Outcomes of persons with coronavirus disease 2019 in hospitals with and without standard treatment with (hydroxy)chloroquine
Edgar Jg. Peters, Didier Collard, Sander Van Assen, Martijn Beudel, Marije K Bomers, Jacqueline Buijs, Lianne R De Haan, Wouter De Ruijter, Renée A Douma, Paul Wg. Elbers, Abraham Goorhuis, Niels C Gritters Van Den Oever, Lieve Ghh. Knarren, Hazra S Moeniralam, Remy Lm. Mostard, Marian Jr. Quanjel, Auke C Reidinga, Roos Renckens, Joop Pw. Van Den Bergh, Imro N Vlasveld, Jonne J Sikkens
Clinical Microbiology and Infection, doi:10.1016/j.cmi.2020.10.004
Objective: To compare survival of individuals with coronavirus disease 2019 (COVID-19) treated in hospitals that either did or did not routinely treat patients with hydroxychloroquine or chloroquine. Methods: We analysed data of COVID-19 patients treated in nine hospitals in the Netherlands. Inclusion dates ranged from 27 February to 15 May 2020, when the Dutch national guidelines no longer supported the use of (hydroxy)chloroquine. Seven hospitals routinely treated patients with (hydroxy)chloroquine, two hospitals did not. Primary outcome was 21-day all-cause mortality. We performed a survival analysis using log-rank test and Cox regression with adjustment for age, sex and covariates based on premorbid health, disease severity and the use of steroids for adult respiratory distress syndrome, including dexamethasone. Results: Among 1949 individuals, 21-day mortality was 21.5% in 1596 patients treated in hospitals that routinely prescribed (hydroxy)chloroquine, and 15.0% in 353 patients treated in hospitals that did not. In the adjusted Cox regression models this difference disappeared, with an adjusted hazard ratio of 1.09 (95% CI 0.81e1.47). When stratified by treatment actually received in individual patients, the use of (hydroxy)chloroquine was associated with an increased 21-day mortality (HR 1.58; 95% CI 1.24e2.02) in the full model.
Transparency declaration The authors declare that they have no conflicts of interest. Funding D. Collard is supported by a ZonMw grant (project no.: 10430022010002).
Contribution of authors All authors have made substantial contributions to the following: the conception and design of the study, or acquisition of data, or analysis and interpretation of data; drafting the article or revising it critically for important intellectual content; and final approval of the version to be submitted.
Appendix A. Supplementary data Supplementary data to this article can be found online at https://doi.org/10.1016/j.cmi.2020.10.004.
References
Catteau, Dauby, Montourcy, Bottieau, Hautekiet et al., Low-dose hydroxychloroquine therapy and mortality in hospitalized patients with COVID-19: a nationwide observational study of 8075 participants, Int J Antimicrob Agents
Fan, Zhang, Liu, Yang, Zheng et al., Connecting hydroxychloroquine in vitro antiviral activity to in vivo concentration for prediction of antiviral effect: a critical step in treating COVID-19 patients, Clin Infect Dis
Fantini, Scala, Chahinian, Yahi, Structural and molecular modelling studies reveal a new mechanism of action of chloroquine and hydroxychloroquine against SARS-CoV-2 infection, Int J Antimicrob Agents
Fiolet, Guihur, Rebeaud, Mulot, Peiffer-Smadja et al., Effect of hydroxychloroquine with or without azithromycin on the mortality of COVID-19 patients: a systematic review and meta-analysis, Clin Microbiol Infect
Gautret, Lagier, Parola, Hoang, Meddeb et al., Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an openlabel non-randomized clinical trial, Int J Antimicrob Agents
Geleris, Sun, Platt, Zucker, Baldwin et al., Observational study of hydroxychloroquine in hospitalized patients with Covid-19, N Engl J Med
Group, Horby, Lim, Emberson, Mafham et al., Dexamethasone in hospitalized patients with Covid-19dpreliminary report, N Engl J Med
Horby, Mafham, Linsell, Bell, Staplin et al., Effect of hydroxychloroquine in hospitalized patients with COVID-19: preliminary results from a multi-centre, randomized, controlled trial, medRxiv
