Calcifediol Treatment and Hospital Mortality Due to COVID-19: A Cohort Study

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 D3) 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 ≥ 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.

[1]  D. Czajkowsky,et al.  The role of vitamin D in reducing SARS-CoV-2 infection: An update , 2021, International Immunopharmacology.

[2]  C. Annweiler,et al.  Learning from previous methodological pitfalls to propose well-designed trials on vitamin D in COVID-19 , 2021, The Journal of Steroid Biochemistry and Molecular Biology.

[3]  D. Meltzer,et al.  Association of Vitamin D Levels, Race/Ethnicity, and Clinical Characteristics With COVID-19 Test Results , 2021, JAMA network open.

[4]  B. Gualano,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. , 2021, JAMA.

[5]  H. May,et al.  Vitamin D supplementation protects against reductions in plasma 25‐hydroxyvitamin D induced by open‐heart surgery: Assess‐d trial , 2021, Physiological reports.

[6]  G. Vitale,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 , 2020, Aging.

[7]  Cameron R. Wolfe,et al.  Baricitinib plus Remdesivir for Hospitalized Adults with Covid-19 , 2020, The New England journal of medicine.

[8]  Joseph M Pappachan,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 , 2020, Nutrients.

[9]  P. Pickkers,et al.  Letter to the Editor: Vitamin D deficiency in COVID-19: Mixing up cause and consequence , 2020, Metabolism.

[10]  N. Sachdeva,et al.  Short term, high-dose vitamin D supplementation for COVID-19 disease: a randomised, placebo-controlled, study (SHADE study) , 2020, Postgraduate Medical Journal.

[11]  John H. White,et al.  Controversies in Vitamin D: A Statement From the Third International Conference , 2020, JBMR plus.

[12]  Marcos Pereira,et al.  Vitamin D deficiency aggravates COVID-19: systematic review and meta-analysis , 2020, Critical reviews in food science and nutrition.

[13]  C. Annweiler,et al.  Vitamin D Supplementation Associated to Better Survival in Hospitalized Frail Elderly COVID-19 Patients: The GERIA-COVID Quasi-Experimental Study , 2020, Nutrients.

[14]  D. Skovronsky,et al.  SARS-CoV-2 Neutralizing Antibody LY-CoV555 in Outpatients with Covid-19 , 2020, The New England journal of medicine.

[15]  Y. Qu,et al.  Could SARS-CoV-2-induced lung injury be attenuated by vitamin D? , 2020, International Journal of Infectious Diseases.

[16]  J. Crespo,et al.  Vitamin D Status in Hospitalized Patients with SARS-CoV-2 Infection , 2020, The Journal of clinical endocrinology and metabolism.

[17]  C. Annweiler,et al.  Vitamin D and survival in COVID-19 patients: A quasi-experimental study , 2020, The Journal of Steroid Biochemistry and Molecular Biology.

[18]  M. Sahraian,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 , 2020, PloS one.

[19]  M. Holick,et al.  SARS-CoV-2 positivity rates associated with circulating 25-hydroxyvitamin D levels , 2020, PloS one.

[20]  G. Guyatt,et al.  A living WHO guideline on drugs for covid-19 , 2020, BMJ.

[21]  U. Merle,et al.  Vitamin D Deficiency and Outcome of COVID-19 Patients , 2020, Nutrients.

[22]  D. Meltzer,et al.  Association of Vitamin D Status and Other Clinical Characteristics With COVID-19 Test Results , 2020, JAMA network open.

[23]  R. Bouillon,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” , 2020, The Journal of Steroid Biochemistry and Molecular Biology.

[24]  Madeleine K. D. Scott,et al.  Systems biological assessment of immunity to mild versus severe COVID-19 infection in humans , 2020, Science.

[25]  N. Forouhi,et al.  Vitamin D for COVID-19: a case to answer? , 2020, The Lancet Diabetes & Endocrinology.

[26]  D. Accili,et al.  MECHANISMS IN ENDOCRINOLOGY: Vitamin D and COVID-19 , 2020, European journal of endocrinology.

[27]  Sharon J Peacock,et al.  Pathophysiology, Transmission, Diagnosis, and Treatment of Coronavirus Disease 2019 (COVID-19): A Review. , 2020, JAMA.

[28]  A. Gorohovski,et al.  Low plasma 25(OH) vitamin D level is associated with increased risk of COVID‐19 infection: an Israeli population‐based study , 2020, medRxiv.

[29]  R. Bouillon,et al.  Vitamin D receptor stimulation to reduce acute respiratory distress syndrome (ARDS) in patients with coronavirus SARS-CoV-2 infections , 2020, The Journal of Steroid Biochemistry and Molecular Biology.

[30]  L. Dodd,et al.  Remdesivir for the Treatment of Covid-19 — Final Report , 2020, The New England journal of medicine.

[31]  R. Kenny,et al.  Vitamin D and Inflammation: Potential Implications for Severity of Covid-19. , 2020, Irish medical journal.

[32]  A. Manca,et al.  25-Hydroxyvitamin D Concentrations Are Lower in Patients with Positive PCR for SARS-CoV-2 , 2020, Nutrients.

[33]  Eun Ji Kim,et al.  Presenting Characteristics, Comorbidities, and Outcomes Among 5700 Patients Hospitalized With COVID-19 in the New York City Area. , 2020, JAMA.

