The First Clinical Trial to Support Vitamin D Therapy For Covid-19
[Updated 27 Sept] Oral calcifediol reduced ICU admission for Covid-19 from 50% to 2%. And key questions about the trial answered.
A study from Spain finally presents the first clinical evidence for the use of vitamin D to treat Covid-19. The study, “Effect of Calcifediol Treatment and best Available Therapy versus best Available Therapy on Intensive Care Unit Admission and Mortality Among Patients Hospitalized for COVID-19: A Pilot Randomized Clinical study,” was published in The Journal of Steroid Biochemistry and Molecular Biology on 29 August. It is called a pilot because the sample size is small, but its randomization and prospective design still make it a robust research.
What the study did and found
Researchers randomly allocated 76 cases of Covid-19 into oral calcifediol (50 patients) or no-calcifediol control (26 patients) groups on the day of the hospital admission. Oral calcifediol was given at high doses at 0.532 mg on the first day and then at 0.266 mg on the third and seventh day, and then weekly until discharge or admission to the intensive care unit (ICU).
Calcifediol, also called 25-hydroxyvitamin D3 (vitamin D3), is the main metabolite (effector) of vitamin D. All patients also received the best available standard care at that time, which was hydroxychloroquine plus azithromycin.
Results revealed that 13 out of 26 patients (50%) in the control group were admitted to ICU, and two died in the end. In the calcifediol group, only one out of 50 (2%) required ICU admission, and none died.
Both calcifediol and control groups had similar baseline characteristics in terms of age, sex, comorbidities (lung, cardiovascular, and kidney diseases, type 2 diabetes, and immunosuppression), and clinical biomarkers of disease severity (oxygen levels, C-reactive protein, interleukin-6, ferritin, D-dimer, lactate dehydrogenase, and lymphocyte count). The only difference is that the control group had a higher prevalence of hypertension than the calcifediol group (57.69% vs. 24.19%).
Results revealed that 13 out of 26 patients (50%) in the control group were admitted to ICU, and two died in the end. In the calcifediol group, only one out of 50 (2%) required ICU admission, and none died. These results were statistically significant, equating to a 93% reduction in odds of ICU admission after adjusting for possible confounders (e.g., hypertension).
“Although this was a small trial, the ICU results are so dramatic that they are statistically highly significant,” stated a featured letter in The BMJ, a top-tier medical journal, in response to this clinical trial.
A few more questions about the study
1. What does the study not tell us?
All patients received standard care. Thus, it is not known if calcifediol would be effective on its own. And calcifediol is a medical drug used to treat parathyroid problems, so it is unclear if normal vitamin D supplementation would achieve the same effect.
Calcifediol is also 3.2-fold more effective than native vitamin D3 supplements in restoring low blood levels of vitamin D3.
The researchers also did not measure the vitamin D3 levels of the patients, but they were probably deficient based on prior population data. Still, it remains uncertain if vitamin D3 levels would affect the efficacy of calcifediol treatment for Covid-19. And other possible confounders in this study that the researchers did not measure are obesity, ethnicity, and socioeconomic status.
2. Why calcifediol over native vitamin D3?
Calcifediol is the actual hormonal effector of vitamin D3. Upon contact with sun rays (UV-B spectrum), the skin makes vitamin D3, which can also be taken as a supplement. The liver then converts vitamin D3 into 25-hydroxyvitamin D3, also called calcifediol or calcidiol that has wide-ranging effects on the immune system and other physiological systems. In this sense, calcifediol is a better biomarker for the body’s stores of vitamin D3.
Calcifediol is also 3.2-fold more effective than native vitamin D3 supplements in restoring low blood levels of vitamin D3. Because normal vitamin D3 needs to undergo liver processing first, which is not required for calcifediol. Another perk of calcifediol is its higher intestinal absorption rate.
Healthy vitamin D status associates with a regulated immune system — characterized by increased B-cells and T-cells but decreased systemic inflammation, disease severity, and mortality…
3. Is the study in line with prior clinical evidence?
The clinical trial from Spain provided the strongest evidence to date that vitamin D3 therapy could work for Covid-19. These results support prior cohort and observational studies that found low vitamin D3 levels (calcifediol) in the blood as an independent risk factor for severe Covid-19, as discussed further here:
Low vitamin D3 status not only increases the risk of greater Covid-19 severity but of positive diagnosis as well. In a September paper in JAMA involving 489 Covid-19 patients, those likely deficient in vitamin D3 had a 1.77-times increased risk of testing positive for Covid-19 than those with likely sufficient levels. The term ‘likely’ is used because vitamin D3 levels were measured one year before Covid-19 testing.
This result agrees with a previously published study paper where researchers found that, in a sample of 107 Covid-19 cases in Switzerland, those tested positive had significantly lower vitamin D3 levels (median 11.1 ng/ml) than those tested negative (22.0 ng/ml) for SARS-CoV-2. And this time, vitamin D levels were measured three days after the testing.
A more recent study of 235 Covid-19 patients discovered that healthy vitamin D status associates with a regulated immune system — characterized by increased B-cells and T-cells but decreased systemic inflammation, disease severity, and mortality — even after adjusting for confounders such as age, sex, BMI, smoking, and comorbidities.
4. How does vitamin D3 help fight Covid-19?
From a mechanistic standpoint, vitamin D3 and Covid-19 both target similar physiological systems — namely the renin-angiotensin system (RAS) and immune system.
A recent breakthrough has uncovered that Covid-19 kills by bradykinin storm, in addition to the cytokine storm. The RAS regulates blood pressure and fluid volume and breaks down bradykinin. According to the bradykinin hypothesis, SARS-CoV-2 dysregulates the RAS via its interaction with the angiotensin-converting enzyme 2 (ACE2) receptor. This leads to the accumulation of bradykinin, which makes blood vessels leaky. This poses multiorgan consequences; for example, it causes leakage of fluid and immune cells into the lungs and breakdown of the blood-brain-barrier.
From a mechanistic standpoint, vitamin D3 and Covid-19 both target similar physiological systems — namely the renin-angiotensin system (RAS) and immune system.
The research team that formulated the bradykinin hypothesis then proposes vitamin D as a potential treatment for Covid-19. This is because vitamin D is one of the very few hormones that regulates the RAS and prevents bradykinin accumulation. Vitamin D also acts as an immunomodulator that keeps inflammation at bay while supporting functions of B-cells and T-cells, which are essential in fighting infections and generating immunological memory. For instance, T-cells must have their vitamin D receptor (VDR) activated to ‘wake up’ form their inactive state.
Short abstract
Finally, there is a pilot randomized controlled trial that supports vitamin D3 therapy for Covid-19. Oral calcifediol reduced the risk of ICU admission by 93% compared to no calcifediol in Covid-19 patients. Specifically, 50% of patients in the control group were admitted to the ICU, and two died in the end. But only 2% of patients receiving calcifediol required ICU admission, and none died.
This trial supports prior evidence that low vitamin D3 status increases the risk of Covid-19 positive diagnosis, greater severity, and mortality. Further, mechanistically speaking, there is no reason why vitamin D3 could not be helpful. Vitamin D3 regulates the RAS and immune system, both of which are critical determinants of how one responds to Covid-19.
