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..
References
Adams, Hewison, Unexpected actions of vitamin D: New perspectives on the regulation of innate and adaptive immunity, Nat. Clin. Pract. Endocrinol. Metab,
doi:10.1038/ncpendmet0716Amrein, Schnedl, Holl, Riedl, Christopher et al., Effect of High-Dose Vitamin D 3 on Hospital Length of Stay in Critically Ill Patients with Vitamin D Deficiency: The VITdAL-ICU randomized clinical trial, JAMA,
doi:10.1001/jama.2014.13204Bennett, Moffitt, Hajagos, Amor, Anand et al., Clinical Characterization and Prediction of Clinical Severity of SARS-CoV-2 Infection Among US Adults Using Data From the US National COVID Cohort Collaborative, JAMA Netw. Open,
doi:10.1001/jamanetworkopen.2021.16901Bhalla, Amento, Clemens, Holick, Krane, Specific high-affinity receptors for 1,25-dihydroxyvitamin D 3 in human peripheral blood mononuclear cells: Presence in monocytes and induction in t lymphocytes following activation, J. Clin. Endocrinol. Metab,
doi:10.1210/jcem-57-6-1308Bilezikian, Bikle, Hewison, Lazaretti-Castro, Formenti et al., Mechanisms in Endocrinology: Vitamin D and COVID-19, Eur. J. Endocrinol,
doi:10.1530/EJE-20-0665Bishop, Ismailova, Dimeloe, Hewison, White, Vitamin D and Immune Regulation: Antibacterial, Antiviral, Anti-Inflammatory, JBMR Plus,
doi:10.1002/jbm4.10405Dancer, Parekh, Lax, D'souza, Zheng et al., Vitamin D deficiency contributes directly to the acute respiratory distress syndrome (ARDS), Thorax,
doi:10.1136/thoraxjnl-2014-206680Fan, Johnson, Johnston, Elangovanraaj, Kothari et al., Monthly trend in mortality and length of stay among coronavirus disease 2019 (COVID-19) patients: Analysis of a nationwide multihospital US database, Infect. Control Hosp. Epidemiol,
doi:10.1017/ice.2021.110Fletcher, Bishop, Harrison, Swift, Cooper et al., Autoimmune disease and interconnections with vitamin D, Endocr. Connect,
doi:10.1530/EC-21-0554Greiller, Martineau, Modulation of the Immune Response to Respiratory Viruses by Vitamin, D. Nutrients,
doi:10.3390/nu7064240Gönen, Alaylıo Glu, Durcan, Özdemir, Şahin et al., Rapid and Effective Vitamin D Supplementation May Present Better Clinical Outcomes in COVID-19 (SARS-CoV-2) Patients by Altering Serum INOS1, IL1B, IFNg, Cathelicidin-LL37, and ICAM1, Nutrients,
doi:10.3390/nu13114047Haendel, Chute, Bennett, Eichmann, Guinney et al., The National COVID Cohort Collaborative (N3C): Rationale, design, infrastructure, and deployment, J. Am. Med. Inform. Assoc,
doi:10.1093/jamia/ocaa196Hastie, Pell, Sattar, Vitamin D and COVID-19 infection and mortality in UK Biobank, Eur. J. Nutr
Ho, Imai, King, Stuart, MatchIt: Nonparametric Preprocessing for Parametric Causal Inference, J. Stat. Softw,
doi:10.18637/jss.v042.i08Hosseini, El Abd, Ducharme, Effects of Vitamin D Supplementation on COVID-19 Related Outcomes: A Systematic Review and Meta-Analysis, Nutrients,
doi:10.3390/nu14102134Langlois, Szwec, D'aragon, Heyland, Manzanares, Vitamin D supplementation in the critically ill: A systematic review and meta-analysis, Clin. Nutr,
doi:10.1016/j.clnu.2017.05.006Looker, Dawson-Hughes, Calvo, Gunter, Sahyoun, Serum 25-hydroxyvitamin D status of adolescents and adults in two seasonal subpopulations from NHANES III, Bone,
doi:10.1016/S8756-3282(02)00692-0Murai, Fernandes, Sales, Pinto, Goessler et al., Effect of a Single High Dose of Vitamin D 3 on Hospital Length of Stay in Patients with Moderate to Severe COVID-19: A Randomized Clinical Trial, JAMA,
doi:10.1001/jama.2020.26848Oristrell, Oliva, Casado, Subirana, Domínguez et al., Vitamin D supplementation and COVID-19 risk: A population-based, cohort study, J. Endocrinol. Investig,
doi:10.1007/s40618-021-01639-9Provvedini, Tsoukas, Deftos, Manolagas, 1 alpha,25-Dihydroxyvitamin D3-binding macromolecules in human B lymphocytes: Effects on immunoglobulin production, J. Immunol
Reis, Fernandes, Sales, Santos, Dos Santos et al., Influence of vitamin D status on hospital length of stay and prognosis in hospitalized patients with moderate to severe COVID-19: A multicenter prospective cohort study, Am. J. Clin. Nutr,
doi:10.1093/ajcn/nqab151Sabico, Enani, Sheshah, Aljohani, Aldisi et al., Effects of a 2-Week 5000 IU versus 1000 IU Vitamin D3 Supplementation on Recovery of Symptoms in Patients with Mild to Moderate COVID-19: A Randomized Clinical Trial, Nutrients,
doi:10.3390/nu13072170Schleicher, Sternberg, Lacher, Sempos, Looker et al., The vitamin D status of the US population from 1988 to 2010 using standardized serum concentrations of 25-hydroxyvitamin D shows recent modest increases, Am. J. Clin. Nutr,
doi:10.3945/ajcn.115.127985Shah, Varna, Sharma, Mavalankar, Does vitamin D supplementation reduce COVID-19 severity?-A systematic review, QJM,
doi:10.1093/qjmed/hcac040Tomaszewska, Rustecka, Lipi Ńska-Opałka, Piprek, Kloc et al., The Role of Vitamin D in COVID-19 and the Impact of Pandemic Restrictions on Vitamin D Blood Content, Front. Pharmacol,
doi:10.3389/fphar.2022.836738White, Emerging Roles of Vitamin D-Induced Antimicrobial Peptides in Antiviral Innate Immunity, Nutrients,
doi:10.3390/nu14020284Wortsman, Matsuoka, Chen, Lu, Holick, Decreased bioavailability of vitamin D in obesity, Am. J. Clin. Nutr,
doi:10.1093/ajcn/72.3.690Zajic, Amrein, Vitamin D deficiency in the ICU: A systematic review, Minerva Endocrinol
Zhang, Leung, Richers, Liu, Remigio et al., Vitamin D Inhibits Monocyte/Macrophage Proinflammatory Cytokine Production by Targeting MAPK Phosphatase-1, J. Immunol,
doi:10.4049/jimmunol.1102412DOI record:
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"abstract": "<jats:p>It 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.</jats:p>",
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