key: cord-306351-ka6asw3m
authors: Alsuliman, Tamim; Alasadi, Lugien; Alkharat, Banan; Srour, Micha; Alrstom, Ali
title: A review of potential treatments to date in COVID-19 patients according to the stage of the disease
date: 2020-05-30
journal: Curr Res Transl Med
DOI: 10.1016/j.retram.2020.05.004
sha: 
doc_id: 306351
cord_uid: ka6asw3m

Abstract Introduction and motivation: Since the end of 2019, the COVID-19 pandemic has affected millions of people worldwide. With the rapid spread of this virus, an immense burden has fallen upon both healthcare and economic systems. As a consequence, there is an unprecedented urgency for researchers and scientific committees from all over the world to find an effective treatment and vaccine. Review Structure: Many potential therapies are currently under investigation, with some, like Hydroxychloroquine, being authorized for emergency use in some countries. The crucial issue is now clearly to find the suitable treatment strategy for patients given comorbidities and the timeline of the illness.Vaccines are also under development and phase 1 clinical trials are rolling. Despite all efforts, no single drug or vaccine has yet been approved. In this review, we aim at presenting the proposed pathophysiological mechanisms of SARS-CoV-2 and to provide clinicians with a brief and solid overview of the current potential treatments classified according to their use at the three different currently proposed disease stages. In light of pathogenesis and proposed clinical classification, this review’s purpose is to summarize and simplify the most important updates on the management and the potential treatment of this emergent disease.

After an incubation period, SARS-CoV-2 invades the mucosal membranes, especially nasal and oralpharyngeal membranes, causing upper respiratory infection with mild symptoms in the first phase. The virus binds to target cells through angiotensin-converting enzyme 2 (ACE2). This activates the serine protease TMPRSS2 for S protein priming ( Figure 2 ) [29] . ACE2 is expressed by epithelial cells of the intestine, lung, kidney, and blood vessels [30] . Treatment in this phase is based essentially on symptomatic relief, supportive and non-specific therapies, such as acetaminophen. The use of virus-targeting treatments may be beneficial in this period in order to stop viral replication [8] .

Although some argue that Hydroxychloroquin (HCQ) can be used early in Stage 1. This use may have negative effects regarding loss of immunization chances due not only to its reduction of viral load, but also to its mmuno-suppressive characteristics [31] .

Isolation remains the cornerstone intervention for containment of COVID-19 as no treatment or vaccination has yet been globally approved. Supplementary oxygen, acetaminophen, and antibiotics should be administered as required. Non-invasive ventilation, intubation and mechanical ventilation might be required for critically ill patients and in cases of respiratory failure in the advanced stages IIb and III. Close monitoring of organ function should be undertaken for early detection of organ failure or septic shock in predisposed patients [5, 12] . Antiviral therapies:

Remdesivir is a phosphoramidate prodrug of an adenosine C-nucleoside that targets the viral RNAdependent RNA polymerase (RdRp) proteins. Working as a nucleotide analogue, this drug has proved its broad-spectrum antiviral activity including the effect against several human and zoonotic coronaviruses including SARS-CoV-2. Since human safety data for Remdesivir are available from several clinical trials that tested Remdesivir's efficacy against Ebola virus, several clinical trials are already being held in the United States and China to investigate its efficacy treating COVID-19 patients [7, 26, 32] . The dose under investigation for treatment of COVID-19 is 200 mg intravenously (IV) on day 1 followed by 100 mg IV daily for up to 10 days, infused over 30-60 minutes [7] . Several trials of Remdesivir treatment on few patients in the United States have shown early promising benefits in cases with severe pneumonia [33, 34] . In a cohort study that included 61 severe COVID-19 patients from different countries, using Remdesivir (200 mg IV. on day 1, then Page 6 of 24 J o u r n a l P r e -p r o o f 100 mg daily for 9 days) led to a clinical improvement in 63% of patients with a median follow-up of 18 days.

The total mortality rate in this study was 13% [35] .

Lopinavir (LPV) is a human immunodeficiency virus 1 (HIV-1) protease inhibitor which is administered in combination with the "booster" ritonavir (RTV), a potent CYP3A4 inhibitor that increases LPV half-life. Even though LPV/RTV was effective against SARS-CoV in tissue cultures, its efficacy against MERS-CoV was controversial. Results of a randomized, controlled, open-label trial that evaluated Lopinavir-Ritonavir vs.

standard of care treatment in adults hospitalized adults with severe COVID-19 were recently published [36] .

