Emerging therapeutics in the management of COVID-19.

Core Tip: As coronavirus disease 2019 continues to affect the global community, researchers are working diligently to determine the efficacy of therapeutic agents to fight this virus in clinical trials. Currently, there is a lack of published literature that comprehensively discusses all of the therapeutic agents under investigation. In this manuscript, we provide readers with a thorough and comprehensive evaluation of the current state of therapeutics including the proposed mechanisms of action, pharmacokinetics, recommended dosages, adverse effects, and efficacy data from clinical trials.

INTRODUCTION

Coronavirus disease 2019 (COVID-19), a disease caused by the novel coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has been labelled a pandemic by the World Health Organization after its emergence from Wuhan, Hubei Province, China in December 2019. It has since infected more than 60 million people worldwide. The presentation of the disease varies, however the most common symptoms include fever, cough, and dyspnea[ 1 - 3 ]. Other possible symptoms include rhinorrhea, sore throat, headache, gastrointestinal (GI) disturbances, and fatigue[ 3 ]. Because of the extensive morbidity and mortality related to COVID-19 infection, researchers and clinicians are racing to find effective therapeutics for the treatment of this disease. On March 28, 2020 the United States Federal Drug Administration (FDA) issued an emergency authorization for chloroquine (CQ) phosphate and hydroxychloroquine (HCQ) sulfate as a treatment for adults and adolescents weighing greater than 50 kg, who are hospitalized, and for whom a clinical trial is not available or feasible[ 4 ]. Furthermore, on May 1, 2020 an emergency authorization was issued for Remdesivir to be used for adults and children with severe disease, defined as SpO 2 less than 94% on room air, requiring supplemental oxygen, mechanical ventilation, or extracorporeal membrane oxygenation (ECMO)[ 4 ]. Clinical trials for numerous therapeutics are on-going worldwide. In this review, we will familiarize readers with the current therapeutics being investigated for the treatment of COVID-19, including their mechanisms of action, rationale for use, adverse effects, and information from clinical trials in the currently published literature. A summary of the therapeutics can be found in monoclonal antibodies (Table 1 ), antivirals (Table 2 ), cell and RNA-based therapies (Table 3 ) and miscellaneous treatment (Table 4 ).

METHODS

A literature review was performed for articles related to therapeutics and clinical trials in the context of the current COVID-19 pandemic. We used PubMed, Google Scholar, and Clinicaltrials.gov to search for articles relative to the topic of interest. We used the following keywords: “COVID-19”, “therapeutics”, “clinical trials”, “treatment”, “FDA”, “ICU”, “mortality”, and “management”. In addition, searches through the references of retrieved articles was also performed. Three reviewers were responsible for performing article selection based on relevance to our topic. Inclusion criteria included both published and pre-published works that were available in English, and articles related to therapeutics and clinical trials for COVID-19 in all settings. We excluded abstracts, non-English articles, and those unrelated to therapeutics and COVID-19.

MONOCLONAL ANTIBODIES

Sarilumab

Chemical composition: Sarilumab (Kevzara) is a fully human monoclonal antibody that acts as an interleukin (IL)-6 receptor antagonist, which leads to blockage of the development of IL-6 mediated inflammation[ 5 ]. It is currently best known for its role in the treatment of rheumatoid arthritis. It is a covalent heterotetramer made up of two disulfide linked heavy chains linked to a kappa light chain[ 6 ].

Mechanism of action: The proposed mechanism of action of Sarilumab against COVID-19 is due to its ability to act as an IL-6 receptor antagonist[ 7 ]. It has been demonstrated that patients with severe COVID-19 infection are more likely to have elevated levels of several biomarkers, including IL-6[ 8 ]. The binding of SARS-CoV-2 to the alveolar epithelial cells leads to the activation of the innate and adaptive immune systems, which leads to the production of several pro-inflammatory cytokines[ 7 ]. IL-6 promotes T-cell activation, B-cell differentiation, and induces the production of acute phase reactants from the liver[ 7 ]. In addition, elevated levels of IL-6 have been associated with cardiovascular diseases such as atherosclerosis, heart failure, angina, and hypertension[ 7 ].

Pharmacokinetics: Sarilumab is shown to be well absorbed in Rheumatoid Arthritis patients[ 6 ]. In one study of the pharmacokinetics of Sarilumab in 1770 patients with rheumatoid arthritis, 631 patients received 150 mg and 682 patients received 200 mg of Sarilumab every two weeks for up to one year[ 6 ]. On average, Tmax was observed between 2 to 4 d[ 6 ]. The volume of distribution at steady state is 7.3 L[ 6 ]. As with other monoclonal antibodies, it is believed to be degraded into peptides and amino acids[ 6 ]. It is not eliminated by either the hepatic or renal systems, but rather it is eliminated predominately through proteolytic pathways[ 6 ].

Adverse effects: There is limited clinical trial data available describing the adverse effects of Sarilumab for the treatment of COVID-19. A review of the use of Sarilumab in the treatment of rheumatoid arthritis along with other disease modifying antirheumatic drugs (DMARDs) found that neutropenia (9.8% to 14.2%), upper respiratory infections (6.4% to 7.1%), elevated alanine aminotransferase (ALT) (6.7% to 6.8%), and local injection site erythema (5.3%) were some of the more common side effects[ 9 ]. When Sarilumab was used as monotherapy, neutropenia (15.6%), nasopharyngitis (6%), and injection site erythema (6.2%) were among the most common side effects[ 9 ].

Dosage: Published clinical trial data for Sarilumab is lacking. Current unpublished data available has suggested using either 200 mg or 400 mg intravenous doses, depending on the study protocol[ 10 , 11 ].

Randomized clinical trials: There are no currently published clinical trials demonstrating efficacy for Sarilumab in the treatment of COVID-19. However, a large phase 2/3, randomized placebo-controlled study of Sarilumab in hospitalized patients with severe COVID-19 is ongoing[ 10 ]. In addition, a case series by Benucci et al [ 11 ] described the clinical course of eight patients hospitalized in Italy with COVID-19. Patients were given 400 mg of Sarilumab in addition to HCQ, azithromycin, darunavir, cobicistat, and enoxaparin at 24 h after hospitalization[ 11 ]. An additional 200 mg dose was given to patients after 48 and 96 h, respectively. In this series, 7 patients saw substantial improvements in their SpO 2 /FiO 2 ratio and were discharged home after testing negative for COVID-19 within 14 d[ 11 ]. Only 1 of the patients, who was 83 years old, died after 13 d[ 11 ]. Further clinical trials are needed to evaluate the efficacy and safety of Sarilumab for the treatment of COVID-19.

Siltuximab

Chemical composition: Siltuximab (Sylvant) is a chimeric monoclonal antibody that acts via inhibition of IL-6, similar to Sarilumab[ 12 ]. It is known for its role in treating a variety of malignancies, including multicentric Castleman’s disease, multiple myeloma, myelodysplastic syndrome, prostate cancer, ovarian cancer, and lung cancer[ 12 ].

Mechanism of action: The primary mechanism of Siltuximab is via binding to and/or neutralization of IL-6[ 12 ]. As discussed previously, IL-6 is a proinflammatory cytokine that has been shown to be elevated in patients suffering from severe COVID-19[ 8 ].

Pharmacokinetics: Siltuximab is primarily distributed within the intravascular space[ 13 ]. It is approved in the United States to be given at doses of 11 mg/kg over the course of a one hour infusion once every three weeks[ 13 ]. The steady state is reached by the sixth dose, accumulating at 1.7 times higher than the concentration achieved via a single dose[ 13 ]. The volume of distribution in a 75 kg man is approximately 4.5 L, and the half-life is approximately 20.6 d[ 13 ]. It is cleared via first order elimination at a rate of 0.23 L per day[ 13 ].

Profit and adverse effects: The safety and efficacy of Siltuximab in the treatment of COVID-19 has not yet been established. Further clinical trials are needed to determine adverse effects of this medication. The most common adverse effects of Siltuximab therapy when used for the purposes of treating Castleman’s disease and Multiple Myeloma include weight gain, hyperuricemia, respiratory infections, rash, and pruritus[ 12 ].

Dosage: In the only clinical trial currently reported from Italy, patients received the standard dose of Siltuximab, 1 1mg/kg IV infusion over the course of one hour[ 14 ]. In addition, a second dose was able to be given at the physician’s discretion[ 14 ].

Randomized clinical trials: Currently, there is no published data regarding the usage of Siltuximab for the treatment of COVID-19. Currently, an unpublished study from Italy evaluated the use of Siltuximab in 21 patients admitted to the hospital with confirmed COVID-19[ 14 ]. All of the patients who were available for follow up had CRP levels normalized (median time to follow up = 8 d). Additionally, 7 patients experienced a reduced need for ventilation, 9 patients experienced clinical stabilization of their position, while 5 patients experienced worsening of their condition described as the need for intubation during the course of the study[ 14 ].

Leronlimab (PRO 140)

Chemical composition: Leronlimab is a humanized immunoglobulin (Ig) G4 monoclonal antibody that acts as a CCR5 antagonist[ 15 ]. It is currently in clinical trials for the treatment of human immunodeficiency virus (HIV)[ 15 ].

Mechanism of action: Leronlimab is a CCR5 receptor antagonist. CCR5 is a fusion co-receptor used by the HIV-1 virion to enter into human cells[ 16 ]. It is thought that the CCR5 receptor plays a role in immune cell trafficking to sites of inflammation, and for this reason there is a potential benefit for the use of this drug in the treatment of COVID-19[ 17 ].

Pharmacokinetics: A clinical trial by Jacobson et al [ 18 ] examined the use of Leronlimab in the treatment of HIV. Subjects were given either placebo, a 162 mg dose, or a 324 mg dose of Leronlimab weekly for three weeks[ 18 ]. The average peak concentration of the drug was 6.1 mg/L and 13.8 mg/L for the 162 mg group and the 324 mg group, respectively[ 18 ]. The average half-life was 3.4 and 3.7 d for each respective group[ 18 ]. There is little information available regarding the metabolism and elimination of Leronlimab.

Adverse effects: There are no documented adverse effects regarding the use of Leronlimab in the treatment of COVID-19. Jacobson et al [ 18 ] found in their study that the most frequent adverse effects of Leronlimab in the treatment of HIV included diarrhea (14%), headache (14%), lymphadenopathy (11%), and hypertension (9%).

Randomized clinical trials: Currently, no published randomized clinical trials have evaluated the use of Leronlimab in the treatment of COVID-19. However, in New York, 10 severely ill patients with COVID-19 have received treatment with Leronlimab[ 17 ]. After three days, eight of these patients showed significant improvement in levels of cytokines, including IL-6, as well as improvements in CD4/CD8 T-cell ratios[ 17 ]. Currently, patients are enrolling in Phase 2 and Phase 2b/3 trials for the use of Leronlimab in the treatment of severe COVID-19[ 17 ].

Programmed cell death inhibitors

Chemical composition: Antibodies that block programmed cell death (PD-1) are known as immune checkpoint inhibitors. Immune checkpoints refer to inhibitory pathways that are crucial for maintaining self-tolerance and controlling the physiologic immune responses in peripheral tissues to minimize tissue damage when responding to pathogenic infections. Many immune checkpoints are initiated by ligand-receptor binding, which allows for blockade by antibodies[ 19 ].

Mechanism of action: When PD-1 binds to its ligand (PD-L1), it has an immunosu-ppressive effect[ 19 ]. PD-1 and its ligands have traditionally been studied for antitumor treatment because of the ability of cancer to dysregulate the expression of these checkpoint proteins, which allows it to escape T-cell mediated cell death.

Pharmacokinetics: The pharmacokinetics of immune checkpoint inhibitors like PD-1 blocking antibodies are impacted by time-varying clearance and the target-mediated drug position[ 20 ]. Differences in patient-specific characteristics only account for some of the variability in the pharmacokinetics of immune checkpoint inhibitors. Immune checkpoint inhibitors appear to have little to no impact on liver and renal function[ 20 ]. They display limited diffusion outside of the vascular space[ 20 ]. They have a long half-life and are cleared through a receptor-mediated mechanism in both linear and nonlinear phases[ 20 ]. Clearance may occur through nonspecific degradation in tissues and plasma[ 21 ].

Adverse effects: There is currently no clinical trial data available describing the adverse effects of PD-1 blocking antibodies in the treatment of COVID-19. Previously reported adverse effects vary including the following disturbances: gastrointestinal (bloody diarrhea, abdominal pain, and pyrexia), hepatic (jaundice, and asymptomatic liver enzyme elevation), endocrine (hypophysitis, hypo/hyperthyroiditis, primary adrenal insufficiency, and hypercalcemia), skin (rash and Stevens-Johnson syndrome), rheumatological (mild arthralgia, myalgia, and arthritis), neurological, renal, pulmonary (pneumonitis), cardiac (myocarditis, myositis), and many others[ 22 ]. It should be noted that the incidence of these adverse effects varies[ 22 ]. In one smaller study of 19 patients receiving PD-1 therapy, some patients experienced flares of pre-existing autoimmune disease with treatment[ 23 ]. Similar results were also seen in patients receiving anti-PD-1 therapy in a larger, multicenter trial[ 24 ].

Dosage: There is limited data regarding dosing for the use of PD-1 inhibitors in the treatment of COVID-19. In one clinical trial, 200 mg of the PD-1 inhibitor Camrelizumab was administered one time intravenously[ 25 ].

Randomized clinical trials: There are no currently published randomized clinical trials regarding the use of PD-1 inhibitors in patients with COVID-19. Researchers at Southeast University in China are currently studying the efficacy of Camrelizumab in patients with severe pneumonia associated with lymphocytopenia in COVID-19 patients in order to restore immunoactivity[ 25 ].

