Vitamin D Levels and Risk of COVID-19

Current knowledge about vitamin D body levels and COVID19 infection: correlation with risk of infection, severity, mortality, supplementation dose, and causality.

September 18, 2020

Laboratories Surveal – Medical Department

Current knowledge about vitamin D body levels and COVID19 infection: correlation with risk of infection, severity, mortality, supplementation dose, and causality

• Vitamin D status and body levels: Vitamin D status below 20-30 ng/mL is associated with more severe disease or with mortality in COVID-19 patients. Data is collected from South Asian, Indonesian, Iranian, and European (Belgian and English) hospitals.
• For mortality in Indonesia, the association between low vitamin D status and COVID19 infection persists after adjusting for age, gender and preexisting conditions. 
• In Italy, hospitalized patients with COVID19 had lower mean vitamin D levels (18.2 ng/mL) than those with mild COVID-19 (30.3 ng/mL). From the patients that were admitted to ICU, those who died had lower baseline vitamin D levels than those who survived (13.2 vs 19.3 ng/mL)
• For severity of COVID19 as judged by the pulmonary CT scan in Belgium, the association between low vitamin D levels and severity of infection is depicted in males only.
• Vitamin D status below 20-35 ng/mL is more weakly associated with infection risk in Switzerland, the United States and England.
  • In Switzerland, 30-35 ng/mL was associated with reduced risk of infection mainly in those over 70 years of age. In England, infection risk correlated with vitamin D status lower than 20 ng/mL, but the infection risk disappeared when adjusted for confounders (although the vitamin D data was from 10-14 years before the pandemic was declared). 
  • In the US, infection risk correlated with vitamin D status lower than 30 ng/mL, but it only became statistically significant after very performing complicated statistical operations. 
• Three studies provide very limited insight into the possibility of a U-shaped curve. A U-shaped curve means that above a certain level of vitamin D the effect on COVID19 will:
  • Either remain the same as the maximum effect reached with levels between 30-40 ng/mL
  • Or that higher levels will have the same effect as lower levels that are 30-40 mg/mL.
    • In Switzerland, there are indications of a U-shaped curve effect in people under the age of 70, but not over the age of 70.
    • In Israel, there are indications of complete absence of infection and even more. Infection risk might be abolished over vitamin D levels of 53 ng/mL, but data is only from people under the age of 50.
    • In the US, data from the Chicago study show that there are suggestions that 40-100 ng/mL gives the same infection risk as 30-40 ng/mL. 
  • The above data may indicate a U-shaped curve restricted to an interaction between age and country.
• In Israel, infection risk and hospitalization was associated with vitamin D status below 30 ng/mL and this largely persisted after adjusting for confounding variables (age, gender, race, comorbidities like diabetes, obesity, etc.…).
• Data collected from different published – or preprints – trials shows that maintaining vitamin D levels in the 30-40 ng/mL range is adequate to secure any of the potential benefits identified in any of the studies done to date. Doing so might reduce the incidence and severity of COVID-19 at little to no risk.
• While all the published or still preprint studies do not all agree with one another on every endpoint evaluated, they unanimously point at the same: Vitamin D levels above 30 ng/mL are associated with a lower risk of COVID-19 infection risk and more strongly with lower severity and mortality. However, some studies show a stronger association between vitamin D levels and COVID-19 infection risk, morbidity and mortality, and others show a weaker association for the same endpoints. Also, and in some studies, adjustment for confounders (age, gender, race, comorbidities like diabetes, obesity, etc.…), makes this association disappear while in others, adjusting for the same confounders strengthens the association. 
• What about the cutoff for vitamin D status/levels? In some studies, the cutoff is lower than 30 ng/mL and in others, it is higher. But all of them suggest that having vitamin D levels above 30 ng/mL or even better between 30-40ng/mL is associated with lower COVID-19 infection risk, severity of disease and mortality. No matter what the supplementation dose with vitamin D: 1000 IU, 2000 IU, 3000 IU or greater (as per the Chicago study), the dose was not associated with the endpoint. The emphasis should be therefore on reaching a minimum of 30 ng/mL no matter the dose as long as safety is respected. 
• While the outdoor air is very safe and getting sunshine will provide many benefits, including synthesis of vitamin D in skin and body, the Northern hemisphere is entering into the 2020 fall and 2021 winter seasons making sunny days and outdoor activities to rely on synthesis of vitamin D in skin less possible. Thus, supplementing with vitamin D to keep levels of 25(OH)D above 30 ng/mL when needed, is an easy practice.

    In summary, with respect to COVID-19, there is no rationale for keeping vitamin D levels any higher than 40 ng/mL. The data is there that it positively impacts risks and the mechanism by which it does so is quite complicated, including acting on ACE₂ receptors, decreasing production of interleukin IL-6, decreasing cytokine storm etc.

    Although higher blood levels of 53 mg/mL might abolish the infection risk as seen in one study in Israel in those under 50 years of age, it is wise to use supplementation means to achieve levels between 30 and 40 ng/mL.

• 24 registered clinical studies (on clinicaltrials.gov) are currently looking at the causality between vitamin D deficiency, supplementation and COVID19 (link attached for your perusal): https://clinicaltrials.gov/ct2/results?term=%22vitamin+d%22&cond=covid-19&age_v=&gndr=&type=Intr&rslt=&Search=Apply

References:

1. Alipio M. Vitamin D supplementation could possibly improve clinical outcomes of patients infected with Coronavirus-2019 (Covid2019)- preprint: Philippines
2. D’Avolio A et al. 25-Hydroxyvitamin D Concentrations Are Lower in Patients with Positive PCR for SARS-CoV-2. Nutrients 2020, 12(5), 1359; https://doi.org/10.3390/nu12051359
3. Busko M. Low Vitamin D in COVID-19 Predicts ICU Admission, Poor Survival – Medscape – Sep 17, 2020
4. Dieter De Smet et al. Vitamin D deficiency as risk factor for severe COVID-19: a convergence of two pandemics. Preprint: MedRxIV. May 2020. https://doi.org/10.1101/2020.05.01.20079376
5. Panagiotou G et al. Low serum 25-hydroxyvitamin D (25[OH]D) levels in patients hospitalized with COVID-19 are associated with greater disease severity: results of a local audit of practice. Preprint: MedRXIV; June 2020. https://doi.org/10.1101/2020.06.21.20136903
6. Meltzer DO et al. Association of Vitamin D Deficiency and Treatment with COVID-19 Incidence. Preprint. MedRxIV; May 2020. https://doi.org/10.1101/2020.05.08.20095893
7. Meltzer DO et al. Association of Vitamin D Status and Other Clinical Characteristics with COVID-19 Test Results. JAMA Network Open. 2020;3(9): e2019722. doi:10.1001/jamanetworkopen.2020.19722
8. Merzon E et al. Low plasma 25(OH) vitamin D level is associated with increased risk of
9. COVID-19 infection: An Israeli population-based study. FEBS; July 2020. doi: 10.1111/FEBS.15495
10. Maghbooli Z et al. Vitamin D Sufficiency Reduced Risk for Morbidity and Mortality in COVID-19 Patients. THELANCET-D-20-12067. July 2020; 13 pages