All Studies Meta Analysis

Effect of Single High Dose Vitamin D Substitution in Hospitalized COVID-19 Patients with Vitamin D Deficiency on Length of Hospital Stay

Jaun et al., Biomedicines, doi:10.3390/biomedicines11051277

Apr 2023

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Vitamin D for COVID-19

8th treatment shown to reduce risk in October 2020, now with p < 0.00000000001 from 122 studies, recognized in 9 countries.

Lower risk for mortality, ICU admission, hospitalization, progression, recovery, cases, and viral clearance.

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RCT late stage patients showing no significant differences with the addition of single dose 140,000IU vitamin D treatment. All patients received vitamin D 800IU daily. There was a non‐significant shorter length of stay for patients with vitamin D deficiency. The SF-12 mental score was significantly lower in the treatment group at baseline.

Cholecalciferol was used in this study. Meta analysis shows that late stage treatment with calcitriol / calcifediol (or paricalcitol, alfacalcidol, etc.) is more effective than cholecalciferol: 69% [47‑82%] lower risk vs. 39% [27‑49%] lower risk. Cholecalciferol requires two hydroxylation steps to become activated - first in the liver to calcifediol, then in the kidney to calcitriol. Calcitriol, paricalcitol, and alfacalcidol are active vitamin D analogs that do not require conversion. This allows them to have more rapid onset of action compared to cholecalciferol. The time delay for cholecalciferol to increase serum calcifediol levels can be 2-3 days, and the delay for converting calcifediol to active calcitriol can be up to 7 days.

Bolus treatment is less effective. Pharmacokinetics and the potential side effects of high bolus doses suggest that ongoing treatment spread over time is more appropriate. Research has confirmed that lower dose regular treatment with vitamin D is more effective than intermittent high-dose bolus treatment for various conditions, including rickets and acute respiratory infections1,2. The biological mechanisms supporting these findings involve the induction of enzymes such as 24-hydroxylase and fibroblast growth factor 23 (FGF23) by high-dose bolus treatments. These enzymes play roles in inactivating vitamin D, which can paradoxically reduce levels of activated vitamin D and suppress its activation for extended periods post-dosage. Evidence indicates that 24-hydroxylase activity may remain elevated for several weeks following a bolus dose, leading to reduced levels of the activated form of vitamin D. Additionally, FGF23 levels can increase for at least three months after a large bolus dose, which also contributes to the suppression of vitamin D activation1.

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risk of death, 50.0% lower, RR 0.50, p = 0.56, treatment 1 of 39 (2.6%), control 2 of 39 (5.1%), NNT 39, odds ratio converted to relative risk.

risk of mechanical ventilation, 300.0% higher, RR 4.00, p = 0.20, treatment 4 of 39 (10.3%), control 1 of 39 (2.6%), odds ratio converted to relative risk.

risk of ICU admission, 32.1% higher, RR 1.32, p = 0.69, treatment 4 of 39 (10.3%), control 4 of 39 (10.3%), odds ratio converted to relative risk.

Effect extraction follows pre-specified rules prioritizing more serious outcomes. Submit updates

1. Griffin et al., Perspective: Vitamin D supplementation prevents rickets and acute respiratory infections when given as daily maintenance but not as intermittent bolus: implications for COVID-19, Clinical Medicine, doi:10.7861/clinmed.2021-0035.sciencedirect.com, doi.org.

2. Martineau et al., Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data, BMJ 2017, 356, doi:10.1136/bmj.i6583.bmj.com, doi.org.

Jaun et al., 25 Apr 2023, Double Blind Randomized Controlled Trial, placebo-controlled, Switzerland, peer-reviewed, 14 authors, study period December 2020 - August 2021, average treatment delay 8.0 days, dosage 140,000IU single dose.

This Paper Vitamin D All

Effect of Single High Dose Vitamin D Substitution in Hospitalized COVID-19 Patients with Vitamin D Deficiency on Length of Hospital Stay

Fabienne Jaun, Maria Boesing, Giorgia Luethi-Corridori, Kristin Abig, Nando Bloch, Stéphanie Giezendanner, Victoria Grillmayr, Philippe Haas, Anne B Leuppi-Taegtmeyer, Jürgen Muser, Andrea Raess, Philipp Schuetz, Michael Brändle, Jörg D Leuppi, Giuseppe Murdaca, Sebastiano Gangemi

doi:10.3390/biomedicines11051277

Vitamin D and its role in the coronavirus-19 disease (COVID-19) pandemic has been controversially discussed, with inconclusive evidence about vitamin D3 (cholecalciferol) supplementation in COVID-19 patients. Vitamin D metabolites play an important role in the initiation of the immune response and can be an easily modifiable risk factor in 25-hydroxyvitamin D3 (25(OH)D3)-deficient patients. This is a multicenter, randomized, placebo-controlled doubleblind trial to compare the effect of a single high dose of vitamin D3 followed by treatment as usual (TAU) of daily vitamin D3 daily until discharge versus placebo plus TAU in hospitalized patients with COVID-19 and 25(OH)D3-deficiency on length hospital stay. We included 40 patients per group and did not observe a significant difference in the median length of hospital stay (6 days in both groups, p = 0.920). We adjusted the length of stay for COVID-19 risk factors (β = 0.44; 95% CI: −2.17-2.22), and center (β = 0.74; 95% CI: −1.25-2.73). The subgroup analysis in patients with severe 25(OH)D3-deficiency (<25 nmol/L) showed a non-significant reduction in the median length of hospital stay in the intervention group (5.5 vs. 9 days, p = 0.299). The competing risk model with death did not reveal significant differences between the group in the length of stay (HR = 0.96, 95% CI 0.62-1.48, p = 0.850). Serum 25(OH)D3 level increased significantly in the intervention group (mean change in nmol/L; intervention: +26.35 vs. control: -2.73, p < 0.001). The intervention with 140,000 IU vitamin D3 + TAU did not significantly shorten the length of hospital stay but was effective and safe for the elevation of serum 25(OH)D3 levels.

Supplementary Materials: The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/biomedicines11051277/s1, Table S1 : Visit procedure and collected information for each patient at different time points during the study. Table S2 : Co-Morbidities at time of randomization. Table S3 : Concomitant medication during hospitalization. Table S4 . Robust linear regression results presenting the effect of group. Intervention vs. Control on time to discharge (from randomization) (univariable and adjusted for COVID-19 risk factors, prognostic imbalances, and center effects. Table S5 : Mean SF-12 mental and SF-12 physical scores at randomization, 28 days and 90 days after randomization. Table S6 : Mixed-effects linear regression results on SF-12 mental and physical outcome with a time and group interaction term. Table S7 : Frequency of self-reported symptoms at day 5 after randomization. Table S8 : Mean vital signs at day 5 after randomization. Table S9 : Frequency of self-reported symptoms at day 10 after randomization. Table S10 : Mean vital signs at day 10 after randomization. Table S11 : Frequency of adverse and serious adverse events occurred during the trial per study group. Table S12 : Levels of calcium, PTH and phosphorus at time of discharge. Conflicts of Interest: The authors declare no conflict of interest, and the funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the..

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Late treatment
is less effective

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