Gimsilumab

Chemical composition: Gimsilumab (KIN-1901) is a fully human monoclonal antibody that antagonizes granulocyte macrophage colony stimulating factor (GM-CSF)[ 26 ]. This monoclonal antibody is fully human and is directed at a proinflammatory cytokine that is thought to play a role in autoimmunity and inflammation[ 26 ].

Mechanism of action: GM-CSF is a hematopoietic growth factor that can stimulate the proliferation of granulocytes and macrophages which can contribute to increased inflammation and cytokine release in COVID-19 patients[ 3 ]. It is found in synovial fluid in patients who have spondylarthritis; therefore, this drug has been studied in the setting of ankylosing spondylitis because it may neutralize the cytokine activity and benefit patients[ 26 ].

Pharmacokinetics: Because this drug is still under investigation and is relatively new, little information is available about the pharmacokinetics of Gimsilumab.

Adverse effects: There is currently no clinical trial data available describing the adverse effects of Gimsilumab in the treatment of COVID-19. Since the drug is still under investigation and is relatively new, little information is available about the adverse effects of Gimsilumab.

Dosage: Dosage information for Gimsilumab as a treatment for COVID 19 is not currently available. One study looking at Gimsilumab in the treatment of ankylosing spondylitis administered single or repeat subcutaneous injections once weekly for four weeks[ 26 ]. A trial for the use of Gimsilumab in patients with COVID-19 is planning to administer high dose Gimsilumab on day one and low dose on day eight of treatment, unless the patient is discharged or no longer in need of supplemental oxygen or ventilator support for over 48 h on day 8[ 27 ]. Unfortunately, specific information regarding what constitutes “high dose” and “low dose” is not available.

Randomized clinical trials: Gimsilumab was originally being studied as a treatment for ankylosing spondylitis and thus far a Phase 1 study has been completed which demonstrated a favorable safety and tolerability profile with no serious adverse events. However, because of its possible applicability in COVID-19, trials will be focused on the prevention of acute respiratory distress syndrome (ARDS) and cytokine storm instead of Phase 2 trials on rheumatic diseases[ 26 ]. It has been found that the percentage of GM-CSF expressing white blood cells are higher in the blood of intensive care unit (ICU)-admitted COVID-19 patients when compared to healthy controls, as well as non-ICU patients[ 28 ]. One study is examining the efficacy and safety of Gimsilumab in people with lung injury or ARDS secondary to COVID-19 infection in a randomized double blinded trial[ 27 ]. This study will have a 2-wk treatment period and a 22-wk follow-up period[ 27 ].

ANTIVIRALS

Arbidol (umifenovir)

Chemical composition: Arbidol{ethyl-6-bromo-4-[(dimethylamino)methyl]-5-hydroxy-1-methyl-2-[(phenylthio)methyl]-indole-3-carboxylate} is a broad-spectrum antiviral compound[ 29 ]. Although it has been used for the treatment and prevention of influenza in Russia and China for decades, it has not been approved for this purpose by the Food and Drug Administration in the United States[ 29 ].

Mechanism of action: The anti-viral mechanism involves inhibition of virus-mediated fusion with the target membrane and a resulting block of virus entry into target cells[ 30 ]. It inhibits viral glycoprotein conformational changes during membrane fusion by interacting with the phospholipid membrane and protein motifs enriched in aromatic residues[ 30 ].

Pharmacokinetics: Regarding metabolism, 33 metabolites of Arbidol have been identified in human plasma, urine, and feces[ 31 ]. The drug is rapidly absorbed when administered orally, with a t max of 1.38 h[ 31 ]. The main biotransformation pathways of Arbidol are sulfoxidation, glucuronidation, sulfate conjugation, and dimethylamine N-demethylation[ 31 ]. The primary urine metabolites are glucuronide and sulfate conjugates[ 31 ]. The liver and intestines are primarily responsible for the metabolism of Arbidol in humans, with CYP3A4 being a major isoform and other P450 enzymes and flavin-containing monooxygenases playing less significant roles in metabolism[ 31 ]. It has a long elimination half-life, which is reported to be 25 h, and high plasma exposure[ 31 ].

Adverse effects: One study reported that 43.7% of patients had digestive upset, such as mild diarrhea and nausea, with Arbidol treatment[ 32 ]. In this study, however, no patients stopped treatment with Arbidol due to adverse effects[ 32 ]. Another study showed an increase in serum uric acid in 2.5% of patients taking Arbidol[ 33 ].

Dosage: Current recommendations for Arbidol dosing are as follows: 200mg orally 3 times a day for no more than 10 d in adults[ 34 ]. In clinical trials, 200 mg orally 3 times a day for 7-10 d or longer is currently being used and investigated[ 33 , 35 - 37 ].

Randomized clinical trials: Zhang et al [ 38 ] conducted a retrospective case-control study to evaluate the efficacy of Arbidol as a post-exposure prophylactic medication on family members and health care workers who were exposed to patients confirmed to have SARS-CoV-2 infection by real-time reverse transcription polymerase chain reaction (RT-PCR) and chest computed tomography (CT) scan. Logistic regression based on the data of the family members and health care workers with Arbidol or Oseltamivir prophylaxis showed that Arbidol post-exposure prophylaxis was protective against the development of COVID-19 [hazard ratio 0.025, 95% confidence interval (CI) 0.003-0.209, P = 0.0006 for family members and hazard ratio 0.056, 95%CI = 0.005-0.662, P = 0.0221 for health care workers][ 38 ]. They suggested Arbidol could reduce the infection risk of the novel coronavirus in hospital and family settings[ 38 ]. Though the study had a number of limitations and warrants further research, most healthcare facilities in China have already adopted the usage of Arbidol as a standard protocol for post-exposure prophylaxis of COVID-19 transmission among its healthcare workers.

ASC09

Chemical composition: ASC09, which is also referred to as TMC-310911, is not currently FDA approved for the treatment of COVID-19[ 39 ]. It is similar in structure to darunavir and is an investigational drug currently under study for use in HIV-1 infections as well as for treatment for COVID-19[ 40 , 41 ].

Mechanism of action: ASC09 is an HIV protease inhibitor[ 39 ]. Regarding HIV-1, the drug binds to the protease enzyme in order to inhibit the cleavage of Gag-Pol polyproteins and Gag polyproteins. This inhibition prevents the formation of mature virus particles capable of infection[ 40 ].

Pharmacokinetics: The drug is metabolized mainly by CYP enzymes[ 42 ]. The terminal elimination half-life of ASC09 ranged from 1.25 to 3.751 h in one study. Multiple oral doses that ranged from 150 mg twice daily to 900 mg twice daily were also studied and showed that the terminal elimination ranged from 12.23 to 16.48 h[ 42 ].

Adverse effects: In one Phase IIa study the authors looked at the adverse effects of ASC09 in HIV patients[ 43 ]. The study found that the most common adverse events were fatigue and nausea, which occurred in at least 10% of the 33 participants[ 43 ]. Gastrointestinal-related adverse effects occurred in approximately 27% of participants[ 43 ]. No deaths or serious adverse events were reported. No adverse events resulted in patient discontinuation of the study. There were rises in liver enzymes in two patients, although the presence of cytomegalovirus hepatitis in one patient may have accounted for this abnormality[ 43 ].

Dosage: Dosage information for ASC09 as a treatment for COVID 19 is not currently available. One clinical trial planned to give ASC09/ritonavir in 300 mg/100 mg tablets twice daily for 14 d[ 44 ].

Randomized clinical trials: To date, there are no completed clinical trials evaluating the efficacy of ASC09 in the treatment of COVID-19. One current clinical trial is set to evaluate the efficiency and safety of ASC09/ritonavir and lopinavir/ritonavir for COVID-19 infections[ 44 ]. The study is a randomized, open-label trial and is estimated to have 160 participants[ 44 ]. Further clinical trials are needed to determine whether ASC09 is an efficacious therapeutic option.

Azvudine

Chemical composition: Azvudine, also known as FNC, is a cytidine analogue. It is a substrate for deoxycytidine kinase and is phosphorylated to deoxycytidine[ 45 ]. Azvudine is used in the treatment of HIV-1 infected patients and has been introduced in large part due to the emergence of resistance against previously created nucleoside analogues, namely 3TC[ 45 ].

Mechanism of action: Azvudine is a nucleoside reverse transcriptase inhibitor (NRTI) that has activity against HIV-1, HIV-2, hepatitis B, and hepatitis C[ 45 ]. The drug is activated after phosphorylation into an NRTI-triphosphate derivative[ 45 ]. As an NRTI-triphosphate derivative, the drug competes with deoxynucleoside triphosphates for incorporation into the viral strand by the enzyme reverse transcriptase[ 45 ]. The NRTI derivative lacks a 3’-OH group, so the incorporation into the viral strand prevents elongation[ 45 ].

Pharmacokinetics: Azvudine is currently being tested in clinical trials for HIV treatment and COVID-19; therefore, there is currently no published information about the pharmacokinetics of Azvudine. Regarding HIV, computer modeling has been used to predict the binding of Azvudine to reverse transcriptase[ 45 ].

Adverse effects: There is currently no clinical trial data available describing the adverse effects of Azvudine in the treatment of COVID-19.

Dosage: Dosage information for Azvudine as a treatment for COVID-19 is not currently available.

Randomized clinical trials: To date, there are no completed clinical trials evaluating the efficacy of Azvudine in the treatment of COVID-19. One clinical trial is studying the efficacy of Azvudine in the treatment of COVID-19-related pneumonia[ 46 ]. The study is a randomized, double blinded, double dummy, parallel controlled study[ 46 ]. Further clinical trials are needed to determine whether Azvudine is an efficacious therapeutic option.

Favilavir/Favipiravir/T-705/Avigan

Chemical composition: Favipiravir (6-fluoro-3-hydroxy-2-pyrazinecarboxamide) is a pyrazine-carboxamide derivative and a pyrazine analogue that was initially approved for use against influenza[ 47 ]. Its activity is primarily against RNA viruses. It has known activity against influenza and has been promising in the treatment of avian influenza. It has been studied for the treatment of Ebola virus, Lassa virus, and COVID-19[ 47 ].

Mechanism of action: Favipiravir is converted to its active form, favipiravir-ribofuranosyl-5'-triphosphate, which then inhibits viral RNA-dependent RNA polymerase. Inhibition of the viral polymerase halts transcription and replication of the viral genome[ 47 ]. It is thought that it is incorporated into an RNA strand, preventing elongation and proliferation of the viral genome[ 48 ]. Favipiravir is also reported to prevent the entry and exit of the virus in host cells[ 49 ].

Pharmacokinetics: Favipiravir is reported to have a bioavailability of 97.6%[ 50 ]. Its volume of distribution is approximately 15-20 L, and 54% of the drug appears to be plasma protein bound with 65% of this fraction being bound to albumin and 6.5% bound to a1-acid glycoprotein[ 50 ]. The drug is predominantly excreted renally, and its elimination half-life is reported to be between 2 to 5.5 h[ 50 ].

Adverse effects: The safety profile of Favipiravir in the treatment of COVID-19 is yet to be established. It is known to cause QT prolongation[ 50 ]. Additionally, it is recommended that cardiac and hepatic monitoring take place during treatment[ 50 ]. Favipiravir is a known teratogen and should be avoided in women who may become or are confirmed to be pregnant[ 48 ].

Dosage: Currently, the safety and efficacy of Favipiravir for the treatment of COVID-19 is being evaluated in a number of clinical trials. As such, there is not currently a proven recommended dosage. Open-label studies in China have used 1600 mg twice daily on the first day of treatment and 600 mg twice daily used for the following 7-10 or 14 d, respectively[ 33 , 51 , 52 ]. There is a need for continued clinical trials to determine an efficacious dose.

Randomized clinical trials: Limited clinical trial data regarding the efficacy of Favipiravir for COVID-19 infections is available. A small, open label, prospective, randomized multicenter study in China evaluated the use of Favipiravir vs Arbidol for patients with COVID-19[ 33 ]. It was found that the use of Favipiravir was associated with a greater degree of clinical recovery, defined as greater than 72 h of temperature less than 36.6 degrees C, respiratory rate less than 24/min, oxygen saturation greater than 98% on room air, and either mild or no cough when compared to Arbidol[ 33 ]. Clinical recovery rates were greater in both moderate (71% vs 56%) and severe cases of COVID-19 (6% vs 0%)[ 33 ]. In an additional open-label, nonrandomized trial of patients in China with non-severe COVID-19 infection, it was found that the use of Favipiravir was associated with decreased median time to viral clearance when compared to a control group receiving lopinavir/ritonavir treatment (4 d vs 11 d)[ 52 ]. The patients also noted improvements on chest CT scan on day 14[ 52 ]. Additional clinical trials are currently underway[ 53 - 55 ].

Xofluvaa (Baloxavir marboxil)

Structure/mechanism of action: Baloxavir marboxil is a cap-dependent endonuclease protein inhibitor that acts on influenza A and B viruses[ 56 , 57 ]. This inhibits mRNA synthesis, thus blocking viral replication[ 56 , 57 ]. It is currently FDA approved for the treatment of acute uncomplicated influenza A and B infections in individuals aged 12 and older who have been symptomatic for no more than 48 h.

Pharmacokinetics: Baloxavir marboxil is metabolized to an active form, Baloxavir acid[ 56 ]. The median time to peak plasma concentration is 4 h, and the mean half-life is 79.1 h[ 56 ]. It is 93 to 94% protein bound, and is primarily excreted in the feces (80%) with smaller amounts being excreted renally (15%)[ 56 ]. It is metabolized by the UGT1A3 and CYP3A4 pathways[ 56 ].

