Positive Effects of Vitamin D Supplementation in Patients Hospitalized for COVID-19: A Randomized, Double-Blind, Placebo-Controlled Trial
Sophie De Niet, Mickaël Trémège, Monte Coffiner, Anne-Francoise Rousseau, Doriane Calmes, Anne-Noelle Frix, Fanny Gester, Muriel Delvaux, Anne-Francoise Dive, Elora Guglielmi, Monique Henket, Alicia Staderoli, Didier Maesen, Renaud Louis, Julien Guiot, Etienne Cavalier
Nutrients, doi:10.3390/nu14153048
Retrospective studies showed a relationship between vitamin D status and COVID-19 severity and mortality, with an inverse relation between SARS-CoV-2 positivity and circulating calcifediol levels. The objective of this pilot study was to investigate the effect of vitamin D supplementation on the length of hospital stay and clinical improvement in patients with vitamin D deficiency hospitalized with COVID-19. The study was randomized, double blind and placebo controlled. A total of 50 subjects were enrolled and received, in addition to the best available COVID therapy, either vitamin D (25,000 IU per day over 4 consecutive days, followed by 25,000 IU per week up to 6 weeks) or placebo. The length of hospital stay decreased significantly in the vitamin D group compared to the placebo group (4 days vs. 8 days; p = 0.003). At Day 7, a significantly lower percentage of patients were still hospitalized in the vitamin D group compared to the placebo group (19% vs. 54%; p = 0.0161), and none of the patients treated with vitamin D were hospitalized after 21 days compared to 14% of the patients treated with placebo. Vitamin D significantly reduced the duration of supplemental oxygen among the patients who needed it (4 days vs. 7 days in the placebo group; p = 0.012) and significantly improved the clinical recovery of the patients, as assessed by the WHO scale (p = 0.0048). In conclusion, this study demonstrated that the clinical outcome of COVID-19 patients requiring hospitalization was improved by administration of vitamin D.
References
Amrein, 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.2014.13204Angelidi, Belanger, Lorinsky, Karamanis, Chamorro-Pareja et al., Vitamin D Status Is Associated With In-Hospital Mortality and Mechanical Ventilation: A Cohort of COVID-19 Hospitalized Patients, Mayo Clin. Proc,
doi:10.1016/j.mayocp.2021.01.001Barnett, Zhao, Koyama, Janz, Wang et al., Vitamin D deficiency and risk of acute lung injury in severe sepsis and severe trauma: A case-control study, Ann. Intensive Care,
doi:10.1186/2110-5820-4-5Braun, Gibbons, Litonjua, Giovannucci, Christopher, Low serum 25-hydroxyvitamin D at critical care initiation is associated with increased mortality, Crit. Care Med,
doi:10.1097/CCM.0b013e31822d74f3Cannata-Andía, Díaz-Sottolano, Fernández, Palomo-Antequera, Herrero-Puente et al., A single-oral bolus of 100,000 IU of cholecalciferol at hospital admission did not improve outcomes in the COVID-19 disease: The COVID-VIT-D-a randomised multicentre international clinical trial, BMC Med,
doi:10.1186/s12916-022-02290-8Castillo, Costa, Barrios, Díaz, Miranda et al., Effect of calcifediol treatment and best available therapy versus best available therapy on intensive care unit admission and mortality among patients hospitalized for COVID-19: A pilot randomized clinical study, J. Steroid Biochem. Mol. Biol,
doi:10.1016/j.jsbmb.2020.105751Cavalier, Faché, Souberbielle, Randomised, Double-Blinded, Placebo-Controlled, Parallel Study of Vitamin D 3 Supplementation with Different Schemes Based on Multiples of 25,000 IU Doses, Int. J. Endocrinol,
doi:10.1155/2013/327265Cavalier, Fraser, Bhattoa, Heijboer, Makris et al., Analytical Performance Specifications for 25-Hydroxyvitamin D Examinations, Nutrients,
doi:10.3390/nu13020431Cavalier, Lukas, Bekaert, Peeters, Le Goff et al., Analytical and clinical evaluation of the new Fujirebio Lumipulse ® G non-competitive assay for 25(OH)-vitamin D and three immunoassays for 25(OH)D in healthy subjects, osteoporotic patients, third trimester pregnant women, healthy African subjects, hemodialyzed and intensive care patients, Clin. Chem. Lab. Med,
