key: cord-0934842-hwzri4i5
authors: Tentolouris, Nikolaos; Samakidou, Georgia; Eleftheriadou, Ioanna; Tentolouris, Anastasios; Jude, Edward B.
title: The effect of vitamin D supplementation on mortality and intensive care unit admission of COVID‐19 patients. A systematic review, meta‐analysis and meta‐regression
date: 2022-01-15
journal: Diabetes Metab Res Rev
DOI: 10.1002/dmrr.3517
sha: a520d549277efd4d5d6a773272b032cdcb6b442d
doc_id: 934842
cord_uid: hwzri4i5

AIMS: The aim of this systematic review and meta‐analysis was to investigate the effect of vitamin D supplementation on mortality and admission to intensive care unit (ICU) of COVID‐19 patients. METHODS: A systematic search of PubMed, Google Scholar, Embase, Web of Science and medRxiv with terms relative to vitamin D supplementation and COVID‐19 was conducted on 26 March 2021. Comprehensive Meta‐Analysis software was used for the quantitative assessment of data and random‐effects model was applied. To investigate the association between the dose of vitamin D and the outcomes of interest, meta‐regression analysis was performed. RESULTS: Two thousand and seventy‐eight patients from nine studies with data on mortality were included (583 received vitamin D supplementation, while 1495 did not). Sixty‐one (10.46%) individuals in the treated group died, compared to 386 (25.81%) in the non‐treated group (odds ratio [OR]: 0.597; 95% CI: 0.318–1.121; p = 0.109). Eight hundred and sixty patients from six studies with data on ICU admission were included (369 received vitamin D supplementation, while 491 did not). Forty‐five (12.19%) individuals in the treated group were admitted to ICU, compared to 129 (26.27%) in the non‐treated group (OR: 0.326; 95% CI: 0.149–0.712; p = 0.005). No significant linear relationship between vitamin D dose and log OR of mortality or log OR of ICU admission was observed. CONCLUSION: This meta‐analysis indicates a beneficial role of vitamin D supplementation on ICU admission, but not on mortality, of COVID‐19 patients. Further research is urgently needed to understand the benefit of vitamin D in COVID‐19.

In late December 2019, the first cases of coronavirus disease 2019 , a disease caused by a novel beta-coronavirus named 'severe acute respiratory syndrome coronavirus 2' (SARS-CoV-2), were reported in Wuhan, China. By March 2020, the disease had already spread globally, leading to the declaration of a pandemic by the World Health Organization. 1 Since then, the global impact of COVID-19 has undoubtedly been tremendous, and until 29 May 2021, there have been approximately 173 million cases and 3.72 million deaths from COVID- 19. 2 The clinical manifestations of COVID-19 range from asymptomatic or mild cases with fever, dry cough and fatigue, to severe and even critical cases with dyspnoea, need for intensive care unit (ICU) admission, acute respiratory distress syndrome (ARDS), and multi-organ failure and death. 1 Some of the risk factors that have been associated with COVID-19 severity are older age, black ethnicity, institutionalisation, immunodeficiency, chronic kidney disease, chronic metabolic diseases (including diabetes) and obesity. 3, 4 Interestingly, several of these factors have also been associated with increased risk of vitamin D deficiency (VDD). 5, 6 The link between VDD and COVID-19 positivity rates and severity has been investigated in several observational studies, 7-17 as well as in systematic reviews and meta-analyses. 18 

This systematic review and meta-analysis was conducted according to the recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA). 23 The Population, Intervention, Comparison, Outcome, Study design approach was used for the development of the research questions (Table S1 ).

The population of interest was adult patients with COVID-19 receiving any form of vitamin D supplementation. 

The outcomes of interest were mortality and ICU admissions.

Randomized trials and certain observational studies (case-control, cross-sectional and observational cohort) involving vitamin D supplementation and reporting on the selected outcomes were included in this systematic review. Articles with distinct features (e.g., clinical case series, case reports, animal or laboratory studies, reviews and non-English articles) and studies not involving vitamin D supplementation were excluded. Two independent researchers (GS and IE) screened the results by titles and abstracts and assessed the selected full-text articles for eligibility. Any disagreements were resolved with re-evaluation and consensus. After the final assessment, 10 records were selected for qualitative and quantitative synthesis, and data from the selected studies were extracted. Of the 10 studies selected, 2 of them were randomized studies 24,25 and 8 were non-randomized studies. [26] [27] [28] [29] [30] [31] [32] [33] In case of missing information from certain studies, corresponding authors were contacted. The detailed PRISMA chart is available in Figure S1 and the characteristics of the included studies in Table 1 and Table S2 .

