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Association between ursodeoxycholic acid use and COVID-19 in individuals with chronic liver disease: a nationwide case-control study in South Korea

Moon et al., Virology Journal, doi:10.1186/s12985-024-02464-1
Aug 2024  
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Severe case 33% Improvement Relative Risk Case 20% UDCA for COVID-19  Moon et al.  Prophylaxis Is prophylaxis with ursodeoxycholic acid beneficial for COVID-19? PSM retrospective 74,074 patients in South Korea (Jan - Dec 2021) Lower severe cases (p=0.038) and fewer cases (p<0.0001) c19early.org Moon et al., Virology J., August 2024 FavorsUDCA Favorscontrol 0 0.5 1 1.5 2+
Retrospective 74,074 individuals with chronic liver disease in South Korea, showing lower risk of COVID-19 infection and related severe outcomes with ursodeoxycholic acid (UDCA) use. The risk reduction was dose-dependent, with greater benefits seen with higher UDCA exposure. Authors hypothesize that UDCA may reduce viral entry by downregulating the ACE2 receptor and modulate the cytokine storm implicated in severe COVID-19.
risk of severe case, 33.0% lower, OR 0.67, p = 0.04, treatment 63 of 733 (8.6%) cases, 88 of 733 (12.0%) controls, NNT 11, case control OR, propensity score matching.
risk of case, 20.0% lower, OR 0.80, p < 0.001, treatment 4,082 of 37,037 (11.0%) cases, 4,752 of 37,037 (12.8%) controls, NNT 23, case control OR, propensity score matching.
Effect extraction follows pre-specified rules prioritizing more serious outcomes. Submit updates
Moon et al., 27 Aug 2024, retrospective, South Korea, peer-reviewed, 6 authors, study period 1 January, 2021 - 31 December, 2021. Contact: p100100@dau.ac.kr.
This PaperUDCAAll
Association between ursodeoxycholic acid use and COVID-19 in individuals with chronic liver disease: a nationwide case-control study in South Korea
Sang Yi Moon, Minkook Son, Yeo Wool Kang, Myeongseok Koh, Jong Yoon Lee, Yang Hyun Baek
Virology Journal, doi:10.1186/s12985-024-02464-1
Background Conflicting evidence exists regarding the effects of ursodeoxycholic acid (UDCA) on coronavirus disease 2019 . This study investigates the association between UDCA administration and COVID-19 infection and its related outcomes in individuals with chronic liver disease (CLD). Methods A customized COVID-19 research database (n = 3,485,376) was created by integrating data from the National Health Insurance Service (NHIS) and the Korea Disease Control and Prevention Agency's COVID-19 databases. The study focused on patients diagnosed with COVID-19 in 2021, using the NHIS data from 365 days before diagnosis. To create comparable groups with and without UDCA administration before COVID-19, we used propensity score matching. The primary endpoint was the first confirmed positive result for severe acute respiratory syndrome coronavirus-2. In addition, we identified severe COVID-19-related outcomes. Subgroup analysis were conducted based on the dose of UDCA exposure. Results Data from 74,074 individuals with CLD was analyzed. The participants' average age was 57.5 years, and 52.1% (19,277) of those in each group were male. Those with prior UDCA exposure had a significantly lower risk of COVID-19 infection (adjusted OR: 0.80, 95% CI [0.76-0.85]) compared to the non-UDCA group. Additionally, the UDCA group had a lower risk of severe ). Subgroup analyses indicated that there was a decrease in COVID-19 infection and its related outcomes with increasing UDCA exposure dose. Conclusions Our large observational study highlights the potential use of readily available UDCA as an adjunctive therapy for COVID-19 in individuals with CLD.