Adverse effects: Currently, only one randomized clinical trial has assessed the use of Baloxavir marboxil in the treatment of COVID-19. Because of this, there is limited data available regarding side effects of Baloxavir marboxil in COVID-19 patients. In studies evaluating the drug for the treatment of patients with influenza, the most common adverse effects were diarrhea (3.2%), bronchitis (2.6%), nasopharyngitis (1.5%), nausea (1.5%), and sinusitis (1.1%), although it was thought that these adverse events were not likely due to the trial regimen[ 58 ].

Dosage: The dosing protocol used in one of the only documented randomized control trials was 80 mg of Baloxavir marboxil once daily on day 1 and day 4[ 59 ]. Additionally, if patients still test positive for COVID-19 on day 7, an additional 80 mg dose can be given[ 59 ]. The total amount of doses given is not to exceed three 80 mg doses[ 59 ].

Randomized clinical trials: Randomized clinical trial data for the use of Baloxavir marboxil in COVID-19 is limited. One exploratory, single center, open-label, randomized control trial in China compared the addition of Baloxavir marboxil to Favipiravir and control along with the current standard antiviral treatment regimen in patients with confirmed COVID-19 infection[ 59 ]. The current standard regimen included either Lopinavir/Ritonavir in combination with inhaled interferon-alpha or Darunavir/Cobicistat and Arbidol in combination with inhaled interferon alpha[ 59 ]. 29 patients were included in the study, and they were assigned to either receive Baloxavir marboxil, Favipiravir, or control, in addition to standard antiviral therapy. Twenty-four patients in the trial tested negative for COVID-19 within 14 d of starting the trial. The percentage of patients turning virus negative was 70%, 77%, and 100% in the Baloxavir group, Favipiravir group, and control group respectively[ 59 ]. Additionally, the daily viral load of the patients in each group was measured throughout the course of the trial, and the addition of Baloxavir or Favipiravir did not appear to improve the time to achieve half viral clearance when compared to control[ 59 ]. Based on this study, there is no evidence that Baloxavir marboxil is an effective treatment against COVID-19 patients. Additional studies may be necessary to confirm these findings.

Remdesivir

Chemical composition: Remdesivir (GS-5734) is a phosphoramidate prodrug of a 1’-cyano-substituted nucleotide analogue[ 60 ]. Its triphosphate form (RDV-TP) resembles adenosine triphosphate (ATP) and is used as a substrate of several viral RNA-dependent RNA polymerase enzymes or complexes. It is a broad-spectrum antiviral medication, with activity against RNA viruses such as Ebola, Marburg, MERS-CoV, SARS-CoV, respiratory syncytial virus (RSV), Nipah virus (NiV), and Hendra virus. It has shown prophylactic and therapeutic efficacy in nonclinical models of these coronaviruses[ 61 - 63 ].

Mechanism of action: Replication of SARS-CoV-2 depends on the viral RNA-dependent RNA polymerase, which is the target of the nucleotide analogue Remdesivir. The SARS-CoV-2 RNA-dependent RNA polymerase is composed of the non-structural proteins nsp8 and nsp12[ 64 ]. Enzyme kinetics indicated that this RNA-dependent RNA polymerase efficiently incorporates the active triphosphate form of Remdesivir into RNA[ 64 ]. Additionally, the mechanism of Remdesivir’s anti-MERS-CoV activity is likely through premature termination of viral RNA transcription as shown in biochemical assays using recombinant EBOV, NiV, and RSV polymerase[ 64 ]. This drug has shown potent inhibitory activity against Remdesivir with intact proof reading and with low level of resistance to target mutations[ 64 ].

Pharmacokinetics: Remdesivir has a short plasma half-life of 0.39 h[ 65 ]. When given to cynomolgus monkeys, a 10 mg/kg dose rapidly distributed to the testes, epididymis, eyes, and brain within 4 h[ 65 ]. Levels measured in the brain were much lower than other tissues due to poor blood-brain barrier penetration, however levels in the brain were detectable at 168 h after the dose was given. It is primarily eliminated renally (74%), with a smaller amount of fecal excretion (18%)[ 66 ].

Adverse effects: During a study by Grein et al [ 67 ], the most common adverse events noted during use of Remdesivir in patients with COVID-19 included rash, diarrhea, hypotension, abnormal liver function and renal impairment. Serious adverse events such as acute kidney injury, septic shock, and multi-organ failure were noted in 23% of patients[ 67 ]. During the study, 60% of participants suffered at least one adverse event and 8% discontinued treatment prematurely[ 67 ].

Dosage: Current dosage recommendation of Remdesivir in COVID-19 is a bolus dose of 200 mg IV diluted in normal saline (0.9%) or 5% dextrose to be given over 60 min on day 1, followed by 100 mg IV to be given diluted over 60 min for the next 9 d[ 66 ].

Randomized clinical trials: Wang et al [ 68 ] enrolled and randomly assigned 237 patients to a treatment group (158 to Remdesivir and 79 to placebo). Remdesivir use was not associated with a difference in time to clinical improvement [hazard ratio 1.23 (95%CI 0.87–1.75)][ 68 ]. Although not statistically significant, patients receiving Remdesivir had a faster time to clinical improvement than those receiving placebo among patients with symptom duration of 10 d or less [hazard ratio 1.52 (0.95-2.43)][ 68 ]. Adverse events were reported in 102 (66%) of 155 Remdesivir recipients vs 50 (64%) of 78 placebo recipients[ 68 ]. Remdesivir was stopped early because of adverse events in 18 (12%) patients vs four (5%) patients who stopped placebo early[ 68 ].

On April 29, 2020, the National Institute of Allergy and Infectious Diseases (NIAID) announced interim results of a randomized controlled trial named ACTT (Adaptive COVID-19 Treatment Trial) involving 1063 patients conducted at 68 sites (47 in United States and 21 in Europe and Asia)[ 69 ]. Preliminary results indicate that the median time to recovery was 11 d for patients treated with Remdesivir compared to 15 d for those who received placebo, thereby suggesting that patients who received Remdesivir had a 31% faster time to recovery than those receiving placebo ( P < 0.001)[ 69 ]. However, the survival benefit with Remdesivir was not statistically significant compared to the control, as the Remdesivir group had a mortality rate of 8.0% compared to 11.6% for the placebo group ( P = 0.059)[ 69 ].

The SIMPLE trial is an open-label, randomized, phase 3 clinical trial comparing the clinical improvement of 5-d (short-course) vs 10-d (long-course) treatment duration of Remdesivir ( n = 397) in hospitalized patients with severe (evidence of pneumonia and reduced oxygen levels, not requiring mechanical ventilation) COVID-19, in addition to the standard of care in 15 countries[ 70 ]. Secondary objectives included rates of adverse events and additional measures of clinical response in both treatment groups. The study showed that the 10-d course had similar outcomes compared to the 5-d course [odds ratio (OR) 0.75, 95%CI 0.51-1.12] assessed on day 14, without any new safety signals[ 70 ]. An exploratory analysis of this study suggested a larger benefit if Remdesivir was initiated within 10 d of symptom onset[ 70 ]. Pooled data from both study arms found that at day 14, 62% vs 49% of participants were discharged from the hospital, if Remdesivir was started within 10 d vs after 10 d of symptoms, respectively[ 70 ].

Beigel et al [ 71 ] conducted a double-blind, randomized, placebo-controlled trial using IV Remdesivir in adults hospitalized with COVID-19 with evidence of lower respiratory tract involvement. Patients were randomly assigned to receive either Remdesivir (200 mg loading dose on day 1, followed by 100 mg daily for up to 9 additional days) or placebo for up to 10 d[ 71 ]. The primary outcome was the time to recovery, defined by either discharge from the hospital or hospitalization for infection-control purposes[ 71 ]. Preliminary results from the 1059 patients (538 assigned to Remdesivir and 521 to placebo) indicated that those who received Remdesivir had a median recovery time of 11 d (95%CI, 9.0 to 12.0) as compared with 15 d (95%CI, 13.0 to 19.0) in those who received placebo (rate ratio for recovery, 1.32; 95%CI, 1.12 to 1.55; P < 0.001)[ 71 ]. The Kaplan-Meier estimates of mortality by 14 d were 7.1% with Remdesivir and 11.9% with placebo (hazard ratio for death, 0.70; 95%CI, 0.47 to 1.04)[ 71 ]. Serious adverse events were reported for 21.1% in the Remdesivir group and 27% in the placebo group. Thus, Remdesivir was superior to placebo in shortening the time to recovery in adults hospitalized with COVID-19 and evidence of lower respiratory tract infection[ 71 ].

CELL AND RNA-BASED THERAPIES

Mesenchymal stem cells

Structural composition: Mesenchymal stem cells (MSCs) are considered to be a highly proliferative, minimally invasive, potential treatment of COVID-19[ 72 ]. MSCs are stem cells that are isolated from various body tissues, including dental pulp, menstruation blood, bone marrow, adipose tissues, buccal fat pad, and the fetal liver[ 72 ]. MSCs are multipotent stem cells and can be expanded easily to a clinical volume[ 73 ]. Clinical trials have not shown adverse reactions to allogeneic MSCs[ 73 ].

Mechanism of action: It is believed that COVID-19 triggers immune system over-activation that is responsible for damaging infected tissue. The immune system produces large amounts of pro-inflammatory factors, inducing a cytokine storm that may induce the overproduction of immune cells[ 74 ]. It is thought that MSCs prevent the cytokine storm by preventing the release of cytokines by the immune system and promoting repair through the reparative properties of stem cells[ 72 ]. Once the MSCs are given through an intravenous injection, the MSC population is trapped in the lung, which may help in the recovery of the lung’s microenvironment, protect alveolar epithelial cells, cure lung dysfunction, and intercept pulmonary fibrosis in COVID-19-related pneumonia[ 75 ].

Adverse effects: There is currently no clinical trial data available describing the adverse effects of MSCs in the treatment of COVID-19.

Dosage: Dosage information for MSCs as a treatment for COVID-19 is not currently available.

Randomized clinical trials: Several clinical trials have been registered to investigate the use of MSCs in the treatment of COVID-19. One study by Leng et al [ 75 ] evaluated the effects of MSC transplantation in 7 patients with COVID-19 pneumonia. At 48 h post MSC transplant, all 7 patients showed improvement of clinical symptoms[ 75 ]. MSCs have shown promise in the treatment of ARDS, inflammation, pneumonia, and sepsis, all of which contribute significantly to mortality in COVID-19 patients[ 76 ]. The safety and efficacy of intravenous MSC therapy has not been shown, and there is some concern about this mode of delivery because of the high levels of procoagulant tissue factor present in MSC infusions[ 76 ]. This could of course be dangerous for patients with COVID-19, who are already thought to be in a hypercoagulable state[ 76 ].

MultiStem

Structural composition: MultiStem is an allogeneic cell therapy made of multipotent adherent bone marrow cells[ 77 ]. MultiStem cells have been studied for the treatment of ischemic stroke, ulcerative colitis, acute myocardial infarction, and graft vs host disease prophylaxis in allogenic hematopoietic stem cell transplant[ 78 ].

Mechanism of action: MultiStem cells appear to be therapeutic due in part to their pro-angiogenic effects and their ability to modulate the immune system[ 79 ]. MultiStem cells lack major histocompatibility complex (MHC) II, which means that they do not create a proliferative response when cultured alongside allogeneic T-cells and ultimately that they reduce T cell proliferation when the T cells are stimulated with irradiated, allogeneic stimulator cells[ 80 ]. MultiStem is also immunosuppressive due to the presence of soluble factors[ 78 ].

Adverse effects: There is currently no clinical trial data available describing the adverse effects of MultiStem in the treatment of COVID-19. One study looked at the administration of MultiStem alongside hematopoietic stem cell transplants[ 81 ]. They found that overall, there was good tolerance to the therapy with no associated infusion toxicity, increased infection incidence, or graft failure[ 81 ].

Dosage: There is currently no clinical trial data available describing the appropriate dosage for MultiStem in the treatment of COVID-19.

Randomized clinical trials: There is currently no clinical trial data available describing the efficacy and safety of MultiStem in the treatment of COVID-19. One clinical trial is hoping to look at the efficacy of MultiStem in the treatment of COVID-19 induced ARDS. The study is a multicenter, open-label, single active treatment arm study followed by a double-blind, randomized, placebo-controlled phase. The goals of this study are to evaluate the safety and efficacy of MultiStem for people with moderate to severe ARDS[ 82 ].

RNA based therapies

Structural composition: Small interfering RNAs, also known as short interfering RNAs, silencing RNAs, or siRNAs, are non-coding, double stranded RNA molecules that are typically 20-25 base pairs in length.

Mechanism of action: SiRNA molecules are capable of regulating gene expression through RNA interference[ 83 ]. RNA interference allows for post-transcriptional gene silencing and degradation of target mRNAs[ 84 ]. SARS-CoV-2 has a protease sequence (specifically in protease 3CL) known as nsp5 that appears to be highly conserved, making this sequence a potential target of siRNA therapeutics[ 85 ]. Other targets that have been considered are the viral helicase and the viral RNA-dependent RNA polymerase[ 85 ]. It is believed that siRNAs can target these highly conserved sequences of SARS-CoV-2 and suppress the viral impact in the lungs, ultimately allowing for treatment of COVID-19 infection[ 86 ].

