APRIL 27, 2020

High-dose chloroquine diphosphate not recommended for severe COVID-19, link between SARS-CoV-2 viral load in sputum and risk of COVID-19 progression

By Denise Baez
NEW YORK -- April 27, 2020 -- In today’s DG Alert, we cover the effect of high versus low doses of chloroquine diphosphate as adjunctive therapy for patients hospitalised with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and the link between SARS-CoV-2 viral load in sputum with risk of coronavirus disease 2019 (COVID-19) progression. 
Preliminary findings of a randomised study published in JAMA Network Open suggest that high doses of chloroquine diphosphate should not be used in critically ill patients with COVID-19 because of its potential safety hazards, especially when taken concurrently with azithromycin and oseltamivir. 
“In this phase 2b randomised clinical trial of 81 patients with COVID-19, an unplanned interim analysis recommended by an independent data safety and monitoring board found that a higher dosage of chloroquine diphosphate for 10 days was associated with more toxic effects and lethality, particularly affecting QTc interval prolongation,” wrote Mayla Gabriela Silva Borba, MD, Fundação de Medicina Tropical Dr Heitor Vieira Dourado, Manaus, Brazil, and colleagues. 
The authors noted that the limited sample size did not allow the study to show any benefit overall regarding treatment efficacy. The findings do not apply to patients with mild disease.
In the study, patients (mean age, 51.1 years; 75.3% were male) were randomised to receive chloroquine diphosphate 600 mg twice daily for 10 days (n = 41) or chloroquine diphosphate 450 mg twice daily on day 1 and once daily for 4 days (n = 40). All patients also received intravenous ceftriaxone 1 g twice daily for 7 days plus azithromycin 500 mg once daily for 5 days starting on day 0. 
Lethality until day 13 -- the primary endpoint -- was 39.0% in the high-dose group (16/41) and 15.0% in the low-dose group (6/40). Viral RNA was detected in 77.5% (31/40) of patients in the low-dose group and in 75.6% (31/41) of patients in high-dose group. 
Of the patients receiving high-dose chloroquine diphosphate, 18.9% experienced QTc interval >500 milliseconds compared with 11.1% of patients receiving low-dose chloroquine diphosphate. 
Two patients in the high-dose group experienced ventricular tachycardia before death, without torsade de pointes. This severe type of arrhythmia is usually facilitated when QTc interval is prolonged. 
“In a unique pandemic situation, health professionals have to choose between offering medical assistance and generating and reporting reliable data -- dichotomy that compromises the ability to generate high-quality evidence for clinical management,” the authors wrote. “However, global recommendations for COVID-19 are being made based on unpowered studies, and because of the chaotic urgency of the situation, drugs are being prescribed in a compassionate manner given the severity of the disease. Chloroquine diphosphate is a safe drug, used for more than 70 years to treat malaria. However, in the context of patients with severe COVID-19, our study raises enough red flags to stop the use of a high-dosage regimen because the risks of toxic effects overcame the benefits.”
Another study, published in Critical Care, found a positive association between sputum viral load and disease severity as well as risk of progression.
Xia Yu, MD, the First Affiliated Hospital, Hangzhou, China, and colleagues compared the baseline viral loads between 30 patients with severe COVID-19 and 62 patients with mild to moderate disease who were admitted from January 19, 2020, to March 19, 2020, at the First Affiliated Hospital of Zhejiang University. 
Patients with severe disease had significantly lower cycle threshold (Ct) values than patients with mild or moderate cases at admission (25 vs 28; P = 0.017), suggesting a higher viral load in the lower respiratory tract. 
Of the patients with mild to moderate COVID-19, 11 became severe during hospitalisation. Higher viral load was observed in sputum specimens from these patients compared with patients who did not become severely ill during hospitalisation (24 vs 29; P = 0.008). 
The Ct values of reverse transcriptase-polymerase chain reaction assays negatively correlated with the probability of progression to severe type in all the patients presenting with mild or moderate disease at admission.
“We found that the viral load of the sputum specimen in the lower respiratory tract tested at baseline is closely related to the severity of COVID-19,” the authors wrote. “More importantly, patients with a higher baseline viral load are more likely to become severe. This finding apparently justifies the concept that early antiviral treatment, if effective, would reduce the risk of progression and thereby the mortality, which has been demonstrated in influenza. In our study, sputum specimens were used, instead of nasopharyngeal and oropharyngeal swabs because it has been shown that samples from lower respiratory tract generally contain a higher level of viral load than nasopharyngeal and oropharyngeal swabs and acquiring swabs is uncomfortable for patients.”
SOURCE: JAMA Network Open, Critical Care