Sars-CoV-2 mortality differs widely by country. Factors contributing to this variation include differences in testing/reporting, access to healthcare resources, and the presence of and public adherence to policy interventions such as social distancing and mask-wearing. However, underlying biological mechanisms may also impact viral mortality. It is important to evaluate biological reasons for the difference in COVID-19 mortality, as failure to do so limits worldwide capacity to develop pharmacologic responses for treatment of infected symptomatic individuals. Furthermore, biological mechanisms affecting viral mortality are critical to providing insight as to why some infected individuals remain asymptomatic while others develop COVID-19. This latter phenomenon was recently observed in a population of individuals experiencing homelessness in Boston, Massachusetts: a stunning 88% of individuals testing positive for Sars-CoV-2 were asymptomatic.1 This is double the otherwise-reported asymptomatic rate of 40–45%.2
One potential biological reason for differences in mortality is vitamin D status. Low vitamin D is known to increase risk of both upper and lower respiratory tract infections.3 A recent (2019) systematic review and meta-analysis clarified that among individuals with vitamin D insufficiency (VDI) in particular, respiratory infection risk is negatively associated with vitamin D levels.4 Thus, vitamin D status is likely relevant for the contemporary pneumotropic Sars-Cov-2 virus.
Vitamin D and the Immune System
Several molecular mechanisms for this relationship between VDI and viral infection have been proposed. Vitamin D normally suppresses Th1 cell proliferation and enhances a shift towards Th2 cellular responses; consequent reductions in interferon-gamma and interleukin (IL)-2 follow.5 Similarly, vitamin D modulates dendritic cell signaling to reduce IL-12 production (which limits development of a Th1 response) and promotes IL-10 (thus inducing a tolerogenic, non-inflammatory response).6 Therefore, Th1 cells are increased in vitamin D insufficiency or deficiency (VDI/VDD). This overall shift towards a pro-inflammatory Th1-dominated state characterizes the immune status of symptomatic COVID-19 patients.7 In addition, vitamin D interferes with enveloped viruses via a cathelicidin-mediated disruption of the viral envelope.5 Cathelicidin is an endogenous anti-microbial peptide; it is upregulated in lung epithelial cells in the presence of vitamin D.8 Cathelicidin-mediated disruption has also been demonstrated for other viral and bacterial pathogens.5,8 Therefore again, low vitamin D status is associated with a reduction in capacity to respond to viral infection.
Supplementation of vitamin D during influenza virus infection has been shown to reduce excessive pro-inflammatory cytokine production, thus limiting inflammation-induced complications (e.g., pulmonary edema).6 Some respiratory viruses, such as respiratory syncytial virus and rhinovirus, downregulate vitamin D receptor levels in human bronchial epithelial cells.9 Exogenous supplementation improved in vitro antiviral activity through the aforementioned vitamin D-mediated cathelicidin pathway.
