RAPID REVIEW Association of Vitamin D Status with COVID-19 Incidence and Outcomes, and Health Equity Considerations 01/20/2021 Key Findings While earlier studies have shown that vitamin D supplementation has a modest impact on the prevention of acute respiratory tract infection, the role of vitamin D to reduce Coronavirus Disease 2019 (COVID-19) incidence and severity remains unknown. Observational studies largely show that lower vitamin D levels are associated with a greater risk of COVID-19 infection and mortality. However, as many studies did not account for important confounders such as comorbidities and socioeconomic status, there is a high risk that there are other reasons for the finding of greater COVID-19 risk. Randomized controlled trials (RCT) of vitamin D for treatment of COVID-19 have not consistently shown a benefit in preventing COVID-19 outcomes such as severe infection or mortality. RCTs of vitamin D for prevention of COVID-19 are currently underway. Racialized individuals bear disproportionate COVID-19 impacts related to inequities in structural determinants of health and the experience of discrimination. The link between vitamin D status and COVID-19 incidence and severity remains uncertain in all patient populations including ethno-racial communities. Ontarians are advised to follow established Canadian recommendations for vitamin D intake and supplementation for general bone health (those over the age of 50 years are recommended to receive 800 to 2000 international units (IU) of vitamin D supplementation per day). Background Vitamin D is a hormone activated in the skin due to exposure to ultraviolet B light (Vitamin D2) and consumed in the diet largely from oily fish (Vitamin D3 also known as cholecalciferol). Vitamin D2 and D3 are converted into active form 1,25(OH)2D by 25-hydroxylation in the liver and 1-hydroxylation in the kidney. 25-hydroxyvitamin D3 is also available as an oral supplement known as calcifediol.1 Vitamin D regulates gene expression most notably within immune cells, which may result in both anti-viral effects and mediation of the inflammatory response in the context of a viral infection.2 A systematic review and meta-analysis enrolling 11,321 participants from 25 RCTs found that vitamin D supplementation was associated with a modest but statistically significant benefit in Association of Vitamin D Status with COVID-19 Incidence and Outcomes, and Health Equity Considerations 1 terms of reduced risk of acute respiratory tract infection (adjusted odds ratio [OR] 0.88, 95% confidence interval [CI] 0.81- 0.96). The effects were most evident in those receiving daily or weekly vitamin D, and those with lower blood levels of baseline Vitamin D (25-hydroxyvitamin D levels <25 nmol/L). A benefit was not observed for more severe outcomes (e.g., hospitalization or mortality).3 There was no difference between groups in serious adverse events (OR 0.98, 95% CI 0.80-1.20).3 A 15-year retrospective cohort of patients ages 50 to 75 years in Germany (99% were of European descent) evaluated the risk of respiratory disease mortality amongst those with vitamin D insufficiency (30-50 nmol/L) and vitamin D deficiency (<30 nmol/L). The authors found that patients with vitamin D insufficiency (adjusted hazard ratio [HR] 2.1, 95% CI: 1.3- 3.2) and deficiency (HR 3.0, 95% CI: 1.8–5.2) were at increased risk for respiratory disease mortality.4 Conversely, a more recent randomized controlled trial published in 2021 analyzing 15,373 older adults who received either vitamin D 60,000 IU monthly or placebo did not find a significant benefit. According to survey and diary data from participants, no difference in respiratory tract infections was found (OR 0.98, 95% CI: 0.93 to 1.02 for survey and OR 0.98, 95%CI: 0.83 to 1.15 for diary).5 Vitamin D insufficiency is common in Canada; approximately 30% of Canadians have insufficient levels.6 Low vitamin D levels appear to be more common in non-white than among white Canadians.7 This is because individuals with more skin pigmentation require more sunlight than those with lighter skin to achieve adequate vitamin D levels.1 The likelihood of deficiency is also higher among people living in higher latitudes in the winter, with reduced sun exposure, with obesity, nursing home residents, and indoor workers.1,8,9 Given the concern for the disproportionate impact of COVID-19 on ethno-racial communities (e.g., racialized groups), questions about the impact of vitamin D status on COVID-19 acquisition and severity in this particular population have been raised.10,11 Reviews and Guidance on Vitamin D and COVID-19 In November 2020, a systematic review and meta-analysis of observational studies evaluating vitamin D and association with COVID-19 in adults was published. The authors included 27 studies and found vitamin D deficiency was not associated with an increased risk of COVID-19 infection (OR 1.35, 95% CI: 0.80–1.88), but was associated with