The two arms of this study included 199 confirmed COVID-19 patients and showed similar 28-day mortality rates and viral load at varying times since onset of symptoms. This study also showed withdrawal of medication in 13 patients in the LPV group due to adverse events (Table 1) . However, the relatively long median time to randomization (13 days) after onset of symptoms is thought to partially explain lack of effectiveness in the COVID-19 arm [37] .

Other clinical trials including Lopinavir/Ritonavir either as monotherapy or mostly in combination with other drugs have been conducted or are still ongoing. Reported data from published investigations are difficult to interpret due to concomitant drug therapies, varying illness severity amongst patients and lack of comparison groups [7, 38] . China, however, has included Lopinavir/Ritonavir in its guidelines at an oral dose of 400 mg/100 mg twice a day for no more than 10 days. But more data are needed from ongoing studies, and caution should be taken regarding adverse effects and the real advantage over standard of care management [7, 22] .

Umifenovir is an antiviral agent that has been used for influenza treatment and has shown activity against SARS-CoV in vitro [7, 39] . Its activity against SARS-CoV-2 was investigated recently at a dose of 200 mg every 8 hours in combination with Lopinavir/Ritonavir in a retrospective cohort Chinese study [39] . Results showed better clinical response in the combination group in comparison with the Lopinavir/Ritonavir monotherapy group. Umifenovir is currently being tested in seven randomized trials for the treatment of COVID-19 [38] .

Anti-endocytosis treatment:

Baricitinib is a selective Janus kinase 1 and Janus kinase 2 (JAK1 and JAK2) inhibitor. The mechanism of action is considered to be by modulation of viral endocytosis. But there are huge concerns that this blockage Page 7 of 24 J o u r n a l P r e -p r o o f may potentiate SARS-Cov2 infection, and there are other safety issues related to this product's administration [40] .

ACE2 was identified as a key receptor for SARS-CoV-2. Data regarding the interaction between COVID-19 severity and Angiotensin converting enzyme 2 (ACE2) receptor inhibition is conflict, and contrary theories have been proposed so far [41, 42] . Initially, concerns were raised on the basis that ACEIs and ARBs led to an increase in the number of ACE2 receptors in the cardiopulmonary circulation in experimental animals, and that this might lead to more severe outcomes due to SARS-CoV-2 infection [43] . On the other hand, ACE2

has been found to protect the lungs from injury. And some data suggest that SARS-CoV-2 down-regulates ACE2 expression after initial engagement with the receptor. This down-regulation of ACE2 activity in the lungs might facilitate lung injury. In a recent in-vitro study hrsACE2 was shown to significantly block early stages of SARS-CoV-2 infections [41, 42] . In a recent retrospective study that included 564 patients, hypertensive patients treated with ACEI/ARB were less likely to develop severe pneumonia, and the study concluded that these drugs might have a protective effect [44] .

Until more data are available, there is no indication for patients treated with ACEIs or ARBS to withhold their treatment (Renin-Angiotensin-Aldosterone System Inhibitors in Patients with COVID-19 [45] .

Camostat Mesylate is a serine protease inhibitor, a drug approved in japan for use in pancreatic inflammation.

It usually blocks TMPRSS2, a protease that was recently shown to be responsible for the coronavirus S protein priming, which is crucial for viral entry into target cells and for viral spread in the infected host as published by Hoffman et al, in Cell, from the German Primate center [29] . Several clinical trials are ongoing comparing Camostat Mesylate as a single agent vs. placebo or in combination with other drugs such as Hydroxychloroquin [46, 47] .

In this stage, pulmonary involvement is well settled, while we note remarkable viral multiplication and pulmonary localized inflammation. Viral pneumonia, with cough, fever and hypoxia (stage IIb: hypoxia defined as a PaO2/FiO2 of <300 mmHg) identify this period [8] . Chest imaging reveals bilateral infiltrates or ground glass opacities [48] . Laboratory tests show increasing lymphopenia while inflammation markers may be normal or slightly elevated [5] .

Normally most hospitalizations occur in this phase. With advanced disease, the virus infects the lower respiratory tract leading to pneumonia and worsens symptoms such as dyspnea and hypoxemia [4, 5, 49] .

