Ursodeoxycholic Acid Does Not Improve COVID-19 Outcome in Hospitalized Patients
Francesca Colapietro, Giovanni Angelotti, Chiara Masetti, Dana Shiffer, Nicola Pugliese, Stella De Nicola, Francesco Carella, Antonio Desai, Monica Ormas, Marta Calatroni, Paolo Omodei, Michele Ciccarelli, Stefano Aliberti, Francesco Reggiani, Michele Bartoletti, Maurizio Cecconi, Ana Lleo, Alessio Aghemo, Antonio Voza
Viruses, doi:10.3390/v15081738
Ursodeoxycholic acid (UDCA) was demonstrated to reduce susceptibility to SARS-CoV-2 infection in vitro and improve infection course in chronic liver diseases. However, real-life evidence is lacking. We analyzed the impact of UDCA on COVID-19 outcomes in patients hospitalized in a tertiary center. Between January 2020 and January 2023, among 3847 patients consecutively hospitalized for COVID19, 57 (=UDCA group) were taking UDCA. The UDCA and the control groups (n = 3790) did not differ concerning comorbidities including diabetes mellitus type 2 (15.8% vs. 12.8%) and neoplasia (12.3% vs. 9.4%). Liver diseases and vaccination rate were more common in the UDCA group (14.0% vs. 2.5% and 54.4% vs. 30.2%, respectively). Overall mortality and CPAP treatment were 22.8 % and 15.7% in the UDCA, and 21.3% and 25.9% in the control group. Mortality was similar (p = 0.243), whereas UDCA was associated with a lower rate of CPAP treatment (OR = 0.76, p < 0.05). Treatment with UDCA was not an independent predictor of survival in patients hospitalized for COVID-19.
Funding: The authors did not receive any financial support in order to complete the study or write the manuscript.
Informed Consent Statement: Not applicable.
Conflicts of Interest: All the authors have given substantial contribution to the completion of this work and have seen and approved the text in the current version. None reported a conflict of interest with respect to this manuscript.
Abbreviations UDCA: ursodeoxycholic acid; PBC: primary biliary cholangitis; CPAP: continuous positive airway pressure; HER: electronic health record; SQL: Structured Query Language; AH: arterial hypertension; DM: diabetes mellitus; CKD: chronic kidney disease; COPD: chronic obstructive pulmonary disease; LFT: liver function test; PLT: platelets; OR: odds ratio; CI: confidence interval; ACE2: angiotensin-converting enzyme 2; FXR: farnesoid X receptor; ICU: intensive care unit; IQR: interquartile range.
References
Beigel, Tomashek, Dodd, Mehta, Zingman et al., Remdesivir for the Treatment of COVID-19-Final Report, N. Engl. J. Med,
doi:10.1056/NEJMoa2007764Brevini, Maes, Webb, John, Fuchs et al., FXR inhibition may protect from SARS-CoV-2 infection by reducing ACE2, Nature,
doi:10.1038/s41586-022-05594-0Cao, Wang, Jian, Xiao, Song et al., Omicron escapes the majority of existing SARS-CoV-2 neutralizing antibodies, Nature,
doi:10.1038/s41586-021-04385-3Foisy, Yakiwchuk, Hughes, Induction effects of ritonavir: Implications for drug interactions, Ann. Pharmacother,
doi:10.1345/aph.1K615Goldman, Lye, Hui, Marks, Bruno et al., Remdesivir for 5 or 10 Days in Patients with Severe COVID-19, N. Engl. J. Med,
