Vitamin D supplementation and COVID-19 risk: a population-based, cohort study
J Oristrell, J C Oliva, E Casado, I Subirana, D Domínguez, A Toloba, A Balado, M Grau
Journal of Endocrinological Investigation, doi:10.1007/s40618-021-01639-9
Purpose To analyze the associations between cholecalciferol or calcifediol supplementation, serum 25-hydroxyvitamin D (25OHD) levels and COVID-19 outcomes in a large population. Methods All individuals ≥ 18 years old living in Barcelona-Central Catalonia (n = 4.6 million) supplemented with cholecalciferol or calcifediol from April 2019 to February 2020 were compared with propensity score-matched untreated controls. Outcome variables were SARS-CoV2 infection, severe COVID-19 and COVID-19 mortality occuring during the first wave of the pandemic. Demographical data, comorbidities, serum 25OHD levels and concomitant pharmacological treatments were collected as covariates. Associations between cholecalciferol or calcifediol use and outcome variables were analyzed using multivariate Cox proportional regression. Results Cholecalciferol supplementation (n = 108,343) was associated with slight protection from SARS-CoV2 infection (n = 4352 [4.0%] vs 9142/216,686 [4.2%] in controls; HR 0.95 [CI 95% 0.91-0.98], p = 0.004). Patients on cholecalciferol treatment achieving 25OHD levels ≥ 30 ng/ml had lower risk of SARS-CoV2 infection, lower risk of severe COVID-19 and lower COVID-19 mortality than unsupplemented 25OHD-deficient patients (56/9474 [0.6%] vs 96/7616 [1.3%]; HR 0.66 [CI 95% 0.46-0.93], p = 0.018). Calcifediol use (n = 134,703) was not associated with reduced risk of SARS-CoV2 infection or mortality in the whole cohort. However, patients on calcifediol treatment achieving serum 25OHD levels ≥ 30 ng/ml also had lower risk of SARS-CoV2 infection, lower risk of severe COVID-19, and lower COVID-19 mortality compared to 25OHD-deficient patients not receiving vitamin D supplements (88/16276 [0.5%] vs 96/7616 [1.3%]; HR 0.56 [CI 95% 0.42-0.76], p < 0.001). Conclusions In this large, population-based study, we observed that patients supplemented with cholecalciferol or calcifediol achieving serum 25OHD levels ≥ 30 ng/ml were associated with better COVID-19 outcomes.
Discussion In this large population-based cohort, we have compared COVID-19 outcomes in patients supplemented with cholecalciferol or calcifediol versus untreated matched controls, finding only a mild reduction in the risk of SARS-CoV2 infection (diagnosed clinically or by PCR) in patients supplemented with cholecalciferol, and a small reduction in
Declarations
Conflicts of interest The authors declare no conflict of interest. The Catalan Agency for Health Quality and Evaluation (AQUAS), a governmental office, offered a data analyst for extracting all the data necessary for the development of this project. They had no role in the design of the study, analyses, interpretation of data; in the writing of the manuscript, or in the decision to publish these results. Institutional review board statement This study was approved by the Institutional Ethics Committee of the Corporació Sanitària Parc Taulí-Universitat Autònoma Barcelona (Project number 2020588). Informed consent Not applicable. Patient and public involvement It was not appropriate or possible to involve patients or the public in the design, or conduct, or reporting, or dissemination plans of our research.
Transparency statement The lead author (J. Oristrell) affirms that the manuscript is an honest, accurate, and transparent account of the study being reported. No important aspects of the study have been omitted, and there were no significant discrepancies from the study as it was planned. Dissemination..
References
Abrishami, Dalili, Torbati, Asgari, Arab-Ahmadi et al., Possible association of vitamin D status with lung involvement and outcome in patients with COVID-19: a retrospective study, Eur J Nutr,
doi:10.1007/s00394-020-02411-0Annweiler, Corvaisier, Gautier, Vitamin D supplementation associated to better survival in hospitalized frail elderly COVID-19 patients: the GERIA-COVID quasi-experimental study, Nutrients
Armaly, Kinaneh, Skorecki, Renal manifestations of COVID-19: physiology and pathophysiology, J Clin Med,
doi:10.3390/jcm10061216Bassatne, Basbous, Chakhtoura, El Zein, Rahme et al., The link between COVID-19 and vitamin D (VIVID): a systematic review and meta-analysis, Metab Clin Exp
Bergman, Lindh, Björkhem-Bergman, Vitamin D and respiratory tract infections: a systematic review and meta-analysis of randomized controlled trials, PLoS ONE
Brunette, Chan, Ferriere, Roberts, Site of 1,25(OH)2 vitamin D3 synthesis in the kidney, Nature
Bscheider, Butcher, Vitamin D immunoregulation through dendritic cells, Immunology,
doi:10.1111/imm.12610Castillo, Costa, Barrios, Effect of calcifediol treatment and best available tehrapy on intensive care unit admission and mortality among patients hospitalized for COVID-19: a pilot randomized clinical study, J Steroid Biochem Mol Biol