Treatment usually relies on supportive measures and the aforementioned anti-viral therapies. In early parts of this stage (IIa), the use of corticosteroids in patients with COVID-19 may be avoided. While in stage IIb, the J o u r n a l P r e -p r o o f use of anti-inflammatory treatment may be permitted, indeed, the presence of hypoxia may indicate the high probability of unfavorable systemic evolution [5, 8] .

Coagulopathy seems to be another issue that affects the prognosis in more severe cases. Importantly, elevated D-dimer levels seem to be a marker to predict severe illness and mortality. Other laboratory findings like hrombocytopenia and prolonged prothrombin time also indicate a hyper-coagulation state in COVID-19

patients. The use of anticoagulant therapy has improved mortality rates in hospitalized patients with markedly elevated D-dimer or those who have sepsis-induced coagulopathy (SIC) score ≥4. With all the emerging evidence, current guidelines recommend a prophylactic dose of low molecular weight heparin (LMWH) for all hospitalized patients in the absence of contraindications [50] [51] [52] In order to eliminate the virus, a good immune status is essential in this phase [4, 53] . Even in elderly and immunocompromised patients, these phases tend to be respected, albeit in presenting different severe clinical manifestations [8] . Treatments potentially investigable in this stage are the following:

Chloroquine (CQ) is a 4-aminoquinoline antimalarial agent that has proven anti-inflammatory and immunomodulatory activities. CQ also has anti-viral properties due to the following mechanisms: blocking virus/cell fusion; interfering with the glycosylation of cellular receptors, lysosomes and autophagosomes impairment; inhibiting viral enzymes ( i.e. viral DNA and RNA polymerase); increasing pH of intracellular vesicles which interferes with pH-dependent viral replication [54] [55] [56] .

Hydroxychloroquine (HCQ) is a derivative of CQ with similar characteristics but with better safety profile [56, 57] . Both drugs have narrow therapeutic range which makes drug-toxicity probable especially with uncontrolled usage. Cardiac toxicity (QT interval prolongation) is the major, and even lethal, concern about usage of these drugs [54, 58] .

In vitro studies have demonstrated CQ efficacy against SARS-CoV-2 [55] . With its known safety profile, clinical investigations have been held in different countries; and at least 18 trials evaluating HCQ or CQ are currently underway worldwide [38, 58] .

A pilot randomized Chinese study [59] investigated HCQ in 30 confirmed COVID-19 cases. Fifteen patients received 400 mg of HCQ per day for 5 days, while others received the conventional treatment. The primary endpoint was COVID-19 nucleic acid negativity in respiratory pharyngeal swab on day 7 after randomization.

The results were comparable between the study and the control group as of day 7. Throat swabs were negative in 13 (86.7%) cases in the HCQ group and in 14 (93.3%) cases in the control group (P ＞ 0.05).

Furthermore, the median duration from hospitalization to virus nucleic acid negative conversion and the median time for body temperature normalization were also comparable between the two groups.

These results are comparable to another Chinese open-label, randomized, controlled trial that included 150 hospitalized COVID-19 patients. HCQ dosage in this study was 1, 200 mg daily for 3 days with a maintenance J o u r n a l P r e -p r o o f dose of 800 mg daily for 2 or 3 weeks depending on illness severity. No difference regarding negative viral conversion was observed between the HCQ and the standard of care group, but significant clinical improvement was noticed in the HCQ group [60] .

A preliminary Brazilian randomized, double-blinded, clinical trial has investigated two different CQ dosages (600 mg twice daily for 10 days vs. 450 mg for 5 days, twice daily only on the first day) in 81 patients with severe COVID-19. All patients received ceftriaxone and azithromycin as well. The high dosage CQ arm had higher QTc prolongation and mortality rates, with no apparent benefit of CQ regarding viral clearance or mortality in either study arms [61] . Of note, only 62 out of the enrolled 81 patients had been confirmed by RT-PCR.