doi:10.1056/NEJMoa2015301John, Bastaich, Webb, Brevini, Moon et al., Ursodeoxycholic acid is associated with a reduction in SARS-CoV-2 infection and reduced severity of COVID-19 in patients with cirrhosis, J. Intern. Med,
doi:10.1111/joim.13630Li, Zhu, Cui, Lin, Li, Protective effect of ursodeoxycholic acid on COVID-19 in patients with chronic liver disease, Front. Cell. Infect. Microbiol,
doi:10.3389/fcimb.2023.1178590Liu, Wang, Ursodeoxycholic acid administration did not reduce susceptibility to SARS-CoV-2 infection in children, Liver Int,
doi:10.1111/liv.15660Mohty, Malard, Abecasis, Aerts, Alaskar et al., Prophylactic, preemptive, and curative treatment for sinusoidal obstruction syndrome/veno-occlusive disease in adult patients: A position statement from an international expert group, Bone Marrow Transplant,
doi:10.1038/s41409-019-0705-zMohty, Malard, Abecassis, Aerts, Alaskar et al., Sinusoidal obstruction syndrome/veno-occlusive disease: Current situation and perspectives-a position statement from the European Society for Blood and Marrow Transplantation (EBMT), Bone Marrow Transplant,
doi:10.1038/bmt.2015.52Pan, Peto, Henao-Restrepo, Preziosi, Sathiyamoorthy et al., Repurposed Antiviral Drugs for COVID-19-Interim WHO Solidarity Trial Results, N. Engl. J. Med,
doi:10.1056/NEJMoa2023184Rosas, Diaz, Gottlieb, Lobo, Robinson et al., Tocilizumab and remdesivir in hospitalized patients with severe COVID-19 pneumonia: A randomized clinical trial, Intensive Care Med,
doi:10.1007/s00134-021-06507-xSun, Lin, Wang, Gao, Ye, Paxlovid in patients who are immunocompromised and hospitalised with SARS-CoV-2 infection, Lancet Infect. Dis,
doi:10.1016/S1473-3099(22)00430-3Tomalka, Suthar, Deeks, Sekaly, Fighting the SARS-CoV-2 pandemic requires a global approach to understanding the heterogeneity of vaccine responses, Nat. Immunol,
doi:10.1038/s41590-022-01130-4Wang, Yang, Song, Oral GS-441524 derivatives: Next-generation inhibitors of SARS-CoV-2 RNA-dependent RNA polymerase, Front. Immunol,
doi:10.3389/fimmu.2022.1015355Wang, Zhang, Du, Du, Zhao et al., Remdesivir in adults with severe COVID-19: A randomised, double-blind, placebo-controlled, multicentre trial, Lancet,
doi:10.1016/S0140-6736(20)31022-9{ 'DOI': '10.3390/v15081738',
'ISSN': ['1999-4915'],
'URL': 'http://dx.doi.org/10.3390/v15081738',
'abstract': '<jats:p>Ursodeoxycholic acid (UDCA) was demonstrated to reduce susceptibility to SARS-CoV-2 '
'infection in vitro and improve infection course in chronic liver diseases. However, real-life '
'evidence is lacking. We analyzed the impact of UDCA on COVID-19 outcomes in patients '
'hospitalized in a tertiary center. Between January 2020 and January 2023, among 3847 patients '
'consecutively hospitalized for COVID19, 57 (=UDCA group) were taking UDCA. The UDCA and the '
'control groups (n = 3790) did not differ concerning comorbidities including diabetes mellitus '
'type 2 (15.8% vs. 12.8%) and neoplasia (12.3% vs. 9.4%). Liver diseases and vaccination rate '
'were more common in the UDCA group (14.0% vs. 2.5% and 54.4% vs. 30.2%, respectively). '
'Overall mortality and CPAP treatment were 22.8 % and 15.7% in the UDCA, and 21.3% and 25.9% '