Pharmacokinetics: Information regarding the pharmacokinetics of RNA based therapy in the treatment for COVID-19 is not currently available.

Adverse effects: There is currently no clinical trial data available describing the adverse effects of RNA based therapy in the treatment of COVID-19. Previous work has shown that though beneficial, siRNA can induce unwanted side effects[ 85 ]. The side effects associated with siRNA therapy may be due to a phenomenon called off-targeting, which is when siRNAs interfere with transcripts besides the target RNA[ 87 ]. The first evidence of this effect was reported in 2003 by Jackson et al [ 89 ] Strategies have been proposed to minimize off-targeting, most of which deal with planning siRNA experiments and designing appropriate siRNA for therapeutics[ 87 ].

Dosage: Dosing information for RNA based therapies as a treatment for COVID-19 is not currently available.

Randomized clinical trials: To date, there are no published clinical trials evaluating the efficacy of RNA based therapy in the treatment of COVID-19. Researchers have previously tested the efficacy of in vitro utilization of amidoamine nanocarriers for siRNA onto lung epithelial cells, which may be useful in targeting SARS-COV-2 because the primary site of infection is the ciliated cells of the human lung[ 86 , 89 ].

MISCELLANEOUS TREATMENT

APN01: recombinant human angiotensin-converting enzyme

Structural composition: APN01 is a soluble, glycosylated recombinant form of the human angiotensin-converting enzyme 2 (rhACE2). It has both antihypertensive and antineoplastic properties[ 90 ].

Mechanism of action: The drug is thought to cleave angiotensin II to form angiotensin-1-7. Angiotensin-1-7 is thought to have a variety of functions, including counteracting the cardiovascular actions of angiotensin II and inhibiting cyclooxygenase-2. It is believed that when pro-inflammatory prostaglandins are made, the angiotensin-1-7 G-protein-coupled receptor Mas is activated, potentially diminishing tumor cell proliferation[ 90 ]. Previous research showed that ACE2 is a key receptor for SARS-CoV-2, and that APN01 could block early stages of SARS-CoV-2 infections, suggesting that treatment with APN01 may be useful in the treatment of COVID-19[ 91 ]. One publication showed that SARS-COV-2 replicates in human blood vessels and kidneys, and this replication may be blocked by APN01[ 91 ]. By binding to the spike protein, rhACE2 can reduce binding to ACE2 at the cell membrane, leading to decreased internalization of SARS-COV-2 and reduced viral load[ 91 ].

Pharmacokinetics: Information regarding the pharmacokinetics of APN01 in the treatment for COVID-19 is not currently available.

Adverse effects: Information regarding the adverse effects of APN01 in the treatment for COVID-19 is currently not available.

Dosage: Dosage information for APN01 as a treatment for COVID-19 is not currently available.

Randomized clinical trials: APN01 is currently in clinical trials for its efficacy in treating COVID-19. One study aims to enroll 200 participants in a randomized, double-blinded study[ 92 ]. In vitro and in vivo studies are needed to truly understand the effects of APN01 in COVID-19 infections.

CQ/HCQ

Structural composition: CQ and HCQ belong to a class of drugs known as 4-Aminoquinolines[ 93 ]. Both have a flat aromatic core and are weakly basic[ 94 ]. CQ has been historically used as an antimalarial and anti-amoebic agent, while HCQ has been used as an antirheumatic agent, as well as more recently as a therapy for the Zika virus and the 2004 SARS outbreaks[ 95 ]. HCQ is a more tolerable and safer derivative of CQ and has potent activity against SARS CoV-2 in vitro [ 96 ]. HCQ differs from CQ due to the presence an N-Hydroxyethyl side chain in place of the N-diethyl group, which makes it more soluble[ 95 ].

Mechanism of action: Numerous mechanisms have been postulated as to how CQ/HCQ achieves its anti-malarial, ani-viral, and anti-rheumatic effects, however the overall picture remains poorly understood. The most common theory is that as they are both weak bases, they tend to accumulate in lysosomes, increasing the pH and disrupting several enzymes that ultimately leads to the inhibition of the post-translational modification of newly synthesized proteins[ 97 ]. This disruption of the protein degradation pathway interferes with antigen processing and can prevent MHC class II mediated antigen presentation resulting in its anti-rheumatic effects[ 97 ]. Another theory is that they may interfere with endosome mediated viral entry secondary to alkalization of the entry endosomes[ 97 ]. This change in endosomal pH also allows CQ/HCQ to downregulate toll-like receptors (TLRs) along with TLR-mediated signal transduction[ 95 ]. They also are known to decrease the production of cytokines such as IL-1, IL-6, and tumor necrosis factor by mononuclear cells[ 98 ].

Pharmacokinetics: CQ/HCQ are absorbed in the upper gastrointestinal tract with the fraction absorbed being approximately 74%[ 93 ]. They are approximately 50% plasma protein bound, with an extremely long half-life (> 40 d)[ 93 , 99 ]. It is believed that the extended half-life is likely due to a large volume of distribution[ 93 ]. They are primarily metabolized by the liver, specifically the CYP3A4 and CYP2C3 enzymes, and are renally cleared[ 93 ]. CQ/HCQ bind strongly to melanin, and can deposit in high concentrations in the eyes and skin[ 100 ].

Adverse effects: CQ/HCQ are both well tolerated medications. The most common side effects include gastrointestinal effects such as nausea, vomiting, dyspepsia and cramps[ 101 ]. It may also cause headaches, tinnitus, itching, and rashes[ 102 ]. The dose limiting side effect is macular retinopathy, however this is more common in CQ as opposed to HCQ[ 103 ] Both medications have QT prolongation effects which may lead to cardiac arrest, especially when combined with Azithromycin, which has been done for the treatment of COVID-19[ 104 ].

Dosage: HCQ dosage consists of 6 d of therapy, with a 400 mg dose given every 12 h for the first day, and 200 mg given every 12 h for the subsequent 5 d[ 105 ]. HCQ was given emergency use authorization by the FDA in March 2020, however, was subsequently revoked in June 2020 due to safety concerns. It is currently not recommended unless a patient is enrolled in a clinical trial[ 106 ].

Randomized clinical trials: HCQ had been implemented in the treatment of COVID-19 prior to any meaningful randomized clinical trials. This was done on the basis of in vitro data as well as an open label non-randomized clinical trial published in March 2020 by Gautret et al [ 105 ]. This trial had enrolled 20 patients to receive HCQ 200 mg three times a day for a total of 10 d[ 105 ]. The control group (16 patients) were patients who had refused treatment or had contraindications to HCQ. The primary endpoint was virologic clearance at day 6 post-inclusion. Results showed that at day 6 post-inclusion, 70% of patients receiving HCQ had achieved virologic clearance as compared to 12.5% in the control group[ 105 ]. The limitations of this study include small sample size as well as lack of randomization and blinding.

The first true randomized control trial to evaluate efficacy of HCQ for treatment COVID-19 was conducted by Tang et al [ 107 ] This was a multi-center, open label, randomized control trial comparing viral clearance at 28 d in 150 patients, randomized to a HCQ arm and a standard of care arm with intention to treat analysis. Patients who had received HCQ received a dose of 600 mg twice daily for three days followed by 400 mg twice daily for 2-3 wk[ 107 ]. The results showed no discernable difference in viral clearance between the HCQ group and standard of care group (85.4% and 81.3% respectively)[ 107 ].

A randomized control trial to assess safety and efficacy of higher doses of CQ was conducted by Borba et al [ 108 ] in March 2020. This was a parallel, double masked, randomized clinical trial involving 81 patients. The participants were divided into two groups, with 41 patients receiving high dose CQ and 40 receiving low dose CQ. High dose CQ was considered 600 mg twice daily for 10 d while low dose was considered 450 mg twice daily for the first day and then once daily for the subsequent 4 d[ 108 ]. Primary outcome was a decrease in mortality by 50% in the high dose group as opposed to the low dose group[ 108 ]. Results demonstrated a higher mortality at day 13 in the high dose group compared to the low dose group (39% and 15% respectively)[ 108 ]. Due to safety concerns secondary to increased adverse effects in the high dose group the trial was discontinued prematurely[ 108 ].

The RECOVERY trial was a UK-based randomized clinical trial to test numerous drugs for COVID-19, including HCQ[ 109 ]. A total of 1542 patients were randomized to HCQ as compared with 3132 randomized to standard of care alone. The primary endpoint was 28-d mortality, which showed no significant difference between the two groups (25.7% HCQ vs 23.5% standard care) [95%CI 0.98-1.26; P = 0.1][ 109 ]. On June 5 th 2020, the chief investigators of the study had released the afore-mentioned preliminary results as well as a statement conveying the lack of any meaningful mortality benefits in patients with COVID-19 and that the investigators have stopped enrolling participants in the HCQ arm of the RECOVERY trial[ 109 ]. The results of the HCQ arm of RECOVERY trial have not been published.

HCQ has also been evaluated as a possible post-exposure prophylaxis agent for COVID-19. This was done in the context of a randomized, double-blinded, placebo-controlled trial[ 110 ]. The study population included adults who had high-risk household or occupational exposure (distance less than 6 ft for more than 10 min without a mask) or moderate risk (the same distance with a face mask but no eye shield) to someone with laboratory confirmed COVID-19[ 110 ]. Within 4 d of exposure, patients were randomly assigned to receive either placebo or HCQ. The primary outcome was the incidence of laboratory-confirmed COVID-19 or illness compatible with COVID-19 within 14 d[ 110 ]. There were 821 asymptomatic participants, and incidence of COVID-19 in the high-risk exposure population did not differ significantly[ 110 ].

Azithromycin

Structural Composition: Azithromycin is an azalide which is a subclass of macrolide antibiotics derived from the prototype Erythromycin[ 111 ]. Azithromycin has a nitrogen added to the 14-membered ring of erythromycin, creating a new 15 membered compound[ 111 ]. The addition of nitrogen creates a dibasic molecule which results in improved antimicrobial activities, pharmacokinetics and fewer side effects as compared with Erythromycin[ 112 ].

Mechanism of action: Azithromycin is a bacteriostatic antibiotic which prevents bacterial growth via inhibition of bacterial protein synthesis by binding to the 50 s ribosomal subunit[ 111 ]. Due to its dibasic nature Azithromycin is taken up by white blood cells (WBC) and fibroblasts resulting in a neutrophilic intracellular:extracellular ratio of 226:1 after 24 h of incubation[ 113 ]. This WBC uptake is believed to be the reason for Azithromycin’s effective intracellular and extracellular activity, as well as increased drug levels localized to the site of infection[ 113 ]. Regarding the mechanism of action against SARS-CoV-2, one in-vitro study suggested that due to its intracellular accumulation, Azithromycin increases the pH of intracellular organelles[ 114 ]. This alteration in pH would interfere with intracellular viral activities, a mechanism very similar to CQ/HCQ[ 114 ]. Another potential mechanism of action is the anti-inflammatory activity shown by macrolides, thus alleviating the proinflammatory state of COVID-19[ 106 ].

Pharmacokinetics: Azithromycin is rapidly absorbed after oral dosing, with excellent tissue penetration and a long half-life of roughly 68 h[ 115 ]. It has a large volume of distribution of approximately 31 L/kg. The primary route of elimination is via biliary excretion[ 116 ]. Approximately 6% of azithromycin is excreted unchanged in urine[ 116 ].

Adverse effects: Azithromycin is generally safe and well tolerated. The most commonly reported side effects are gastrointestinal and include nausea, diarrhea and abdominal pain[ 117 ]. Rash, transaminitis, and hepatomegaly have also been seen with azithromycin[ 117 ]. Rarely it may cause QT interval prolongation and should be used with caution when administering to patients concomitantly with other QT-prolonging drugs such as CQ/HCQ[ 117 ].

Dosage: Since the outbreak of COVID-19, many clinicians are using Azithromycin off-label, usually concomitantly with HCQ. Due to lack of supporting evidence regarding its efficacy, it is no longer used in the treatment of COVID-19. It was given as a 500 mg dose on day 1, followed by 250 mg for the next four days for a total of a 5-d treatment course[ 105 ]. Currently it is only recommended that Azithromycin be administered in the context of clinical trials[ 106 ].

Randomized clinical trials: All clinical trials conducted utilizing Azithromycin for the treatment of COVID-19 have been performed in the context of Azithromycin being administered as an adjunct to CQ/HCQ. The are no well-controlled, prospective, randomized clinical trials evaluating the efficacy of azithromycin for the treatment of COVID-19.

Colchicine

Structural composition: Colchicine is a tricyclic, lipid soluble alkaloid. Its chemical formula is N-(5,6,7,9, tetrahydro-1,2,3,10, tetramethoxy-9 oxobenzo[a] hep-tain-7-yl) acetamide. Colchicine has long been used for the treatment of gout, but has since been known to be used in the treatment of several disorders including familial Mediterranean fever, primary biliary cirrhosis, psoriasis, sarcoidosis, scleroderma, amyloidosis, pericarditis, Sweet syndrome, and Behcet’s disease[ 118 ].

Mechanism of action: There are several proposed mechanisms regarding the potential efficacy of Colchicine as a therapeutic for COVID-19. First, Colchicine is believed to exert its anti-inflammatory effects through binding to beta-tubulin in neutrophils[ 119 ]. This allows for the inhibition of assembly and polymerization of microtubules, interfering with several cellular functions. This includes production of chemokines and decreasing neutrophil degranulation, chemotaxis, and phagocytosis[ 119 ]. Additionally, Colchicine has been shown to be an inhibitor of the NLRP3 inflammasome, which plays a major role in the pathophysiology of ARDS[ 120 ]. Several SARS-CoV-2 proteins have been hypothesized to activate the NLP3 inflammasome, thus leading to the development of ARDS[ 120 ]. Inactivation of the neutrophilic function and inhibition of the NLP3 inflammasome lead to the anti-inflammatory and cytokine suppression effects that may contribute to Colchicine’s potential mechanism against COVID-19.

