Evidence reviews for the use of vitamin D supplementation as prevention and treatment of COVID-19

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Evidence reviews for the use of vitamin D supplementation as prevention and treatment of COVID-19

Vitamin D for COVID-19

Evidence review A

NICE Guideline, No. 187

London: National Institute for Health and Care Excellence (NICE); 2020 Dec.

ISBN-13: 978-1-4731-3942-8

1. Vitamin D for COVID-19 prevention and treatment

1.1. Review question

What is the clinical effectiveness and safety of vitamin D supplementation for the treatment of COVID-19 in adults, young people and children?

1.1.1. Introduction

Vitamin D is hypothesised to have a role in the immune response to respiratory viruses and can potentially mitigate the inflammatory response. During the COVID-19 pandemic, treatments are being explored as options for managing the disease. Therefore, it has been suggested vitamin D could improve outcomes in people diagnosed with confirmed COVID-19. The 2 major forms of vitamin D, vitamin D₃ (cholecalciferol) and vitamin D₂ (ergocalciferol), are licensed for the prevention and treatment of vitamin D deficiency and are taken by many people who have vitamin D deficiency. The review aims to assess if vitamin D can be used in all people regardless of vitamin D status as a safe treatment option, alone or in combination with other therapies, to treat COVID-19.

1.1.2. Summary of the protocol

Table 1

PICO table for review question 1.

1.1.3. Methods and process

This evidence review was developed using the methods and process described in Developing NICE guidelines: the manual. Methods specific to this review question are described in the review protocol in appendix A.

Risk of bias in randomised controlled trials was assessed by using the Cochrane risk of bias tool (2.0). Results of the risk of bias assessments can be found alongside the evidence table for each study (Appendix D.1.1). Grading of Recommendations Assessment, Development and Evaluation (GRADE) was used to present results and to evaluate the quality of evidence by outcomes (see Appendix E). GRADE assessment domains include risk of bias, inconsistency, indirectness, and imprecision. Outcomes start at High, for example, for a randomised controlled trial, and can be marked down 1 or 2 levels for each domain through to Moderate, Low and Very Low evidence. Each of the evidence quality ratings are explained below:

High – Further research is very unlikely to change our confidence in the estimate of effect.

Moderate – Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.

Low – Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.

Very low – Any estimate of effect is very uncertain.

Declarations of interest of the expert panel members who developed the guideline recommendations were recorded according to NICE’s conflicts of interest policy.

1.1.4. Effectiveness evidence

1.1.4.1. Included studies

One search was conducted for all 3 reviews questions, which returned 640 results. For review question 1, after screening, 3 were considered at full text and 1 study was included.

1.1.4.2. Excluded studies

Three studies were screened at full text; the 2 excluded studies can be found in Appendix G.

1.1.5. Summary of studies included in the effectiveness and prognostic evidence

Table 2

Summary of studies included in the evidence review.

See appendix D.1 for full evidence tables.

1.1.6. Summary of the effectiveness evidence

One study reported 2 outcomes concerning people who had been admitted to hospital with COVID-19: admission to intensive care and mortality. Evidence quality was graded as very low because of a very serious risk of bias and the low number of participants in the study (n=76).

The number of people who were admitted to ICU in the calcifediol arm (n=50) was 1 (2%) and in the standard care only arm (n=26) was 13 (50%). An adjusted multivariable model reported that people who received calcifediol treatment plus standard care were less likely to be admitted to intensive care than people who received standard care only, OR 0.03 (95% CI 0.003 to 0.25) [adjusted for hypertension and diabetes as prevalence differed between arms].

Mortality was reported as number of deaths. There were 0 deaths in the calcifediol treatment plus standard care arm and 2 deaths in the standard care only arm, (OR 0.097, 95%CI 0.004 to 2.099).

See appendix E for full GRADE tables.

1.1.7. Economic evidence

Economic evidence was not considered for this review.

1.2. Review question

What is the clinical effectiveness and safety of vitamin D supplementation for the prevention of SARS CoV2 infection (and subsequent COVID-19) in adults, young people and children?

1.2.1. Introduction

The current COVID-19 pandemic is caused by transmission of SARS-CoV-2 between people. Lowering the infection rate is important in keeping hospital admissions manageable and preventing death and illness. A range of different approaches have been taken for lowering the infection rate. One option that has been suggested is vitamin D supplementation because it has been hypothesised to be involved in the body’s immune response and could mitigate the inflammatory response. This review aims to assess if vitamin D supplementation can prevent SARS CoV2 infection and subsequent COVID-19.

1.2.2. Summary of the protocol

Table 3

PICO table for review question 2.

1.2.3. Methods and process

Risk of bias in randomised controlled trials was assessed by using the Cochrane risk of bias tool (2.0). Results of the risk of bias assessments can be found alongside the evidence table for each study (Appendix D). Grading of Recommendations Assessment, Development and Evaluation (GRADE) was used to present results and to evaluate the quality of evidence by outcomes (see Appendix E). GRADE assessment domains include risk of bias, inconsistency, indirectness, and imprecision. Outcomes start at High, for example, from a randomised controlled trial, can be marked down 1 or 2 levels for each domain through to Moderate, Low and Very Low evidence. Each of the evidence quality ratings are explained below:

High – Further research is very unlikely to change our confidence in the estimate of effect.

Moderate – Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.

Low – Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.

Very low – Any estimate of effect is very uncertain.

Declarations of interest of the expert panel members who developed the guideline recommendations were recorded according to NICE’s conflicts of interest policy.

1.2.4. Effectiveness evidence

1.2.4.1. Included studies

One search was conducted for all 3 evidence reviews, which returned 640 results. For review question 2, after screening, 2 studies were at full text considered and no studies were included.

1.2.4.2. Excluded studies

Two studies were considered at full text. All were excluded and can be found with reasons in Appendix G.

1.2.5. Summary of the effectiveness evidence

No evidence relevant to the protocol was found for this question.

1.2.6. Economic evidence

Economic evidence was not considered for this review.

1.3. Review question

Is vitamin D status independently associated with susceptibility to developing COVID-19, severity of COVID-19, and poorer outcomes from COVID-19 in adults, young people and children?

1.3.1. Introduction

The COVID-19 pandemic has affected countries differently. Some have hypothesised that the differences are in part caused by people’s vitamin D status. It has also been suggested that the higher incidence of SARS CoV2 infection in older people and ethnic minorities could be partly explained by lower serum vitamin D, which is more common in these groups. The aim of this review is to assess if there is an association between vitamin D status and incidence of SARS CoV2 infection, poorer outcomes, and COVID-19 severity.

1.3.2. Summary of the protocol

Table 4

protocol summary for review question 3.

1.3.3. Methods and process

Studies included in this review were anticipated to be cohort, case-control and cross-sectional designs analysing associations between vitamin D using regression adjusting for confounding variables. Regression analyses reveal relationships among variables and adjustment attempts to eliminate the effect of other factors to assess if the variable in question is independently associated with an outcome. In the example of vitamin D, older people have low vitamin D and poorer COVID-19 outcomes. A regression analysis without any adjustment will not infer whether age or vitamin D, or both, are associated with poorer COVID-19 outcomes. A regression model adjusted for age will allow us to see associations, including vitamin D, that are not due to age. This can be done with numerous measurable variables but does not mean that all factors have been accounted for. Many other factors are associated both with COVID-19 outcomes and with vitamin D status, for example obesity, ethnicity, diabetes, socioeconomic status, household crowding and urban place of residence. For this reason, only studies that reported multivariable (adjusted) models for outcomes of interest were considered because at least some confounding variables are considered in these models.

However, it is noteworthy that associations demonstrated in an adjusted model do not imply that the relationships are causal. There are other factors that could be influencing the association that were not adjusted for. Association should not be confused with causality. This is especially important when many variables are studied in a complex public health scenario. In this scenario spurious associations can arise because the large number of factors studies makes it possible that an association could be discovered by chance or because of multicollinearity, explored below.

Studies on associations can be used to form the basis for hypothesis testing for causality. Therefore, association studies are usually published to inform future research. It was not expected that many published RCTs would be available for vitamin D as treatment or prevention at this stage of the pandemic. This is because association studies can generate hypotheses and guide timely and costly RCTs. However, there are a number of methodological and statistical considerations that need to be taken into account when interpreting findings from association studies. Firstly, to assess whether there is a confirmed or scientifically proven biological plausibility between the dependent variable and outcome of interest. Caution is required if the hypothesis of the relationship is based on indirect association, that is if A is caused by B, A is similar to C, therefore C must also be caused by B.

Another consideration that needs careful interpretation in any multivariable analysis is the issue of multicollinearity, meaning 2 or more variables are associated with each other. The mediating and moderating effect from other variables (for example confounding variables or other independent variables in the model) need to be explored before concluding the association between the dependent variable and outcome of interest. This is because the model assumption that a change in the independent variable will lead to a change in the dependent variable while all other variables are held constant will be violated. Without these considerations, estimates for this association will be imprecise and small changes to the raw data may generate large changes to the model results.

There are also several statistical principles in multivariable analysis that are either not commonly conducted by researchers or poorly reported. For example, the lack of goodness-of-fit testing, lack of residual analysis, the family-wise error rate (due to multiple comparisons in a multivariable model) is not adjusted, violation of assumption of normality, lack of cross-validation, and others. All data was extracted from the studies in relation to these principles, where available.

All the elements above need careful assessment in order to decide the quality of the study and whether the concluded association is valid. As the studies that were included were looking at association, the risk of bias checklist used was the QUIPS checklist. This checklist has domains that considers the above issues. A modified version of Grading of Recommendations Assessment, Development and Evaluation (GRADE) was used to present results and to evaluate the quality of evidence by outcomes (see Appendix E). Only outcomes that had been adjusted for covariates were presented, all conducted through multivariable analysis. When unadjusted (univariable) values were presented, they were included in the modified GRADE table for reference. In modified GRADE, the assessment domains include risk of bias, inconsistency, indirectness, and imprecision. For observational studies, outcomes start at Low (for example, cohort study and case control study) can be marked down 1 or 2 levels for each domain through to Very Low evidence. Evidence quality can be raised 1 or levels in specific circumstances: if the effect estimate is large or if the effect shows a dose-response curve. Each of the evidence quality ratings are explained below:

High – Further research is very unlikely to change our confidence in the estimate of effect.

Moderate – Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.

Low – Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.

Very low – Any estimate of effect is very uncertain.

Declarations of interest of the expert panel members who developed the guideline recommendations were recorded according to NICE’s conflicts of interest policy.

1.3.4. Association evidence

1.3.4.1. Included studies

One search was conducted for all 3 evidence reviews, which returned 640 results. For review question 3, after screening, 69 studies were considered at full text and 12 studies were included.

Twelve studies were identified as pre-prints and listed as references but data was not extracted from them for this review as they have not yet been peer reviewed. One extra study in preprint was identified through stakeholder consultation and included in the list of preprints. This made a total of 13 preprint studies.

1.3.4.2. Excluded studies

Sixty-nine studies were considered at full text. Forty-five were excluded; reasons for exclusion can be found in Appendix G.

1.3.5. Summary of studies included in the effectiveness and prognostic evidence

Table 5

Summary of studies included in the evidence review.

See appendix D.2 for full evidence tables.

1.3.6. Summary of the association evidence

Twelve studies reported on how vitamin D status associated with COVID-19 outcomes. Outcomes included COVID-19 cases, COVID-19 severity including hospitalisation and mechanical ventilation, and mortality. Studies reported vitamin D status differently. Some measured associations between outcomes and linear vitamin D concentrations. Whereas others used cut-offs to define deficiency and assessed the risk of an outcome by comparing people considered vitamin D deficient and vitamin D sufficient. All outcomes were rated as very low quality of evidence. Evidence was downgraded for high risk of bias, indirectness, and imprecision due to the number of factors adjusted and low participant numbers.

