Hydroxychloroquine, azithromycin and methylprednisolone and in hospital survival in severe COVID-19 pneumonia
Ronaldo C Go, Themba Nyirenda
Frontiers in Pharmacology, doi:10.3389/fphar.2022.935370
Introduction: Severe COVID-19 pneumonia has two phases that are not mutually exclusive. Repurposed drugs target only one phase and the association of combination therapy to survival is unknown. Objective: To determine the association of hydroxychloroquine, azithromycin, and methylprednisolone versus methylprednisolone only to in hospital survival. Methods: This is a secondary analysis of a retrospective cohort of patients admitted for severe covid-19 in 13 hospitals in New Jersey, United States from March-June 2020. Propensity score match with 11 variables was constructed between those who received no methylprednisolone and methylprednisolone. Multivariate Cox regression was used for risk of in hospital mortality. Measurements and main results: There were 759 patients, 380 in no methylprednisolone and 379 with methylprednisolone. Multivariate Cox regression shows that methylprednisolone, hydroxychloroquine, and azithromycin had prolonged survival compared to methylprednisolone alone [HR 0.45 (95% CI 0.22,0.91 p < 0.03)]. In patients who received hydroxychloroquine and azithromycin, those who also received high dose methylprednisolone were associated with worse survival compared to those who received low dose methylprednisolone (HR = 1.642; 95% CI 1.053 to 2.562; p = 0.0287). Nursing home residents [HR 2.77 (95% CI 1.67, 4.59 p < 0.0001)], coronary artery disease [HR 2.93 (95% CI 1.31, 3.15 p = 0.001), and invasive mechanical ventilation [HR 3.02 (95% CI 1.71,5.34 p = 0.0001)] were independently associated with worse survival.
Ethics statement The studies involving human participants were reviewed and approved by Hackensack Meridian Health Institutional Review Board. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.
Author contributions RG developed the concept, performed data entry, analysis and wrote most of the manuscript. TN performed the statistics and wrote some of the manuscript.
Conflict of interest RG receiving consulting fees to participate in research design on long term follow-up in COVID-19 sponsored by Hoffmann LaRoche -Genentech. The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Publisher's note All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
Supplementary material The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fphar. 2022.935370/full#supplementary-material
References
Al-Tarbsheh, Chong, Oweis, Saha, Feustel et al., SARS-CoV-2 viral shedding and transmission dynamics: Implications of WHO COVID-19 discharge guidelines, N. Engl. J. Med,
doi:10.3389/fmed.2021.648660Bellani, Laffey, Pham, Fan, Brochard et al., None
Brault, Zerbib, Kontar, Fouquet, Carpentier et al., None
Burnham, Janssen, Riches, Moss, Downey, None
Canzano, Brambilla, Porro, Cosentino, Tortorici et al., Platelet and endothelial activation as potential mechanisms behind the thrombotic complications of COVID-19 patients, JACC. Basic Transl. Sci,
doi:10.1016/j.jacbts.2020.12.009Cavalcanti, Zampieri, Rosa, Azevedo, Veiga et al., None
Chow, Rahnavard, Gomberg-Maitland, Chatterjee, Patodi et al., Association of early aspirin use with in-hospital mortality in patients with moderate COVID-19, JAMA Netw. Open,
doi:10.1001/jamanetworkopen.2022.3890Echeverría-Esnal, Martin-Ontiyuelo, Navarrete-Rouco, De-Antonio Cuscó, Ferrández et al., Azithromycin in the treatment of COVID-19: A review, Expert Rev. anti. Infect. Ther,
doi:10.1080/14787210.2020.1813024Fiolet, Guihur, Rebeaud, Mulot, Peiffer-Smadja et al., Effect of hydroxychloroquine with or without azithromycin on the mortality of coronavirus disease 2019 (COVID-19) patients: A systematic review and meta-analysis, Clin. Microbiol. Infect,
doi:10.1016/j.cmi.2020.08.022Go, Shah, Nyirenda, Methylprednisolone and 60 Days in hospital survival in coronavirus disease 2019 pneumonia, Crit. Care Explor,
