Association of Vitamin D Status with COVID-19 Incidence and Outcomes, and Health Equity Considerations

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).

While the majority of studies were observational in design (retrospective cohort n=21, prospective cohort n=10, ecological n=7, case control n=6, cross-sectional n=4, quasi-experimental n=2, case series n=1), there were 3 RCTs. There was broad geographic representation across Europe, Asia, and the United States (US); however, no studies were performed in Africa, Oceania, or specifically in Canada. The most common locations of studies were the UK (n=7), Italy (n=5), US (n=5), and Iran (n=4). Studies were most commonly performed in hospital settings (n=29), followed by the community (n=8), and a mix between hospitalized patients and those from the community (n=8). The majority of studies were performed exclusively in the adult population (n=46), with 5 of those studies focusing solely on older adults and one study evaluating children.

Forty three of 54 (80%) of studies evaluated the association between vitamin D levels and COVID-19 outcomes and the remaining 13 (24%) evaluated the association between oral vitamin D supplementation and COVID-19 outcomes. Two studies evaluated both vitamin D levels and supplementation.

The most common COVID-19 outcomes evaluated were COVID-19 mortality (n=30), COVID-19 incidence (n=24), and COVID-19 severity of infection (e.g., intensive care unit (ICU) admission, need for respiratory support including supplemental oxygenation or mechanical ventilation) (n=15). Hospitalization for COVID-19 was measured in three studies. Vitamin D Levels and ASSOCIATION with COVID-19 Forty-three observational studies evaluated the association between vitamin D serum levels and COVID- 19 outcomes (Table 1). The majority of studies measured vitamin D levels (25-Hydroxyvitamin D) (n=39/43, 90.7%), whereas fewer studies indicated simply vitamin D or D3 levels (n=3/43, 7.0%), and 1 study (n=1/43, 2.3%) evaluated a billing code for vitamin D deficiency. Studies defined vitamin D deficiency/insufficiency heterogeneously ranging from <10 ng/mL to <30 ng/mL and <25 nmol/L to <50 nmol/L. The prevalence of vitamin D deficiency/insufficiency was high in most studies (median 57.0%, interquartile range [IQR] 39.1-75.3).

Association of Vitamin D Status with COVID-19 Incidence and Outcomes, and Health Equity Considerations 4

COVID-19 INCIDENCE Most studies found an inverse association between vitamin D levels and COVID-19 incidence (n=17/22, 77.3%) with 2 studies resulting in indeterminate findings (n=2/22, 9.0%) (Table 1). COVID-19 SEVERITY AND MORTALITY In roughly half of studies, higher vitamin D levels were associated with lower COVID-19 severity (n=6/12, 50.0%) and lower mortality risk (n=14/24, 58.3%). However, nine studies (n=9/24, 37.5%) found no association between vitamin D levels and mortality, and 1 study (n=1/24, 4.1%) found that higher vitamin D levels were associated with increased mortality risk.

Meta-analysis of the 12 studies that reported mortality event counts data showed a relative risk (RR) of 0.47 for mortality in patients with higher vitamin D levels (95% CI 0.28-0.81). See Figure 1.1.

Figure 1.1 Vitamin D Levels and Association with COVID-19 Mortality

Vitamin D Supplementation and Association with COVID-19 Thirteen studies evaluated the association between oral vitamin D supplementation and COVID-19 outcomes. Vitamin D regimens were heterogeneous ranging from single bolus to daily dosing; however, many observational studies did not indicate the dose of vitamin D received (Table 2). One cohort study included magnesium and Vitamin B12 in combination with Vitamin D as part of the supplementation regimen.

Most studies (n=7/13, 53.8%) evaluated the role of vitamin D supplementation for prevention, prior to COVID-19 diagnosis whereas two studies (n=2/13, 15.4%) evaluated vitamin D supplementation either prior to COVID-19 or shortly after diagnosis, three studies (n=3/13, 23.1%) evaluated vitamin D supplementation for treatment of COVID-19. Ten of 13 (77%) studies were observational, and 3 were RCTs (n=3/13, 23.1%), all evaluating the role of vitamin D for treatment following COVID-19 diagnosis).62,66,67 (See Appendix B for Summary of RCTs) COVID-19 INCIDENCE Two observational studies (n=2/13, 15.4%) evaluated the association between vitamin D supplementation and COVID-19 incidence. Both of these studies found that vitamin D intake was associated with a significantly reduced risk of acquiring COVID-19.

