The Impact of Serum Levels of Vitamin D3 and Its Metabolites on the Prognosis and Disease Severity of COVID-19
Hani M J Khojah, Sameh A Ahmed, Sultan S Al-Thagfan, Yaser M Alahmadi, Yasser A Abdou
Nutrients, doi:10.3390/nu14245329
Vitamin D is among the increasingly consumed dietary supplements during the COVID-19 pandemic. It plays a regulatory role in the immune system and moderates the renin-angiotensin system, which is implicated in infection pathogenesis. However, the investigation of serum levels of vitamin D3 forms and their relative ratios in COVID-19 patients is worth investigation to understand the impacts of disease severity. Hence, we investigated the serum levels of vitamin D3 (cholecalciferol) and its metabolites (calcifediol and calcitriol), in addition to their relative ratios and correlations with angiotensin-converting enzyme 2 (ACE2), interleukin-6 (Il-6), and neutrophil-lymphocyte ratio (NLR) in COVID-19 patients compared with healthy controls. Oropharyngeal specimens were collected from the study subjects for polymerase chain reaction testing for COVID-19. Whole blood samples were obtained for blood count and NLR testing, and sera were used for the analysis of the levels of the vitamin and its metabolites, ACE2, and IL-6. We enrolled 103 patients and 50 controls. ACE2, Il-6, and NLR were significantly higher in the patients group (72.37 ± 18.67 vs. 32.36 ± 11.27 U/L, 95.84 ± 25.23 vs. 2.76 ± 0.62 pg/mL, and 1.61 ± 0.30 vs. 1.07 ± 0.16, respectively). Cholecalciferol, calcifediol, and calcitriol were significantly lower in patients (18.50 ± 5.36 vs. 29.13 ± 4.94 ng/mL, 14.60 ± 3.30 vs. 23.10 ± 3.02 ng/mL, and 42.90 ± 8.44 vs. 65.15 ± 7.11 pg/mL, respectively). However, their relative ratios were normal in both groups. Levels of the vitamin and metabolites were strongly positively, strongly negatively, and moderately negatively correlated with ACE2, Il-6, and NLR, respectively. COVID-19 infection severity is associated with a significant decrease in vitamin D3 and its metabolites in a parallel pattern, and with a significant increase in ACE2, Il-6, and NLR. Higher levels of vitamin D and its metabolites are potentially protective against severe infection.
Conflicts of Interest: The authors declare no conflict of interest.
References
Ahmed, Butler, Dargham, Latif, Chidiac et al., Vitamin D3 metabolite ratio as an indicator of vitamin D status and its association with diabetes complications, BMC Endocr. Disord,
doi:10.1186/s12902-020-00641-1
Ahmed, Khojah, Al-Thagfan, Alahmadi, Mohammed, An ultrasensitive UHPLC-ESI-MS/MS method augmented with a controlled microwave derivatization reaction for quantitation of vitamin D3 and its major metabolites in COVID-19 patients, Talanta,
doi:10.1016/j.talanta.2022.123497
Al-Thagfan, Alolayan, Ahmed, Emara, Awadallah, Impacts of deficiency in vitamin D derivatives on disease severity in adult bronchial asthma patients, Pulm. Pharmacol. Ther,
doi:10.1016/j.pupt.2021.102073
Ali, Role of vitamin D in preventing of COVID-19 infection, progression and severity, J. Infect. Public Health
Bartley, Vitamin, Emerging roles in infection and immunity, Expert Rev. Anti-Infect. Ther,
doi:10.1586/eri.10.102
Bartoszko, Siemieniuk, Kum, Qasim, Zeraatkar et al., Prophylaxis against covid-19: Living systematic review and network meta-analysis, BMJ,
doi:10.1136/bmj.n949
