The unfinished story of hydroxychloroquine in COVID-19: the
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Uncontrolled inflammation, partly related to activated macrophages, is widely recognized as an independent cause of clinical deterioration and mortality in hospitalised COVID-19 patients. Following the results of the RECOVERY trial and of an additional meta-analysis, corticosteroids are now recommended as a standard of care for hospitalized patients with severe and critical COVID-19. Importantly, the benefit of this anti-inflammatory intervention has been observed with a low dose of dexamethasone, while observational studies using higher dosage of corticosteroids have not reported any favourable effect on mortality.

The observation that early HCQ treatment after admission at low dosage (2400?mg in total) is associated with lower risk of admission in ICU coincides with large observational studies showing a lower mortality rate in patients exposed to HCQ therapy compared to no or other treatment. Of note, in all these studies and in contrast to the RECOVERY trial, low doses of HCQ (less than 2.5 gr. in total) were used, often soon after admission. Another recent large cohort study of patients on low-dose HCQ for inflammatory disorders reported an association between chronic HCQ use and reduced mortality following SARS-CoV-2 infection.

HCQ has been used as anti-inflammatory drug for decades as therapy of inflammatory disorders and its impact on inflammatory responses is well documented. HCQ inhibits the production of the pro-inflammatory cytokines interleukin (IL)-6, TNF-alpha and IL-1-beta by activated macrophages, which are notoriously associated with COVID-19 severity and also the production of chemotactic cytokines involved in the recruitment of pro-inflammatory cells in the lungs. In line with this, an Italian study suggests that the benefit of HCQ was restricted to patients with elevated C-reactive protein levels.

Thrombotic events are another well recognized complication of severe COVID-19 and the presence of lupus anticoagulant has been reported in hospitalised COVID-19. HCQ therapy has been associated with a decrease of lupus anticoagulant levels as well as of platelet activation and thrombotic events in lupus patients. Interestingly, B cell abnormalities similar to those reported in autoimmune disease such as active lupus were reported in patients with severe COVID-19.

HCQ has no antiviral activity in vivo against SARS-CoV-2 as shown in pre-clinical models such as Syrian hamsters, non-human primates and human lung cells, and should therefore not be used as antiviral therapy in COVID-19. However, to further understand the positive effects observed in large observational studies that used HCQ off-label in the early months of the pandemic, the hypothesis of an anti-inflammatory action should not be discarded.

Researchers suggest that ongoing trials evaluating HCQ specifically look at its effect on inflammatory parameters with add-on studies if necessary. In the same line, ongoing trials are investigating colchicine to prevent hospitalisation in SARS-CoV-2 infected subjects, and the rationale is based on anti-inflammatory properties, that are partly shared by HCQ, i.e. inhibition of pro-inflammatory cytokines and chemotaxis of pro-inflammatory cells.