Calcifediol Treatment and Hospital Mortality Due to COVID-19: A Cohort Study
Juan F Alcala-Diaz, Laura Limia-Perez, Ricardo Gomez-Huelgas, Maria D Martin-Escalante, Begoña Cortes-Rodriguez, Jose L Zambrana-Garcia, Marta Entrenas-Castillo, Ana I Perez-Caballero, Maria D López-Carmona, Javier Garcia-Alegria, Aquiles Lozano Rodríguez-Mancheño, Maria Del Sol Arenas-De Larriva, Luis M Pérez-Belmonte, Irwin Jungreis, Roger Bouillon, Jose Manual Quesada-Gomez, Jose Lopez-Miranda
Nutrients, doi:10.3390/nu13061760
Context. Calcifediol has been proposed as a potential treatment for COVID-19 patients. Objective: To compare the administration or not of oral calcifediol on mortality risk of patients hospitalized because of COVID-19. Design: Retrospective, multicenter, open, non-randomized cohort study. Settings: Hospitalized care. Patients: Patients with laboratory-confirmed COVID-19 between 5 February and 5 May 2020 in five hospitals in the South of Spain. Intervention: Patients received calcifediol (25-hydroxyvitamin D 3 ) treatment (0.266 mg/capsule, 2 capsules on entry and then one capsule on day 3, 7, 14, 21, and 28) or not. Main Outcome Measure: In-hospital mortality during the first 30 days after admission. Results: A total of 537 patients were hospitalized with COVID-19 (317 males (59%), median age, 70 years), and 79 (14.7%) received calcifediol treatment. Overall, in-hospital mortality during the first 30 days was 17.5%. The OR of death for patients receiving calcifediol (mortality rate of 5%) was 0.22 (95% CI, 0.08 to 0.61) compared to patients not receiving such treatment (mortality rate of 20%; p < 0.01). Patients who received calcifediol after admission were more likely than those not receiving treatment to have comorbidity and a lower rate of CURB-65 score for pneumonia severity ≥ 3 (one point for each of confusion, urea > 7 mmol/L, respiratory rate ≥ 30/min, systolic blood pressure < 90 mm Hg or diastolic blood pressure ≤ 60 mm Hg, and age Nutrients 2021, 13, 1760. https://doi.org/10.3390/nu13061760 https://www.mdpi.com/journal/nutrients ≥ 65 years), acute respiratory distress syndrome (moderate or severe), c-reactive protein, chronic kidney disease, and blood urea nitrogen. In a multivariable logistic regression model, adjusting for confounders, there were significant differences in mortality for patients receiving calcifediol compared with patients not receiving it (OR = 0.16 (95% CI 0.03 to 0.80). Conclusion: Among patients hospitalized with COVID-19, treatment with calcifediol, compared with those not receiving calcifediol, was significantly associated with lower in-hospital mortality during the first 30 days. The observational design and sample size may limit the interpretation of these findings.
Informed Consent Statement: Informed consent was obtained from all subjects involved in the study.
Conflicts of Interest: JFAD received lecture fees from Bayer, Grunenthal Pharma, Esteve, Ferrer, and Boehringer Ingelheim outside the submitted work. LLP received lecture fees from Gebro Pharma S.A., Boehringer Ingelheim, Pfizer, Mylan, Almirall, SANOFI, and ESTEVE outside the submitted work. IJ, RGH, MDME, BCR, JLZG, MEC, AIPC, MDLC, JGA, ALRM, MDSAL, and LMPB have nothing to declare. RB received lecture fees from Abiogen, Faes Farma, Fresenius, and Proctor and Gamble outside the submitted work. JMQG received lecture fees from FAES Farma (Spain) and Amgen related to vitamin D-these activities in no way influenced the writing of the present manuscript. JLM received lecture fees from AMGEN, SANOFI, FERRER, Laboratorios Dr. Esteve, and Boehringer Ingelheim-Lilly outside the submitted work. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.