Lee, Little, A practical guide to propensity score analysis for applied clinical research, Behav Res Ther
Petrilli, Jones, Yang, Rajagopalan, Donnell et al., Factors associated with hospital admission and critical illness among 5279 people with coronavirus disease 2019 in New York City: prospective cohort study, BMJ
Prokop, Van Everdingen, Van, Vellinga, Quarles Van Ufford et al., CO-RADSda categorical CT assessment scheme for patients with suspected COVID-19: definition and evaluation, Radiology
Risk, Use of hydroxychloroquine in hospitalised COVID-19 patients is associated with reduced mortality: findings from the observational multicentre Italian CORIST study, Eur J Intern Med
Rosenberg, Dufort, Udo, Wilberschied, Kumar et al., Association of treatment with hydroxychloroquine or azithromycin with inhospital mortality in patients with COVID-19 in New York State, JAMA
Tang, Cao, Han, Wang, Chen et al., Hydroxychloroquine in patients with mainly mild to moderate coronavirus disease 2019: open label, randomised controlled trial, BMJ
Wulff, Ejlskov, Multiple imputation by chained equations in Praxis: guidelines and review, Electron J Business Res Meth
Yang, Yu, Xu, Shu, Xia et al., Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a singlecentered, retrospective, observational study, Lancet Respir Med
Yao, Ye, Zhang, Cui, Huang et al., Vitro Antiviral activity and projection of optimized dosing design of hydroxychloroquine for the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Clin Infect Dis
{ 'indexed': {'date-parts': [[2024, 3, 1]], 'date-time': '2024-03-01T06:30:36Z', 'timestamp': 1709274636397},
'reference-count': 17,
'publisher': 'Elsevier BV',
'issue': '2',
'license': [ { 'start': { 'date-parts': [[2021, 2, 1]],
'date-time': '2021-02-01T00:00:00Z',
'timestamp': 1612137600000},
'content-version': 'tdm',
'delay-in-days': 0,
'URL': 'https://www.elsevier.com/tdm/userlicense/1.0/'},
{ 'start': { 'date-parts': [[2020, 10, 13]],
'date-time': '2020-10-13T00:00:00Z',
'timestamp': 1602547200000},
'content-version': 'vor',
'delay-in-days': 0,
'URL': 'http://creativecommons.org/licenses/by/4.0/'}],
'funder': [ { 'DOI': '10.13039/501100001826',
'name': 'ZonMw',
'doi-asserted-by': 'publisher',
'award': ['10430022010002']}],
'content-domain': {'domain': [], 'crossmark-restriction': False},
'published-print': {'date-parts': [[2021, 2]]},
'DOI': '10.1016/j.cmi.2020.10.004',
'type': 'journal-article',
'created': { 'date-parts': [[2020, 10, 14]],
'date-time': '2020-10-14T07:28:36Z',
'timestamp': 1602660516000},
'page': '264-268',
'source': 'Crossref',
'is-referenced-by-count': 10,
'title': 'Outcomes of persons with coronavirus disease 2019 in hospitals with and without standard '
'treatment with (hydroxy)chloroquine',
'prefix': '10.1016',
'volume': '27',
'author': [ {'given': 'Edgar JG.', 'family': 'Peters', 'sequence': 'first', 'affiliation': []},
{'given': 'Didier', 'family': 'Collard', 'sequence': 'additional', 'affiliation': []},
{'given': 'Sander', 'family': 'Van Assen', 'sequence': 'additional', 'affiliation': []},
{'given': 'Martijn', 'family': 'Beudel', 'sequence': 'additional', 'affiliation': []},
{'given': 'Marije K.', 'family': 'Bomers', 'sequence': 'additional', 'affiliation': []},
{'given': 'Jacqueline', 'family': 'Buijs', 'sequence': 'additional', 'affiliation': []},
{'given': 'Lianne R.', 'family': 'De Haan', 'sequence': 'additional', 'affiliation': []},
{'given': 'Wouter', 'family': 'De Ruijter', 'sequence': 'additional', 'affiliation': []},
{'given': 'Renée A.', 'family': 'Douma', 'sequence': 'additional', 'affiliation': []},
{'given': 'Paul WG.', 'family': 'Elbers', 'sequence': 'additional', 'affiliation': []},
{'given': 'Abraham', 'family': 'Goorhuis', 'sequence': 'additional', 'affiliation': []},
{ 'given': 'Niels C.',
'family': 'Gritters van den Oever',
'sequence': 'additional',
'affiliation': []},
{'given': 'Lieve GHH.', 'family': 'Knarren', 'sequence': 'additional', 'affiliation': []},
