Vitamin D and COVID-19 severity and related mortality: a prospective study in Italy
Irene Campi, Luigi Gennari, Daniela Merlotti, Christian Mingiano, Alessandro Frosali, Luca Giovanelli, Camilla Torlasco, Martino F Pengo, Francesca Heilbron, Davide Soranna, Antonella Zambon, Marta Di Stefano, Carmen Aresta, Marco Bonomi, Biagio Cangiano, Vittoria Favero, Letizia Fatti, Giovanni Battista Perego, Iacopo Chiodini, Gianfranco Parati, Luca Persani
BMC Infectious Diseases, doi:10.1186/s12879-021-06281-7
Background: Vitamin D deficiency has been suggested to favor a poorer outcome of Coronavirus disease-19 . We aimed to assess if 25-hydroxyvitamin-D (25OHD) levels are associated with interleukin 6 (IL-6) levels and with disease severity and mortality in COVID-19. Methods: We prospectively studied 103 in-patients admitted to a Northern-Italian hospital (age 66.1 ± 14.1 years, 70 males) for severely-symptomatic COVID-19. Fifty-two subjects with SARS-CoV-2 infection but mild COVID-19 symptoms (mildly-symptomatic COVID-19 patients) and 206 subjects without SARS-CoV-2 infection were controls. We measured 25OHD and IL-6 levels at admission and focused on respiratory outcome during hospitalization. Results: Severely-symptomatic COVID-19 patients had lower 25OHD levels (18.2 ± 11.4 ng/mL) than mildly-symptomatic COVID-19 patients and non-SARS-CoV-2-infected controls (30.3 ± 8.5 ng/mL and 25.4 ± 9.4 ng/mL, respectively, p < 0.0001 for both comparisons). 25OHD and IL-6 levels were respectively lower and higher in severely-symptomatic COVID-19 patients admitted to intensive care Unit [(ICU), 14.4 ± 8.6 ng/mL and 43.0 (19.0-56.0) pg/mL, respectively], than in those not requiring ICU admission [22.4 ± 1.4 ng/mL, p = 0.0001 and 16.0 (8.0-32.0) pg/mL, p = 0.0002, respectively]. Similar differences were found when comparing COVID-19 patients who died in hospital [13.2 ± 6.4 ng/mL and 45.0 (28.0-99.0) pg/mL] with survivors [19.3 ± 12.0 ng/mL, p = 0.035 and 21.0 (10.5-45.9) pg/mL, p = 0.018, respectively). 25OHD levels inversely correlated with: i) IL-6 levels (ρ − 0.284, p = 0.004); ii) the subsequent need of the ICU admission [relative risk, RR 0.99, 95% confidence interval (95%CI) 0.98-1.00, p = 0.011] regardless of age, gender, presence of at least 1 comorbidity among obesity, diabetes, arterial hypertension, creatinine, IL-6 and lactate dehydrogenase levels, neutrophil cells, lymphocytes and platelets count; iii) mortality (RR 0.97, 95%CI, 0.95-0.99, p = 0.011) regardless of age, gender, presence of diabetes, IL-6 and C-reactive protein and lactate dehydrogenase levels, neutrophil cells, lymphocytes and platelets count.
Authors' contributions IC1: data collection, analysis and interpretation of the data, preparation of the manuscript. LG1: data collection, analysis and interpretation of the data, preparation of the manuscript. DM: data collection and analysis, preparation of the manuscript. CM data collection and analysis. AF: data collection and analysis. LG2: data collection and analysis. CT: data collection and analysis. MFP: data collection and analysis. FH data collection and analysis. D S: data analysis and statistics. AZ: data analysis and statistics. MD: data collection and analysis. CA: data collection and analysis. MB: data collection and analysis and revision of the manuscript. BC: data collection and analysis. VF: data collection and analysis. LF: data collection and analysis. GBP: data collection and analysis and revision of the manuscript. IC2: data collection, analysis and interpretation of the data, preparation of the manuscript. GP: data collection, analysis and interpretation of the data, preparation of the manuscript. LP: data analysis and interpretation, preparation of the manuscript. All authors have read and approved the final version of the manuscript.
