Vitamin D – contrary to vitamin K – does not associate with clinical outcome in hospitalized COVID-19 patients
Jona Walk, Anton S M Dofferhoff, Jody M W Van Den Ouweland, Henny Van Daal, Dr Rob Janssen
doi:10.1101/2020.11.07.20227512
SARS-CoV-2 causes remarkably variable disease from asymptomatic individuals to respiratory insufficiency and coagulopathy. Vitamin K deficiency was recently found to associate with clinical outcome in a cohort of COVID-19 patients. Vitamin D has been hypothesized to reduce disease susceptibility by modulating inflammation, yet little is known about its role in disease severity. Considering the critical interaction between vitamin K and vitamin D in calcium and elastic fiber metabolism, we determined vitamin D status in the same cohort of 135 hospitalized COVID-19 patients by measuring blood 25(OH)D levels. We found no difference in vitamin D status between those with good and poor outcome (defined as intubation and/or death). Instead, we found vitamin D sufficient persons (25(OH)D >50 nmol/L) had accelerated elastic fiber degradation compared to those with mild deficiency (25(OH)D 25-50 nmol/L). Based on these findings, we hypothesize that vitamin D might have both favorable anti-inflammatory and unfavorable pro-calcification effects during COVID-19 and that vitamin K might compensate for the latter.
References
Basalyga, Elastin degradation and calcification in an abdominal aorta injury model: role of matrix metalloproteinases, Circulation
Boraldi, The mineralization process of insoluble elastin fibrillar structures: Ionic environment vs degradation, Int J Biol Macromol
Bouvet, Sequential activation of matrix metalloproteinase 9 and transforming growth factor beta in arterial elastocalcinosis, Arterioscler Thromb Vasc Biol
Cipriani, Effect of a single oral dose of 600,000 IU of cholecalciferol on serum calciotropic hormones in young subjects with vitamin D deficiency: a prospective intervention study, J Clin Endocrinol Metab
D'avolio, 25-Hydroxyvitamin D Concentrations Are Lower in Patients with Positive PCR for SARS-CoV-2, Nutrients
Dirks, Various calibration procedures result in optimal standardization of routinely used 25(OH)D ID-LC-MS/MS methods, Clin Chim Acta
Dofferhoff, Reduced vitamin K status as a potentially modifiable risk factor of severe COVID-19, Clin Infect Dis
Fraser, Price, Induction of matrix Gla protein synthesis during prolonged 1,25-dihydroxyvitamin D3 treatment of osteosarcoma cells, Calcif Tissue Int
Greiller, Martineau, Modulation of the immune response to respiratory viruses by vitamin D, Nutrients
Hastie, Vitamin D concentrations and COVID-19 infection in UK Biobank, Diabetes Metab Syndr
Honardoost, Ghavideldarestani, Khamseh, Role of vitamin D in pathogenesis and severity of COVID-19 infection, Arch Physiol Biochem
Janssen, Vitamin K metabolism as the potential missing link between lung damage and thromboembolism in Coronavirus disease 2019, Br J Nutr
Janssens, Vitamin D and chronic obstructive pulmonary disease: hype or reality?, Lancet Respir Med
Lee, Elastin calcification in the rat subdermal model is accompanied by up-regulation of degradative and osteogenic cellular responses, Am J Pathol
Luo, Spontaneous calcification of arteries and cartilage in mice lacking matrix GLA protein, Nature
Martineau, Forouhi, Vitamin D for COVID-19: a case to answer?, Lancet Diabetes Endocrinol
Mccann, Ames, Vitamin, an example of triage theory: is micronutrient inadequacy linked to diseases of aging?, Am J Clin Nutr
Mehta, Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data, Lancet
Niederhoffer, Aortic calcification produced by vitamin D3 plus nicotine, J Vasc Res
Panagiotou, Low serum 25-hydroxyvitamin D (25[OH]D) levels in patients hospitalized with COVID-19 are associated with greater disease severity, Clin Endocrinol
Price, Buckley, Williamson, The amino bisphosphonate ibandronate prevents vitamin D toxicity and inhibits vitamin D-induced calcification of arteries, cartilage, lungs and kidneys in rats, J Nutr
