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Circ Arrhythm Electrophysiol ; 13(11): e008937, 2020 11.
Article in English | MEDLINE | ID: covidwho-945067


BACKGROUND: The severe acute respiratory syndrome coronavirus 2 (SARs-CoV-2) has resulted in a global pandemic. Hydroxychloroquine±azithromycin have been widely used to treat coronavirus disease 2019 (COVID-19) despite a paucity of evidence regarding efficacy. The incidence of torsade de pointes remains unknown. Widespread use of these medications forced overwhelmed health care systems to search for ways to effectively monitor these patients while simultaneously trying to minimize health care provider exposure and use of personal protective equipment. METHODS: Patients with COVID-19 positive who received hydroxychloroquine±azithromycin across 13 hospitals between March 1 and April 15 were included in this study. A comprehensive search of the electronic medical records was performed using a proprietary python script to identify any mention of QT prolongation, ventricular tachy-arrhythmias and cardiac arrest. RESULTS: The primary outcome of torsade de pointes was observed in 1 (0.015%) out of 6476 hospitalized patients with COVID-19 receiving hydroxychloroquine±azithromycin. Sixty-seven (1.03%) had hydroxychloroquine±azithromycin held or discontinued due to an average QT prolongation of 60.5±40.5 ms from a baseline QTc of 473.7±35.9 ms to a peak QTc of 532.6±31.6 ms. Of these patients, hydroxychloroquine±azithromycin were discontinued in 58 patients (86.6%), while one or more doses of therapy were held in the remaining nine (13.4%). A simplified approach to monitoring for QT prolongation and arrythmia was implemented on April 5. There were no deaths related to the medications with the simplified monitoring approach and health care provider exposure was reduced. CONCLUSIONS: The risk of torsade de pointes is low in hospitalized patients with COVID-19 receiving hydroxychloroquine±azithromycin therapy.

Antiviral Agents/adverse effects , Azithromycin/adverse effects , COVID-19/drug therapy , Delivery of Health Care , Heart Conduction System/drug effects , Hydroxychloroquine/adverse effects , Torsades de Pointes/chemically induced , Action Potentials/drug effects , Adolescent , Adult , Aged , Antiviral Agents/administration & dosage , Azithromycin/administration & dosage , COVID-19/diagnosis , Cardiotoxicity , Female , Heart Conduction System/physiopathology , Heart Rate/drug effects , Hospitalization , Humans , Hydroxychloroquine/administration & dosage , Male , Middle Aged , New York , Patient Safety , Retrospective Studies , Risk Assessment , Risk Factors , Time Factors , Torsades de Pointes/diagnosis , Torsades de Pointes/physiopathology , Treatment Outcome , Young Adult
Circ Arrhythm Electrophysiol ; 13(8): e008627, 2020 08.
Article in English | MEDLINE | ID: covidwho-641777


BACKGROUND: During acute infections, the risk of malignant ventricular arrhythmias is increased, partly because of a higher propensity to develop QTc prolongation. Although it is generally believed that QTc changes almost exclusively result from concomitant treatment with QT-prolonging antimicrobials, direct effects of inflammatory cytokines on ventricular repolarization are increasingly recognized. We hypothesized that systemic inflammation per se can significantly prolong QTc during acute infections, via cytokine-mediated changes in K+ channel expression. METHODS: We evaluated (1) the frequency of QTc prolongation and its association with inflammatory markers, in patients with different types of acute infections, during active disease and remission; (2) the prevalence of acute infections in a cohort of consecutive patients with Torsades de Pointes; (3) the relationship between K+ channel mRNA levels in ventricles and peripheral blood mononuclear cells and their changes in patients with acute infection over time. RESULTS: In patients with acute infections, regardless of concomitant QT-prolonging antimicrobial treatments, QTc was significantly prolonged but rapidly normalized in parallel to CRP (C-reactive protein) and cytokine level reduction. Consistently in the Torsades de Pointes cohort, concomitant acute infections were highly prevalent (30%), despite only a minority (25%) of these cases were treated with QT-prolonging antimicrobials. KCNJ2 K+ channel expression in peripheral blood mononuclear cell, which strongly correlated to that in ventricles, inversely associated to CRP and IL (interleukin)-1 changes in acute infection patients. CONCLUSIONS: During acute infections, systemic inflammation rapidly induces cytokine-mediated ventricular electrical remodeling and significant QTc prolongation, regardless concomitant antimicrobial therapy. Although transient, these changes may significantly increase the risk of life-threatening ventricular arrhythmia in these patients. It is timely and warranted to transpose these findings to the current coronavirus disease 2019 (COVID-19) pandemic, in which both increased amounts of circulating cytokines and cardiac arrhythmias are demonstrated along with a frequent concomitant treatment with several QT-prolonging drugs. Graphic Abstract: A graphic abstract is available for this article.