In addition, we calculated the dose of vitamin D, cholecalciferol or calcifediol supplementation post-diagnosis of COVID-19, and the dose was averaged and expressed as dose per month.

The risk of bias assessment was performed by two independent reviewers (GS and IE) and any discrepancy was settled through re-evaluation and consensus. The version 2 of the Cochrane riskof-bias tool for randomized trials (RoB 2 tool) was used for the assessment of risk of bias of randomized trials. 34 Each outcome of the included randomized trials was evaluated through the process of signalling questions for the presence of bias in the randomisation process, due to deviations from intended intervention, due to missing outcome data, in measurement of the outcome and in selection of the reported results. Based on the response to each aforementioned domain, an overall judgement regarding the risk of bias of the outcome of interest was made (high, some concerns or low). The robvis tool was used for the production of the final images. 35 The ROBINS-I tool was used for the assessment of risk of bias of non-randomized trials. 36 (Figure 1 ).

Though three studies favoured the intervention arm, the degree of impact varied among the studies. In addition, significant heterogeneity was found in terms of between-study variance (Q statistic = 21.27, p = 0.006, I 2 = 62.40%) and that resulted in deviation from funnel shape ( Figure S2 ). In terms of publication bias, the Egger's and Begg's tests showed the absence of any significant publication bias (p > 0.05) ( Table 2 ). The quality of the evidence regarding the effect of vitamin D supplementation on mortality of COVID-19 patients assessed with the GRADE approach was judged as 'very low' (Table 3) .

Random-effect meta-regression analysis was applied to estimate functional relationship of log OR of mortality and vitamin D dose; it was found that the regression coefficient of the slope was 0.0000 (p = 0.72294), suggesting that there is no significant linear relationship between vitamin D dose and log OR of mortality (Table S3 , Figure S3 ).

In addition, in the analysis of variance of random-effect metaregression analysis of log OR of mortality on dose of vitamin D, Q values of the model (0.12569), the residual (7.31725), and the total (7.44295) were not significant, implying that the relationship between vitamin D dose and mortality were not significant, deviations among log OR values of mortality and regression line were also not significant, and that the amount of total variance is lower than we would expect based on within-study error, respectively (Table S3) .

A total of 860 patients from 6 studies hospitalised for COVID-19

were also included in this meta-analysis with available data for the need of ICU as outcome; of them, 369 received vitamin D supplementation and 45 (12.19%) were admitted to ICU. 24 (Figure 2 ).

Though two studies favoured the intervention arm, the degree of impact varied among the studies. In addition, significant heterogeneity was found in terms of between-study variance (Q statistic = 12.53, p = 0.028, I 2 = 60.09%) and that resulted in deviation from funnel shape (Supplementary Figure 4) . In terms of publication bias, the Egger's and Begg's tests showed that there was significant publication bias (p < 0.05) ( Table 2 ). The quality of the evidence regarding the effect of vitamin D supplementation on ICU admission of COVID-19 patients assessed with the GRADE approach was judged as 'very low' (Table 3) .

Random-effect meta-regression analysis was applied to estimate functional relationship of log OR of ICU admission and vitamin D dose; it was found that the regression coefficient of the slope was 0.0000 (p = 0.96331), suggesting that there is no significant linear relationship between vitamin D dose and log OR of ICU admission (Table S4 , Figure S5 ) variance is lower than we would expect based on within-study error, respectively (Table S4) . (Figures S8 and S9 ).

In this systematic review and meta-analysis we examined the effect of vitamin D supplementation on mortality and ICU admission rates of patients with COVID-19. We found that vitamin D supplementation was associated with a significant reduction of the risk for ICU admission, while as far as mortality is concerned, no significant benefit was observed. Moreover, no significant relationship was found between the administered dose of vitamin D and either mortality or ICU admission. The quality of the evidence based on the GRADE approach is characterised as "very low" for both outcomes of interest ( Table 3) .

