Vitamin D isn't actually a vitamin, but a steroid pre-hormone produced in the skin in strong sunlight which is then converted into an active hormone by the liver and kidneys. As well as supporting healthy bones, vitamin D supports key functions in many organs, including the brain, muscle and the immune system.
A fast building number of studies have linked the vitamin D deficiency with more severe COVID-19 symptoms. For example, inverse associations were found in European countries between serum 25-hydroxyvitamin D (25(OH)D) concentration and the number of COVID-19 cases, as well as with mortality. However, according to the current study, no large well-designed randomised controlled trial (RCT) have tested the effect of vitamin D supplements on COVID-19 outcomes.
The main objective of this hospital based quasi-experimental study (an empirical interventional study used to estimate the causal impact of an intervention on target population without random assignment) was to determine whether vitamin D supplementation taken either regularly during the preceding year or after the diagnosis of COVID-19 was effective in improving survival among frail elderly COVID-19 patients.
Data of the GERIA-COVID study were retrospectively collected from 77 patients’ (78−100 years; 49.4% women) hospitalised in the geriatric acute care unit of Angers University Hospital, France, in March–May 2020.
The regular intake of bolus vitamin D supplements over the preceding year was systematically noted from the primary care physicians’ prescriptions and sought by questioning the patients and their relatives. “Group 1” was defined as all COVID-19 patients who had received vitamin D supplements over the preceding year. No patient in Group 1 received additional supplements following the diagnosis of COVID-19.
“Group 2” was defined as the COVID-19 patients usually not supplemented with vitamin D, but who received an oral supplement of 80,000 IU vitamin D3 within a few hours of the diagnosis of COVID-19.
Finally, “Group 3” was defined as the Comparator group, i.e., all COVID-19 patients who had received no vitamin D supplements; the absence of vitamin D treatment being mostly explained by the patients’ refusal to be supplemented, since vitamin D supplementation is recommended with no biological testing in all patients over 65 years of age in France.
Seventeen participants experienced severe COVID-19, 62 survived at day 14, while 15 died. Irrespective of all measured potential confounders, regular vitamin D3 supplementation was associated with less severe COVID-19 and better survival rate but being supplemented with 80,000 IU vitamin D3 after the diagnosis of COVID-19 was not associated with improved COVID-19 outcomes.
The researchers say further large prospective, preferentially interventional studies are needed to confirm whether higher-dose bolus of vitamin D3 given after the diagnosis of COVID-19 is able to improve its prognosis. They assume that vitamin D supplementation initiated after the diagnosis of COVID-19 was started too late to be effective, or the dose of 80,000 IU was too low to generate protective effects in a very short time - a hypothesis tested in the ongoing COVIT-TRIAL RCT.
The report concludes: "Previous meta-analyses found that high dose prophylactic vitamin D supplementation was able to reduce the risk of respiratory tract infections. Based on this observation, we and others are conducting an RCT, the COVIT-TRIAL study, designed to test the effect of high-dose versus standard-dose vitamin D3 on 14-day mortality in COVID-19 older patients.
"While waiting for the recruitment of this RCT to be completed, the findings of the present quasi-experimental study strongly suggest benefits of regular vitamin D3 supplementation on COVID-19 outcomes and survival, which reinforces the recommendations of some scientific societies to supplement all elderly people with vitamin D, in order to improve COVID-19 mortality.
"Additionally, our results support the observation that a single standard dose of 80,000 IU vitamin D3 initiated after the diagnosis of COVID-19 brings no significant benefit on COVID-19 outcomes, which justifies using low-dose vitamin D supplements as a comparator in the COVIT-TRIAL study to determine the effect of higher-dose vitamin D supplements on the prognosis of COVID-19."
Mechanisms of action
According to the present report, how vitamin D supplementation improves COVID-19 outcomes and survival is not fully elucidated but four mechanisms are likely: regulation of i) the RAS, ii) the innate and adaptive cellular immunity, iii) the physical barriers, and iv) the host frailty and comorbidities.
The report states: "First, vitamin D reduces pulmonary permeability in animal models of acute respiratory distress syndrome (ARDS) by modulating the activity of RAS and the expression of the angiotensin-2 converting enzyme (ACE2). This action is crucial since SARS-CoV-2 reportedly uses ACE2 as a receptor to infect host cells, and downregulates ACE2 expression. ACE2 is expressed in many organs, including the endothelium and the pulmonary alveolar epithelial cells, where it has protective effects against inflammation.
"During COVID-19, downregulation of ACE2 results in an inflammatory chain reaction, the cytokine storm, complicated by ARDS. In contrast, a study in rats with chemicallyinduced ARDS showed that the administration of vitamin D increased the levels of ACE2 mRNA and proteins.
"Second, many studies have described the antiviral effects of vitamin D, which works either by induction of antimicrobial peptides with direct antiviral activity against enveloped and non-enveloped viruses, or by immunomodulatory and anti-inflammatory effects. These are potentially important during COVID-19 to limit the cytokine storm. Vitamin D can prevent ARDS by reducing the production of pro-inflammatory Th1 cytokines, such as TNFα and interferon γ. It also increases the expression of anti-inflammatory cytokines by macrophages.
"Third, vitamin D stabilizes physical barriers. These barriers are made up of closely linked cells to prevent outside agents (such as viruses) from reaching tissues susceptible to viral infection. Although viruses alter the integrity of the cell junction, vitamin D contributes to the maintenance of functional tight junctions via E-cadherin.
"Fourth, the literature over the past decade on the non-bone effects of vitamin D has repeatedly reported that hypovitaminosis D is accompanied by various comorbidities including diabetes mellitus, hypertension, chronic cardiovascular and respiratory diseases, and cancers, all conditions that are associated with an increased risk of COVID-19 worsening and death. Prolonged hypovitaminosis D may thus be considered as a factor of poor prognosis of COVID-19, potentiating the risk of cardiorespiratory severity in frail older adults infected with SARS-CoV-2."
Annweiler. C., et al
"Vitamin D Supplementation Associated to Better Survival in Hospitalized Frail Elderly COVID-19 Patients: The GERIA-COVID Quasi-Experimental Study"