'in the control group. Mortality was similar (p = 0.243), whereas UDCA was associated with a '
'lower rate of CPAP treatment (OR = 0.76, p < 0.05). Treatment with UDCA was not an '
'independent predictor of survival in patients hospitalized for COVID-19.</jats:p>',
'alternative-id': ['v15081738'],
'author': [ { 'ORCID': 'http://orcid.org/0000-0002-7520-744X',
'affiliation': [ { 'name': 'Department of Biomedical Sciences, Humanitas University, Pieve '
'Emanuele, 20072 Milan, Italy'},
{ 'name': 'Division of Internal Medicine and Hepatology, Department of '
'Gastroenterology, Humanitas Research Hospital IRCCS, 20089 '
'Milan, Italy'}],
'authenticated-orcid': False,
'family': 'Colapietro',
'given': 'Francesca',
'sequence': 'first'},
{ 'affiliation': [ { 'name': 'Department of Biomedical Sciences, Humanitas University, Pieve '
'Emanuele, 20072 Milan, Italy'},
{ 'name': 'Humanitas Artificial Intelligence Center, Humanitas Research '
'Hospital IRCCS, 20089 Milan, Italy'}],
'family': 'Angelotti',
'given': 'Giovanni',
'sequence': 'additional'},
{ 'affiliation': [ { 'name': 'Division of Internal Medicine and Hepatology, Department of '
'Gastroenterology, Humanitas Research Hospital IRCCS, 20089 '
'Milan, Italy'}],
'family': 'Masetti',
'given': 'Chiara',
'sequence': 'additional'},
{ 'affiliation': [ { 'name': 'Department of Biomedical Sciences, Humanitas University, Pieve '
'Emanuele, 20072 Milan, Italy'},
{ 'name': 'Emergency Department, Humanitas Research Hospital IRCCS, 20089 '
'Milan, Italy'}],
'family': 'Shiffer',
'given': 'Dana',
'sequence': 'additional'},
{ 'ORCID': 'http://orcid.org/0000-0001-6466-1412',
'affiliation': [ { 'name': 'Department of Biomedical Sciences, Humanitas University, Pieve '
'Emanuele, 20072 Milan, Italy'},
{ 'name': 'Division of Internal Medicine and Hepatology, Department of '
'Gastroenterology, Humanitas Research Hospital IRCCS, 20089 '
'Milan, Italy'}],
'authenticated-orcid': False,
'family': 'Pugliese',
'given': 'Nicola',
'sequence': 'additional'},
{ 'affiliation': [ { 'name': 'Division of Internal Medicine and Hepatology, Department of '
'Gastroenterology, Humanitas Research Hospital IRCCS, 20089 '
'Milan, Italy'}],
'family': 'De Nicola',
'given': 'Stella',
'sequence': 'additional'},
{ 'affiliation': [ { 'name': 'Department of Biomedical Sciences, Humanitas University, Pieve '
'Emanuele, 20072 Milan, Italy'}],
'family': 'Carella',
'given': 'Francesco',
'sequence': 'additional'},
{ 'ORCID': 'http://orcid.org/0000-0003-4674-4905',
'affiliation': [ { 'name': 'Department of Biomedical Sciences, Humanitas University, Pieve '
'Emanuele, 20072 Milan, Italy'},
{ 'name': 'Emergency Department, Humanitas Research Hospital IRCCS, 20089 '
'Milan, Italy'}],
'authenticated-orcid': False,
'family': 'Desai',
'given': 'Antonio',
'sequence': 'additional'},
{ 'affiliation': [ { 'name': 'Division of Internal Medicine and Hepatology, Department of '
'Gastroenterology, Humanitas Research Hospital IRCCS, 20089 '
'Milan, Italy'}],
'family': 'Ormas',
'given': 'Monica',
'sequence': 'additional'},
{ 'ORCID': 'http://orcid.org/0000-0003-4204-758X',