References
Amrein, Sourij, Wagner, Holl, Pieber et al., Short-term effects of high-dose oral vitamin D3 in critically ill vitamin D deficient patients: A randomized, double-blind, placebo-controlled pilot study, Crit. Care,
doi:10.1186/cc10120Andrukhov, Andrukhova, Hulan, Tang, Bantleon et al., Both 25-hydroxyvitamin-D3 and 1,25-dihydroxyvitamin-D3 reduces inflammatory response in human periodontal ligament cells, PLoS ONE,
doi:10.1371/journal.pone.0090301Annweiler, Corvaisier, Gautier, Dubee, Legrand et al., Vitamin D Supplementation Associated to Better Survival in Hospitalized Frail Elderly COVID-19 Patients: The GERIA-COVID Quasi-Experimental Study, Nutrients,
doi:10.3390/nu12113377Annweiler, Hanotte, Grandin De L'eprevier, Sabatier, Lafaie et al., Vitamin D and survival in COVID-19 patients: A quasi-experimental study, J. Steroid Biochem. Mol. Biol,
doi:10.1016/j.jsbmb.2020.105771Annweiler, Mercat, Souberbielle, Learning from previous methodological pitfalls to propose well-designed trials on vitamin D in COVID-19, J. Steroid Biochem. Mol. Biol,
doi:10.1016/j.jsbmb.2021.105901Arunachalam, Wimmers, Mok, Perera, Scott et al., Systems biological assessment of immunity to mild versus severe COVID-19 infection in humans, Science,
doi:10.1126/science.abc6261Barker, May, Doty, Lappe, Knowlton et al., Vitamin D supplementation protects against reductions in plasma 25-hydroxyvitamin D induced by open-heart surgery: Assess-d trial, Physiol. Rep,
doi:10.14814/phy2.14747Barnaby, Becker, Chelico, Presenting Characteristics, Comorbidities, and Outcomes Among 5700 Patients Hospitalized With COVID-19 in the New York City Area, JAMA,
doi:10.1001/jama.2020.6775Beigel, Tomashek, Dodd, Mehta, Zingman et al., Remdesivir for the Treatment of Covid-19-Final Report, N. Engl. J. Med,
doi:10.1056/NEJMoa2007764Bilezikian, Bikle, Hewison, Lazaretti-Castro, Formenti et al., MECHANISMS IN ENDOCRINOLOGY: Vitamin D and COVID-19, Eur. J. Endocrinol
Bouillon, Marcocci, Carmeliet, Bikle, White et al., Skeletal and Extraskeletal Actions of Vitamin D: Current Evidence and Outstanding Questions, Endocr. Rev,
doi:10.1210/er.2018-00126Cangiano, Fatti, Danesi, Gazzano, Croci et al., Mortality in an Italian nursing home during COVID-19 pandemic: Correlation with gender, age, ADL, vitamin D supplementation, and limitations of the diagnostic tests, Aging,
doi:10.18632/aging.202307Castillo, Entrenas Costa, Vaquero Barrios, Alcala Diaz, Lopez 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.2020.105751Chen, Nirula, Heller, Gottlieb, Boscia et al., SARS-CoV-2 Neutralizing Antibody LY-CoV555 in Outpatients with Covid-19, N. Engl. J. Med,
doi:10.1056/NEJMoa2029849Chen, Zhou, Dong, Qu, Gong et al., Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: A descriptive study, Lancet
D'avolio, Avataneo, Manca, Cusato, De Nicolo et al., 25-Hydroxyvitamin D Concentrations Are Lower in Patients with Positive PCR for SARS-CoV-2, Nutrients,
doi:10.3390/nu12051359Dancer, Parekh, Lax, D'souza, Zheng et al., Vitamin D deficiency contributes directly to the acute respiratory distress syndrome (ARDS), Thorax,
doi:10.1136/thoraxjnl-2014-206680Force, Ranieri, Rubenfeld, Thompson, Ferguson et al., Acute respiratory distress syndrome: The Berlin Definition, JAMA,