{'given': 'Hazra S.', 'family': 'Moeniralam', 'sequence': 'additional', 'affiliation': []},
{'given': 'Remy LM.', 'family': 'Mostard', 'sequence': 'additional', 'affiliation': []},
{'given': 'Marian JR.', 'family': 'Quanjel', 'sequence': 'additional', 'affiliation': []},
{'given': 'Auke C.', 'family': 'Reidinga', 'sequence': 'additional', 'affiliation': []},
{'given': 'Roos', 'family': 'Renckens', 'sequence': 'additional', 'affiliation': []},
{'given': 'Joop PW.', 'family': 'Van Den Bergh', 'sequence': 'additional', 'affiliation': []},
{'given': 'Imro N.', 'family': 'Vlasveld', 'sequence': 'additional', 'affiliation': []},
{'given': 'Jonne J.', 'family': 'Sikkens', 'sequence': 'additional', 'affiliation': []}],
'member': '78',
'reference': [ { 'key': '10.1016/j.cmi.2020.10.004_bib1',
'doi-asserted-by': 'crossref',
'first-page': '2493',
'DOI': '10.1001/jama.2020.8630',
'article-title': 'Association of treatment with hydroxychloroquine or azithromycin with '
'in-hospital mortality in patients with COVID-19 in New York State',
'volume': '323',
'author': 'Rosenberg',
'year': '2020',
'journal-title': 'JAMA'},
{ 'key': '10.1016/j.cmi.2020.10.004_bib2',
'doi-asserted-by': 'crossref',
'first-page': '2411',
'DOI': '10.1056/NEJMoa2012410',
'article-title': 'Observational study of hydroxychloroquine in hospitalized patients with '
'Covid-19',
'volume': '382',
'author': 'Geleris',
'year': '2020',
'journal-title': 'N\xa0Engl J Med'},
{ 'key': '10.1016/j.cmi.2020.10.004_bib3',
'doi-asserted-by': 'crossref',
'first-page': '105949',
'DOI': '10.1016/j.ijantimicag.2020.105949',
'article-title': 'Hydroxychloroquine and azithromycin as a treatment of COVID-19: results '
'of an open-label non-randomized clinical trial',
'volume': '56',
'author': 'Gautret',
'year': '2020',
'journal-title': 'Int J Antimicrob Agents'},
{ 'key': '10.1016/j.cmi.2020.10.004_bib4',
'article-title': 'Use of hydroxychloroquine in hospitalised COVID-19 patients is '
'associated with reduced mortality: findings from the observational '
'multicentre Italian CORIST study',
'author': 'Covid',
'year': '2020',
'journal-title': 'Eur J Intern Med'},
{ 'key': '10.1016/j.cmi.2020.10.004_bib5',
'doi-asserted-by': 'crossref',
'first-page': '106144',
'DOI': '10.1016/j.ijantimicag.2020.106144',
'article-title': 'Low-dose hydroxychloroquine therapy and mortality in hospitalized '
'patients with COVID-19: a nationwide observational study of 8075 '
'participants',
'volume': '56',
'author': 'Catteau',
'year': '2020',
'journal-title': 'Int J Antimicrob Agents'},
{ 'key': '10.1016/j.cmi.2020.10.004_bib6',
'doi-asserted-by': 'crossref',
'first-page': '19',
'DOI': '10.1016/j.cmi.2020.08.022',
'article-title': 'Effect of hydroxychloroquine with or without azithromycin on the '
'mortality of COVID-19 patients: a systematic review and meta-analysis',
'volume': '27',
'author': 'Fiolet',
'year': '2021',
'journal-title': 'Clin Microbiol Infect'},
{ 'key': '10.1016/j.cmi.2020.10.004_bib7',
'doi-asserted-by': 'crossref',
'first-page': 'm1849',
'DOI': '10.1136/bmj.m1849',
'article-title': 'Hydroxychloroquine in patients with mainly mild to moderate coronavirus '
'disease 2019: open label, randomised controlled trial',
'volume': '369',
'author': 'Tang',
'year': '2020',
'journal-title': 'BMJ'},
{ 'key': '10.1016/j.cmi.2020.10.004_bib8',
'article-title': 'Effect of hydroxychloroquine in hospitalized patients with COVID-19: '
'preliminary results from a multi-centre, randomized, controlled trial',
'author': 'Horby',
'year': '2020',
'journal-title': 'medRxiv'},
{ 'key': '10.1016/j.cmi.2020.10.004_bib10',
'doi-asserted-by': 'crossref',
'first-page': 'E97',
'DOI': '10.1148/radiol.2020201473',
'article-title': 'CO-RADS—a categorical CT assessment scheme for patients with suspected '
'COVID-19: definition and evaluation',
'volume': '296',
'author': 'Prokop',
'year': '2020',
'journal-title': 'Radiology'},
{ 'key': '10.1016/j.cmi.2020.10.004_bib11',
'first-page': '41',
