The US is breaking new records in the number of daily deaths caused by COVID-19. The impressive speed with which several vaccines have been developed and implemented is not at all impressive. However, we must face the grim predictions that our national death toll will exceed 500,000 Americans before large-scale vaccinations can get 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 COVID-19 – vitamin D deficiency.
For any COVID-19 risk factor, such as obesity, hypertension, or diabetes, strong correlational data are sufficient to inform clinical care, as in 1964 surgeon General Luther Terry Smoking and health report. This groundbreaking publication, which saved tens of millions of lives from lung cancer, was based on a causal analysis by an advisory committee. The team analyzed existing data and relied on the work of Sir Austin Bradford Hill and Sir Richard Doll who examined the rise in lung cancer in the UK. Hill subsequently highlighted the standards that were the result of their investigation, now known as Hill’s criteria for causation. . He assumed that correlational data can be used to deduce causality by meeting different criteria, such as consistency, specificity, timeliness, and dose response. Vitamin D deficiency, associated with harmful effects on innate and adaptive immunity, has many small but growing data sets that meet all of Hill’s criteria as a risk factor for severe COVID-19. And unlike other risk factors, it can be acutely altered.
Jain and colleagues studied 154 patients who presented to a medical center for 6 weeks. When deaths were assessed on the basis of vitamin D deficiency (serum 25-OH-D <20 ng / ml), the mortality rate was 21%, compared to only 3% for those with higher levels. More striking was that vitamin D deficiency was found in 97% of seriously ill patients requiring ICU hospitalization, but only in 33% of asymptomatic cases, suggesting that low levels are a necessary component of severe COVID-19. This is one of many studies this year that correlate low levels of vitamin D with an aggravated course of COVID-19, according to a meta-analysis by Pereira and colleagues.
However, to confirm Hill’s criteria, some experimental evidence is not only recommended but also necessary, and small randomized studies with aggressive vitamin D replenishment have shown positive results. Rastogi and colleagues treated 40 people with mild COVID-19 and vitamin D deficiency (25-OH-D <20 ng / ml) with placebo or 420,000 IU colecalciferol (vitamin D3) in a nano-emulsion with rapid action divided into seven days, ie 60,000 IU (1,500 μg) per day. The results showed that supplementation helped eliminate the virus faster - 63% of treated patients tested negative for SARS-CoV-2 by day 14, compared with only 21% in the placebo group. In addition, the treated group showed a decrease in fibrinogen levels, which are thought to contribute to the increased risk of thrombotic events in COVID-19.
Castillo’s team in Cordoba, Spain, randomized 76 patients hospitalized with COVID-19 in a 2: 1 ratio to receive either open calcifediol or no supplements, 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 stronger than vitamin D3, followed by 266 μg weekly thereafter. Of the patients treated, only 2% (1 in 50) needed hospitalization in the ICU, compared to 50% (13 of 26) in the untreated group. In addition, 8% of untreated patients died compared to none in the intervention group. Although vitamin D deficiency was not identified upon admission, the researchers cite a report that 25-OH-D levels in Cordoba in winter are deficient, averaging 16 ng / ml. The use of a study population that is prone to vitamin D deficiency makes this a good study to examine the benefits of aggressively correcting this deficiency in COVID-19. As far as we know, only one critical care program in the US has adopted such an aggressive replenishment protocol in COVID-19 treatment.
There is more evidence to indicate this direction. Using a quasi-experimental approach, Annweiler and colleagues analyzed the elderly elderly patients hospitalized for COVID-19 in France. The researchers obtained records for those who received regular bolus vitamin D3 supplementation – 20,000 to 50,000 IU per month, a common practice in French nursing homes – and for those who did not. Only 10% of those who received regular supplements progressed to severe COVID-19, compared with 31% of the group that was not supplemented. 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 colecalciferol at the time of diagnosis of COVID-19. This group did better than the one that did not get any, but the result did not reach statistical significance, suggesting that the dose may have been too low or came too late.
We found a study pending peer review that failed to show 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. Unlike calcifediol, it can take a week or more for the body to convert vitamin D3 to its active form. In addition, being soluble in fat, the body competes against adipose tissue to procure the required amount, requiring higher doses of obesity (average 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 of this kind are not new. An Austrian study conducted in 2014 on 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 did not show benefits, revealing a possible shortcoming of many vitamin D studies - should they focus on results only for those with deficiencies?
It is not yet common practice to check serum 25-OH-D levels in hospitalized patients with COVID-19, even though many practitioners prescribe supplementation 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. . Toxicity was not observed in people who reported taking doses of up to 20,000 IU per day, an amount roughly equivalent to what is generated by a sunny summer afternoon on the skin. (Various 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 have no observed side effects.)
It is our responsibility as doctors not to wait for perfect evidence when making decisions about life and death. Given the safety profile of vitamin D, the 40% prevalence of vitamin D deficiency in the US 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 has the potential to save thousands of lives and should be one of the highest public health priorities.
Richard H. Carmona, MD, MPH, was the 17th general surgeon of the United States and is now a distinguished professor of public health and commander of the COVID-19 incident at the University of Arizona. Vatsal G. Thakkar, MD, is an integrative psychiatrist, founder of Rimbursify and can be tracked on Twitter. John C. Umhau, MD, MPH, is a retired commander in the U.S. Public Health Service and has published over forty peer-reviewed research articles.