Is hydroxychloroquine beneficial for COVID-19 patients?

Abstract

The outbreak of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was first reported in December 2019. As similar cases rapidly emerged around the world1,2,3, the World Health Organization (WHO) declared a public health emergency of international concern on January 30, 2020 and pronounced the rapidly spreading coronavirus outbreak as a pandemic on March 11, 20204. The virus has reached almost all countries of the globe. As of June 3, 2020, the accumulated confirmed cases reached 6,479,405 with more than 383,013 deaths worldwide. The urgent and emergency care of COVID-19 patients calls for effective drugs, in addition to the beneficial effects of remdesivir5, to control the disease and halt the pandemic. hydroxychloroquine wiki


US FDA approved hydroxychloroquine (HCQ) and chloroquine (CQ) for COVID-19 as an Emergency Use Authorization (EUA) with cautions issued soon after

HCQ exerts strong immunomodulatory effects

Despite widespread clinical use of CQ and HCQ in the treatment of inflammatory rheumatic diseases and virus infection, the underlying therapeutic effects and cellular mechanisms of these drugs remain largely unknown. Various modes of action have been proposed to explain the therapeutic and/or adverse effects of CQ and HCQ in COVID-19 patients, although most of the evidence is based on in vitro studies. CQ is a potent inhibitor of autophagy20,21,22,23 and cell death24,25, affecting distinct cell function26,27 and survival28,29, and its derivative HCQ30 has similar properties inhibiting autophagy. In vitro experiments in tissue culture have shown that CQ and HCQ can increase endosomal pH, prevent virus-cell fusion, and interfere with glycosylation of the ACE2 receptor and thus the binding of the SARS-CoV-2 S protein to ACE231 (Fig. ). On the other hand, we have proposed that the strong anti-inflammatory capacity of CQ and HCQ, which prevents autoimmune flare-ups and organ damages32, plays a more important role in controlling SARS-CoV-2 infection. The possible mechanisms of the anti-inflammatory effects of CQ and HCQ are mainly related to preventing antigen processing and interrupting molecular pathways involved in immune activation, subsequently resulting in the reduction of pro-inflammatory cytokine secretion33,34.


Is hydroxychloroquine beneficial for COVID-19 patients?

Could HCQ and CQ have protective vascular effects in COVID-19 patients?

Vascular complications, including endothelium damage and vasculitis-like manifestations, are common traits in severe COVID-19 patients. In some patients vessel hyperplasia, vessel wall thickening, lumen stenosis accompanied by focal hemorrhage and thrombosis have been detected3. Conditions of severe vessel failure aggravate organ ischemia, tissue edema, and overall inflammation. This leads to the suggestion that SARS-CoV-2 may have a direct effect on endothelial cells (ECs), which also express ACE2 receptors. Such hypothesis is supported by findings showing that SARS-CoV-2 can indeed infect human blood vessel organoids50 and by post-mortem histological analysis of COVID-19 patient’s organs51 showing endothelitis and EC inflammatory cell death. These findings provide a strong rationale for the use of HCQ and CQ to alleviate these severe COVID-19 manifestations, since these drugs combine anti-inflammatory, anti-thrombosis21,52 and vascular protective effects21 (Fig. 2). We have previously shown that CQ has anti-angiogenic, tumor vessel normalizing properties in murine models of melanoma, without inducing EC death21. The EC effects induced by CQ included increased vessel barrier function, which alleviated tumor hypoxia. The vascular protective effects of HCQ and CQ, if validated, may be particularly relevant in patients with pre-existing diseases associated to vascular damage, like e.g. in diabetes, hypertension, and obesityhydroxychloroquine mechanism of action



Is hydroxychloroquine beneficial for COVID-19 patients?

Conclusion

Taken together, given the fast-increasing number of COVID-19 patients and the urgent need for effective and safe drugs in the clinic, CQ and HCQ have potential, but controversial, characteristics to combat pathological inflammation associated with COVID-19. The recommendation CQ and HCQ as a preventive medication for healthy and asymptomatic infected persons48, even for patients experiencing only mild symptoms in the early-stage of SARS-CoV-2 infection because of the immunosuppressive effects of the two drugs will diminish specific antiviral immunity, or as late stages therapeutic, still waits a proper double blind clinical trial. However, HCQ has been hypothesized to help controlling distinct effects of SARS-CoV-2 infection, as described above and compared to CQ, HCQ confers similar antiviral and anti-inflammatory effects while has fewer side effects, indicating HCQ is a more optimal selection for treating COVID-19. Importantly, when HCQ is used to treat COVID-19 patients, individual immune profiles should be thoroughly evaluated and considered. The above consideration offers a clear rational for a systematic evaluation of efficacy at the clinical level.hydroxychloroquine for arthritis


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