Communicable Diseases/metabolism , Cytokines/metabolism , Heart Arrest/metabolism , Heart Rate , Heart Ventricles/metabolism , Inflammation/metabolism , Leukocytes, Mononuclear/metabolism , Potassium Channels, Inwardly Rectifying/metabolism , Torsades de Pointes/metabolism , Action Potentials , Acute Disease , Adult , Aged , Aged, 80 and over , Anti-Infective Agents/adverse effects , Communicable Diseases/drug therapy , Communicable Diseases/epidemiology , Communicable Diseases/physiopathology , Female , Heart Arrest/epidemiology , Heart Arrest/physiopathology , Heart Rate/drug effects , Heart Ventricles/drug effects , Heart Ventricles/physiopathology , Humans , Inflammation/epidemiology , Inflammation/physiopathology , Leukocytes, Mononuclear/drug effects , Male , Middle Aged , Potassium Channels, Inwardly Rectifying/genetics , Prevalence , Risk Factors , Signal Transduction , Time Factors , Torsades de Pointes/epidemiology , Torsades de Pointes/physiopathology , Young Adult
Infection ; 48(5): 779-782, 2020 Oct.
Article in English | MEDLINE | ID: covidwho-276775


At present, there is no definitive antiviral treatment for coronavirus disease 2019 (COVID-19). We describe our early experience with remdesivir in four critically ill COVID-19 patients. Patients received a 200 mg loading dose, followed by 100 mg daily intravenously for up to 10 days. All patients had been previously treated with other antivirals before remdesivir initiation. One patient experienced a torsade de pointes requiring cardiac resuscitation and one died due to multiple organ failure. Three patients showed biochemical signs of liver injury. Lymphocyte count increased in all patients soon after remdesivir initiation. Nasal swab SARS-CoV-2 RNA became negative in three of four patients after 3 days of therapy. We observed an in vivo virological effect of remdesivir in four critically ill, COVID-19 patients, coupled with a significant burden of adverse events. Although limited by the low number of subjects studied, our preliminary experience may be relevant for clinicians treating COVID-19.

Adenosine Monophosphate/analogs & derivatives , Alanine/analogs & derivatives , Antiviral Agents/administration & dosage , Betacoronavirus/drug effects , Coronavirus Infections/drug therapy , Pneumonia, Viral/drug therapy , RNA, Viral/blood , Adenosine Monophosphate/administration & dosage , Adenosine Monophosphate/adverse effects , Alanine/administration & dosage , Alanine/adverse effects , Antiviral Agents/adverse effects , Betacoronavirus/immunology , COVID-19 , Chemical and Drug Induced Liver Injury/diagnosis , Chemical and Drug Induced Liver Injury/etiology , Chemical and Drug Induced Liver Injury/physiopathology , Chemical and Drug Induced Liver Injury/virology , Convalescence , Coronavirus Infections/virology , Critical Illness , Darunavir/administration & dosage , Darunavir/adverse effects , Drug Administration Schedule , Drug Combinations , Fatal Outcome , Humans , Hydroxychloroquine/administration & dosage , Hydroxychloroquine/adverse effects , Lopinavir/administration & dosage , Lopinavir/adverse effects , Multiple Organ Failure/chemically induced , Multiple Organ Failure/diagnosis , Multiple Organ Failure/physiopathology , Multiple Organ Failure/virology , Pandemics , Pneumonia, Viral/virology , Ritonavir/administration & dosage , Ritonavir/adverse effects , SARS-CoV-2 , Torsades de Pointes/chemically induced , Torsades de Pointes/diagnosis , Torsades de Pointes/physiopathology , Torsades de Pointes/virology