key: cord-0800266-p94qntyb
authors: Wang, Zhen; Joshi, Avni; Leopold, Kaitlin; Jackson, Sarah; Christensen, Stephanie; Nayfeh, Tarek; Mohammed, Khaled; Creo, Ana; Tebben, Peter; Kumar, Seema
title: Association of vitamin D deficiency with COVID‐19 infection severity: Systematic review and meta‐analysis
date: 2021-07-12
journal: Clin Endocrinol (Oxf)
DOI: 10.1111/cen.14540
sha: 5b9e2da60d736bc3b97a54264dab3672cd306e75
doc_id: 800266
cord_uid: p94qntyb

BACKGROUND: We sought to evaluate the association between vitamin D deficiency and the severity of coronavirus disease 2019 (COVID‐19) infection. METHODS: Multiple databases from 1 January 2019 to 3 December 2020 were searched for observational studies evaluating the association between vitamin D deficiency and severity of COVID‐19 infection. Independent reviewers selected studies and extracted data for the review. The main outcomes of interest were mortality, hospital admission, length of hospital stay and intensive care unit admission. RESULTS: Seventeen observational studies with 2756 patients were included in the analyses. Vitamin D deficiency was associated with significantly higher mortality (odds ratio [OR]: 2.47, 95% confidence interval [CI]: 1.50–4.05; 12 studies; hazard ratio [HR]: 4.11, 95% CI: 2.40–7.04; 3 studies), higher rates of hospital admissions (OR: 2.18, 95% CI: 1.48–3.21; 3 studies) and longer hospital stays (0.52 days; 95% CI: 0.25–0.80; 2 studies) as compared to nonvitamin D deficient status. Subgroup analyses based on different cut‐offs for defining vitamin D deficiency, study geographic locations and latitude also showed similar trends. CONCLUSIONS: Vitamin D deficiency is associated with greater severity of COVID‐19 infection. Further studies are warranted to determine if vitamin D supplementation can decrease the severity of COVID‐19.

States. 4 Many of the abovementioned risk factors are not modifiable, hence it is important to identify modifiable factors that might contribute to COVID-19 infection severity. Diet and nutrition have important implications in immune functioning and infection risk, especially vitamin D level. 5 Vitamin D may be one potentially modifiable risk factor postulated to modulate COVID-19 infection severity. 6 Vitamin D, in addition to its role in skeletal health, may modulate immune regulation. 7 The vitamin D receptor is present in a variety of cells involved in immune regulation, including monocytes, activated T and B lymphocytes and dendritic cells. Vitamin D has been shown to impact cytokine synthesis, lymphocyte proliferation, antibody production, monocyte activation and cell-mediated immunity. 7 A systematic review and meta-analysis of 25 randomised, double-blind placebo-controlled trials of supplementation with vitamin D 3 or vitamin D 2 of any duration found that vitamin D supplementation was beneficial in reducing the risk of acute respiratory tract infection. 8 There is a conflicting opinion on the role of vitamin D in impacting the risk of COVID-19, with some studies suggesting that vitamin D deficiency increases the risk of COVID-19 infection 9,10 while others did not find a significant association. 11 Similarly, there is conflicting evidence on whether vitamin D deficiency is associated with greater severity of COVID-19 infection. [12] [13] [14] [15] [16] [17] To further investigate this relationship and obtain greater clarity on this issue, we conducted this systematic review and meta-analysis to evaluate the association between vitamin D deficiency and the severity of COVID-19 infection.

The Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed to report this systematic review and meta-analysis. 18 

We conducted a comprehensive database search, including MED-

Citations and Daily, Embase, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews and Scopus, from 1 January 2019 to 3 December 2020. Reference mining of existing systematic reviews/meta-analyses, preprint medical literature from medRxiv. org, and relevant primary studies were conducted to identify additional studies. An experienced medical librarian, with input from the study investigators, developed the search strategy ( Figure 1 ) and conducted the literature search. 19 we used the 25(OH)D cut-offs defined by each study. We included observational studies without restrictions on publication language, study location, or patient population. Studies were excluded if they evaluated vitamin D supplements, vitamin D insufficiency only, or suspected COVID-19 cases (including those evaluated by radiology only, without confirmatory PCR or antigen-based testing). We also excluded in vitro studies, and studies without original data (e.g., opinion, editorial and narrative review).

Pairs of reviewers, working independently, screened titles and abstracts of all references. Studies included by either reviewer were included for full-text screening. Pairs of independent reviewers screened the full text of the eligible studies. Conflicts between the reviewers were resolved by a third investigator.

A pilot-tested standardised data extraction form was developed to extract study characteristics and outcomes of interest. Reviewers worked independently to extract study details. A second reviewer reviewed data and resolved inconsistencies.