Vitamin D also suppresses CD26, a presumed adhesion molecule for Sars-Cov-2 virus host cell entry.10 Given these links between vitamin D status and COVID-19, calls for vitamin D supplementation among vulnerable groups have been made: older adults, nursing home residents, individuals with diabetes mellitus or obesity, individuals with darker skin, health care workers, and individuals who smoke.10
Epidemiology of VDI and VDD
The Endocrine Society defines VDI and VDD as serum 25(OH)D levels below 75 nmol/L (30 ng/mL) or 50 nmol/L (20 ng/mL)11. VDI is one of the most common nutritional deficiencies worldwide.12 Traditionally, VDI and VDD risk is highest among pregnant women, children, older individuals, institutionalized populations, and non-Western Immigrants.13 A study of healthy French adults demonstrated 80.3% with vitamin D levels < 30 ng/mL and 34.6% with vitamin D levels below 20 ng/mL.14 In this same study, VDI of < 20 ng/mL was associated with older age, living at a higher latitude, BMI > 24 kg/m2, or having been sampled between the winter months of January and March.14 Globally, winter months consistently demonstrate increased VDI.13,15 The positive association between latitude and vitamin D status is stronger among Caucasians than non-Caucasians.16 However, among a geographically-representative study of healthy Chinese adults, younger adults (18–39 years) had lower vitamin D levels than older adults (> 49 years), possibly due to increased time spent indoors by working, young adults.17 No significant geographic differences were noted according to distance from the equator (and hence sunlight exposure), which the authors ascribed to the study’s inclusion of coastal cities where fish consumption is high.17 Finally, low vitamin D status can occur for a variety of factors even at low-latitude countries; a study of healthy adults in Syria found a positive association between VDI and female gender, and VDI and hijab-wearing; seasonality of VDI was noted in men, but not women for this study as well.18
Within the United States, the National Health and Nutrition Examination Survey has demonstrated increased risk for VDI among the following: African-American individuals, individuals with obesity, and individuals who self-rate as generally having poor health. Over one third of all US adults have VDD, and prevalence is also increasing among younger populations.12 There is a significant ethnic difference in VDI, with higher prevalence noted among non-Hispanic blacks as compared to non-Hispanic whites.13 This difference according to skin pigmentation is largely due to differences in dermal metabolism of relevant vitamin D precursors. Older adults often similarly demonstrate lower levels of vitamin D due to reduced dermal metabolism.13 In addition, VDI also parallels US socioeconomic disparities; socioeconomic achievement, measured by completion of a college degree, is significantly negatively associated with VDI.19Among respondents with available vitamin D level data, 82% of African-Americans had VDI, followed by 69.2% of Hispanics.20
The factors associated with low vitamin D status are similar to those risk factors associated with COVID-19.21 Given the global importance of understanding the biological mechanisms underlying morbidity and mortality of Sars-CoV-2, the goal of this study is to evaluate the country-level relationship between COVID-19 mortality and VDD. Because vitamin D levels and clinical outcomes have been shown to be more pronounced among patients with lower vitamin D status,4 VDD was specifically selected as the condition of analysis for this study.
Early investigations of this relationship have reported associations between population level vitamin D levels and COVID-19 impact in terms of population case rate, case mortality rate and population mortality rate22–25. However, these studies have relatively small sample sizes, focus on homogenous European populations, and are cross-sectional in nature, and thus do not provide insight to the impacts over time as the epidemic unfolded. Additionally, these studies did not justify the use of Pearson correlation or regression to assess the relationship, which assumes distribution of rates are normally distributed. To better understand the potential association between COVID-19 mortality and vitamin D deficiency in international populations, this study will assess determinants of COVID-19 deaths during the initial outbreak period in each country. We have focused on the number of deaths as it is clinically significant representation of disease severity and impact and it does not depend on testing strategies in each country.
Cumulative infectious disease death curves are typically visualized on a logarithmic-scale as early infectious disease growth is exponential. Over time, the exponential growth slows due to disease management and control (i.e. “flatten the curve”) and reduced population susceptibility (i.e. herd immunity, risk factors), resulting in an “S” shaped curve. Figure 1 shows the COVID-19 death curve for France from March 6 through July 20, 2020. An exponential growth model for the first 30 days indicated deaths were doubling approximately every 3 days, then the rate of increase began to slow. Many factors influence the shape and scale of the cumulative death curve for a country, including population size, the prevalence of risk factors like age and health status, and disease control measures.
COVID-19 has disproportionately impacted older individuals. In the US, it is estimated that 80% of the deaths are in people 65 years or older26. In addition to age-related changes in vitamin D metabolism, modifiable determinants of deficiency within older adult or elderly populations include medication polypharmacy, inadequate nutrition, and lifestyle changes lowering natural sun exposure.27–30 Therefore, we have conducted an ecological country-level study of the relationship between the rate of vitamin D deficiency among older adults and cumulative COVID-19 deaths in countries during the initial outbreak period.