The potential protective actions of vitamin D against COVID- 

Egger's test Another issue that has risen is whether the impact of vitamin D supplementation should be considered in the setting of pre-existing deficiency or insufficiency, as supplementation irrespectively of baseline levels is not expected to be beneficial. 39 Indeed, levels of 25

(OH)D are not measured in all studies included in this meta-analysis.

However, even in the cases of measured levels, there is controversy regarding the impact of time of measurement. 25(OH)D is largely bound to vitamin D binding protein and albumin, whose concentrations tend to decrease during acute illness, as a negative acute phase response. 44 Consequently, the interpretation of these levels in Publication bias strongly suspected (funnel plot asymmetry). e The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). Four other systematic-reviews and meta-analyses on the effect of vitamin D supplementation on mortality and ICU admissions of COVID-19 patients were retrieved from database searching. 45, 46 The first one, 45 that included 532 COVID-19 patients from three studies, concluded that vitamin D supplementation was associated with significant lower rates of ICU admission (p < 0.0001), while no significant benefit for mortality was observed; these findings are similar to the results of our study. However, compared to that study, our meta-analysis includes a larger number of patients because at the time we performed our search more studies had been published.

Moreover, as previously explained, we decided a priori to use the random-effects model, which we believe to be more appropriate for this meta-analysis due to different designs of the included studies, while in the aforementioned study the significant result was obtained with the application of fixed effect model. The second metaanalysis, which was obtained from a preprint server, 46 concluded that vitamin D supplementation significantly reduced the incidence of the composite outcome of ICU admission/mortality; the association remained significant when adjusted risk estimates were analysed. 47 On the contrary, another recent analysis of 467 patients with COVID-19 that aimed to investigate the effect of vitamin D supplementation on clinical outcomes, including ICU admission and mortality, did not find any significant association. 48 However, this meta-analysis included only randomized and quasi-experimental trials; consequently, the number of the included patients was small. Another distinction of this meta-analysis from ours and the previously mentioned is that vitamin D was administration was prospective after the diagnosis of COVID-19; as previously mentioned the possible influence of the time of vitamin D administration remains to de elucidated. Additionally, an important asset of our study is the meta-regression analysis regarding the relationship between the administered dose of vitamin D and the outcomes of interest, an approach that had not been applied in the abovementioned studies.

This meta-analysis has several limitations. Firstly, due to the scarcity of RCTs at the moment of data collection, non-randomized studies have been included. The included studies differ as far as their design and sample size is concerned, and most of them present a high risk of bias (Figures S10 and S11 , Table S2) 

The findings of the present meta-analysis support a beneficial role of vitamin D supplementation in the rates of ICU admission in COVID-19 patients. However, validation of these findings from high-quality RCTs is necessary.

Characteristics of SARS-CoV-2 and COVID-19

An interactive web-based dashboard to track COVID-19 in real time

Risk factors for severe and critically ill COVID-19 patients: a review

Vitamin D and its potential benefit for the COVID-19 pandemic

The vitamin D deficiency pandemic: approaches for diagnosis, treatment and prevention

Vitamin D status as a predictor of Covid-19 risk in Black, Asian and other ethnic minority groups in the UK

Vitamin D concentrations and COVID-19 infection in UK Biobank

SARS-CoV-2 positivity rates associated with circulating 25-hydroxyvitamin D levels

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

Association of vitamin D status and other clinical characteristics with COVID-19 test results

Low serum 25-hydroxyvitamin D (25[OH]D) levels in patients hospitalized with COVID-19 are associated with greater disease severity

Impact of vitamin D deficiency on COVID-19 -A prospective analysis from the CovILD registry

Vitamin D status and COVID-19 clinical outcomes in hospitalized patients

Low 25-hydroxyvitamin D levels on admission to the intensive care unit may predispose COVID-19 pneumonia patients to a higher 28-day mortality risk: a pilot study on a Greek ICU cohort

Vitamin D status is associated with in-hospital mortality and mechanical ventilation: a cohort of COVID-19 hospitalized patients

Association of vitamin D status with hospital morbidity and mortality in adult hospitalized COVID-19 patients

Vitamin D and COVID-19 infection and mortality in UK Biobank

Therapeutic and prognostic role of vitamin D for COVID-19 infection: a systematic review and meta-analysis of 43 observational studies