Supplementary Information The online version contains supplementary material available at https://doi. org/10.1186/s12985-024-02464-1. Supplementary Material 1 Supplementary Material 2 Author contributions Sang Yi Moon and Minkook Son contributed equally to this work as first authors. Dr. S. Moon, M. Son, and Y. Baek had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Concept and design: S. Moon, M. SonAcquisition, analysis, or interpretation of data: S. Moon, M. Son. Drafting of the manuscript: S. Moon, M. Son. Critical review of the manuscript for important intellectual content: Y, Kang, Y. Baek. Statistical analysis: M. Son. Administrative, technical, or material support: Y. Baek. Supervision: Y. Baek. All authors reviewed the manuscript. Declarations Ethics approval and consent to participate The Dong-A University College of Medicine Institutional Review Board exempted this retrospective study from review due to its design (utilizing de-identified, publicly available clinical data for analysis) (DAUHIRB-EXP-23-026). Consent for publication Not applicable. Additional information This study used the database of the KDCA and the NHIS for policy and academic research. The research number of this study is KDCA-NHIS-2023-1-567. The KDCA is the Korea Disease Control and Prevention Agency, Republic of Korea. The NHIS is the National Health Insurance Service, Republic of Korea. ..
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' 'Exploring the impact of ursodeoxycholic acid therapy on COVID-19 in a ' 'real-word setting. J Med Virol. 2024;96:e29418.', 'journal-title': 'J Med Virol'}, { 'key': '2464_CR23', 'unstructured': 'Nation Health Insurance Data Sharing Service. 2024. ' '[https://nhiss.nhis.or.kr/bd/ab/bdaba000eng.do]'}, { 'key': '2464_CR24', 'unstructured': 'ATC/DDD, Index. 2024. ' '[https://atcddd.fhi.no/atc_ddd_index/code=A05AA02]'}, { 'key': '2464_CR25', 'doi-asserted-by': 'publisher', 'first-page': '676', 'DOI': '10.1093/aje/kwq433', 'volume': '173', 'author': 'H Quan', 'year': '2011', 'unstructured': 'Quan H, Li B, Couris CM, Fushimi K, Graham P, Hider P, Januel JM, ' 'Sundararajan V. Updating and validating the Charlson comorbidity index ' 'and score for risk adjustment in hospital discharge abstracts using data ' 'from 6 countries. Am J Epidemiol. 2011;173:676–82.', 'journal-title': 'Am J Epidemiol'}, { 'key': '2464_CR26', 'doi-asserted-by': 'publisher', 'first-page': '3295', 'DOI': '10.1016/j.jacc.2019.04.052', 'volume': '73', 'author': 'SR Lee', 'year': '2019', 'unstructured': 'Lee SR, Lee HJ, Choi EK, Han KD, Jung JH, Cha MJ, Oh S, Lip GYH. Direct ' 'oral anticoagulants in patients with Atrial Fibrillation and Liver ' 'Disease. J Am Coll Cardiol. 2019;73:3295–308.', 'journal-title': 'J Am Coll Cardiol'}, { 'key': '2464_CR27', 'doi-asserted-by': 'publisher', 'first-page': 'e3085', 'DOI': '10.1093/cid/ciaa1624', 'volume': '73', 'author': 'VS Fan', 'year': '2021', 'unstructured': 'Fan VS, Dominitz JA, Eastment MC, Locke ER, Green P, Berry K, O’Hare AM, ' 'Shah JA, Crothers K, Ioannou GN. Risk factors for testing positive for ' 'severe Acute Respiratory Syndrome Coronavirus 2 in a National United ' 'States Healthcare System. 