'affiliation': [ { 'name': 'Department of Biomedical Sciences, Humanitas University, Pieve '
'Emanuele, 20072 Milan, Italy'},
{ 'name': 'Nephrology and Dialysis Unit, Humanitas Research Hospital IRCCS, '
'20089 Milan, Italy'}],
'authenticated-orcid': False,
'family': 'Calatroni',
'given': 'Marta',
'sequence': 'additional'},
{ 'affiliation': [ { 'name': 'Department of Gastroenterology, Division of Gastroenterology and '
'Digestive Endoscopy, Humanitas Research Hospital IRCCS, 20089 '
'Milan, Italy'}],
'family': 'Omodei',
'given': 'Paolo',
'sequence': 'additional'},
{ 'affiliation': [ { 'name': 'Division of Respiratory Medicine, Humanitas Research Hospital '
'IRCCS, 20089 Milan, Italy'}],
'family': 'Ciccarelli',
'given': 'Michele',
'sequence': 'additional'},
{ 'affiliation': [ { 'name': 'Department of Biomedical Sciences, Humanitas University, Pieve '
'Emanuele, 20072 Milan, Italy'},
{ 'name': 'Division of Respiratory Medicine, Humanitas Research Hospital '
'IRCCS, 20089 Milan, Italy'}],
'family': 'Aliberti',
'given': 'Stefano',
'sequence': 'additional'},
{ 'affiliation': [ { 'name': 'Department of Biomedical Sciences, Humanitas University, Pieve '
'Emanuele, 20072 Milan, Italy'},
{ 'name': 'Nephrology and Dialysis Unit, Humanitas Research Hospital IRCCS, '
'20089 Milan, Italy'}],
'family': 'Reggiani',
'given': 'Francesco',
'sequence': 'additional'},
{ 'affiliation': [ { 'name': 'Department of Biomedical Sciences, Humanitas University, Pieve '
'Emanuele, 20072 Milan, Italy'},
{ 'name': 'Infectious Disease Unit, Humanitas Research Hospital IRCSS, '
'20089 Milan, Italy'}],
'family': 'Bartoletti',
'given': 'Michele',
'sequence': 'additional'},
{ 'affiliation': [ { 'name': 'Department of Biomedical Sciences, Humanitas University, Pieve '
'Emanuele, 20072 Milan, Italy'},
{ 'name': 'Department of Anaesthesia and Intensive Care, Humanitas '
'University IRCCS, 20090 Milan, Italy'}],
'family': 'Cecconi',
'given': 'Maurizio',
'sequence': 'additional'},
{ 'ORCID': 'http://orcid.org/0000-0002-0561-7902',
'affiliation': [ { 'name': 'Department of Biomedical Sciences, Humanitas University, Pieve '
'Emanuele, 20072 Milan, Italy'},
{ 'name': 'Division of Internal Medicine and Hepatology, Department of '
'Gastroenterology, Humanitas Research Hospital IRCCS, 20089 '
'Milan, Italy'}],
'authenticated-orcid': False,
'family': 'Lleo',
'given': 'Ana',
'sequence': 'additional'},
{ 'affiliation': [ { 'name': 'Department of Biomedical Sciences, Humanitas University, Pieve '
'Emanuele, 20072 Milan, Italy'},
{ 'name': 'Division of Internal Medicine and Hepatology, Department of '
'Gastroenterology, Humanitas Research Hospital IRCCS, 20089 '
'Milan, Italy'}],
'family': 'Aghemo',
'given': 'Alessio',
'sequence': 'additional'},
{ 'ORCID': 'http://orcid.org/0000-0001-7309-6929',
'affiliation': [ { 'name': 'Department of Biomedical Sciences, Humanitas University, Pieve '
'Emanuele, 20072 Milan, Italy'},
{ 'name': 'Emergency Department, Humanitas Research Hospital IRCCS, 20089 '
'Milan, Italy'}],
'authenticated-orcid': False,
'family': 'Voza',
'given': 'Antonio',
'sequence': 'additional'}],