Association of Vitamin D Status with COVID-19 Incidence and Outcomes, and Health Equity Considerations 5

COVID-19 SEVERITY AND MORTALITY Vitamin D supplementation did not consistently show a benefit in reducing COVID-19 severity or preventing mortality. Two studies (n=2/5, 40.0%) found that vitamin D supplementation was associated with reduced COVID-19 severity and four studies (n=4/7, 57.1%) showed an association between vitamin D supplementation and reduced mortality. Of the studies reporting mortality data, vitamin D supplementation was associated with a numerically lower but non-statistically significant risk of mortality either in the observational studies, randomized controlled studies, or combined (combined pooled RR 0.64, 95% confidence interval 0.29 to 1.41) (Figure 1.2).

Figure 1.2 Vitamin D Supplementation and Association with COVID-19 Mortality

Adjustment for Confounders Of 51 observational studies included, 33 (63.7%) adjusted for potential confounding variables as part of the statistical methods (Table 1). The most common variables accounted for include sex (n=32/51, 62.7%), age (31/51, 60.8%), and comorbidities (28/51, 54.9%). Less common confounders that were accounted for included body mass index (BMI) and/or obesity (10/51, 19.6%) and smoking status (6/51, 11.7%). Health Equity Considerations In general, studies reported on patient demographics such as age and in most cases comorbidities such as chronic diseases. Most studies also reported on gender/sex although it should be noted that these terms were not specifically defined and therefore used interchangeably. Less than half of studies (n=22/54, 41%) reported information relevant to other PROGRESS categories. The most commonly reported categories were race/ethnicity (n= 17),8,19,21,22,25,28,29,32,33,39,46,49,53,56,64–66 socioeconomic status (n= 7),31–33,45,47,53,64 occupation (n= 4),8,29,31,61 and education (n= 3).31,61,64 Table 3 summarizes reporting of PROGRESS categories and how these were incorporated in study analysis, results and/or conclusions as they pertain to vitamin D status.

The extent that race/ethnicity was incorporated within the 17 studies was highly variable. Four studies only included race/ethnicity in describing patient characteristics,19,21,49,66 three studies included

Association of Vitamin D Status with COVID-19 Incidence and Outcomes, and Health Equity Considerations 6 race/ethnicity in study analysis related to COVID-19 outcomes in general,46,64,65 and 10 explicitly included race/ethnicity in study analysis, results or conclusions specific to vitamin D status.8,22,25,28,29,32,33,39,53,56 The findings of these studies were mixed: 2 studies found race/ethnicity to be associated with vitamin D status;8,29 however, 5 studies found a lack of association.22,25,32,39,53 One study found that vitamin D insufficiency/deficiency was not independently associated with COVID-19 infection or mortality after adjustment for race/ethnicity.33 In two studies, due to uniformity in the race/ethnicity of the population being studied, race/ethnicity did not appear to be a confounder28 or limitation for generalizability.56 Study Limitations Study quality was not formally assessed as part of this review; however, the following important study limitations should be considered:

 Since most studies on vitamin D level and COVID-19 are observational, there is a potential for confounding. For example, the “healthy user effect” may be a confounder in that patients more likely to receive vitamin D supplementation and/or have higher vitamin D levels at baseline are less likely to become infected due to other factors related to their health (e.g., access to care, socioeconomic factors), rather than vitamin D status itself.

 Vitamin D is considered a negative acute-phase reactant where levels are known to decrease during an acute illness. As a result, measurement of vitamin D concentrations on or during admission for COVID-19 may not be representative of levels prior to illness.69

 There was a high degree of heterogeneity in vitamin D supplementation dose and regimens used, with several studies not reporting dosing, compromising the generalizability of these findings.

 While several studies found an association between low vitamin D levels and COVID-19, there is a lack of RCT data evaluating the association between vitamin D supplementation and COVID-19.

 About 40% of studies reported on PROGRESS categories other than age, sex/gender and comorbidities; however, the use of this information to inform importance and relevance of outcomes for specific populations including ethno-racial communities was very limited.

 Race/ethnicity was the most commonly reported category. The small number of studies that incorporated this factor in analysis reported mixed results on whether race/ethnicity was associated with vitamin D status.

