By Shin Jie Yong
-A Pilot Randomised Clinical study,” was published in The Journal of Steroid Biochemistry and Molecular Biology this August 29.
It’s called a pilot because the sample size is still small, but its randomisation and prospective design still make it a robust research.
What the study did and found
Researchers randomly allocated 76 confirmed cases of Covid-19 into either 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, is the main metabolite (effector) of vitamin D3.
All patients also received the best available standard care at that time, which was hydroxychloroquine plus azithromycin. Note that this study was conducted a few months ago when hydroxychloroquine has not yet been proven as ineffective for Covid-19, the study authors admitted.
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 per cent versus 24.19 per cent).
Results revealed that 13 out of 26 patients (50 per cent) in the control group were admitted to ICU, and two died in the end. In the calcifediol group, only one out of 50 (2 per cent) required ICU admission, and none died.
These results were statistically significant, equating to a 93 per cent reduction in odds of ICU admission after adjusting for possible confounders – including hypertension.
“Our pilot study demonstrated that administration of a high dose of calcifediol…significantly reduced the need for ICU treatment of patients requiring hospitalisation due to proven Covid-19,” the study authors noted.
They added: “Calcifediol seems to be able to reduce the severity of the disease, but larger trials with groups properly matched will be required to show a definitive answer.”
There are a few more questions about the study, the first being: 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.
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.
Second: 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.
Third: 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.
Low vitamin D3 status not only increases the risk of greater Covid-19 severity but of positive diagnosis as well.
In a paper published September in JAMA Network Open 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 paper in Nutrients in April where investigators 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 vitamin D3 measurement was done three days after the testing.
Fourth: How does vitamin D3 help fight Covid-19?
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.
Finally, there is a pilot randomised controlled clinical trial that supports vitamin D3 therapy for Covid-19. Oral calcifediol (the main metabolite of vitamin D3) reduced the risk of ICU admission by 93 per cent compared to no calcifediol in Covid-19 patients.
Specifically, 50 per cent of patients in the control group were admitted to the ICU, and two died in the end. But only 2 per cent of patients receiving calcifediol required ICU admission, and none died.
This clinical trial supports prior evidence that low vitamin D3 status increases the risk of more severe Covid-19 and positive Covid-19 diagnosis.
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.
- First published in Microbial Instincts. Shin Jie Yong, a published academic author, is a neurobiology postgraduate.