doi:10.1515/cclm-2015-0923Cavalier, Lukas, Crine, Peeters, Carlisi et al., Evaluation of automated immunoassays for 25(OH)-vitamin D determination in different critical populations before and after standardization of the assays, Clin. Chim. Acta Int. J. Clin. Chem,
doi:10.1016/j.cca.2014.01.026Coussens, The role of UV radiation and vitamin D in the seasonality and outcomes of infectious disease, Photochem. Photobiol. Sci,
doi:10.1039/c6pp00355aDe Niet, Coffiner, Da Silva, Jandrain, Souberbielle et al., A Randomized Study to Compare a Monthly to a Daily Administration of Vitamin D 3 Supplementation, Nutrients,
doi:10.3390/nu10060659Dijkman, Jebbink, Deijs, Milewska, Pyrc et al., Replication-dependent downregulation of cellular angiotensin-converting enzyme 2 protein expression by human coronavirus NL63, J. Gen. Virol,
doi:10.1099/vir.0.043919-0Dopico, Evangelou, Ferreira, Guo, Pekalski et al., Widespread seasonal gene expression reveals annual differences in human immunity and physiology, Nat. Commun,
doi:10.1038/ncomms8000Fabbri, Infante, Ricordi, Editorial-Vitamin D status: A key modulator of innate immunity and natural defense from acute viral respiratory infections, Eur. Rev. Med. Pharmacol. Sci,
doi:10.26355/eurrev_202004_20876Golpour, Bereswill, Heimesaat, Antimicrobial and Immune-Modulatory Effects of Vitamin D Provide Promising Antibiotics-Independent Approaches to Tackle Bacterial Infections-Lessons Learnt from a Literature Survey, Eur. J. Microbiol. Immunol,
doi:10.1556/1886.2019.00014Gombart, Pierre, Maggini, A Review of Micronutrients and the Immune System-Working in Harmony to Reduce the Risk of Infection, Nutrients,
doi:10.3390/nu12010236Grant, 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/nu7064240Han, Jones, Tangpricha, Brown, Hao et al., High Dose Vitamin D Administration in Ventilated Intensive Care Unit Patients: A Pilot Double Blind Randomized Controlled Trial, J. Clin. Transl. Endocrinol,
doi:10.1016/j.jcte.2016.04.004Hansdottir, Monick, Hinde, Lovan, Look et al., Respiratory epithelial cells convert inactive vitamin D to its active form: Potential effects on host defense, J. Immunol. Baltim. Md,
doi:10.4049/jimmunol.181.10.7090Higgins, Wischmeyer, Queensland, Sillau, Sufit et al., Relationship of vitamin D deficiency to clinical outcomes in critically ill patients, JPEN J. Parenter. Enter. Nutr,
doi:10.1177/0148607112444449Jolliffe, Camargo, Sluyter, Aglipay, Aloia et al., Vitamin D supplementation to prevent acute respiratory infections: A systematic review and meta-analysis of aggregate data from randomised controlled trials, Lancet Diabetes Endocrinol,
doi:10.1016/S2213-8587(21)00051-6Jolliffe, Griffiths, Martineau, Vitamin D in the prevention of acute respiratory infection: Systematic review of clinical studies, J. Steroid Biochem. Mol. Biol,
doi:10.1016/j.jsbmb.2012.11.017Kaufman, Niles, Kroll, Bi, Holick, SARS-CoV-2 positivity rates associated with circulating 25-hydroxyvitamin D levels, PLoS ONE,
doi:10.1371/journal.pone.0239252Kempker, West, Kempker, Siwamogsatham, Alvarez et al., Vitamin D status and the risk for hospital-acquired infections in critically ill adults: A prospective cohort study, PLoS ONE,
doi:10.1371/journal.pone.0122136Mcnally, Menon, Chakraborty, Fisher, Williams et al., The association of vitamin D status with pediatric critical illness, Pediatrics,
doi:10.1542/peds.2011-3059Meltzer, 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.2020.19722Milani, Simonetti, Edefonti, Lava, Agostoni et al., Seasonal variability of the vitamin D effect on physical fitness in adolescents, Sci. Rep,
doi:10.1038/s41598-020-80511-xMoromizato, Litonjua, Braun, Gibbons, Giovannucci et al., Association of low serum 25-hydroxyvitamin D levels and sepsis in the critically ill, Crit. Care Med,
doi:10.1097/CCM.0b013e31829eb7afMurai, 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.2020.26848Nair, Lee, Reynolds, Nguyen, Myburgh et al., Significant perturbation of vitamin Dparathyroid-calcium axis and adverse clinical outcomes in critically ill patients, Intensive Care Med,