Pharmacokinetics: After administration, Colchicine is absorbed in the jejunum and ileum[ 121 ]. The peak plasma concentration after oral administration occurs between roughly 30 and 90 min [ 119 , 121 ]. The half-life is thought to be between 9.3 and 10.6 h, and bioavailability has been shown to range from 24% to 88%[ 119 , 122 ]. Colchicine is thought to be widely taken up by tissues, and its protein binding is between 10% and 31%[ 119 , 121 ]. It is thought to be metabolized by the cytochrome P450 CYP3A4 (20%) and it is excreted primarily via the feces[ 118 , 119 ]. It is also thought that 10%-20% of the available metabolites are excreted via the urine[ 118 ].

Adverse effects: There is currently no clinical trial data available describing the adverse effects of colchicine in the treatment of COVID-19. Colchicine is thought to be generally safe and well tolerated, although the therapeutic window is narrow[ 118 ]. Current data suggests that side effects of Colchicine in non COVID-19 use includes GI side effects such as vomiting, diarrhea, cramping, and abdominal pain[ 118 , 119 ]. Additionally, leukopenia and neuromuscular complications are rare side effects that have been reported[ 118 ].

Dosage: Dosage information for Colchicine as a treatment for COVID 19 is not currently available.

Randomized clinical trials: To date, there are no published clinical trials evaluating the efficacy of Colchicine in the treatment of COVID-19. A retrospective study by Gendelman et al [ 123 ] examined the protective role of Colchicine against COVID-19 by determining the rate of baseline usage of the drug in patients with RT-PCR confirmed COVID-19 infection and those who tested negative. The total sample included 14520 subjects, of which 1317 tested positive. There was no significant difference found in Colchicine usage between those who tested positive (0.53%) and those who tested negative (0.48%)[ 123 ]. This retrospective study did not suggest a protective effect of Colchicine against COVID-19. Further clinical trials are needed to determine whether Colchicine is an efficacious therapeutic option.

Corticosteroids/methylprednisolone

Structural composition: Methylprednisolone is a glucocorticoid that is a prednisolone derivative. It is more potent than prednisone[ 124 ]. Methylprednisolone exists in both a succinate formulation (Solu-Medrol), and an acetate suspension (Depo-Medrol).

Mechanism of action: It is speculated that the anti-inflammatory and antifibrotic properties of corticosteroids may prevent an extensive cytokine response, which would result in a faster resolution of pneumonia and systemic inflammation[ 125 , 126 ]. Methylprednisolone is a corticosteroid; therefore, it binds to the glucocorticoid receptor and inhibits proinflammatory signals and promotes anti-inflammatory signals[ 127 ]. The binding of the drug to the glucocorticoid receptor alters gene expression, leading to downstream effects over the course of hours to days[ 127 ]. These effects may be anti-inflammatory when administered at lower doses, or immunosuppressive when administered at higher doses[ 127 ].

Pharmacokinetics: The bioavailability of oral methylprednisolone acetate is 89.9%, and the average volume of distribution is approximately 1.38 L/kg[ 128 , 129 ]. It is 76.8% protein bound in plasma[ 129 ]. It is thought that the drug is metabolized mostly by 20-ketosteroid reductases and 11beta-hydroxysteroid dehydrogenases[ 129 ]. The half-life is 2.3 h[ 128 , 129 ]. Its clearance rate is 336mL/h/kg on average[ 129 ]. One study in animals showed 25-31% of the drug was eliminated in urine while 44-52% was eliminated via fecal route[ 130 ].

Adverse effects: Information regarding adverse events related specifically to COVID-19 infections is not available. One study of methylprednisolone use in Kawasaki disease showed that adverse effects included sinus bradycardia, hyperglycemia, and hypertension[ 131 ]. Hypothalamic-pituitary-adrenal (HPA) suppression is also possible with methylprednisolone administration[ 132 ].

Dosage: One retrospective study used 1-2 mg per kg daily IV for 5-7 d[ 133 ]. A randomized control study administered 40 mg IV every 12 h for 5 d[ 134 ].

Randomized clinical trials: One multicenter, open label randomized controlled study completed in China compared the use of methylprednisolone paired with standard care in patients that had progressed to acute respiratory failure. The results of this study have not yet been published[ 134 ]. Additional studies regarding the efficacy of methylprednisolone have been completed. One retrospective, observational single-center study collected data from 201 confirmed COVID-19 infected patients who had pneumonia that progressed to ARDS[ 135 ]. In these patients, methylprednisolone appeared to reduce the risk of death[ 135 ]. In another retrospective, observational single-center study, data was collected from 46 patients who had severe, confirmed COVID-19 pneumonia that progressed to acute respiratory failure. The study found that methylprednisolone use was associated with shortened disease and improved clinical symptoms (including fever and hypoxia)[ 133 ].

As part of the RECOVERY trial, dexamethasone has been evaluated as a potential treatment for COVID-19[ 137 ]. This was a controlled, open-label, adaptive trial in which a total of 2114 patients were allocated to receive Dexamethasone (6 mg once daily for up to 10 d) and 4321 were allocated to usual standard of care[ 136 ]. The primary outcome was all-cause mortality at 28-d post randomization[ 136 ]. Preliminary results showed a decrease in mortality in the Dexamethasone arm as opposed to the standard of care arm (22.9% vs 25.7% mortality respectively)[ 136 ]. It was also noted that there were variations in the proportional and absolute mortality rate reductions based on the level of ventilatory support that patients initially required[ 136 ]. Dexamethasone decreased mortality by one-third in patients receiving mechanical ventilation (29.3% vs 41.4% mortality) and by one-fifth in those who were receiving non-invasive oxygenation (23.3% vs 26.2% mortality)[ 136 ].

Ivermectin

Structural composition: Ivermectin is a semisynthetic derivative of avermectin B1, consisting of an 90:10 mixture of 22,23-dihydro-avermectin B1a and 22,23-dihydro-avermectin B1b[ 137 , 138 ]. Avermectins are a group a pentacyclic sixteen-membered lactones derived from the soil bacterium Streptomyces avermitilis[ 139 ]. It is a broad spectrum antiparasitic, however it has shown antiviral activity against a number of pathogens including dengue virus, yellow fever virus, and HIV1 virus, among others[ 140 - 142 ].

Mechanism of action: Although the potential mechanism of action of Ivermectin against SARS-CoV-2 is unknown, the novel coronavirus SARS-CoV-2 is very similar to the better studied SARS-CoV. They are both single-stranded positive sense RNA viruses, and SARS-CoV is thought to utilize IMPalpha/B1, a heterodimer responsible for integrase protein nuclear import[ 143 ]. It is thought that Ivermectin may play a role in inhibiting viral nuclear import into the host cell through its interactions with IMPalpha/B1[ 143 ].

Pharmacokinetics: Ivermectin is only approved for oral administration in humans. Following oral administration, plasma concentrations are similar to the dose received[ 138 ]. It is widely distributed in the human body, bound strongly to plasma proteins at 93.2%[ 137 ]. After administration, the compound has been found to be present in adipose tissue, skin, fascia, and nodule[ 137 ]. It is found at highest concentrations in adipose tissue[ 137 ]. The drug is metabolized by the cytochrome P450 system, and is excreted almost exclusively in feces over a 12 d period, with only 1% of the dose given being excreted in the urine[ 137 , 138 ].

Adverse effects: The adverse effects of Ivermectin as a therapy for COVID-19 are unknown, however it is thought to be very well tolerated in the treatment of parasitic infections. Side effects noted from clinical trials include fatigue (0.9%), abdominal pain (0.9%), anorexia (0.9%), constipation (0.9%), diarrhea (1.8%), nausea (1.8%), dizziness (2.8%), vertigo (0.9%), tremor (0.9%) and Mazzotti reaction, including arthralgias, lymph node enlargement and tenderness, edema, and urticarial rash[ 138 ].

Dosage: No human trials have been published regarding the usage of Ivermectin as a treatment modality for COVID-19. For the treatment of strongyloidiasis, Ivermectin is given as a single oral dose providing 200 mcg per kilogram of body weight[ 138 ]. For Onchocerciasis, a single dose providing 150 mcg per kilogram of bodyweight is given[ 138 ].

Randomized clinical trials: To date, there have been no studies published regarding the efficacy of Ivermectin as a potential treatment for COVID-19 in humans. However, Caly et al [ 143 ] tested the anti-viral effects of Ivermectin against COVID-19 infected Vero/hSLAM cells in vitro, and found that at 24 h, the amount of viral RNA was reduced by 93% in the infected cells. At 48 h, there was greater than 5000 fold decrease in the amount of viral RNA seen in COVID-19 infected cells[ 143 ]. There was no toxicity observed in any of the samples during the study[ 143 ]. While this is promising, clinical trials are needed to determine the safety and efficacy of Ivermectin as a potential treatment for COVID-19.

Convalescent plasma

Mechanism of action: Convalescent plasma is the collection of plasma from an individual who has previously been infected with COVID-19 and developed antibodies. Administration of the plasma from patients with resolved infections leads to passive immunization, and reception of these antibodies in those who are currently sick may lead to reduced symptom burden and mortality. The use of convalescent plasma during pandemics is not a new trend, as it was used during the SARS, MERS, Ebola, and H1N1 pandemics as well[ 144 - 147 ]. Theoretically, the use of convalescent plasma should be given to infected patients early in the course of illness before the immune system has had the time to develop antibodies on its own.

Adverse events: Adverse effects have varied. Li et al [ 148 ] reported adverse events in 2 of 52 patients receiving convalescent plasma, which included transfusion reactions such as febrile non-hemolytic and severe transfusion associated dyspnea. Shen et al [ 149 ] reported no adverse events in 5 critically ill patients receiving convalescent plasma. Finally, a study by Duan et al [ 150 ] found no serious adverse events in 10 ICU patients receiving plasma, however one patient did develop an evanescent facial red spot.

Dosage: Dosing of convalescent plasma for the treatment of COVID-19 has varied among the current available studies. Dosage of convalescent plasma given in a clinical trial by Li et al [ 148 ] was 4-13 mL/kg of recipient body weight, transfused at 10 mL for 15 min, followed by 100 mL per hour. Shen et al [ 149 ] gave 200-250 mL twice on the same day as collection from the donor. Lastly, Duan et al [ 150 ] gave patients one dose of 200 mL of convalescent plasma.

Randomized clinical trials: Li et al [ 148 ] performed an open-label, multicenter, randomized clinical trial at 7 hospitals in Wuhan, China. The trial enrolled 103 patients hospitalized with COVID-19. Fifty-two patients received convalescent plasma in addition to standard treatment (based on Chinese national treatment guidelines and hospital practice guidelines for COVID-19) and 51 patients received standard treatment alone[ 148 ]. Patients received plasma at a dose of 4-13 mL/kg of recipient body weight[ 148 ]. The primary outcome was time to clinical improvement within a 28 d period, defined as either discharge or a reduction of 2 points on a 6 point COVID-19 severity scale[ 148 ]. For all patients, the authors found no significant difference between the convalescent plasma group and control (51.9% vs 43.1%; P = 0.26)[ 148 ]. Furthermore, there was no significant difference in 28 d mortality between the two groups (15.7% vs 24.0%; P = 0.30)[ 148 ]. Adverse events were reported in two patients receiving convalescent plasma treatment, both of which were transfusion related reactions[ 148 ]. This trial did not demonstrate significant time to improvement in patients receiving convalescent plasma for the treatment of COVID-19.

Shen et al [ 149 ] describe a case series of 5 critically ill patients in Shenzhen, China with COVID-19 and ARDS receiving convalescent plasma in addition to antiviral agents. The patients received two transfusions of 200-250 mL of convalescent plasma in one day. In this trial, viral load declined and was negative in all five patients within 12 d of treatment[ 149 ]. Furthermore, all patients saw reductions in temperature within 3 d, improvements in chest imaging, and improvements in PaO2/FiO2 ratio. Four of five patients receiving mechanical ventilation no longer required respiratory support within 9 d of receiving convalescent plasma[ 149 ]. No adverse events were reported. Although this study was a small case series, and there were no controls, it shows promise for the use of convalescent plasma in the treatment of COVID-19.

Lastly, Duan et al [ 150 ] performed a pilot study including 10 patients with severe COVID-19. Patients received a single 200 mL dose of convalescent plasma in addition to various antiviral therapies and intravenous methylprednisolone. Within 3 d, all 10 patients had significant improvement in their symptoms including fever, cough, shortness of breath, and chest pain[ 150 ]. Additionally, 2 of 3 patients receiving mechanical ventilation were weaned to high flow nasal cannula, and one patient was able to discontinue high flow nasal cannula[ 150 ]. All patients showed improvement of pulmonary lesions on CT after transfusion. Lastly, neutralizing antibody titers increased in 5 patients, and viral RNA decreased to undetectable levels in 3 patients after 2 d, three patients after 3 d, and one patient after 6 d[ 150 ]. This trial, again, was performed without controls. It does however show promise for the use of convalescent plasma in patients with severe COVID-19.

