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The SARS-CoV-2 virus responsible for the COVID-19 pandemic has generated an explosion of interest both in the mechanisms of infection leading to dissemination and expression of this disease, and in potential risk factors that may have a mechanistic basis for disease propagation or control. Vitamin D has emerged as a factor that may be involved in these two areas. The focus of this article is to apply our current understanding of vitamin D as a facilitator of immunocompetence both with regard to innate and adaptive immunity and to consider how this may relate to COVID-19 disease. There are also intriguing potential links to vitamin D as a factor in the cytokine storm that portends some of the most serious consequences of SARS-CoV-2 infection, such as the acute respiratory distress syndrome. Moreover, cardiac and coagulopathic features of COVID-19 disease deserve attention as they may also be related to vitamin D. Finally, we review the current clinical data associating vitamin D with SARS-CoV-2 infection, a putative clinical link that at this time must still be considered hypothetical.



Summary of molecular features that could link vitamin D to COVID-19 infection

The innate immune system is the first line of defense against invading pathogens, such as viruses. It is prebuilt, relying on constitutive expression of pattern recognition receptors like TLRs to identify such pathogens. 1,25(OH)2D enhances that defense by inducing antimicrobial peptides such as cathelicidin that lead to viral destruction and clearance by several mechanisms, helps recruit neutrophils, monocytes/macrophages, and dendritic cells which further the killing and clearance of these pathogens, and initiates the adaptive immune response. While beneficial acutely, chronic activation of the innate immune response is not necessarily beneficial, and can result in a cytokine storm. 1,25(OH)2D works to curtail this chronic innate immune response through a number of mechanisms including down regulation of TLRs and direction inhibition of TNF/NFκB and IFNγ signaling pathways. The adaptive immune system provides a more specific response, but takes longer to develop, although once developed provides a powerful response against invading organisms. However, this response if not controlled can also be destructive. Vitamin D, via its active metabolite 1,25(OH)2D, regulates adaptive immunity by limiting the maturation of dendritic cells, limiting their ability to present antigen to T cells, and shifting the T cell profile from the proinflammatory Th1 and Th17 subsets to Th2 and Treg subsets, which inhibit the proinflammatory processes. Although these results come from studies with a variety of pathogens, viral and bacterial, the relevance of these protective actions on SARS-CoV-2 merits further investigation.




Lower 25-OHD concentrations are associated with a higher risk for infections, especially from the respiratory tract (139). Seeking a link to acute respiratory infections, Sabetta et al. measured monthly 25-OHD concentrations in 198 healthy adults and followed them during fall and winter (140). Individuals with 25-OHD concentrations ≥38 ng/mL had a two-fold lower risk of viral acute respiratory infections and faster recovery, compared to those with lower concentrations (P < 0.0001). Other studies have also found an association between lower levels of 25-OHD and higher risk of acute respiratory infections but with different thresholds. Nevertheless, they are consistent in showing that the lower the 25-OHD concentration, the greater the risk for acute respiratory infections. Generally, higher-risk occurred at 25-OHD concentrations below 20 ng/mL, but in a retrospective study of 14 108 individuals from the National Health and Nutrition Examination Survey, levels <30 ng/mL were associated with 58% higher odds of acute respiratory infections (141142143).

Recently, Martineau et al. reported the effects of Vitamin D supplementation to prevent acute respiratory infections (144). This meta-analysis included 25 randomized double-blind placebo-controlled trials with individual data from 10 933 patients across the lifespan. Vitamin D supplementation decreased risk of respiratory tract infections by 12%. A stronger protective effect was observed in those with baseline levels of 25-OHD <10 ng/mL compared with those with a baseline levels > 10 ng/mL. This protective effect was much more evident in those receiving daily or weekly doses of vitamin D in contrast to those receiving bolus doses. When combining the daily and weekly doses, the protective effect was more evident at baseline concentrations <10 ng/mL but also at baseline levels ≥10 ng/mL.



Clinical data linking Vitamin D to COVID-19 infection

In a small study (n = 20) of hospitalized COVID-19 patients, vitamin D insufficiency (defined as levels of 25-OHD < 30 ng/mL) was present in 75% of the overall cohort and in 85% of those who required ICU care (n = 13) (145). Additionally, an analysis of COVID-19 severity based on survey vitamin D status in Europe suggested that countries with highest rate of vitamin D deficiency are associated with highest rates of infection and death (146). Furthermore, a preliminary study from the United States has found a strong correlation of vitamin D deficiency with mortality and other aspects of poorer outcome (147).