Declarations
Ethics approval and consent to participate The study was approved by the ethics committee of our Institution (Ethical Committee, Istituto Auxologico Italiano). The participants or their familiar, when needed as in the case of ICU admitted patients, gave written informed consent before taking part in the..
References
Annweiler, Corvaisier, Gautier, Dubée, 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/nu12113377Bouillon, Marcocci, Carmeliet, White, Hughes et al., Skeletal and Extraskeletal actions of vitamin D: current evidence and outstanding questions, Endocr Rev,
doi:10.1210/er.2018-00126Bouillon, Safety of High-Dose Vitamin D Supplementation, J Clin Endocrinol Metab
Bouillon, Schuit, Antonio, Rastinejad, Vitamin D binding protein: a historic overview, Front Endocrinol
Camargo Ca, Martineau, Vitamin D to prevent COVID-19: recommendations for the design of clinical trials, FEBS J,
doi:10.1111/febs.15534Cangiano, 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.202307Capra, Rossi, Mattioli, Romanelli, Scarpazza et al., Impact of low dose tocilizumab on mortality rate in patients with COVID-19 related pneumonia, Eur J Intern Med,
doi:10.1016/j.ejim.2020.05.009Castillo, 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.2020.105751Charoenngam, Shirvani, Reddy, Vodopivec, Apovian et al., Association of Vitamin D Status with Hospital Morbidity and Mortality in adult hospitalized patients with COVID-19, Endocr Pract,
doi:10.1016/j.eprac.2021.02.013Cook, Marshall, Fowler, Chi-square test Lactate dehydrogenase normal values: 8-300 mU/mL; Fibrinogen normal values: 2.0-4.0 mg/dL; Leukocyte normal values: 4,
doi:10.1001/jama.2020.5775Cummings, Baldwin, Abrams, Jacobson, Meyer et al., Epidemiology, clinical course, outcomes of critically ill adults with COVID-19 in new York City: a prospective cohort study, Lancet,
doi:10.1016/S0140-6736(20)31189-2Demir, Demir, Aygun, Vitamin D deficiency is associated with COVID-19 positivity and severity of the disease, J Med Virol,
doi:10.1002/jmv.26832Duca, Piva, Focà, Latronico, Rizzi, Calculated Decisions: Brescia-COVID Respiratory Severity Scale (BCRSS)/Algorithm, Emerg Med Pract
Ghosn, Chaimani, Evrenoglou, Davidson, Graña et al., Interleukin-6 blocking agents for treating COVID-19: a living systematic review, Cochrane Database Syst Rev
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/nu12040988Hars, Mendes, Serratrice, Herrmann, Gold et al., Sexspecific association between vitamin D deficiency and COVID-19 mortality in older patients, Osteoporos Int
Hastie, Mackay, Ho, Celis-Morales, Katikireddi et al., Vitamin D concentrations and COVID-19 infection in UK biobank, Diabetes Metab Syndr,
doi:10.1016/j.dsx.2020.04.050Hastie, Pell, Sattar, Vitamin D and COVID-19 infection and mortality in UK biobank, Eur J Nutr
Havers, Smeaton, Gupte, Detrick, Bollinger et al., 25-Hydroxyvitamin D insufficiency and deficiency is associated with HIV disease progression and virological failure post-antiretroviral therapy initiation in diverse multinational settings, J Infect Dis,
doi:10.1093/infdis/jiu259Hernández, Nan, Fernandez-Ayala, García-Unzueta, Hernández-Hernández et al., Vitamin D status in hospitalized patients with SARS-CoV-2 infection, J Clin Endocrinol Metab,
doi:10.1210/clinem/dgaa733Hoffmann, Kleine-Weber, Schroeder, Krüger, Herrler et al., SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor, Cell,