doi:10.1097/CCE.0000000000000493Gottlieb, Vaca, Paredes, Mera, Webb et al., Early remdesivir to prevent progression to severe COVID-19 in outpatients, N. Engl. J. Med,
doi:10.1056/NEJMoa2116846Grieco, Maggiore, Roca, Spinelli, Patel et al., Non-invasive ventilatory support and high-flow nasal oxygen as firstline treatment of acute hypoxemic respiratory failure and ARDS, Intensive Care Med,
doi:10.1007/s00134-021-06459-2Haudebourg, Perier, Tuffet, De Prost, Razazi et al., Respiratory mechanics of COVID-19-versus non-COVID-19-associated acute respiratory distress syndrome, Am. J. Respir. Crit. Care Med
Kalil, Patterson, Mehta, Tomashek, Wolfe et al., Baricitinib plus remdesivir for hospitalized adults with covid-19, N. Engl. J. Med,
doi:10.1056/NEJMoa2031994Mehta, Li, Goodwin, Risk factors associated with SARS-CoV-2 infections, hospitalization, and mortality among US nursing home residents, Frontiers in Pharmacology frontiersin
Papoutsi, Giannakoulis, Xourgia, Routsi, Kotanidou, None
Patel, Decuir, Abrams, Campbell, Godfred-Cato et al., None
Rosenberg, Dufort, Udo, Wilberschied, Kumar et al., Association of treatment with hydroxychloroquine or azithromycin with in-hospital mortality in patients with COVID-19 in New York state, JAMA,
doi:10.1001/jama.2020.8630Réa-Neto, Bernardelli, Câmara, Reese, Queiroga et al., An open-label randomized controlled trial evaluating the efficacy of chloroquine/hydroxychloroquine in severe COVID-19 patients, N. Engl. J. Med,
doi:10.1016/S0140-6736(21)00676-0Siempos, Effect of timing of intubation on clinical outcomes of critically ill patients with COVID-19: A systematic review and meta-analysis of nonrandomized cohort studies, Crit. Care,
doi:10.1186/s13054-021-03540-6Sullivan, Zazzeron, Berra, Noninvasive respiratory support for COVID-19 patients: When, for whom, and how?, J. intensive care,
doi:10.1186/s40560-021-00593-1Tang, Bigelow, Sheikh, Peters, Zenilman et al., Outcomes of nursing home COVID-19 patients by initial symptoms and comorbidity: Results of universal testing of 1970 residents, J. Am. Med. Dir. Assoc,
doi:10.1016/j.jamda.2020.10.011Tobin, Laghi, Jubran, Kampen, Van De Vijver et al., Duration and key determinants of infectious virus shedding in hospitalized patients with coronavirus disease, Ann. Intensive Care,
doi:10.1186/s13613-020-00724-1Vincent, Bergeron, Benjannet, Chloroquine is a potent inhibitor of SARS coronavirus infection and spread, Virol. J,
doi:10.1186/1743-422X-2-69Wang, Cao, Zhang, Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro, Cell Res,
doi:10.1038/s41422-020-0282-0Weaver, Das, Saffaran, Yehya, Scott et al., High risk of patient self-inflicted lung injury in COVID-19 with frequently encountered spontaneous breathing patterns: A computational modelling study,
doi:10.1186/s13613-021-00904-7Yao, Ye, Zhang, Cui, Huang et al., 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), Clin. Infect. Dis,
doi:10.1093/cid/ciaa237{ 'indexed': { 'date-parts': [[2023, 11, 14]],
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'abstract': '<jats:p><jats:bold>Introduction:</jats:bold> Severe COVID-19 pneumonia has two phases that '
'are not mutually exclusive. Repurposed drugs target only one phase and the association of '
'combination therapy to survival is unknown.</jats:p><jats:p><jats:bold>Objective:</jats:bold> '
'To determine the association of hydroxychloroquine, azithromycin, and methylprednisolone '
'versus methylprednisolone only to in hospital '
'survival.</jats:p><jats:p><jats:bold>Methods:</jats:bold> This is a secondary analysis of a '
'retrospective cohort of patients admitted for severe covid-19 in 13 hospitals in New Jersey, '
'United States from March–June 2020. Propensity score match with 11 variables was constructed '
'between those who received no methylprednisolone and methylprednisolone. Multivariate Cox '