 Some studies adjusted for race/ethnicity as a potential confounding factor or identified a lack of diversity in race/ethnicity in the study population which precluded the assessment of the interaction between vitamin D levels and race/ethnicity with respect to COVID-19 incidence and/or outcomes. Vitamin D and COVID-19 Randomized Trials Underway  As of January 6, 2021, 30 interventional trials are registered at ClinicalTrials.gov related to vitamin D and COVID-19. Most studies are still recruiting (n=16), 10 have not yet begun recruiting, two are active but not recruiting, and two have recently been completed. Nine studies focus on vitamin D as a preventative measure and 21 studies will address vitamin D for treatment of COVID-19.70

Association of Vitamin D Status with COVID-19 Incidence and Outcomes, and Health Equity Considerations 7

Canadian Recommendations for Vitamin D Daily Intake Health Canada recommends Canadians receive sufficient amounts of vitamin D largely for the purpose of bone health.

 Recommended dietary reference allowance (DRA) per day for vitamin D are as follows71:

 age 4-70 years: 600 international units (IU)

 age >71 years: 800 IU

 Vitamin D intake from food and supplements combined is largely inadequate for the Canadian population (54 to 84% inadequate depending on age and gender, assuming minimal sun exposure).

 Given the prevalence of inadequate intake, Health Canada recommends those over the age of 50 years receive a daily vitamin D supplement (400 IU).71

Osteoporosis Canada recommends that all Canadian adults take a vitamin D supplement (specifically, vitamin D3 or cholecalciferol) year-round72:

 Healthy adults between 19-50 years of age, including pregnant or breastfeeding women, require 400-1,000 IU daily;

 Those over 50 or younger adults at high risk (with osteoporosis, multiple fractures, or conditions affecting vitamin D absorption) should receive 800-2,000 IU daily.

Given that vitamin D intake is inadequate for many Canadians, supplementation as per the above recommendations is appropriate for most individuals. Oral vitamin D3 supplementation has a wide therapeutic window and is associated with a low incidence of adverse effects,73 does not require a prescription for doses 1000 IU or lower,74 and is relatively low cost ($0.02 to $0.04 per 1000 IU). Conclusions  The impact of vitamin D status on COVID-19 incidence and severity is uncertain. Emerging data suggest that lower vitamin D levels or lack of vitamin D supplementation is associated with a greater risk of COVID-19 incidence and severity. There is a risk for confounding given the largely retrospective and uncontrolled nature of the data that are currently available.

 Randomized trials of vitamin D for treatment of COVID-19 have not consistently shown a benefit in preventing severe infection or mortality.

 Meta-analysis of mortality data found that although higher vitamin D levels are associated with lower COVID-19 mortality risk, this benefit was not as evident for vitamin D supplementation.

 While awaiting the results of RCTs of vitamin D for prevention of COVID-19 currently underway, Ontarians should follow current Canadian recommendations for vitamin D intake and supplementation for general bone health.

Association of Vitamin D Status with COVID-19 Incidence and Outcomes, and Health Equity Considerations 8

Table 1. Studies Evaluating Vitamin D Levels and Association with COVID-19 Outcomes

Vitamin D Levels Adjusted Historic for Vitamin D al =H Confounde Levels Sampl rs? Associated Author Study type Location Setting pre Outcome e size COVID= (e.g., age, with P sex, and/or Improved comorbidit Outcome? during- ies) COVID= D

Yes COVID-19 Abdollahi A Case Control Iran Hospital 402 D Yes Incidence

Abrishami A Retrospective Cohort Iran Hospital 73 D Yes COVID-19 Mortality Yes

Saudi Alguwaihes A Retrospective Cohort Hospital 439 D COVID-19 Mortality Yes Arabia Yes

Anjum S Prospective Cohort Pakistan Hospital 140 D No COVID-19 Mortality Yes

Hospital, Arvinte C Retrospective Cohort US 21 D COVID-19 Mortality No Critically Ill Yes

Baktash V Prospective Cohort UK Hospital 105 D No COVID-19 Mortality No

Hospital, Carpagnano G Retrospective Cohort Italy 42 D COVID-19 Mortality Yes Critically Ill Yes

Association of Vitamin D Status with COVID-19 Incidence and Outcomes, and Health Equity Considerations 9

No – Cereda E Prospective Cohort Italy Hospital 129 D COVID-19 Mortality increased Yes mortality