doi:10.1007/s00134-012-2713-yOlliver, Spelmink, Hiew, Meyer-Hoffert, Henriques-Normark et al., Immunomodulatory effects of vitamin D on innate and adaptive immune responses to Streptococcus pneumoniae, J. Infect Dis,
doi:10.1093/infdis/jit355Quraishi, Litonjua, Moromizato, Gibbons, Camargo et al., Association between prehospital vitamin D status and hospital-acquired Clostridium difficile infections, JPEN J. Parenter. Enter. Nutr,
doi:10.1177/0148607113511991Rondanelli, Miccono, Lamburghini, Avanzato, Riva et al., Self-Care for Common Colds: The Pivotal Role of Vitamin D, Vitamin C, Zinc, and Echinacea in Three Main Immune Interactive Clusters (Physical Barriers, Innate and Adaptive Immunity) Involved during an Episode of Common Colds-Practical Advice on Dosages and on the Time to Take These Nutrients/Botanicals in order to Prevent or Treat Common Colds, Evid.-Based Complement. Altern. Med. ECAM,
doi:10.1155/2018/5813095Schleck, Souberbielle, Jandrain, Da Silva, De Niet et al., Double-Blind, Parallel Study to Evaluate the Dose-Response of Three Different Vitamin D Treatment Schemes on the 25-Hydroxyvitamin D Serum Concentration in Patients with Vitamin D Deficiency, Nutrients,
doi:10.3390/nu7075227Teymoori-Rad, Marashi, Vitamin D and COVID-19: From potential therapeutic effects to unanswered questions, Rev. Med. Virol,
doi:10.1002/rmv.2159Thickett, Moromizato, Litonjua, Amrein, Quraishi et al., Association between prehospital vitamin D status and incident acute respiratory failure in critically ill patients: A retrospective cohort study, BMJ Open Respir. Res,
doi:10.1136/bmjresp-2014-000074Wei, Christakos, Mechanisms Underlying the Regulation of Innate and Adaptive Immunity by Vitamin D, Nutrients,
doi:10.3390/nu7105392Who, Working Group on the Clinical Characterisation and Management of COVID-19 infection. A minimal common outcome measure set for COVID-19 clinical research, Lancet Infect Dis,
doi:10.1016/S1473-3099(20)30483-7Wise, Camara, Sempos, Lukas, Le Goff et al., Vitamin D Standardization Program (VDSP) intralaboratory study for the assessment of 25-hydroxyvitamin D assay variability and bias, J. Steroid Biochem. Mol. Biol,
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'abstract': '<jats:p>Retrospective studies showed a relationship between vitamin D status and COVID-19 '
'severity and mortality, with an inverse relation between SARS-CoV-2 positivity and '
'circulating calcifediol levels. The objective of this pilot study was to investigate the '
'effect of vitamin D supplementation on the length of hospital stay and clinical improvement '
'in patients with vitamin D deficiency hospitalized with COVID-19. The study was randomized, '
'double blind and placebo controlled. A total of 50 subjects were enrolled and received, in '
'addition to the best available COVID therapy, either vitamin D (25,000 IU per day over 4 '
'consecutive days, followed by 25,000 IU per week up to 6 weeks) or placebo. The length of '
'hospital stay decreased significantly in the vitamin D group compared to the placebo group (4 '
'days vs. 8 days; p = 0.003). At Day 7, a significantly lower percentage of patients were '
'still hospitalized in the vitamin D group compared to the placebo group (19% vs. 54%; p = '
'0.0161), and none of the patients treated with vitamin D were hospitalized after 21 days '
'compared to 14% of the patients treated with placebo. Vitamin D significantly reduced the '
'duration of supplemental oxygen among the patients who needed it (4 days vs. 7 days in the '
'placebo group; p = 0.012) and significantly improved the clinical recovery of the patients, '
'as assessed by the WHO scale (p = 0.0048). In conclusion, this study demonstrated that the '
'clinical outcome of COVID-19 patients requiring hospitalization was improved by '
'administration of vitamin D.</jats:p>',
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