Prospective on the treatment/management of COVID-19 illness
Treatment of COVID19 illness should be customized based on the stage of infection and the health conditions. The early stage of virus infection involves viral replication resulting in tissue damage and immune system activation. At this stage, the body relies on the immune system to combat virus replication. Thus, antiviral treatment would be a promising avenue in addition to non-immunosuppressive pain and fever management drugs, such as acetaminophen.
For mild infection, the treatment should include antiviral drugs and moderate anti-inflammatory drugs. Auranofin is a useful anti-inflammatory drug that reduces cytokine production and stimulates cell-mediated immunity (Walz, DiMartino, Griswold, Intoccia & Flanagan, 1983). It is a gold salt used in treating inflammatory arthritis and has antiviral activity (Roder & Thomson, 2015). Targeting specific, prominent cytokines in COVID-19 disease represents another method of controlling the acute inflammation. Several cytokine inhibitors could be useful in treating acute inflammation during severe COVID-19 infection. The cytokine inhibitors include: 1) Tumour necrosis factor (TNF)-α inhibitors (monoclonal antibodies infliximab, adalimumab, the TNF-α-receptor fusion protein etanercept). 2) the interleukin (IL)-1 inhibitor (anakinra) (Doan & Massarotti, 2005). 3) IL1β inhibitors (rilonacept and monoclonal antibodies canakinumab and gevokizumab) (Peiro, Lorenzo, Carraro & Sanchez-Ferrer, 2017). 4) IL6 inhibitor (tocilizumab), a humanized monoclonal antibody specific for the IL-6 receptor (IL-6R) (Hennigan & Kavanaugh, 2008). Since children experience such mild COVID-19 symptoms, the antiviral and pain management drugs can be used even at the mild infection.
The severe or late stage of COVID-19 illness involves a devastating inflammatory lung disorder due to cytokine storm that is associated with multiple organ dysfunction leading to high mortality. Therefore, targeting prominent cytokines like TNF-α, IL-6 could be useful. The malfunction of ACE2 due to SARS-COV-2 infection leads to accumulation of ANG II in the blood, especially in older men and patients with metabolic syndromes. Increasing ACE and decreased ACE2 activity in human lung epithelial cells contribute to lung injury (Wosten-van Asperen et al., 2011; Zhang et al., 2015). A very recent study described the transcriptional signature of the SARS-COV-2 infection showing that infection increased ACE expression and decreased ACE2 (Daniel Blanco-Melo & https://doi.org/10.1101/2020.03.24.004655). Thus, treatment with ACE2-activating compounds could be helpful to attenuate lung injury, hypertension, and diabetic kidney disease during the infection (some of these activators are mentioned above). A recombinant human ACE2 (GSK2586881) was used in phase IIa of the clinical trial to treat acute respiratory disorder syndrome. The use of twice-daily doses of GSK2586881 infusion resulted in a rapid decrease in plasma Ang II levels and an increase in Ang 1-7 and Ang 1-5 levels, as well as a trend towards a decrease in plasma IL-6 concentrations (Khan et al., 2017). Such treatment could be beneficial to COVID-19 patients at severe stage of disease. IL-6 concentrations have especially been noticed to be elevated at this stage of infection.
CytoDyn’s, the manufacturer of leronlimab (A humanized IgG4 mAb that antagonist CCR5) claims that their clinical trial data from cancer patients indicate this mAb can block Treg and macrophages that translate into an immunomodulatory response. They also claim that in a pilot study at a New York City hospital, some of the severally ill COVID-19 patients responded positively after given leronlimab. The molecule reduces cytokine storm by lowering IL-6 and TNF-a. It also imparts immune restoration in the CD8+ T lymphocytes (2020, April 9.; 2020.). The manufacturer is working with US-FDA to initiate a clinical trial of eronlimab to treat COVID-19 patients. In Table 1 , we included all ongoing trials related to therapeutic intervention against COVID-19 that have completed recruiting, are currently recruiting, or have yet to start recruiting patients. Hydroxychloroquine/ Chloroquine, in combination with Azithromycin is included in most of the trials. While Azithromycin is an antibacterial drug having anti-inflammatory actions, Hydroxychloroquine enters the lysosomes of malaria parasites, inhibits their ability of hemoglobin hydrolysis, and blocks their replication cycle (Fox, 1993). It also reduces the inflammatory response of immune cells by interfering with the dimerization of a and ß chain of MHC II complexes. It is likely that Hydroxychloroquine blocks fusion and entry of SARS-CoV and SARS-CoV-2 by raising the pH of endosomes (Vincent et al., 2005). It also altered the glycosylation pattern of ACE2, thereby it may reduce the binding affinity of SARS-CoV-2 with ACE-2, the primary receptor of viral cell entry (Wang et al., 2020b). Most of the other drugs that are at different stages of the trial are antiviral with the established mechanism of action against different RNA viruses, or are immunomodulatory agents mainly used to suppress the cytokine storm observed in most of the critically ill patients. Pulmonary edema due to inflammatory exudation is a joint presentation of critically ill patients of COVID-19 (Zhang et al., 2020b). Vascular endothelial growth factors (VEGFs) are a potent inducer of vascular permeability (Bates, 2010). Bevacizumab, a monoclonal antibody binds to VEGF to prevent angiogenesis. To prevent Pulmonary edema in severally ill patients, Bevacizumab may be a viable option and is considered in clinical trials. Tetrandrine isolated from traditional herbs from China has anti-viral effects against Human Coronavirus OC43 (Kim et al., 2019), and is used in trials to treat COVID-19 patients.