Rucker, Calcium binding to elastin, Adv Exp Med Biol
Schurgers, Uitto, Reutelingsperger, Vitamin K-dependent carboxylation of matrix Gla-protein: a crucial switch to control ectopic mineralization, Trends Mol Med
Turino, Matrix elastin: a promising biomarker for chronic obstructive pulmonary disease, Am J Respir Crit Care Med
Ueland, Distinct and early increase in circulating MMP-9 in COVID-19 patients with respiratory failure, J Infect
Van Ballegooijen, Joint association of vitamins D and K status with longterm outcomes in stable kidney transplant recipients, Nephrol Dial Transplant
Van Ballegooijen, The Synergistic Interplay between Vitamins D and K for Bone and Cardiovascular Health: A Narrative Review, Int J Endocrinol
Winter, High prevalence of vitamin D deficiency in the south-west Netherlands
Zweifler, Esler, Factors influencing the choice of antihypertensive agents, Postgrad Med
{ 'institution': [{'name': 'medRxiv'}],
'indexed': { 'date-parts': [[2023, 10, 30]],
'date-time': '2023-10-30T17:09:15Z',
'timestamp': 1698685755766},
'posted': {'date-parts': [[2020, 11, 9]]},
'group-title': 'Infectious Diseases (except HIV/AIDS)',
'reference-count': 32,
'publisher': 'Cold Spring Harbor Laboratory',
'content-domain': {'domain': [], 'crossmark-restriction': False},
'accepted': {'date-parts': [[2020, 11, 9]]},
'abstract': '<jats:title>Abstract</jats:title><jats:p>SARS-CoV-2 causes remarkably variable disease from '
'asymptomatic individuals to respiratory insufficiency and coagulopathy. Vitamin K deficiency '
'was recently found to associate with clinical outcome in a cohort of COVID-19 patients. '
'Vitamin D has been hypothesized to reduce disease susceptibility by modulating inflammation, '
'yet little is known about its role in disease severity. Considering the critical interaction '
'between vitamin K and vitamin D in calcium and elastic fiber metabolism, we determined '
'vitamin D status in the same cohort of 135 hospitalized COVID-19 patients by measuring blood '
'25(OH)D levels. We found no difference in vitamin D status between those with good and poor '
'outcome (defined as intubation and/or death). Instead, we found vitamin D sufficient persons '
'(25(OH)D >50 nmol/L) had accelerated elastic fiber degradation compared to those with mild '
'deficiency (25(OH)D 25-50 nmol/L). Based on these findings, we hypothesize that vitamin D '
'might have both favorable anti-inflammatory and unfavorable pro-calcification effects during '
'COVID-19 and that vitamin K might compensate for the latter.</jats:p>',
'DOI': '10.1101/2020.11.07.20227512',
'type': 'posted-content',
'created': {'date-parts': [[2020, 11, 9]], 'date-time': '2020-11-09T23:50:12Z', 'timestamp': 1604965812000},
'source': 'Crossref',
'is-referenced-by-count': 8,
'title': 'Vitamin D – contrary to vitamin K – does not associate with clinical outcome in hospitalized '
'COVID-19 patients',
'prefix': '10.1101',
'author': [ { 'ORCID': 'http://orcid.org/0000-0002-9420-4578',
'authenticated-orcid': False,
'given': 'Jona',
'family': 'Walk',
'sequence': 'first',
'affiliation': []},
{'given': 'Anton S.M.', 'family': 'Dofferhoff', 'sequence': 'additional', 'affiliation': []},
{ 'given': 'Jody M.W.',
'family': 'van den Ouweland',
'sequence': 'additional',
'affiliation': []},
{'given': 'Henny', 'family': 'van Daal', 'sequence': 'additional', 'affiliation': []},
{'given': 'Rob', 'family': 'Janssen', 'sequence': 'additional', 'affiliation': []}],
'member': '246',
'reference': [ { 'key': '2020111116550947000_2020.11.07.20227512v1.1',
'doi-asserted-by': 'crossref',
'unstructured': 'Janssen, R. , et al., Vitamin K metabolism as the potential missing link '
'between lung damage and thromboembolism in Coronavirus disease 2019. Br '
'J Nutr, 2020: p. 1–8.',
'DOI': '10.1017/S0007114520003979'},
{ 'key': '2020111116550947000_2020.11.07.20227512v1.2',
