key: cord-1040423-8hvve871
authors: Ghasemian, R.; Shamshirian, A.; Heydari, K.; Malekan, M.; Alizadeh-Navaei, R.; Ebrahimzadeh, M. A.; Jafarpour, H.; Rezaei Shahmirzadi, A.; Khodabandeh, M.; Seyfari, B.; Sedaghat, M.; Motamedzadeh, A.; Dadgostar, E.; Aalinezhad, M.; Behnamfar, M.; Asadi, A.; Zarandi, B.; Razzaghi, N.; Yaghoubi Naei, V.; Hessami, A.; Azizi, S.; Mohseni, A. R.; Shamshirian, D.
title: The Role of Vitamin D in The Age of COVID-19: A Systematic Review and Meta-Analysis Along with an Ecological Approach
date: 2020-06-08
journal: nan
DOI: 10.1101/2020.06.05.20123554
sha: d0d23ebcc6ac28f8e961b49dbd008cfa96bd8579
doc_id: 1040423
cord_uid: 8hvve871

Background: Following emerge of a novel coronavirus from Wuhan, China, in December 2019, it has affected the whole world and after months of efforts by the medical communities, there is still no specific approach for prevention and treatment against the Coronavirus Disease 2019 (COVID-19). Evidence recommends that vitamin D might be an important supportive agent for the immune system, mainly in cytokine response regulation against COVID-19. Hence, we carried out a rapid systematic review and meta-analysis along with an ecological investigation in order to maximize the use of everything that exists about the role of vitamin D in the COVID-19. Methods: A systematic search was performed in PubMed, Scopus, Embase, Cochrane Library, Web of Science and Google Scholar (intitle) as well as preprint database of medRxiv, bioRxiv, Research Square, preprints.org, search engine of ScienceDirect and a rapid search through famous journals up to May 26, 2020. Studies focused on the role of vitamin D in confirmed COVID-19 patients were entered into the systematic review. Along with our main aim, to find the second objective: correlation of global vitamin D status and COVID-19 recovery and mortality we carried out a literature search in PubMed database to identify the national or regional studies reported the vitamin D status globally. CMA v. 2.2.064 and SPSS v.16 were used for data analysis. Results: Out of nine studies entered into our systematic review, six studies containing 3,822 participants entered into the meta-analysis. The meta-analysis indicated that 46.5% of COVID-19 patients were suffering from vitamin D deficiency (95% CI, 28.2%-65.8%) and in 43.3% of patients, levels of vitamin D were insufficient (95% CI, 27.4%-60.8%). In regard to our ecological investigation on 51 countries including 408,748 participants, analyses indicated no correlation between vitamin D levels and recovery rate (r= 0.041) as well as mortality rate (r=-0.073) globally. However, given latitude, a small reverse correlation between mortality rate and vitamin D status was observed throughout the globe (r= -0.177). In Asia, a medium direct correlation was observed for recovery rate (r= 0.317) and a significant reveres correlation for mortality rate (r= -0.700) with vitamin D status in such patients. In Europe, there were no correlations for both recovery (r= 0.040) and mortality rate (r= -0.035). In Middle East, the recovery rate (r= 0.267) and mortality rate (r= -0.217) showed a medium correlation. In North and Sought America, surprisingly, both recovery and mortality rate demonstrated a direct correlation respectively (r= 1.000, r=0.500). In Oceania, unexpectedly, recovery (r= -1.000) and mortality (r= -1.000) rates were in considerable reverse correlation with vitamin D levels. Conclusion: In this systematic review and meta-analysis with an ecological approach, we found a high percentage of COVID-19 patients who suffer from vitamin D deficiency or insufficiency. Much more important, our ecological investigation resulted in substantial direct and reverse correlations between recovery and mortality rates of COVID-19 patients with vitamin D status in different countries. Considering latitudes, a small reverse correlation between vitamin D status and mortality rate was found globally. It seems that populations with lower levels of vitamin D might be more susceptible to the novel coronavirus infection. Nevertheless, due to multiple limitations, if this study does not allow to quantify a value of the Vitamin D with full confidence, it allows at least to know what the Vitamin D might be and that it would be prudent to invest in this direction through comprehensive large randomized clinical trials.

Following emerge of a novel coronavirus from Wuhan, China, in December 2019, the respiratory syndrome coronavirus 2 (SARS-CoV-2) has affected the whole world and declared as a pandemic by World Health Organization (WHO) on March 26, 2020 1 . According to Worldometer metrics, this novel virus has been responsible for approximately 6,615,298 infections, of which 3, 195 ,971 cases are recovered and 388,759 cases were died worldwide up to June 4, 2020.