Association between vitamin D status and COVID-19 cases

Six studies explored the association between vitamin D status and COVID-19 incidence. Some studies found a negative association between vitamin D status and COVID-19 incidence. Whether studies measured vitamin D as a linear scale or compared people with vitamin D deficiency to people without did not have an impact on whether a significant association was found.

Three studies assessed the linear association between vitamin D concentration measured and the risk of COVID-19 cases and 1 found a significant association, OR 0.984 (95% CI 0.983 to 0.986) N=191,779 (Kaufman 2020). Conversely, another study did not find an association, OR 1.00 (0.998 to 1.01) N=349,017 (Hastie 2020). This study also demonstrated that ethnicity did not impact on the association between vitamin D status and COVID-19 cases. However, it is difficult to provide a definite effect estimate due to lack of power in this analysis. Raisi-Esrabragh 2020 used the same UK Biobank database for their analysis as Hastie 2020. There was no association found between vitamin D status COVID-19 cases, OR 1.00 (1.00 to 1.00), N=4510. However, the UK Biobank study measured serum vitamin D during initial recruitment in 2006–2010. Serum vitamin D fluctuates and a lag of at least 10 years means the recorded concentrations may not be reflective of current concentrations. Hastie 2020 and Kaufman 2020 used data from everyone that was available in their databases, but Raisi-Esrabragh 2020 only used data from people who had taken a SARS CoV2 test. The difference between the results of the studies that used the UK Biobank data and the Kaufman study may have arisen between the two populations that are included in the analyses. The UK Biobank data has a lower proportion of ethnic minorities and includes a more people from higher socioeconomic groups.

Within the same study, Hastie 2020 also assessed association between receiving a positive COVID-19 test in 2 groups, people who were vitamin D deficient (<25nmol/L) and people who were insufficient (<50nmol/L) were compared with people with serum concentrations above the thresholds. Both analyses showed no difference in COVID-19 cases between people above and below the thresholds, <25nmol/L OR 0.92 (95% CI 0.71 to 1.21), <50nmol/L OR 0.88 (95% CI 0.72 to 1.08). Meltzer 2020 used the same threshold for deficiency, <50nmol/L and demonstrated an association between vitamin D deficiency and COVID-19 cases, OR 1.77 (95% CI 1.12 to 2.81). However, this study did not adjust for demographic factors, such as sex, gender and ethnicity, that are known to have an impact on COVID-19 case rates. Merzon 2020 did control for demographic variables and found that people with suboptimal serum vitamin D (<75nmol/L) were more likely to contract COVID-19 than people above the threshold OR 1.5 (95% CI 1.13 to 1.98).

Effects are presented as OR/HR (95% CI) in Table 6 unless otherwise stated.

Table 6

Summary of evidence for the association between vitamin D status and COVID-19 cases.

Association between vitamin D status and COVID-19 severity

Seven studies reported on the association between vitamin D status and COVID-19 severity. Measures for severity included the WHO Ordinal Scale for Clinical Improvement (OSCI) score, composite outcomes, mortality, and hospitalisation.

Two studies report on composite outcomes. Hernandez 2020 did not find a significant association between vitamin D level in nmol/L and the composite outcome of admission to the intensive care unit (ICU), requirement for mechanical ventilation, or in-hospital mortality, OR 1.13 (95% CI 0.27 to 4.77), n=197. Macaya 2020 also did not find an association between vitamin D deficiency (<50nmol/L) and the composite outcome death, admission to ICU, and/or need for higher oxygen flow than that provided by a nasal cannula, OR 3.2 (95% CI 0.99 to 11.4). Radujkovic 2020 did find a significant association between suboptimal vitamin D (<30 nmol/L) and the composite outcome mechanical ventilation and death, HR 6.12 (95% CI 2.79 to 13.42), n=185. The difference between these studies may lie in which factors were adjusted for in the multivariable analysis.

Results associating vitamin D status with COVID-19 severity scores were mixed. Ye 2020 used the guidelines of the National Health Commission of China to define severe/critical cases. The study found an association between vitamin D deficiency and severe/critical COVID-19, OR 15.18 (95% CI 1.23 to 187.45). Annweiler 2020a used OSCI scores ≥5 to define severe COVID-19 and included 3 groups: people classed as vitamin D sufficient if they received supplements for a year before COVID-19 diagnosis, people who received vitamin D bolus when diagnosed with COVID-19, and people who had not received any supplementation. Compared with no supplementation, supplementation for a year was significantly negatively associated with having severe COVID-19, OR 0.08 (95% CI 0.01 to 0.81), but there was no difference when only receiving a bolus when diagnosed, OR 0.46 (95% CI 0.07 to 2.85).

Four studies reported mortality as a standalone outcome. 3 studies found that a higher measured vitamin D status (Karahan 2020, linear vitamin D measurement) or supplementation before diagnosis (Annweiler 2020, within a month before or up to a week after diagnosis; Annweiler 2020a, supplemented for a year before diagnosis) were negatively associated with death post COVID-19 diagnosis, OR 0.92 (95% CI 0.88 to 0.98), HR 0.11 (95% CI 0.03 to 0.48) and HR 0.07 (95% CI 0.01 to 0.61, respectively. Radujkovic 2020 also found that suboptimal serum vitamin D (<30nmol/L) was associated with higher mortality rate, HR 14.73 (95% CI 4.16 to 52.19). However, receiving a vitamin D bolus when diagnosed with COVID-19 was as associated with death as no supplementation (HR 0.37 (95% CI 0.06 to 2.21), Annweiler 2020a).

Hospitalisation for COVID-19 symptoms was reported as a standalone outcome in 1 study (Merzon 2020). Suboptimal vitamin D levels (<75 nmol/L) were as associated with hospitalisation as higher vitamin D, OR 1.95 (95% CI 0.99 to 4.78).

Effects are presented as OR/HR (95% CI) in table 7.

Table 7

Summary of evidence for the association between vitamin D status and COVID-19 severity.

See appendix E for full GRADE tables.

1.3.7. Economic evidence

No economic evidence was considered for this review.

1.3.9. References – included studies

1.3.9.1. Treatment

Entrenas Castillo, Marta, Entrenas Costa, Luis Manuel, Vaquero Barrios, José Manuel et al. (2020) “Effect of calcifediol treatment and best available therapy versus best available therapy on intensive care unit admission and mortality among patients hospitalized for COVID-19: A pilot randomized clinical study”;. J Steroid Biochem Mol Biol 203: 105751–105751 [PMC free article: PMC7456194] [PubMed: 32871238]

1.3.9.2. Association

Annweiler, Cedric, Hanotte, Berangere, de l’Eprevier, Claire Grandin et al. (2020) Vitamin D and survival in COVID-19 patients: A quasi-experimental study. The Journal of steroid biochemistry and molecular biology: 105771 [PMC free article: PMC7553119] [PubMed: 33065275]
Annweiler, Gaelle, Corvaisier, Mathieu, Gautier, Jennifer et al. (2020) Vitamin D Supplementation Associated to Better Survival in Hospitalized Frail Elderly COVID-19 Patients: The GERIA-COVID Quasi-Experimental Study. Nutrients 12(11) [PMC free article: PMC7693938] [PubMed: 33147894]
Hastie, Claire E, Mackay, Daniel F, Ho, Frederick et al. (2020) Vitamin D concentrations and COVID-19 infection in UK Biobank. Diabetes & metabolic syndrome 14(4): 561–565 [PMC free article: PMC7204679] [PubMed: 32413819]
Hernandez, JL, Nan, D, Fernandez-Ayala, M et al. (2020) Vitamin D Status in Hospitalized Patients With SARS-CoV-2 Infection. The Journal of Clinical Endocrinology & Metabolism
Karahan, S. and Katkat, F. (2020) Impact of Serum 25(OH) Vitamin D Level on Mortality in Patients with COVID-19 in Turkey. Journal of Nutrition, Health and Aging [PMC free article: PMC7533663] [PubMed: 33491033]
Kaufman, Harvey W, Niles, Justin K, Kroll, Martin H et al. (2020) SARS-CoV-2 positivity rates associated with circulating 25-hydroxyvitamin D levels. PloS one 15(9): e0239252 [PMC free article: PMC7498100] [PubMed: 32941512]
Macaya, Fernando, Espejo Paeres, Carolina, Valls, Adrian et al. (2020) Interaction between age and vitamin D deficiency in severe COVID-19 infection. Nutricion hospitalaria 37(5): 1039–1042 [PubMed: 32960622]
Meltzer, David O, Best, Thomas J, Zhang, Hui et al. (2020) Association of Vitamin D Status and Other Clinical Characteristics With COVID-19 Test Results. JAMA network open 3(9): e2019722 [PMC free article: PMC7489852] [PubMed: 32880651]
Merzon, Eugene, Tworowski, Dmitry, Gorohovski, Alessandro et al. (2020) Low plasma 25(OH) vitamin D level is associated with increased risk of COVID-19 infection: an Israeli population-based study. The FEBS journal [PMC free article: PMC7404739] [PubMed: 32700398]
Radujkovic, Aleksandar, Hippchen, Theresa, Tiwari-Heckler, Shilpa et al. (2020) Vitamin D Deficiency and Outcome of COVID-19 Patients. Nutrients 12(9) [PMC free article: PMC7551780] [PubMed: 32927735]
Raisi-Estabragh, Zahra, McCracken, Celeste, Bethell, Mae S et al. (2020) Greater risk of severe COVID-19 in Black, Asian and Minority Ethnic populations is not explained by cardiometabolic, socioeconomic or behavioural factors, or by 25(OH)-vitamin D status: study of 1326 cases from the UK Biobank. Journal of public health (Oxford, England) 42(3): 451–460 [PMC free article: PMC7449237] [PubMed: 32556213]
Ye, Kun, Tang, Fen, Liao, Xin et al. (2020) Does Serum Vitamin D Level Affect COVID-19 Infection and Its Severity?-A Case-Control Study. Journal of the American College of Nutrition: 1–8 [PubMed: 33048028]

1.3.9.3. Other

Hastie, C.E., Mackay, D.F., Ho, F. et al. (2020) Corrigendum to “Vitamin D concentrations and COVID-19 infection in UK Biobank” [Diabetes Metabol Syndr: Clin Res Rev 2020 14 (4) 561–5] (Diabetes & Metabolic Syndrome: Clinical Research & Reviews (2020) 14(4) (561–565), (S1871402120301156), (10.1016/j.dsx.2020.04.050)). Diabetes and Metabolic Syndrome: Clinical Research and Reviews 14(5): 1315–1316 [PMC free article: PMC7377702] [PubMed: 32755828]

