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.