Vitamin D and Lung Outcomes in Elderly COVID-19 Patients
Alberto Sulli, Emanuele Gotelli, Andrea Casabella, Sabrina Paolino, Carmen Pizzorni, Elisa Alessandri, Marco Grosso, Diego Ferone, Vanessa Smith, Maurizio Cutolo
Nutrients, doi:10.3390/nu13030717
Background and aim: Vitamin D deficiency is frequently reported in patients with SARS-CoV-2 infection. The aim of this study was to correlate the 25OH-Vitamin D serum concentrations with clinical parameters of lung involvement, in elderly patients hospitalized for SARS-CoV-2 infection. Methods: Sixty-five consecutive COVID-19 patients (mean age 76 ± 13 years) and sixtyfive sex-and age-matched control subjects (CNT) were analyzed. The following clinical parameters, including comorbidities, were collected at admission: type of pulmonary involvement, respiratory parameters (PaO 2 , SO 2 , PaCO 2 , PaO 2 /FiO 2 ), laboratory parameters (including 25OH-vitamin D, D-dimer, C-reactive protein). Results: Significantly lower vitamin D serum levels were found in COVID-19 patients than in CNT (median 7.9 vs. 16.3 ng/mL, p = 0.001). Interestingly, a statistically significant positive correlation was observed between vitamin D serum levels and PaO 2 (p = 0.03), SO 2 (p = 0.05), PaO 2 /FiO 2 (p = 0.02), while a statistically significant negative correlation was found between vitamin D serum levels and D-dimer (p = 0.04), C-reactive protein (p = 0.04) and percentage of O 2 in a venturi mask (p = 0.04). A negative correlation was also observed between vitamin D serum levels and severity of radiologic pulmonary involvement, evaluated by computed tomography: in particular, vitamin D was found significantly lower in COVID-19 patients with either multiple lung consolidations (p = 0.0001) or diffuse/severe interstitial lung involvement than in those with mild involvement (p = 0.05). Finally, significantly lower vitamin D serum levels were found in the elderly COVID-19 patients who died during hospitalization, compared to those who survived (median 3.0 vs. 8.4 ng/mL, p = 0.046). Conclusions: This study confirms that 25OH-vitamin D serum deficiency is associated with more severe lung involvement, longer disease duration and risk of death, in elderly COVID-19 patients. The detection of low vitamin D levels also in younger COVID-19 patients with less comorbidities further suggests vitamin D deficiency as crucial risk factor at any age.
Conflicts of Interest: All Authors declare no conflict of interest concerning this manuscript.
References
Adorini, Penna, Control of autoimmune diseases by the vitamin D endocrine system, Nat. Clin. Pract. Rheumatol,
doi:10.1038/ncprheum0855
Aibana, Huang, Aboud, Arnedo-Pena, Becerra et al., Vitamin D status and risk of incident tuberculosis disease: A nested case-control study, systematic review, and individual-participant data meta-analysis, PLoS Med,
doi:10.1371/journal.pmed.1002907
Berry, Hesketh, Power, Hypponen, Vitamin D status has a linear association with seasonal infections and lung function in British adults, Br. J. Nutr,
doi:10.1017/S0007114511001991
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
Bourgonje, Abdulle, Timens, Hillebrands, Navis et al., Angiotensin-converting enzyme 2 (ACE2), SARS-CoV-2 and the pathophysiology of coronavirus disease 2019 (COVID-19), J. Pathol,
doi:10.1002/path.5471
Carpagnano, Di Lecce, Quaranta, Zito, Buonamico et al., Vitamin D deficiency as a predictor of poor prognosis in patients with acute respiratory failure due to COVID-19, J. Endocrinol. Invest,