doi:10.1016/j.cell.2020.02.052Ilie, 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, Camargo, Jr, Sluyter, Aglipay 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)00051-6Kaufman, Niles, Kroll, Bi, Holick, SARS-CoV-2 positivity rates associated with circulating 25-hydroxyvitamin D levels, PLoS One
Kong, 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.2013-1146Li, Cao, Zhang, Xu, Wang, Metabolic healthy obesity, vitamin D status, and risk of COVID-19, Aging Dis,
doi:10.14336/AD.2020.1108Lips, Cashman, Lamberg-Allardt, Bischoff-Ferrari, Obermayer-Pietsch et al., Current vitamin D status in European and Middle East countries and strategies to prevent vitamin D deficiency: a position statement of the European calcified tissue society, Eur J Endocrinol
Maghbooli, 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.0239799Martineau, Jolliffe, Hooper, Greenberg, Aloia et al., Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data, Br Med J
Mcgonagle, Sharif, 'regan, Bridgewood, The Role of Cytokines including Interleukin-6 in COVID-19 induced Pneumonia and Macrophage Activation Syndrome-Like Disease, Autoimmun Rev
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.2020.19722Merlotti, Rendina, Muscariello, Picchioni, Alessandri et al., Preventive role of vitamin D supplementation for acute phase reaction after bisphosphonate infusion in Paget's disease, J Clin Endocrinol Metab
Merzon, Tworowski, Gorohovski, Vinker, 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.2020.26848Panagiotou, Tee, Ihsan, Athar, Marchitelli et al., Low serum 25-hydroxyvitamin D (25[OH]D) levels in patients hospitalised with COVID-19 are associated with greater disease severity, Clin Endocrinol,
doi:10.1111/cen.14276Phokela, Peleg, Moya, Alcorn, Regulation of human pulmonary surfactant protein gene expression by 1alpha,25-dihydroxyvitamin D3, Am J Physiol Lung Cell Mol Physiol
Quesada-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, Vitamin D deficiency and outcome of COVID-19 patients, Nutrients,
doi:10.3390/nu12092757Raisi-Estabragh, Mccracken, Bethell, Cooper, Cooper et al., Greater risk of severe COVID-19 in Black, Asian and Minority Ethnic populations is not explained by cardiometabolic, socioeconomic or behavioural factors, or by 25(OH)-vitamin D status: study of 1326 cases from the UK Biobank, J Public Heal
Rastogi, 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
Reid, Knox, Talwar, Reilly, Blackwell et al., Acute changes in the systemic inflammatory response is associated with transient decreases in circulating 25-hydroxyvitamin D concentrations following elective knee arthoplasty, Ann Clin Biochem
Rhodes, Subramanian, Laird, Kenny, Editorial: low population mortality from COVID-19 in countries south of latitude 35 degrees north supports vitamin D as a factor determining severity, Aliment Pharmacol Ther,
doi:10.1111/apt.15777Sarzi-Puttini, Sirotti, Marotto, Ardizzone, Rizzardini, COVID-19, cytokines and immunosuppression: what can we learn from severe acute respiratory syndrome?, Clin Exp Rheumatol
Smet, Smet, Herroelen, Gryspeerdt, Martens, Serum 25(OH)D level on hospital admission associated with COVID-19 stage and mortality, Am J Clin Pathol,
doi:10.1093/ajcp/aqaa252Tsujino, Ushikoshi-Nakayama, Yamazakj, Matsumoto, Saito, Pulmonary activation of vitamin D3 and preventive effect against interstitial pneumonia, J Clin Biochem Nutr,
doi:10.3164/jcbn.19-48Xu, Han, Li, Wang, Fu et al., Effective treatment of severe COVID-19 patients with tocilizumab, Proc Natl Acad Sci U S A
Zou, A modified Poisson regression approach to prospective studies with binary data, Am J Epidemiol,
doi:10.1093/aje/kwh090
