Association of In-Hospital Antimalarial–Macrolide Therapy With 3–6-Month Cardiac Electrophysiological Outcomes in Survivors of Severe COVID-19: A Matched Retrospective Cohort Study

DOI record: { "DOI": "10.21203/rs.3.rs-11342547/v1", "URL": "http://dx.doi.org/10.21203/rs.3.rs-11342547/v1", "abstract": "<title>Abstract</title>\n <p>\n <bold>Background:</bold>\n During the early phase of the COVID-19 pandemic, antimalarial agents and macrolide antibiotics were widely used because of their proposed antiviral and immunomodulatory effects. However, their potential to prolong ventricular repolarization and increase the risk of arrhythmias raised concerns about their cardiac electrophysiological effects. Available evidence has predominantly focused on electrophysiological effects during acute treatment, whereas post-recovery outcomes remain less well characterized.\n <bold>Objectives:</bold>\n To evaluate cardiac electrophysiological outcomes 3–6 months after hospitalization for severe COVID-19 pneumonia and compare these outcomes according to in-hospital exposure to combined antimalarial–macrolide therapy.\n <bold>Methods:</bold>\n We conducted a retrospective matched cohort study including adults hospitalized for severe COVID-19 pneumonia between March and June 2020. Patients exposed to hydroxychloroquine or chloroquine in combination with azithromycin or clarithromycin were matched 1:1 by sex and age (±3 years) with patients who did not receive either drug class. Cardiovascular assessment 3–6 months after hospitalization included a 12-lead electrocardiogram and 24-hour Holter monitoring. QTc interval, conduction abnormalities, arrhythmias, and heart rate variability (HRV) were evaluated.\n <bold>Results:</bold>\n Eighty-six patients were included (43 exposed and 43 unexposed). Follow-up QTc intervals were similar between groups (420.0 vs. 423.1 ms;\n <italic>p</italic>\n =0.762), and QTc prolongation was uncommon. No malignant ventricular arrhythmias or clinically significant conduction abnormalities were identified. Exposed patients had a higher prevalence of sinus bradycardia, a lower resting heart rate on electrocardiography, and higher HRV as assessed by the standard deviation of normal-to-normal intervals (SDNN). However, unexposed patients exhibited a greater inflammatory burden during hospitalization, more frequent intensive care unit admissions, and longer hospital stays.\n <bold>Conclusion:</bold>\n In this cohort of survivors of severe COVID-19, short-term in-hospital exposure to combined antimalarial–macrolide therapy was not associated with persistent QTc prolongation or clinically significant electrophysiological abnormalities at 3–6 months. Differences in heart rate and HRV should be interpreted with caution, given potential residual confounding due to acute disease severity.\n </p>", "accepted": { "date-parts": [ [ 2026, 10, 12 ] ] }, "author": [ { "affiliation": [ { "name": "Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán" } ], "family": "Sharma", "given": "Shubhang Sharma", "role": [ { "role": "author", "vocabulary": "crossref" } ], "sequence": "first" }, { "affiliation": [ { "name": "Universidad Nacional Autónoma de México" } ], "family": "Ramírez-González", "given": "Julia", "role": [ { "role": "author", "vocabulary": "crossref" } ], "sequence": "additional" }, { "affiliation": [ { "name": "Universidad Nacional Autónoma de México" } ], "family": "Chávez-Fernández", "given": "Raúl", "role": [ { "role": "author", "vocabulary": "crossref" } ], "sequence": "additional" }, { "affiliation": [ { "name": "Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán" } ], "family": "Galindo-Uribe", "given": "Jaime", "role": [ { "role": "author", "vocabulary": "crossref" } ], "sequence": "additional" }, { "affiliation": [ { "name": "Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán" } ], "family": "Rivera-Figueroa", "given": "Jaime", "role": [ { "role": "author", "vocabulary": "crossref" } ], "sequence": "additional" }, { "affiliation": [ { "name": "Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán" } ], "family": "Payro-Ramírez", "given": "Gerardo", "role": [ { "role": "author", "vocabulary": "crossref" } ], "sequence": "additional" }, { "affiliation": [ { "name": "Universidad Nacional Autónoma de México" } ], "family": "Hernández", "given": "Alejandra", "role": [ { "role": "author", "vocabulary": "crossref" } ], "sequence": "additional" }, { "affiliation": [ { "name": "Universidad Nacional Autónoma de México" } ], "family": "Ramos-Pérez", "given": "Fátima", "role": [ { "role": "author", "vocabulary": "crossref" } ], "sequence": "additional" }, { "affiliation": [ { "name": "Universidad Nacional Autónoma de México" } ], "family": "Hernández-Franco", "given": "Berenice", "role": [ { "role": "author", "vocabulary": "crossref" } ], "sequence": "additional" }, { "affiliation": [ { "name": "Universidad Nacional Autónoma de México" } ], "family": "Torres-Partida", "given": "Diana", "role": [ { "role": "author", "vocabulary": "crossref" } ], "sequence": "additional" }, { "affiliation": [ { "name": "Universidad Nacional Autónoma de México" } ], "family": "Pacheco-Domínguez", "given": "Reyna", "role": [ { "role": "author", "vocabulary": "crossref" } ], "sequence": "additional" } ], "container-title": [], "content-domain": { "crossmark-restriction": false, "domain": [] }, "created": { "date-parts": [ [ 2026, 10, 14 ] ], "date-time": "2026-10-14T09:30:02Z", "timestamp": 1791970202000 }, "deposited": { "date-parts": [ [ 2026, 10, 16 ] ], "date-time": "2026-10-16T05:25:22Z", "timestamp": 1792128322000 }, "group-title": "In Review", "indexed": { "date-parts": [ [ 2026, 10, 16 ] ], "date-time": "2026-10-16T05:49:21Z", "timestamp": 1792129761441, "version": "4.4.0" }, "institution": [ { "name": "Research Square" } ], "is-referenced-by-count": 0, "issued": { "date-parts": [ [ 2026, 10, 14 ] ] }, "license": [ { "URL": "https://creativecommons.org/licenses/by/4.0/", "content-version": "unspecified", "delay-in-days": 0, "start": { "date-parts": [ [ 2026, 10, 14 ] ], "date-time": "2026-10-14T00:00:00Z", "timestamp": 1791936000000 } } ], "link": [ { "URL": "https://www.researchsquare.com/article/rs-11342547/v1", "content-type": "text/html", "content-version": "vor", "intended-application": "text-mining" }, { "URL": "https://www.researchsquare.com/article/rs-11342547/v1.html", "content-type": "unspecified", "content-version": "vor", "intended-application": "similarity-checking" } ], "member": "297", "original-title": [], "posted": { "date-parts": [ [ 2026, 10, 14 ] ] }, "prefix": "10.21203", "published": { "date-parts": [ [ 2026, 10, 14 ] ] }, "publisher": "Springer Science and Business Media LLC", "reference": [ { "DOI": "10.1186/1743-422X-2-69", "article-title": "Chloroquine is a potent inhibitor of SARS coronavirus infection and spread", "author": "Vincent MJ", "doi-asserted-by": "publisher", "first-page": "22", "journal-title": "Virol. 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