ECMO

ECMO is often used as a last resort in patients with critical pulmonary or cardiovascular compromise. ECMO has various configurations that can be altered based on the needs of the patient. The potential use of ECMO has been a hot topic in recent discussions. Positive ECMO experiences in critically ill patients infected with Middle Eastern respiratory syndrome (MERS) has encouraged some to use ECMO in those infected with COVID-19[ 151 ]. Theoretically, it is possible for ECMO to be used in COVID-19 infected patients to support cardiac and pulmonary function; however, the efficacy and validity in the clinical setting remains unanswered.

Mechanism of action: Most often, COVID-19 patients who may benefit from ECMO are those with ARDS refractory to standard treatment. Patients in this clinical stage have impaired gas exchange due to alveolar inflammation and edema. Therefore, patients require oxygenation assistance. There are several configurations of ECMO. Veno-venous ECMO (V-V ECMO drains blood from a large peripheral vein, oxygenates it via a synthetic lung and returns it to the circulation via a large peripheral vein. Newly oxygenated blood then flows through the normal circulatory pathways to provide oxygen to the rest of the body. V-V ECMO settings require that the patient’s heart is functioning appropriately to ensure adequate blood distribution[ 152 ]. Suggested criteria for V-V ECMO use are PaO2/FiO2 < 100 mmHg, PCO2 > 60 mmHg, and/or arterial pH < 7.2[ 153 ].

When a patient’s cardiovascular function is compromised, such as with COVID-19-induced myocarditis, veno-arterial ECMO (V-A ECMO) is the preferred ECMO configuration. In V-A ECMO, venous blood is drained, oxygenated via a synthetic lung and finally returned to the patient’s circulatory system via a large peripheral artery that drains towards the aorta. The ECMO-induced increase in aortic blood flow improves peripheral perfusion[ 154 ]. V-V/V-A ECMO may be modified in difficult circumstances, such as those with superimposed sepsis or multi-organ dysfunction, in order to add extra lumen and convert the ECMO system from a double lumen to a triple lumen ECMO system. The additional lumen may help optimize settings per patient requirements[ 155 ].

Randomized clinical trials: To date, there are no published clinical trials evaluating the efficacy of ECMO in the treatment of COVID-19. ECMO has been used in patients who have been confirmed to have COVID-19 and in those suspected to have COVID-19 but whose status has not been confirmed. There has been some published work on the efficacy of ECMO despite the lack of clinical trials. One preliminary study form China showed a high mortality rate for COVID-related ARDS patients, reporting a mortality of 50% in a cohort of 28 patients[ 156 ]. A pooled analysis of the data from China, which included the data for 562 COVID-19 patients, studied the effects of ECMO and non-ECMO treatment in the 46% of patients who developed ARDS. Those who did not get treated with ECMO had a mortality rate of 70.9%, while those treated with ECMO had a mortality of 94.1%[ 157 ]. While some data exists that may speak to the efficacy and validity of using ECMO in those infected with COVID-19, there is still a need for randomized clinical trials to understand the effects of this therapy.

CONCLUSION

The COVID-19 pandemic has placed a tremendous burden on our healthcare systems, as well as on researchers and clinicians who are racing to find therapeutics that may be beneficial in combatting this morbid disease. Currently, there is no single treatment that has been proven to provide significant benefit in reducing morbidity and mortality. There are many clinical trials for numerous different therapeutic agents currently underway. By looking back and measuring successful strategies from previous pandemics in addition to carrying out ongoing research, we provide ourselves with the greatest opportunity to find treatments that are beneficial. It is reasonable that we continue to work together as a global community to explore different treatment modalities.

Conflict-of-interest statement: The authors declare no conflict of interests for this article.

Manuscript source: Unsolicited manuscript

Peer-review started: September 18, 2020

First decision: December 1, 2020

Article in press: December 13, 2020

Specialty type: Virology

Country/Territory of origin: United States

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P-Reviewer: Chen YD, Rajcani J S-Editor: Gao CC L-Editor: A P-Editor: Xing YX

1 Bhatraju PK Ghassemieh BJ Nichols M Kim R Jerome KR Nalla AK Greninger AL Pipavath S Wurfel MM Evans L Kritek PA West TE Luks A Gerbino A Dale CR Goldman JD O'Mahony S Mikacenic C Covid-19 in Critically Ill Patients in the Seattle Region - Case Series N Engl J Med 2020 382 2012 2022 32227758 10.1056/NEJMoa2004500 PMC7143164

2 Guan WJ Ni ZY Hu Y Liang WH Ou CQ He JX Liu L Shan H Lei CL Hui DSC Du B Li LJ Zeng G Yuen KY Chen RC Tang CL Wang T Chen PY Xiang J Li SY Wang JL Liang ZJ Peng YX Wei L Liu Y Hu YH Peng P Wang JM Liu JY Chen Z Li G Zheng ZJ Qiu SQ Luo J Ye CJ Zhu SY Zhong NS China Medical Treatment Expert Group for Covid-19 Clinical Characteristics of Coronavirus Disease 2019 in China N Engl J Med 2020 382 1708 1720 32109013 10.1056/NEJMoa2002032 PMC7092819

3 Huang C Wang Y Li X Ren L Zhao J Hu Y Zhang L Fan G Xu J Gu X Cheng Z Yu T Xia J Wei Y Wu W Xie X Yin W Li H Liu M Xiao Y Gao H Guo L Xie J Wang G Jiang R Gao Z Jin Q Wang J Cao B Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China Lancet 2020 395 497 506 31986264 10.1016/S0140-6736(20)30183-5 PMC7159299

4 U.S. Food and Drug Administration Emergency Use Authorization. [cited 2020 July 16]. Available from: https://www.fda.gov/emergency-preparedness-and-response/mcm-legal-regulatory-and-policy-framework/emergency-use-authorization#coviddrugs

5 Huizinga TW Fleischmann RM Jasson M Radin AR van Adelsberg J Fiore S Huang X Yancopoulos GD Stahl N Genovese MC Sarilumab, a fully human monoclonal antibody against IL-6Rα in patients with rheumatoid arthritis and an inadequate response to methotrexate: efficacy and safety results from the randomised SARIL-RA-MOBILITY Part A trial Ann Rheum Dis 2014 73 1626 1634 24297381 10.1136/annrheumdis-2013-204405 PMC4145418

6 Sanofi-Aventis Canada Inc KEVZARATM. [cited 2020 July 16]. Available from: https://pdf.hres.ca/dpd_pm/00037766.PDF

7 Zhang C Wu Z Li JW Zhao H Wang GQ Cytokine release syndrome in severe COVID-19: interleukin-6 receptor antagonist tocilizumab may be the key to reduce mortality Int J Antimicrob Agents 2020 55 105954 32234467 10.1016/j.ijantimicag.2020.105954 PMC7118634

8 Zhou F Yu T Du R Fan G Liu Y Liu Z Xiang J Wang Y Song B Gu X Guan L Wei Y Li H Wu X Xu J Tu S Zhang Y Chen H Cao B Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study Lancet 2020 395 1054 1062 32171076 10.1016/S0140-6736(20)30566-3 PMC7270627

9 Lamb YN Deeks ED Sarilumab: A Review in Moderate to Severe Rheumatoid Arthritis Drugs 2018 78 929 940 29931592 10.1007/s40265-018-0929-z

10 Shares Magazine Sanofi and Regeneron provide update on U.S. Phase 2/3 adaptive-designed trial in hospitalized COVID-19 patients. [cited 2020 July 15]. Available from: https://www.sharesmagazine.co.uk/news/market/6894211/Sanofi-and-Regeneron-provide-update-on-US-Phase-2-3-adaptive-designed-trial-in-hospitalized-COVID-19-patients

11 Benucci M Giannasi G Cecchini P Gobbi FL Damiani A Grossi V Infantino M Manfredi M COVID-19 pneumonia treated with Sarilumab: A clinical series of eight patients J Med Virol 2020 92 2368 2370 32472703 10.1002/jmv.26062 PMC7300861

12 Chen R Chen B Siltuximab (CNTO 328): a promising option for human malignancies Drug Des Devel Ther 2015 9 3455 3458 10.2147/DDDT.S86438 PMC4494175 26170629

13 Sarosiek S Shah R Munshi NC Review of siltuximab in the treatment of multicentric Castleman's disease Ther Adv Hematol 2016 7 360 366 27904739 10.1177/2040620716653745 PMC5089324

14 Gritti G Raimondi F Ripamonti D Riva I Landi F Alborghetti L Frigeni M Damiani M Mico C Fagiuoli S Cosentini R Lorini F Gandini L Novelli L Morgan J Owens B Kanhai K Reljanovic G Rizzi M Di Marco F Rambaldi A IL-6 signalling pathway inactivation with siltuximab in patients with COVID-19 respiratory failure: an observational cohort study. medRxiv. 2020

15 Miao M De Clercq E Li G Clinical significance of chemokine receptor antagonists Expert Opin Drug Metab Toxicol 2020 16 11 30 31903790 10.1080/17425255.2020.1711884

16 Trkola A Ketas TJ Nagashima KA Zhao L Cilliers T Morris L Moore JP Maddon PJ Olson WC Potent, broad-spectrum inhibition of human immunodeficiency virus type 1 by the CCR5 monoclonal antibody PRO 140 J Virol 2001 75 579 588 11134270 10.1128/JVI.75.2.579-588.2001 PMC113953

17 CytoDyn Treatment with CytoDyn's Leronlimab Indicates Significant Trend Toward Immunological Restoration in Severely Ill COVID-19 Patients. [cited 2020 July 16]. Available from: https://www.cytodyn.com/newsroom/press-releases/detail/405/treatment-with-cytodyns-leronlimab-indicates-significant

18 Jacobson JM Thompson MA Lalezari JP Saag MS Zingman BS D'Ambrosio P Stambler N Rotshteyn Y Marozsan AJ Maddon PJ Morris SA Olson WC Anti-HIV-1 activity of weekly or biweekly treatment with subcutaneous PRO 140, a CCR5 monoclonal antibody J Infect Dis 2010 201 1481 1487 20377413 10.1086/652190 PMC2856743

19 Pardoll DM The blockade of immune checkpoints in cancer immunotherapy Nat Rev Cancer 2012 12 252 264 22437870 10.1038/nrc3239 PMC4856023

20 Centanni M Moes DJAR Trocóniz IF Ciccolini J van Hasselt JGC Clinical Pharmacokinetics and Pharmacodynamics of Immune Checkpoint Inhibitors Clin Pharmacokinet 2019 58 835 857 30815848 10.1007/s40262-019-00748-2 PMC6584248

21 Keizer RJ Huitema AD Schellens JH Beijnen JH Clinical pharmacokinetics of therapeutic monoclonal antibodies Clin Pharmacokinet 2010 49 493 507 20608753 10.2165/11531280-000000000-00000

22 Spiers L Coupe N Payne M Toxicities associated with checkpoint inhibitors-an overview Rheumatology (Oxford) 2019 58 vii7 vii16 31816085 10.1093/rheumatology/kez418 PMC6900917

23 Gutzmer R Koop A Meier F Hassel JC Terheyden P Zimmer L Heinzerling L Ugurel S Pföhler C Gesierich A Livingstone E Satzger I Kähler KC German Dermatooncology Group (DeCOG) Programmed cell death protein-1 (PD-1) inhibitor therapy in patients with advanced melanoma and preexisting autoimmunity or ipilimumab-triggered autoimmunity Eur J Cancer 2017 75 24 32 28214654 10.1016/j.ejca.2016.12.038

24 Menzies AM Johnson DB Ramanujam S Atkinson VG Wong ANM Park JJ McQuade JL Shoushtari AN Tsai KK Eroglu Z Klein O Hassel JC Sosman JA Guminski A Sullivan RJ Ribas A Carlino MS Davies MA Sandhu SK Long GV Anti-PD-1 therapy in patients with advanced melanoma and preexisting autoimmune disorders or major toxicity with ipilimumab Ann Oncol 2017 28 368 376 27687304 10.1093/annonc/mdw443

25 Southeast University China Immunoregulatory Therapy for 2019-nCoV. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000 [cited 2020 July 15]. Available from: https://clinicaltrials.gov/ct2/show/NCT04268537 NLM Identifier: NCT04268537

26 Kinevant Sciences GmbH Phase 1 Study With KIN-1901 in Healthy Subjects and Subjects With Ankylosing Spondylitis. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000 [cited 2020 July 15]. Available from: https://clinicaltrials.gov/ct2/show/NCT04205851 NLM Identifier: NCT04205851

27 Kinevant Sciences GmbH A Study to Assess the Efficacy and Safety of Gimsilumab in Subjects With Lung Injury or Acute Respiratory Distress Syndrome Secondary to COVID-19 (BREATHE). In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000 [cited 2020 July 15]. Available from: https://clinicaltrials.gov/ct2/show/NCT04351243 NLM Identifier: NCT04351243

28 Zhou Y Fu B Zheng X Wang D Zhao C Qi Y Sun R Tian Z Xu X Wei H Aberrant pathogenic GM-CSF+ T cells and inflammatory CD14+CD16+ monocytes in severe pulmonary syndrome patients of a new coronavirus. bioRxiv. 2020.