doi:10.1001/jama.2012.5669Giustina, Bouillon, Binkley, Sempos, Adler et al., Controversies in Vitamin D: A Statement from the Third International Conference, JBMR Plus
Grant, Boucher, Bhattoa, Lahore, Why vitamin D clinical trials should be based on 25-hydroxyvitamin D concentrations, J. Steroid Biochem. Mol. Biol,
doi:10.1016/j.jsbmb.2017.08.009Grant, 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/nu12040988Group, Horby, Lim, Emberson, Mafham et al., Dexamethasone in Hospitalized Patients with Covid-19, N. Engl. J. Med,
doi:10.1056/NEJMoa2021436Hansdottir, Monick, Hinde, Lovan, Look et al., Respiratory epithelial cells convert inactive vitamin D to its active form: Potential effects on host defense, J. Immunol,
doi:10.4049/jimmunol.181.10.7090Heaney, Guidelines for optimizing design and analysis of clinical studies of nutrient effects, Nutr. Rev
Hernandez, Nan, Fernandez-Ayala, Garcia-Unzueta, Hernandez-Hernandez et al., Vitamin D Status in Hospitalized Patients with SARS-CoV-2
Ilie, Stefanescu, Smith, The role of vitamin D in the prevention of coronavirus disease 2019 infection and mortality, Aging Clin. Exp. Res,
doi:10.1007/s40520-020-01570-8Jolliffe, Stefanidis, Wang, Kermani, Dimitrov et al., Vitamin D Metabolism Is Dysregulated in Asthma and Chronic Obstructive Pulmonary Disease, Am. J. Respir. Crit. Care Med,
doi:10.1164/rccm.201909-1867OCKalil, Patterson, Mehta, Tomashek, Wolfe et al., Baricitinib plus Remdesivir for Hospitalized Adults with Covid-19, N. Engl. J. Med,
doi:10.1056/NEJMoa2031994Kaufman, Niles, Kroll, Bi, Holick, SARS-CoV-2 positivity rates associated with circulating 25-hydroxyvitamin D levels, PLoS ONE,
doi:10.1371/journal.pone.0239252Kong, Zhu, Shi, Liu, Chen et al., VDR attenuates acute lung injury by blocking Ang-2-Tie-2 pathway and renin-angiotensin system, Mol. Endocrinol,
doi:10.1210/me.2013-1146Laird, Rhodes, Kenny, Vitamin, and Inflammation: Potential Implications for Severity of Covid-19, Ir. Med. J
Lamontagne, Agoritsas, Macdonald, Leo, Diaz et al., A living WHO guideline on drugs for covid-19, BMJ,
doi:10.1136/bmj.m3379Lim, Van Der Eerden, Laing, Boersma, Karalus et al., Defining community acquired pneumonia severity on presentation to hospital: An international derivation and validation study, Thorax,
doi:10.1136/thorax.58.5.377Ling, 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/nu12123799Maghbooli, Sahraian, Ebrahimi, Pazoki, Kafan et al., Vitamin D sufficiency, a serum 25-hydroxyvitamin D at least 30 ng/mL reduced risk for adverse clinical outcomes in patients with COVID-19 infection, PLoS ONE,
doi:10.1371/journal.pone.0239799Mata-Granados, Luque De Castro, Quesada Gomez, Inappropriate serum levels of retinol, alpha-tocopherol, 25 hydroxyvitamin D3 and 24,25 dihydroxyvitamin D3 levels in healthy Spanish adults: Simultaneous assessment by HPLC, Clin. Biochem,
doi:10.1016/j.clinbiochem.2008.02.003Meltzer, Best, Zhang, Vokes, Arora et al., Association of Vitamin D Levels, Race/Ethnicity, and Clinical Characteristics With COVID-19 Test Results, JAMA Netw. Open,
doi:10.1001/jamanetworkopen.2021.4117Meltzer, 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, Golan Cohen et al., Low plasma 25(OH) vitamin D level is associated with increased risk of COVID-19 infection: An Israeli population-based study, FEBS J,