On the other hand, data emerging from other ongoing Chinese trials have demonstrated that CQ phosphate is superior to a control treatment in the following areas: pneumonia exacerbation inhibition, imaging findings improvement, virus negative conversion promoting, and disease course shortening [62] . Additionally, a randomized Chinese cohort of 62 in-hospital patients with COVID-19 showed that HCQ may help shorten the time to clinical recovery [63] . Gautret, P. et al, reported promising results in two studies in France [64, 65] . In these studies, researchers investigated the efficacy of HCQ in combination with azithromycin for the treatment of confirmed COVID-19 patients. In the first study, a significant reduction in viral carriage on day 6 post inclusion compared to control group was noticed. Meanwhile, the second study reports a rapid fall in nasopharyngeal viral load on day 7 (83%) and day 8 (93%) which was confirmed by PCR. In addition, virus cultures were negative in 97.5% patients on day 5. This allowed rapid discharge with a mean length of stay of five days. HCQ dosage used in these studies was 600 mg per day for 10 days.

Combining all in-vitro and in-vivo data, some countries have authorized treating hospitalized patients, with some conditions, with CQ and HCQ [22, 27, 28] . However, there are serious concerns raised regarding its usage. For example, clinical data from reliable randomized controlled studies are still missing, and data published to date lacks homogeneity in terms of recommended dose concentration, treatment duration, and severity of patient illness [58] .

Recently, the American Thoracic Society has released interim guidance on treating COVID-19. For hospitalized patients with pneumonia, HCQ and CQ may be used on a case-by-case basis, but clinicians must consider the potential benefit/risk ratio and the patient's condition must be severe. For outpatients with COVID-19 or hospitalized patients without pneumonia there are no specific recommendations [66] . In contrast, the Surviving Sepsis Campaign announced that there's insufficient evidence to declare a recommendation on the use of CQ and HCQ in critically ill adults with COVID-19 [67] . The Infectious Diseases Society of America (IDSA), on the other hand, in its recently published guidelines [68] has recommended HCQ/CQ (+/-azithromycin) in the context of clinical trials only. Clinical data regarding this combination in the treatment of COVID-19 patients is still lacking, but several clinical trials are currently being conducted [38, 69] .

The WHO has launched a multinational trial called "solidarity trial". This trial will test the four most promising coronavirus treatments remdesivir, lopinavir/ritonavir, lopinavir/ritonavir plus interferon b, Hydroxychloroquin with the aim to end the pandemic [70] .

Ivermectin is a broad spectrum anti-parasitic drug, but it has also shown anti-viral activity in vitro with its confirmed ability to inhibit integrase protein (IN) nuclear import and HIV-1 replication. It has also shown its ability to inhibit nuclear import of host and viral proteins [71, 72] . A recent in vitro study tested the antiviral activity of ivermectin against SARS-CoV-2 [72] . Ivermectin treatment resulted in 99.8% reduction in all viral material within 48 h compared to control samples. These results made the authors propose Ivermectin as a possible treatment for COVID-19 since it's an FDA approved drug with a known safety profile.

Nitazoxanide has shown in vitro activity against SARS CoV-2 with known broad antiviral activity against other viruses like influenza and rotavirus. The mechanism of action is believed to be due to interference with viral replication by targeting host regulated pathways rather than virus-specific pathways. In addition to its antiviral activity, it inhibits the production of pro-inflammatory cytokines TNF-, IL-2, IL-4, I-5, IL-6, IL-8 and IL10. No clinical information is yet available on the efficacy of Nitazoxanide in the treatment of COVID-19 [7, 73] .

This is the most severe stage in this disease stage classification and luckily it concerns a fewer number of patients with ARDS and cytokine storm syndrome (CSS) being the hallmark of the pathogenesis [8, 74] . In these severe cases, virus replication and tissue damage continue, especially in the lungs and other ACE2 expressing organs, which leads to an even higher increase in pro-inflammatory cytokines released by macrophages and granulocytes [49, 53] . High levels of pro-inflammatory cytokines such as Interleukin 1b (IL- Among these cytokines, several have been suggested as a potential therapeutic target. IL-1, for example, is activated after the binding between COVID-19 and toll-like receptors (TLR). Released IL-1 mediates lung inflammation, fever and fibrosis. IL-1 is also known for its important role in the progression of pulmonary fibrosis [49] . IL-6 is also an important cytokine during respiratory viral infections, and it has been reported that, during this COVID-19 pandemic, it has been correlated with pulmonary infection severity in ICU patients [49, 75] . Both IL-1 and IL-6 have been presented as potential therapeutic targets [74, 75] .