'container-title': 'Viruses',
'container-title-short': 'Viruses',
'content-domain': {'crossmark-restriction': False, 'domain': []},
'created': {'date-parts': [[2023, 8, 14]], 'date-time': '2023-08-14T14:20:14Z', 'timestamp': 1692022814000},
'deposited': { 'date-parts': [[2023, 8, 15]],
'date-time': '2023-08-15T15:40:14Z',
'timestamp': 1692114014000},
'indexed': {'date-parts': [[2023, 9, 22]], 'date-time': '2023-09-22T07:49:53Z', 'timestamp': 1695368993154},
'is-referenced-by-count': 1,
'issue': '8',
'issued': {'date-parts': [[2023, 8, 14]]},
'journal-issue': {'issue': '8', 'published-online': {'date-parts': [[2023, 8]]}},
'language': 'en',
'license': [ { 'URL': 'https://creativecommons.org/licenses/by/4.0/',
'content-version': 'vor',
'delay-in-days': 0,
'start': { 'date-parts': [[2023, 8, 14]],
'date-time': '2023-08-14T00:00:00Z',
'timestamp': 1691971200000}}],
'link': [ { 'URL': 'https://www.mdpi.com/1999-4915/15/8/1738/pdf',
'content-type': 'unspecified',
'content-version': 'vor',
'intended-application': 'similarity-checking'}],
'member': '1968',
'original-title': [],
'page': '1738',
'prefix': '10.3390',
'published': {'date-parts': [[2023, 8, 14]]},
'published-online': {'date-parts': [[2023, 8, 14]]},
'publisher': 'MDPI AG',
'reference': [ { 'key': 'ref_1',
'unstructured': '(2023, February 16). Therapeutics and COVID-19. Available online: '
'https://www.who.int/teams/health-care-readiness/COVID-19/therapeutics.'},
{ 'DOI': '10.1016/j.ejmech.2023.115503',
'article-title': 'Bench-to-bedside: Innovation of small molecule anti-SARS-CoV-2 drugs in '
'China',
'author': 'Yang',
'doi-asserted-by': 'crossref',
'first-page': '115503',
'journal-title': 'Eur. J. Med. Chem.',
'key': 'ref_2',
'volume': '257',
'year': '2023'},
{ 'DOI': '10.1038/s41590-022-01130-4',
'article-title': 'Fighting the SARS-CoV-2 pandemic requires a global approach to '
'understanding the heterogeneity of vaccine responses',
'author': 'Tomalka',
'doi-asserted-by': 'crossref',
'first-page': '360',
'journal-title': 'Nat. Immunol.',
'key': 'ref_3',
'volume': '23',
'year': '2022'},
{ 'DOI': '10.1056/NEJMoa2007764',
'article-title': 'Remdesivir for the Treatment of COVID-19—Final Report',
'author': 'Beigel',
'doi-asserted-by': 'crossref',
'first-page': '1813',
'journal-title': 'N. Engl. J. Med.',
'key': 'ref_4',
'volume': '383',
'year': '2020'},
{ 'DOI': '10.1056/NEJMoa2015301',
'article-title': 'Remdesivir for 5 or 10 Days in Patients with Severe COVID-19',
'author': 'Goldman',
'doi-asserted-by': 'crossref',
'first-page': '1827',
'journal-title': 'N. Engl. J. Med.',
'key': 'ref_5',
'volume': '383',
'year': '2020'},
{ 'DOI': '10.1016/S0140-6736(20)31022-9',
'article-title': 'Remdesivir in adults with severe COVID-19: A randomised, double-blind, '
'placebo-controlled, multicentre trial',
'author': 'Wang',
'doi-asserted-by': 'crossref',
'first-page': '1569',
'journal-title': 'Lancet',
'key': 'ref_6',
'volume': '395',
'year': '2020'},
{ 'DOI': '10.1007/s00134-021-06507-x',
'article-title': 'Tocilizumab and remdesivir in hospitalized patients with severe '
'COVID-19 pneumonia: A randomized clinical trial',
