4.1 Current therapies
The most commonly one involves the use of hydroxychloroquine (HCQ) as the first-line therapy because of its anti-inflammatory and immunomodulatory effects (Hu et al., 2017). Based on the international guidelines, HCQ is reported to be utilized either alone or in combination with other drugs including, systemic corticosteroids, Tocilizumab (TCZ), macrolide Aazithromycin, antiviral Lopinavir/Ritonavir and anticoagulant Enoxaparin (Mehra et al., 2020; Rosenberg et al., 2020). However, the use of HCQ is lately recorded to have many restrictions due to increased risk of serious cardiac arrhythmias. Additionally, either HCQ or CQ is no longer authorized by FDA to treat COVID-19 (Joyce et al., 2013).
Moreover, current COVID-19 treatment protocol also recommends the use of oral anti-inflammatory steroids, however they may paradoxically exaggerate COVID-19-associated neutrophilia (Fukakusa et al., 2005). In addition, due to their local and systemic harmful adverse effects, steroids may be inappropriate drug of choice for vulnerable patients with pre-existing hypertension, diabetes, or cardiovascular diseases, which represent the most susceptible group to be infected with COVID-19 (Varga et al., 2020). That pushed clinicians to search for additional or alternative anti-inflammatory treatments that can efficiently control the neutrophilic component of COVID-19 apart from steroid related complications.
TCZ, a humanized monoclonal antibody acted by blocking IL-6 receptors, has been suggested for COVID-19 patients to suppress the inflammatory storm and minimize the mortality (Fu et al., 2020). However, some studies showed that TCZ may effectively reduce both fever and inflammatory markers, but with no satisfactory clinical outcomes inferred for the critically ill COVID-19 patients (Campochiaro et al., 2020; Dastan et al., 2020). As documented, this medication may also raise both blood pressure and lipid levels, which are considered the main risk factors exaggerating the severity in COVID-19 patients of cardiovascular (CV) diseases (Rao et al., 2015). Furthermore, anti-interleukin therapy is expected to worse the post-COVID-19 pulmonary fibrosis (George et al., 2020; Silva et al., 2020).
As regards azithromycin, various clinical evidences revealed that it could exert a great role against both Acute Respiratory Distress Syndrome (SARS) and Middle East Respiratory Syndrome (MERS), that prompted scientists to strongly suggest it as a potential treatment for COVID-19. Azithromycin was detected to possess anti-inflammatory and immunomodulating actions in addition to antiviral properties because of its ability to minimize the production of pro-inflammatory cytokines particularly IL-6 and TNF-α, noxious oxidative radicals as well as to improve T-helper functions. However, the preliminary studies have demonstrated that using azithromycin should be in caution due to its potential arrhythmogenic threat, especially in highly risk COVID-19 patients (Pani et al., 2020).
Moreover, provision should be also taken to mitigate the cardiac risk, especially after adding lopinavir/ritonavir into the current treatment protocol for COVID-19 (Gérard et al., 2020). Lopinavir acts as anti-HIV protease inhibitor via inhibiting the action of 3CLpro, thus disrupting the viral replication and release from host cells. Recentin-vitro study indicates that lopinavir can also exhibit antiviral activity against SARS-CoV-2, with which ritonavir can be added as a booster. However, there is a contradictory survey concluded that the use of lopinavir/ritonavir shows no significant reduction in the mortality rate within the severely ill COVID-19 patients (Owa and Owa, 2020).