In addition to potential shock, stage III is also marked by extra-pulmonary involvement, such as vasoplegia, myocarditis, and organ failure. Treatment is essentially based on the use of immunomodulatory therapies in order to improve systemic inflammation and to block consequent organ failure. The use of corticosteroids may be helpful in this phase, generally in tandem with the use of cytokine inhibitors. Intravenous immune globulin (IVIG) may also be considered as an immune system modulator. Rapid application of such a treatment plan can potentially enhance patient prognosis, which is basically poor in this stage [8, 77, 78] .

Using corticosteroids to treat severe pneumonia due to COVID-19 is still controversial. The WHO recommends against the routine use of corticosteroids in these patients [12] . Data from clinical trials are widely variable in terms of participants included and results reported, that's why clinical judgment should be based on a case-by-case approach. Delayed viral clearance and infection susceptibility are two major concerns that come with corticosteroid usage in COVID-19 patients [7, 45, 69] . In a recent release, the Surviving Sepsis Campaign has suggested systemic corticosteroid administration for ARDS adult patients with COVID-19 who are mechanically ventilated. On the other hand, recommends against corticosteroid use in adults without ARDS [67] . Five randomized controlled trials investigating methylprednisolone in COVID-19 patients are also currently registered [38] .

A-Bio-immune-modulatory treatments:

Immunoglobulins have been widely used in medical practice, and their use has shown clinical benefits in previous studies of SARS and MERS. IVIG is currently under investigation for treatment of COVD-19 [38, 69, 77] . A case series of 3 severe COVID-19 patients who received high-dose IVIG (0.3-0.5 g/kg/day) for five days was reported [77] . All patients experienced clinical improvement shortly after administration.

However, other therapeutic agents were administered for these patients including antivirals and a short course of steroids.

In a pre-print retrospective study [78] , authors reported the data of 10 severe COVID-19 patients who didn't respond to a combination of low-dose corticosteroid (40-80 mg/d) and immunoglobulin (10 g/d) but have 

Considering the genetic relation between SARS-CoV-2 and SARS-CoV-1 some argue that it may be considered for further verification as a potential therapeutic, as 10 of 12 SARS patients were reported, in a 2004 publication, to have an uneventful recovery after treatment with this product [4, 79] .

The FDA has recently approved convalescent plasma for serious or immediately life-threatening COVID-19

infections under emergency Investigational New Drug Application (eINDs) [80] . Convalescent plasma has been previously studied during other epidemics including H1N1 influenza virus pandemic, SARS-CoV-1 epidemic, and the MERS-CoV epidemic. Recently, a preliminary case series of five intubated COVID-19 patients with ARDS showed promising results. These patients received 400 mL of convalescent plasma containing neutralizing SARS-CoV-2-specific antibody (IgG) from recovered COVID-19 donors. All patients had gradual clinical and radiological improvement within 3 days and four patients no longer required respiratory support by day 9, viral loads also became negative within 12 days after transfusion. Seven clinical trials are currently registered [7, 38, 81] .

Tocilizumab is a monoclonal antibody (mAb) that inhibits the IL-6 Receptor. As mentioned earlier, IL-6 plays a key role in respiratory viral infections and in CRS which is linked to poorer prognosis and higher mortality rate in COVID-19 patients. Tocilizumab is approved for the treatment of rheumatoid arthritis and its safety and efficacy profile has previously been well studied [7, 74] .

Preliminary data [82] included cases of 21 severe and critical pneumonia in COVID-19 confirmed patients who showed clinical and radiological improvement in 75.0% (severe pneumonia) and 90.5% (critical pneumonia) of participants. Lymphocyte count also returned to normal in 52.6% of cases on day 5 of drug administration.

All patients received 400 mg of intravenous Tocilizumab once, and three patients, due to persistent fever, received another 400 mg dose after 12 hours.

Despite promising primary data, when it comes to studies regarding optimal timing and IL-6 threshold of Tocilizumab administration during the course of COVID-19, information is still lacking from larger, controlled, long-term studies. Moreover, IL-6 monitoring might be an obstacle in some institutions, and its adverse effects bacterial infection susceptibility, neutropenia and thrombocytopenia should be considered when a clinical decision is to be made. Two clinical trials are ongoing right now which might provide further needed information [7, 38] .

Leronlimab is a humanized IgG4 monoclonal antibodies that blocks CC chemokine cellular receptor 5 (CCR5) and plays a key role in several immunological processes. Leronlimab is being evaluated for HIV and breast cancer treatment and it is believed to have an antiviral activity while mitigating the cytokine storm. Some claim that Leronlimab has achieved preliminary results in a few severe cases of COVID-19 [83, 84] .