Beyerstedt, Casaro, Rangel, COVID-19: Angiotensin-converting enzyme 2 (ACE2) expression and tissue susceptibility to SARS-CoV-2 infection, Eur. J. Clin. Microbiol. Infect. Dis. Off. Publ. Eur. Soc. Clin. Microbiol,
doi:10.1007/s10096-020-04138-6
Cantorna, Snyder, Lin, Yang, Vitamin D and 1,25(OH)2D Regulation of T cells, Nutrients,
doi:10.3390/nu7043011
Demir, Durmaz, A Comparison of vitamin D deficiency with neutrophil lymphocyte ratio and CRP levels in Covid-19 patients, Med. Sci. Discov,
doi:10.36472/msd.v8i5.537
Feldman, Pike, None
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
Guo, Cao, Hong, Tan, Chen et al., The origin, transmission and clinical therapies on coronavirus disease 2019 (COVID-19) outbreak-An update on the status, Mil. Med. Res
Honardoost, Ghavideldarestani, Khamseh, Role of vitamin D in pathogenesis and severity of COVID-19 infection, Arch. Physiol. Biochem,
doi:10.1080/13813455.2020.1792505
Hunter, Jones, IL-6 as a keystone cytokine in health and disease, Nat. Immunol,
doi:10.1038/ni.3153
Jones, Prosser, Chapter 3-The Activating Enzymes of Vitamin D Metabolism (25-and 1α-Hydroxylases
Kamphuis, Junt, Waibler, Forster, Kalinke, Type I interferons directly regulate lymphocyte recirculation and cause transient blood lymphopenia, Blood,
doi:10.1182/blood-2006-06-027599
Khojah, Community pharmacy services and preparedness during COVID-19 outbreak in Madinah, Saudi Arabia, Saudi Pharm. J,
doi:10.1016/j.jsps.2020.09.004
Kuhn, Li, Choe, Farzan, Angiotensin-Converting Enzyme 2: A Functional Receptor for SARS Coronavirus, Cell Mol. Life Sci,
doi:10.1007/s00018-004-4242-5
Kulda, Vitamin D metabolism, Vnitr. Lek
Lagunas-Rangel, Neutrophil-to-lymphocyte ratio and lymphocyte-to-C-reactive protein ratio in patients with severe coronavirus disease 2019 (COVID-19): A meta-analysis, J. Med. Virol,
doi:10.1002/jmv.25819
Magro, SARS-CoV-2 and COVID-19: Is interleukin-6 (IL-6) the 'culprit lesion' of ARDS onset? What is there besides Tocilizumab? SGP130Fc, Cytokine X,
doi:10.1016/j.cytox.2020.100029
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
Mardani, Alamdary, Nasab, Gholami, Ahmadi et al., Association of vitamin D with the modulation of the disease severity in COVID-19, Virus Res,
doi:10.1016/j.virusres.2020.198148
Mukattash, Alkhalidy, Alzu'bi, Abu-Farha, Itani et al., Dietary supplements intake during the second wave of COVID-19 pandemic: A multinational Middle Eastern study, Eur. J. Integr. Med,
doi:10.1016/j.eujim.2022.102102
Munshi, Hussein, Toraih, Elshazli, Jardak et al., Vitamin D insufficiency as a potential culprit in critical COVID-19 patients, J. Med. Virol
Pasquali, Tartaglione, Rotondi, Muci, Mandanici et al., Calcitriol/calcifediol ratio: An indicator of vitamin D hydroxylation efficiency?, BBA Clin,
doi:10.1016/j.bbacli.2015.03.004
Raisi-Estabragh, Martineau, Curtis, Moon, Darling et al., Vitamin D and coronavirus disease 2019 (COVID-19): Rapid evidence review, Aging Clin. Exp. Res,
doi:10.1007/s40520-021-01894-z
Sabaka, Koščálová, Straka, Hodosy, Lipták et al., Role of interleukin 6 as a predictive factor for a severe course of Covid-19: Retrospective data analysis of patients from a long-term care facility during Covid-19 outbreak, BMC Infect. Dis,
doi:10.1186/s12879-021-05945-8
Shenoy, Ferreira, Qi, Fraga-Silva, Díez-Freire et al., The Angiotensin-Converting Enzyme 2/Angiogenesis-(1-7)/Mas Axis Confers Cardiopulmonary Protection against Lung Fibrosis and Pulmonary Hypertension, Am. J. Respir. Crit. Care Med,
doi:10.1164/rccm.200912-1840OC
