COVID-19: The possible medical strategies

In late 2019, a pandemic crisis started in Wuhan, China, swept the whole world. The disease is caused by the SARS-CoV-19 virus that belongs to the corona family of viruses. The virus mainly caused failure of respiration, and led to many deaths worldwide. The main focus of research and medicine is to fi nd more about the virus, as well as the development of eff ective preventive and therapeutic measures. While many trials and opinions have been published, which might support or contradict each other, this article tries to provide a simplifi ed viewpoint about the disease. We highly recommend the therapeutic strategies to include drug combinations that can target the pathogenesis at many levels. For example, a combination of an eff ective anti-viral Remdesivir, soulable ACE2, and an immune modulator.

• It replicates its genetic material through RNAdependent RNA polymerase • It translates its proteins in cell ribosomes • Newly synthesized RNA and proteins assemble and spread to new cells as the infected cells die [1].
What happens in the lungs?
The infection stimulates the resident macrophages and immune cells to start a call of in lammation. This involves the secretion of important mediators; IL1β, IL6 & TNFα, and increased vascular permeability. This leads to the following:

Abstract
In late 2019, a pandemic crisis started in Wuhan, China, swept the whole world. The disease is caused by the SARS-CoV-19 virus that belongs to the corona family of viruses. The virus mainly caused failure of respiration, and led to many deaths worldwide. The main focus of research and medicine is to fi nd more about the virus, as well as the development of eff ective preventive and therapeutic measures. While many trials and opinions have been published, which might support or contradict each other, this article tries to provide a simplifi ed viewpoint about the disease. We highly recommend the therapeutic strategies to include drug combinations that can target the pathogenesis at many levels. For example, a combination of an eff ective anti-viral Remdesivir, soulable ACE2, and an immune modulator. However, throat swab and PCR or genetic sequancing are the reliable con irmatory tests [1].
As ACE2 is mainly expressed in lungs, kidneys, gastrointestinal tract (GIT), and blood vessels, this might explain some of the COVID-19 induced clinical manifestaions, such as thrombo-embolism, dementia symptoms, renal and GIT viral localizations, thus the expected modes of transmission. Such manifestations are to be well considered within the therapeutic strategy, for example, the application of adequate anticoagulation [2]. https://mohammedshehatta1.wixsite.com/website/post/ sars-cov-2-covid-19

Translational pathophysiology
• SARS-CoV-2 infects its target cells through the attachment to cell surface receptor enzyme molecules, ACE2.
• The virus attachment to the receptor blocks its protective roles, aggrevating tissue damage.
• Some important drugs that are widely used in our current medical practice, such as ibuprofen and angiotensin receptor blockers (ARBs), upregulates ACE2 expression, which might favor COVID-19 infection!! [3,4]. However, increased ACE2 expression might favor its protective functions, attenuating the disease manifestations!!

Possible strategies
Prevention is the best strategy • Clinical trials are conducted to test the ef icacy of those drugs against SARS-CoV-2.

• Remdesivir & Ciclesonide are examples
• Remdesivir showed the most satisfactory results and is either approved or under approval as the sole reliable anti-COVID-19 therapy, where its application to severely ill COVID-19 patients resulted in clinical improvement in 36 of 53 patients (68%) [5].

Support against respiratory failure
As the COVID-19 infection results in respiratory failure, respiratory support is essential for patient's survival. In the intensive care, the critically ill patients are supported with mechanical ventilation. The aim is to maintain the necessary oxygenation, where CPAP machines could help in case of ventilators shortage.

Immunity Modulation
(1) Active immunization • Thanks to the scienti ic efforts, the antigenic epitopes of the SARS-CoV-2 have been identi ied, where the genomic similarities between SARS-CoV-2 and SARS-CoV reach up to 76.5%. Thus, mRNA vaccine is under development and clinical validation.
• A coronavirus vaccine tested on humans has yielded promising early clinical data from the phase 1 study led by the National Institute of Allergy and Infectious Diseases (NIAID), the biotech company Moderna announced in a news release.
• Although didn't publish detailed data in a preprint or a scienti ic journal, the company said in its press release that all 45 participants across 3 study arms receiving different doses -25, 100 or 250 micrograms of the vaccine -seroconverted 2 weeks after their irst dose.
• Antibodies from 8 participants, who received doses of 25 and 100 micrograms, were tested for their ability to neutralize live SARS-CoV-2 in vitro, and all the 8 participants had neutralizing antibodies in amounts equal to or greater than those found in recovered patients.
(2) Passive immunization • Not all infected persons die or even develop critical illness.
• Age, comorbidities, lung health, smoking, the amplitude of the immune reaction, and other factors, may determin the clinical outcome.
• Recovered patients develop antibodies and immunity against the SARS-CoV-2, which could be transferred to critically ill patients.
(3) Cytokine storm modulation As previously explained, the body reaction to the virus might be worse than the infection itself, eliciting an immune reaction and releasing huge amounts of in lammatory cytokines that circulates freely in the body and lead to multiorgan failure, especially respiratory and renal failures. Thus, control of such an immune reaction is a therapeutic target, as important as the control of viral replication. CD24Fc • Is a recombinant fusion protein composed of the extracellular domain of the mature human glycoprotein CD24 linked to a human immunoglobulin G1 (IgG1) Fc domain, with potential immune checkpoint inhibitory, anti-in lammatory and antineoplastic activities.
• Upon administration, the CD24 extracellular domain-IgG1 Fc domain recombinant fusion protein CD24Fc binds to injured cell components, also called DAMPs (Danger-Associated Molecular Patterns), thereby preventing the interaction of DAMPs with toll-like receptors (TLRs) and inhibiting both nuclear factor-kappa B (NFkB) activation and secretion of in lammatory cytokines.
• In addition, CD24Fc binds to and activates Siglec G/10, a sialic acid-binding immunoglobulintype lectin, and stimulates SHP-1-mediated inhibitory signaling, preventing NFkB activation and secretion of in lammatory mediators, which further prevents in lammatory responses.
• Phase I clinical trial demonstrated its safety and ability to attenuate the expression of multiple in lammatory cytokines.
• Phase II clinical trial in patients of hematopoietic stem cell transplantation demonstrated its ability to attenuate severe (Grade 3-4) acute graft vs. host disease (GVHD), in which the transplanted T cells attack the recipient target tissues.

