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Don’t Let COVID-19 Patients Die With Vitamin D Deficiency - Jan 5, 2021

— Don’t Let COVID-19 Patients Die With Vitamin D Deficiency - We can't wait for perfect evidence


by Richard H. Carmona, MD, MPH, Vatsal G. Thakkar, MD, and John C. Umhau, MD, MPH January 5, 2021

The following is a copy of MedPage Today

The U.S. is breaking new records in the number of daily deaths from COVID-19. The breakneck speed with which several vaccines have been developed and deployed is nothing short of breathtaking. Yet we still have to confront the grim prediction that our national death toll will exceed 500,000 Americans before widespread vaccinations can dig us out of this crisis. The response to the pandemic, therefore, should include an effort to aggressively eliminate what is becoming apparent as a morbidity and mortality risk factor in COVID-19 — vitamin D deficiency.

For any COVID-19 risk factor, like obesity, hypertension, or diabetes, strong correlational data is sufficient to inform clinical care, as in Surgeon General Luther Terry's 1964 Report on Smoking and Health. This groundbreaking publication, which has saved tens of millions of lives from lung cancer, was based on a causation analysis by an advisory committee. The team reviewed existing data and drew on the work of Sir Austin Bradford Hill and Sir Richard Doll who had examined the increase in lung cancer cases in the U.K. Hill later outlined the standards that were the result of their inquiry, now known as Hill's criteria for causation. He surmised that correlational data can be used to infer causality by satisfying various criteria such as consistency, specificity, temporality, and dose-responsiveness. Vitamin D deficiency, associated with deleterious effects on innate and adaptive immunity, has many small but growing datasets that satisfy all of Hill's criteria as a risk factor for severe COVID-19. And unlike other risk factors, it can be acutely modified.

Jain and colleagues studied 154 patients who presented to a medical center over 6 weeks. When deaths were evaluated on the basis of vitamin D deficiency (serum 25-OH-D <20 ng/mL), the fatality rate was 21%, compared to only 3% for those with higher levels. More striking was that vitamin D deficiency was found in 97% of severely ill patients who required ICU admission but in only 33% of asymptomatic cases, suggesting that low levels are a necessary component of severe COVID-19. This is one of numerous studies this year establishing the correlation of low vitamin D levels with an aggravated course of COVID-19, as a meta-analysis by Pereira and colleagues reveals.

Yet to firm up Hill's criteria, some experimental evidence is not only recommended but necessary, and small randomized trials with aggressive vitamin D replenishment have shown positive results. Rastogi and colleagues treated 40 individuals with mild COVID-19 and vitamin D deficiency (25-OH-D <20 ng/mL) with either placebo or 420,000 IU of cholecalciferol (vitamin D3) in a fast-acting nano-emulsion divided over seven days, i.e., 60,000 IU (1,500 μg) per day. The results showed that supplementation helped clear the virus faster — 63% of the treated patients tested negative for SARS-CoV-2 by the 14th day compared to only 21% of the placebo group. In addition, the treated group showed a decrease in levels of fibrinogen, which is thought to contribute to the higher risk of thrombotic events in COVID-19.

Castillo's team in Cordoba, Spain, randomized 76 hospitalized COVID-19 patients in a 2:1 ratio to receive either open-label calcifediol or no supplementation, in addition to standard care. The intervention group received 1,064 μg of this fast-acting vitamin D analogue in the first week three times more potent than vitamin D3, followed by 266 μg weekly thereafter. Of the treated patients, only 2% (1 out of 50) needed ICU admission compared to 50% (13 of 26) of the untreated group. In addition, 8% of the untreated patients died, compared to none in the intervention group. Though vitamin D deficiency was not identified on admission, the researchers cite a report that the 25-OH-D levels in Cordoba in wintertime are deficient, averaging 16 ng/mL. Using a study population that skews towards vitamin D deficiency makes this a good study to examine the benefits of aggressively correcting this deficiency in COVID-19. To our knowledge, only one critical care program in the U.S. has adopted a replenishment protocol this aggressive in their treatment of COVID-19.

There's more evidence pointing in this direction. Using a quasi-experimental approach, Annweiler and colleagues looked at frail, elderly patients hospitalized for COVID-19 in France. The researchers obtained records for those who regularly received bolus vitamin D3 supplementation — 20,000 to 50,000 IU per month, a common practice in French nursing homes — and those who did not. Only 10% of those who received regular supplementation progressed to severe COVID-19 compared to 31% of the non-supplemented group. In addition, 14-day mortality rates were only 7% in the supplemented group compared to the same 31% in the non-supplemented group. The researchers also identified a third group of patients — those who were given a single dose of 80,000 IU of cholecalciferol at the time of their COVID-19 diagnosis. This group fared better than the group that got none, but the outcome did not reach statistical significance, suggesting that the dose might have been too low or came too late.

We did discover one study awaiting peer-review which failed to show benefits of treating vitamin D deficiency in COVID-19. Researchers administered a single dose (200,000 IU of vitamin D3) to patients ten days after COVID-19 symptoms first appeared. Unlike calcifediol, it can take a week or longer for the body to convert vitamin D3 to its active form. In addition, being fat-soluble, the body competes against adipose tissue to procure the necessary amount, requiring higher doses in obesity (the average BMI in this study was 31.6). Compare the dose given here to the standard protocol to correct vitamin D deficiency in healthy outpatients, who are routinely given a total of 600,000 IU divided over twelve weeks, at 50,000 IU per week.

Data like this are not new. A 2014 Austrian study of 475 patients showed that supplementation with 540,000 IU of vitamin D3 followed by 90,000 IU per month cut the hospital mortality rate in half for ICU patients with severe vitamin D deficiency (25-OH-D level <12 ng/ml). Patients with higher levels did not show benefit, bringing to light a possible shortcoming of many vitamin D trials — should they focus on outcomes only for those who are deficient?

It's not yet common practice to check serum 25-OH-D levels in COVID-19 inpatients, even though many practitioners are prescribing supplementation at typical (and possibly insufficient) doses. A Canadian study of 22,214 supplemented individuals found that 1,000 IU of daily cholecalciferol increased 25-OH-D levels by an average of only 4.8 ng/mL with diminishing returns for each additional increment of 1,000 IU per day. Toxicity was not seen in people who reported taking doses as high as 20,000 IU per day, an amount roughly equivalent to what's generated by an afternoon of summer sun on the skin. (Various medical societies state that doses only up to 4,000 IU of vitamin D per day are safe without medical supervision, and that up to 10,000 IU per day showed no observed adverse effects.)

It is our responsibility as physicians not to wait for perfect evidence when making life-and-death decisions. Given the safety profile of vitamin D, the 40% prevalence of vitamin D deficiency in the U.S., and the fact that this season will likely be the deadliest phase of the pandemic to date, we need to act now. Identifying and eradicating vitamin D deficiency with early and aggressive supplementation in COVID-19 has the potential to save thousands of lives and should be one of our highest public health priorities.


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