Low vitamin D status is associated with coronavirus disease 2019 outcomes: a systematic review and meta-analysis

Association of vitamin D status with SARS-CoV-2 infection or COVID-19 severity: a systematic review and metaanalysis

The link between COVID-19 and VItamin D (VIVID): a systematic review and meta-analysis

Low serum 25-hydroxyvitamin D (vitamin D) level is associated with susceptibility to COVID-19, severity, and mortality: a systematic review and metaanalysis

The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration

Effect of a single high dose of vitamin D3 on hospital length of stay in patients with moderate to severe COVID-19: a randomized clinical trial

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

Vitamin D supplementation associated to better survival in hospitalized frail elderly COVID-19 patients: the GERIA-COVID quasi-experimental study

Vitamin D supplementation and outcomes in coronavirus disease 2019 (COVID-19) patients from the outbreak area of Lombardy

Vitamin D status in hospitalized patients with SARS-CoV-2 infection

Lack of association of baseline 25-hydroxyvitamin D levels with disease severity and mortality in Indian patients hospitalized for COVID-19

High-dose cholecalciferol booster therapy is associated with a reduced risk of mortality in patients with COVID-19: a cross-sectional multi-centre observational study

Mortality in an Italian nursing home during COVID-19 pandemic: correlation with gender, age, ADL, vitamin D supplementation, and limitations of the diagnostic tests

Cohort study to evaluate the effect of vitamin D, magnesium, and vitamin B(12) in combination on progression to severe outcomes in older patients with coronavirus (COVID-19)

Effectiveness of in-hospital cholecalciferol use on clinical outcomes in comorbid COVID-19 patients: a hypothesis-generating study

RoB 2: a revised tool for assessing risk of bias in randomised trials

Risk-of-bias visualization (robvis): an R package and Shiny web app for visualizing risk-of-bias assessments

ROBINS-I: a tool for assessing risk of bias in non-randomised studies of interventions

Cochrane Handbook for Systematic Reviews of Interventions Version

Accessed 10/25/2021. www.training.cochrane.org/ handbook 38. GRADEpro GDT: GRADEpro Guideline Development Tool

Vitamin D and COVID-19: evidence and recommendations for supplementation

Mechanisms IN endocrinology: vitamin D and COVID-19

COVID-19 -does this disease kill due to imbalance of the renin angiotensin system (RAS) caused by genetic and gender differences in the response to viral ACE 2 attack?

Perspective: vitamin D supplementation prevents rickets and acute respiratory infections when given as daily maintenance but not as intermittent bolus: implications for COVID-19

Mineral Metabolism. Williams Textbook of Endocrinology. 1. 14th ed. Elsevier -Health Sciences Division

Perspective: vitamin D deficiency and COVID-19 severity -plausibly linked by latitude, ethnicity, impacts on cytokines, ACE2 and thrombosis

Vitamin D supplementation, COVID-19 and disease severity: a meta-analysis

The impact of vitamin D supplementation on mortality rate and clinical outcomes of COVID-19 patients: a systematic review and metaanalysis. medRxiv

Vitamin D supplementation and clinical outcomes in COVID-19: a systematic review and meta-analysis

Vitamin D supplementation and COVID-19 treatment: a systematic review and meta-analysis

The effect of vitamin D supplementation on mortality and intensive care unit admission of COVID-19 patients. A systematic review, metaanalysis and meta-regression

There was no funding source for this study. All authors had full access to all the data in the study and the corresponding author had final responsibility for the decision to submit for publication.

The authors declare they have no conflict of interest.

This study did not involve human participants or animal research.This work was based on already produced and published data.

Georgia Samakidou and Ioanna Eleftheriadou determined the search strategy, screened the selected studies and extracted the data.Nikolaos Tentolouris and Anastasios Tentolouris performed the statistical analysis. All authors participated in the writing and revision of this paper. All authors have read and approved this final manuscript.

The data that supports the findings of this study are available in the supplementary material of this article.

https://orcid.org/0000-0003-0615-2534Georgia Samakidou https://orcid.org/0000-0001-5567-8044

The peer review history for this article is available at https://publons. com/publon/10.1002/dmrr.3517.