Reply to letter to the editor to “clinical significance of micronutrient supplements in patients with coronavirus disease 2019: A comprehensive systematic review and meta-analysis”

Dear Editor,

We would like to extend our gratitude to Dr. Graaff and his colleague for their comments on our meta-analysis [1]. The authors pointed out an error that was made in Table 3 and Figure 3 concerning the inclusion of the data of Cédric Annweiler et al. [2] (2020) in the vitamin D cohort. That study compared a treatment group (57 patients) with a control group (9 patients) [2]; the mortality in these groups was 10 and 5 patients, respectively [2]. The authors proposed that vitamin D might lower the mortality in COVID-19, given the positive results of that study [2]. We applaud the authors for bringing this mistake to our attention. We updated our literature search regarding mortality and vitamin D and corrected the error mentioned by the authors. Of note, the study by Lakkireddy et al. [3] was retracted due to multiple publication concerns. Therefore, we excluded this study [3] in our updated analysis. To improve the level of evidence and reduce the risk of publication bias, we performed an updated literature search of PubMed, Embase, and Web of Science databases until May 22nd, 2022. Meta-analysis was conducted by the Mantel-Haenszel method within a random-effect model.

A total of 18 studies including 5285 patients with COVID-19 were included. Overall, vitamin D supplementation did not reduce the risk of mortality among COVID-19 patients compared to standard-of-care (risk ratio [RR] 0.70, 95% confidence interval [CI] 0.47–1.04, P = 0.08, I² = 79%, Fig. 1 A). Subgroup analysis showed also that vitamin D supplementation was not associated with a mortality benefit regardless of whether vitamin D was received pre COVID-19 (RR 0.79, 95% CI 0.41–1.54, P = 0.49, I² = 78%) or post COVID-19 (RR 0.64, 95% CI 0.41–1.01, P = 0.06, I² = 70%) (Fig. 1B). Lastly, our results remained consistent regardless of whether the study designs were non-randomized studies (RR 0.66, 95% CI 0.42–1.06, P = 0.08, I² = 84%) or randomized controlled trials [RCTs] (RR 0.94, 95% CI 0.46–1.94, P = 0.87, I² = 34) (Fig. 1C).

Fig. 1.

(A) Forest plot of studies comparing vitamin D supplementation and standard-of-care regarding mortality, (B) Subgroup analysis of studies that supplemented vitamin D pre and post COVID-19 diagnosis, (C) Subgroup analysis based on study design (non-randomized studies versus randomized controlled trials) for mortality.

Our data suggested that vitamin D supplementation does not reduce mortality risk among patients with COVID-19. As opposed to RCTs, there was a trend of lower mortality in the vitamin D group compared to standard-of-care among non-randomized studies, but it did not reach statistical significance. This trend was mainly driven by non-randomized and observational studies rather than RCTs. Our meta-analysis is hampered by the inclusion of studies that reported mortality at multiple time points and the significant heterogeneity in the measurement of mortality. Based on our updated data, we still believe that the available literature does not support the mortality benefit of vitamin D supplementation in COVID-19. Given the number of ongoing studies, the hope is that the upcoming RCTs may provide more information regarding the effectiveness of vitamin D supplementation in managing COVID-19.

Author contributions

AB and MM designed the study, reviewed the literature, collected, analyzed, and interpreted the data, and drafted the manuscript. RA critically revised the manuscript. All authors read and approved the final manuscript.

Grants and funding

None.

Conflict of interest

All authors declare no conflicts of interest.