'regression was used for risk of in hospital '
'mortality.</jats:p><jats:p><jats:bold>Measurements and main results:</jats:bold> There were '
'759 patients, 380 in no methylprednisolone and 379 with methylprednisolone. Multivariate Cox '
'regression shows that methylprednisolone, hydroxychloroquine, and azithromycin had prolonged '
'survival compared to methylprednisolone alone [HR 0.45 (95% CI 0.22,0.91\xa0'
'<jats:italic>p</jats:italic> &lt; 0.03)]. In patients who received hydroxychloroquine and '
'azithromycin, those who also received high dose methylprednisolone were associated with worse '
'survival compared to those who received low dose methylprednisolone (HR = 1.642; 95% CI 1.053 '
'to 2.562; <jats:italic>p</jats:italic> = 0.0287). Nursing home residents [HR 2.77 (95% CI '
'1.67, 4.59\xa0<jats:italic>p</jats:italic> &lt; 0.0001)], coronary artery disease [HR '
'2.93 (95% CI 1.31, 3.15\xa0<jats:italic>p</jats:italic> = 0.001), and invasive mechanical '
'ventilation [HR 3.02 (95% CI 1.71,5.34\xa0<jats:italic>p</jats:italic> = 0.0001)] were '
'independently associated with worse '
'survival.</jats:p><jats:p><jats:bold>Conclusion:</jats:bold> Combination therapy was '
'associated with improved survival compared to monotherapy. However, nursing home residents, '
'coronary artery disease, and mechanical ventilation were independently associated with '
'mortality. Larger randomized controlled studies are needed to confirm conclusions.</jats:p>',
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'respiratory distress syndrome in intensive care units in 50 countries',
'volume': '315',
'author': 'Bellani',
'year': '2016',
'journal-title': 'JAMA'},
{ 'key': 'B5',
'doi-asserted-by': 'publisher',
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'DOI': '10.1164/rccm.202005-2025LE',
'article-title': 'COVID-19- versus non-COVID-19-related acute respiratory distress '
'syndrome: Differences and similarities',
'volume': '202',
'author': 'Brault',
'year': '2020',
'journal-title': 'Am. J. Respir. Crit. Care Med.'},
{ 'key': 'B6',
'doi-asserted-by': 'publisher',
'first-page': '276',
'DOI': '10.1183/09031936.00196412',
'article-title': 'The fibroproliferative response in acute respiratory distress syndrome: '
'Mechanisms and clinical significance',
'volume': '32',
'author': 'Burnham',
'year': '2013',
'journal-title': 'Eur. Respir. J.'},
{ 'key': 'B7',
'doi-asserted-by': 'publisher',
'first-page': '202',
'DOI': '10.1016/j.jacbts.2020.12.009',
'article-title': 'Platelet and endothelial activation as potential mechanisms behind the '
'thrombotic complications of COVID-19 patients',
'volume': '6',
'author': 'Canzano',
'year': '2021',
'journal-title': 'JACC. Basic Transl. Sci.'},
{ 'key': 'B8',
'doi-asserted-by': 'publisher',
'first-page': '2041',
'DOI': '10.1056/NEJMoa2019014',
'article-title': 'Hydroxychloroquine with or without azithromycin in mild-to-moderate '
'covid-19',
'volume': '383',
'author': 'Cavalcanti',
'year': '2020',
'journal-title': 'N. Engl. J. Med.'},
{ 'key': 'B9',
'doi-asserted-by': 'publisher',
'first-page': '69',
'DOI': '10.1016/j.jcv.2004.03.003',
'article-title': 'In vitro susceptibility of 10 clinical isolates of SARS coronavirus to '
'selected antiviral compounds.',
'volume': '31',
'author': 'Chen',
'year': '2004',
'journal-title': 'J. Clin. Virol.'},
{ 'key': 'B10',
'doi-asserted-by': 'publisher',
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'DOI': '10.1001/jamanetworkopen.2022.3890',
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'volume': '5',
'author': 'Chow',
'year': '2022',
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'doi-asserted-by': 'publisher',
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'DOI': '10.1080/14787210.2020.1813024',
'article-title': 'Azithromycin in the treatment of COVID-19: A review',
'volume': '19',
'author': 'Echeverría-Esnal',
'year': '2021',
'journal-title': 'Expert Rev. anti. Infect. Ther.'},