'doi-asserted-by': 'crossref',
'unstructured': 'Dofferhoff, A.S.M. , et al., Reduced vitamin K status as a potentially '
'modifiable risk factor of severe COVID-19. Clin Infect Dis, 2020.',
'DOI': '10.20944/preprints202004.0457.v1'},
{ 'key': '2020111116550947000_2020.11.07.20227512v1.3',
'doi-asserted-by': 'publisher',
'DOI': '10.3945/ajcn.2009.27930'},
{ 'key': '2020111116550947000_2020.11.07.20227512v1.4',
'doi-asserted-by': 'publisher',
'DOI': '10.1161/ATVBAHA.107.153056'},
{ 'key': '2020111116550947000_2020.11.07.20227512v1.5',
'doi-asserted-by': 'publisher',
'DOI': '10.1038/386078a0'},
{ 'key': '2020111116550947000_2020.11.07.20227512v1.6',
'doi-asserted-by': 'publisher',
'DOI': '10.1016/j.molmed.2012.12.008'},
{ 'issue': '9',
'key': '2020111116550947000_2020.11.07.20227512v1.7',
'doi-asserted-by': 'crossref',
'first-page': '735',
'DOI': '10.1016/S2213-8587(20)30268-0',
'article-title': 'Vitamin D for COVID-19: a case to answer?',
'volume': '8',
'year': '2020',
'journal-title': 'Lancet Diabetes Endocrinol'},
{ 'key': '2020111116550947000_2020.11.07.20227512v1.8',
'doi-asserted-by': 'crossref',
'unstructured': 'Panagiotou, G. , 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 (Oxf), 2020.',
'DOI': '10.1111/cen.14276'},
{ 'issue': '10',
'key': '2020111116550947000_2020.11.07.20227512v1.9',
'doi-asserted-by': 'crossref',
'first-page': '804',
'DOI': '10.1016/S2213-2600(13)70102-4',
'article-title': 'Vitamin D and chronic obstructive pulmonary disease: hype or reality?',
'volume': '1',
'year': '2013',
'journal-title': 'Lancet Respir Med'},
{ 'key': '2020111116550947000_2020.11.07.20227512v1.10',
'doi-asserted-by': 'publisher',
'DOI': '10.1016/S0140-6736(20)30628-0'},
{ 'key': '2020111116550947000_2020.11.07.20227512v1.11',
'doi-asserted-by': 'publisher',
'DOI': '10.1136/bmj.i6583'},
{ 'key': '2020111116550947000_2020.11.07.20227512v1.12',
'doi-asserted-by': 'crossref',
'unstructured': 'D’Avolio, A. , et al., 25-Hydroxyvitamin D Concentrations Are Lower in '
'Patients with Positive PCR for SARS-CoV-2. Nutrients, 2020. 12(5).',
'DOI': '10.3390/nu12051359'},
{ 'issue': '4',
'key': '2020111116550947000_2020.11.07.20227512v1.13',
'doi-asserted-by': 'crossref',
'first-page': '561',
'DOI': '10.1016/j.dsx.2020.04.050',
'article-title': 'Vitamin D concentrations and COVID-19 infection in UK Biobank',
'volume': '14',
'year': '2020',
'journal-title': 'Diabetes Metab Syndr'},
{ 'key': '2020111116550947000_2020.11.07.20227512v1.14',
'unstructured': 'van Ballegooijen, A.J. , et al., The Synergistic Interplay between '
'Vitamins D and K for Bone and Cardiovascular Health: A Narrative Review. '
'Int J Endocrinol, 2017. 2017: p. 7454376.'},
{ 'issue': '11',
'key': '2020111116550947000_2020.11.07.20227512v1.15',
'doi-asserted-by': 'crossref',
'first-page': '2910',
'DOI': '10.1093/jn/131.11.2910',
'article-title': 'The amino bisphosphonate ibandronate prevents vitamin D toxicity and '
'inhibits vitamin D-induced calcification of arteries, cartilage, lungs '
'and kidneys in rats',
'volume': '131',
'year': '2001',
'journal-title': 'J Nutr'},
{ 'issue': '7',
'key': '2020111116550947000_2020.11.07.20227512v1.16',
'first-page': '81',
'article-title': 'Factors influencing the choice of antihypertensive agents',
'volume': '60',
'year': '1976',
'journal-title': 'Postgrad Med'},
{ 'issue': '4',
'key': '2020111116550947000_2020.11.07.20227512v1.17',
'doi-asserted-by': 'crossref',
'first-page': '270',
'DOI': '10.1007/BF02555007',
'article-title': 'Induction of matrix Gla protein synthesis during prolonged '
'1,25-dihydroxyvitamin D3 treatment of osteosarcoma cells',
'volume': '46',
'year': '1990',
'journal-title': 'Calcif Tissue Int'},
{ 'key': '2020111116550947000_2020.11.07.20227512v1.18',
'doi-asserted-by': 'crossref',
'first-page': '49',
'DOI': '10.1016/j.cca.2016.08.016',
'article-title': 'Various calibration procedures result in optimal standardization of '
'routinely used 25(OH)D ID-LC-MS/MS methods',