'author': 'Rosas',
'doi-asserted-by': 'crossref',
'first-page': '1258',
'journal-title': 'Intensive Care Med.',
'key': 'ref_7',
'volume': '47',
'year': '2021'},
{ 'DOI': '10.1056/NEJMoa2023184',
'doi-asserted-by': 'crossref',
'key': 'ref_8',
'unstructured': 'WHO Solidarity Trial Consortium, Pan, H., Peto, R., Henao-Restrepo, '
'A.-M., Preziosi, M.-P., Sathiyamoorthy, V., Abdool Karim, Q., '
'Alejandria, M.M., Hernández García, C., and Kieny, M.-P.. (2021). '
'Repurposed Antiviral Drugs for COVID-19—Interim WHO Solidarity Trial '
'Results. N. Engl. J. Med., 384, 497–511.'},
{ 'DOI': '10.3389/fimmu.2022.1015355',
'article-title': 'Oral GS-441524 derivatives: Next-generation inhibitors of SARS-CoV-2 '
'RNA-dependent RNA polymerase',
'author': 'Wang',
'doi-asserted-by': 'crossref',
'first-page': '1015355',
'journal-title': 'Front. Immunol.',
'key': 'ref_9',
'volume': '13',
'year': '2022'},
{ 'DOI': '10.1016/S1473-3099(22)00430-3',
'article-title': 'Paxlovid in patients who are immunocompromised and hospitalised with '
'SARS-CoV-2 infection',
'author': 'Sun',
'doi-asserted-by': 'crossref',
'first-page': '1279',
'journal-title': 'Lancet Infect. Dis.',
'key': 'ref_10',
'volume': '22',
'year': '2022'},
{ 'DOI': '10.1016/S2213-2600(22)00192-8',
'article-title': 'The future of Paxlovid for COVID-19',
'author': 'Burki',
'doi-asserted-by': 'crossref',
'first-page': 'e68',
'journal-title': 'Lancet Respir. Med.',
'key': 'ref_11',
'volume': '10',
'year': '2022'},
{ 'key': 'ref_12',
'unstructured': '(2023, July 28). Multiple Pathways for SARS-CoV-2 Resistance to '
'Nirmatrelvir|Nature. Available online: '
'https://www.nature.com/articles/s41586-022-05514-2.'},
{ 'DOI': '10.1345/aph.1K615',
'article-title': 'Induction effects of ritonavir: Implications for drug interactions',
'author': 'Foisy',
'doi-asserted-by': 'crossref',
'first-page': '1048',
'journal-title': 'Ann. Pharmacother.',
'key': 'ref_13',
'volume': '42',
'year': '2008'},
{ 'DOI': '10.1016/j.jbc.2021.100867',
'article-title': 'Decoding molnupiravir-induced mutagenesis in SARS-CoV-2',
'doi-asserted-by': 'crossref',
'first-page': '100867',
'journal-title': 'J. Biol. Chem.',
'key': 'ref_14',
'volume': '297',
'year': '2021'},
{ 'DOI': '10.1016/S0140-6736(20)31607-X',
'article-title': 'Primary biliary cholangitis',
'author': 'Lleo',
'doi-asserted-by': 'crossref',
'first-page': '1915',
'journal-title': 'Lancet',
'key': 'ref_15',
'volume': '396',
'year': '2020'},
{ 'DOI': '10.1038/bmt.2015.52',
'article-title': 'Sinusoidal obstruction syndrome/veno-occlusive disease: Current '
'situation and perspectives-a position statement from the European '
'Society for Blood and Marrow Transplantation (EBMT)',
'author': 'Mohty',
'doi-asserted-by': 'crossref',
'first-page': '781',
'journal-title': 'Bone Marrow Transplant.',
'key': 'ref_16',
'volume': '50',
'year': '2015'},
{ 'DOI': '10.1038/s41586-022-05594-0',
'article-title': 'FXR inhibition may protect from SARS-CoV-2 infection by reducing ACE2',
'author': 'Brevini',
'doi-asserted-by': 'crossref',
'first-page': '134',
'journal-title': 'Nature',
'key': 'ref_17',
'volume': '615',
'year': '2022'},