29 Leneva IA Russell RJ Boriskin YS Hay AJ Characteristics of arbidol-resistant mutants of influenza virus: implications for the mechanism of anti-influenza action of arbidol Antiviral Res 2009 81 132 140 19028526 10.1016/j.antiviral.2008.10.009

30 Teissier E Zandomeneghi G Loquet A Lavillette D Lavergne JP Montserret R Cosset FL Böckmann A Meier BH Penin F Pécheur EI Mechanism of inhibition of enveloped virus membrane fusion by the antiviral drug arbidol PLoS One 2011 6 e15874 21283579 10.1371/journal.pone.0015874 PMC3026800

31 Deng P Zhong D Yu K Zhang Y Wang T Chen X Pharmacokinetics, metabolism, and excretion of the antiviral drug arbidol in humans Antimicrob Agents Chemother 2013 57 1743 1755 23357765 10.1128/AAC.02282-12 PMC3623363

32 Deng L Li C Zeng Q Liu X Li X Zhang H Hong Z Xia J Arbidol combined with LPV/r versus LPV/r alone against Corona Virus Disease 2019: A retrospective cohort study J Infect 2020 81 e1 e5 10.1016/j.jinf.2020.03.002 PMC7156152 32171872

33 Chen C Zhang Y Huang J Yin P Cheng Z Wu J Chen S Zhang Y Chen B Lu M Luo Y Ju L Zhang J Wang X Favipiravir versus Arbidol for COVID-19: A Randomized Clinical Trial. medRxiv. 2020

34 Dong L Hu S Gao J Discovering drugs to treat coronavirus disease 2019 (COVID-19) Drug Discov Ther 2020 14 58 60 32147628 10.5582/ddt.2020.01012

35 Zhu Z Lu Z Xu T Chen C Yang G Zha T Lu J Xue Y Arbidol monotherapy is superior to lopinavir/ritonavir in treating COVID-19 J Infect 2020 81 e21 e23 32283143 10.1016/j.jinf.2020.03.060 PMC7195393

36 Guangzhou 8th People's Hospital The Efficacy of Lopinavir Plus Ritonavir and Arbidol Against Novel Coronavirus Infection (ELACOI). In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000 [cited 2020 March 31]. Available from: https://clinicaltrials.gov/ct2/show/study/NCT04252885 NLM Identifier: NCT04252885

37 Jieming QU Clinical Study of Arbidol Hydrochloride Tablets in the Treatment of Pneumonia Caused by Novel Coronavirus. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000 [cited 2020 April 1]. Available from: https://clinicaltrials.gov/ct2/show/study/NCT04260594 NLM Identifier: NCT04260594

38 Zhang JN Wang WJ Peng B Peng W Zhang YS Wang YL Wan Y Chang J Mao L Miao XP Li YN Zhou YF Hu B Potential of Arbidol for Post-exposure Prophylaxis of COVID-19 Transmission: A Preliminary Report of a Retrospective Cohort Study Curr Med Sci 2020 40 480 485 32474860 10.1007/s11596-020-2203-3 PMC7260450

39 Copertino Jr DC, Lima B, Duarte R, Wilkin T, Gulick R, Mulder Rougvie MD, Nixon D. Antiretroviral Drug Activity and Potential for Pre-Exposure Prophylaxis Against COVID-19 and HIV Infection. 2020 10.1080/07391102.2021.1901144 PMC8448789 33734021

40 National Institutes of Health TMC-310911. [cited 2020 July 15]. Available from: https://aidsinfo.nih.gov/drugs/549/tmc-310911/0/professional

41 Harrison C Coronavirus puts drug repurposing on the fast track Nat Biotechnol 2020 38 379 381 32205870 10.1038/d41587-020-00003-1

42 Hoetelmans RM Dierynck I Smyej I Meyvisch P Jacquemyn B Marien K Simmen K Verloes R Safety and pharmacokinetics of the HIV-1 protease inhibitor TMC310911 coadministered with ritonavir in healthy participants: results from 2 phase 1 studies J Acquir Immune Defic Syndr 2014 65 299 305 24121757 10.1097/QAI.0000000000000011

43 Stellbrink HJ Arastéh K Schürmann D Stephan C Dierynck I Smyej I Hoetelmans RM Truyers C Meyvisch P Jacquemyn B Mariën K Simmen K Verloes R Antiviral activity, pharmacokinetics, and safety of the HIV-1 protease inhibitor TMC310911, coadministered with ritonavir, in treatment-naive HIV-1-infected patients J Acquir Immune Defic Syndr 2014 65 283 289 24121756 10.1097/QAI.0000000000000003

44 First Affiliated Hospital of Zhejiang University Evaluating and Comparing the Safety and Efficiency of ASC09/Ritonavir and Lopinavir/Ritonavir for Novel Coronavirus Infection. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000 [cited 2020 July 15]. Available from: https://clinicaltrials.gov/ct2/show/NCT04261907 NLM Identifier: NCT04261907

45 Wang RR Yang QH Luo RH Peng YM Dai SX Zhang XJ Chen H Cui XQ Liu YJ Huang JF Chang JB Zheng YT Azvudine, a novel nucleoside reverse transcriptase inhibitor showed good drug combination features and better inhibition on drug-resistant strains than lamivudine in vitro PLoS One 2014 9 e105617 25144636 10.1371/journal.pone.0105617 PMC4140803

46 HeNan Sincere Biotech Co, Ltd A Clinical Trial for Azvudine in the Treatment of Novel Coronavirus Pneumonia (COVID-19). In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000 [cited 2020 July 15]. Available from: https://clinicaltrials.gov/ct2/show/NCT04425772 NLM Identifier: NCT04425772

47 Furuta Y Komeno T Nakamura T Favipiravir (T-705), a broad spectrum inhibitor of viral RNA polymerase Proc Jpn Acad Ser B Phys Biol Sci 2017 93 449 463 10.2183/pjab.93.027 PMC5713175 28769016

48 Japanese Pharmaceuticals and Medical Devices Agency (PMDA) Report on the Deliberation Results. [cited 2020 July 26]. Available from: https://www.pmda.go.jp/files/000210319.pdf

49 National Center for Biotechnology Information PubChem Database. Favipiravir. [cited 2020 July 10]. Available from: https://pubchem.ncbi.nlm.nih.gov/compound/Favipiravir

50 Madelain V Nguyen TH Olivo A de Lamballerie X Guedj J Taburet AM Mentré F Ebola Virus Infection: Review of the Pharmacokinetic and Pharmacodynamic Properties of Drugs Considered for Testing in Human Efficacy Trials Clin Pharmacokinet 2016 55 907 923 26798032 10.1007/s40262-015-0364-1 PMC5680399

51 American Society of Health-System Pharmacists Assessment of Evidence for COVID-19-Related Treatments. [cited 2020 July 26]. Available from: https://www.ashp.org/-/media/assets/pharmacy-practice/resource-centers/Coronavirus/docs/ASHP-COVID-19-Evidence-Table.ashx?la=en&hash=B414CC64FD64E1AE8CA47AD753BA744EDF4FFB8C

52 Cai Q Yang M Liu D Chen J Shu D Xia J Liao X Gu Y Cai Q Yang Y Shen C Li X Peng L Huang D Zhang J Zhang S Wang F Liu J Chen L Chen S Wang Z Zhang Z Cao R Zhong W Liu Y Liu L Experimental Treatment with Favipiravir for COVID-19: An Open-Label Control Study Engineering (Beijing) 2020 6 1192 1198 32346491 10.1016/j.eng.2020.03.007 PMC7185795

53 Ministry of Health Turkey Efficacy and Safety of Hydroxychloroquine and Favipiravir in the Treatment of Mild to Moderate COVID-19. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000 [cited 2020 July 15]. Available from: https://clinicaltrials.gov/ct2/show/NCT04411433 NLM Identifier: NCT04411433

54 Stanford University Oral Favipiravir Compared to Placebo in Subjects With Mild COVID-19. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000 [cited 2020 July 15]. Available from: https://clinicaltrials.gov/ct2/show/NCT04346628 NLM Identifier: NCT04346628

55 King Abdullah International Medical Research Center FAvipiravir and HydroxyChloroquine Combination Therapy (FACCT). In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000 [cited 2020 July 15]. Available from: https://clinicaltrials.gov/ct2/show/NCT04392973 NLM Identifier: NCT04392973

56 Baker DE Baloxavir Marboxil Hosp Pharm 2019 54 165 169 31205326 10.1177/0018578719841044 PMC6535926

57 Mifsud EJ Hayden FG Hurt AC Antivirals targeting the polymerase complex of influenza viruses Antiviral Res 2019 169 104545 31247246 10.1016/j.antiviral.2019.104545

58 Hayden FG Sugaya N Hirotsu N Lee N de Jong MD Hurt AC Ishida T Sekino H Yamada K Portsmouth S Kawaguchi K Shishido T Arai M Tsuchiya K Uehara T Watanabe A Baloxavir Marboxil Investigators Group Baloxavir Marboxil for Uncomplicated Influenza in Adults and Adolescents N Engl J Med 2018 379 913 923 30184455 10.1056/NEJMoa1716197

59 Lou Y Liu L Qiu Y Clinical Outcomes and Plasma Concentrations of Baloxavir Marboxil and Favipiravir in COVID-19 Patients: an Exploratory Randomized, Controlled Trial. medRxiv. 2020. 10.1016/j.ejps.2020.105631 PMC7585719 33115675

60 Siegel D Hui HC Doerffler E Clarke MO Chun K Zhang L Neville S Carra E Lew W Ross B Wang Q Wolfe L Jordan R Soloveva V Knox J Perry J Perron M Stray KM Barauskas O Feng JY Xu Y Lee G Rheingold AL Ray AS Bannister R Strickley R Swaminathan S Lee WA Bavari S Cihlar T Lo MK Warren TK Mackman RL Discovery and Synthesis of a Phosphoramidate Prodrug of a Pyrrolo[2,1-f][triazin-4-amino] Adenine C-Nucleoside (GS-5734) for the Treatment of Ebola and Emerging Viruses J Med Chem 2017 60 1648 1661 28124907 10.1021/acs.jmedchem.6b01594

61 de Wit E Feldmann F Cronin J Jordan R Okumura A Thomas T Scott D Cihlar T Feldmann H Prophylactic and therapeutic remdesivir (GS-5734) treatment in the rhesus macaque model of MERS-CoV infection Proc Natl Acad Sci USA 2020 117 6771 6776 32054787 10.1073/pnas.1922083117 PMC7104368

62 Sheahan TP Sims AC Leist SR Schäfer A Won J Brown AJ Montgomery SA Hogg A Babusis D Clarke MO Spahn JE Bauer L Sellers S Porter D Feng JY Cihlar T Jordan R Denison MR Baric RS Comparative therapeutic efficacy of remdesivir and combination lopinavir, ritonavir, and interferon beta against MERS-CoV Nat Commun 2020 11 222 31924756 10.1038/s41467-019-13940-6 PMC6954302

63 Wang M Cao R Zhang L Yang X Liu J Xu M Shi Z Hu Z Zhong W Xiao G Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro Cell Res 2020 30 269 271 32020029 10.1038/s41422-020-0282-0 PMC7054408

64 Gordon CJ Tchesnokov EP Woolner E Perry JK Feng JY Porter DP Götte M Remdesivir is a direct-acting antiviral that inhibits RNA-dependent RNA polymerase from severe acute respiratory syndrome coronavirus 2 with high potency J Biol Chem 2020 295 6785 6797 32284326 10.1074/jbc.RA120.013679 PMC7242698

65 Warren TK Jordan R Lo MK Ray AS Mackman RL Soloveva V Siegel D Perron M Bannister R Hui HC Larson N Strickley R Wells J Stuthman KS Van Tongeren SA Garza NL Donnelly G Shurtleff AC Retterer CJ Gharaibeh D Zamani R Kenny T Eaton BP Grimes E Welch LS Gomba L Wilhelmsen CL Nichols DK Nuss JE Nagle ER Kugelman JR Palacios G Doerffler E Neville S Carra E Clarke MO Zhang L Lew W Ross B Wang Q Chun K Wolfe L Babusis D Park Y Stray KM Trancheva I Feng JY Barauskas O Xu Y Wong P Braun MR Flint M McMullan LK Chen SS Fearns R Swaminathan S Mayers DL Spiropoulou CF Lee WA Nichol ST Cihlar T Bavari S Therapeutic efficacy of the small molecule GS-5734 against Ebola virus in rhesus monkeys Nature 2016 531 381 385 26934220 10.1038/nature17180 PMC5551389

66 U.S. Food and Drug Administration Fact Sheet for Health Care Providers Emergency use Authorization (EUA) of Remdesivir. [cited 2020 July 27]. Available from: https://www.fda.gov/media/137566/download

67 Grein J Ohmagari N Shin D Diaz G Asperges E Castagna A Feldt T Green G Green ML Lescure FX Nicastri E Oda R Yo K Quiros-Roldan E Studemeister A Redinski J Ahmed S Bernett J Chelliah D Chen D Chihara S Cohen SH Cunningham J D'Arminio Monforte A Ismail S Kato H Lapadula G L'Her E Maeno T Majumder S Massari M Mora-Rillo M Mutoh Y Nguyen D Verweij E Zoufaly A Osinusi AO DeZure A Zhao Y Zhong L Chokkalingam A Elboudwarej E Telep L Timbs L Henne I Sellers S Cao H Tan SK Winterbourne L Desai P Mera R Gaggar A Myers RP Brainard DM Childs R Flanigan T Compassionate Use of Remdesivir for Patients with Severe Covid-19 N Engl J Med 2020 382 2327 2336 32275812 10.1056/NEJMoa2007016 PMC7169476

68 Wang Y Zhang D Du G Du R Zhao J Jin Y Fu S Gao L Cheng Z Lu Q Hu Y Luo G Wang K Lu Y Li H Wang S Ruan S Yang C Mei C Wang Y Ding D Wu F Tang X Ye X Ye Y Liu B Yang J Yin W Wang A Fan G Zhou F Liu Z Gu X Xu J Shang L Zhang Y Cao L Guo T Wan Y Qin H Jiang Y Jaki T Hayden FG Horby PW Cao B Wang C Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial Lancet 2020 395 1569 1578 32423584 10.1016/S0140-6736(20)31022-9 PMC7190303