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' '2022;28:425–72.', 'journal-title': 'Clin Mol Hepatol'}, { 'key': '2464_CR30', 'doi-asserted-by': 'publisher', 'first-page': '620', 'DOI': '10.5009/gnl220420', 'volume': '17', 'author': 'J-I Chang', 'year': '2023', 'unstructured': 'Chang J-I, Kim JH, Sinn DH, Cho J-Y, Kim KM, Oh JH, Park Y, Sohn W, Goh ' 'MJ, Kang W, et al. Clinical outcomes and validation of Ursodeoxycholic ' 'Acid Response scores in patients with Korean primary biliary ' 'cholangitis: a Multicenter Cohort Study. Gut Liver. 2023;17:620–8.', 'journal-title': 'Gut Liver'}, { 'issue': 'Suppl 1', 'key': '2464_CR31', 'doi-asserted-by': 'publisher', 'first-page': 'S3', 'DOI': '10.1016/S2210-7401(12)70015-3', 'volume': '36', 'author': 'R Poupon', 'year': '2012', 'unstructured': 'Poupon R. Ursodeoxycholic acid and bile-acid mimetics as therapeutic ' 'agents for cholestatic liver diseases: an overview of their mechanisms ' 'of action. Clin Res Hepatol Gastroenterol. 2012;36(Suppl 1):S3–12.', 'journal-title': 'Clin Res Hepatol Gastroenterol'}, { 'key': '2464_CR32', 'doi-asserted-by': 'publisher', 'first-page': '105', 'DOI': '10.5483/BMBRep.2016.49.2.173', 'volume': '49', 'author': 'AR Oh', 'year': '2016', 'unstructured': 'Oh AR, Bae JS, Lee J, Shin E, Oh BC, Park SC, Cha JY. Ursodeoxycholic ' 'acid decreases age-related adiposity and inflammation in mice. BMB Rep. ' '2016;49:105–10.', 'journal-title': 'BMB Rep'}, { 'key': '2464_CR33', 'doi-asserted-by': 'publisher', 'first-page': 'G427', 'DOI': '10.1152/ajpgi.00205.2012', 'volume': '305', 'author': 'T Takigawa', 'year': '2013', 'unstructured': 'Takigawa T, Miyazaki H, Kinoshita M, Kawarabayashi N, Nishiyama K, ' 'Hatsuse K, Ono S, Saitoh D, Seki S, Yamamoto J. Glucocorticoid ' 'receptor-dependent immunomodulatory effect of ursodeoxycholic acid on ' 'liver lymphocytes in mice. Am J Physiol Gastrointest Liver Physiol. ' '2013;305:G427–438.', 'journal-title': 'Am J Physiol Gastrointest Liver Physiol'}, { 'key': '2464_CR34', 'doi-asserted-by': 'publisher', 'first-page': 'G735', 'DOI': '10.1152/ajpgi.90321.2008', 'volume': '295', 'author': 'K Okada', 'year': '2008', 'unstructured': 'Okada K, Shoda J, Taguchi K, Maher JM, Ishizaki K, Inoue Y, Ohtsuki M, ' 'Goto N, Takeda K, Utsunomiya H, et al. Ursodeoxycholic acid stimulates ' 'Nrf2-mediated hepatocellular transport, detoxification, and ' 'antioxidative stress systems in mice. Am J Physiol Gastrointest Liver ' 'Physiol. 2008;295:G735–747.', 'journal-title': 'Am J Physiol Gastrointest Liver Physiol'}, { 'key': '2464_CR35', 'doi-asserted-by': 'publisher', 'first-page': '134', 'DOI': '10.1016/S1665-2681(19)31792-2', 'volume': '8', 'author': 'GA El-Sherbiny', 'year': '2009', 'unstructured': 'El-Sherbiny GA, Taye A, Abdel-Raheem IT. Role of ursodeoxycholic acid in ' 'prevention of hepatotoxicity caused by Amoxicillin-clavulanic acid in ' 'rats. Ann Hepatol. 2009;8:134–40.', 'journal-title': 'Ann Hepatol'}, { 'key': '2464_CR36', 'doi-asserted-by': 'publisher', 'first-page': '523', 'DOI': '10.1111/liv.13562', 'volume': '38', 'author': 'M Mueller', 'year': '2018', 'unstructured': 'Mueller M, Castro RE, Thorell A, Marschall HU, Auer N, Herac M, ' 'Rodrigues CMP, Trauner M. Ursodeoxycholic acid: effects on hepatic ' 'unfolded protein response, apoptosis and oxidative stress in morbidly ' 'obese patients. Liver Int. 2018;38:523–31.', 'journal-title': 'Liver Int'}, { 'key': '2464_CR37', 'doi-asserted-by': 'publisher', 'first-page': '905', 