1.3.9.4. Pre-prints

Abu Z M Dayem, Ullah, Lavanya, Sivapalan, Claude, Chelala et al. COVID-19 in patients with hepatobiliary and pancreatic diseases in East London: A single-centre cohort study.
Aduragbemi A, Faniyi, Sebastian T, Lugg, Sian E, Faustini et al. Vitamin D status and seroconversion for COVID-19 in UK healthcare workers who isolated for COVID-19 like symptoms during the 2020 pandemic.
Ariel, Israel, Assi Albert, Cicurel, Ilan, Feldhamer et al. The link between vitamin D deficiency and Covid-19 in a large population.
Chang, Timothy S, Ding, Yi, Freund, Malika K et al. (2020) Prior diagnoses and medications as risk factors for COVID-19 in a Los Angeles Health System. medRxiv : the preprint server for health sciences
Claire E, Hastie; Jill P, Pell; Naveed, Sattar Short Communication: Vitamin D and COVID-19 infection and mortality in UK Biobank. [PMC free article: PMC7449523] [PubMed: 32851419]
Grigorios, Panagiotou, Su Ann, Tee, Yasir, Ihsan et al. Low serum 25-hydroxyvitamin D (25D) levels in patients hospitalised with COVID-19 are associated with greater disease severity: results of a local audit of practice.
Isaac Z, Pugach and Sofya, Pugach Strong Correlation Between Prevalence of Severe Vitamin D Deficiency and Population Mortality Rate from COVID-19 in Europe. [PMC free article: PMC7957444] [PubMed: 33721102]
Jie, Chen, Lixia, Xie, Xing, Yuan et al. Low serum vitamin D level and COVID-19 infection and outcomes, a multivariate meta-analysis.
Li, Mengyuan, Zhang, Zhilan, Cao, Wenxiu et al. (2020) Identifying novel factors associated with COVID-19 transmission and fatality using the machine learning approach. The Science of the total environment: 142810 [PMC free article: PMC7550892] [PubMed: 33097268]
Li X, van Geffen J, van Weele M et al. (2020) Genetically-predicted vitamin D status, ambient UVB during the pandemic and COVID-19 risk in UK Biobank: Mendelian Randomisation study.
Mendy, Angelico, Apewokin, Senu, Wells, Anjanette A et al. (2020) Factors Associated with Hospitalization and Disease Severity in a Racially and Ethnically Diverse Population of COVID-19 Patients. medRxiv: the preprint server for health sciences
Panagiotou, G., Tee, S.A., Ihsan, Y. et al. (2020) Original publication: Low serum 25-hydroxyvitamin D (25[OH]D) levels in patients hospitalized with COVID-19 are associated with greater disease severity. Clinical Endocrinology [PubMed: 32780518]
Raharusun, Prabowo, Priambada, Sadiah, Budiarti, Cahni et al. (2020) Patterns of COVID-19 Mortality and Vitamin D: An Indonesian Study.

Appendices

Appendix A. Review protocols

Appendix B. Literature search strategies

Deduplication against the previous review was used to draw out any new references, rather than date limiting in any individual source.

Medline ALL

Search looked at 2002 to October 27th 2020

exp Vitamin D/ (59709)
exp Vitamin D Deficiency/ (28155)
((vitamin* adj5 D*2) or vitaminD*2).af. (99557)
(ergocalciferol* or calciferol* or vs041h42xc or dihydrotachysterol* or dihydrotachysterin* or calcamine or 67-96-9 or r5lm3h112r or Hydroxyvitamin D*2 or 25Hydroxyvitamin D*2 or HydroxyvitaminD*2 or 25HydroxyvitaminD*2 or hydroxycalciferol* or 25hydroxycalciferol* or hydroxyergocalciferol* or 25hydroxyergocalciferol* or ercalcidiol or “25(OH)D” or 21343-40-8 or alfacalcidol*).af. (24782)
(cholecalciferol* or colecalciferol* or calciol or 67-97-0 or 1c6v77qf41 or hydroxycholecalciferol* or hydroxycolecalciferol* or 25hydroxycholecalciferol* or 25hydroxycolecalciferol* or calcifediol* or calcidiol* or “19356-17-3” or p6yz13c99q or t0wxw8f54e or dihydroxycholecalciferol* or dihydroxycolecalciferol* or 25dihydroxycholecalciferol* or 25dihydroxycolecalciferol* or dihydroxyvitamin D*2 or 25dihydroxyvitamin* or dihydroxyvitaminD*2 or calcitriol* or 32222-06-3 or 40013-87-4 or 55721-11-4).af. (38720)
or/1–5 (120807)
exp coronavirus/ (39116)
exp Coronavirus Infections/ (42273)
((corona* or corono*) adj1 (virus* or viral* or virinae*)).ti,ab,kw,kf. (2176)
(coronavirus* or coronovirus* or coronavirinae* or CoV or HCoV* or Betacoronavirus* or Betacoronovirus*).ti,ab,kw,kf. (49098)
(“2019-nCoV*” or 2019nCoV* or “19-nCoV*” or 19nCoV* or nCoV2019* or “nCoV-2019*” or nCoV19* or “nCoV-19*” or “COVID-19*” or COVID19* or “COVID-2019*” or COVID2019* or “HCoV-19*” or HCoV19* or “HCoV-2019*” or HCoV2019* or “2019 novel*” or Ncov* or “n-cov” or “SARS-CoV-2*” or “SARSCoV-2*” or “SARSCoV2*” or “SARS-CoV2*” or SARSCov19* or “SARS-Cov19*” or “SARSCov-19*” or “SARS-Cov-19*” or SARSCov2019* or “SARS-Cov2019*” or “SARSCov-2019*” or “SARS-Cov-2019*” or SARS2* or “SARS-2*” or SARScoronavirus2* or “SARS-coronavirus-2*” or “SARScoronavirus 2*” or “SARS coronavirus2*” or SARScoronovirus2* or “SARS-coronovirus-2*” or “SARScoronovirus 2*” or “SARS coronovirus2*” or covid).ti,ab,kw,kf. (65326)
(respiratory* adj2 (symptom* or disease* or illness* or condition*) adj5 (Wuhan* or Hubei* or China* or Chinese* or Huanan*)).ti,ab,kw,kf. (301)
((“seafood market*” or “food market*”) adj10 (Wuhan* or Hubei* or China* or Chinese* or Huanan*)).ti,ab,kw,kf. (85)
(pneumonia* adj3 (Wuhan* or Hubei* or China* or Chinese* or Huanan*)).ti,ab,kw,kf. (527)
((outbreak* or wildlife* or pandemic* or epidemic*) adj1 (Wuhan* or Hubei* or China* or Chinese* or Huanan*)).ti,ab,kw,kf. (316)
Middle East Respiratory Syndrome Coronavirus/ (1371)
(“middle east respiratory syndrome*” or “middle eastern respiratory syndrome*” or MERSCoV* or “MERS-CoV*” or MERS).ti,ab,kw,kf. (5948)
(“severe acute respiratory syndrome*” or SARS).ti,ab,kw,kf. (32888)
(“SARS-CoV-1*” or “SARSCoV-1*” or “SARSCoV1*” or “SARS-CoV1*” or SARSCoV or “SARS-CoV” or SARS1* or “SARS-1*” or SARScoronavirus1* or “SARS-coronavirus-1*” or “SARScoronavirus 1*” or “SARS coronavirus1*” or SARScoronovirus1* or “SARS-coronovirus-1*” or “SARScoronovirus 1*” or “SARS coronovirus1*”).ti,ab,kw,kf. (23577)
or/7–19 (95256)
6 and 20 (290)
21 (290)
limit 22 to (english language and yr=“2002 -Current”) (288)
animals/ not (humans/ and animals/) (4716381)
23 not 24 (283)

Embase

2002 to October 27th 2020

exp vitamin D/ (144538)
vitamin D deficiency/ (30650)
((vitamin* adj5 D*2) or vitaminD*2).af. (152453)
(ergocalciferol* or calciferol* or vs041h42xc or dihydrotachysterol* or dihydrotachysterin* or calcamine or 67-96-9 or r5lm3h112r or Hydroxyvitamin D*2 or 25Hydroxyvitamin D*2 or HydroxyvitaminD*2 or 25HydroxyvitaminD*2 or hydroxycalciferol* or 25hydroxycalciferol* or hydroxyergocalciferol* or 25hydroxyergocalciferol* or ercalcidiol or “25(OH)D” or 21343-40-8 or alfacalcidol*).af. (46690)
(cholecalciferol* or colecalciferol* or calciol or 67-97-0 or 1c6v77qf41 or hydroxycholecalciferol* or hydroxycolecalciferol* or 25hydroxycholecalciferol* or 25hydroxycolecalciferol* or calcifediol* or calcidiol* or “19356-17-3” or p6yz13c99q or t0wxw8f54e or dihydroxycholecalciferol* or dihydroxycolecalciferol* or 25dihydroxycholecalciferol* or 25dihydroxycolecalciferol* or dihydroxyvitamin D*2 or 25dihydroxyvitamin* or dihydroxyvitaminD*2 or calcitriol* or 32222-06-3 or 40013-87-4 or 55721-11-4).af. (62783)
or/1–5 (184996)
exp Coronavirinae/ (20645)
exp Coronavirus infection/ (22005)
(“coronavirus disease 2019” or “severe acute respiratory syndrome coronavirus 2”).sh,dj. (59354)
((corona* or corono*) adj1 (virus* or viral* or virinae*)).ti,ab,kw. (1675)
(coronavirus* or coronovirus* or coronavirinae* or CoV or HCoV* or Betacoronavirus* or Betacoronovirus*).ti,ab,kw. (49400)
(“2019-nCoV*” or 2019nCoV* or “19-nCoV*” or 19nCoV* or nCoV2019* or “nCoV-2019*” or nCoV19* or “nCoV-19*” or “COVID-19*” or COVID19* or “COVID-2019*” or COVID2019* or “HCoV-19*” or HCoV19* or “HCoV-2019*” or HCoV2019* or “2019 novel*” or Ncov* or “n-cov” or “SARS-CoV-2*” or “SARSCoV-2*” or “SARSCoV2*” or “SARS-CoV2*” or SARSCov19* or “SARS-Cov19*” or “SARSCov-19*” or “SARS-Cov-19*” or SARSCov2019* or “SARS-Cov2019*” or “SARSCov-2019*” or “SARS-Cov-2019*” or SARS2* or “SARS-2*” or SARScoronavirus2* or “SARS-coronavirus-2*” or “SARScoronavirus 2*” or “SARS coronavirus2*” or SARScoronovirus2* or “SARS-coronovirus-2*” or “SARScoronovirus 2*” or “SARS coronovirus2*” or covid).ti,ab,kw. (62449)
(respiratory* adj2 (symptom* or disease* or illness* or condition*) adj5 (Wuhan* or Hubei* or China* or Chinese* or Huanan*)).ti,ab,kw. (372)
((“seafood market*” or “food market*”) adj10 (Wuhan* or Hubei* or China* or Chinese* or Huanan*)).ti,ab,kw. (93)
(pneumonia* adj3 (Wuhan* or Hubei* or China* or Chinese* or Huanan*)).ti,ab,kw. (583)
((outbreak* or wildlife* or pandemic* or epidemic*) adj1 (Wuhan* or Hubei* or China* or Chinese* or Huanan*)).ti,ab,kw. (146)
Middle East respiratory syndrome/ (1633)
(“middle east respiratory syndrome*” or “middle eastern respiratory syndrome*” or MERSCoV* or “MERS-CoV*” or MERS).ti,ab,kw. (6425)
(“severe acute respiratory syndrome*” or SARS).ti,ab,kw. (32952)
(“SARS-CoV-1*” or “SARSCoV-1*” or “SARSCoV1*” or “SARS-CoV1*” or SARSCoV or “SARS-CoV” or SARS1* or “SARS-1*” or SARScoronavirus1* or “SARS-coronavirus-1*” or “SARScoronavirus 1*” or “SARS coronavirus1*” or SARScoronovirus1* or “SARS-coronovirus-1*” or “SARScoronovirus 1*” or “SARS coronovirus1*”).ti,ab,kw. (22626)
or/7–20 (99755)
limit 21 to medline (25815)
21 not 22 (73940)
6 and 23 (413)
nonhuman/ not (human/ and nonhuman/) (4724889)
24 not 25 (398)
limit 26 to (english language and yr=“2002 -Current”) (388)