COVID-19 Chang T Case Control US Hospital 625 P Yes Yes Incidence

Switzerl Hospital and COVID-19 D'Avolio A Retrospective Cohort 107 D Yes and Community No Incidence

10 Ecological or Cross- Indeterminat Daneshkhah A Multiple Country level countr H COVID-19 Mortality sectional e ies No

De Smet D Retrospective Cohort Belgium Hospital 186 D Yes COVID-19 Mortality Yes

COVID-19 Faniyi A Cross-sectional UK Community 392 D Yes Yes Incidence

COVID-19 Ferrari D Retrospective Cohort Italy Hospital 347 D No No Incidence

Association of Vitamin D Status with COVID-19 Incidence and Outcomes, and Health Equity Considerations 10

COVID-19 Indeterminat Hamza A Cross-sectional Pakistan Not stated 168 D Yes Incidence e

348,59 COVID-19 Hastie C (a) Retrospective Cohort UK Community H No 8 Yes Incidence

341,48 Hastie C (b) Retrospective Cohort UK Community H COVID-19 Mortality No 4 Yes

COVID-19 Yes, Incidence Hernandez J Case Control Spain Hospital 394 D No COVID-19 Severity No Yes COVID-19 Mortality

20 COVID-19 Ecological or Cross- Yes Ilie P Europe Country level countr H Incidence sectional Yes ies No COVID-19 Mortality

South COVID-19 Im J Case Control Hospital 200 D Yes Korea No Incidence

Association of Vitamin D Status with COVID-19 Incidence and Outcomes, and Health Equity Considerations 11

COVID-19 Yes Jain A Prospective Cohort India Hospital 154 D Mortality, ICU No Admission Yes

Karahan S Retrospective Cohort Turkey Hospital 149 D Yes COVID-19 Mortality Yes

191,77 COVID-19 Kaufman H Retrospective Cohort US Community P Yes 9 Yes Incidence

COVID-19 Kerget B Prospective Cohort Turkey Hospital 88 D Yes No Incidence

12 Ecological or Cross- Laird E Europe Country level countr H COVID-19 Mortality Yes sectional ies No

COVID-19 Yes Incidence Luo X Cross-sectional China Hospital 895 D Yes COVID-19 Severity, Yes COVID-19 Mortality No

Association of Vitamin D Status with COVID-19 Incidence and Outcomes, and Health Equity Considerations 12

Macaya F Retrospective Cohort Spain Hospital 80 P or D Yes COVID-19 Severity No

COVID-19 Mardani R Retrospective Cohort Iran Community 123 D Yes No Incidence

46 COVID-19 Ecological or Cross- Yes Mariani J Multiple Country level countr H Incidence sectional Yes ies Yes COVID-19 Mortality

Hospital and COVID-19 Meltzer D Retrospective Cohort US 489 P Yes Community Yes Incidence

Yes COVID-19 Hospital and not Hospitalization Mendy A Retrospective Cohort US 689 Community stated COVID-19 Severity, Yes COVID-19 Mortality Yes Yes

7807 not COVID-19 Merzon E Israel Yes Retrospective Cohort Community stated Yes Incidence

Association of Vitamin D Status with COVID-19 Incidence and Outcomes, and Health Equity Considerations 13

28 states COVID-19 and 8 Yes Padhi S India H Incidence union Yes Ecological or Cross- territo COVID-19 Mortality sectional Regional level ries No

134 ICU Admission No Panagiotou G UK D Retrospective Cohort Hospital Yes COVID-19 Mortality No

Indonesi 10 COVID-19 Indeterminat Pinzon R D Case Series a Hospital No Incidence e

Hospital and 109 Pizzini A Austria D COVID-19 Severity No Prospective Cohort Community No

German 185 COVID-19 Severity, Yes Radujkovic A Hospital and D Prospective Cohort y Community Yes COVID-19 Mortality Yes

4510 COVID-19 Raisi-Estabragh UK H No Prospective Cohort Community Yes Incidence

Association of Vitamin D Status with COVID-19 Incidence and Outcomes, and Health Equity Considerations 14

20 COVID-19 Yes countr Incidence Singh S Ecological or Cross- Europe country level - H ies No sectional not defined No COVID-19 Mortality

39 COVID-19 Severity, No Vassiliou A (a) Greece D Retrospective Cohort Hospital No COVID-19 Mortality No

Hospital, 30 Vassiliou A (b) Greece D COVID-19 Mortality Yes Prospective Cohort Critically Ill No

Hospital and 142 Ye K China D COVID-19 Severity Yes Case Control Community Yes

85 COVID-19 Yes Yilmaz K Turkey D Incidence No Retrospective Cohort Hospital No COVID-19 Severity

Association of Vitamin D Status with COVID-19 Incidence and Outcomes, and Health Equity Considerations 15

Table 2. Studies Evaluating Vitamin D Supplementation and Association with COVID-19 Outcomes

Sampl Treatme Vitamin D Study Locatio nt or Associated with Author Setting e Vitamin D Dose Outcome Type n Preventi Improved Size on Outcome?

