High-Dose Cholecalciferol Booster Therapy is Associated with a Reduced Risk of Mortality in Patients with COVID-19: A Cross-Sectional Multi-Centre Observational Study

Abstract

The worldwide pandemic of 2019 novel coronavirus disease (COVID-19) has posed the most substantial and severe public health issue for several generations, and therapeutic options have not yet been optimised. Vitamin D (in its “parent” form, cholecalciferol) has been proposed in the pharmacological management of COVID-19 by various sources. We aimed to determine whether COVID-19 mortality was affected by serum 25-hydroxyvitamin D (25(OH)D) levels, vitamin D status, or cholecalciferol therapy, and to elucidate any other predictors of COVID-19 mortality. Patients hospitalised with COVID-19 were opportunistically recruited from three UK hospitals, and their data were collected retrospectively. Logistic regression was used to determine any relationships between COVID-19 mortality and potential predictors, including 25(OH)D levels and cholecalciferol booster therapy. A total of 986 participants with COVID-19 were studied, of whom 151 (16.0%) received cholecalciferol booster therapy. In the primary cohort of 444 patients, cholecalciferol booster therapy was associated with a reduced risk of COVID-19 mortality, following adjustment for potential confounders (ORadj 0.13, 95% CI 0.05–0.35, p < 0.001). This finding was replicated in a validation cohort of 541 patients (ORadj 0.38, 95% CI 0.17–0.84, p = 0.018). In this observational study, treatment with cholecalciferol booster therapy, regardless of baseline serum 25(OH)D levels, appears to be associated with a reduced risk of mortality in acute in-patients admitted with COVID-19. Further work with large population studies needs to be carried out to determine adequate serum 25(OH)D levels, as well as multi-dose clinical trials of cholecalciferol therapy to assess maximum efficacy.

Vitamin D deficiency, secondary hyperparathyroidism and respiratory insufficiency in hospitalized patients with COVID-19

“…In previous studies, hospitalized patients with COVID-19 receiving vitamin D3 [20,21] or calcifediol [42] showed a less severe outcome of disease as compared to those not receiving vitamin D supplements. Moreover, a high-dose oral vitamin D supplementation helped to achieve SARS-CoV-2 RNA negativity in greater proportion of asymptomatic vitamin D-deficient individuals with SARS-CoV-2 infection along with a significant decrease in inflammatory markers [43].…”

“…Some studies provided evidence that subjects exposed to vitamin D deficiency may develop a more severe COVID-19 [13][14][15][16], whereas other studies failed to find such an association [17][18][19]. Moreover, the effects of vitamin D supplementation on clinical outcome of COVID-19 is still a matter of uncertainty [20][21][22]. Variability in clinical end-points may explain the heterogeneity of results of these studies evaluating the impact of hypovitaminosis D and its treatment on COVID-19 outcome.…”

High-dose vitamin C infusion for the treatment of critically ill COVID-19

“…Although this study received significant criticism from the National Institute for Health and Care Excellence (NICE) in the UK [159], an independent follow-up statistical analysis supported the findings of the study with respect to the results of cholecalciferol treatment [160]. Another trial of 986 patients hospitalized for COVID-19 in three UK hospitals administered cholecalciferol supplementation (≥ 280,000 IU in a time period of 7 weeks) to 151 patients and found an association with a reduced risk of COVID-19 mortality, regardless of baseline 25-hydroxyvitamin D levels [161]. However, a double-blind, randomized, placebo-controlled trial of 240 hospitalized COVID-19 patients in São Paulo, Brazil administered a single 200,000 IU oral dose of vitamin D. While levels of 25-hydroxyvitamin D did increase from 21% to ~27% (p = 0.001) and the supplementation was well tolerated, there was no reduction in the length of hospital stay or mortality and no change to any other relevant secondary outcomes [162].…”

Mild COVID-19 manifestation in multiple risk factor patient on methotrexate, who had been treated with UVB phototherapy and had sufficient plasma 25-OH-vitamin D3 level

“…Namely, since time when the possible favorable effects of vitamin D3 in COVID-19 patients have been proposed 14,15 , several well designed and convincing studies have clearly shown association between vitamin D deficiency and more severe COVID-19 clinical manifestations [16][17][18][19][20]46 . Recent interventional studies provide further evidence on beneficial and protective impact of vitamin D3 among COVID-19 patients [21][22][23][24] . Protective vitamin D3 mechanisms in COVID-19 patients are presumed to be multiple, including potent immunomodulatory activity, antiviral peptide induction, enhancement of physical barrier integrity and even direct interference with viral replication [13][14][15]47 .…”

“…Namely, many "pre-corona" studies have found antiviral, immunomodulatory, and anti-inflammatory properties of vitamin D3 13 , suggesting this data could be extrapolated to SARS-CoV-2 infection 14,15 . Assumptions on beneficial effects of vitamin D3 in COVID-19 patients have recently been verified by several convincing clinical and interventional studies [16][17][18][19][20][21][22][23][24] . The importance of this topic is highlighted by data showing that the global pandemic of hypovitaminosis Dis being ongoing concomitantly with the COVID-19 pandemic [25][26][27][28] .…”