Cochrane Database of Systematic Reviews (CDSR) & CENTRAL

Issue 10 of 12, 2020

ID Search

#1.: MeSH descriptor: [Vitamin D] explode all trees
#2.: MeSH descriptor: [Vitamin D Deficiency] explode all trees
#3.: ((vitamin* near/5 D*) or vitaminD*)
#4.: (ergocalciferol* or calciferol* or vs041h42xc or dihydrotachysterol* or dihydrotachysterin* or calcamine or “67-96-9” or “r5lm3h112r” or “Hydroxyvitamin D*” or “25Hydroxyvitamin D*” or “HydroxyvitaminD*” or “25HydroxyvitaminD*” or hydroxycalciferol* or 25hydroxycalciferol* or hydroxyergocalciferol* or 25hydroxyergocalciferol* or ercalcidiol or “25(OH)D” or “21343-40-8” or alfacalcidol*)
#5.: (cholecalciferol* or colecalciferol* or calciol or “67-97-0” or 1c6v77qf41 or hydroxycholecalciferol* or hydroxycolecalciferol* or 25hydroxycholecalciferol* or 25hydroxycolecalciferol* or calcifediol* or calcidiol* or “19356-17-3” or p6yz13c99q or t0wxw8f54e or dihydroxycholecalciferol* or dihydroxycolecalciferol* or 25dihydroxycholecalciferol* or 25dihydroxycolecalciferol* or dihydroxyvitamin D* or 25dihydroxyvitamin* or dihydroxyvitaminD* or calcitriol* or “32222-06-3” or “40013-87-4” or “55721-11-4”)
#6.: #1 or #2 or #3 or #4 or #5
#7.: MeSH descriptor: [Coronavirus] explode all trees
#8.: MeSH descriptor: [Coronavirus Infections] explode all trees
#9.: ((corona* or corono*) near/1 (virus* or viral* or virinae*)):ti,ab,kw
#10.: (coronavirus* or coronovirus* or coronavirinae* or CoV or HCoV* or Betacoronavirus* or Betacoronovirus*):ti,ab,kw
#11.: (“2019 nCoV” or 2019nCoV* or “19 nCoV” or 19nCoV* or nCoV2019* or “nCoV 2019” or nCoV19* or “nCoV 19” or “COVID 19” or COVID19* or “COVID 2019” or COVID2019* or “HCoV 19” or HCoV19* or “HCoV 2019” or HCoV2019* or “2019 novel” or Ncov* or “n cov” or “SARS CoV 2” or “SARSCoV 2” or “SARSCoV2” or “SARS CoV2” or SARSCov19* or “SARS Cov19” or “SARSCov 19” or “SARS Cov 19” or SARSCov2019* or “SARS Cov2019” or “SARSCov 2019” or “SARS Cov 2019” or SARS2* or “SARS 2” or SARScoronavirus2* or “SARS coronavirus 2” or “SARScoronavirus 2” or “SARS coronavirus2” or SARScoronovirus2* or “SARS coronovirus 2” or “SARScoronovirus 2” or “SARS coronovirus2” or covid):ti,ab,kw
#12.: (respiratory* near/2 (symptom* or disease* or illness* or condition*) near/5 (Wuhan* or Hubei* or China* or Chinese* or Huanan*)):ti,ab,kw
#13.: ((“seafood market” or “seafood markets” or “food market” or “food markets”) near/10 (Wuhan* or Hubei* or China* or Chinese* or Huanan*)):ti,ab,kw
#14.: (pneumonia* near/3 (Wuhan* or Hubei* or China* or Chinese* or Huanan*)):ti,ab,kw
#15.: ((outbreak* or wildlife* or pandemic* or epidemic*) near/1 (Wuhan* or Hubei* or China* or Chinese* or Huanan*)):ti,ab,kw
#16.: MeSH descriptor: [Middle East Respiratory Syndrome Coronavirus] explode all trees
#17.: (“middle east respiratory syndrome” or “middle eastern respiratory syndrome” or “middle east respiratory syndromes” or “middle eastern respiratory syndromes” or MERSCoV* or “MERS CoV” or MERS):ti,ab,kw
#18.: (“severe acute respiratory syndrome” or “severe acute respiratory syndromes” or SARS):ti,ab,kw
#19.: (“SARS CoV 1” or “SARSCoV 1” or “SARSCoV1” or “SARS CoV1” or SARSCoV or SARS CoV or SARS1 or “SARS 1” or SARScoronavirus1 or “SARS coronavirus 1” or “SARScoronavirus 1” or “SARS coronavirus1” or SARScoronovirus1 or “SARS coronovirus 1” or “SARScoronovirus 1” or “SARS coronovirus1”):ti,ab,kw
#20.: {or #7–#19}
#21.: #6 and #20
#22.: (clinicaltrials or trialsearch):so
#23.: #21 not #22

MedRxiv & BioRxiv preprints

This database comprises a full copy of the medRxiv and bioRxiv Covid-19/SARS-CoV-2 collection, which was downloaded via a custom feed. The EPPI database feed was run at 8am on the 23^rd October 2020 before being sifted for relevance to the vitamin D topic. We did not use the native interface in MedRxiv or BioRxiv due to problems with the search functionality and data extraction options.

1 additional result was identified by searching for references from the medRxiv and bioRxiv Covid-19/SARS-CoV-2 collection that had appeared in our custom feed between 8am on the 23^rd October and 10am on the 29^th October 2020. This set of references have not previously been assessed by NICE for relevance to the vitamin D topic. The following terms were searched for in the title and abstract fields of these records in EPPI reviewer: vitamin; hydroxyvitamin; dihydroxyvitamin, ergocalciferol; calciferol; cholecalciferol; colecalciferol (combined with the Boolean ‘OR’).

Note that EPPI Reviewer 5 automatically truncates search terms.

World Health Organization Global research on coronavirus disease (COVID-19)

Search conducted 29/10/2020.

tw:(“vitamin D” OR “vitamin D1” OR “vitamin D2” OR “vitamin D3” OR “vitamin D4” OR “vitamin D5” OR hydroxyvitamin OR dihydroxyvitamin OR ergocalciferol OR calciferol OR cholecalciferol OR colecalciferol)

348 results

Clinicaltrials.gov

Search conducted 29/10/2020.

Condition: covid OR ncov OR 2019nCoV OR covid19 OR SARS OR (Severe Acute Respiratory Syndrome) OR Coronavirus OR corona OR orthocoronavirinae OR MERS OR (middle respiratory syndrome)

Other terms: (Vitamin (d OR d1 OR d2 OR d3 OR d4 OR d5)) OR hydroxyvitamin OR dihydroxyvitamin OR ergocalciferol OR calciferol OR cholecalciferol OR colecalciferol

Appendix C. Effectiveness & association evidence study selection

C.1.1. Review question 1

Figure 1. Review question 1

C.1.2. Review question 2

Figure 2. Review question 2

C.1.3. Review question 3

Figure 3. Review question 3

Appendix D. Effectiveness & association evidence

D.1. Effectiveness evidence

D.1.1. Vitamin D as treatment

D.1.1.1. Entrenas Castillo 2020 (PDF, 254K)

D.2. Association evidence

D.2.1.1. Annweiler 2020 (PDF, 238K)

D.2.1.2. Annweiler 2020a (PDF, 261K)

D.2.1.3. Hastie 2020 (PDF, 259K)

D.2.1.4. Hernandez 2020 (PDF, 312K)

D.2.1.5. Karahan 2020 (PDF, 254K)

D.2.1.6. Kaufman 2020 (PDF, 201K)

D.2.1.7. Macaya 2020 (PDF, 247K)

D.2.1.8. Meltzer 2020 (PDF, 323K)

D.2.1.9. Merzon 2020 (PDF, 206K)

D.2.1.10. Radujkovic 2020 (PDF, 280K)

D.2.1.11. Raisi-Estabragh 2020 (PDF, 221K)

D.2.1.12. Ye 2020 (PDF, 243K)

Appendix E. GRADE tables

E.1.1. Effectiveness of vitamin D as a COVID-19 treatment

E.1.1.1. Effectiveness of vitamin D supplement as treatment for COVID-19

Quality assessment							Number of participants		Effect		Quality
No of studies	Design	Risk of bias	Inconsistency	Indirectness	Imprecision	Other considerations	Intervention	Control	Univariate 95%CI	Multivariable 95%CI	Quality
Odds ratio: ICU admission (follow-up: 2 months or until death; Better indicated by lower values)
1¹	randomised trial	very serious²	no serious inconsistency	no serious indirectness	no serious imprecision	low number of participants	50	26	OR 0.02 (0.002 to 0.17)	Adj OR 0.03³ (0.003 to 0.25)	VERY LOW
Odds ratio: mortality (follow-up: 2 months; Better indicated by lower values)
1¹	randomised trial	very serious²	no serious inconsistency	no serious indirectness	no serious imprecision	low number of participants	50	26	OR 0.097⁴ (0.004 to 2.99)	-	VERY LOW

1: Entrenas Castillo 2020
2: Downgraded by 2 levels: Reported outcome, mortality, not analysed in multivariable analysis. Only ICU was reported in this way, even though they are both listed on the clinical trials register as outcomes. Adjustment for multivariable analysis not fully explored or reported, only hypertension and diabetes are reported as definitively included in the model but does include “others”.
3: Diabetes and hypertension were unbalanced after randomisation so were adjusted for in multivariable analysis.
4: No events in intervention arm. 2 events in control arm. NICE-calculated OR.

E.1.2. Effectiveness of vitamin as a COVID-19 preventative measure

No evidence found

E.1.3. Association between vitamin D status and COVID-19 outcomes

E.1.3.1. Association between vitamin D status and COVID-19 cases

Quality assessment							Effect		Quality
No of studies	Design N	Risk of bias	Inconsistency	Indirectness	Imprecision	Other considerations	Univariate 95%CI	Multivariable 95%CI	Quality
Vitamin D status definition: Vitamin D level (nmol/L)
1¹	Case control Cases n=449 Control n=348,598	Very serious¹⁵	no serious inconsistency	very serious indirectness¹³	no serious imprecision	none	OR 0.99 (0.99 to 0.999)	Adj OR 1.00² (0.998 to 1.01)	VERY LOW
1³	Case control Cases n=1326 Control n=3184	Very serious¹⁵	no serious inconsistency	serious indirectness¹³	no serious imprecision	none	OR 1 (0.99 to 1)	Adj OR 1⁴ (1 to 1)	VERY LOW
Vitamin D status definition: Vitamin D level (ng/ml)
1⁵	Case control Cases n=197 Control n=197	Serious¹⁶	no serious inconsistency	No serious indirectness⁶	Very serious imprecision⁷	none	_	Mean difference⁸ Case=11.9 ng/ml Control=21.2 ng/ml MD= −9.3 ng/ml (p<0.0001)	VERY LOW
1⁹	Cohort N=191,779 Unclear no. of positive cases	Very serious¹⁵	no serious inconsistency	Very serious indirectness¹⁰	no serious imprecision	none	_	Adj OR 0.984¹¹ (0.983 to 0.986)	VERY LOW
Vitamin D status definition: Vitamin D level (nmol/L)*Ethnicity interaction term¹⁹
1¹	Case control Cases n=449 Control n=348,598	Very serious¹⁵	no serious inconsistency	serious indirectness²	no serious imprecision	none	_	Adj OR 0.90² (0.66 to 1.23)	VERY LOW
Vitamin D status definition: Vitamin D deficient (<25 nmol/L)
1¹	Case control Cases n=449 Control n=348,598	Very serious¹⁵	no serious inconsistency	serious indirectness¹³	no serious imprecision	none	OR 1.37 (1.07 to 1.76)	Adj OR 0.92² (0.71 to 1.21)	VERY LOW
Vitamin D status definition: Vitamin D insufficient (<50 nmol/L)
1¹	Case control Cases n=449 Control n=348,598	Very serious¹⁵	no serious inconsistency	serious indirectness¹³	no serious imprecision	none	OR 1.19 (0.99 to 1.44)	Adj OR 0.88² (0.72 to 1.08)	VERY LOW
Vitamin D status definition: Vitamin D deficient (<20 ng/mL)
1¹²	Cohort Positive n=71 Negative n=418	Serious¹⁶	no serious inconsistency	serious indirectness²⁰	no serious imprecision	none	_	Adj OR 1.77¹⁴ (1.12 to 2.81)	VERY LOW
Vitamin D status definition: Vitamin D suboptimal (<30 ng/mL)
1¹⁷	Case control Cases n=782 Control n=7025	serious¹⁶	no serious inconsistency	serious indirectness²⁰	no serious imprecision	none	OR 1.58 (1.24 to 2.01)	Adj OR 1.5¹⁸ (1.13 to 1.98)	VERY LOW