After months of efforts by the medical communities, there is still no specific approach for prevention and treatment against the Coronavirus Disease 2019 . Also, competition of pandemic with infodemic has led to many controversies and challenges globally.

In this regard, one of the hottest topics these days is the role of Vitamin D in prevention or treatment of COVID-19. Several functions such as modulating adaptive immune system and cell-mediated immunity, as well as increase of antioxidative-related genes expression have been proven for Vitamin D as an adjuvant in the prevention and treatment of acute respiratory infections 2, 3 . According to available investigations, it seems that such functions lead to cytokine storm suppression and avoid Acute Respiratory Distress Syndrome (ARDS), which has been studied on other pandemics and infectious diseases in recent years [4] [5] [6] .

To best of our knowledge, unfortunately, after several months there is no adequate high-quality data on different treatments regimen, which raises questions about gaps in scientific works. In this occasion, when there is an essential need for controlled randomized trials, it is surprising to see only observational studies without a control group or non-randomized controlled studies with retrospective nature covering a small number of patients.

The same issue is debatable for 25-hydroxyvitamin D (25(OH)D); hence, concerning all of the limitations and analyze difficulties, we carried out a rapid systematic review and meta-analysis with great caution and sensitivity in order to try for maximizing the use of everything that exists about the role of this vitamin in the COVID-19. Additionally, along with this systematic review, we also performed an ecological evaluation to find any relations between global status of vitamin D and COVID-19 recovery/mortality rates. To be honest, we know that working on observational studies give an overestimation of the required value. Therefore, whatever the result with the vitamin D we can present that the result, by our approaches, is also an overestimation of reality; which is very fascinating in itself to get in the current situation, especially through what we found in our ecological approach.

The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline was considered for study plan. A systematic search through databases of PubMed, Scopus, Embase, Cochrane Library, Web of Science and Google Scholar (intitle) as well as preprint database of medRxiv, bioRxiv, Research Square, preprints.org, search engine of ScienceDirect and a rapid search through famous journals was done up to May 26, 2020. Moreover, to obtain more data we considered gray literatures and references of eligible papers. The search strategy included all MeSH terms and free keywords found for COVID-19, SARS-CoV-2, and Vitamin D. There was no time/location/ language limitation in this search.

Four researchers have screened and selected the papers independently and the supervisor solved the disagreements. Studies met the following criteria included into meta-analysis: 1) comparative or non-comparative studies with retrospective or prospective nature; and 2) studies reported the role of vitamin D in confirmed COVID-19 patients. Studies were excluded if they were: 1) in vitro studies, experimental studies, reviews; 2) duplicate publications.

Two researchers (H.J and M.M) have evaluated quality assessment of the papers and extracted data from selected papers. The supervisor (D.Sh) resolved any disagreements in this step. Data extraction checklist included the name of the first author, publication year, region of study, number of patients, comorbidity, vitamin D Status, serum 25-hydrovitamin D levels, ethnicity, mean age, medication dosage, treatment duration, adverse effects, radiological results, and mortality. The modified Newcastle-Ottawa Scale (NOS) checklist for cross-sectional studies was used to value the studies, concerning various aspects of the methodology and study process.

According to risk factors such as older age, male, obesity, underlying chronic disorders, higher latitudes, darker skin pigmentation etc., which are common between Vitamin D deficiency and COVID-19 toward the severity of the condition, despite the various possible explanations, we hypothesize that vitamin D plays a role in severity of responses to COVID-19 and vitamin D deficiency can be in correlation with COVID-19 mortality rate and recovery rate.

In this regard, alongside with our main objective, to find the second aim as an ecological investigation we carried out a literature search in PubMed database for identifying the national or regional studies reported the vitamin D status throughout the world. Data of infection, mortality and recovery of COVID-19 cases were gathered from the Worldometer metrics. The meta-analysis was done between all of the published studies in each region for pooling vitamin D mean levels.

In this case, according to an international conference on "Controversies in Vitamin D" 7 , vitamin D cut-off points were considered as follows: 

I-square (I 2 ) statistic was used for heterogeneity evaluation. Following Cochrane Handbook for Systematic Reviews of Interventions 8 , the I 2 was interpreted as follows: "0% to 40%: might not be important; 30% to 60%: may represent moderate heterogeneity; 50% to 90%: may represent substantial heterogeneity; 75% to 100%: considerable heterogeneity. The importance of the observed value of I 2 depends on (i) magnitude and direction of effects and (ii) strength of evidence for heterogeneity (e.g. P-value from the chi-squared test, or a confidence interval for I 2 )." Thus, random-effects model was used for pooling the outcomes in case of heterogeneity; otherwise, the inverse variance fixed-effect model was used. Forest plots were presented to visualize the degree of variation between studies.