doi:10.1007/s40618-020-01370-x
Charoenngam, Holick, Immunologic Effects of Vitamin D on Human Health and Disease, Nutrients,
doi:10.3390/nu12072097
Cianferotti, Bertoldo, Bischoff-Ferrari, Bruyere, Cooper et al., Vitamin D supplementation in the prevention and management of major chronic diseases not related to mineral homeostasis in adults: Research for evidence and a scientific statement from the European society for clinical and economic aspects of osteoporosis and osteoarthritis (ESCEO), Endocrine
Cutolo, Further emergent evidence for the vitamin D endocrine system involvement in autoimmune rheumatic disease risk and prognosis, Ann. Rheum. Dis,
doi:10.1136/annrheumdis-2012-202538
Cutolo, Paolino, Sulli, Smith, Pizzorni et al., steroid hormones, and autoimmunity, Ann. N. Y. Acad. Sci,
doi:10.1111/nyas.12432
Cutolo, Plebani, Shoenfeld, Adorini, Tincani, Vitamin D endocrine system and the immune response in rheumatic diseases, Vitam. Horm
Dall'ara, Cutolo, Andreoli, Tincani, Paolino, Vitamin D and systemic lupus erythematous: A review of immunological and clinical aspects, Clin. Exp. Rheumatol
Giustina, Formenti, Preventing a covid-19 pandemic Can high prevalence of severe hypovitaminosis D play a role in the high impact of Covid infection in Italy?, BMJ
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/nu12040988
Grosse, Grosse, Salzer, Dünser, Motz et al., Analysis of cardiopulmonary findings in COVID-19 fatalities: High incidence of pulmonary artery thrombi and acute suppurative bronchopneumonia, Cardiovasc. Pathol,
doi:10.1016/j.carpath.2020.107263
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.2020.04.050
Hill, Granic, Davies, Collerton, Martin-Ruiz et al., Serum 25-hydroxyvitamin D concentration and its determinants in the very old: The Newcastle 85+ Study, Osteoporos. Int,
doi:10.1007/s00198-015-3366-9
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
Im, Je, Baek, Chung, Kwon et al., Nutritional status of patients with coronavirus disease 2019 (COVID-19), Int. J. Infect Dis,
doi:10.1016/j.ijid.2020.08.018
Kaminetzky, Moore, Fansiwala, Babb, Kaminetzky et al., Pulmonary Embolism on CTPA in COVID-19 Patients, Radiol. Cardiothorac. Imaging,
doi:10.1148/ryct.2020200308
Kommoss, Schwab, Tavernar, Schreck, Wagner et al., The Pathology of Severe COVID-19-Related Lung Damage, Dtsch. Arztebl. Int
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.2013-1146
Kuba, Imai, Rao, Gao, Guo et al., A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus-induced lung injury, Nat. Med,
doi:10.1038/nm1267
Kühn, Trotz, Stangl, Prevalence of vitamin D insufficiency and evidence for disease prevention in the older population, Z. Gerontol. Geriatr,
doi:10.1007/s00391-018-1390-z
Lu, Zhang, Ma, Yue, Zou et al., Link between community-acquired pneumonia and vitamin D levels in older patients, Z. Gerontol. Geriatr,
doi:10.1007/s00391-017-1237-z
Lu, Zhao, Li, Niu, Yang et al., Genomic characterisation and epidemiology of 2019 novel coronavirus: Implications for virus origins and receptor binding, Lancet
Machado, Ferro Aissa, Ribeiro, Antunes, Vitamin D supplementation alters the expression of genes associated with hypertension and did not induce DNA damage in rats, J. Toxicol. Environ. Health A,
doi:10.1080/15287394.2019.1592044
Malek Mahdavi, A brief review of interplay between vitamin D and angiotensin-converting enzyme 2: Implications for a potential treatment for COVID-19, Rev. Med. Virol,
doi:10.1002/rmv.2119
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,
doi:10.1136/bmj.i6583
