2022Vitamin D Supplementation & Frontline Healthcare Workers
Apr 30, 2022 19:38:00 GMT
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Post by deborah on Apr 30, 2022 19:38:00 GMT
Efficacy and Safety of Vitamin D Supplementation to Prevent COVID-19 in Frontline Healthcare Workers. A Randomized Clinical Trial
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Discussion
The results of our double-blind, placebo-controlled, prospective study demonstrate that VD supplementation is effective in preventing SARS-CoV-2 infection in high risk, frontline healthcare personnel. Furthermore, the protective effect of VD supplementation was independent of basal serum concentrations of 25-hydroxyvitamin D3. We have thus confirmed and extended the results of previous cross-sectional and intervention studies whereby vitamin sufficiency was found to be associated with better COVID-19 outcomes, including a lower requirement for intensive care unit admission and mortality rate (7,17). To our knowledge, this is the first controlled study evaluating the role of VD supplementation as a prophylactic measure to prevent SARS-Cov-2 infection and therefore has profound clinical and public health implications.
VD is known to modulate the immune system (6,24). Both, the nuclear vitamin D receptor (VDR) and the vitamin D metabolizing enzymes are expressed in virtually all cells of the innate and adaptive immune system, including macrophages, dendritic cells and activated B and T cells. All these cells are thus, capable of locally synthesizing the active VD metabolite 1,25(OH)2 D3, which exerts genomic and nongenomic actions. Exogenous VD reduces the production of inflammatory mediators and of reactive oxygen species in neutrophils by activating the 5-lipoxygenase gene and by suppressing the cyclooxygenase gene. Locally produced 1,25(OH)2 D3 promotes macrophage differentiation and activation and reduces the production of proinflammatory mediators such as interleukin (IL)-1β, IL-6 and TNF-α. Active VD interferes with the maturation and differentiation of dendritic cells promoting a tolerogenic phenotype characterized by a reduced secretion of proinflammatory cytokines (IL-1B, IL-6, IL23) and an increased production of IL-10 and TNF-α. 1,25(OH)2 D3 promotes B-cell apoptosis, inhibits memory B-cell formation, and prevents B-cell differentiation into immunoglobulin-producing plasma cells. Both, the VDR and the VD metabolizing enzymes gene expression is up regulated in human CD4+ and CD8+ T cells. In general, vitamin D deficiency is associated with an increased risk for various autoimmune and infectious diseases (24). Thus, VD potentially interferes with some of the pathways used by SARS-CoV-2 to enter and replicate in the bronchial epithelium. It is well known that VD inhibits renin expression and the angiotensin converting enzyme (25). It also favors an anti-inflammatory over a pro-inflammatory immune state, potentially preventing progression to more severe forms of the disease and promotes an antioxidant environment in the lungs impairing the replication capacity of the virus, which may result in a reduction of the viral load (26). Thus, the above pathophysiological considerations pertaining the relationship between VD and SARS-Cov-2 are in line with our findings. VD supplementation was equally effective in preventing SARS-Cov-2 infection in high-risk healthcare workers, regardless of the basal concentrations of 25-hydroxyvitamin D3. Our results show that the protective effect of VD was achieved with a medium dose (4,000 IU/d), during a short period of time (one-month), and with only a mild increase of the vitamin concentration (8.8 ng/mL), suggesting that the intake of VD plays a role in preventing SARS-CoV-2 infection in high exposure periods, even though the adequate VD status is not reached. Nevertheless, these results highlight the need for further studies to identify the appropriate dose required to provide the optimal protective effect ([27], [28], [29], [30], [31]).
The more frequently reported AEs were headache, intestinal transit alterations, nausea, abdominal pain, and fatigue, coinciding with VD-associated collateral effects. Nevertheless, the frequency and type of AEs were comparable between groups, which suggests that the perception of such symptoms may have been related to the acute stress derived from long working periods, or with the fear of acquiring COVID-19 as proposed by others (32).
The main strengths of our study are the randomized and experimental design, the inclusion of a highly exposed population, the use of a gold standard method to determine 25-hydroxyvitamin D3, and the fact that it was conducted before vaccines against SARS-CoV-2 were available. Nevertheless, we recognize that the high proportion of participants who did not complete follow-up could lead to misinterpretation of the results by not identifying subjects with the disease among those who dropped the study. To deal with such situation, we performed an active surveillance on the hospitals’ epidemiological records systems searching for dropouts among the confirmed SARS-CoV-2 positive, but none was identified. In addition, the association persisted in the ITT analysis, and confirmed after including confounders in the analysis.
