High Doses of Vitamin D as an Emergency Alternative in COVID-19: A Proposal for Further Investigation

Opinion and Proposal
Drs. Felipe Inserra, Walter Manucha, Carlos Tajer, Leon Ferder

Coronavirus infection generates a greater risk of complications and mortality in elderly, hypertensive, diabetic patients or patients with previous cardiorespiratory diseases. From the initial reports on the evolution of patients in China, the country of origin of the epidemic, it was observed that patients with the previously mentioned clinical conditions had 3 or 4 times more respiratory symptoms, hospitalizations and mortality than those who did not have it. they presented. ,

Hypertension was a risk factor that led to different speculations. A publication in the British Medical Journal proposed, based on basic research, the hypothesis that drugs that block the renin angiotensin aldosterone system (RAAS), ACEIs and ARBs, could have been a risk factor for patients who contracted COVID. -19, given its mechanism of action, increases the production of angiotensin-converting enzyme 2 (ACE2).

Experimental work has reliably shown that the use of these drugs increases ACE2 levels. ACE2 is the receptor to which coronaviruses, both SARS CoV and SARS Cov2 (COVID-19), bind to enter the cell. , . The question raised by the authors and reaffirmed in a more recent editorial letter is that the increase in ACE2 would increase the viral load, which would explain the greater morbidity and mortality.

The information from the first reports from China has not reported on whether patients received drugs that block the RAAS and its relationship with clinical evolution. However, there is no data that shows causality between an increase in ACE2 and an increase in mortality from COVID-19. The work does not describe how the patients took ACEIs or ARBs, and based on indirect information, it is presumed that only 1/3 of them were complying with these treatments; Nor does the work show that HTN or diabetes were independent risk predictors.  

The international scientific societies, including those in our country linked to this issue, (SAHA, SAC, FAC) agreed that to date there is no evidence to suggest that we should modify the treatments that block the RAAS in patients, and that suspending them is a very high risk.

Other authors have proposed a different view, with the hypothesis of a possible protective action of RAAS blockers in COVID-19 infection. . Two clinical trials have already been registered that will evaluate the action of Losartan on the evolution of the viral infection, but they have not yet started. (Clinicaltrials.gov #NCT04312009 and #NCT04311177).

The basis for the hypothesis of the usefulness of RAAS blockers derives from the fact that the COVID-19 virus enters the cell by binding to ACE2 receptors and decreases its intracellular levels. ACE2, unlike classic ACE, degrades angiotensin II, so the reduction induced by the virus accentuates the pathogenic action of angiotensin II at the lung level. ACE2 levels exert a protective level of the lung parenchyma.

There is additional evidence that higher levels of ACE2 at the lung tissue level are relevant in the defense process against respiratory viral infections, since they attenuate the massive release of cytokines and the consequent generalized inflammatory infiltrate that leads to serious respiratory complications. The initial suggestion of suspending drugs that block the RAAS may thus be a counterproductive strategy for the patient’s evolution, not only by unstabilizing blood pressure levels at a complex clinical moment but also by the possibility of eliminating the protective factor of increased blood pressure. RCT2 on the pathogenesis of COVID-19 at the lung level.

So much so that a protocol for the administration of soluble recombinant human ACE2 was developed (Clinicaltrials.gov #NCT04287686) with the objective that acting as a kind of circulating receptor it could function by trapping viruses and its administration in patients with COVID-19 could contribute to mitigate the disease, reducing respiratory complications and saving their lives. It was being evaluated by the FDA, but on March 17 it was withdrawn before recruiting began.

Vitamin D and the renin-angiotensin system

Another way to counterbalance the RAAS, especially ACE2, is through the administration of adequate doses of Vitamin D.

Thus, higher levels of one of the two parts are inversely associated with lower levels of the other. There is abundant evidence that the administration of Vitamin D attenuates RAAS activity at the circulating level, but more importantly at the tissue and intracellular level. In this way, it attenuates the inflammatory cascade that the greater activity of the RAAS favors.

Vitamin D reduces the activity of ACE and increases the activity of ACE2, which has a protective effect at the lung level, restoring the ACE/ACE2 balance. Restoring this balance through the administration of vitamin D seems key to reducing respiratory events in experimental models.

Low levels of vitamin D are associated with an increase in respiratory infections and in controlled clinical trials the administration of vitamin D has also exerted a protective effect against infections in patients without pathology or with chronic obstructive pulmonary disease.

Different trials and their systematic review through meta-analysis have been published and most of them report benefits in reducing respiratory symptoms, in several of them with oral vitamin D supplementation. Recently, potential benefits have also been reported in Dengue virus infections.

Faced with this devastating epidemic for which we lack effective treatments, we propose to explore the potential protective effect of high daily doses of Vitamin D, which can rapidly increase blood and tissue levels of it, with the intention of counterbalancing the RAAS and thus improving the COVID-19 infection, and its respiratory complications.

The central idea of ​​the proposal to give Vitamin D to the general population, particularly the most exposed to achieve elevation of blood and tissue levels of Vitamin D, can generate a favorable balance of some components of the RAAS and also of its own anti-inflammatory effect. We believe that this population strategy can provide some beneficial alternative in the defense against the virus with practically no adverse effects, as has been demonstrated in the review of more than 76,000 patients included in controlled trials with the provision of vitamin D.

Another alternative that we are working on is the development of controlled protocols with different contexts of people at risk or already infected, evaluating pathophysiological aspects and clinical events.

It is not a treatment that can kill viruses, nor is it the dreamed-of vaccine that can prevent contagion.

But the contribution of vitamin D can improve the conditions of patients so that they can defend themselves with greater chances of COVID-19 and perhaps also Dengue and other viruses.

As we finished writing the article, we realized that fortunately we are not the only ones thinking this direction; There is a work sent in the last few hours for publication and also suggestions from the English Ministry of Health and editorials in high-impact international media suggesting this alternative.