'DOI': '10.1007/s10096-020-04138-6', 'volume': '40', 'author': 'S Beyerstedt', 'year': '2021', 'unstructured': 'Beyerstedt S, Casaro EB, Rangel ÉB. COVID-19: angiotensin-converting ' 'enzyme 2 (ACE2) expression and tissue susceptibility to SARS-CoV-2 ' 'infection. Eur J Clin Microbiol Infect Dis. 2021;40:905–19.', 'journal-title': 'Eur J Clin Microbiol Infect Dis'}, { 'key': '2464_CR38', 'doi-asserted-by': 'crossref', 'unstructured': 'Fiorucci S, Urbani G, Biagioli M, Sepe V, Distrutti E, Zampella A. Bile ' 'acids and bile acid activated receptors in the treatment of Covid-19. ' 'Biochem Pharmacol 2023:115983.', 'DOI': '10.1016/j.bcp.2023.115983'}, { 'key': '2464_CR39', 'doi-asserted-by': 'publisher', 'first-page': '572885', 'DOI': '10.3389/fchem.2020.572885', 'volume': '8', 'author': 'A Carino', 'year': '2020', 'unstructured': 'Carino A, Moraca F, Fiorillo B, Marchianò S, Sepe V, Biagioli M, ' 'Finamore C, Bozza S, Francisci D, Distrutti E, et al. Hijacking ' 'SARS-CoV-2/ACE2 receptor Interaction by Natural and semi-synthetic ' 'Steroidal agents acting on functional pockets on the receptor binding ' 'domain. Front Chem. 2020;8:572885.', 'journal-title': 'Front Chem'}, { 'key': '2464_CR40', 'doi-asserted-by': 'publisher', 'first-page': '196', 'DOI': '10.1021/acs.jcim.1c01126', 'volume': '62', 'author': 'B Fiorillo', 'year': '2022', 'unstructured': 'Fiorillo B, Marchianò S, Moraca F, Sepe V, Carino A, Rapacciuolo P, ' 'Biagioli M, Limongelli V, Zampella A, Catalanotti B, Fiorucci S. ' 'Discovery of bile acid derivatives as potent ACE2 activators by virtual ' 'screening and essential dynamics. J Chem Inf Model. 2022;62:196–209.', 'journal-title': 'J Chem Inf Model'}, { 'key': '2464_CR41', 'doi-asserted-by': 'publisher', 'first-page': 'e0180673', 'DOI': '10.1371/journal.pone.0180673', 'volume': '12', 'author': 'WK Ko', 'year': '2017', 'unstructured': 'Ko WK, Lee SH, Kim SJ, Jo MJ, Kumar H, Han IB, Sohn S. Anti-inflammatory ' 'effects of ursodeoxycholic acid by lipopolysaccharide-stimulated ' 'inflammatory responses in RAW 264.7 macrophages. PLoS ONE. ' '2017;12:e0180673.', 'journal-title': 'PLoS ONE'}, { 'key': '2464_CR42', 'doi-asserted-by': 'publisher', 'first-page': '109897', 'DOI': '10.1016/j.mehy.2020.109897', 'volume': '143', 'author': 'S Abdulrab', 'year': '2020', 'unstructured': 'Abdulrab S, Al-Maweri S, Halboub E. Ursodeoxycholic acid as a candidate ' 'therapeutic to alleviate and/or prevent COVID-19-associated cytokine ' 'storm. Med Hypotheses. 2020;143:109897.', 'journal-title': 'Med Hypotheses'}, { 'key': '2464_CR43', 'doi-asserted-by': 'publisher', 'first-page': '1019', 'DOI': '10.1053/j.gastro.2023.01.014', 'volume': '164', 'author': 'K Prayitno', 'year': '2023', 'unstructured': 'Prayitno K, Bhat M. Repurposing UDCA, an FXR inhibitor, to prevent ' 'SARS-Cov-2 infection. Gastroenterology. 2023;164:1019–20.', 'journal-title': 'Gastroenterology'}, { 'key': '2464_CR44', 'doi-asserted-by': 'publisher', 'first-page': '100664', 'DOI': '10.1016/j.lanepe.2023.100664', 'volume': '30', 'author': 'S Contreras', 'year': '2023', 'unstructured': 'Contreras S, Iftekhar EN, Priesemann V. From emergency response to ' 'long-term management: the many faces of the endemic state of COVID-19. ' 'Lancet Reg Health Eur. 2023;30:100664.', 'journal-title': 'Lancet Reg Health Eur'}, { 'key': '2464_CR45', 'doi-asserted-by': 