Meta-analysis was performed using Comprehensive Meta-Analysis (CMA) v. 2.2.064 software. Pooling of effect sizes was done with 95% Confident Interval (CI). Fixed/randomeffects model was used according to heterogeneities. In case of zero frequency, the correction value of 0.1 was used.

Correlation of mortality and recovery rates in COVID-19 patients with vitamin D status was evaluated using Spearman's rank correlation coefficient (r). According to Cohen's classification of effect width 9 , value of r=0.1 was considered as small effect, r=0.25 as medium effect and r=0.4 as large effect. The P-value less than 0.05 was considered statistically significant. Data were analyzed using SPSS software version 16 (SPSS Inc., Chicago, IL, U.S.A.).

Begg's and Egger's tests as well as funnel plot was used for publication bias evaluation. Pvalue less than 0.05 was considered as statistically significant.

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The copyright holder for this preprint this version posted June 8, 2020. . https://doi.org/10.1101/2020.06.05.20123554 doi: medRxiv preprint

The first search through databases resulted in 790 papers. After removing duplicated papers and first step screening based on title and abstract, 41 papers were assessed for eligibility. Finally, nine papers entered into qualitative synthesis, of which six papers entered into the meta-analysis. PRISMA flow diagram for the study selection process presented in Figure 1 . 

Among the six studies included in meta-analysis, all of them were designed in retrospective nature. The studies' sample size ranged from 10 to 780 including 3,822 participants. Characteristics of studies entered into the systematic review presented in Table 1 .

. CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted June 8, 2020. 

Results of quality assessment for studies entered into meta-analysis based on modified version of NOS tool for cross-sectional studies were fair.

Results of Begg's and Egger's tests in effect size meta-analysis showed no significant publication bias (PB=1.00; PE=0.44). The funnel plot for publication bias of studies presented in Fig. 2 .

The meta-analysis of event rates showed that 46.5% of COVID-19 patients were suffering from vitamin D deficiency (95% CI, 28.2%-65.8%) and in 43.3% of patients, levels of vitamin D were lower than the normal range (95% CI, 27.4%-60.8%) (Fig. 3) . Table 2 .

The world vitamin D distribution map and its relations with recovery rate as well as mortality are presented in Fig. 4 . Considering mean levels of vitamin D, SARS-CoV-2 infection as well as COVID-19 mortality and recovery data throughout the world, Spearman's rank correlation coefficient analyses indicated no correlation between vitamin D levels and recovery rate (r= 0.041) as well as mortality rate (r=-0.073) globally.

In detail, in Asia with overall mean levels of 57.326 25(OH)D (95% CI, 56.959-57.693) a substantial direct correlation was observed between vitamin D status and recovery rate (r= 0.317) as well as a significant reverse correlation for the mortality rate (r= -0.700). In Europe, there were no correlations for both recovery (r= 0.040) and mortality rate (r= -0.035). In Middle East, although there was a direct correlation between recovery rate and vitamin D status (r= 0.267); also, mortality rate was mediumly in reverse correlation with vitamin D status (r= -0.217). In North America, surprisingly, both recovery (r= 1.000) and mortality rates (r= 1.000) were highly correlated to the vitamin D levels. In Sought America, both recovery rate (r=0.500) and mortality rate (r=0.500) were in a significant direct correlation with 25(OH)D levels. In Oceania, unexpectedly, recovery (r= -1.000) and mortality (r= -1.000) rates were in substantial reverse correlation with 25(OH)D levels.

Considering latitude factor as an adjustment for countries in latitudes higher than ±50°, partial correlation analysis showed a small reverse correlation between mortality rate and vitamin D status throughout the globe (r= -0.177), but no correlation was observed for recovery rate (r= -0.072). This analysis showed a direct correlation in case of mortality rate in Europe r= 0.164. 

Although comparing global statistics of COVID-19 outcomes is difficult, it is clear that the mortality rate is higher in several countries. It seems that various factors such as age, healthcare system quality, general health status, socioeconomic status, etc. Nonetheless, one of the underestimated factors, which might be associated with COVID-19 outcome is the vitamin D status in every populations. Investigations on respiratory infections indicated that 25hydroxyvitamin D can effectively induce the host defense peptides against bacterial or viral agents and vitamin D insufficiency/deficiency can lead to non-communicable as well as infectious diseases 2, 94, 95 . The other potential role of vitamin D is reduction of inflammatory induced following SARS-CoV-2 infection. In fact, vitamin D affects the renin-angiotensin system pathway and promotes the expression of angiotensin-converting enzyme 2 (ACE2), which downregulates by SARS-CoV-2 96 .