1: Hastie 2020
2: Adjusted for ethnicity, sex, month of assessment, Townsend deprivation quintile, household income, self-reported health rating, smoking status, BMI category, age at assessment, diabetes, SBP, DBP, and long-standing illness, disability or infirmity.
3: Raisi-Esrabragh 2020
4: Adjusted for sex, age and ethnicity.
5: Hernandez 2020
6: No downgrade as the historical control is in 2019, assuming population profiles have not changed since.
7: Downgrade 2 levels: small sample size assessed against [n = 100+50i], where i = number of independent variables adjusted.
8: Adjusted for age, smoking, hypertension, diabetes mellitus, history of cardiovascular events, immunosuppression, body mass index, serum corrected calcium, glomerular filtration rate and the month of vitamin D determination.
9: Kaufman 2020
10: Downgrade 2 levels: Vitamin status data was historical (preceding 12 months) where vitamin level may have changed before SAR-CoV-2 testing. Also, the outcome is SAR-CoV-2 positive, not COVID-19 (unclear proportion of asymptomatic positive cases).
11: Adjusted for gender, age, latitudes, ethnicity.
12: Meltzer 2020
13: Downgrade 2 level: Vitamin D status and demographic data are over a decade old.
14: Adjusted for hypertension, diabetes, chronic pulmonary disease, pulmonary circulation disorders, depression, immunosuppression, liver disease, and chronic kidney disease.
15: Downgrade 2 levels: high risk of bias assessed by QUIPS checklist.
16: Downgrade 1 level: moderate risk of bias assessed by QUIPS checklist.
17: Merzon 2020
18: Adjusted for multiple conditions and demographic variables.
19: This means to explore whether Ethnicity is an effect moderator of vitamin D level which impacts on its association with COVID-19 cases. The non-significant result suggested ethnicity has no interaction with vitamin D level and its association with COVID-19 cases.
20: Downgrade 1 level: Vitamin D status are historical.

E.1.3.2. Association between vitamin D status and severity of COVID-19

Quality assessment							Effect		Quality
No of studies	Design N	Risk of bias	Inconsistency	Indirectness	Imprecision	Other considerations	Univariate 95%CI	Multivariable 95%CI	Quality
Vitamin D status definition: Vitamin D level (nmol/L) Severity definition: composite severity endpoint (admission to the intensive care unit (ICU), requirement for mechanical ventilation, or in-hospital mortality)
1¹	Case series² n=197	Very serious¹³	no serious inconsistency	no serious indirectness	very serious imprecision³	none	OR 1.55 (0.66 to 3.65)	Adj OR 1.13⁴ (0.27 to 4.77)	VERY LOW
Vitamin D status definition: Vitamin D suboptimal (<12 ng/ml) Severity definition: composite endpoint including mechanical ventilation and death
1⁵	Cohort n=185	Serious²⁰	no serious inconsistency	no serious indirectness	very serious imprecision³	none	HR 7.66 (3.53 to 16.63)	Adj HR 6.12⁶ (2.79 to 13.42)	VERY LOW
Vitamin D status definition: Vitamin D deficiency (<50 nmol/L) Severity definition: severe/critical cases defined as having one of the following: breathing rate >30/min, O² saturation ≤93% at rest, PaO2/FiO2 ≤mmHg or lung imaging shows significant progression, respiratory failure (PaO² <60mmHg), shock, organ failures that requires ICU care
1⁷	Case control COVID-19 positive n=60	Very serious¹³	no serious inconsistency	no serious indirectness	very serious imprecision³	none	OR 7.11 (1.36 to 37.16)	Adj OR 15.18⁸ (1.23 to 187.45)	VERY LOW
Vitamin D status definition: Vitamin D level (ng/mL) Severity definition (univariate): Moderate – fever and pulmonary symptoms with pneumonia. Severe-Critical – respiratory distress, O² saturation ≤93% at rest, PaO2/FiO2 ≤mmHg or chest imaging shows lesion, respiratory failure (mechanical ventilation), shock, organ failures that requires ICU care Severity definition (multivariable): Mortality
1⁹	Cohort n=149	Serious²⁰	no serious inconsistency	serious indirectness²⁴	very serious imprecision⁷	none	Mean difference (SD) Moderate = 26.3 (8.4) Severe-Critical = 10.1 (6.2) MD = −16.2 (−18.6 to −13.8)	Adj OR 0.92¹⁰ (0.88 to 0.98)	VERY LOW
Vitamin D status definition: Vitamin D deficiency as <20 ng/mL Severity definition: composite outcome defining severity of COVID-19 included death, admission to ICU, and/or need for higher oxygen flow than that provided by a nasal cannula.
1¹¹	Case series n=80	Very serious¹³	no serious inconsistency	no serious indirectness	very serious imprecision³	none	_	Adj OR 3.2¹² (0.9 to 11.4)	VERY LOW
Vitamin D status definition: vitamin D sufficient if received a vitamin D booster supplement within a month of COVID-19 diagnosis. Severity definition: mortality, follow-up up to 2 months.
1¹⁴	Cohort n=66	Very serious¹³	no serious inconsistency	serious indirectness²⁵	very serious imprecision³	none	HR 0.21 (0.07 to 0.63)	Adj HR 0.11¹⁵ (0.03 to 0.48)	VERY LOW
Vitamin D status definition: vitamin D sufficient if received vitamin D supplements for a year before COVID-19 diagnosis Severity definition: 14-day COVID-19 mortality
1¹⁶	Cohort n=77	Very serious¹³	no serious inconsistency	no serious indirectness	very serious imprecision³	none	_	Adj HR 0.07¹⁷ (0.01 to 0.61)	VERY LOW
Vitamin D status definition: vitamin D sufficient if received vitamin D supplement when diagnosed with COVID-19 Severity definition: 14-day COVID-19 mortality
1¹⁶	Cohort n=77	Very serious¹³	no serious inconsistency	no serious indirectness	very serious imprecision³	none	_	Adj HR 0.37¹⁷ (0.06 to 2.21)	VERY LOW
Vitamin D status definition: vitamin D sufficient if received vitamin D supplements for a year before COVID-19 diagnosis Severity definition: Severe COVID-19 – OSCI score ≥ 5
1¹⁶	Cohort n=77	Very serious¹³	no serious inconsistency	no serious indirectness	very serious imprecision³	none	_	Adj OR 0.08¹⁷ (0.01 to 0.81)	VERY LOW
Vitamin D status definition: vitamin D sufficient if received vitamin D supplement when diagnosed with COVID-19 Severity definition: Severe COVID-19 – OSCI score ≥ 5
1¹⁶	Cohort n=77	Very serious¹³	no serious inconsistency	no serious indirectness	very serious imprecision³	none	_	Adj OR 0.46¹⁷ (0.07 to 2.85)	VERY LOW
Vitamin D status definition: Vitamin D suboptimal (<30 ng/mL) Severity definition: hospitalisation for COVID-19 symptoms
1¹⁸	Case control n=7807	Serious²⁰	no serious inconsistency	serious indirectness¹⁹	no serious imprecision	none	OR 2.09 (1.01 to 4.31)	Adj OR 1.95²¹ (0.99 to 4.78)	LOW
Vitamin D status definition: Vitamin D suboptimal (<12 nmol/L) Severity definition: mortality
1²²	Cohort n=185	Serious²⁰	no serious inconsistency	no serious indirectness	very serious imprecision³	none	HR 18.05 (5.14 to 63.43)	Adj HR 14.73²³ (4.16 to 52.19)	VERY LOW

1: Hernandez 2020
2: This is sub-analysis of cases only from Hernandez 2020.
3: Downgrade 2 levels: very small sample size assessed against [n = 100+50i], where i = number of independent variables adjusted.
4: Adjusted for age, smoking, hypertension, diabetes mellitus, history of cardiovascular events, immunosuppression, body mass index, serum corrected calcium, glomerular filtration rate and the month of vitamin D determination.
5: Radujkovic 2020
6: Adjusted for age, gender and comorbidities. Includes values for whole cohort not for inpatients only.
7: Ye 2020 – values presented in GRADE table are compared with mild/moderate cases.
8: Adjusted for age, sex and comorbidities.
9: Karahan 2020 – Cohort of COVID-19 positive patients with moderate or severe/critical condition.
10: Adjusted for age, smoking, hyperlipidaemia, diabetes mellitus, chronic kidney disease, chronic atrial fibrillation, congestive heart failure, acute kidney injury, eGFR, haemoglobin, neutrophil count.
11: Macaya 2020
12: Adjusted for age, gender, obesity, severe CKD, cardiac disease.
13: Downgrade 2 levels: high risk of bias assessed by QUIPS checklist.
14: Annweiler 2020
15: Adjusted for age, gender, number of drugs daily taken, functional abilities, nutritional status, COVID-19 treatment with corticosteroids and/or hydroxychloroquine and/or dedicated antibiotics, and hospitalization for COVID-19.
16: Annweiler 2020a
17: Compared with non-supplemented group diagnosed with COVID-19. Adjusted for age, gender, GIR score, severe undernutrition, history of cancer, history of hypertension, history of cardiomyopathy, glycated haemoglobin, number of acute health problems, use of antibiotics, use of systemic corticosteroids, use of treatments of respiratory disorders.
18: Merzon 2020
19: Historic vitamin D values used for association.
20: Downgrade 1 level: moderate risk of bias assessed by QUIPS checklist.
21: Adjusted for multiple conditions and demographic variables.
22: Radujkovic 2020
23: Adjusted for age, gender, comorbidity.
24: Downgrade 1 level: People with mild severity of COVID-19 were purposely excluded.
25: Downgraded 1 level: vitamin dosing occurs before and after infection diagnosis causing problems with temporal separation of events.