[34]  Lee Smith,et al.  The role of vitamin D in the prevention of coronavirus disease 2019 infection and mortality , 2020, Aging Clinical and Experimental Research.

[35]  D. Thickett,et al.  Vitamin D attenuates lung injury via stimulating epithelial repair, reducing epithelial cell apoptosis and inhibits TGF-β induced epithelial to mesenchymal transition. , 2020, Biochemical pharmacology.

[36]  W. Grant,et al.  Evidence that Vitamin D Supplementation Could Reduce Risk of Influenza and COVID-19 Infections and Deaths , 2020, Nutrients.

[37]  John H. White,et al.  Vitamin D Metabolism is Dysregulated in Asthma and Chronic Obstructive Pulmonary Disease. , 2020, American journal of respiratory and critical care medicine.

[38]  Ting Yu,et al.  Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study , 2020, The Lancet.

[39]  G. Gao,et al.  A Novel Coronavirus from Patients with Pneumonia in China, 2019 , 2020, The New England journal of medicine.

[40]  R. Bouillon,et al.  Vitamin D Metabolism Revised: Fall of Dogmas , 2019, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[41]  H. Møller,et al.  25(OH)D3 and 1.25(OH)2D3 inhibits TNF-α expression in human monocyte derived macrophages , 2019, PloS one.

[42]  John H. White,et al.  Skeletal and Extraskeletal Actions of Vitamin D: Current Evidence and Outstanding Questions , 2018, Endocrine reviews.

[43]  Sang-Bum Hong,et al.  Effect of vitamin D deficiency in Korean patients with acute respiratory distress syndrome , 2018, The Korean journal of internal medicine.

[44]  R. Bouillon,et al.  Is calcifediol better than cholecalciferol for vitamin D supplementation? , 2018, Osteoporosis International.

[45]  Daniel Brodie,et al.  Acute Respiratory Distress Syndrome: Advances in Diagnosis and Treatment , 2018, JAMA.

[46]  Q. Luo,et al.  Vitamin D alleviates lipopolysaccharide-induced acute lung injury via regulation of the renin-angiotensin system , 2017, Molecular medicine reports.

[47]  B. Boucher,et al.  Why vitamin D clinical trials should be based on 25-hydroxyvitamin D concentrations , 2017, The Journal of Steroid Biochemistry and Molecular Biology.

[48]  J. M. Quesada-Gomez,et al.  Vitamin D3 and calcidiol are not equipotent , 2016, The Journal of Steroid Biochemistry and Molecular Biology.

[49]  Jianhua Fu,et al.  Vitamin D/VDR signaling attenuates lipopolysaccharide-induced acute lung injury by maintaining the integrity of the pulmonary epithelial barrier , 2015, Molecular medicine reports.

[50]  E. Giovannucci,et al.  Association between prehospital vitamin D status and incident acute respiratory failure in critically ill patients: a retrospective cohort study , 2015, BMJ Open Respiratory Research.

[51]  G. Perkins,et al.  Vitamin D deficiency contributes directly to the acute respiratory distress syndrome (ARDS) , 2015, Thorax.

[52]  H. Bantleon,et al.  Both 25-Hydroxyvitamin-D3 and 1,25-Dihydroxyvitamin-D3 Reduces Inflammatory Response in Human Periodontal Ligament Cells , 2014, PloS one.

[53]  H. Bischoff-Ferrari,et al.  Pharmacokinetics of oral vitamin D3 and calcifediol. , 2014, Bone.

[54]  I. Bhan,et al.  VDR attenuates acute lung injury by blocking Ang-2-Tie-2 pathway and renin-angiotensin system. , 2013, Molecular endocrinology.

[55]  L. Rodríguez-Mañas,et al.  Low calcium intake and inadequate vitamin D status in postmenopausal osteoporotic women , 2013, The Journal of Steroid Biochemistry and Molecular Biology.

[56]  R. Gama,et al.  Vitamin D: a negative acute phase reactant , 2013, Journal of Clinical Pathology.

[57]  Arthur S Slutsky,et al.  Acute Respiratory Distress Syndrome The Berlin Definition , 2012 .

[58]  T. 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 , 2011, Critical care.

[59]  G. Hunninghake,et al.  Respiratory Epithelial Cells Convert Inactive Vitamin D to Its Active Form: Potential Effects on Host Defense1 , 2008, The Journal of Immunology.

[60]  J. M. Mata-Granados,et al.  Inappropriate serum levels of retinol, alpha-tocopherol, 25 hydroxyvitamin D3 and 24,25 dihydroxyvitamin D3 levels in healthy Spanish adults: simultaneous assessment by HPLC. , 2008, Clinical biochemistry.

[61]  W. Lim,et al.  Defining community acquired pneumonia severity on presentation to hospital: an international derivation and validation study , 2003, Thorax.

[62]  A. B. Hill.  The Environment and Disease: Association or Causation? , 1965, Proceedings of the Royal Society of Medicine.

[63]  W. Lim,et al.  Dexamethasone in Hospitalized Patients with Covid-19 , 2021 .

[64]  R. Heaney.  Guidelines for optimizing design and analysis of clinical studies of nutrient effects. , 2014, Nutrition reviews.

[65]  H. Bischoff-Ferrari,et al.  Pharmacokinetics of oral vitamin D(3) and calcifediol. , 2014, Bone.