Mesenchymal Stem Cells
• Mesenchymal stem cells (MSCs) are multipotent stromal cells that could be derived from adult bone marrow, as well as other tissues. These cells have the ability to differentiate into many cell lines, which gives a great hope that MSCs could be a magic regenerative therapy to restore damaged tissue.
• Mesenchymal stem cells are very tolerated by the immune system, where they can attenuate the immunity through modulating T cell activation and proliferation, either by a direct cell-cell interaction or via soluble factors.
• IL10 is one of the major anti-in lammatory cytokine that down regulates the expression of cytokines in the T helper-1 cells, as well as the major histocompatibility class II antigens and costimulatory molecules on the surface of macrophages. Moreover, IL10 antagonizes the activity of NF-κB and is capable of suppressing the production of IL8 in a dose dependent manner.
• While the endothelial adhesiveness increases signi icantly upon IL1β, TNFα, IFNγ, and Lipopolysaccharide stimulation, which increases the leukocytic (macrophages and lymphocytes) migration, TGFβ, secreted by MSCs, has the ability to block these effects in a dose dependent manner.
• PGE2 functions towards the inhibition of the proliferation, differentiation and function of the antigen presenting, as well as the cytotoxic cells, including the dendritic cells, macrophages and natural killer (NK) cells.
• Thus MSCs have proved ability to modulate the adverse immune response and in lammation, as well as clinical safety in early phases of clinical trials.
(4) Hydroxychloroquine • Is a drug used to treat malaria, lupus erythematosus and rheumatoid arthritis.
• It can attenuate in lammation through interfering with the antigen processing & presentation, which is necessary to stimulate CD4+ T cells , thus, it can be used as an immunity modulator to protect against the cytokine storm [8].
• Moreover, chloroquine analogs are able to inhibit the endosomal acidi ication and show an invitro antiviral activity at high micromolar concentrations against a broad range of emerging viruses, including COVID-19 [9].
• Clinical trials are being conducted for potential covid-19 application. However, the initial results show no evidence of a favourable clinical outcome. In other words, the in-vitro reported antiviral activities are still not reproducible clinically. In addition, the drug itself might have serious side effects [10,11].
• Treatment using rh-ACE2 may exert dual functions: Slow down the viral entry into target cells and hence the viral spread Protect the lung from injury ( Figure 2) [13].
GSK2586881 is a rh-ACE2 that has been studied in Phase I trials few years ago for potential lung protection. Further investigations in Phase II trials con irmed its safety, the ability of signi icantly increase the levels of Ang1-7 and Ang1-5, as well as a tendency to decrease IL6 levels in plasma [14].

MSAM recommendations
Based on our translational immunology viewpoint, we think that SARS-CoV-2 can differ than in luenza in the fact that: • Both types of viruses infect pulmonary cells causing cells to die.
• Both infections trigger in lammatory responses up to cytokine storm.
• In luenza viruses interact with sialic acid residues of target cells surface glycans, keeping the protective roles of ACE2 intact.
• SARS-CoV-2 interacts with ACE2 of the target cells, abolishing its important protective signaling.
Accordingly, we highly recommend the therapeutic strategies to include drug combinations that can target the pathogenesis at many levels. For example, a combination of an effective anti-viral Remdesivir, soulable ACE2, and an immune modulator.
Alined with our recommendation, the early data from a small trial conducted by the University of Hong Kong has demonstrated promise for the COVID-19 treatment with a combination of HIV medicine lopinavir-ritonavir, hepatitis drug ribavirin, and multiple sclerosis therapy interferon beta. Such a combination demonstrates a strong anti-viral approach, combined with an immune modulator IF-ß, and resulted in signi icant relive of symptoms, and reduction of the viral shedding duration and hospital stay in 86 patients with mild to moderate COVID-19, compared to 41 control patients [15].

Confl icts of interest
MSAM for medical consultations provide medical advisory services. This work is part of our contribution to the battle against the COVID-19 pandemy. There is no funding or commercial relations between MSAM for medical consultations and any of the products mentioned in the article.