Treatme Quasi- Vitamin D3 80,000 IU Annweiler Long-term nt/ COVID-19 Experime France 66 bolus in week following Yes C Care mortality ntal Preventi COVID or previous month on

Regular oral vitamin D (e.g., 50,000 IU/month or Treatme Yes – but only for Quasi- 80-100,000 IU every 2-3 Annweiler nt/ COVID-19 regular Experime France Hospital 77 months before COVID-19) C mortality supplementation ntal Preventi vs. 80,000 IU within "few group on hours" of COVID-19 vs. no supplementation

Cross- Hospital and Preventi COVID-19 Bagheri M Iran 510 Not stated Yes sectional Community on hospitalization

COVID-19 Prospecti Hospital and Preventi mortality, No Cereda E Italy 324 >25,000 IU over 3 months ve Cohort Community on COVID-19 No hospitalization

Randomiz Calcifediol 0.532 mg PO COVID-19 Entrenas ed Treatme Yes Spain Hospital 76 day 1, 0.266 mg on day 3, mortality, Castillo M Controlle nt 7 and weekly vs. placebo Yes d ICU Admission

Association of Vitamin D Status with COVID-19 Incidence and Outcomes, and Health Equity Considerations 16

Sampl Treatme Vitamin D Study Locatio nt or Associated with Author Setting e Vitamin D Dose Outcome Type n Preventi Improved Size on Outcome?

Case Preventi COVID-19 Fasano A Italy Community 1486 Not stated Yes Control on incidence

ICU Admission, No COVID-19 Hernande Case Preventi Spain Hospital 216 Not stated Severity, No z J Control on COVID-19 No mortality

Multip le Preventi COVID-19 Li M Ecological Multiple Not stated countr Not stated Yes on incidence ies and states

Retrospec Preventi High-dose cholecalciferol COVID-19 Ling S tive UK Hospital 444 Yes on therapy mortality Cohort

Retrospec Preventi Macaya F tive Spain Hospital 80 Not stated COVID-19 severity No on Cohort

Length of Stay, Randomiz No Single oral dose of ed Treatme ICU Admission, Murai I Brazil Hospital 240 200,000 IU of vitamin D3 No Controlle nt vs. placebo COVID-19 d No Mortality

Association of Vitamin D Status with COVID-19 Incidence and Outcomes, and Health Equity Considerations 17

Sampl Treatme Vitamin D Study Locatio nt or Associated with Author Setting e Vitamin D Dose Outcome Type n Preventi Improved Size on Outcome?

Randomiz 60000 IU of ed Treatme COVID-19 Rastogi A India Hospital 40 cholecalciferol daily for 7 Yes Controlle nt negativity days vs. placebo d

Retrospec Vitamin D3 1000 IU daily Singapo Treatme Tan C tive Hospital 43 (along with Magnesium COVID-19 severity Yes re nt Cohort and Vitamin B12)

Association of Vitamin D Status with COVID-19 Incidence and Outcomes, and Health Equity Considerations 18

Table 3: Studies reporting on PROGRESS Categories*

Vitamin D PROGRESS+ Categories Author Status Inclusion in Study Analysis, Results & Conclusions Reported** Evaluated

Nationality: Saudi, Arab (non-Saudi), Filipino, Alguwaihes Levels Bangladeshi, Pakistani, Indian, Afghani, Descriptive only; included in table of patient demographics. A Others.

Arvinte C Levels Race (Caucasian or Hispanic) Descriptive only; included in table of patient demographics.

Education: Illiterate, High school, Supplementa Undergraduate, Postgraduate Included in binary regression test; education and occupation Bagheri M tion were not identified as risk factors for hospitalization. (Prevention) Occupation: Unemployed, Worker, Employee, Retired, House wife, Free lancer

Characteristics of vitamin D-replete and deficient groups in the Ethnicity (Caucasian, South Asian, East Asian, Baktash V Levels COVID-19-positive arm were found to be comparable. Ethnicity Afro-Caribbean) did not influence outcomes in this cohort.

