D concentrations <25nmol/L receiving bolus dosing regimens-Null and borderline statistically signifi-cant results for analyses of these outcomes may have arisen as a consequence of type 2 error-data relating to adherence to study drugs were not available for all participants-Definitions of acute respiratory tract infection are diverse, multi-etiological, and vary in clinical diagnosis |
| Jolliffe et al., 2019 | 1 – systematic review and meta-analysis | -Double-blind RCTs of vitamin D3, vitamin D2, or 25-hydroxyvitamin D (25[OH]D) supplementation for any duration, with a placebo or low-dose vitamin D control-database inception to May 1, 2020-approved by a research ethics committee====-1528 articles identified, 46 RCTs included, N = -75, 541 participants, aged 0–95 years | Variable amongst individual included RCTs acute respiratory infection incidence was collected prospectively and prespecified as an efficacy outcome This SR/MA analyzed the primary outcome ofproportion of participants who had one or more ARIs Secondary outcomes:-URI, LRI, emergency department attendance for an ARI, hospital admissionfor an ARI, death due to ARI or respiratoryfailure; use of antibiotics to treat an ARI; absence fromwork or school due to an ARI; serious adverse events; adverse reactions to vitamin D | Protective effects of supplementation were observed in trials in which —vitamin D was given in a daily dosing regimen –at daily dose equivalents of 400–1000 IU –for a duration of 12 months or less –to participants aged 1·00–15·99 years at enrolment 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 | -Heterogeneity between included studies-Despite thelarge number of trials overall, only eleven compared theeffects of lower-dose versus higher-dose vitamin Dsupplementation-unable to investigate race or ethnicity and obesity aspotential effect-modifiers-unable to account forother factors that might influence the protective effect of vitamin D supplementation in the prevention of ARIs(eg, taking the supplement with or without food), orsecular trends that would influence trial- unable to control for concurrent use of standard dose vitamin D supplementsor multivitamins in the placebo group -funnel plot suggests that the overall effect size might have been overestimated due to publication bias |
| Cho et al., 2023 | 1 – systematic review and meta-analysis | -Through June 2021-RCTs that reported the efficacy of vitamin D supplements in the prevention of ARIs using outcome measures with dichotomous variables-Studies were stratified using the Cochrane Risk of Bias Tool and the Jadad scale =====-Out of 390 trials searched from the database, a total of 30 RCTs involving 30,263 participants were included in the final analysis | Variable amongst individual included studies This SR/MA extracted the primary outcome of frequency of respiratory infections, including URIs (n = 23), LRIs (n = 6), and both URIs and LRIs (n = 1) | Vitamin D supplementation showed no significant effect in the prevention of ARIs Subgroup meta-analysis: vitamin D supplementation was effective in daily supplementation and short-term supplementation However, beneficial effects disappeared in the subgroup meta-analysis of high-quality studies | -Baseline concentration of the 25(OH)D was not considered, -Publication bias was found in this study, which means that trials showing an increasing risk of or no effect on ARIs by vitamin D supplementation might not be published. This favors the conclusion that there is no preventive effect of vitamin D supplements on ARIs. -Several RCTs included were not designed specifically to investigate the efficacy of vitamin D supplements on ARIs as a primary endpoint |
| Jia et al., 2024 | 1 – systematic review and meta-analysis | -Through February 2024-RCTs evaluating the effects of supplementary vitamin D3, vitamin D2, or 25(OH)D, regardless of dosage or duration, to prevent ARI in adults 50 years of age or older were included====12 trials, 41552 participants | Variable amongst individual RCTs Only studies with ARI as a prespecified efficacy outcome were included, however, the preventive effect of vitamin D supplements on ARIs was not the primary outcome in several included trials This SR/MA extracted incidence of acute respiratory tract infection as its primary outcome | No significant effect of vitamin D supplementation on the risk of ARI was observed for any of the subgroups (baseline 25(OH)D concentration, control treatments, dose frequency, study duration, and participants’ condition) There was a possibility, although not statistically significant, that vitamin D may reduce the risk of ARI in patients with a baseline 25(OH)D concentration <50 nmol/L | -Clinical and statistical heterogeneity between included studies-Unable to evaluate the differences in the preventive effect on ARIs between individuals with vitamin D deficiency and those with normal vitamin D levels-Analysis based on study-level data rather than individual patient data, which limited the power of our analysis and the investigation of potential effect-modifiers. |