Smit, Marinosci, Agoritsas, Calmy, Prophylaxis for COVID-19: A systematic review, Clin. Microbiol. Infect. Off. Publ. Eur. Soc. Clin. Microbiol. Infect. Dis,
doi:10.1016/j.cmi.2021.01.013
Smolders, Van Den Ouweland, Geven, Pickkers, Kox, Letter to the Editor: Vitamin D deficiency in COVID-19: Mixing up cause and consequence, Metabolism,
doi:10.1016/j.metabol.2020.154434
Szarpak, Rafique, Gasecka, Chirico, Gawel et al., A systematic review and meta-analysis of effect of vitamin D levels on the incidence of COVID-19, Cardiol. J
Słomka, Kowalewski, Żekanowska, Coronavirus Disease 2019 (COVID-19): A Short Review on Hematological Manifestations, Pathogens,
doi:10.3390/pathogens9060493
Takayama, Kato, The Vitamin D3 1alpha-Hydroxylase Gene and Its Regulation by Active Vitamin D3, Biosci. Biotechnol. Biochem,
doi:10.1271/bbb.100684
Teymoori-Rad, Shokri, Salimi, Marashi, The interplay between vitamin D and viral infections, Rev. Med. Virol,
doi:10.1002/rmv.2032
Thomas, Stefanoni, Dzieciatkowska, Issaian, Nemkov et al., Evidence of Structural Protein Damage and Membrane Lipid Remodeling in Red Blood Cells from COVID-19
Urena-Torres, Souberbielle, Pharmacologic role of vitamin D natural products, Curr. Vasc. Pharmacol
Vanherwegen, Gysemans, Mathieu, Regulation of Immune Function by Vitamin D and Its Use in Diseases of Immunity, Endocrinol. Metab. Clin. N. Am,
doi:10.1016/j.ecl.2017.07.010
Warner, Rajapaksha, Shackel, Herath, ACE2: From protection of liver disease to propagation of COVID-19, Clin. Sci,
doi:10.1042/CS20201268
{ 'indexed': { 'date-parts': [[2022, 12, 16]],
'date-time': '2022-12-16T06:16:46Z',
'timestamp': 1671171406505},
'reference-count': 48,
'publisher': 'MDPI AG',
'issue': '24',
'license': [ { 'start': { 'date-parts': [[2022, 12, 15]],
'date-time': '2022-12-15T00:00:00Z',
'timestamp': 1671062400000},
'content-version': 'vor',
'delay-in-days': 0,
'URL': 'https://creativecommons.org/licenses/by/4.0/'}],
'funder': [ { 'name': 'Deputyship for Research and Innovation, Ministry of Education, Saudi Arabia',
'award': ['112/442']}],
'content-domain': {'domain': [], 'crossmark-restriction': False},
'abstract': '<jats:p>Vitamin D is among the increasingly consumed dietary supplements during the COVID-19 '
'pandemic. It plays a regulatory role in the immune system and moderates the renin–angiotensin '
'system, which is implicated in infection pathogenesis. However, the investigation of serum '
'levels of vitamin D3 forms and their relative ratios in COVID-19 patients is worth '
'investigation to understand the impacts of disease severity. Hence, we investigated the serum '
'levels of vitamin D3 (cholecalciferol) and its metabolites (calcifediol and calcitriol), in '
'addition to their relative ratios and correlations with angiotensin-converting enzyme 2 '
'(ACE2), interleukin-6 (Il-6), and neutrophil–lymphocyte ratio (NLR) in COVID-19 patients '
'compared with healthy controls. Oropharyngeal specimens were collected from the study '
'subjects for polymerase chain reaction testing for COVID-19. Whole blood samples were '
'obtained for blood count and NLR testing, and sera were used for the analysis of the levels '
'of the vitamin and its metabolites, ACE2, and IL-6. We enrolled 103 patients and 50 controls. '
'ACE2, Il-6, and NLR were significantly higher in the patients group (72.37 ± 18.67 vs. 32.36 '
'± 11.27 U/L, 95.84 ± 25.23 vs. 2.76 ± 0.62 pg/mL, and 1.61 ± 0.30 vs. 1.07 ± 0.16, '