Race: Black of African American, Asian, American Indian or Alaska Native, Other, Race and ethnicity included in logistic regression models Chang T Levels Unknown examining risk of testing positive and severe disease; no data Ethnicity: Hispanic or Latino, Not Hispanic or on impact of race or ethnicity on vitamin D deficiency. Latino, Unknown

Vitamin D deficiency was independently associated with COVID- De Smet D Levels Ethnicity 19 mortality and not confounded by ethnicity as all study participants were Whites of European descent.

Association of Vitamin D Status with COVID-19 Incidence and Outcomes, and Health Equity Considerations 19

Vitamin D PROGRESS+ Categories Author Status Inclusion in Study Analysis, Results & Conclusions Reported** Evaluated

Ethnicity: White, BAME(Black Asian and Minority Ethnic), not stated Ethnicity and job role were included in backwards logistic Job role: Junior doctor, consultant, junior regression; BAME and seroconversion were significant Faniyi A Levels nurse, senior nurse, physiotherapist, independent risk factors for vitamin D deficiency; only VDD was laboratory worker, radiology/theatre a significant independent risk factor for developing staff/pharmacy, secretary/administrator, seroconversion. health care assistant/phlebotomist,

Occupation: office worker, labour worker, house wife Residence: rural, urban Hamza A Levels Descriptive only; included in table of patient demographics SES (lower, middle, upper class) Education: primary, middle, matriculation, intermediate, graduate, uneducated

Vitamin D insufficiency or deficiency was not independently Ethnicity: White, Black, South Asian, Other associated with COVID-19 infection or mortality after Hastie C (a) Levels SES – Townsend deprivation quintile adjustment for confounders. However black ethnicity, SES were amongst variables that were significantly associated COVID-19 Household income mortality in multivariable analysis.

Univariable and multivariable logistic regression analyses were performed for the association between vitamin D and Ethnicity: White, Black, South Asian, Other Hastie C (b) Levels confirmed COVID-19, and the association between ethnicity and SES – Townsend deprivation quintile both Vitamin D and COVID-19. There was no evidence to support a potential role for vitamin D level and risk of COVID-19 infection overall or to account for differences between ethnic

Association of Vitamin D Status with COVID-19 Incidence and Outcomes, and Health Equity Considerations 20

Vitamin D PROGRESS+ Categories Author Status Inclusion in Study Analysis, Results & Conclusions Reported** Evaluated groups. There was no significant interaction between ethnicity and vitamin D deficiency.

Race/ethnicity: estimated proportions Multivariable logistic regression analysis adjusting for all reported by zip code: predominately black included demographic factors resulted in a strong negative Kaufman H Levels non-Hispanic, predominantly Hispanic, correlation between vitamin D levels and SARS-CoV-2 infection predominantly white non-Hispanic. which persisted across latitude, ethnicity, sex and age.

Percentage of urban population Race: White, Black, Asian, Arab Supplementa tion Religion: Islam, Christianism, Buddhism, Other Included in logistic regression model to identify factors Li M (Prevention) Education associated with COVID-19 cases, death and case fatality rates.

Gini index (income inequality)

Supplementa Non-Caucasian ethnicity was included in logistic regression to Ethnicity: Caucasian, South Asian, East Asian, Ling S tion analyse predictor variables for potential associations with African Caribbean, other (Prevention) COVID-19 mortality.

Gross Domestic Product (GDP) for 2019: Word GDP included in multivariate Poisson regression models to Mariani J Bank’s Data Bank (billions of USD as indicator assess association between COVID-19 indicators and vitamin D for socioeconomic level) deficiency.

Race: White, race other than White (Black or African American, Asian/Mideast Indian, Compared with patients who were not vitamin D deficient, Meltzer D Levels multiple) patients who were vitamin D deficient were more likely to be “race other than White” (Fisher exact test, p<0.001). Ethnicity: Hispanic, non-Hispanic

Association of Vitamin D Status with COVID-19 Incidence and Outcomes, and Health Equity Considerations 21

Vitamin D PROGRESS+ Categories Author Status Inclusion in Study Analysis, Results & Conclusions Reported** Evaluated Employee Status: employee of UChicago, not UChicago employee

Race/ethnicity included in logistic regression modeling to Race/Ethnicity: white, non-Hispanic Black, Mendy A Levels identify the factors associated with hospitalization and severe Hispanic, other COVID-19.