Appendix F. Ongoing studies (clinicaltrials.gov)

Search date: 29/10/2020

F.1.1. Prevention

F.1.1.1. As monotherapy

Double-blind randomized design comparing 1000 I.U. vitamin D versus matched placebo in healthy young adults. (Reducing Asymptomatic Infection With Vitamin D in Coronavirus Disease).

https://ClinicalTrials.gov/show/NCT04476680

Parallel-group, placebo-controlled trial of vitamin D3 supplementation for the Prevention of COVID-19 With Oral Vitamin D Supplemental Therapy in Essential healthcare Teams (PROTECT).

https://ClinicalTrials.gov/show/NCT04483635

A multicenter randomized double-blinded placebo-controlled clinical trial with parallel groups design to investigate the Preventive and Therapeutic Effects of Oral 25-hydroxyvitamin D3 on Coronavirus (COVID-19) in Adults.

https://ClinicalTrials.gov/show/NCT04386850

Blinded randomized clinical trial on the efficacy of Vitamin D Supplementation to Prevent the Risk of Acquiring or Evolving Into the Severe Form of COVID-19 in Healthcare Workers Caring for Patients With the Disease.

https://ClinicalTrials.gov/show/NCT04535791

Phase 3 Randomised Controlled Trial of Vitamin D Supplementation to Reduce Risk and Severity of COVID-19 and Other Acute Respiratory Infections in the UK Population

https://ClinicalTrials.gov/show/NCT04579640

F.1.1.2. As combination therapy

Open-label RCT of vitamin D3 2000 IU (50 μg) plus 30 mg of zinc gluconate per day for 2 months versus usual care in adults >60 years who are ‘institutionalised’ but asymptomatic. Incidence of COVID-19 infection is a secondary outcome (Seguy D. Impact of Zinc and Vitamin D3 Supplementation on the Survival of Aged Patients Infected With COVID-19 (ZnD3-CoVici)

https://clinicaltrials.gov/ct2/show/NCT04351490

Single group open-label study of a combination of hydroxychloroquine, vitamins C and D (form not specified), and zinc as prophylaxis in healthy healthcare workers who are at risk of COVID-19 (Haza S. A Study of Hydroxychloroquine, Vitamin C, Vitamin D, and Zinc for the Prevention of COVID-19 Infection (HELPCOVID-19)

https://clinicaltrials.gov/ct2/show/record/NCT04335084

Open label RCT investigating interventions to prevent progression of COVID-19. Interventions include hydroxychloroquine, azithromycin, zinc, vitamin D, vitamin B12 with or without vitamin C. (International ALLIANCE Study of Therapies to Prevent Progression of COVID-19)

https://clinicaltrials.gov/ct2/show/NCT04395768

A Randomized, Double-Blind, Placebo-Controlled Phase IIa Study of Hydroxychloroquine, Vitamin C, Vitamin D, and Zinc for the Prevention of COVID-19 Infection on medical workers who at elevated risk of COVID-19 due to exposure to positive patients in the Emergency Department or Intensive Care Unit.

https://ClinicalTrials.gov/show/NCT04335084

A prospective, double-blind, randomized, placebo-controlled study in two distinct cohorts to evaluate the efficacy and safety of hydroxychloroquine (with vitamin D) in the prevention of COVID-19 infection.

https://ClinicalTrials.gov/show/NCT04372017

F.1.2. Treatment

F.1.2.1. As monotherapy

Randomised controlled trial of a single oral dose of 25,000 IU (625 μg) vitamin D (form not specified) versus usual care in patients who are infected with SARS-CoV-2 but do not have severe symptoms (Castillo MJ. Vitamin D on Prevention and Treatment of COVID-19 (COVITD-19)

https://clinicaltrials.gov/ct2/show/NCT04334005

RCT comparing single doses of vitamin D3, 50,000 IU to 200,000 IU (1250 Vs 5000 μg) in people with COVID-19 pneumonia >75 years of age, or >70 with low oxygen saturations (Annweiler C. COvid-19 and Vitamin D Supplementation: a Multicenter Randomized Controlled Trial of High Dose Versus Standard Dose Vitamin D3 in High-risk COVID-19 Patients (CoVitTrial)

https://clinicaltrials.gov/ct2/show/record/NCT04344041

RCT comparing vitamin D3 (500,000 IU single dose) to placebo in adults admitted to hospital with COVID-19. Primary outcomes are respiratory SOFA at one week and need for high dose oxygen or mechanical ventilation at 30 days. (Cholecalciferol to Improve the Outcomes of COVID-19 Patients (CARED))

https://clinicaltrials.gov/ct2/show/NCT04411446

Single group open-label study of vitamin D supplementation (form not specified) in adults with COVID-19 and vitamin D deficiency (threshold for deficiency not defined). Participants to receive 2 weeks of vitamin D supplementation (10–15,000 IU based on age), with a further 3 weeks treatment if vitamin D levels remain low. Outcomes include 25(OH)D level and COVID-19 symptoms. (Vitamin D Testing and Treatment for COVID 19)

https://clinicaltrials.gov/ct2/show/NCT04407286

Randomised controlled trial comparing 2 doses of vitamin D3 (50,000 IU twice/once weekly and 1,000 IU daily) with low dose vitamin D3 in adults with COVID-19. Primary outcome: COVID-19 symptom recovery at 3 weeks. (Vitamin D and COVID-19 Management)

https://clinicaltrials.gov/ct2/show/NCT04385940

A Cluster-Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy of Vitamin D3 Supplementation to Reduce Disease Severity in Persons With Newly Diagnosed COVID-19 Infection and to Prevent Infection in Household Members.

https://ClinicalTrials.gov/show/NCT04536298

Randomized Controlled Trial of High Dose of Vitamin D as Compared With Placebo to Prevent Complications Among COVID-19 Patients.

https://ClinicalTrials.gov/show/NCT04411446

Open label randomised parallel study on the Prevention and Treatment With Calcifediol of COVID-19 Coronavirus-induced Acute Respiratory Syndrome (SARS).

https://ClinicalTrials.gov/show/NCT04366908

A Multicentre Randomized Controlled Trial of High Dose Versus Standard Dose Vitamin D3 in High-risk COVID-19 Patients (CoVitTrial).

https://ClinicalTrials.gov/show/NCT04344041

Vitamin D Supplementation in Patients With COVID-19: A Randomized, Double-blind, Placebo-controlled Trial.

https://ClinicalTrials.gov/show/NCT04449718

Randomised parallel trial on the Effect of Vitamin D Administration on Prevention and Treatment of Mild Forms of Suspected Covid-19.

https://ClinicalTrials.gov/show/NCT04334005

Randomised Parallel Trial on The Role of Vitamin D in Mitigating COVID-19 Infection Severity: Focusing on Reducing Health Disparities in South Carolina (VitD-COVID19).

https://ClinicalTrials.gov/show/NCT04482673

Randomised Parallel Trial To determine the efficacy of high dose Vitamin D (an over-the-counter nutritional supplement) in preventing immune-related complications in outpatients with confirmed SARS-CoV-2 infection.

https://ClinicalTrials.gov/show/NCT04489628

An open label treatment study for people with COVID 19 and low levels of vitamin D.

https://ClinicalTrials.gov/show/NCT04407286

Randomised Parallel Trial on the Effect of Vitamin D on Morbidity and Mortality of the COVID-19 (COVID-VIT-D).

https://ClinicalTrials.gov/show/NCT04552951

High Dose Vitamin-D Substitution in Patients With COVID-19: a Randomized Controlled, Multi Centre Study (VitCov).

https://ClinicalTrials.gov/show/NCT04525820

A double blind, randomized, controlled three weeks clinical trial on the efficacy of vitamin D (daily low dose versus weekly high dose) in COVID-19 patients in order to determine the relationship between baseline vitamin D deficiency and clinical characteristics and to asses patients’ response to vitamin D supplementation in week three and determine its association with disease progression and recovery.

https://ClinicalTrials.gov/show/NCT04385940

Efficacy of Vitamin D Treatment in Paediatric Patients Hospitalized by COVID-19: Open Controlled Clinical Trial.

https://ClinicalTrials.gov/show/NCT04502667

Randomised Double Blind Controlled Study on Short Term, High Dose Vitamin D Supplementation for COVID-19 (SHADE).

https://ClinicalTrials.gov/show/NCT04459247

F.1.2.2. As combination therapy

Single group open-label study of a combination of hydroxychloroquine, vitamins C and D (form not specified), and zinc plus azithromycin as treatment for COVID-19 (Haza S. A Study of Quintuple Therapy to Treat COVID-19 Infection (HAZDpaC)

https://clinicaltrials.gov/ct2/show/NCT04334512

Open-label RCT of vitamin D (form not specified; 50,000 IU once weekly for 2/52) added to aspirin 81 mg daily for 2/52. Investigating whether early treatment with aspirin and vitamin D in COVID-19 can mitigate COVID-19-associated coagulopathy and reduce hospitalization rates. (The LEAD COVID-19 Trial: Low-risk, Early Aspirin and Vitamin D to Reduce COVID-19 Hospitalizations)

https://clinicaltrials.gov/ct2/show/NCT04363840

Open label randomised parallel study on the Impact of Zinc and Vitamin D3 Supplementation on the Survival of Institutionalized Aged Patients Infected With COVID-19.

https://ClinicalTrials.gov/show/NCT04351490

Multi-center, prospective, randomized controlled trial is to investigate low-risk, early treatment with aspirin and vitamin D in COVID-19 can mitigate the prothrombotic state and reduce hospitalization rates. (The LEAD COVID-19 Trial).

https://ClinicalTrials.gov/show/NCT04363840

A Randomized, Double-Blind, Placebo-Controlled Phase IIa Study of Quintuple Therapy (Hydroxychloroquine, Azithromycin, Vitamin C, Vitamin D, and Zinc) to Treat COVID-19 Infection.

https://ClinicalTrials.gov/show/NCT04334512

A Phase II Double-Blind Randomized Placebo-Controlled Trial of Combination Therapy (Ivermectin, Doxycycline Hcl, Zinc, Vitamin D3, Vitamin C) to Treat COVID-19 Infection.

https://ClinicalTrials.gov/show/NCT04482686

Proof-of-concept Open-label Randomized Dose-response Comparison Study of Famotidine Plus Vitamins C and D3 for Adults With Probable COVID-19.

https://ClinicalTrials.gov/show/NCT04565392

Randomized Double-Blind Placebo-Controlled Proof-of-Concept Trial of a Plant Polyphenol (with Vitamin D3) for the Outpatient Treatment of Mild Coronavirus Disease (COVID-19).

https://ClinicalTrials.gov/show/NCT04400890

Therapies to Prevent Progression of COVID-19, Including Hydroxychloroquine, Azithromycin, Zinc, Vitamin D, Vitamin B12 With or Without Vitamin C, a Multi-centre, International, Randomized Trial: The International ALLIANCE Study.

https://ClinicalTrials.gov/show/NCT04395768

A Non-Randomised Pilot Study for COVID-19 Outpatient Treatment With the Combination of Ivermectin-azithromycin-cholecalciferol.

https://ClinicalTrials.gov/show/NCT04399746

F.1.3. Association between vitamin D status and COVID-19

Case-control study investigating whether serum 25(OH)D level correlates to COVID-19 disease severity in people not treated in critical care. (Do Vitamin D Levels Really Correlated With Disease Severity in COVID-19 Patients? (COVIDVIT))

https://clinicaltrials.gov/ct2/show/NCT04394390

Case-series investigating differences in vitamin D blood levels between COVID-19 patients with different degrees of disease severity (mild-severe disease compared with patients requiring critical care). (VITACOV: Vitamin D Polymorphisms and Severity of COVID-19 Infection)

https://clinicaltrials.gov/ct2/show/NCT04370808

Case-control study investigating serum zinc, vitamin D and vitamin B12 levels in pregnant women with COVID-19. (Evaluation of the Relationship Between Zinc Vitamin D and b12 Levels in the Covid-19 Positive Pregnant Women)

https://clinicaltrials.gov/ct2/show/NCT04407572

Case-control study investigating whether vitamin D levels affect outcomes in COVID-19 infection and whether vitamin D deficiency is associated with increased risk. (Investigating the Role of Vitamin D in the Morbidity of COVID-19 Patients)

https://clinicaltrials.gov/ct2/show/NCT04386044

Prospective cohort study investigating the association between vitamin D deficiency and worse outcomes in people admitted to hospital for COVID-19. (Increased Risk of Severe Coronavirus Disease 2019 in Patients With Vitamin D Deficiency (COVIT-D))

https://clinicaltrials.gov/ct2/show/NCT04403932

Retrospective Pilot Study of Vitamin D Status and Immune-inflammatory Status in Different UK Populations With COVID-19 Infection

https://ClinicalTrials.gov/show/NCT04519034

Prognostic Factors and Outcomes of COVID-19 Cases in Ethiopia: Multi-Site Cohort Study. To determine the epidemiological and clinical features of COVID-19 cases, immunological and virological courses, interaction with nutritional status, and response to treatment for COVID-19 patients admitted to treatment centers in Ethiopia.