Cereda, Bogliolo, Lobascio, Vitamin D supplementation and outcomes in coronavirus disease 2019 (COVID-19) patients from the outbreak area of Lombardy, Italy, Nutrition,
doi:10.1016/j.nut.2020.111055Dusso, Tokumoto, Defective renal maintenance of the vitamin D endocrine system impairs vitamin D renoprotection: a downward spiral in kidney disease, Kidney Int
Grant, Lahore, Mcdonnell, Baggerly, French et al., Evidence that vitamin D supplementation could reduce risk of influenza and COVID-19 infections and deaths, Nutrients,
doi:10.3390/nu12040988Greiller, Martineau, Modulation of the immune response to respiratory viruses by vitamin D, Nutrients,
doi:10.3390/nu7064240Haussler, Professor, Jurutka, Vitamin D receptor (VDR)-mediated actions of 1α,25(OH) 2 vitamin D 3 : genomic and non-genomic mechanisms, Best Pract Res Clin Endocrinol Metab
Hernández, Nan, Fernández-Ayala, García-Unzueta, Hernández-Hernández et al., Vitamin D status in hospitalized patients with SARS-CoV2 infection, J Clin Endocrinol Metab,
doi:10.1210/clinem/dgaa733Hilger, Friedel, Herr, Rausch, Roos et al., A systematic review of vitamin D status in populations worldwide, Br J Nutr,
doi:10.1017/S0007114513001840Kassambara, Kosinski, Biecek, Survminer: drawing survival curves using 'ggplot2
Kaufman, Niles, Kroll, Bi, Holick, SARS-CoV-2 positivity rates associated with circulating 25-hydroxyvitamin D levels, PLoS ONE,
doi:10.1371/journal.pone.0239252Kazemi, Mohammadi, Aghababaee, Golzarand, Clark et al., Association of vitamin D status with SARS-CoV2 infection or COVID-19 severity: a systematic review and meta-analysis, Adv Nutr,
doi:10.1093/advances/nmab012Kong, Zhu, Shi, VDR attenuates acute lung injury by blocking Ang-2-Tie-2 pathway and renin-angiotensin system, Mol Endocrinol,
doi:10.1210/me.2013-1146Kongsbak, Levring, Geisler, Von Essen Mr, The vitamin D receptor an T cell function, Front Immunol
Lely, Hamming, Van Goor, Navis, Renal ACE2 expression in human kidney disease, J Pathol
Levey, Stevens, Schmid, CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration). A new equation to estimate glomerular filtration rate, Ann Intern Med
Ling, Broad, Murphy, Pappachan, Pardesi-Newton et al., 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, Nutrients,
doi:10.3390/nu12123799Loucera, Peña-Chilet, Medina, Muñoyerro-Muñiz, Villegas et al., Real-world evidence of calcifediol use and mortality rate of COVID-19 hospitalized in a large cohort of 16,401 Andalusian patients,
doi:10.1101/2021.04.27.21255937Luo, Liao, Shen, Li, Cheng, Vitamin D deficiency is associated with COVID-19 incidence and disease severity in Chinese people, J Nutr
Martineau, Jolliffe, Hooper, Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data, BMJ
Meltzer, Best, Zhang, Vokes, Arora et al., Association of vitamin D status and other clinical characteristics with COVID-19 test results, JAMA Netw Open,
doi:10.1001/jamanetworkopen.2020.19722Merzon, Tworowski, Gorohovski, Vinker, Cohen, Low plasma 25(OH) vitamin D level is associated with increased risk of COVID-19 infection: an Israeli populationbased study, FEBS J,
doi:10.1111/febs.15495Murai, Fernandes, Sales, Effect of a single high dose of vitamin D3 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, Subirana, Casado, Domínguez et al., Association of calcitriol supplementation with reduced COVID-19 mortality in patients with chronic kidney disease:a population-based study, Biomedicines,
doi:10.3390/biomedicines9050509Peelen, Knippenberg, Muris, Thewissen, Smolders et al., Effects of vitamin D on the peripheral adaptive immune system: a review, Autoimmun Rev
Pereira, Damascena, Azevedo, De Almeida, Da Mota, Vitamin D deficiency aggravates COVID-19: systematic review and meta-analysis, Crit Rev Food Sci Nutr,
doi:10.1080/10408398.2020.1841090Pérez Castrillón, Casado, Gudino, COVID-19 and vitamin D. Position paper of the Spanish Society for Bone Research and Mineral Metabolism (SEIOMM), Rev Osteoporos Metab Miner
Radujkovic, Hippchen, Tiwari-Heckler, Dreher, Boxberger, Vitamin D deficiency and outcome of COVID-19 patients, Nutrients,
doi:10.3390/nu12092757Rastogi, Bhansali, Khare, Short term, highdose vitamin D supplementation for COVID-19 disease: a randomised, placebo-controlled, study (SHADE study), Postgrad Med J,
doi:10.1136/postgradmedj-2020-139065Sekhon, Multivariate and propensity score matching software with automated balance Optimization: the matching package for R, J Stat Soft
Teymoori-Rad, Marashi, Vitamin D and COVID-19: from potential therapeutic effects to unanswered qüestions, Rev Med Virol,
doi:10.1002/rmv.2159Therneau, A package for survival analysis in R. R package version 3
Werion, Belkhir, Perrot, Schmit, Aydin et al., SARS-CoV-2 causes a specific dysfunction of the kidney proximal tubule, Kidney Int
Williamson, Walker, Bhaskaran, Factors associated with COVID-19-related death using OpenSAFELY, Nature
Xu, Yang, Chen, Vitamin D alleviates lipopolysaccharide-induced acute lung injury via regulation of the reninangiotensin system, Mol Med Rep,
doi:10.3892/mmr.2017.7546Yoshida, Bohn, Package 'tableone' for R