Recently, Ilie et al. observed a significant negative correlation between historical mean25-OHD concentrations per European country with COVID-19 mortality and number of cases (148). Following similar reasoning, Marik et al. observed a higher fatality rate for COVID-19 for Northern (>40°N latitude) vs Southern states (6.0% vs 3.5%, P < 0.001) in the US (149). Very recently, Gennari et al. reports lower levels of 25-OHD levels among patients hospitalized with COVID-19 in Italy (150). In the aggregate, these data suggest a potential deleterious effect of vitamin D deficiency on risk and outcome in COVID-19 disease.

D’Avolio et al. investigated retrospectively 25-OHD concentrations in 107 patients who were tested for COVID-19 by nasopharyngeal swab from March 1 to April 14, 2020, in a single hospital from Switzerland (151). The median 25-OHD level was 22.2 ng/mL, similar to the median of a control cohort from the same period in 2019 (24.6 ng/mL). In the 27 individuals with PCR positivity for SARS-COVID-2, the median 25-OHD was 11.1 ng/mL while in those who were PCR negative, the median was 24.6 ng/mL; P < 0.004. This relationship, however, was not found by Hastie et al. using UK biobank data (152). They investigated 449 individuals with confirmed COVID-19 infection who had 25-OHD concentrations obtained 10 years before. The initial inverse association disappeared after adjustment for confounders. Male sex, poorer health status, socioeconomic deprivation, age, BMI, and ethnicity were predictive factors for COVID-19 in a multivariable logistic regression. Curiously, they could also not find any association of this viral infection with diabetes, blood pressures, or smoking. Grant et al. have provided evidence that vitamin D supplementation might be associated with reduce risk of COVID-19 infections and deaths (153).

It is intriguing that, Italy and Spain, which have been heavily affected by COVID-19 are among the European Countries with the highest prevalence of hypovitaminosis D (142). In a sampling of 700 Italian women, 60-80 years old, 25-OHD levels were reported to be lower than 12 ng/mL in 76% (154). Moreover, prevalence of hypovitaminosis D was reported in up to 32% of healthy postmenopausal women in winter and more than 80% in institutionalized individuals (155). Diabetes and obesity, recognized risk factors for the disease or for its severity, are characterized by poor vitamin D status and elevated vitamin D requirements (154156). In the vast majority of hospitalized elderly Italian subjects, hypovitaminosis D was present with more than half showing severe vitamin D deficiency. Lack of vitamin D also correlated with inflammatory parameters (157).

Endogenous levels of 25-OHD are dependent, to variable extent on sun irradiation, particularly in those countries where foods are not fortified in vitamin D. Low vitamin D status could potentially be a mechanistic link between age, comorbidities and increased susceptibility to complications and mortality due to COVID-19 at least in some countries (9148). However, in Italy, vitamin D is predominantly prescribed to post-menopausal women with osteoporosis and for this reason, it can be hypothesized that older men are, at least in part, more vulnerable to the most serious consequences of the infection on this basis (153158)

The available clinical data, in brief, are still very preliminary with regard to vitamin D status and COVID-19 disease. Many reports, to date, have been published without rigorous peer-review, are retrospective, and only associative. Caution is, therefore necessary in interpreting the data. Nevertheless, recent publications consistently show a higher prevalence of vitamin D deficiency in patients presenting with severe forms of COVID-19 (153). In addition, putative mechanisms underlying vitamin D’s role in immunity and non-skeletal actions, would provide support for the hypothesis advanced that vitamin D deficiency is a risk factor for the disease and/or its adverse outcome. Clearly, there are other factors to consider that include not only established risk factors (159160161) but also local public health measures that are taken to control the spread of the SARS-CoV-2 virus.

An increasing number of clinical trials are being registered to investigate the effect of vitamin D supplementation or 25-OHD levels on various COVID-19 outcomes (159). Until the results of these trials are known, a prudent, general health measure is to ensure vitamin D sufficiency. For most individuals worldwide, this recommendation comes with the need for vitamin D supplementation in order to maintain adequate circulating levels of 25-OHD.





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