https://ClinicalTrials.gov/show/NCT04584424

Observational study to investigating the Role of Vitamin D in the Morbidity of COVID-19 Patients.

https://ClinicalTrials.gov/show/NCT04386044

An observational study on Vitamin D-related Polymorphisms and Vitamin D Levels as Risk Biomarkers of COVID-19 Infection Severity. (VITACOV).

https://ClinicalTrials.gov/show/NCT04370808

Prospective Cohort Study to Determine the Association Between Vitamin D Deficiency and Severity of the Disease in Patients With Coronavirus Disease.

https://ClinicalTrials.gov/show/NCT04403932

A Case-Control Study on N-terminal Pro B-type Natriuretic Peptide and Vitamin D Levels as Prognostic Markers in COVID-19 Pneumonia.

https://ClinicalTrials.gov/show/NCT04487951

A Case-Control Study to investigate Whether Vitamin D Levels Really Correlated With Disease Severity in COVID-19 Patients. (COVIDVIT)

https://ClinicalTrials.gov/show/NCT04394390

Retrospective observational unicentric study in nursing-home residents with COVID-19. Health status monitoring data available until May 15, 2020. For all participants, gender, age, disability, history and comorbidities, treatments, date of last vitamin D3 supplementation, results of last blood test, date of suspicion / diagnosis of COVID-19, COVID-19 OSCI score, and eventual hospitalization or death (surveillance data available until May 15, 2020) are collected.

https://ClinicalTrials.gov/show/NCT04435119

A case=Control Study of the Relationship Between Zinc Vitamin D and b12 Levels in the Covid-19 Positive Pregnant Women.

https://ClinicalTrials.gov/show/NCT04407572

Appendix G. Excluded studies

G.1.1. Treatment

Study

Code [Reason]

Lee, Joseph, van Hecke, Oliver, Roberts, Nia et al. (2020) Vitamin D: A rapid review of the evidence for treatment or prevention in COVID-19.

- Not a peer-reviewed publication

A review published by CEBM posted as a webpage and not peer-reviewed.

Tan, Chuen Wen, Ho, Liam Pock, Kalimuddin, Shirin et al. (2020) Cohort study to evaluate effect of vitamin D, magnesium, and vitamin B12 in combination on severe outcome progression in older patients with coronavirus (COVID-19). Nutrition (Burbank, Los Angeles County, Calif.) 7980: 111017 [PMC free article: PMC7832811] [PubMed: 33039952]

- Comparator in study does not match that specified in protocol

Vitamin D was used as a combination therapy, which was not balanced in the comparator arm.

G.1.2. Prevention

Study	Code [Reason]
Sharma, S.K., Mudgal, S.K., Pai, V.S. et al. (2020) Vitamin d: A cheap yet effective bullet against coronavirus disease-19 - are we convinced yet?. National Journal of Physiology, Pharmacy and Pharmacology 10(7): 511–518	- Review article but not a systematic review
Yousfi, Narimen, Bragazzi, Nicola Luigi, Briki, Walid et al. (2020) The COVID-19 pandemic: how to maintain a healthy immune system during the lockdown - a multidisciplinary approach with special focus on athletes. Biology of sport 37(3): 211–216 [PMC free article: PMC7433333] [PubMed: 32879542]	- Review article but not a systematic review

G.1.3. Association

Study	Code [Reason]
Abrishami, Alireza, Dalili, Nooshin, Mohammadi Torbati, Peyman et al. (2020) Possible association of vitamin D status with lung involvement and outcome in patients with COVID-19: a retrospective study. European journal of nutrition [PMC free article: PMC7595877] [PubMed: 33123774]	- Study does not contain any relevant predictive values Unclear what had been adjusted in the meta-analysis.
Alexander, Jan, Tinkov, Alexey, Strand, Tor A et al. (2020) Early Nutritional Interventions with Zinc, Selenium and Vitamin D for Raising Anti-Viral Resistance Against Progressive COVID-19. Nutrients 12(8) [PMC free article: PMC7468884] [PubMed: 32784601]	- Review article but not a systematic review
Ali, Nurshad (2020) Role of vitamin D in preventing of COVID-19 infection, progression and severity. Journal of infection and public health 13(10): 1373–1380 [PMC free article: PMC7305922] [PubMed: 32605780]	- Review article but not a systematic review
Anonymous (2020) Do Low Vitamin D Levels Increase COVID-19 Risk?. The American journal of nursing 120(11): 16 [PubMed: 33105209]	- Not a relevant study design Letter to the journal
Arvinte, Cristian; Singh, Maharaj; Marik, Paul E (2020) Serum Levels of Vitamin C and Vitamin D in a Cohort of Critically Ill COVID-19 Patients of a North American Community Hospital Intensive Care Unit in May 2020: A Pilot Study. Medicine in drug discovery 8: 100064 [PMC free article: PMC7499070] [PubMed: 32964205]	- Study does not contain any relevant predictive values Dependent variable of interest is vitamin C, not vitamin D.
Baktash, Vadir, Hosack, Tom, Patel, Nishil et al. (2020) Vitamin D status and outcomes for hospitalised older patients with COVID-19. Postgraduate medical journal [PMC free article: PMC7456620] [PubMed: 32855214]	- Study does not contain any relevant predictive values Unadjusted analyses
Benskin, Linda L (2020) A Basic Review of the Preliminary Evidence That COVID-19 Risk and Severity Is Increased in Vitamin D Deficiency. Frontiers in public health 8: 513 [PMC free article: PMC7513835] [PubMed: 33014983]	- Review article but not a systematic review
Carpagnano, G E, Di Lecce, V, Quaranta, V N et al. (2020) Vitamin D deficiency as a predictor of poor prognosis in patients with acute respiratory failure due to COVID-19. Journal of endocrinological investigation [PMC free article: PMC7415009] [PubMed: 32772324]	- Study does not contain any relevant predictive values Unadjusted analysis.
D’Avolio, Antonio, Avataneo, Valeria, Manca, Alessandra et al. (2020) 25-Hydroxyvitamin D Concentrations Are Lower in Patients with Positive PCR for SARS-CoV-2. Nutrients 12(5) [PMC free article: PMC7285131] [PubMed: 32397511]	- Study does not contain any relevant predictive values Unadjusted analysis.
de Lucena, Thays Maria Costa, da Silva Santos, Ariane Fernandes, de Lima, Brenda Regina et al. (2020) Mechanism of inflammatory response in associated comorbidities in COVID-19. Diabetes & metabolic syndrome 14(4): 597–600 [PMC free article: PMC7215143] [PubMed: 32417709]	- Review article but not a systematic review Review methodology states that it systematically searched databases but no review protocol was provided. Review details physiology of vitamin D in the immune response but does not provide studies that show effectiveness of vitamin D in prevention or treatment, or the association between vitamin D status and covid-19 infection.
Eugene, Merzon, Dmitry, Tworowski, Alessandro, Gorohovski et al. Low plasma 25(OH) vitamin D3 level is associated with increased risk of COVID-19 infection: an Israeli population-based study. [PMC free article: PMC7404739] [PubMed: 32700398]	- Duplicate reference
Fasano, Alfonso, Cereda, Emanuele, Barichella, Michela et al. (2020) COVID-19 in Parkinson’s Disease Patients Living in Lombardy, Italy. Mov. Disord [PMC free article: PMC7300944] [PubMed: 32484584]	- Study does not contain any relevant predictive values The study included ‘probable’ unconfirmed cases in the analysis, and the analysis is unadjusted.
Fasano, Alfonso, Cereda, Emanuele, Barichella, Michela et al. (2020) COVID-19 in Parkinson’s Disease Patients Living in Lombardy, Italy. Movement disorders : official journal of the Movement Disorder Society 35(7): 1089–1093 [PMC free article: PMC7300944] [PubMed: 32484584]	- Study does not contain any relevant predictive values The study included ‘probable’ unconfirmed cases in the analysis, and the analysis is unadjusted.
Faul, J.L., Kerley, C.P., Love, B. et al. (2020) Vitamin d deficiency and ards after sars-cov-2 infection. Irish Medical Journal 113(5): p84 [PubMed: 32603575]	- Study does not contain any relevant predictive values Unadjusted analysis.
Galmes, Sebastia; Serra, Francisca; Palou, Andreu (2020) Current State of Evidence: Influence of Nutritional and Nutrigenetic Factors on Immunity in the COVID-19 Pandemic Framework. Nutrients 12(9) [PMC free article: PMC7551697] [PubMed: 32911778]	- Study does not contain any relevant predictive values Ecological study using countries’ population mineral intake as parameter, then simple correlation to COVID-19 incidence or death.
Goncalves, T.J.M., Goncalves, S.E.A.B., Guarnieri, A. et al. (2020) Prevalence of obesity and hypovitaminosis D in elderly with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Clinical Nutrition ESPEN [PMC free article: PMC7552968] [PubMed: 33183522]	- Study does not contain any relevant predictive values Unadjusted analysis.
Gromova, O. A.; Yu, T. I.; Kh, G. G. (2020) COVID-19 pandemic: Protective role of vitamin D. Farmakoekonomika 13(2): 132–145	- Study not reported in English Published in Russian
Haj Bloukh, Samir, Edis, Zehra, Shaikh, Annis A et al. (2020) A Look Behind the Scenes at COVID-19: National Strategies of Infection Control and Their Impact on Mortality. International journal of environmental research and public health 17(15) [PMC free article: PMC7432648] [PubMed: 32759816]	- Study does not contain any relevant predictive values Narrative review of ecological studies using worldwide geographical distribution of SARS CoV2 from ECDC - Review article but not a systematic review
Hamza, A., Ahmed, M., Ahmed, K. et al. (2020) Role of Vitamin D in Pathogenesis and Severity of Coronavirus Disease 2019 (COVID-19) Infection. Pakistan Journal of Medical and Health Sciences 14(2): 462–465	- Study does not contain any relevant predictive values Unadjusted values.
Hribar, Casey A; Cobbold, Peter H; Church, Frank C (2020) Potential Role of Vitamin D in the Elderly to Resist COVID-19 and to Slow Progression of Parkinson’s Disease. Brain sciences 10(5) [PMC free article: PMC7287983] [PubMed: 32397275]	- Review article but not a systematic review
Ilie, Petre Cristian; Stefanescu, Simina; Smith, Lee (2020) The role of vitamin D in the prevention of coronavirus disease 2019 infection and mortality. Aging clinical and experimental research [PMC free article: PMC7202265] [PubMed: 32377965]	- Study does not contain any relevant predictive values Unadjusted analysis.
Im, Jae Hyoung, Je, Young Soo, Baek, Jihyeon et al. (2020) Nutritional status of patients with COVID-19. International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases 100: 390–393 [PMC free article: PMC7418699] [PubMed: 32795605]	- Study does not contain any relevant predictive values Unadjusted analysis.
Jovic, Thomas H, Ali, Stephen R, Ibrahim, Nader et al. (2020) Could Vitamins Help in the Fight Against COVID-19?. Nutrients 12(9) [PMC free article: PMC7551685] [PubMed: 32842513]	- Review article but not a systematic review - Does not contain a cohort of people and therefore no extractable data Also included animal studies.
Kara, Murat, Ekiz, Timur, Ricci, Vincenzo et al. (2020) ‘Scientific Strabismus’ or Two Related Pandemics: COVID-19 & Vitamin D Deficiency. The British journal of nutrition: 1–20 [PMC free article: PMC7300194] [PubMed: 32393401]	- Study does not contain any relevant predictive values Unadjusted analysis.
Karonova, T. L.; Andreeva, A. T.; Vashukova, M. A. (2020) serum 25(oH)D level in patients with CoVID-19. Jurnal Infektologii 12(3): 21–27	- Study not reported in English Reported in Russian. Only abstract in English.
Karonova, T.L., Vashukova, M.A., Gusev, D.A. et al. (2020) Vitamin D deficiency as a factor for immunity stimulation and lower risk of acute respiratory infections and COVID-19. Arter. Hypertens. 3(26): 295–303	- Study not reported in English Publication only available in Russian.
Laird, E.; Rhodes, J.; Kenny, R.A. (2020) Vitamin D and inflammation: Potential implications for severity of Covid-19. Irish Medical Journal 113(5): p81 [PubMed: 32603576]	- Study does not contain any relevant predictive values Unadjusted analysis.
Macaya, Fernando, Espejo Paeres, Carolina, Valls, Adrian et al. (2020) Interaction between age and vitamin D deficiency in severe COVID-19 infection Interaccion entre la edad y el deficit de vitamina D en la COVID-19 grave. Nutricion hospitalaria [PubMed: 32960622]	- Duplicate reference
Maghbooli, Zhila, Sahraian, Mohammad Ali, Ebrahimi, Mehdi et al. (2020) Vitamin D sufficiency, a serum 25-hydroxyvitamin D at least 30 ng/mL reduced risk for adverse clinical outcomes in patients with COVID-19 infection. PloS one 15(9): e0239799 [PMC free article: PMC7518605] [PubMed: 32976513]	- Study does not contain any relevant predictive values Multivariable analysis was conducted, but only p values were reported. Univariate analyses were reported more fully, but were not adjusted for confounding variables as specified in the protocol.
Mardani, R, Alamdary, A, Mousavi Nasab, S D et al. (2020) Association of vitamin D with the modulation of the disease severity in COVID-19. Virus research 289: 198148 [PMC free article: PMC7455115] [PubMed: 32866536]	- Study does not contain outcomes of interest Only reports indirect outcome of interest (simple correlation with ACE level).
McKenna, M.J. and Flynn, M.A.T. (2020) Covid-19, cocooning and vitamin d intake requirements. Irish Medical Journal 113(5): p79 [PubMed: 32603573]	- Not a peer-reviewed publication - Study does not contain any relevant predictive values - Data not reported in an extractable format
Munshi, Ruhul, Hussein, Mohammad H, Toraih, Eman A et al. (2020) Vitamin D insufficiency as a potential culprit in critical COVID-19 patients. Journal of medical virology	- Study does not contain any relevant predictive values Systematic review does not meet protocol inclusion criteria, also using flawed statistical analysis (pooling unadjusted data that with severe heterogeneity with I² = 99.1%).
Namayandeh, S. M. (2020) Vitamin D and coronavirus disease (COVID-19);is deficiency and maintenance supplementation therapy necessary?. Journal of Nutrition and Food Security 5(3): 187–191	- Review article but not a systematic review
Orru, B, Szekeres-Bartho, J, Bizzarri, M et al. (2020) Inhibitory effects of Vitamin D on inflammation and IL-6 release. A further support for COVID-19 management?. European review for medical and pharmacological sciences 24(15): 8187–8193 [PubMed: 32767348]	- Review article but not a systematic review
Padhi, S., Suvankar, S., Panda, V.K. et al. (2020) Lower levels of vitamin D are associated with SARS-CoV-2 infection and mortality in the Indian population: An observational study. International Immunopharmacology 88: 107001 [PMC free article: PMC7489890] [PubMed: 33182040]	- Study does not contain any relevant predictive values Unclear where the study obtained the vitamin D status data. - Study does not contain outcomes of interest Study reports simple unadjusted correlation r.
Pereira, Marcos, Dantas Damascena, Alialdo, Galvao Azevedo, Laylla Mirella et al. (2020) Vitamin D deficiency aggravates COVID-19: systematic review and meta-analysis. Critical reviews in food science and nutrition: 1–9 [PubMed: 34384300]	- Study does not contain any relevant predictive values Inappropriate meta-analysis: heterogenous baseline characteristics of index studies, point estimates from index studies some are adjusted (on different variables) and some are unadjusted.
Pizzini, Alex, Aichner, Magdalena, Sahanic, Sabina et al. (2020) Impact of Vitamin D Deficiency on COVID-19-A Prospective Analysis from the CovILD Registry. Nutrients 12(9) [PMC free article: PMC7551662] [PubMed: 32932831]	- Study does not contain any relevant predictive values Unadjusted analysis.
Roselin, C. and Parameshwari, S. (2020) Role of vitamin d in boosting immunity against covid-19. International Journal of Research in Pharmaceutical Sciences 11(specialissue1): 425–429	- Review article but not a systematic review
Rozga, Mary, Cheng, Feon W., Moloney, Lisa et al. (2020) Effects of Micronutrients or Conditional Amino Acids on COVID-19 Related Outcomes: An Evidence Analysis Center Scoping Review. Journal of the Academy of Nutrition and Dietetics	- Does not contain a population of people with COVID-19 One study was identified that assess the effect of cholecalciferol in patients with ventilator-related pneumonia.
Singh, S K; Jain, Rujul; Singh, Shipra (2020) Vitamin D deficiency in patients with diabetes and COVID- 19 infection. Diabetes & metabolic syndrome 14(5): 1033–1035 [PMC free article: PMC7332933] [PubMed: 32640414]	- Review article but not a systematic review
Singh, Samer; Kaur, Rajinder; Singh, Rakesh Kumar (2020) Revisiting the role of vitamin D levels in the prevention of COVID-19 infection and mortality in European countries post infections peak. Aging clinical and experimental research 32(8): 1609–1612 [PMC free article: PMC7426200] [PubMed: 32797388]	- Study does not contain any relevant predictive values Unclear where the study obtained the vitamin D status data, no baseline characteristics data. - Study does not contain outcomes of interest Results presented as simple unadjusted correlation r.
Tan, Si Heng Sharon, Hong, Choon Chiet, Saha, Soura et al. (2020) Medications in COVID-19 patients: summarizing the current literature from an orthopaedic perspective. International orthopaedics [PMC free article: PMC7244258] [PubMed: 32445030]	- Data not reported in an extractable format - Study does not contain outcomes of interest
Yalcin Bahat, Pinar, Aldikactioglu Talmac, Merve, Bestel, Aysegul et al. (2020) Micronutrients in COVID-19 Positive Pregnancies. Cureus 12(9): e10609 [PMC free article: PMC7515144] [PubMed: 32983745]	- Study does not contain outcomes of interest Outcomes were blood levels of micronutrients including vitamin D. No correlation between vitamin D status and disease severity or any other outcome relevant to the review protocol was reported. - Not a relevant study design Case series of pregnant women who tested positive for SARS-CoV2 infection and had their blood vitamin D levels measured.
Yilmaz, Kamil and Sen, Velat (2020) Is vitamin D deficiency a risk factor for COVID-19 in children?. Pediatric pulmonology [PMC free article: PMC7675606] [PubMed: 33017102]	- Study does not contain any relevant predictive values Unadjusted analysis.
Yousfi, Narimen, Bragazzi, Nicola Luigi, Briki, Walid et al. (2020) The COVID-19 pandemic: how to maintain a healthy immune system during the lockdown - a multidisciplinary approach with special focus on athletes. Biology of sport 37(3): 211–216 [PMC free article: PMC7433333] [PubMed: 32879542]	- Review article but not a systematic review