'volume': '462',
'year': '2016',
'journal-title': 'Clin Chim Acta'},
{ 'key': '2020111116550947000_2020.11.07.20227512v1.19',
'doi-asserted-by': 'publisher',
'DOI': '10.3390/nu7064240'},
{ 'key': '2020111116550947000_2020.11.07.20227512v1.20',
'first-page': 'A8167',
'article-title': '[High prevalence of vitamin D deficiency in the south-west Netherlands]',
'volume': '159',
'year': '2015',
'journal-title': 'Ned Tijdschr Geneeskd'},
{ 'issue': '3',
'key': '2020111116550947000_2020.11.07.20227512v1.21',
'doi-asserted-by': 'crossref',
'first-page': 'e41',
'DOI': '10.1016/j.jinf.2020.06.061',
'article-title': 'Distinct and early increase in circulating MMP-9 in COVID-19 patients '
'with respiratory failure',
'volume': '81',
'year': '2020',
'journal-title': 'J Infect'},
{ 'key': '2020111116550947000_2020.11.07.20227512v1.22',
'doi-asserted-by': 'publisher',
'DOI': '10.1164/rccm.201103-0450PP'},
{ 'key': '2020111116550947000_2020.11.07.20227512v1.23',
'doi-asserted-by': 'crossref',
'unstructured': 'Honardoost, M. , M. Ghavideldarestani , and M.E. Khamseh , Role of '
'vitamin D in pathogenesis and severity of COVID-19 infection. Arch '
'Physiol Biochem, 2020: p. 1–7.',
'DOI': '10.1080/13813455.2020.1792505'},
{ 'key': '2020111116550947000_2020.11.07.20227512v1.24',
'doi-asserted-by': 'publisher',
'DOI': '10.1210/jc.2010-0502'},
{ 'issue': '0',
'key': '2020111116550947000_2020.11.07.20227512v1.25',
'first-page': '185',
'article-title': 'Calcium binding to elastin',
'volume': '48',
'year': '1974',
'journal-title': 'Adv Exp Med Biol'},
{ 'key': '2020111116550947000_2020.11.07.20227512v1.26',
'doi-asserted-by': 'publisher',
'DOI': '10.1161/01.CIR.0000148367.08413.E9'},
{ 'key': '2020111116550947000_2020.11.07.20227512v1.27',
'doi-asserted-by': 'crossref',
'first-page': '693',
'DOI': '10.1016/j.ijbiomac.2020.01.250',
'article-title': 'The mineralization process of insoluble elastin fibrillar structures: '
'Ionic environment vs degradation',
'volume': '149',
'year': '2020',
'journal-title': 'Int J Biol Macromol'},
{ 'key': '2020111116550947000_2020.11.07.20227512v1.28',
'doi-asserted-by': 'publisher',
'DOI': '10.1159/000159247'},
{ 'key': '2020111116550947000_2020.11.07.20227512v1.29',
'doi-asserted-by': 'publisher',
'DOI': '10.2353/ajpath.2006.050338'},
{ 'issue': '4',
'key': '2020111116550947000_2020.11.07.20227512v1.30',
'doi-asserted-by': 'crossref',
'first-page': '706',
'DOI': '10.1093/ndt/gfy399',
'article-title': 'Joint association of vitamins D and K status with long-term outcomes in '
'stable kidney transplant recipients',
'volume': '35',
'year': '2020',
'journal-title': 'Nephrol Dial Transplant'},
{ 'key': '2020111116550947000_2020.11.07.20227512v1.31',
'doi-asserted-by': 'crossref',
'unstructured': 'Piscaer, I. , et al., Low Vitamin K Status Is Associated with Increased '
'Elastin Degradation in Chronic Obstructive Pulmonary Disease. J Clin '
'Med, 2019. 8(8).',
'DOI': '10.3390/jcm8081116'},
{ 'key': '2020111116550947000_2020.11.07.20227512v1.32',
'doi-asserted-by': 'crossref',
'first-page': '105751',
'DOI': '10.1016/j.jsbmb.2020.105751',
'article-title': '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',
'volume': '203',
'year': '2020',
'journal-title': 'J Steroid Biochem Mol Biol'}],
'container-title': [],
'original-title': [],
'link': [ { 'URL': 'https://syndication.highwire.org/content/doi/10.1101/2020.11.07.20227512',
'content-type': 'unspecified',
'content-version': 'vor',
'intended-application': 'similarity-checking'}],
'deposited': { 'date-parts': [[2020, 11, 12]],
'date-time': '2020-11-12T00:55:49Z',
'timestamp': 1605142549000},
'score': 1,
'resource': {'primary': {'URL': 'http://medrxiv.org/lookup/doi/10.1101/2020.11.07.20227512'}},
'subtitle': [],
'short-title': [],
'issued': {'date-parts': [[2020, 11, 9]]},
'references-count': 32,
'URL': 'http://dx.doi.org/10.1101/2020.11.07.20227512',
'relation': {},
'published': {'date-parts': [[2020, 11, 9]]},
'subtype': 'preprint'}
