Association of Vitamin D Prescribing and Clinical Outcomes in Adults Hospitalized with COVID-19

Fairfield et al., Nutrients, doi:10.3390/nu14153073

Jul 2022

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N3C retrospective showing higher risk with vitamin D treatment for hospitalized patients. As noted by authors, confounding by indication may be significant. The more extreme ventilation result, which is a significant outlier among all studies, is consistent with such confounding. Timing, dose, and duration of treatment were not used.

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: 65% [41‑79%] lower risk vs. 39% [26‑49%] 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.

This is the 91st of 118 COVID-19 controlled studies for vitamin D, which collectively show efficacy with p<0.0000000001 (1 in 30 sextillion). 29 studies are RCTs, which show efficacy with p=0.0000035.

This study is excluded in the after exclusion results of meta analysis: substantial unadjusted confounding by indication likely.

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risk of death, 8.9% higher, RR 1.09, p < 0.001, treatment 3,653 of 28,993 (12.6%), control 13,185 of 129,842 (10.2%), odds ratio converted to relative risk.

risk of mechanical ventilation, 40.8% higher, RR 1.41, p < 0.001, treatment 4,897 of 28,993 (16.9%), control 15,520 of 129,842 (12.0%), odds ratio converted to relative risk.

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

Fairfield et al., 26 Jul 2022, retrospective, USA, peer-reviewed, 10 authors, study period 1 January, 2020 - 31 July, 2021, dosage not specified.

Contact: kathleen.fairfield@mainehealth.org (corresponding author), kimberly.murray@mainehealth.org, susan.santangelo@mainehealth.org, clifford.rosen@mainehealth.org, alfred.anzalone@unmc.edu, william-beasley@ouhsc.edu, makhodaverdi@hsc.wvu.edu, slhodder@hsc.wvu.edu, owlhealthworks@gmail.com.

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Association of Vitamin D Prescribing and Clinical Outcomes in Adults Hospitalized with COVID-19

Kathleen M Fairfield, Kimberly A Murray, A Jerrod Anzalone, William Beasley, Maryam Khodaverdi, Sally L Hodder, Jeremy Harper, Susan Santangelo, Clifford J Rosen

Nutrients, doi:10.3390/nu14153073

BackgroundIt is unclear whether vitamin D benefits inpatients with COVID-19. Objective: To examine the relationship between vitamin D and COVID-19 outcomes. Design: Cohort study. Setting: National COVID Cohort Collaborative (N3C) database. Patients: 158,835 patients with confirmed COVID-19 and a sub-cohort with severe disease (n = 81,381) hospitalized between 1 January 2020 and 31 July 2021. Methods: We identified vitamin D prescribing using codes for vitamin D and its derivatives. We created a sub-cohort defined as having severe disease as those who required mechanical ventilation or extracorporeal membrane oxygenation (ECMO), had hospitalization >5 days, or hospitalization ending in death or hospice. Using logistic regression, we adjusted for age, sex, race, BMI, Charlson Comorbidity Index, and urban/rural residence, time period, and study site. Outcomes of interest were death or transfer to hospice, longer length of stay, and mechanical ventilation/ECMO. Results: Patients treated with vitamin D were older, had more comorbidities, and higher BMI compared with patients who did not receive vitamin D. Vitamin D treatment was associated with an increased odds of death or referral for hospice (adjusted odds ratio (AOR) 1.10: 95% CI 1.05-1.14), hospital stay >5 days (AOR 1.78: 95% CI 1.74-1.83), and increased odds of mechanical ventilation/ECMO (AOR 1.49: 95% CI 1.44-1.55). In the sub-cohort of severe COVID-19, vitamin D decreased the odds of death or hospice (AOR 0.90, 95% CI 0.86-0.94), but increased the odds of hospital stay longer >5 days (AOR 2.03, 95% CI 1.87-2.21) and mechanical ventilation/ECMO (AOR 1.16, 95% CI 1.12-1.21). Limitations: Our findings could reflect more aggressive treatment due to higher severity. Conclusion: Vitamin D treatment was associated with greater odds of extended hospitalization, mechanical ventilation/ECMO, and death or hospice referral.

Author Contributions: Conceptualization, K.M.F., C.J.R., S.L.H. and K.A.M.; methodology, K.M.F., K.A.M., W.B. and C.J.R.; validation, J.H., W.B., A.J.A. and N3C Consortium; formal analysis, K.A.M., M.K., A.J.A. and K.M.F.; investigation, C.J.R. and S.L.H.; resources, S.S.; writing-original draft preparation, K.M.F. and K.A.M.; writing-review and editing, C.J.R. and S.S.; project administration, K.A.M.; funding acquisition, C.J.R., S.L.H. and S.S. All authors have read and agreed to the published version of the manuscript. Funding: The project described was supported by the National Institute of General Medical Sciences, 5U54GM104942-04. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. Authorship was determined using ICMJE recommendations. Institutional Review Board Statement: The N3C data transfer to NCATS is performed under a Johns Hopkins University Reliance Protocol # IRB00249128 or individual site agreements with NIH. The study was conducted in accordance with the Declaration of Helsinki, and approved by the Institutional Review Board above. Informed Consent Statement: Patient consent was waived due to the fact this is a retrospective observational study using data from electronic medical records, and obtaining consent was not possible. Data Availability Statement: All diagnostic, medication, procedure, and laboratory concepts used in this study are available in Supplementary Table S7 . Raw code..

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Late treatment
is less effective

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