Evidence reviews underpinning recommendations 1.1 to 1.3 and research recommendations in the NICE guideline

These evidence reviews were developed by Centre for Guidelines Methods and Economics Team

Disclaimer: The recommendations in this guideline represent the view of NICE, arrived at after careful consideration of the evidence available. When exercising their judgement, professionals are expected to take this guideline fully into account, alongside the individual needs, preferences and values of their patients or service users. The recommendations in this guideline are not mandatory and the guideline does not override the responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or their carer or guardian.

Local commissioners and/or providers have a responsibility to enable the guideline to be applied when individual health professionals and their patients or service users wish to use it. They should do so in the context of local and national priorities for funding and developing services, and in light of their duties to have due regard to the need to eliminate unlawful discrimination, to advance equality of opportunity and to reduce health inequalities. Nothing in this guideline should be interpreted in a way that would be inconsistent with compliance with those duties.

NICE guidelines cover health and care in England. Decisions on how they apply in other UK countries are made by ministers in the Welsh Government, Scottish Government, and Northern Ireland Executive. All NICE guidance is subject to regular review and may be updated or withdrawn.

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Evidence reviews for the use of vitamin D supplementation as prevention and treatment of COVID-19: Vitamin D for COVID-19: Evidence review A. London: National Institute for Health and Care Excellence (NICE); 2020 Dec. (NICE Guideline, No. 187.)
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Evidence reviews for the use of vitamin D supplementation as prevention and trea...
Evidence reviews for the use of vitamin D supplementation as prevention and treatment of COVID-19
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Evidence reviews for the use of vitamin D supplementation as prevention and treatment of COVID-19

1. Vitamin D for COVID-19 prevention and treatment

1.1. Review question

1.1.1. Introduction

1.1.2. Summary of the protocol

1.1.3. Methods and process

1.1.4. Effectiveness evidence

1.1.4.1. Included studies

1.1.4.2. Excluded studies

1.1.5. Summary of studies included in the effectiveness and prognostic evidence

1.1.6. Summary of the effectiveness evidence

1.1.7. Economic evidence

1.2. Review question

1.2.1. Introduction

1.2.2. Summary of the protocol

1.2.3. Methods and process

1.2.4. Effectiveness evidence

1.2.4.1. Included studies

1.2.4.2. Excluded studies

1.2.5. Summary of the effectiveness evidence

1.2.6. Economic evidence

1.3. Review question

1.3.1. Introduction

1.3.2. Summary of the protocol

1.3.3. Methods and process

1.3.4. Association evidence

1.3.4.1. Included studies

1.3.4.2. Excluded studies

1.3.5. Summary of studies included in the effectiveness and prognostic evidence

1.3.6. Summary of the association evidence

Association between vitamin D status and COVID-19 cases

Association between vitamin D status and COVID-19 severity

1.3.7. Economic evidence

1.3.9. References – included studies

1.3.9.1. Treatment

1.3.9.2. Association

1.3.9.3. Other

1.3.9.4. Pre-prints

Appendices

Appendix A. Review protocols

A.1.1. Review question 1

A.1.2. Review question 2

A.1.3. Review question 3

Appendix B. Literature search strategies

Medline ALL

Embase

Cochrane Database of Systematic Reviews (CDSR) & CENTRAL

MedRxiv & BioRxiv preprints

World Health Organization Global research on coronavirus disease (COVID-19)

Appendix C. Effectiveness & association evidence study selection

C.1.1. Review question 1

C.1.2. Review question 2

C.1.3. Review question 3

Appendix D. Effectiveness & association evidence

D.1. Effectiveness evidence

D.1.1. Vitamin D as treatment

D.2. Association evidence

Appendix E. GRADE tables

E.1.1. Effectiveness of vitamin D as a COVID-19 treatment

E.1.1.1. Effectiveness of vitamin D supplement as treatment for COVID-19

E.1.2. Effectiveness of vitamin as a COVID-19 preventative measure

E.1.3. Association between vitamin D status and COVID-19 outcomes

E.1.3.1. Association between vitamin D status and COVID-19 cases

E.1.3.2. Association between vitamin D status and severity of COVID-19

Appendix F. Ongoing studies (clinicaltrials.gov)

F.1.1. Prevention

F.1.1.1. As monotherapy

F.1.1.2. As combination therapy

F.1.2. Treatment

F.1.2.1. As monotherapy

F.1.2.2. As combination therapy

F.1.3. Association between vitamin D status and COVID-19

Appendix G. Excluded studies

G.1.1. Treatment

G.1.2. Prevention

G.1.3. Association

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