'publisher', 'first-page': '588', 'DOI': '10.1016/S2213-2600(23)00217-5', 'volume': '11', 'author': 'T Burki', 'year': '2023', 'unstructured': 'Burki T. WHO ends the COVID-19 public health emergency. Lancet Respir ' 'Med. 2023;11:588.', 'journal-title': 'Lancet Respir Med'}, { 'key': '2464_CR46', 'doi-asserted-by': 'publisher', 'first-page': '2851', 'DOI': '10.1097/JS9.0000000000000513', 'volume': '109', 'author': 'R Sarker', 'year': '2023', 'unstructured': 'Sarker R, Roknuzzaman ASM, Hossain MJ, Bhuiyan MA, Islam MR. The WHO ' 'declares COVID-19 is no longer a public health emergency of ' 'international concern: benefits, challenges, and necessary precautions ' 'to come back to normal life. Int J Surg. 2023;109:2851–2.', 'journal-title': 'Int J Surg'}, { 'key': '2464_CR47', 'doi-asserted-by': 'publisher', 'first-page': 'e2313', 'DOI': '10.1002/rmv.2313', 'volume': '32', 'author': 'I Hadj Hassine', 'year': '2022', 'unstructured': 'Hadj Hassine I. Covid-19 vaccines and variants of concern: a review. 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Vaccine refusal, ' 'mandatory immunization, and the risks of vaccine-preventable diseases. N ' 'Engl J Med. 2009;360:1981–8.', 'journal-title': 'N Engl J Med'}, { 'key': '2464_CR51', 'doi-asserted-by': 'publisher', 'first-page': 'e0265496', 'DOI': '10.1371/journal.pone.0265496', 'volume': '17', 'author': 'DN Roy', 'year': '2022', 'unstructured': 'Roy DN, Biswas M, Islam E, Azam MS. Potential factors influencing ' 'COVID-19 vaccine acceptance and hesitancy: a systematic review. PLoS ' 'ONE. 2022;17:e0265496.', 'journal-title': 'PLoS ONE'}, { 'key': '2464_CR52', 'doi-asserted-by': 'publisher', 'first-page': '29', 'DOI': '10.1186/s13223-018-0250-0', 'volume': '14', 'author': 'HJ Park', 'year': '2018', 'unstructured': 'Park HJ, Byun MK, Kim HJ, Ahn CM, Rhee CK, Kim K, Kim BY, Bae HW, Yoo ' 'KH. Regular follow-up visits reduce the risk for asthma exacerbation ' 'requiring admission in Korean adults with asthma. Allergy Asthma Clin ' 'Immunol. 2018;14:29.', 'journal-title': 'Allergy Asthma Clin Immunol'}, { 'key': '2464_CR53', 'doi-asserted-by': 'publisher', 'first-page': '6049', 'DOI': '10.1038/s41598-020-63064-x', 'volume': '10', 'author': 'HJ Park', 'year': '2020', 'unstructured': 'Park HJ, Byun MK, Kim T, Rhee CK, Kim K, Kim BY, Ahn SI, Jo YU, Yoo KH. ' 'Frequent outpatient visits prevent exacerbation of Chronic Obstructive ' 'Pulmonary Disease. Sci Rep. 2020;10:6049.', 'journal-title': 'Sci Rep'}, { 'key': '2464_CR54', 'doi-asserted-by': 'publisher', 'first-page': '717', 'DOI': '10.1093/ije/dyaa033', 'volume': '49', 'author': 'NC Peeri', 'year': '2020', 'unstructured': 'Peeri NC, Shrestha N, Rahman MS, Zaki R, Tan Z, Bibi S, Baghbanzadeh M, ' 'Aghamohammadi N, Zhang W, Haque U. The SARS, MERS and novel coronavirus ' '(COVID-19) epidemics, the newest and biggest global health threats: what ' 'lessons have we learned? Int J Epidemiol. 