'respectively). Cholecalciferol, calcifediol, and calcitriol were significantly lower in '
'patients (18.50 ± 5.36 vs. 29.13 ± 4.94 ng/mL, 14.60 ± 3.30 vs. 23.10 ± 3.02 ng/mL, and 42.90 '
'± 8.44 vs. 65.15 ± 7.11 pg/mL, respectively). However, their relative ratios were normal in '
'both groups. Levels of the vitamin and metabolites were strongly positively, strongly '
'negatively, and moderately negatively correlated with ACE2, Il-6, and NLR, respectively. '
'COVID-19 infection severity is associated with a significant decrease in vitamin D3 and its '
'metabolites in a parallel pattern, and with a significant increase in ACE2, Il-6, and NLR. '
'Higher levels of vitamin D and its metabolites are potentially protective against severe '
'infection.</jats:p>',
'DOI': '10.3390/nu14245329',
'type': 'journal-article',
'created': { 'date-parts': [[2022, 12, 15]],
'date-time': '2022-12-15T09:54:14Z',
'timestamp': 1671098054000},
'page': '5329',
'source': 'Crossref',
'is-referenced-by-count': 0,
'title': 'The Impact of Serum Levels of Vitamin D3 and Its Metabolites on the Prognosis and Disease '
'Severity of COVID-19',
'prefix': '10.3390',
'volume': '14',
'author': [ { 'ORCID': 'http://orcid.org/0000-0002-0586-1526',
'authenticated-orcid': False,
'given': 'Hani M. J.',
'family': 'Khojah',
'sequence': 'first',
'affiliation': []},
{ 'ORCID': 'http://orcid.org/0000-0001-9624-6846',
'authenticated-orcid': False,
'given': 'Sameh A.',
'family': 'Ahmed',
'sequence': 'additional',
'affiliation': []},
{'given': 'Sultan S.', 'family': 'Al-Thagfan', 'sequence': 'additional', 'affiliation': []},
{ 'ORCID': 'http://orcid.org/0000-0001-6578-385X',
'authenticated-orcid': False,
'given': 'Yaser M.',
'family': 'Alahmadi',
'sequence': 'additional',
'affiliation': []},
{'given': 'Yasser A.', 'family': 'Abdou', 'sequence': 'additional', 'affiliation': []}],
'member': '1968',
'published-online': {'date-parts': [[2022, 12, 15]]},
'reference': [ { 'key': 'ref_1',
'doi-asserted-by': 'crossref',
'first-page': '549',
'DOI': '10.1152/physiolgenomics.00089.2020',
'article-title': 'The COVID-19 pandemic: A global health crisis',
'volume': '52',
'author': 'Pollard',
'year': '2020',
'journal-title': 'Physiol. Genom.'},
{ 'key': 'ref_2',
'doi-asserted-by': 'crossref',
'first-page': 'n949',
'DOI': '10.1136/bmj.n949',
'article-title': 'Prophylaxis against covid-19: Living systematic review and network '
'meta-analysis',
'volume': '373',
'author': 'Bartoszko',
'year': '2021',
'journal-title': 'BMJ'},
{ 'key': 'ref_3',
'first-page': '532',
'article-title': 'Prophylaxis for COVID-19: A systematic review',
'volume': '27',
'author': 'Smit',
'year': '2021',
'journal-title': 'Clin. Microbiol. Infect. Off. Publ. Eur. Soc. Clin. Microbiol. Infect. '
'Dis.'},
{ 'key': 'ref_4',
'doi-asserted-by': 'crossref',
'first-page': '1402',
'DOI': '10.1016/j.jsps.2020.09.004',
'article-title': 'Community pharmacy services and preparedness during COVID-19 outbreak '
'in Madinah, Saudi Arabia',
'volume': '28',
'author': 'Khojah',
'year': '2020',
'journal-title': 'Saudi Pharm. J.'},
{ 'key': 'ref_5',
'doi-asserted-by': 'crossref',
'first-page': '102102',
'DOI': '10.1016/j.eujim.2022.102102',
'article-title': 'Dietary supplements intake during the second wave of COVID-19 pandemic: '
'A multinational Middle Eastern study',
'volume': '49',
'author': 'Mukattash',
'year': '2022',
'journal-title': 'Eur. J. Integr. Med.'},
{ 'key': 'ref_6',
'doi-asserted-by': 'crossref',
