key: cord-324288-qgxswltx
authors: Padhi, Sunali; Suvankar, Subham; Panda, Venketesh K.; Pati, Abhijit; Panda, Aditya K
title: Lower levels of vitamin D are associated with SARS-CoV-2 infection and mortality in the Indian population: an observational study
date: 2020-09-14
journal: Int Immunopharmacol
DOI: 10.1016/j.intimp.2020.107001
sha: 
doc_id: 324288
cord_uid: qgxswltx

BACKGROUND: The role of vitamin D in the susceptibility and severity of various viral diseases has been well documented. Recently, some reports highlighted the possible importance of vitamin D in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Although India receives adequate sunlight throughout the year, the majority of Indians are deficient in vitamin D levels. In the present study, we hypothesized that vitamin D deficiency would be associated with the SARS-CoV-2 infection rate and mortality in the Indian population. MATERIALS AND METHODS: SARS-CoV-2 infection and mortality data were obtained from the Government of India's official website (accessed on 16(th) August 2020). Various literature databases like PubMed and Google Scholar were searched to find the mean of 25-hydroxyvitamin D [25(OH)D] levels in different states and union territories of India, Pearson correlation was carried out to investigate the possible link between mean 25(OH)D levels and SARS-CoV-2 infection and mortality per million of the population. RESULTS: An inverse correlation was observed between the mean level of 25(OH)D and SARS-CoV-2 infection rate (r= -0.43, p= 0.02) and mortality rate (r= -0.42, p= 0.02). CONCLUSIONS: The present observational study revealed an association of vitamin D with SARS-CoV-2 infection and related mortality. Further studies are required to validate our observations.

Novel coronavirus disease 2019 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was first reported in Wuhan, China, in December 2019 [1] and has spread worldwide to 215 countries till date (https://www.worldometers.info/coronavirus/). On 11th March 2020, COVID-19 disease was declared a global pandemic by the World Health Organization (WHO)(https://www.who.int/dg/speeches/detail/who-director-general-s-openingremarks-at-the-media-briefing-on-covid-19---11-march-2020). India reported the first case of COVID-19 in a student who returned from Wuhan University China in Thrissur district of Kerala state on 30 th January 2020 (https://www.cnbc.com/2020/01/30/india-confirms-first-case-of-thecoronavirus.html). As on 16 th August 2020, 2.59 million of SARS-CoV-2 infected cases has been reported in India, and a total of 50,431 death has been encountered. Maharashtra and Tamil Nadu states contributed the maximum number of infected cases and posed a high mortality of SARS-CoV-2 infected patients in India.

Individual immune systems, which are determined by several factors, play a major role in the susceptibility and pathogenesis of viral diseases. The importance of vitamin D in the modulation of both innate and adaptive immune systems has been demonstrated [2] . In the skin, provitamin D 3 (7-dehydrocholesterol) is converted to previtamin D 3 after exposure to Ultraviolet-B (UVB) radition. The previtamin D 3 is transported to the liver and hydroxylated at 25 th carbon atom.

The active metabolites 1,25(OH) vitamin D 3 is hydroxylated for the second time at C-1 at the kidneys [3] . Furthermore, 1-hydroxylation of vitamin D 3 is also reported in macrophages, monocytes, B and T lymphocytes [4] .Vitamin D deficiency has been associated with susceptibility to a wide range of viral infections, such as Human Immunodeficiency Virus, Influenza Virus, Epstein -Barr Virus, Hepatitis B, Human Respiratory Syncytial Virus [5] . However, the role of vitamin D in SARS-CoV-2 infection is not well understood. Some recent investigations have highlighted the beneficial role of vitamin D against SARS-CoV-2 infection and related clinical severity [6] [7] [8] [9] [10] [11] [12] [13] , by modulating the immune system [14] . In addition, a recent study in UK population reported the worst morbidity outcome in older patients with vitamin D deficiency [13] .

Although India is close to the equator and receives a large amount of sunlight throughout the year, most of the Indian population (50-90%) is deficient in vitamin D [15] . In addition, 

We investigated the correlation between vitamin D and COVID-19 disease in the Indian population to minimize the effect of various confounding factors such as ethnicity, latitude, health facility, etc. India is comprised of twenty-eight states and eight union territories (UTs) and estimated inhabitants of 1380 million equivalent to 17.7% of the total world population. Vitamin D levels in healthy adults were searched through PubMed and Google Scholar in the Indian population. All relevant articles were screened, and data such as the author's name, year of publication, number of healthy subjects enrolled for the analysis, mean ± standard deviation or median, interquartile range of vitamin D were extracted.

SARS-CoV-2 data such as the number of cases, death figures, and the number of recovered persons were obtained from the official website of the Ministry of Health and Family Welfare, Govt. of India (www.mohfw.gov.in accessed on 16/08/2020). The population of each state and UTs were gathered from data of census performed in the year 2011 (https://censusindia.gov.in/2011common/censusdata2011.html). SARS-CoV-2 cases per million and death per million were calculated by using the census-2011 data. Based on suggestions how to present numerical data appropriately [16] , the infection rate per million were converted into multiples of ten. Dearth rate and mean vitamin D levels were represented in whole numbers.

Data on levels of 25(OH)D in the median and interquartile range were converted in to mean ± standard deviation format as described earlier [17] . The mean 25(OH)D levels in a state or UT with more than one report were pooled (https://home.ubalt.edu/ntsbarsh/Businessstat/otherapplets/Pooled.htm). The Pearson correlation test performed a correlation of mean 25(OH)D levels with SARS-CoV-2 infection and mortality rate. All statistical analysis was carried out by GraphPad Prism 8.3.0. A p-value <0.05 was considered as statistically significant. (Table 1) 

This study is the first of its kind to investigate the association of vitamin D with SARS- April 2020) [19] . However, after updating data on 12 th May 2020, the relationship was disappeared [21] . Further, a recent report highlighted a higher chance of SARS-CoV-2 infected patients being admitted to an intensive care unit compared to those with insufficient or sufficient levels of vitamin D in the UK population [9] . The risk of hospitalization in SARS-CoV-2 infected subjects with lower levels of 25(OH)D was higher in the Israeli cohort [7] . A recent analysis revealed lower mortality rates of COVID-19 in the equatorial region compared to geographical areas away from the equatorial line [22] , as confounding factors for SARS-CoV-2 related death [23] . Severe vitamin D deficiencies have been associated with those confounding diseases such as CKD [24] , COPD [25] , cerebrovascular disease [26] , and CHD [27] .

Although several clinical trials have been registered to investigate the role of vitamin D supplementation in the treatment of SARS-CoV-2 patients (https:/clinicaltrials.gov/ct2/results?cond=Covid19&term=vitamin+d&cntry=&state=&city=&dis t=) majority of these trials are in the enrolment phase or have yet to be started. A recent study has

shown that the administration of 1000 IU of vitamin D per day to four patients infected with SARS-CoV-2 leads to normalization of vitamin D levels, improved clinical condition, decreased oxygen requirements, reduced inflammatory markers, and shorter hospital stays [8] . In addition, another hospital-based randomised clinical study found that the use of calcifediol in infected SARS-CoV-2 subjects minimised the need for intensive care and reduced disease severity [28] . These [132] [133] [134] [135] [136] [137] [138] Note: SARS-CoV-2 data was accessed on 16.08.2020 

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