| Rejnmark et al., 2017 | 1 – systematic review and meta-analysis | -through December 1st, 2016-SRs published in English within the last 10 years on findings from RCTs testing effects of vitamin D supplementations on selected outcomes-only included SRs reporting summary data in terms of MAs on effects of treatment with calciferol (vitamin D2 or D3) or activated vitamin D analogues in their summary estimate, as long as the majority (>50%) of included studies were on calciferol-The search for SRs on effects of vitamin D supplementation on risk of RTIs identified 10 SRs, among which seven reported MAs on pooled data from RCTs on risk of RTIs in response to vitamin D supplementation The seven MAs included data from a total of 30 RCTs. | 23/30 (77%) of the RCTs investigated effects of vitamin D supplementation as a primary outcome, the remaining as a secondary outcome With some variability in phrasing or stratification between studies, this SR with MA evaluated the risk of respiratory tract infection by analysis of rate of infection amongst included data | A beneficial effect of vitamin D supplementation on risk of infections was found in nine (30%) of the trials Vitamin D supplementation was found to significantly reduce risk of RTI by approximately 40% in 2 MAs 1 MA, which excluded studies which were considered to be of low quality in terms of a modified Jadad score ≤ 3, found no beneficial effects of vitamin D supplementation on risk of RTI A recent individual patient data analysis (IPD) showed a significantly reduced risk of acute RTI. Sub-group analyses suggested protective effects in response to daily or weekly vitamin D dose, but not in response to one or more bolus doses protective effects were stronger in those with a baseline 25OHD <25 nmol/L than in those with a baseline 25OHD ≥25 nmol/L | -Only two studies were of a large scale with more than 1000 participants-Most studies had a relatively short duration-Only one of the trials had low 25OHD levels (< 50 nmol/L) as inclusion criteria and mean 25OHD levels at baseline were only reported in two-thirds of the studies among which only seven trials reported mean levels below 50 nmol/L |
Conclusion(s):
Jolliffe et al: 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 1-16 years
Martineau et al.: Vitamin D supplementation was safe and it protected against acute respiratory tract infection overall. Patients who were very vitamin D deficient and those not receiving bolus doses experienced the most benefit.
Cho et al: Vitamin D supplementation has no clinical effect in the prevention of ARIs. Although subgroup analysis found vitamin D supplementation to be effective in daily and short-term supplementation, this was only seen in low-quality studies and disappeared in the subgroup meta-analysis of high-quality studies.
Jia et al: Vitamin D supplementation among older adults probably results in little to no difference in the incidence of ARIs. However, further evidence is needed, particularly for individuals with vitamin D deficiency.
Rejnmark et al.: The overall findings suggest a beneficial effect of vitamin D on respiratory tract infections. However, most published studies on effects of vitamin D supplementation on risk of RTI have been relatively small and of short duration without specifically addressing effects in populations with vitamin D insufficiency. Furthermore, the populations studied have varied widely from newborns to elderly as well as effects of a wide range of different types of infections, raising the question whether results from such different settings can be merged into MA reporting summary estimates.
Two of my included articles found a significant protective benefit of vitamin D supplementation against respiratory viruses, another two find no clinical effect, and one supports the potential benefit of vitamin D on the rate of respiratory infections while acknowledging that the studies they analyzed are not of the highest quality to strongly support such a conclusion. In other words, recent studies vary and even contradict each other significantly. The two studies that found a significantly overall protective benefit of vitamin D supplementation against respiratory viruses are the oldest studies I analyzed, and did not highlight any subgroup analysis considering the quality of studies. The three studies that found little to no effect are newer studies that included the most recent RCTs and also specifically did subgroup analyses considering the quality of each study included. It is important to consider these factors while developing my clinical bottom.
Clinical Bottom Line:
It remains equivocal whether or not Vitamin D supplementation prevents viral respiratory infections in adult patients. Although multiple high quality studies have found a statistically significant benefit, this effect disappears in more recent analyses that include analysis of only high quality studies, according to objective criteria such as JADDAD or AMSTAR grading. Therefore, weighing the evidence, I must value the findings of the newer, larger, and more rigorous analyses by Cho, Jia, and Rejnmark more than I do the older and less rigorous analyses. Also of note, the Jolliffe and Martineau articles share some authors, so their respective findings might be biased to validate each other. Therefore, vitamin D supplementation does not have a large magnitude of effect on the prevention of viral infection. Most articles found no effect, and some concluded the possibility of a small effect. Therefore, I can confidently conclude the effect is little to none. Considering clinical significance, I would still suggest that my patients who are hoping to prevent viral respiratory infections take vitamin D supplementation. There does seem to be potential for some overall beneficial effect without much risk for adverse events, so I think the potential benefit of supplementation outweighs any very low risk. Specifically, I would tell them that multiple analyses found that smaller daily dosing seems to carry more benefit than more intense dosing regimens, and there seems to be a higher potential benefit in patients who are Vitamin D deficient, and in pediatric patients. I would be sure to emphasize that the effect of vitamin D supplementation on the rate of respiratory infection requires more research in the future, so I would not endorse to my patients that this supplementation prevents respiratory infections with any certainty. It’s also important to keep in mind that correlation does not equal causation, as many studies noted the limitation that patients who take Vitamin D supplements may or may not also be taking other vitamin supplements or be generally healthier/more active in maintaining their health. Overall, newer studies contradict older studies, so this research question requires more analysis in the future.
