Dear Editor,
I read with interest the retrospective cohort study published in the International Journal of Infectious Diseases by Arshad et al., who report that treatment with Hydroxychloroquine (HCQ) alone and in combination with Azithromycin was associated with a reduction in COVID-19 associated mortality. I congratulate the authors, but I have noted a few limitations in the study, which may constrain the application of the study's results in routine clinical practice.
The authors utilized a hospital-based protocol for administration of HCQ; 82% of their patients received HCQ within the first 24 h of admission, and 91% within the first 48 h of admission. However, there is no mention of the duration between the onset of symptoms and the administration of the first dose of HCQ. While considering HCQ as a treatment strategy for COVID-19, the timing of administration of HCQ in relation to the onset of symptoms is an important factor to consider. Firstly, the manifestations of Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) infection are related to viral replication in the respiratory system in the initial stages and later multi-organ manifestations are related to the immune response of the body, although active viral replication in later stages of the disease cannot be ruled out conclusively. Accordingly, Anti-virals are supposedly effective in the early stages, while immunomodulatory therapy is effective in later and severe disease stages (Cao, 2020, Sanders et al., 2020). It is notable that in the present study, concomitant use of steroids in patients receiving Hydroxychloroquine was more than the non-treated group. So, in the absence of this critical information about the duration between the onset of symptoms and administration of the first dose of HCQ, it seems difficult to interpret whether the positive effects were due to HCQ or steroids. HCQ is touted for the treatment of COVID-19 primarily based on its anti-viral properties; thus, the timing of administration becomes crucial for a meaningful assessment of study results.
Secondly, HCQ concentrates in the lungs after initial doses (Schrezenmeier and Dörner, 2020), and that is the time when its effect is supposed to be maximized. Administration of HCQ late in the course of the disease may not be that effective.
Thirdly, they utilized maximal modified Sequential Organ Failure Assessment (mSOFA) scores for classifying patient disease severity. It has been recently shown that this score is not accurate for predicting the severity of disease in COVID-19 patients (Ferreira et al., 2020).
Fourthly, a QTc interval-based algorithm specifically designed to ensure the safe use of Hydroxychloroquine was utilized. This is a very safe practice, but it might have resulted in the exclusion of high cardiac risk patients. COVID-19 is a multisystem disease, and the disease itself promotes a pro-arrhythmic milieu with prolonged QT intervals at baseline (Ferner and Aronson, 2020, Malviya, 2020). Risk assessment of HCQ therapy is not complete if such patients are excluded.
Finally, the mechanism of action of HCQ is a part of its broad anti-viral and immunomodulatory properties; no specific pharmacologic actions are described for SARS-CoV-2 infection (Yao et al., 2020, Savarino et al., 2003). The majority of recent publications on HCQ for treating COVID-19 are limited by poor methodological quality and by and large have shown negative or neutral results (Rubin et al., 2020, Alexander et al., 2020). Whether HCQ as an initial anti-viral agent prevents the progression to severe disease is not clearly known. In severe disease with multisystem involvement and the pro-arrhythmic milieu of COVID, HCQ's pharmacokinetics is not well studied; consequently, its safety cannot be commented upon in severe disease.
Before this drug is routinely recommended, there is absolutely no substitute for properly conducted randomized trials, for such drug interventions have public health importance.
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References
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