The US breaks new records in the number of daily deaths due to COVID-19. The incredible speed with which various vaccines have been developed and deployed is nothing short of breathtaking. Yet we still have to face the grim prediction that our national death toll will exceed 500,000 Americans before broad vaccinations can dig us out of this crisis. The response to the pandemic should therefore include an attempt to aggressively eliminate what appears to be a risk factor for diseases and deaths in COVID-19 – vitamin D deficiency.
For any COVID-19 risk factor, such as obesity, high blood pressure or diabetes, strong correlation data are sufficient to inform clinical care, as in Surgeon General Luther Terry’s 1964 Smoking and health report. This groundbreaking publication, which saved tens of millions of lives from lung cancer, is based on a causal analysis by an advisory committee. The team reviewed the existing data and examined the work of Sir Austin Bradford Hill and Sir Richard Doll, who examined the increase in cases of lung cancer in the UK. Hill later set out the standards that resulted from their investigation, now known as Hill’s Criteria for Cause. He suspects that correlation data can be used to deduce causality by meeting different criteria, such as consistency, specificity, temporality, and dose-responsiveness. Vitamin D deficiency, which is associated with detrimental effects on innate and adaptable immunity, has very 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 sharply adjusted.
Jain and colleagues studied 154 patients who were presented at a medical center for 6 weeks. When deaths were evaluated for 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 the seriously ill patients requiring ICU admission, but in only 33% of the asymptomatic cases, indicating that low levels are an essential component of severe COVID-19. This is one of the many studies that have determined the correlation of low vitamin D levels with an exacerbated course of COVID-19, as evidenced by a meta-analysis by Pereira and colleagues.
Nevertheless, experimental evidence is not only recommended, but also necessary, to establish Hill’s criteria, and small randomized trials with aggressive vitamin D supplementation 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 cholecalciferol (vitamin D3) in a fast-acting nano-emulsion, divided into seven days, ie 60,000 IU (1,500 μg) per day. The results showed that supplementation helped to clear up the virus faster - 63% of the treated patients tested negative for SARS-CoV-2 by the 14th day, compared with only 21% of the placebo group. In addition, the treated group showed a decrease in fibrinogen levels, presumably contributing to the higher risk of thrombotic events in COVID-19.
Castillo’s team in Cordoba, Spain, randomized 76 COVID-19 patients admitted to the hospital in a 2: 1 ratio to receive, in addition to standard care, either open calcipediol or no supplement. 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. Of the treated patients, only 2% (1 in 50) required ICU admission, compared with 50% (13 of 26) of the untreated group. In addition, 8% of the untreated patients died, compared with no one in the intervention group. Although no vitamin D deficiency has been identified, the researchers report that the 25-OH-D levels in Cordoba are deficient during the winter, averaging 16 ng / ml. The use of a study population that is skewed to vitamin D deficiency makes it a good study to investigate the benefits of aggressive correction of this deficiency in COVID-19. To our knowledge, only one critical care program in the US has adopted a supplement protocol that has been aggressive in their treatment of COVID-19.
There is more evidence pointing in this direction. Using a quasi-experimental approach, Annweiler and colleagues looked at debilitated, elderly patients admitted to hospital for COVID-19 in France. The researchers found records for those who regularly received vitamin D3 supplementation from bolus – 20,000 to 50,000 IU per month, a common practice in French nursing homes – and those who did not. Only 10% of those added regularly progressed to severe COVID-19, compared with 31% of the non-complementary group. In addition, the 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 received a single dose of 80,000 IU cholecalciferol at the time of their COVID-19 diagnosis. This group performed better than the group that did not receive, but the result did not reach statistical significance, indicating that the dose may have been too low or too late.
We did discover one study awaiting peer review that could not demonstrate the benefits of treating vitamin D deficiency in COVID-19. Researchers administered a single dose (200,000 IU vitamin D3) to patients ten days after the onset of COVID-19 symptoms. Unlike calcipediol, it can take a week or more before the body converts vitamin D3 into its active form. Because the body is also fat-soluble, it 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 to correct vitamin D deficiency in healthy outpatients, who regularly receive a total of 600,000 IU divided over twelve weeks, at 50,000 IU per week.
Data like this are not new. An Austrian study in 2014 among 475 patients showed that supplementation with 540,000 IU vitamin D3 followed by 90,000 IU per month halved the hospital mortality rate for ICU patients with severe vitamin D deficiency (25-OH-D level <12 ng / ml). Patients with higher levels showed no benefit, which revealed the possible shortcoming of many vitamin D trials. Should they only focus on the outcomes for those with a deficit?
It has not yet been widely used to monitor serum 25-OH-D levels in COVID-19 inpatients, although many practitioners prescribe supplements in typical (and possibly inadequate) doses. A Canadian study of 22,214 individuals supplemented found that 1000 IU daily of cholecalciferol increased 25-OH-D levels by an average of only 4.8 ng / ml, with decreasing yields for each additional increment of 1000 IU per day. . Toxicity was not seen in people who reported taking doses as high as 20,000 IU per day, an amount approximately equal to that generated by an afternoon summer sun on the skin. (Several medical associations state that doses up to 4,000 IU of vitamin D per day are safe without medical supervision, and that up to 10,000 IU per day has 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% incidence of vitamin D deficiency in the US and the fact that this season is likely to be the deadliest phase of the pandemic to date, we must act now. Identifying and eradicating vitamin D deficiency with early and aggressive supplements in COVID-19 can save thousands of lives and should be one of our top public health priorities.
Richard H. Carmona, Managing Director, MPH, was the 17th Surgeon-General of the United States and is now a leading professor of public health and COVID-19 attacking commander at the University of Arizona. Vatsal G. Thakkar, managing director, is an integrative psychiatrist, a founder of Reimbursify, and can be followed on Twitter. John C. Umhau, MD, MPH, is a retired commander in the U.S. Public Health Service and has published more than forty peer-reviewed research articles.