'article-title': 'Multiple imputation by chained equations in Praxis: guidelines and '
'review',
'volume': '15',
'author': 'Wulff',
'year': '2017',
'journal-title': 'Electron J Business Res Meth'},
{ 'key': '10.1016/j.cmi.2020.10.004_bib12',
'doi-asserted-by': 'crossref',
'first-page': '475',
'DOI': '10.1016/S2213-2600(20)30079-5',
'article-title': 'Clinical course and outcomes of critically ill patients with SARS-CoV-2 '
'pneumonia in Wuhan, China: a single-centered, retrospective, '
'observational study',
'volume': '8',
'author': 'Yang',
'year': '2020',
'journal-title': 'Lancet Respir Med'},
{ 'key': '10.1016/j.cmi.2020.10.004_bib13',
'doi-asserted-by': 'crossref',
'first-page': 'm1966',
'DOI': '10.1136/bmj.m1966',
'article-title': 'Factors associated with hospital admission and critical illness among '
'5279 people with coronavirus disease 2019 in New York City: prospective '
'cohort study',
'volume': '369',
'author': 'Petrilli',
'year': '2020',
'journal-title': 'BMJ'},
{ 'key': '10.1016/j.cmi.2020.10.004_bib14',
'doi-asserted-by': 'crossref',
'first-page': '76',
'DOI': '10.1016/j.brat.2017.01.005',
'article-title': 'A\xa0practical guide to propensity score analysis for applied clinical '
'research',
'volume': '98',
'author': 'Lee',
'year': '2017',
'journal-title': 'Behav Res Ther'},
{ 'key': '10.1016/j.cmi.2020.10.004_bib15',
'article-title': 'Dexamethasone in hospitalized patients with Covid-19—preliminary report',
'author': 'Group',
'year': '2020',
'journal-title': 'N\xa0Engl J Med'},
{ 'key': '10.1016/j.cmi.2020.10.004_bib17',
'doi-asserted-by': 'crossref',
'first-page': '105960',
'DOI': '10.1016/j.ijantimicag.2020.105960',
'article-title': 'Structural and molecular modelling studies reveal a new mechanism of '
'action of chloroquine and hydroxychloroquine against SARS-CoV-2 '
'infection',
'volume': '55',
'author': 'Fantini',
'year': '2020',
'journal-title': 'Int J Antimicrob Agents'},
{ 'key': '10.1016/j.cmi.2020.10.004_bib18',
'doi-asserted-by': 'crossref',
'DOI': '10.1093/cid/ciaa623',
'article-title': 'Connecting hydroxychloroquine in vitro antiviral activity to in vivo '
'concentration for prediction of antiviral effect: a critical step in '
'treating COVID-19 patients',
'author': 'Fan',
'year': '2020',
'journal-title': 'Clin Infect Dis'},
{ 'key': '10.1016/j.cmi.2020.10.004_bib19',
'doi-asserted-by': 'crossref',
'first-page': '732',
'DOI': '10.1093/cid/ciaa237',
'article-title': 'In Vitro Antiviral activity and projection of optimized dosing design '
'of hydroxychloroquine for the treatment of severe acute respiratory '
'syndrome coronavirus 2 (SARS-CoV-2)',
'volume': '71',
'author': 'Yao',
'year': '2020',
'journal-title': 'Clin Infect Dis'}],
'container-title': 'Clinical Microbiology and Infection',
'original-title': [],
'language': 'en',
'link': [ { 'URL': 'https://api.elsevier.com/content/article/PII:S1198743X20306157?httpAccept=text/xml',
'content-type': 'text/xml',
'content-version': 'vor',
'intended-application': 'text-mining'},
{ 'URL': 'https://api.elsevier.com/content/article/PII:S1198743X20306157?httpAccept=text/plain',
'content-type': 'text/plain',
'content-version': 'vor',
'intended-application': 'text-mining'}],
'deposited': { 'date-parts': [[2021, 2, 27]],
'date-time': '2021-02-27T15:10:59Z',
'timestamp': 1614438659000},
'score': 1,
'resource': {'primary': {'URL': 'https://linkinghub.elsevier.com/retrieve/pii/S1198743X20306157'}},
'subtitle': [],
'short-title': [],
'issued': {'date-parts': [[2021, 2]]},
'references-count': 17,
'journal-issue': {'issue': '2', 'published-print': {'date-parts': [[2021, 2]]}},
'alternative-id': ['S1198743X20306157'],
'URL': 'http://dx.doi.org/10.1016/j.cmi.2020.10.004',
'relation': { 'has-preprint': [ { 'id-type': 'doi',
'id': '10.1101/2020.08.14.20173369',
'asserted-by': 'object'}]},
'ISSN': ['1198-743X'],
'subject': ['Infectious Diseases', 'Microbiology (medical)', 'General Medicine'],
'container-title-short': 'Clinical Microbiology and Infection',
'published': {'date-parts': [[2021, 2]]}}