Bevacizumab is an approved treatment for multiple cancers. It is a humanized monoclonal antibody that prevents the association between vascular endothelial growth factor (VEGF) and endothelial receptors Flt-1 and KDR, and it may reduce the levels of VEGF caused by hypoxia and severe inflammation. Eventually, it might suppress the edema in patients with COVID-19. Bevacizumab is currently being tested in a Chinese randomized controlled trial [7, 69] .

C-Anti-interleukin 1:

Anakinra® is an IL-1 receptor antagonist. As mentioned earlier, IL-6 seems to have a key role in the respiratory viral infections and in progression of pulmonary fibrosis. So Anakinra® has been suggested as possible adjunctive treatment. But, to the best of our knowledge, no in-vitro or clinical data are available [7, 49] D-Cell-based therapy:

The Italian College of Anesthesia, Analgesia Resuscitation and Intensive Care has reported recent guidelines to treat coronavirus patients. It includes a statement that stem cells could have a serious potential to treat COVID-19 by decreasing the number of patients admitted to the ICU and discharging them quickly [85] .

MSC can theoretically inhibit immune system overreaction and improve the microenvironment that promotes endogenous repair which could potentially protect alveolar epithelial cells. This would, in theory, prevent pulmonary fibrosis and also improve lung function [86, 87] .

The published studies are from China, including a small cohort 7 in the treatment group and 3 in the control group [86] and a case report [88] . Some expect that clinical trials may be, nowadays or very soon, recruiting.

The available data shows some promise in managing COVID-19 illness, especially in critically ill patients that could be treated under a compassionate-use protocol [89] .

CYNK-001 (intravenous infusion of natural killer (NK) cells) is the name of yet another trial that has enrolled COVID-19 patients. It aims to boost immune systems of patients at risk of more severe disease and those starting to show symptoms by applying CYNK-001. The mechanism has been slowing virus replication [90] . Prevention:

An urgent response to the brisk expansion of COVID-19 has been evoked throughout scientific communities in order to develop an effective vaccine. Rapid genome sequencing and potential molecular targets have been identified, and more than 20 vaccines are currently under investigation. Some of these vaccines have shown effectiveness in preclinical studies, while still others are already in phase I clinical trials [94] [95] [96] .

Until the final approval of a given vaccine and its effective distribution, an approach based on early case detection and isolating, laboratory testing, contact tracing and quarantining (as recommended by the WHO) seem the most effective way to prevent further spread of SARS-CoV-2 [6, 97] .

Growing evidence suggests a link between universal BCG vaccination policy and reduced morbidity and mortality for COVID-19. Comparing Italy to Japan, for example, the first case of COVID-19 appeared in Japan earlier than in Italy, but Japan has maintained a low mortality rate despite not implementing restrictive social isolation measures [98] . Another study found that the mortality rate has been 4.28/million in countries with a BCG program compared to 40/million in countries without such a program [99] .

To date, the efficacy of BCG vaccine on preventing COVID-19 is controversial due to many limitations, one being the reality of comparing countries in different phases of the pandemic. This association might be clearer with upcoming data.

Tuberculosis vaccine (VPM1002), on the other hand, is a new vaccine based on the old BCG vaccine. The idea is that in many studies conducted on mice, the vaccinated mice had lower influenza, lower serum viral load, and less lung damage. It is claimed that the BCG vaccine may activate the immune system against viruses and possibly decrease COVID-19 mortality rates [100] .

While the complete pathophysiology of COVID-19 needs to be better understood, urgent research for rapid solutions based on already established knowledge is still ongoing.

Page 15 of 24 J o u r n a l P r e -p r o o f For many physicians, these new potential strategies may be seductive. Although the disastrous situation currently faced by many countries may explain the attractiveness of such treatments, the urgent need for a cure does not justify any use which is unauthorized by national health regulatory authorities.

Meanwhile, as the world waits for a widely approved treatment, preventive interventions coupled with clear local and international management guidelines must be always respected in order to lessen the damage and permit more exhaustive and conclusive research to be conducted.

