The US breaks new records in the number of daily deaths from COVID-19. The dizzying speed with which several vaccines have been developed and deployed is still impressive. Still, we still have to face the painful prediction that our national death toll will exceed 500,000 Americans before widespread vaccinations can pull us out of this crisis. The response to the pandemic, therefore, should include an effort to aggressively eliminate what becomes evident as a risk factor for morbidity and mortality in vitamin D deficiency of COVID-19.
For any COVID-19 risk factor, such as obesity, hypertension, or diabetes, there are enough correlational data to inform clinical care, as in 1964 general surgeon Luther Terry. Report on smoking and health. This groundbreaking publication, which has saved tens of millions of lives from lung cancer, was based on a causal analysis by an advisory committee. The team reviewed existing data and relied on the work of Sir Austin Bradford Hill and Sir Richard Doll who had examined the rise in lung cancer cases in the UK. causality. He assumed that correlational data can be used to infer causality by meeting various criteria such as consistency, specificity, temporality, and dose response capacity. Vitamin D deficiency, associated with detrimental effects on innate and adaptive immunity, has many small but growing data sets that meet all of Hill’s criteria as a severe COVID-19 risk factor. And, unlike other risk factors, it can be sharply modified.
Jain and colleagues studied 154 patients who presented to a medical center for 6 weeks. When deaths were assessed based on vitamin D deficiency (serum 25-OH-D <20 ng / mL), the mortality rate was 21%, compared with only 3% of people with higher levels. More striking was that vitamin D deficiency was found in 97% of severe patients who needed ICU admission, but only in 33% of asymptomatic cases, suggesting that low levels are a necessary component of COVID- 19 sever. This is one of numerous studies this year that establishes the correlation of low vitamin D levels with an aggravated course of COVID-19, as revealed by a meta-analysis by Pereira and colleagues.
However, to confirm Hill’s criteria, not only is some experimental testing recommended, but it is necessary, and small randomized trials with aggressive vitamin D replacement 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 placebo or 420,000 IU colecalciferol (vitamin D3) in an action nanoemulsion. rapid divided into seven days, i.e., 60,000 IU (1,500 μg) per day. The results showed that supplementation helped eliminate the virus more quickly: 63% of treated patients tested negative for SARS-CoV-2 on day 14 compared to only 21% in the placebo group. In addition, the treated group showed a decrease in fibrinogen levels, which is thought to contribute to the increased risk of thrombotic events in COVID-19.
The Castillo team in Córdoba, Spain, randomized 76 hospitalized COVID-19 patients with a 2: 1 ratio to receive open-label or non-supplemented calcifediol, in addition to standard care. The intervention group received 1,064 μg of this fast-acting vitamin D analog in the first week three times more potent than vitamin D3, followed by 266 μg weekly thereafter. Of the treated patients, only 2% (1 in 50) needed ICU admission compared to 50% (13 of 26) in the untreated group. In addition, 8% of untreated patients died, compared with none from the intervention group. Although vitamin D deficiency at admission was not identified, the researchers cite a report that 25-OH-D levels in Córdoba in winter are deficient, averaging 16 ng / ml. The use of a study population that biases toward 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 such an aggressive replacement protocol in the treatment of COVID-19.
There is more evidence pointing in that direction. Using a quasi-experimental approach, Annweiler and colleagues examined elderly and frail patients hospitalized for COVID-19 in France. The researchers obtained records for those who regularly received bolus vitamin D3 supplements (between 20,000 and 50,000 IU per month, a common practice in French nursing homes) and those who did not. Only 10% of those who received regular supplements switched to severe COVID-19 compared with 31% of the non-supplemented group. In addition, 14-day mortality rates were only 7% in the supplemented group compared with the same 31% in the non-supplemented group. The researchers also identified a third group of patients: those who received a single dose of 80,000 IU of cholecalciferol at the time of diagnosis of COVID-19. This group worked better than the group that did not get any, but the result did not reach statistical significance, suggesting that the dose may have been too low or arrived too late.
We discovered a study pending peer review that did not demonstrate the benefits of treating vitamin D deficiency in COVID-19. The researchers administered a single dose (200,000 IU of vitamin D3) to patients ten days after COVID-19 symptoms appeared. Unlike calcifediol, the body can take a week or more to convert vitamin D3 into its active form. In addition, being fat-soluble, the body competes against adipose tissue to obtain the required amount, which requires higher doses of obesity (the mean BMI in this study was 31.6). Compare the dose given here with the standard protocol for correcting vitamin D deficiency in healthy outpatients, who are usually given a total of 600,000 IU divided into twelve weeks, at 50,000 IU per week.
Data like this is not new. An Austrian study conducted in 2014 with 475 patients showed that supplementation with 540,000 IU of vitamin D3 followed by 90,000 IU per month halved the hospital mortality rate in patients with ICU with severe vitamin D deficiency (level 25- OH-D <12 ng / ml). Patients with higher levels showed no benefit, highlighting a possible deficiency of many vitamin D trials: should they focus on outcomes only for those with deficiency?
It is not yet common practice to check serum 25-OH-D levels in hospitalized patients with COVID-19, although many professionals prescribe supplements at typical (and possibly insufficient) doses. A Canadian study of 22,214 supplemented people found that 1,000 IU of cholecalciferol daily increased 25-OH-D levels by an average of only 4.8 ng / ml, with decreasing yields for each additional increase of 1,000 IU per day. No toxicity was observed in people who reported taking doses of up to 20,000 IU per day, an amount roughly equivalent to that generated by a summer sunny afternoon on the skin. (Several medical companies claim that doses of 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 adverse effects).
As doctors, it is our responsibility not to wait for perfect evidence when making decisions about life or death. Given the safety profile of vitamin D, the 40% prevalence of vitamin D deficiency in the United States, and the fact that this season will probably be the deadliest phase of the pandemic to date, we need to act now. Identifying and eradicating vitamin D deficiency with early and aggressive COVID-19 supplements can save thousands of lives and should be one of our highest public health priorities.
Richard H. Carmona, MD, MPH, was the 17th U.S. surgeon general and is now a distinguished public health professor and incident commander at COVID-19 at the University of Arizona. Vatsal G. Thakkar, MD, is an integrative psychiatrist, founder of Reimbursify and can be followed Twitter. John C. Umhau, MD, MPH, is a retired commander of the U.S. Public Health Service and has published more than forty peer-reviewed research articles.