'first-page': '1359',
'DOI': '10.1586/eri.10.102',
'article-title': 'Vitamin D: Emerging roles in infection and immunity',
'volume': '8',
'author': 'Bartley',
'year': '2010',
'journal-title': 'Expert Rev. Anti-Infect. Ther.'},
{ 'key': 'ref_7',
'doi-asserted-by': 'crossref',
'first-page': '1061',
'DOI': '10.1016/j.ecl.2017.07.010',
'article-title': 'Regulation of Immune Function by Vitamin D and Its Use in Diseases of '
'Immunity',
'volume': '46',
'author': 'Vanherwegen',
'year': '2017',
'journal-title': 'Endocrinol. Metab. Clin. N. Am.'},
{ 'key': 'ref_8',
'doi-asserted-by': 'crossref',
'first-page': '265',
'DOI': '10.1007/s11154-021-09679-5',
'article-title': 'Vitamin D, infections and immunity',
'volume': '23',
'author': 'Ismailova',
'year': '2021',
'journal-title': 'Rev. Endocr. Metab. Disord.'},
{ 'key': 'ref_9',
'first-page': 'e2119',
'article-title': 'A brief review of interplay between vitamin D and '
'angiotensin-converting enzyme 2: Implications for a potential treatment '
'for COVID-19',
'volume': '30',
'year': '2020',
'journal-title': 'Rev. Med. Virol.'},
{ 'key': 'ref_10',
'doi-asserted-by': 'crossref',
'first-page': '905',
'DOI': '10.1007/s10096-020-04138-6',
'article-title': 'COVID-19: Angiotensin-converting enzyme 2 (ACE2) expression and tissue '
'susceptibility to SARS-CoV-2 infection',
'volume': '40',
'author': 'Beyerstedt',
'year': '2021',
'journal-title': 'Eur. J. Clin. Microbiol. Infect. Dis. Off. Publ. Eur. Soc. Clin. '
'Microbiol.'},
{ 'key': 'ref_11',
'doi-asserted-by': 'crossref',
'first-page': '2738',
'DOI': '10.1007/s00018-004-4242-5',
'article-title': 'Angiotensin-Converting Enzyme 2: A Functional Receptor for SARS '
'Coronavirus',
'volume': '61',
'author': 'Kuhn',
'year': '2004',
'journal-title': 'Cell Mol. Life Sci.'},
{ 'key': 'ref_12',
'doi-asserted-by': 'crossref',
'first-page': '3137',
'DOI': '10.1042/CS20201268',
'article-title': 'ACE2: From protection of liver disease to propagation of COVID-19',
'volume': '134',
'author': 'Warner',
'year': '2020',
'journal-title': 'Clin. Sci.'},
{ 'key': 'ref_13',
'doi-asserted-by': 'crossref',
'first-page': '291',
'DOI': '10.1016/j.tips.2004.04.001',
'article-title': 'ACE2: From vasopeptidase to SARS virus receptor',
'volume': '25',
'author': 'Turner',
'year': '2004',
'journal-title': 'Trends Pharmacol. Sci.'},
{ 'key': 'ref_14',
'doi-asserted-by': 'crossref',
'first-page': '867',
'DOI': '10.1007/s00408-020-00408-4',
'article-title': 'ACE2: The Major Cell Entry Receptor for SARS-CoV-2',
'volume': '198',
'author': 'Scialo',
'year': '2021',
'journal-title': 'Lung'},
{ 'key': 'ref_15',
'doi-asserted-by': 'crossref',
'first-page': '196',
'DOI': '10.1016/j.ijid.2020.10.059',
'article-title': 'Could SARS-CoV-2-induced lung injury be attenuated by vitamin D?',
'volume': '102',
'author': 'Xiao',
'year': '2020',
'journal-title': 'Int. J. Infect. Dis.'},
{ 'key': 'ref_16',
'doi-asserted-by': 'crossref',
'first-page': '338',
'DOI': '10.1016/j.amjms.2020.07.018',
'article-title': 'Can a Combination of AT1R Antagonist and Vitamin D Treat the Lung '
'Complication of COVID-19?',
'volume': '360',
'author': 'Rafiullah',
'year': '2020',
'journal-title': 'Am. J. Med. Sci.'},
{ 'key': 'ref_17',
'doi-asserted-by': 'crossref',
'first-page': '1',
'DOI': '10.1080/13813455.2020.1792505',
'article-title': 'Role of vitamin D in pathogenesis and severity of COVID-19 infection',
'volume': '126',
'author': 'Honardoost',
'year': '2020',
