QT prolongation associated with hydroxychloroquine and protease inhibitors in COVID-19.

WHAT IS KNOWN AND OBJECTIVE: Hydroxychloroquine and protease inhibitors were widely used as off-label treatment options for COVID-19 but the safety data of these drugs among the COVID-19 population are largely lacking. Drug-induced QTc prolongation is a known adverse reaction of hydroxychloroquine, especially during chronic treatment. However, when administered concurrently with potential pro-arrhythmic drugs such as protease inhibitors, the risk of QTc prolongation imposed on these patients is not known. We aim to investigate the incidence of QTc prolongation events and potential factors associated with its occurrence in COVID-19 population. METHODS: We included 446 SARS-CoV-2 RT-PCR-positive patients taking at least one treatment drug for COVID-19 within a period of one month (March-April 2020). In addition to COVID-19-related treatment (HCQ/PI), concomitant drugs with risks of QTc prolongation were considered. We defined QTc prolongation as QTc interval of ≥470 ms in postpubertal males, and ≥480 ms in postpubertal females. RESULTS AND DISCUSSION: QTc prolongation events occurred in 28/446 (6.3%) patients with an incidence rate of 1 case per 100 person-days. A total of 26/28 (93%) patients who had prolonged QTc intervals received at least two pro-QT drugs. Multivariate analysis showed that HCQ and PI combination therapy had five times higher odds of QTc prolongation as compared to HCQ-only therapy after controlling for age, cardiovascular disease, SIRS and the use of concurrent QTc-prolonging agents besides HCQ and/or PI (OR 5.2; 95% CI, 1.11-24.49; p = 0.036). Independent of drug therapy, presence of SIRS resulted in four times higher odds of QTc prolongation (OR 4.3; 95% CI, 1.66-11.06; p = 0.003). In HCQ-PI combination group, having concomitant pro-QT drugs led to four times higher odds of QTc prolongation (OR 3.8; 95% CI, 1.53-9.73; p = 0.004). Four patients who had prolonged QTc intervals died but none were cardiac-related deaths. WHAT IS NEW AND CONCLUSION: In our cohort, hydroxychloroquine monotherapy had low potential to increase QTc intervals. However, when given concurrently with protease inhibitors which have possible or conditional risk, the odds of QTc prolongation increased fivefold. Interestingly, independent of drug therapy, the presence of systemic inflammatory response syndrome (SIRS) resulted in four times higher odds of QTc prolongation, leading to the postulation that some QTc events seen in COVID-19 patients may be due to the disease itself. ECG monitoring should be continued for at least a week from the initiation of treatment.

Clinical Characteristics and Risk Factors for Severity of COVID-19 Infections in Malaysia (preprint)

Background: COVID-19 emerged as a major public health outbreak in China in late 2019. Malaysia reported its first imported case on 25 January 2020, and adopted a policy of extensive contact tracing and hospitalizing of all patients, regardless of severity. We describe clinical characteristics of COVID-19 patients nationwide and determine the risk factors associated with disease severity.Method: Clinical records of all RT-PCR confirmed COVID-19 patients admitted to 18 designated hospitals in Malaysia between 1 February and 30 April 2020 with complete outcomes were retrieved. Epidemiological history, co-morbidities, clinical features, investigations, management and complications were captured using REDCap database. Variables were compared among patients with mild and severe diseases. Univariate and multivariate regression analyses were used to identify determinants for disease severity.Findings:The sample comprised of 5889 cases (median age 34 years, male 71·7%). Majority were mild (92%) and 3·3% required intensive care with 80% admitted within the first 5 days. Older age (> 51 years), fever, cough, diarrhoea, breathlessness, tachypnoea, abnormal chest radiographs and high serum CRP (≥5mg/dL) on admission were significant determinants for disease severity (p < 0·05). The case fatality rate was 1·2% and the three commonest complications were liver injuries (6·7%), kidney injuries (4%), and acute respiratory distress syndrome (2·3%).Interpretations: Lower case fatality rate was contributed by young patients with mild presenting COVID-19 and early hospitalisation. Abnormal chest radiographic findings in symptomatic elderly with tachypnoea require close monitoring in first 5 days to detect early deterioration.Funding Statement: Supported by NIH, MalaysiaDeclaration of Interests: None to declare.Ethics Approval Statement: The study was registered with the National Medical Research Register (NMRR-20-580- 54339) and approved by the Medical Research and Ethics Committee, Ministry of Health, Malaysia (KKM/NIHSEC/P20-706).

Clinical characteristics and risk factors for severe COVID-19 infections in Malaysia: A nationwide observational study.

BACKGROUND: COVID-19 emerged as a major public health outbreak in late 2019. Malaysia reported its first imported case on 25th January 2020, and adopted a policy of extensive contact tracing and hospitalising of all cases. We describe the clinical characteristics of COVID-19 cases nationwide and determine the risk factors associated with disease severity. METHOD: Clinical records of all RT-PCR confirmed COVID-19 cases aged ≥12 years admitted to 18 designated hospitals in Malaysia between 1st February and 30th May 2020 with complete outcomes were retrieved. Epidemiological history, co-morbidities, clinical features, investigations, management and complications were captured using REDCap database. Variables were compared between mild and severe diseases. Univariate and multivariate regression were used to identify determinants for disease severity. FINDINGS: The sample comprised of 5889 cases (median age 34 years, male 71.7%). Majority were mild (92%), and 3.3% required intensive care, with 80% admitted within the first five days. Older age (≥51 years), underlying chronic kidney disease and chronic pulmonary disease, fever, cough, diarrhoea, breathlessness, tachypnoea, abnormal chest radiographs and high serum CRP (≥5 mg/dL) on admission were significant determinants for severity (p<0.05). The case fatality rate was 1.2%, and the three commonest complications were liver injuries (6.7%), kidney injuries (4%), and acute respiratory distress syndrome (2.3%). INTERPRETATIONS: Lower case fatality rate was possibly contributed by young cases with mild diseases and early hospitalisation. Abnormal chest radiographic findings in elderly with tachypnoea require close monitoring in the first five days to detect early deterioration.