Vitamin D deficiency, secondary hyperparathyroidism and respiratory insufficiency in hospitalized patients with COVID-19
G Mazziotti, E Lavezzi, A Brunetti, M Mirani, G Favacchio, A Pizzocaro, M T Sandri, A Di Pasquale, A Voza, M Ciccarelli, A G Lania
Journal of Endocrinological Investigation, doi:10.1007/s40618-021-01535-2
Purpose Hypovitaminosis D has emerged as potential risk factor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in the general population with variable effects on the outcome of the coronavirus disease-19 . The aim of this retrospective single-center study was to investigate the impact of hypovitaminosis D and secondary hyperparathyroidism on respiratory outcomes of COVID-19. Methods Three-hundred-forty-eight consecutive patients hospitalized for COVID-19 at the IRCCS Humanitas Research Hospital, Rozzano, Milan (Italy) were evaluated for arterial partial pressure oxygen (PaO2)/fraction of inspired oxygen (FiO2) ratio, serum 25hydroxy-vitamin D [25(OH)D], parathyroid hormone (PTH) and inflammatory parameters at study entry and need of ventilation during the hospital stay. Results In the entire population, vitamin D deficiency (i.e., 25(OH)D values < 12 ng/mL) was significantly associated with acute hypoxemic respiratory failure at the study entry [adjusted odds ratio (OR) 2.48, 95% confidence interval 1.29-4.74; P = 0.006], independently of age and sex of subjects, serum calcium and inflammatory parameters. In patients evaluated for serum PTH (97 cases), secondary hyperparathyroidism combined with vitamin D deficiency was significantly associated with acute hypoxemic respiratory failure at study entry (P = 0.001) and need of ventilation during the hospital stay (P = 0.031).
Conclusion This study provides evidence that vitamin D deficiency, when associated with secondary hyperparathyroidism, may negatively impact the clinical outcome of SARS-CoV-2-related pneumonia.
Supplementary Information The online version contains supplementary material available at https ://doi.org/10.1007/s4061 8-021-01535 -2.
Compliance with ethical standards Conflict of interest All the authors do not have conflict of interest that is relevant to the subject matter or materials included in this work.
Ethics approval All the procedures performed in the study were in accordance with the ethical standards of the Ethics Committee of IRCCS Humanitas Research Hospital, Rozzano-Milan, Italy, and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Informed consent Informed consent was obtained from all the individual partecipants included in the study. Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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/nu12113377
Bergman, The link between vitamin D and COVID-19: distinguishing facts from fiction, J Intern Med,
doi:10.1111/joim.13158
Bifulco, Ciccarelli, Bruzzese, Dipasquale, Lania et al., The benefit of statins in SARS-CoV-2 patients: further metabolic and prospective clinical studies are needed, Endocrine,
doi:10.1007/s12020-020-02550-8
Bilezikian, Bikle, Hewison, Lazaretti-Castro, Formenti et al., Mechanisms in endocrinology: vitamin D and COVID-19, Eur J Endocrinol,
doi:10.1530/eje-20-0665
Carpagnano, Lecce, Quaranta, Zito, Buonamico et al., None
Castillo, 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.2020.105751
Cellini, Piccini, Ferrante, Carrone, Olivetti et al., Secondary hyperparathyroidism and thoracic vertebral fractures in heart failure middle-aged patients: a 3-year prospective study, J Endocrinol Invest,
doi:10.1007/s40618-020-01237-1
Cereda, Bogliolo, Lobascio, Barichella, Zecchinelli et al., Vitamin D supplementation and outcomes in coronavirus disease 2019 (COVID-19) patients from the outbreak area of Lombardy,
doi:10.1016/j.nut.2020.111055
D'avolio, Avataneo, Manca, Cusato, Nicolò et al., 25-Hydroxyvitamin D concentrations are lower in patients with positive PCR for SARS-CoV-2, Nutrients,
doi:10.3390/nu12051359
De Oliveira, Khatua, Noel, Kostenko, Bag et al., Pancreatic triglyceride lipase mediates lipotoxic systemic inflammation, J Clin Investig,
doi:10.1172/jci132767
Ellinghaus, Degenhardt, Bujanda, Buti, Albillos et al., Genomewide association study of severe Covid-19 with respiratory failure, N Engl J Med,
doi:10.1056/NEJMoa2020283
Filippo, Formenti, Rovere-Querini, Carlucci, Conte et al., Hypocalcemia is highly prevalent and predicts hospitalization in patients with COVID-19, Endocrine,
doi:10.1007/s12020-020-02383-5
Giménez, Inserra, Ferder, García, Manucha, Vitamin D deficiency in African Americans is associated with a high risk of severe disease and mortality by SARS-CoV-2, J Hum Hypertens,
doi:10.1038/s41371-020-00398-z
Grasselli, Zangrillo, Zanella, Antonelli, Cabrini et al., Baseline characteristics and outcomes of 1591 patients infected with SARS-CoV-2 admitted to ICUs of the Lombardy region, Italy, JAMA,
doi:10.1001/jama.2020.5394
Guan, Ni, Hu, Liang, Ou et al., Clinical characteristics of coronavirus disease 2019 in China, N Engl J Med,
doi:10.1056/NEJMoa2002032
Hernández, 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/dgaa733