2020;49:717–26.', 'journal-title': 'Int J Epidemiol'}], 'container-title': 'Virology Journal', 'original-title': [], 'language': 'en', 'link': [ { 'URL': 'https://link.springer.com/content/pdf/10.1186/s12985-024-02464-1.pdf', 'content-type': 'application/pdf', 'content-version': 'vor', 'intended-application': 'text-mining'}, { 'URL': 'https://link.springer.com/article/10.1186/s12985-024-02464-1/fulltext.html', 'content-type': 'text/html', 'content-version': 'vor', 'intended-application': 'text-mining'}, { 'URL': 'https://link.springer.com/content/pdf/10.1186/s12985-024-02464-1.pdf', 'content-type': 'application/pdf', 'content-version': 'vor', 'intended-application': 'similarity-checking'}], 'deposited': { 'date-parts': [[2024, 8, 27]], 'date-time': '2024-08-27T19:02:23Z', 'timestamp': 1724785343000}, 'score': 1, 'resource': {'primary': {'URL': 'https://virologyj.biomedcentral.com/articles/10.1186/s12985-024-02464-1'}}, 'subtitle': [], 'short-title': [], 'issued': {'date-parts': [[2024, 8, 27]]}, 'references-count': 54, 'journal-issue': {'issue': '1', 'published-online': {'date-parts': [[2024, 12]]}}, 'alternative-id': ['2464'], 'URL': 'http://dx.doi.org/10.1186/s12985-024-02464-1', 'relation': {}, 'ISSN': ['1743-422X'], 'subject': [], 'container-title-short': 'Virol J', 'published': {'date-parts': [[2024, 8, 27]]}, 'assertion': [ { 'value': '22 May 2024', 'order': 1, 'name': 'received', 'label': 'Received', 'group': {'name': 'ArticleHistory', 'label': 'Article History'}}, { 'value': '7 August 2024', 'order': 2, 'name': 'accepted', 'label': 'Accepted', 'group': {'name': 'ArticleHistory', 'label': 'Article History'}}, { 'value': '27 August 2024', 'order': 3, 'name': 'first_online', 'label': 'First Online', 'group': {'name': 'ArticleHistory', 'label': 'Article History'}}, {'order': 1, 'name': 'Ethics', 'group': {'name': 'EthicsHeading', 'label': 'Declarations'}}, { 'value': 'The Dong-A University College of Medicine Institutional Review Board exempted ' 'this retrospective study from review due to its design (utilizing ' 'de-identified, publicly available clinical data for analysis) ' '(DAUHIRB-EXP-23-026).', 'order': 2, 'name': 'Ethics', 'group': {'name': 'EthicsHeading', 'label': 'Ethics approval and consent to participate'}}, { 'value': 'Not applicable.', 'order': 3, 'name': 'Ethics', 'group': {'name': 'EthicsHeading', 'label': 'Consent for publication'}}, { 'value': 'This study used the database of the KDCA and the NHIS for policy and academic ' 'research. The research number of this study is KDCA-NHIS-2023-1-567. The KDCA ' 'is the Korea Disease Control and Prevention Agency, Republic of Korea. The NHIS ' 'is the National Health Insurance Service, Republic of Korea.', 'order': 4, 'name': 'Ethics', 'group': {'name': 'EthicsHeading', 'label': 'Additional information'}}, { 'value': 'The authors declare no competing interests.', 'order': 5, 'name': 'Ethics', 'group': {'name': 'EthicsHeading', 'label': 'Competing interests'}}], 'article-number': '202'}
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Please send us corrections, updates, or comments. c19early involves the extraction of 100,000+ datapoints from thousands of papers. Community updates help ensure high accuracy. Treatments and other interventions are complementary. All practical, effective, and safe means should be used based on risk/benefit analysis. No treatment or intervention is 100% available and effective for all current and future variants. We do not provide medical advice. Before taking any medication, consult a qualified physician who can provide personalized advice and details of risks and benefits based on your medical history and situation. FLCCC and WCH provide treatment protocols.
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