The ongoing COVID-19 pandemic has affected millions across the globe not only physically but also psychologically and economically. It has highlighted many gaps in our knowledge of human physiology, including genetic-biochemical reactions of infection and immune regulatory response to challenges with unknown etiology. Studies have been conducted to understand the patients’ characteristics in the first and second waves of the pandemic. With the emergence of newer mutant strains, the second wave was more intense in terms of oxygen and ventilation requirement, disease spread, and positivity rate as reported by Jain VK et al. [15]. They also reported increased breathlessness and infectivity rate among younger patients in the second wave. Overall, COVID-19 has resulted in a huge loss of human life. Thus, it is of paramount importance to investigate the risk factors for the transmission of SARS-CoV-2 infection as well as the clinical course of COVID-19.
During the pandemic, several studies have attempted to decipher the plausible role of micronutrients in protecting against COVID-19 severity and mortality. One such micronutrient is vit D. Earlier studies have shown a correlation between incidences of respiratory tract viral infection and 25-hydroxyvitamin D levels [16].
In this scenario, deciphering the plausible role of micronutrients in protecting against COVID-19 severity and mortality, especially vitamin D deficiency may represent an easily modifiable risk factor, particularly considering the limited cost and the safety of vitamin D supplementation. Interestingly, 50% of the present study cohort was deficient in vit D, yet the findings from our study observed no significant correlation between vit D status (deficient, insufficient, and sufficient) and COVID-19 severity and mortality. Our data corroborated with findings from other studies. Jevalikar et al. in a tertiary care center in New Delhi, India carried out a prospective, observational study and observed that 48.2% (n = 197/410) of their study population was deficient in vit D. The authors found no association between levels of vit D and COVID-19 severity and mortality. They also concluded that vit D deficiency was not associated with levels of inflammatory markers [7]. Another study comprising people from 24 Asian countries observed that the number of patients with COVID-19 infections and mortalities did not show a significant correlation when the mean Vit D levels were used alone but when the other confounding factors were taken into account, the number of COVID-19 infections and mortalities were significantly correlated [17]. A study carried out an analysis on 348,598 subjects obtained from UK Biobank data. Among these, 449 subjects were diagnosed with COVID-19 infection. They did not find any association between levels of vit D and COVID-19 infection either on univariate or multivariate analyses [18]. Hernandez et al. in a cohort of 216 COVID-19 patients also found no association between vit D deficiency and COVID-19 severity including ICU admission, mechanical ventilation, and mortality [8]. A meta-analysis and systematic review of 26 studies including 8176 COVID-19 patients observed no association of the risk of COVID-19 infection with vit D deficiency. However, vit D deficient subjects had significantly severe disease [19].
On the contrary, a few studies differ in their outcomes with respect to the role of vit D in COVID-19. Very recently, Dror et al. observed that patients with insufficient vit D levels prior to infection, had severe COVID-19 and increased mortality rate during hospitalization [20]. Israel and colleagues analyzed the level of vit D in 5,76,455/13,59,399 subjects between 2010 to 2019. Of these, 52,405 were subsequently COVID-19 positive and 5,24,050 served as controls. A significant association of lower levels of vit D with the risk of SARS-CoV-2 infection was noted [21]. Hyoung et al. in their study found that 67% of mild COVID-19 patients were deficient in vit D at the time of presentation. They further elucidated that 80% of the vit D deficient subjects had severe disease and required mechanical ventilation [5]. Two other independent studies carried out by Kaufman et al. and Meltzer et al. found lower levels of vit D correlated with SARS-CoV-2 positivity [22, 23]. Other small cohort studies detected a positive association between vit D deficiency/insufficiency and COVID-19 severity [6, 24–28].
Thus, literature regarding the association between vit D levels and COVID-19 severity is equivocal. The variability in findings may be attributed to the different cohorts of patients wherein some studies included asymptomatic or mild cases while others included only moderate to severe cases. Moreover, some studies had a very low sample size.
Further using Mann Whitney test/Chi-squared test, we performed a comparison between the levels of vit D, diseases’ status (severity), survival/mortality rate, and the effect of pre-existing comorbidities among COVID-19 patients of waves 1 and 2. Our analysis did not show any significant correlation between levels of vit D, disease severity, and comorbid conditions except for existing hypertension (p = 0.036) among those who had insufficient vit D levels. An interesting observation in our study was the survival status among COVID-19 patients with deficient/insufficient vit D. Although a distinct outcome was observed between waves 1 and 2, it appears to be independent of levels of vit D.
To the best of our knowledge, this is the first study to highlight that lower levels of vit D are not responsible for poor prognosis in COVID-19 infected Indian patients comparing both the first and second waves of the pandemic in India. In fact, a recent study carried out by two of the investigators of this team showed that 79.05% of Indians suffer from vitamin D deficiency (hypovitaminosis), and an additional 10.88% have insufficient vitamin D levels (unpublished; EC/05/19/1525). Knowing this fact, our study analysis provided a very useful outcome, especially for Indian patients suffering from SARS-CoV-2 infection.
To further substantiate our findings, we performed the coefficient correlation analysis of levels of IL6, ferritin, and CRP among the COVID-19 patients and their vit D levels. The study revealed that levels of the above markers of cytokine storm, the hallmark of COVID-19 severity were not significantly higher among vit D deficient COVID-19 patients. This outcome reflects the data of our analysis that showed that the severity of the disease does not correlate to vit D levels. Pizzini et al., in their study of 109 patients, observed that vit D deficiency did not correlate with levels of pro-inflammatory cytokines (IL-6, CRP, ferritin, and D-dimer) [29]. Another recent study by Jevalikar et al. also showed no statistical significance between vit D deficiency and disease severity and inflammatory markers (IL-6, CRP, and ferritin) in a cohort of 410 COVID-19 patients [7].
Although this study was carried out before the third wave (Omicron variant), the resulting outcome most likely will not be affected since the SARS-CoV-2 virus has not changed substantially to negate the effect of vit D. In this study, vit D was not re-evaluated before discharge and hence those on supplementation were not mentioned. There is need to find out the mechanistic pathway responsible that could have a direct or indirect role in COVID-19.