Concerning all of the limitations and no adequate high-quality data about relation of vitamin D status and COVID-19 after several months, we have conducted this systematic review and metaanalysis in order to maximize the use of every available data, which would give us an overview toward further studies like what we have done recently on the effectiveness of hydroxychloroquine in COVID-19 patients 97 , which have underestimated first, but the value was revealed after a while. We also hypothesize that vitamin D deficiency can be in correlation with COVID-19 mortality rates and recovery rate, which has studied through an ecological strategy.

Unfortunately, there were no clinical trials and high-quality data regarding the role of vitamin D in COVID-19. According to available data entered into our meta-analysis, we could only find that approximately half of the patients infected with SARS-CoV-2 were suffering from vitamin D deficiency and this vitamin was insufficient in about 43% of them. In case of relation between vitamin D levels and mortality/recovery rate of COVID-19 patients, some researchers were reported the dependence of COVID-19 morbidity and mortality to the latitude 99, 100 ; similarly, our hypothetical strategy and big data analysis resulted several direct and reverse correlations in this regard. A quick look at the Fig. 5 shows that there is no regular relation for mortality or recovery rate by increasing vitamin D levels, but significant fluctuations observe regarding each country.

Despite the fluctuation, considering latitudes, showed a small reverse correlation between vitamin D status and mortality rate worldwide, which indicates that populations with lower levels of vitamin D might be in higher risk of SARS-CoV-2 infection. However, focusing on continents and countries one by one, indicates interesting findings in this case. For example, vitamin D status in Asia, Middle East, Africa and Oceania is correlated to the mortality reversely, whereas, it is in direct correlation with mortality in both North and Sought America. This might attract the considerations to the racial and ethnic aspects of the subject in different regions and populations 101, 102 . In case of recovery rate, while most of the continents indicated a direct correlation with vitamin D status, Africa and Oceania are significantly showed a reverse correlation in this regard. Considering Table 2 , in Africa, the highest mean levels of vitamin D is related to Guinea-Bissau and Tanzania. This finding might be due to the numerous challenges such as human resource, health care systems budgetary, poor management, etc. in such regions [103] [104] [105] , which unavoidably affects the subject significantly. About Oceania, it seems that extremely high rate of recovery in both Australia and New Zealand led to this statistical outcome.

Ultimately, to best of our knowledge, this is the most comprehensive systematic review that carried out a meta-analysis for investigating the role of vitamin D in COVID-19 patients along with a wide ecological consideration. However, after releasing outcomes of underway mentioned RCTs, an updated systematic review and meta-analysis on this subject could be more conclusive and reliable.

It is worth noticing that the current meta-analysis includes the following limitations:1) studies entered into the meta-analysis were observational and cross-sectional; thus, comparative analyses were not applicable in first part of study; 2) There are inevitable challenges with reliability of data due to different strategies in testing (e.g. vitamin D measurement, COVID-19 test, etc.), various subpopulations, etc. in both first part and ecological part of study; 3) other immunomodulator factors (e.g. vitamin C, zinc, selenium, etc.), which might be effective in the outcome of COVID-19 patients, have not considered in included studies; and 4) type II statistical errors following studies with small sample size. Eventually, to overcome the limitations and bias, results of the study should be confirmed by robustly large multicentral randomized clinical trials.

The conditional evidence recommends that vitamin D might be an important supportive agent for the immune system, mainly in cytokine response regulation against pathogens. In this systematic review and meta-analysis along with an ecological approach, we found a high percentage of COVID-19 patients who suffer from vitamin D deficiency or insufficiency. More importantly, our ecological investigation resulted in substantial direct and reverse correlations between recovery and mortality rate of COVID-19 patients with vitamin D status respectively in different countries. Considering latitudes, a small reverse correlation between vitamin D status and mortality rate was found throughout the world. Altogether, it seems that populations with lower levels of vitamin D might be in higher risk of SARS-CoV-2 infection. However, further large clinical trials following comprehensive meta-analysis should be taken into account in order to achieve more reliable findings. Additionally, due to multiple limitations, if this study does not allow to quantify a "value" of the 

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The authors declare that they have no conflict of interests.

None.