The US is breaking new records in the number of daily deaths from COVID-19. The breakneck speed at 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 widespread vaccinations can get us out of this crisis. The response to the pandemic must therefore include an effort to aggressively eliminate what becomes apparent as a morbidity and mortality risk factor in COVID-19 – vitamin D deficiency.
For any COVID-19 risk factor, such as 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 causality 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 investigated the increase in lung cancer cases in the UK. Hill later outlined the standards that resulted from their research, now known as Hill’s causation criteria. He suspected that correlational data can be used to infer causality by meeting various criteria such as consistency, specificity, temporality and dose sensitivity. Vitamin D deficiency, associated with deleterious 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 changed acutely.
Jain and colleagues studied 154 patients who came to a medical center for 6 weeks. When deaths were evaluated based on vitamin D deficiency (serum 25-OH-D <20 ng / ml), the death rate was 21%, compared to only 3% for those with higher levels. More notably, vitamin D deficiency was found in 97% of critically ill patients requiring IC admission, but in only 33% of asymptomatic cases, suggesting that low levels are a necessary part of severe COVID-19. This is one of several studies this year showing the correlation between low vitamin D levels and an exacerbated course of COVID-19, as a meta-analysis by Pereira and colleagues reveals.
But to bolster Hill’s criteria, some experimental evidence is not only recommended, but necessary, and small randomized trials of aggressive vitamin D supplementation have shown positive results. Rastogi and colleagues treated 40 subjects 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 nanoemulsion 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 on the 14th day, compared to only 21% of the placebo group. In addition, the treated group showed a decrease in fibrinogen levels, which is believed to contribute to the higher risk of thrombotic events with COVID-19.
Castillo’s team in Cordoba, Spain, randomized 76 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 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) required admission to the ICU 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. Although vitamin D deficiency was not established on admission, the researchers cite a report that the 25-OH-D levels in Cordoba are deficient in winter, averaging 16 ng / ml. Using a study population skewed toward vitamin D deficiency makes this a good study to explore the benefits of aggressively correcting this COVID-19 deficiency. To our knowledge, only one intensive care program in the US has adopted such an aggressive additional protocol in the treatment of COVID-19.
There is 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 collected data from those who received regular 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, 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 were receiving a single dose of 80,000 IU cholecalciferol at the time of their COVID-19 diagnosis. This group fared better than the group that did not receive one, but the outcome did not reach statistical significance, suggesting that the dose may have been too low or too late.
We found one study pending peer review that showed no benefits from treating vitamin D deficiency in COVID-19. Researchers administered a single dose (200,000 IU of vitamin D3) to patients ten days after the symptoms of COVID-19 first appeared. Unlike calcifediol, it can take a week or more for the body to convert vitamin D3 to its active form. In addition, because it is fat soluble, the body competes with adipose tissue to obtain the necessary amount, requiring higher doses in 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 routinely receive a total of 600,000 IU over 12 weeks, versus 50,000 IU per week.
Such data is not new. A 2014 Austrian study of 475 patients showed that supplementation with 540,000 IU vitamin D3 followed by 90,000 IU per month halved hospital deaths for ICU patients with severe vitamin D deficiency (25-OH-D level <12 ng / ml) . Patients with higher levels showed no benefit, revealing a potential deficiency of many vitamin D studies - should they just focus on the results for those deficient?
It is not yet common practice to monitor serum 25-OH-D levels in COVID-19 patients, even though many doctors prescribe supplementation with typical (and possibly inadequate) doses. A Canadian study of 22,214 supplemented individuals found that 1,000 IU daily cholecalciferol increased 25-OH-D levels by an average of only 4.8 ng / mL with decreasing efficacy for each additional 1,000 IU per day increase. No toxicity was observed in people who reported taking doses as high as 20,000 IU per day, an amount approximately equivalent to that generated by an afternoon summer sun on the skin. (Several medical societies state 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 observed adverse effects.)
It is our responsibility as doctors not to wait for perfect proof when making life or death decisions. Given the safety profile of vitamin D, the 40% prevalence of vitamin D deficiency in the US and the fact that this season is likely to be the deadliest phase of the pandemic yet, we need to act now. Identifying and eradicating vitamin D deficiency with early and aggressive COVID-19 supplementation can save thousands of lives and should be one of our highest public health priorities.
Richard H. Carmona, MD, MPH, was the 17th US Surgeon General and is now a leading professor of public health and COVID-19 incident commander at the University of Arizona. Vatsal G. Thakkar, MD, is an integrative psychiatrist, a founder of Reimbursify, and can be followed at Twitter. John C. Umhau, MD, MPH, is a retired commander with the US Public Health Service and has published more than 40 peer-reviewed research papers.