increased severity (OR 1.81, 95% CI: 1.41–2.21) and mortality (OR 1.82, 95% CI: 1.06–2.58). However, the quality of studies was generally low with 74% (n=23) of studies classified as high risk of bias.12 The authors did not evaluate studies using vitamin D supplementation to prevent or manage COVID-19. In December 2020, a comprehensive narrative evidence synthesis on vitamin D and COVID-19 was published by the Royal Society in the United Kingdom (UK). The authors recommended vitamin D supplementation for all individuals to ensure immune health and that those likely to be deficient should consider taking a higher dose.1 However, no quality appraisal or meta- analysis was performed. In December 2020, the National Institute for Health and Care Excellence (NICE) and Public Health England published rapid guidance based on a literature review, existing national guidance, and expert opinion to advise on the use of vitamin D for prevention or treatment of Association of Vitamin D Status with COVID-19 Incidence and Outcomes, and Health Equity Considerations 2 COVID-19. The guidelines conclude that there is insufficient evidence to support vitamin D supplementation solely to prevent or manage COVID-19 and indicate that research is needed. Given the other known benefits of vitamin D supplementation, NICE guidelines suggest that people follow existing UK government guidance on taking a vitamin D supplement to maintain bone and muscle health. 13 Objectives and Scope To update existing data, quantify the association of vitamin D status with COVID-19 outcomes, evaluate the potential health equity considerations associated with both vitamin D status and COVID-19, and apply to an Ontario context, we undertook a rapid review of the literature. This rapid review evaluates the association between vitamin D status (either vitamin D levels and/or vitamin D supplementation) and COVID-19 incidence and outcomes (severity, mortality) and also explores health equity considerations. Methods A rapid review was selected as the most appropriate approach to provide a timely synthesis. A rapid review is a knowledge synthesis simlar to a systematic review where steps are taken to ensure a timely response (e.g., lack of duplicate screening, reduced number of databases screened, no quality appraisal).14 On December 18, 2020, Public Health Ontario (PHO) Library Services conducted a primary literature search in Medline and Embase databases on the Ovid platform, using the search concepts: COVID-19 AND Vitamin D. Search strategy is available upon request. Observational or intervention studies evaluating the association between vitamin D levels and/or supplementation and COVID-19 incidence, severity, and/or mortality were included. Articles that were exclusively letters to the editor, commentaries, or narrative reviews were excluded. Preprint results from Ovid Medline (i.e. studies funded by the National Institute of Health) were included. Title and abstract screening, full-text screening and data extraction were performed by a single author. Data extraction was confirmed by a second author. For the purpose of this review, Vitamin D supplementation prior to COVID-19 diagnosis was considered prevention and vitamin D supplementation after COVID-19 diagnosis was considered treatment. Data were extracted from studies providing COVID-19 mortality event counts and used to perform an unadjusted random-effects meta-analysis to evaluate the association between vitamin D status and COVID-19 mortality (Mantel‐Haenszel method using RevMan version 5). Mortality was selected as this was the most common outcome for which event count data were reported. The following resources were used to guide exploration of health equity considerations: The PRISMA-Equity extension which outlines reporting guidelines for systematic reviews with a focus on health equity recommends that consideration for importance and relevance of outcomes be given across place of residence, race/ethnicity, Association of Vitamin D Status with COVID-19 Incidence and Outcomes, and Health Equity Considerations 3 occupation, gender, religion, education, socioeconomic status (SES) and social capital (“PROGRESS” categories), plus additional factors such as age, sexual orientation and disability.15 The Health Equity Impact Assessment (HEIA) tool was developed by the Ontario Ministry of Health to support improved health equity and is a decision support tool designed to help identify and address potential unintended health impacts of a policy, program or initiative on specific population groups, including ethno-racial communities (e.g., racial/racialized or cultural minorities).16 Results After removal of duplicates, 511 titles and abstracts were screened and 89 full-text studies were reviewed for inclusion. A total of 54 studies evaluating vitamin D levels,17–43,8,44–58 vitamin D supplementation,24,34,43,59–68 and COVID-19 outcomes were included (See Appendix A for study flow diagram).