Clinical evidence
Overall, whilst tetracycline’s direct anti-viral activity against SARS-CoV2 is not yet strongly supported by experimental data, their above described beneficial mechanisms in ARDS can be directly translated to COVID-19-induced ARDS. Furthermore, our hypothesis of the therapeutic potential of repurposing tetracyclines for COVID-19 treatment is getting the support of the clinical reports published up to date. These are scarce, but positive and promising. For example, rapid clinical improvement was reported in 4 high risk COVID-19 patients after doxycycline treatment (Yates et al., 2020). A multicenter prospective observational study including 38 COVID-19 patients treated with tetracyclines reported a remarkable resolution of mild symptoms within the first week of treatment (Gironi et al., 2020). In a larger study, early treatment with doxycycline in 89 high-risk COVID-19 patients was associated with early clinical recovery, decreased hospitalization and decreased mortality (Alam et al., 2020). Furthermore, doxycycline has been used for COVID-19 treatment in combination with hydroxychloroquine or lopinavir, reporting an overall 4.2% fatality rate vs 27% and 23% for monotherapy, respectively (Cag et al., 2021). In another study, in combination with ivermectin, doxycycline helped to reduce disease progression and the time to recovery in patients with severe COVID-19. The mortality rate was also reduced from 22.72% to 0% compared to standard care with azithromycin (Hashim et al., 2020). Altogether, we believe that these reports provide sufficient clinical evidence to support the inclusion of tetracyclines in ARDS and COVID-19 therapeutic management.