SES included in multivariate analysis to determine association SES: low-medium, high-medium defined based Merzon E Levels between low plasma vitamin D and risk of COVID-19 infection on home address and hospitalization.

Supplementa Included in table of patient demographics; proportions were Murai I tion Race: White, Brown, Black, Asian compared to ensure balanced randomization. (Treatment)

Panagiotou Ethnicity: Caucasian, Asian, Afro-Caribbean, Ethnicity included in table of patient demographics; no Levels G other difference between ICU and non-ICU patient groups.

Ethnicity: White, BAME (Black [Caribbean, African, any other Black background], Asian [Indian, Pakistani, Bangladeshi, any other Asian background], Chinese, Mixed [White and Black Caribbean, White and Black African, Ethnicity included in multivariate logistic regression models Raisi- White and Asian, any other mixed testing role of vitamin D in determining risk of COVID-19. The Estabragh Levels background] ‘other), SES: Townsend sex and ethnicity differential pattern of COVID-19 is not A deprivation score, type of housing: communal adequately explained by variations in vitamin D levels. living space (flat, apartment, sheltered accommodation), stand-alone housing (house, bungalow) Household size

Association of Vitamin D Status with COVID-19 Incidence and Outcomes, and Health Equity Considerations 22

Vitamin D PROGRESS+ Categories Author Status Inclusion in Study Analysis, Results & Conclusions Reported** Evaluated Intergenerational cohabitation: number of generations in household

Vassiliou A Levels Ethnicity: Greek Greek-only ethnicity stated as a limitation of the study. (b)

Descriptive only; area included in table of patient Ye K Levels Area: Urban, Rural demographics. *other than age, gender and comorbidities, **categories, subcategories and definitions are as per individual study

Association of Vitamin D Status with COVID-19 Incidence and Outcomes, and Health Equity Considerations 23

Appendix A. Study Flow Diagram

Association of Vitamin D Status with COVID-19 Incidence and Outcomes, and Health Equity Considerations 24

Appendix B. Summary of RCTs of Vitamin D Supplementation for Treatment of COVID-19  A pilot open-label RCT of 76 hospitalized patients in Spain is the first published randomized study to evaluate the role of vitamin D in early management of COVID-19. Participants were randomized to vitamin D (an activated form of vitamin D - oral calcifediol 0.532 mg on day 1, followed by 0.266 mg on days 3 and 7, then weekly until ICU admission or discharge) or control in a 2:1 ratio. The study met their desired sample size of 75 patients for an estimated 5% difference in ICU admission between treatment and placebo and attrition rate of 12%. Patients treated with vitamin D were less likely to require ICU admission compared to those in the control group (2% vs 50% respectively, adjusted OR 0.03, 95% confidence interval 0.003 to 0.25). No patients receiving vitamin D died and 2 in control group died (statistical significant not assessed).62

 In contrast to the above study, a non-peer reviewed pre-print study found opposing results with vitamin D3 supplementation in severe COVID-19 treatment. This double-blind, multi-centre, RCT in Brazil enrolled 240 patients with severe COVID-19 (hospitalized with elevated respiratory rate, reduced oxygen saturation, or risk factors for complications) to receive either a single dose of 200,000 IU of vitamin D3 orally or placebo. This study also met desired sample size of 208 patients assuming a 50% difference in length of stay between treatment and placebo and a 15% drop out rate. No significant difference was detected in hospital length of stay, admission to ICU, mechanical ventilation, or mortality.66

 A randomized, placebo-controlled, trial evaluated 40 hospitalized adults with COVID-19 (asymptomatic or mild symptoms). Patients were randomized to either 60,000 IU of cholecalciferol orally daily for 7 days with the goal of achieving 25(OH)D level>50 ng/ml or placebo for 7 days. Ten of 16 (62.5%) of patients in the vitamin D arm achieved the primary outcome of SARS-CoV-2 RNA PCR negative compared to five of 24 (20.8%) in the placebo arm. However, the authors did not evaluate clinical outcomes such as COVID-19 severity or mortality.67

Association of Vitamin D Status with COVID-19 Incidence and Outcomes, and Health Equity Considerations 25

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