TA has received honorarium from Biotest France SAS. Biotest AG commercializes Pentaglobin®. Symptomatic treatment is a basic step in all clinical stages of the disease, with oxygen therapy here reflecting all interventions that may be needed from nasal cannula to mechanical ventilation. While some argue that antiviral therapy (especially Remdesivir) could be considered for some patients in Stage I of the disease, other preserve it for the Stage II patients. Ribavirin and IFNα-2b in particular, in our opinion shouldn't be considered in the management of Stage I. More severe cases (Stage III) need more extensive interventions by adding immunomodulatory treatments to the previous management steps in the attempt to contain the hyperinflammatory response.

*These treatments might also be investigated in both stage II and III. **These treatments might also be investigated in stage III. ***These treatments are mainly investigated in stage III. Hydroxychloroquine (HCQ) targets several levels of viral infection. It changes the glycosylation of ACE2 to inhibit virus entry. Being a weak base, it also affects endosomal activity by increasing, the pH of acidic intracellular organelles. Finally, it interferes with RNA replication by targeting the polymerase. In severe and critical cases, macrophage activation leads to an uncontrolled and lethal inflammatory process known as "cytokine storm syndromes" driven by the release of multiple cytokines; IL-6 plays a key role in this process.

Tocilizumab is a monoclonal antibody that inhibits the IL-6 Receptor which might mitigate the inflammatory response.

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Clinical trials on drug repositioning for COVID-19 treatment

Solidarity" clinical trial for COVID-19 treatments 2020

Ivermectin is a specific inhibitor of importin α/βmediated nuclear import able to inhibit replication of HIV-1 and dengue virus

The FDA-approved Drug Ivermectin inhibits the replication of SARS-CoV-2 in vitro

Nitazoxanide, a new drug candidate for the treatment of Middle East respiratory syndrome coronavirus

COVID-19: consider cytokine storm syndromes and immunosuppression

Pathogenic T cells and inflammatory monocytes incite inflammatory storm in severe COVID-19 patients

The use of anti-inflammatory drugs in the treatment of people with severe coronavirus disease 2019 (COVID-19): The experience of clinical immunologists from China

Short-Term Moderate-Dose Corticosteroid Plus Immunoglobulin Effectively Reverses COVID-19 Patients Who Have Failed Low-Dose Therapy

Pentaglobin in steroid-resistant severe acute respiratory syndrome

Revised Information for Investigational COVID-19 Convalescent Plasma. FDA 2020

Treatment of 5 Critically Ill Patients With COVID-19 With Convalescent Plasma

Effective Treatment of Severe COVID-19 Patients with Tocilizumab

Antibodies to watch in 2020

Leronlimab Used in Seven Patients with Severe COVID-19 Demonstrated Promise with Two Intubated Patients in ICU, Removed from ICU and Extubated with Reduced Pulmonary Inflammation

Transplantation of ACE2-Mesenchymal Stem Cells Improves the Outcome of Patients with COVID-19 Pneumonia

MSC Based Therapies-New Perspectives for the Injured Lung

Clinical remission of a critically ill COVID-19 patient treated by human umbilical cord mesenchymal stem cells

Expanded Umbilical Cord Mesenchymal Stem Cells (UC-MSCs) as a Therapeutic Strategy in Managing Critically Ill COVID-19 Patients: The Case for Compassionate Use

Center for Drug Evaluation and Research. Investigational New Drug (IND) Application. FDA 2020

Use of siltuximab in patients with COVID-19 pneumonia requiring ventilatory support

Potential interventions for novel coronavirus in China: A systematic review

An orally bioavailable broad-spectrum antiviral inhibits SARS-CoV-2 in human airway epithelial cell cultures and multiple coronaviruses in mice

NIH clinical trial of investigational vaccine for COVID-19 begins. National Institutes of Health (NIH) 2020

Microneedle array delivered recombinant coronavirus vaccines: Immunogenicity and rapid translational development

WHO. DRAFT landscape of COVID-19 candidate vaccines 2020

Critical preparedness, readiness and response actions for COVID-19 Interim guidance 2020

Correlation between universal BCG vaccination policy and reduced morbidity and mortality for COVID-19: an epidemiological study

BCG vaccination may be protective against Covid

BCG as a Case Study for Precision Vaccine Development: Lessons From Vaccine Heterogeneity, Trained Immunity, and Immune Ontogeny

The authors thank Rachel Tipton, Hasan Iessa, PhD., and Danah El-Refaie for the proof reading of this manuscript and Layth Sliman for the technical support.