Holick, Binkley, Bischoff-Ferrari, Gordon, Hanley et al., Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline, J Clin Endocrinol Metab,
doi:10.1210/jc.2011-0385
Holick, The vitamin D deficiency pandemic: approaches for diagnosis, treatment and prevention, Rev Endocr Metab Disord,
doi:10.1007/s11154-017-9424-1
Isaia, Giorgino, Rini, Bevilacqua, Maugeri et al., Prevalence of hypovitaminosis D in elderly women in Italy: clinical consequences and risk factors, Osteoporosis Int,
doi:10.1007/s00198-003-1390-7
Jain, Parsanathan, Achari, Kanikarla-Marie, Bocchini, Glutathione stimulates vitamin D regulatory and glucosemetabolism genes, lowers oxidative stress and inflammation, and increases 25-hydroxy-vitamin D levels in blood: a novel approach to treat 25-hydroxyvitamin D deficiency, Antioxid Redox Signal,
doi:10.1089/ars.2017.7462
Kuba, Imai, Ohto-Nakanishi, Penninger, Trilogy of ACE2: a peptidase in the renin-angiotensin system, a SARS receptor, and a partner for amino acid transporters, Pharmacol Ther,
doi:10.1016/j.pharmthera.2010.06.003
Lania, Sandri, Cellini, Mirani, Lavezzi et al., Thyrotoxicosis in patients with COVID-19: the THYRCOV study, Eur J Endocrinol,
doi:10.1530/eje-20-0335
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/nu12123799
Liu, Han, Wu, Gong, Tian, Prevalence and predictive value of hypocalcemia in severe COVID-19 patients, J Infect Public Health,
doi:10.1016/j.jiph.2020.05.029
Lodigiani, Iapichino, Carenzo, Cecconi, Ferrazzi et al., Venous and arterial thromboembolic complications in COVID-19 patients admitted to an academic hospital in Milan, Italy, Thromb Res,
doi:10.1016/j.thromres.2020.04.024
Luo, Liao, Shen, Li, Cheng, Vitamin D deficiency is inversely associated with COVID-19 incidence and disease severity in Chinese people, J Nutr,
doi:10.1093/jn/nxaa332
Martineau, Jolliffe, Hooper, Greenberg, Aloia et al., Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data, BMJ (Clin Res Ed),
doi:10.1136/bmj.i6583
Mccarty, Secondary hyperparathyroidism promotes the acute phase response-A rationale for supplemental vitamin D in prevention of vascular events in the elderly, Med Hypotheses,
doi:10.1016/j.mehy.2004.03.041
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.2020.19722
Mirani, Favacchio, Carrone, Betella, Biamonte et al., Impact of comorbidities and glycemia at admission and dipeptidyl peptidase 4 inhibitors in patients with type 2 diabetes with COVID-19: a case series from an academic hospital in Lombardy, Italy Diabetes care,
doi:10.2337/dc20-1340
Palermo, Sanesi, Colaianni, Tabacco, Naciu et al., A novel interplay between irisin and PTH: from basic studies to clinical evidence in hyperparathyroidism, J Clin Endocrinol Metab,
doi:10.1210/jc.2018-02216
Palmieri, Palmer, Noce, Meli, Giuliano et al., Differences in the clinical characteristics of COVID-19 patients who died in hospital during different phases of the pandemic: national data from Italy, Aging Clin Exp Res,
doi:10.1007/s40520-020-01764-0
Pizzini, Aichner, Sahanic, Böhm, Egger et al., Impact of vitamin D deficiency on COVID-19-a prospective analysis from the CovILD Registry, Nutrients,
doi:10.1016/j.clnu.2020.10.055
Rastogi, Bhansali, Khare, Suri, Yaddanapudi et al., Short term, high-dose vitamin D supplementation for COVID-19 disease: a randomised, placebocontrolled, study (SHADE study), Postgrad Med J,
doi:10.1136/postgradmedj-2020-139065
Romagnoli, Caravella, Scarnecchia, Martinez, Minisola, Hypovitaminosis D in an Italian population of healthy subjects and hospitalized patients, Br J Nutr
Rosen, Abrams, Aloia, Brannon, Clinton et al., IOM committee members respond to Endocrine Society vitamin D guideline, J Clin Endocrinol Metab,
doi:10.1210/jc.2011-2218
Sabetta, Depetrillo, Cipriani, Smardin, Burns et al., Serum 25-hydroxyvitamin d and the incidence of acute viral respiratory tract infections in healthy adults, PLoS ONE,
doi:10.1371/journal.pone.0011088
Section, Vademecum for the treatment of people with COVID-19. Edition 2.0, 13, Le Infezioni in Med
Sempos, Heijboer, Bikle, Bollerslev, Bouillon et al., Vitamin D assays and the definition of hypovitaminosis D: results from the first international conference on controversies in vitamin D, Br J Clin Pharmacol,
doi:10.1111/bcp.13652
Shi, Liu, Yao, Xing, Zhao et al., Chronic vitamin D deficiency induces lung fibrosis through activation of the renin-angiotensin system, Sci Rep,
doi:10.1038/s41598-017-03474-6
Singh, Khatua, El-Kurdi, Rood, Mechanistic basis and therapeutic relevance of hypocalcemia during severe COVID-19 infection, Endocrine,
doi:10.1007/s12020-020-02530-y
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/aqaa252
Sun, Zhang, Zou, Liu, Li et al., Serum calcium as a biomarker of clinical severity and prognosis in patients with coronavirus disease, Aging,
doi:10.18632/aging.103526
Thomas, Stefanoni, Reisz, Nemkov, Bertolone et al., COVID-19 infection alters kynurenine and fatty acid metabolism, correlating with IL-6 levels and renal status, JCI Insight,
doi:10.1172/jci.insight.140327
Zeng, Deng, Cui, Zhang, Dai et al., A predictive model for the severity of COVID-19 in elderly patients, Aging,
doi:10.18632/aging.103980