doi:10.1111/febs.15495Murai, Fernandes, Sales, Pinto, Goessler et al., 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.2020.26848Navarro-Valverde, Sosa-Henriquez, Alhambra-Exposito, Quesada-Gomez, Vitamin D3 and calcidiol are not equipotent, J. Steroid Biochem. Mol. Biol,
doi:10.1016/j.jsbmb.2016.01.014Park, Lee, Hong, Lim, Koh et al., Effect of vitamin D deficiency in Korean patients with acute respiratory distress syndrome, Korean J. Intern Med,
doi:10.3904/kjim.2017.380Pereira, Dantas Damascena, Galvao Azevedo, De Almeida Oliveira, Da Mota Santana, Vitamin D deficiency aggravates COVID-19: Systematic review and meta-analysis, Crit. Rev. Food Sci. Nutr,
doi:10.1080/10408398.2020.1841090Quesada-Gomez, Bouillon, Is calcifediol better than cholecalciferol for vitamin D supplementation?, Osteoporos. Int,
doi:10.1007/s00198-018-4520-yQuesada-Gomez, Diaz-Curiel, Sosa-Henriquez, Malouf-Sierra, Nogues-Solan et al., Low calcium intake and inadequate vitamin D status in postmenopausal osteoporotic women, J. Steroid Biochem. Mol. Biol,
doi:10.1016/j.jsbmb.2012.10.013Quesada-Gomez, Entrenas-Castillo, Bouillon, Vitamin D receptor stimulation to reduce acute respiratory distress syndrome (ARDS) in patients with coronavirus SARS-CoV-2 infections: Revised Ms SBMB 2020_166, J. Steroid. Biochem. Mol. Biol,
doi:10.1016/j.jsbmb.2020.105719Radujkovic, Hippchen, Tiwari-Heckler, Dreher, Boxberger et al., Vitamin D Deficiency and Outcome of COVID-19 Patients, Nutrients,
doi:10.3390/nu12092757Rafique, Rejnmark, Heickendorff, Moller, OH)D3 and 1.25(OH)2D3 inhibits TNF-alpha expression in human monocyte derived macrophages, PLoS ONE,
doi:10.1371/journal.pone.0215383Rastogi, Bhansali, Khare, Suri, Yaddanapudi et al., Short term, high-dose vitamin D supplementation for COVID-19 disease: A randomised, placebo-controlled, study (SHADE study), Postgrad. Med. J,
doi:10.1136/postgradmedj-2020-139065Richardson, Hirsch, Narasimhan, Crawford, Mcginn et al., the Northwell COVID-19 Research Consortium
Shah Alam, Czajkowsky, Aminul Islam, Ataur Rahman, The role of vitamin D in reducing SARS-CoV-2 infection: An update, Int. Immunopharmacol,
doi:10.1016/j.intimp.2021.107686Shi, Liu, Fu, Xu, Wu et al., Vitamin D/VDR signaling attenuates lipopolysaccharideinduced acute lung injury by maintaining the integrity of the pulmonary epithelial barrier, Mol. Med. Rep,
doi:10.3892/mmr.2015.4685Smolders, Van Den Ouweland, Geven, Pickkers, Kox, Letter to the Editor: Vitamin D deficiency in COVID-19: Mixing up cause and consequence, Metabolism Clin. Exp,
doi:10.1016/j.metabol.2020.154434Thickett, 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-2014-000074Wiersinga, Rhodes, Cheng, Peacock, Prescott, Pathophysiology, Transmission, Diagnosis, and Treatment of Coronavirus Disease 2019 (COVID-19): A Review, JAMA,
doi:10.1001/jama.2020.12839Xu, Yang, Chen, Luo, Zhang et al., Vitamin D alleviates lipopolysaccharideinduced acute lung injury via regulation of the reninangiotensin system, Mol. Med. Rep,
doi:10.3892/mmr.2017.7546Zheng, Yang, Hu, Li, Wang et al., Vitamin D attenuates lung injury via stimulating epithelial repair, reducing epithelial cell apoptosis and inhibits TGF-beta induced epithelial to mesenchymal transition, Biochem. Pharmacol,
doi:10.1016/j.bcp.2020.113955Zhu, Zhang, Wang, Li, Yang et al., A Novel Coronavirus from Patients with Pneumonia in China, N. Engl. J. Med,
doi:10.1056/NEJMoa2001017
