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Effect of Vitamin D3 supplementation vs. dietary-hygienic measures on SARS-COV-2 infection rates in hospital workers with 25-hydroxyvitamin D3 [25(OH)D3] levels >20 ng/mL

Romero-Ibarguengoitia et al., medRxiv, doi:10.1101/2022.07.12.22277450, NCT04810949

Jul 2022

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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, hospitalization, progression, recovery, cases, and viral clearance.

No treatment is 100% effective. Protocols combine treatments.

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RCT healthcare workers with vitamin D levels between 20-100 ng/mL, 43 treated with vitamin D 52,000 IU monthly, and 42 with dietary-hygienic measures, which were also focused on increasing vitamin D, including sun exposure for at least 10 minutes per day between 10:00-18:00, and consuming foods rich in vitamin D. There was significantly lower risk of COVID-19 with supplementation vs. diet/sun. Authors also report on patients with levels <20 ng/mL where treatment was recommended for all patients, however many patients declined treatment. In these non-randomized patients, lower risk was seen at 4 months with vitamin D supplementation, however there was no significant difference at 6 months.

Interpretation of the results is difficult because all groups had intervention aimed at increasing vitamin D. Supplemented patients showed greater improvement in levels, however dietary/sun patients could have a therapeutic advantage due to regular versus monthly consumption, and due to other benefits of the dietary/sun intervention. Authors indicate they asked patients monthly about consumption of food with vitamin D, however no results are provided.

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 hospitalization, 73.7% higher, RR 1.74, p = 1.00, treatment 2 of 38 (5.3%), control 1 of 33 (3.0%), G1 vs. G2.

risk of case, 79.0% lower, HR 0.21, p = 0.008, treatment 5 of 38 (13.2%), control 13 of 33 (39.4%), NNT 3.8, 6 months, Cox proportional hazards, G1 vs. G2.

risk of case, 59.1% lower, RR 0.41, p = 0.04, treatment 6 of 43 (14.0%), control 14 of 41 (34.1%), NNT 5.0, 4 months, G1 vs. G2.

risk of case, 79.1% lower, RR 0.21, p = 0.003, treatment 3 of 43 (7.0%), control 14 of 42 (33.3%), NNT 3.8, 3 months, G1 vs. G2.

risk of ICU admission, 57.1% lower, RR 0.43, p = 1.00, treatment 0 of 24 (0.0%), control 1 of 72 (1.4%), NNT 72, relative risk is not 0 because of continuity correction due to zero events (with reciprocal of the contrasting arm), G3 vs. G4.

risk of hospitalization, 350.0% higher, RR 4.50, p = 0.10, treatment 3 of 24 (12.5%), control 2 of 72 (2.8%), G3 vs. G4.

risk of case, 15.0% higher, HR 1.15, p = 0.72, treatment 9 of 24 (37.5%), control 29 of 72 (40.3%), 6 months, Cox proportional hazards, G3 vs. G4.

risk of case, 32.1% lower, RR 0.68, p = 0.35, treatment 7 of 27 (25.9%), control 29 of 76 (38.2%), NNT 8.2, 4 months, G3 vs. G4.

risk of case, 22.2% lower, RR 0.78, p = 0.64, treatment 7 of 28 (25.0%), control 27 of 84 (32.1%), NNT 14, 3 months, G3 vs. G4.

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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.

Romero-Ibarguengoitia et al., 15 Jul 2022, Randomized Controlled Trial, Mexico, preprint, mean age 44.4, 5 authors, study period May 2020 - August 2020, dosage 52,000IU single dose, monthly, this trial compares with another treatment - results may be better when compared to placebo, trial NCT04810949 (history). Contact: drgzzcantu@gmail.com.

This Paper Vitamin D All

Effect of Vitamin D3 supplementation vs. dietary-hygienic measures on SARS-COV-2 infection rates in hospital workers with 25-hydroxyvitamin D3 [25(OH)D3] levels ≥20 ng/mL

Maria Elena Romero-Ibarguengoitia, Dalia Gutiérrez-González, Carlos Cantú-López, Miguel Angel Sanz-Sánchez, Arnulfo González-Cantú

doi:10.1101/2022.07.12.22277450

Background. There is scant information on the effect of supplementation with vitamin D 3 in SARS-COV-2 infection cases when patient D3] levels are between 20-100ng/mL. Our aim was to evaluate the effect of supplementation with vitamin D 3 vs. dietary-hygienic measures on the SARS-COV-2 infection rate in participants with serum 25(OH)D 3 levels >20ng/mL. Methods. We invited hospital workers with 25(OH)D 3 levels between 20-100 ng/mL and no previous SARS-COV-2 infection; they were randomized as follows: treatment options were a) vitamin D 3 supplementation (52,000 IU monthly, G1) or b) dietary-hygienic measures (G2). We conducted a 3-to 6-month follow-up of SARS-COV-2 infections. Participants with 25(OH)D 3 levels <20 ng/mL were also analyzed. We divided these latter participants depending on whether they were supplemented (G3) or not (G4). Results. We analyzed 198 participants, with an average age of 44.4 (SD 9) years, and 130 (65.7%) were women. G1 had less cases of SARS-COV-2 infection than G2 after a follow-up of 3-to 6months (p<0.05). There were no differences between G3 and G4 at the 3-and 6-month follow-up cutoff points (p>0.05). Using mixed effect Cox regression analysis in 164 participants that completed six months of follow-up, vitamin D 3 supplementation appeared to act as a protective factor against SARS-COV-2 infection (HR 0.21, p=0.008) in G1 and G2. None of the participants treated with the supplementation doses had serum 25(OH)D 3 levels > 100ng/mL. Conclusion. Vitamin D 3 supplementation in participants with 25(OH)D 3 levels between 20-100 ng/mL have a lower rate of SARS-COV-2 infection in comparison with the use of dietaryhygienic measures at six months follow-up.

Competing interests: The author(s) have no conflicts of interest to declare. Ethics Statement: This research project was approved by the local IRB of the Universidad de Monterrey (Ref. 30062020-a-CN-CI ). An informed consent form was obtained from each participant. . Disclosure The authors have no potential conflicts of interest associated with this study. Author Approval: all authors read an approved the final version of the manuscript. Protocol access: This study protocol can be reviewed in Clinicaltrials.gov. supplementation; G2: 25(OH)D3 >20 ng/mL without supplementation; G3: 25(OH)D3 <20 ng/mL with supplementation; G4 25(OH)D3 <20 ng/mL without supplementation.

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