'journal-title': 'Arch. Physiol. Biochem.'},
{ 'key': 'ref_18',
'doi-asserted-by': 'crossref',
'first-page': '278',
'DOI': '10.2174/15701611113119990020',
'article-title': 'Pharmacologic role of vitamin D natural products',
'volume': '12',
'author': 'Souberbielle',
'year': '2014',
'journal-title': 'Curr. Vasc. Pharmacol.'},
{ 'key': 'ref_19',
'first-page': '400',
'article-title': 'Vitamin D metabolism',
'volume': '58',
'author': 'Kulda',
'year': '2012',
'journal-title': 'Vnitr. Lek.'},
{ 'key': 'ref_20',
'doi-asserted-by': 'crossref',
'first-page': 'S3',
'DOI': '10.1053/ajkd.2001.28111',
'article-title': 'Therapeutic uses of vitamin D analogues',
'volume': '38',
'author': 'Brown',
'year': '2001',
'journal-title': 'Am. J. Kidney Dis. Off. J. Natl. Kidney Found.'},
{ 'key': 'ref_21',
'unstructured': 'Feldman, D., Pike, J.W., Adams, J.S.B.T.-V.D., and Third, E. (2011). '
'Chapter 3-The Activating Enzymes of Vitamin D Metabolism (25- and '
'1α-Hydroxylases), Academic Press.'},
{ 'key': 'ref_22',
'doi-asserted-by': 'crossref',
'first-page': '208',
'DOI': '10.1271/bbb.100684',
'article-title': 'The Vitamin D3 1alpha-Hydroxylase Gene and Its Regulation by Active '
'Vitamin D3',
'volume': '75',
'author': 'Takayama',
'year': '2011',
'journal-title': 'Biosci. Biotechnol. Biochem.'},
{ 'key': 'ref_23',
'doi-asserted-by': 'crossref',
'unstructured': 'Ahmed, L.H.M., Butler, A.E., Dargham, S.R., Latif, A., Chidiac, O.M., '
'Atkin, S.L., and Abi Khalil, C. (2020). Vitamin D3 metabolite ratio as '
'an indicator of vitamin D status and its association with diabetes '
'complications. BMC Endocr. Disord., 20.',
'DOI': '10.1186/s12902-020-00641-1'},
{ 'key': 'ref_24',
'doi-asserted-by': 'crossref',
'first-page': '251',
'DOI': '10.1016/j.bbacli.2015.03.004',
'article-title': 'Calcitriol/calcifediol ratio: An indicator of vitamin D hydroxylation '
'efficiency?',
'volume': '3',
'author': 'Pasquali',
'year': '2015',
'journal-title': 'BBA Clin.'},
{ 'key': 'ref_25',
'doi-asserted-by': 'crossref',
'first-page': '198148',
'DOI': '10.1016/j.virusres.2020.198148',
'article-title': 'Association of vitamin D with the modulation of the disease severity in '
'COVID-19',
'volume': '289',
'author': 'Mardani',
'year': '2020',
'journal-title': 'Virus Res.'},
{ 'key': 'ref_26',
'doi-asserted-by': 'crossref',
'first-page': '2031',
'DOI': '10.1007/s40520-021-01894-z',
'article-title': 'Vitamin D and coronavirus disease 2019 (COVID-19): Rapid evidence '
'review',
'volume': '33',
'author': 'Martineau',
'year': '2021',
'journal-title': 'Aging Clin. Exp. Res.'},
{ 'key': 'ref_27',
'doi-asserted-by': 'crossref',
'first-page': '647',
'DOI': '10.5603/CJ.a2021.0072',
'article-title': 'A systematic review and meta-analysis of effect of vitamin D levels on '
'the incidence of COVID-19',
'volume': '28',
'author': 'Szarpak',
'year': '2021',
'journal-title': 'Cardiol. J.'},
{ 'key': 'ref_28',
'doi-asserted-by': 'crossref',
'first-page': '733',
'DOI': '10.1002/jmv.26360',
'article-title': 'Vitamin D insufficiency as a potential culprit in critical COVID-19 '
'patients',
'volume': '93',
'author': 'Munshi',
'year': '2021',
'journal-title': 'J. Med. Virol.'},
{ 'key': 'ref_29',
'doi-asserted-by': 'crossref',
'first-page': 'e2032',
'DOI': '10.1002/rmv.2032',
'article-title': 'The interplay between vitamin D and viral infections',
'volume': '29',
'author': 'Shokri',
'year': '2019',
'journal-title': 'Rev. Med. Virol.'},
{ 'key': 'ref_30',
'first-page': '11',