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'mortality of coronavirus disease 2019 (COVID-19) patients: A systematic '
'review and meta-analysis',
'volume': '27',
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'author': 'Go',
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'volume': '6',
'author': 'Liu',
'year': '2020',
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'year': '2021',
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'doi-asserted-by': 'publisher',
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'volume': '25',
'author': 'Papoutsi',
'year': '2021',
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'author': 'Patel',
'year': '2021',
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'volume': '11',
'author': 'Réa-Neto',
'year': '2021',
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{ 'key': 'B26',
'doi-asserted-by': 'publisher',
'first-page': '2030',
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'volume': '383',
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'year': '2020',
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'author': 'Horby',
'year': '2021',
'journal-title': 'N. Engl. J. Med.'},
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'doi-asserted-by': 'publisher',
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'volume': '397',
'year': '2021',
'journal-title': 'Lancet'},
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'doi-asserted-by': 'publisher',
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'volume': '323',
'author': 'Rosenberg',
'year': '2020',
'journal-title': 'JAMA.'},
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'volume': '10',
'author': 'Sullivan',
'year': '2022',
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'DOI': '10.1016/j.jamda.2020.10.011',
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'comorbidity: Results of universal testing of 1970 residents',
'volume': '21',
'author': 'Tang',
'year': '2020',
'journal-title': 'J. Am. Med. Dir. Assoc.'},
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'doi-asserted-by': 'publisher',
'first-page': '24',
'DOI': '10.1186/s13613-020-00724-1',
'article-title': 'P-SILI is not justification for intubation of COVID-19 patients. Ann. '
'Intensive Care',
'volume': '105',
'author': 'Tobin',
'year': '2020',
'journal-title': 'Ann. Intensive Care'},
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'doi-asserted-by': 'publisher',
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'DOI': '10.1038/s41467-020-20568-4',
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'volume': '12',
'author': 'van Kampen',
'year': '2021',
'journal-title': 'Nat. Commun.'},
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'first-page': '69',
'DOI': '10.1186/1743-422X-2-69',
'article-title': 'Chloroquine is a potent inhibitor of SARS coronavirus infection and '
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'volume': '2',
'author': 'Vincent',
'year': '2005',
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'DOI': '10.1038/s41422-020-0282-0',
'article-title': 'Remdesivir and chloroquine effectively inhibit the recently emerged '
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'volume': '30',
'author': 'Wang',
'year': '2020',
'journal-title': 'Cell Res.'},
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'doi-asserted-by': 'publisher',
'first-page': '109',
'DOI': '10.1186/s13613-021-00904-7',
'article-title': 'High risk of patient self-inflicted lung injury in COVID-19 with '
'frequently encountered spontaneous breathing patterns: A computational '
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'volume': '11',
'author': 'Weaver',
'year': '2021',
'journal-title': 'Ann. Intensive Care'},
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'unstructured': 'World health organization (WHO) coronavirus disease 19 dashboard\n'
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