In conclusion, the findings of our study indicate that VD protects against SARS-CoV-2 infection in highly exposed individuals, regardless VD status and with relatively few side effects.
link
Discussion
The results of our double-blind, placebo-controlled, prospective study demonstrate that VD supplementation is effective in preventing SARS-CoV-2 infection in high risk, frontline healthcare personnel. Furthermore, the protective effect of VD supplementation was independent of basal serum concentrations of 25-hydroxyvitamin D3. We have thus confirmed and extended the results of previous cross-sectional and intervention studies whereby vitamin sufficiency was found to be associated with better COVID-19 outcomes, including a lower requirement for intensive care unit admission and mortality rate (7,17). To our knowledge, this is the first controlled study evaluating the role of VD supplementation as a prophylactic measure to prevent SARS-Cov-2 infection and therefore has profound clinical and public health implications.
VD is known to modulate the immune system (6,24). Both, the nuclear vitamin D receptor (VDR) and the vitamin D metabolizing enzymes are expressed in virtually all cells of the innate and adaptive immune system, including macrophages, dendritic cells and activated B and T cells. All these cells are thus, capable of locally synthesizing the active VD metabolite 1,25(OH)2 D3, which exerts genomic and nongenomic actions. Exogenous VD reduces the production of inflammatory mediators and of reactive oxygen species in neutrophils by activating the 5-lipoxygenase gene and by suppressing the cyclooxygenase gene. Locally produced 1,25(OH)2 D3 promotes macrophage differentiation and activation and reduces the production of proinflammatory mediators such as interleukin (IL)-1β, IL-6 and TNF-α. Active VD interferes with the maturation and differentiation of dendritic cells promoting a tolerogenic phenotype characterized by a reduced secretion of proinflammatory cytokines (IL-1B, IL-6, IL23) and an increased production of IL-10 and TNF-α. 1,25(OH)2 D3 promotes B-cell apoptosis, inhibits memory B-cell formation, and prevents B-cell differentiation into immunoglobulin-producing plasma cells. Both, the VDR and the VD metabolizing enzymes gene expression is up regulated in human CD4+ and CD8+ T cells. In general, vitamin D deficiency is associated with an increased risk for various autoimmune and infectious diseases (24). Thus, VD potentially interferes with some of the pathways used by SARS-CoV-2 to enter and replicate in the bronchial epithelium. It is well known that VD inhibits renin expression and the angiotensin converting enzyme (25). It also favors an anti-inflammatory over a pro-inflammatory immune state, potentially preventing progression to more severe forms of the disease and promotes an antioxidant environment in the lungs impairing the replication capacity of the virus, which may result in a reduction of the viral load (26). Thus, the above pathophysiological considerations pertaining the relationship between VD and SARS-Cov-2 are in line with our findings. VD supplementation was equally effective in preventing SARS-Cov-2 infection in high-risk healthcare workers, regardless of the basal concentrations of 25-hydroxyvitamin D3. Our results show that the protective effect of VD was achieved with a medium dose (4,000 IU/d), during a short period of time (one-month), and with only a mild increase of the vitamin concentration (8.8 ng/mL), suggesting that the intake of VD plays a role in preventing SARS-CoV-2 infection in high exposure periods, even though the adequate VD status is not reached. Nevertheless, these results highlight the need for further studies to identify the appropriate dose required to provide the optimal protective effect ([27], [28], [29], [30], [31]).
The more frequently reported AEs were headache, intestinal transit alterations, nausea, abdominal pain, and fatigue, coinciding with VD-associated collateral effects. Nevertheless, the frequency and type of AEs were comparable between groups, which suggests that the perception of such symptoms may have been related to the acute stress derived from long working periods, or with the fear of acquiring COVID-19 as proposed by others (32).
The main strengths of our study are the randomized and experimental design, the inclusion of a highly exposed population, the use of a gold standard method to determine 25-hydroxyvitamin D3, and the fact that it was conducted before vaccines against SARS-CoV-2 were available. Nevertheless, we recognize that the high proportion of participants who did not complete follow-up could lead to misinterpretation of the results by not identifying subjects with the disease among those who dropped the study. To deal with such situation, we performed an active surveillance on the hospitals’ epidemiological records systems searching for dropouts among the confirmed SARS-CoV-2 positive, but none was identified. In addition, the association persisted in the ITT analysis, and confirmed after including confounders in the analysis.
In conclusion, the findings of our study indicate that VD protects against SARS-CoV-2 infection in highly exposed individuals, regardless VD status and with relatively few side effects.