'article-title': 'The origin, transmission and clinical therapies on coronavirus disease '
'2019 (COVID-19) outbreak—An update on the status',
'volume': '7',
'author': 'Guo',
'year': '2020',
'journal-title': 'Mil. Med. Res.'},
{ 'key': 'ref_31',
'doi-asserted-by': 'crossref',
'first-page': '1373',
'DOI': '10.1016/j.jiph.2020.06.021',
'article-title': 'Role of vitamin D in preventing of COVID-19 infection, progression and '
'severity',
'volume': '13',
'author': 'Ali',
'year': '2020',
'journal-title': 'J. Infect. Public Health'},
{ 'key': 'ref_32',
'doi-asserted-by': 'crossref',
'unstructured': 'Grant, W.B., Lahore, H., McDonnell, S.L., Baggerly, C.A., French, C.B., '
'Aliano, J.L., and Bhattoa, H.P. (2020). Evidence that Vitamin D '
'Supplementation Could Reduce Risk of Influenza and COVID-19 Infections '
'and Deaths. Nutrients, 12.',
'DOI': '10.20944/preprints202003.0235.v2'},
{ 'key': 'ref_33',
'doi-asserted-by': 'crossref',
'first-page': '3011',
'DOI': '10.3390/nu7043011',
'article-title': 'Vitamin D and 1,25(OH)2D Regulation of T cells',
'volume': '7',
'author': 'Cantorna',
'year': '2015',
'journal-title': 'Nutrients'},
{ 'key': 'ref_34',
'doi-asserted-by': 'crossref',
'unstructured': 'Sabaka, P., Koščálová, A., Straka, I., Hodosy, J., Lipták, R., '
'Kmotorková, B., Kachlíková, M., and Kušnírová, A. (2021). Role of '
'interleukin 6 as a predictive factor for a severe course of Covid-19: '
'Retrospective data analysis of patients from a long-term care facility '
'during Covid-19 outbreak. BMC Infect. Dis., 21.',
'DOI': '10.1186/s12879-021-05945-8'},
{ 'key': 'ref_35',
'doi-asserted-by': 'crossref',
'first-page': '100029',
'DOI': '10.1016/j.cytox.2020.100029',
'article-title': 'SARS-CoV-2 and COVID-19: Is interleukin-6 (IL-6) the ‘culprit lesion’ '
'of ARDS onset? What is there besides Tocilizumab? SGP130Fc',
'volume': '2',
'author': 'Magro',
'year': '2020',
'journal-title': 'Cytokine X'},
{ 'key': 'ref_36',
'doi-asserted-by': 'crossref',
'first-page': '448',
'DOI': '10.1038/ni.3153',
'article-title': 'IL-6 as a keystone cytokine in health and disease',
'volume': '16',
'author': 'Hunter',
'year': '2015',
'journal-title': 'Nat. Immunol.'},
{ 'key': 'ref_37',
'doi-asserted-by': 'crossref',
'first-page': '1733',
'DOI': '10.1002/jmv.25819',
'article-title': 'Neutrophil-to-lymphocyte ratio and lymphocyte-to-C-reactive protein '
'ratio in patients with severe coronavirus disease 2019 (COVID-19): A '
'meta-analysis',
'volume': '92',
'year': '2020',
'journal-title': 'J. Med. Virol.'},
{ 'key': 'ref_38',
'doi-asserted-by': 'crossref',
'first-page': '306',
'DOI': '10.36472/msd.v8i5.537',
'article-title': 'A Comparison of vitamin D deficiency with neutrophil lymphocyte ratio '
'and CRP levels in Covid-19 patients',
'volume': '8',
'author': 'Demir',
'year': '2021',
'journal-title': 'Med. Sci. Discov.'},
{ 'key': 'ref_39',
'doi-asserted-by': 'crossref',
'first-page': '123497',
'DOI': '10.1016/j.talanta.2022.123497',
'article-title': 'An ultrasensitive UHPLC-ESI-MS/MS method augmented with a controlled '
'microwave derivatization reaction for quantitation of vitamin D3 and '
'its major metabolites in COVID-19 patients',
'volume': '246',
'author': 'Ahmed',
'year': '2022',
'journal-title': 'Talanta'},
{ 'key': 'ref_40',
'doi-asserted-by': 'crossref',
'first-page': '102073',
'DOI': '10.1016/j.pupt.2021.102073',
'article-title': 'Impacts of deficiency in vitamin D derivatives on disease severity in '
'adult bronchial asthma patients',