{ 'DOI': '10.1038/s41586-021-04385-3',
'article-title': 'Omicron escapes the majority of existing SARS-CoV-2 neutralizing '
'antibodies',
'author': 'Cao',
'doi-asserted-by': 'crossref',
'first-page': '657',
'journal-title': 'Nature',
'key': 'ref_18',
'volume': '602',
'year': '2022'},
{ 'DOI': '10.2165/00003495-198427020-00001',
'article-title': 'Ursodeoxycholic acid: A review of its pharmacological properties and '
'therapeutic efficacy',
'author': 'Ward',
'doi-asserted-by': 'crossref',
'first-page': '95',
'journal-title': 'Drugs',
'key': 'ref_19',
'volume': '27',
'year': '1984'},
{ 'DOI': '10.3109/00365529409103618',
'article-title': 'Pharmacology of ursodeoxycholic acid, an enterohepatic drug',
'author': 'Hofmann',
'doi-asserted-by': 'crossref',
'first-page': '1',
'journal-title': 'Scand. J. Gastroenterol. Suppl.',
'key': 'ref_20',
'volume': '204',
'year': '1994'},
{ 'DOI': '10.1097/00007890-198712000-00011',
'article-title': 'Venoocclusive disease of the liver following bone marrow '
'transplantation',
'author': 'Jones',
'doi-asserted-by': 'crossref',
'first-page': '778',
'journal-title': 'Transplantation',
'key': 'ref_21',
'volume': '44',
'year': '1987'},
{ 'DOI': '10.1038/s41409-019-0705-z',
'article-title': 'Prophylactic, preemptive, and curative treatment for sinusoidal '
'obstruction syndrome/veno-occlusive disease in adult patients: A '
'position statement from an international expert group',
'author': 'Mohty',
'doi-asserted-by': 'crossref',
'first-page': '485',
'journal-title': 'Bone Marrow Transplant.',
'key': 'ref_22',
'volume': '55',
'year': '2020'},
{ 'DOI': '10.1111/liv.15660',
'article-title': 'Ursodeoxycholic acid administration did not reduce susceptibility to '
'SARS-CoV-2 infection in children',
'author': 'Liu',
'doi-asserted-by': 'crossref',
'first-page': '1950',
'journal-title': 'Liver Int.',
'key': 'ref_23',
'volume': '43',
'year': '1950'},
{ 'DOI': '10.1111/joim.13630',
'article-title': 'Ursodeoxycholic acid is associated with a reduction in SARS-CoV-2 '
'infection and reduced severity of COVID-19 in patients with cirrhosis',
'author': 'John',
'doi-asserted-by': 'crossref',
'first-page': '636',
'journal-title': 'J. Intern. Med.',
'key': 'ref_24',
'volume': '293',
'year': '2023'},
{ 'DOI': '10.3389/fcimb.2023.1178590',
'article-title': 'Protective effect of ursodeoxycholic acid on COVID-19 in patients with '
'chronic liver disease',
'author': 'Li',
'doi-asserted-by': 'crossref',
'first-page': '1178590',
'journal-title': 'Front. Cell. Infect. Microbiol.',
'key': 'ref_25',
'volume': '13',
'year': '2023'},
{ 'key': 'ref_26',
'unstructured': '(2023, August 08). Liverpool COVID-19 Interactions. Available online: '
'https://www.covid19-druginteractions.org/checker.'}],
'reference-count': 26,
'references-count': 26,
'relation': {},
'resource': {'primary': {'URL': 'https://www.mdpi.com/1999-4915/15/8/1738'}},
'score': 1,
'short-title': [],
'source': 'Crossref',
'subject': ['Virology', 'Infectious Diseases'],
'subtitle': [],
'title': 'Ursodeoxycholic Acid Does Not Improve COVID-19 Outcome in Hospitalized Patients',
'type': 'journal-article',
'volume': '15'}
