It has been hypothesized that vitamin D could help prevent or decrease the severity of COVID-19 infection by regulating the renin-angiotensin system and by enhancing innate or adaptive immunity. In vitro studies suggest that vitamin D may also decrease the severity of the cytokine storm, which contributes to morbidity and mortality in patients with severe COVID-19 disease. In observational studies, COVID-19 patients with lower serum concentrations of 25-hydroxyvitamin D had worse outcomes, when compared with patients with higher 25-hydroxyvitamin D levels. This latter finding does not necessarily suggest that vitamin D sufficiency confers protection against COVID-19. That is because 25-hydroxyvitamin D levels decline in response to inflammation, so a low 25-hydroxyvitamin D level may be an effect, rather than a cause of more severe disease. Nevertheless, because vitamin D is inexpensive, usually safe for short-term use even in relatively high doses, and widely available throughout the world, its potential as a treatment for COVID-19 deserves serious consideration. At the time of this writing, two clinical trials have been published, and the results are very encouraging.
In one study, which the authors described as a quasi-experimental study, data were collected retrospectively on 66 frail elderly individuals (mean age, 87.7 years) living in a nursing home in France who had been infected with COVID-19 in March or April of 2020. Because of the high prevalence of vitamin D deficiency in the French nursing home population, all residents of this nursing home regularly receive vitamin D3 supplements from the nursing staff. The dosage is 80,000 IU, given as a single oral dose, every two to three months. The COVID-19 patients were divided into two groups. The intervention group (n = 57) included those who received their regular dose of vitamin D either in the week after the onset of COVID-19 or in the previous month. The control group (n = 9) consisted of patients who did not receive vitamin D during those time periods. The patients were followed until May 15, 2020, a mean of 36 days after diagnosis. The primary outcome was death due to COVID-19. The secondary outcome was disease severity, which was measured by the World Health Organization’s Ordinal Scale for Clinical Improvement (OSCI) during the most severe acute phase of the disease for each patient. OSCI scores range from 0 to 8, with 0 indicating benign disease and 8 indicating death. An OSCI score of 4 corresponds to the use of oxygen and a score of 6 corresponds to intubation and the use of a ventilator. During the follow-up period, 15 people died and 51 survived. The mortality rate was significantly lower in the intervention group than in the control group (17.5% vs. 55.6%; p = 0.023). In addition, the mean OSCI score was significantly lower in the intervention group than in the control group, both before (-2.96 points; p = 0.002) and after (-3.84 points; p = 0.001) adjustment for potential confounding variables.
A second recent study was a randomized controlled trial that examined the effect of calcifediol in patients hospitalized with COVID-19. Calcifediol is more commonly known as 25-hydroxyvitamin D, which is a normal metabolite of vitamin D. It is approved by the US Food and Drug Administration as a prescription drug for the treatment of secondary hyperparathyroidism in patients with stage 3 or 4 chronic kidney disease. The new study enrolled 76 patients (mean age, 53 years) hospitalized in Cordoba, Spain, who had a positive polymerase chain reaction (PCR) test for COVID-19, a clinical picture of acute respiratory infection, and radiographic evidence of viral pneumonia. The patients received best-available therapy (including hydroxychloroquine and azithromycin) and were randomly assigned to receive in a 2:1 ratio, oral calcifediol (n = 50) or no calcifediol (control group; n = 26). The dosage of calcifediol was 0.532 mg on the day of admission, 0.266 mg on days 3 and 7, and then 0.256 mg once a week until discharge or admission to the intensive care unit (ICU). The proportion of patients who required admission to the ICU was significantly lower in the calcifediol group than in the control group (2% vs. 50%; p < 0.001). After adjustment for potential confounding variables (such as hypertension or type 2 diabetes), the risk ratio for ICU admission was 0.03 (95% confidence interval, 0.003-0.25). The death rate was 0% in the calcifediol group and 7.7% in the control group (p value not stated).
Vitamin D is converted in vivo to calcifediol, so it would be reasonable to assume that vitamin D would also have some degree of efficacy against COVID-19. That assumption is supported by the quasi-experimental study reviewed above. Widespread use of calcifediol for COVID-19 is not feasible, because it is a prescription drug and because it is very expensive (more than $1,200 for a course of treatment). In contrast, vitamin D is inexpensive and can be obtained without a prescription. Vitamin D therefore seems to be a better candidate than calcifediol for routine use during the COVID-19 pandemic.
It is not clear what dosage of vitamin D would be equivalent to the dosages of calcifediol used in the study described above. A dose of 0.532 mg of vitamin D3 (the amount of calcifediol given on the first day) is equal to 21,200 IU. However, calcifediol is considered to be more potent than vitamin D because it produces greater increases in serum 25-hydroxyvitamin D concentrations.
The available evidence suggests that it is important to maintain adequate vitamin D status during the pandemic, and that short-term vigorous vitamin D supplementation may be beneficial for people who become infected with COVID-19. Vitamin D may be used in combination with other potentially beneficial treatments for COVID-19, such as probiotics.
Alan R. Gaby, MD
TOWNSEND LETTER – JANUARY 2021, Pgs. 87-88
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