We evaluated the risk of bias of the included studies using the modified Newcastle-Ottawa Scale, in terms of representativeness of study cohort, ascertainment of exposure, comparability between groups, outcome data source and assessment of outcome (Appendix Table S1 ). 20 

Odds ratio (OR) or hazard ratio (HR) for binary outcomes (mortality, hospital admission, ICU admission) and mean difference for the continuous outcome (length of hospital stay) were extracted or calculated. The DerSimonian-Laird random-effects model with Hartung-Knapp-Sidik-Jonkman variance correction was used to combine studies if the number of studies included in the analysis was larger than 3. 21 The fixed-effect model based on the Mantel and Haenszel method was adopted when the number of studies was 3 or less. Treatment arm continuity corrections were used to adjust double-zero-event studies (i.e., 0 event in both groups). 22 Heterogeneity across studies was measured using the I 2 indicator, in which I 2 > 50% suggests substantial heterogeneity. To further explore heterogeneity, we conducted prespecified subgroup analyses based on serum 25(OH)D cut-off levels used to define vitamin D deficiency (12, 20 and 25 ng/ml) and geographic regions (Europe, Asia, Middle East and North America). The latitudes of the study areas were evaluated, which were identified as the latitudinal coordinates of the geographic centroid of the study areas extracted from Google Map and categorised based on 5°increments from the equator. Publication bias was evaluated quantitatively using the asymmetry test of funnel plots and Egger's regression test when the number of studies included in a meta-analysis was larger than 10. Two-sided p-value less than .05 was deemed to be statistically significant. All statistical analyses were conducted using Stata version 16.1 (Stata LLP Corp).

Our literature search identified 560 citations. Seventeen observational studies with 2756 eligible patients who met our inclusion criteria were included in the analyses ( Figure 1 and Table 1 ). [12] [13] [14] [15] [16] [17] [23] [24] [25] [26] [27] [28] [29] [30] [31] [32] [33] The studies included only adult patients; and the majority (70.6%) evaluated only hospitalised COVID-19 cases.

Vitamin D deficiency was defined as total 25(OH)D) level less than 12 ng/ml (seven studies), less than 20 ng/ml (eight studies) and less than 25 ng/ml (one study). Mendy et al. 16 did not specify the 25(OH) D levels used to classify vitamin D deficiency and instead based the diagnosis on the International Classifications of Diseases 10 code for deficiency. Nine studies were conducted in Europe, one in the United States, five in Asia and two in the Middle East. Details of study characteristics can be found in Table 1 .

The overall risk of bias of the included studies was high due to a lack of control of confounding variables (Appendix Table S1 ). We did not find potential publication bias for mortality, though we were unable to statistically evaluate publication bias for the other outcomes.

Of the 17 included studies, 14 compared vitamin D deficiency with normal vitamin D status, while the remaining 3 studies quantified vitamin D status qualitatively, which was categorised as deficiency, insufficiency and normal. For these three studies, outcomes in those with vitamin D deficiency were compared with the normal and insufficiency group combined. Vitamin D deficiency was associated with significantly higher mortality (OR: 2.47, 95% CI: 1.50-4.05; Our findings are largely in agreement with two recent systematic reviews on this topic. 41, 42 but differ from findings from a recent review by Bassatne et al. 43 who reported a statistically nonsignificant trend between serum 25(OH)D level less than 20 ng/ml and an increased risk of mortality and ICU admission. These differences are related to very different criteria used for the selection of studies in the review by Bassatne et al. 43 We included studies with PCR-confirmed positive COVID-19 with 25(OH)D levels drawn within 3 months of COVID-19 diagnosis and a comparison group (vitamin D deficiency vs. nondeficiency).

As a result, more studies were included in the meta-analyses reported in the current study.

Our study has several strengths. We included only studies with laboratory confirmation of COVID-19 infection. We were able to examine the associations between vitamin D deficiency and severity in COVID-19 using different cut-offs for defining vitamin D deficiency. We found that these associations were noted at both 25(OH) D cut-offs (<12 and <20 ng/ml). We also conducted additional analysis on any variation in the association between vitamin D deficiency and COVID-19 infection severity among different latitudes, as the mortality from COVID-19 has been noted to be lower in countries south of latitude 35°North. 6 We also examined the relationship between vitamin D deficiency and COVID-19 severity in different geographic and cultural regions as ethnic and cultural factors likely play a role independent of latitude.

A limitation of our study is the inability to independently assess the impact of associated confounding variables, such as obesity, dark skin colour, non-White race, diabetes and advancing age, all of which are risk factors for both greater severity of COVID-19 infection and vitamin D deficiency. Most of the included studies did not adjust for any confounding variables, including weight status, race and age and therefore these results mainly represent an association and may not predict causality. Another limitation is that the age range in our study was limited as most studies included middle age and elderly patients. Children were not included in our study, as there were not enough studies assessing COVID-19 infection severity and vitamin D levels. Hence, our results may not be generalisable to the pediatric population. The cut-offs used to define vitamin-D deficiency varied among the studies due to a lack of consensus on optimal levels of 25(OH)D. 19 However, subgroup analyses suggested these associa- 

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The authors declare that there are no conflict of interests.

All authors have made substantial contributions to conception and design, or acquisition of data, or analysis and interpretation of data.All authors have given final approval of the version to be published.