'volume': '70',
'author': 'Alolayan',
'year': '2021',
'journal-title': 'Pulm. Pharmacol. Ther.'},
{ 'key': 'ref_41',
'doi-asserted-by': 'crossref',
'first-page': '51',
'DOI': '10.4161/derm.24494',
'article-title': 'Sunlight and Vitamin D',
'volume': '5',
'author': 'Wacker',
'year': '2013',
'journal-title': 'Dermato-Endocrinol.'},
{ 'key': 'ref_42',
'doi-asserted-by': 'crossref',
'first-page': '154434',
'DOI': '10.1016/j.metabol.2020.154434',
'article-title': 'Letter to the Editor: Vitamin D deficiency in COVID-19: Mixing up cause '
'and consequence',
'volume': '115',
'author': 'Smolders',
'year': '2021',
'journal-title': 'Metabolism'},
{ 'key': 'ref_43',
'doi-asserted-by': 'crossref',
'unstructured': 'Słomka, A., Kowalewski, M., and Żekanowska, E. (2020). Coronavirus '
'Disease 2019 (COVID-19): A Short Review on Hematological Manifestations. '
'Pathogens, 9.',
'DOI': '10.3390/pathogens9060493'},
{ 'key': 'ref_44',
'doi-asserted-by': 'crossref',
'first-page': '4455',
'DOI': '10.1021/acs.jproteome.0c00606',
'article-title': 'Evidence of Structural Protein Damage and Membrane Lipid Remodeling in '
'Red Blood Cells from COVID-19 Patients',
'volume': '19',
'author': 'Thomas',
'year': '2020',
'journal-title': 'J. Proteome Res.'},
{ 'key': 'ref_45',
'doi-asserted-by': 'crossref',
'first-page': '3253',
'DOI': '10.1182/blood-2006-06-027599',
'article-title': 'Type I interferons directly regulate lymphocyte recirculation and cause '
'transient blood lymphopenia',
'volume': '108',
'author': 'Kamphuis',
'year': '2006',
'journal-title': 'Blood'},
{ 'key': 'ref_46',
'doi-asserted-by': 'crossref',
'first-page': '1065',
'DOI': '10.1164/rccm.200912-1840OC',
'article-title': 'The Angiotensin-Converting Enzyme 2/Angiogenesis-(1–7)/Mas Axis Confers '
'Cardiopulmonary Protection against Lung Fibrosis and Pulmonary '
'Hypertension',
'volume': '182',
'author': 'Shenoy',
'year': '2010',
'journal-title': 'Am. J. Respir. Crit. Care Med.'},
{ 'key': 'ref_47',
'doi-asserted-by': 'crossref',
'first-page': '2167',
'DOI': '10.1007/s00467-011-2071-y',
'article-title': 'Can vitamin D slow down the progression of chronic kidney disease?',
'volume': '27',
'author': 'Shroff',
'year': '2012',
'journal-title': 'Pediatr. Nephrol.'},
{ 'key': 'ref_48',
'doi-asserted-by': 'crossref',
'first-page': '266',
'DOI': '10.1111/j.1525-139X.2005.18402.x',
'article-title': 'Vitamin D in Health and Disease: Vitamin D for Health and in Chronic '
'Kidney Disease',
'volume': '18',
'author': 'Holick',
'year': '2005',
'journal-title': 'Semin. Dial.'}],
'container-title': 'Nutrients',
'original-title': [],
'language': 'en',
'link': [ { 'URL': 'https://www.mdpi.com/2072-6643/14/24/5329/pdf',
'content-type': 'unspecified',
'content-version': 'vor',
'intended-application': 'similarity-checking'}],
'deposited': { 'date-parts': [[2022, 12, 15]],
'date-time': '2022-12-15T10:17:10Z',
'timestamp': 1671099430000},
'score': 1,
'resource': {'primary': {'URL': 'https://www.mdpi.com/2072-6643/14/24/5329'}},
'subtitle': [],
'short-title': [],
'issued': {'date-parts': [[2022, 12, 15]]},
'references-count': 48,
'journal-issue': {'issue': '24', 'published-online': {'date-parts': [[2022, 12]]}},
'alternative-id': ['nu14245329'],
'URL': 'http://dx.doi.org/10.3390/nu14245329',
'relation': {},
'ISSN': ['2072-6643'],
'subject': ['Food Science', 'Nutrition and Dietetics'],
'container-title-short': 'Nutrients',
'published': {'date-parts': [[2022, 12, 15]]}}