Mcgonagle, O'donnell, Sharif, Emery, Bridgewood, Immune mechanisms of pulmonary intravascular coagulopathy in COVID-19 pneumonia, Lancet Rheumatol,
doi:10.1016/S2665-9913(20)30121-1
Mohammad, Mishra, Ashraf, Emerging role of vitamin D and its associated molecules in pathways related to pathogenesis of thrombosis, Biomolecules,
doi:10.3390/biom9110649
Munshi, Hussein, Toraih, Elshazli, Jardak et al., Vitamin D insufficiency as a potential culprit in critical COVID-19 patients, J. Med. Virol,
doi:10.1002/jmv.26360
Orgaz-Molina, Buendia-Eisman, Arrabal-Polo, Ruiz, Arias-Santiago, Deficiency of serum concentration of 25-hydroxyvitamin D in psoriatic patients: A case-control study, J. Am. Acad. Derm,
doi:10.1016/j.jaad.2012.01.040
Panagiotou, Tee, Ihsan, Athar, Marchitelli et al., Low serum 25-hydroxyvitamin D (25[OH]D) levels in patients hospitalized with COVID-19 are associated with greater disease severity, Clin. Endocrinol,
doi:10.1111/cen.14276
Pereira, Dantas Damascena, Galvão Azevedo, De Almeida Oliveira, Da Mota Santana, Vitamin D deficiency aggravates COVID-19: Systematic review and meta-analysis, Crit. Rev. Food Sci. Nutr,
doi:10.1080/10408398.2020.1841090
Phokela, Peleg, Moya, Alcorn, Regulation of human pulmonary surfactant protein gene expression by 1alpha,25-dihydroxyvitamin D3, Am. J. Physiol. Lung Cell Mol. Physiol,
doi:10.1152/ajplung.00129.2004
Ranieri, Rubenfeld, Thompson, Ferguson, Caldwell et al., Acute respiratory distress syndrome: The Berlin Definition, JAMA
Rehan, Torday, Peleg, Gennaro, Vouros et al., 1Alpha,25-dihydroxy-3-epi-vitamin D3, a natural metabolite of 1alpha,25dihydroxy vitamin D3: Production and biological activity studies in pulmonary alveolar type II cells, Mol. Genet. Metab,
doi:10.1016/S1096-7192(02)00022-7
Rhodes, Subramanian, Laird, Griffin, Kenny, Perspective: Vitamin D deficiency and COVID-19 severityplausibly linked by latitude, ethnicity, impacts on cytokines, ACE2 and thrombosis, J. Intern. Med,
doi:10.1111/joim.13149
Sakka, Connors, Hékimian, Martin-Toutain, Crichi et al., Association between D-Dimer levels and mortality in patients with coronavirus disease 2019 (COVID-19): A systematic review and pooled analysis, J. Med. Vasc,
doi:10.1016/j.jdmv.2020.05.003
Science, Maguire, Russell, Smieja, Walter et al., Low serum 25-hydroxyvitamin D level and risk of upper respiratory tract infection in children and adolescents, Clin. Infect Dis,
doi:10.1093/cid/cit289
Trombetta, Smith, Gotelli, Ghio, Paolino et al., Vitamin D deficiency and clinical correlations in systemic sclerosis patients: A retrospective analysis for possible future developments, PLoS ONE,
doi:10.1371/journal.pone.0179062
Vojinovic, Tincani, Sulli, Soldano, Andreoli et al., European multicentre pilot survey to assess vitamin D status in rheumatoid arthritis patients and early development of a new Patient Reported Outcome questionnaire (D-PRO), Autoimmun. Rev,
doi:10.1016/j.autrev.2017.03.002
Wang, Koh, Pang, Association between micronutrient deficiency and acute respiratory infections in healthy adults: A systematic review of observational studies, Nutr. J,
doi:10.1186/s12937-019-0507-6
Xu, Chen, Wang, Feng, Zhou et al., Evolution of the novel coronavirus from the ongoing Wuhan outbreak and modeling of its spike protein for risk of human transmission, Sci. China Life Sci,
doi:10.1007/s11427-020-1637-5
Zhou, Yang, Zhang, Li, Liu et al., Clinical Course of 195 Critically ILL COVID-19 Patients, A Retrospective Multi-Center Study, Shock,
doi:10.1097/SHK.0000000000001629