69 National Institutes of Health NIH clinical trial shows Remdesivir accelerates recovery from advanced COVID-19. [cited 2020 July 27]. Available from: https://www.nih.gov/news-events/news-releases/nih-clinical-trial-shows-remdesivir-accelerates-recovery-advanced-covid-19

70 Gilead Sciences Study to Evaluate the Safety and Antiviral Activity of Remdesivir (GS-5734™) in Participants With Severe Coronavirus Disease (COVID-19). In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000 [cited July 15, 2020]. Available from: https://clinicaltrials.gov/ct2/show/NCT04292899 NLM Identifier: NCT04292899

71 Beigel JH Tomashek KM Dodd LE Remdesivir for the Treatment of Covid-19 - Preliminary Report. Reply N Engl J Med 2020 383 994 32649078 10.1056/NEJMc2022236

72 Golchin A Seyedjafari E Ardeshirylajimi A Mesenchymal Stem Cell Therapy for COVID-19: Present or Future Stem Cell Rev Rep 2020 16 427 433 32281052 10.1007/s12015-020-09973-w PMC7152513

73 Golchin A Farahany TZ Khojasteh A Soleimanifar F Ardeshirylajimi A The Clinical Trials of Mesenchymal Stem Cell Therapy in Skin Diseases: An Update and Concise Review Curr Stem Cell Res Ther 2019 14 22 33 30210006 10.2174/1574888X13666180913123424

74 Mehta P McAuley DF Brown M Sanchez E Tattersall RS Manson JJ HLH Across Speciality Collaboration UK COVID-19: consider cytokine storm syndromes and immunosuppression Lancet 2020 395 1033 1034 32192578 10.1016/S0140-6736(20)30628-0 PMC7270045

75 Leng Z Zhu R Hou W Feng Y Yang Y Han Q Shan G Meng F Du D Wang S Fan J Wang W Deng L Shi H Li H Hu Z Zhang F Gao J Liu H Li X Zhao Y Yin K He X Gao Z Wang Y Yang B Jin R Stambler I Lim LW Su H Moskalev A Cano A Chakrabarti S Min KJ Ellison-Hughes G Caruso C Jin K Zhao RC Transplantation of ACE2 - Mesenchymal Stem Cells Improves the Outcome of Patients with COVID-19 Pneumonia Aging Dis 2020 11 216 228 32257537 10.14336/AD.2020.0228 PMC7069465

76 Moll G Drzeniek N Kamhieh-Milz J Geissler S Volk HD Reinke P MSC Therapies for COVID-19: Importance of Patient Coagulopathy, Thromboprophylaxis, Cell Product Quality and Mode of Delivery for Treatment Safety and Efficacy Front Immunol 2020 11 1091 32574263 10.3389/fimmu.2020.01091 PMC7249852

77 Hess DC Sila CA Furlan AJ Wechsler LR Switzer JA Mays RW A double-blind placebo-controlled clinical evaluation of MultiStem for the treatment of ischemic stroke Int J Stroke 2014 9 381 386 23692637 10.1111/ijs.12065

78 Vaes B Van't Hof W Deans R Pinxteren J Application of MultiStem(®) Allogeneic Cells for Immunomodulatory Therapy: Clinical Progress and Pre-Clinical Challenges in Prophylaxis for Graft Versus Host Disease Front Immunol 2012 3 345 23205020 10.3389/fimmu.2012.00345 PMC3506828

79 Jacobs SA Roobrouck VD Verfaillie CM Van Gool SW Immunological characteristics of human mesenchymal stem cells and multipotent adult progenitor cells Immunol Cell Biol 2013 91 32 39 23295415 10.1038/icb.2012.64 PMC3540326

80 Jacobs SA Pinxteren J Roobrouck VD Luyckx A van't Hof W Deans R Verfaillie CM Waer M Billiau AD Van Gool SW Human multipotent adult progenitor cells are nonimmunogenic and exert potent immunomodulatory effects on alloreactive T-cell responses Cell Transplant 2013 22 1915 1928 23031260 10.3727/096368912X657369

81 Maziarz RT Devos T Bachier CR Goldstein SC Leis JF Devine SM Meyers G Gajewski JL Maertens J Deans RJ Van't Hof W Lazarus HM Single and multiple dose MultiStem (multipotent adult progenitor cell) therapy prophylaxis of acute graft-versus-host disease in myeloablative allogeneic hematopoietic cell transplantation: a phase 1 trial Biol Blood Marrow Transplant 2015 21 720 728 25555450 10.1016/j.bbmt.2014.12.025

82 Athersys Inc MultiStem Administration for COVID-19 Induced ARDS (MACoVIA) (MACoVIA). In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000 [cited 2020 July 15]. Available from: https://clinicaltrials.gov/ct2/show/NCT04367077 NLM Identifier: NCT04367077

83 Liu C Zhou Q Li Y Garner LV Watkins SP Carter LJ Smoot J Gregg AC Daniels AD Jervey S Albaiu D Research and Development on Therapeutic Agents and Vaccines for COVID-19 and Related Human Coronavirus Diseases ACS Cent Sci 2020 6 315 331 32226821 10.1021/acscentsci.0c00272 PMC10467574

84 Elbashir SM Harborth J Lendeckel W Yalcin A Weber K Tuschl T Duplexes of 21-nucleotide RNAs mediate RNA interference in cultured mammalian cells Nature 2001 411 494 498 11373684 10.1038/35078107

85 Wu F Zhao S Yu B Chen YM Wang W Song ZG Hu Y Tao ZW Tian JH Pei YY Yuan ML Zhang YL Dai FH Liu Y Wang QM Zheng JJ Xu L Holmes EC Zhang YZ A new coronavirus associated with human respiratory disease in China Nature 2020 579 265 269 32015508 10.1038/s41586-020-2008-3 PMC7094943

86 Ghosh S Firdous SM Nath A siRNA could be a potential therapy for COVID-19 EXCLI J 2020 19 528 531 32398976 10.17179/excli2020-1328 PMC7214778

87 Scaggiante B Dapas B Farra R Grassi M Pozzato G Giansante C Fiotti N Grassi G Improving siRNA bio-distribution and minimizing side effects Curr Drug Metab 2011 12 11 23 21222588 10.2174/138920011794520017

88 Jackson AL Bartz SR Schelter J Kobayashi SV Burchard J Mao M Li B Cavet G Linsley PS Expression profiling reveals off-target gene regulation by RNAi Nat Biotechnol 2003 21 635 637 12754523 10.1038/nbt831

89 Conti DS Brewer D Grashik J Avasarala S da Rocha SR Poly(amidoamine) dendrimer nanocarriers and their aerosol formulations for siRNA delivery to the lung epithelium Mol Pharm 2014 11 1808 1822 24811243 10.1021/mp4006358 PMC4051247

90 National Cancer Institute Recombinant human angiotensin converting enzyme 2 APN01. [cited 2020 July 29]. Available from: https://www.cancer.gov/publications/dictionaries/cancer-drug/def/recombinant-human-angiotensin-converting-enzyme-2-apn01

91 Monteil V Kwon H Prado P Hagelkrüys A Wimmer RA Stahl M Leopoldi A Garreta E Hurtado Del Pozo C Prosper F Romero JP Wirnsberger G Zhang H Slutsky AS Conder R Montserrat N Mirazimi A Penninger JM Inhibition of SARS-CoV-2 Infections in Engineered Human Tissues Using Clinical-Grade Soluble Human ACE2. Cell 2020; 181 : 905-913 e7 10.1016/j.cell.2020.04.004 PMC7181998 32333836

92 Apeiron Biologics Recombinant Human Angiotensin-converting Enzyme 2 (rhACE2) as a Treatment for Patients With COVID-19 (APN01-COVID-19). In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000 [cited 2020 July 15]. Available from: https://clinicaltrials.gov/ct2/show/NCT04335136 NLM Identifier: NCT04335136

93 Collins KP Jackson KM Gustafson DL Hydroxychloroquine: A Physiologically-Based Pharmacokinetic Model in the Context of Cancer-Related Autophagy Modulation J Pharmacol Exp Ther 2018 365 447 459 29438998 10.1124/jpet.117.245639 PMC5931434

94 Schrezenmeier E Dörner T Mechanisms of action of hydroxychloroquine and chloroquine: implications for rheumatology Nat Rev Rheumatol 2020 16 155 166 32034323 10.1038/s41584-020-0372-x

95 Sahraei Z Shabani M Shokouhi S Saffaei A Aminoquinolines against coronavirus disease 2019 (COVID-19): chloroquine or hydroxychloroquine Int J Antimicrob Agents 2020 55 105945 32194152 10.1016/j.ijantimicag.2020.105945 PMC7156117

96 Meo SA Klonoff DC Akram J Efficacy of chloroquine and hydroxychloroquine in the treatment of COVID-19 Eur Rev Med Pharmacol Sci 2020 24 4539 4547 32373993 10.26355/eurrev_202004_21038

97 Savarino A Boelaert JR Cassone A Majori G Cauda R Effects of chloroquine on viral infections: an old drug against today's diseases? Lancet Infect Dis 2003 3 722 727 14592603 10.1016/S1473-3099(03)00806-5 PMC7128816

98 van den Borne BE Dijkmans BA de Rooij HH le Cessie S Verweij CL Chloroquine and hydroxychloroquine equally affect tumor necrosis factor-alpha, interleukin 6, and interferon-gamma production by peripheral blood mononuclear cells J Rheumatol 1997 24 55 60 9002011

99 Tett S Cutler D Day R Antimalarials in rheumatic diseases Baillieres Clin Rheumatol 1990 4 467 489 2093438 10.1016/s0950-3579(05)80004-4

100 Rainsford KD Parke AL Clifford-Rashotte M Kean WF Therapy and pharmacological properties of hydroxychloroquine and chloroquine in treatment of systemic lupus erythematosus, rheumatoid arthritis and related diseases Inflammopharmacology 2015 23 231 269 26246395 10.1007/s10787-015-0239-y

101 Srinivasa A Tosounidou S Gordon C Increased Incidence of Gastrointestinal Side Effects in Patients Taking Hydroxychloroquine: A Brand-related Issue? J Rheumatol 2017 44 398 10.3899/jrheum.161063 28250164

102 Ruiz-Irastorza G Ramos-Casals M Brito-Zeron P Khamashta MA Clinical efficacy and side effects of antimalarials in systemic lupus erythematosus: a systematic review Ann Rheum Dis 2010 69 20 28 19103632 10.1136/ard.2008.101766

103 Jorge A Ung C Young LH Melles RB Choi HK Hydroxychloroquine retinopathy - implications of research advances for rheumatology care Nat Rev Rheumatol 2018 14 693 703 30401979 10.1038/s41584-018-0111-8

104 Chen CY Wang FL Lin CC Chronic hydroxychloroquine use associated with QT prolongation and refractory ventricular arrhythmia Clin Toxicol (Phila) 2006 44 173 175 16615675 10.1080/15563650500514558

105 Gautret P Lagier JC Parola P Hoang VT Meddeb L Mailhe M Doudier B Courjon J Giordanengo V Vieira VE Tissot Dupont H Honoré S Colson P Chabrière E La Scola B Rolain JM Brouqui P Raoult D Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial Int J Antimicrob Agents 2020 56 105949 32205204 10.1016/j.ijantimicag.2020.105949 PMC7102549

106 Bhimraj A Morgan RL Shumaker AH Lavergne V Baden L Cheng VC Edwards KM Gandhi R Muller WJ O'Horo JC Shoham S Murad MH Mustafa RA Sultan S Falck-Ytter Y Infectious Diseases Society of America Guidelines on the Treatment and Management of Patients with COVID-19 Clin Infect Dis 2020 10.1093/cid/ciaa478 PMC7197612 32338708

107 Tang W Cao Z Han M Wang Z Chen J Sun W Wu Y Xiao W Liu S Chen E Chen W Wang X Yang J Lin J Zhao Q Yan Y Xie Z Li D Yang Y Liu L Qu J Ning G Shi G Xie Q Hydroxychloroquine in patients with mainly mild to moderate coronavirus disease 2019: open label, randomised controlled trial BMJ 2020 369 m1849 32409561 10.1136/bmj.m1849 PMC7221473

108 Borba MGS Val FFA Sampaio VS Alexandre MAA Melo GC Brito M Mourão MPG Brito-Sousa JD Baía-da-Silva D Guerra MVF Hajjar LA Pinto RC Balieiro AAS Pacheco AGF Santos JDO Jr Naveca FG Xavier MS Siqueira AM Schwarzbold A Croda J Nogueira ML Romero GAS Bassat Q Fontes CJ Albuquerque BC Daniel-Ribeiro CT Monteiro WM Lacerda MVG CloroCovid-19 Team Effect of High vs Low Doses of Chloroquine Diphosphate as Adjunctive Therapy for Patients Hospitalized With Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection: A Randomized Clinical Trial JAMA Netw Open 2020 3 e208857 32330277 10.1001/jamanetworkopen.2020.8857 PMC12124691

109 Horby P Landray M No clinical benefit from use of hydroxychloroquine in hospitalised patients with COVID-19. [cited 2020 July 28]. Available from: https://www.recoverytrial.net/news/statement-from-the-chief-investigators-of-the-randomised-evaluation-of-covid-19-therapy-recovery-trial-on-hydroxychloroquine-5-june-2020-no-clinical-benefit-from-use-of-hydroxychloroquine-in-hospitalised-patients-with-covid-19

110 Boulware DR Pullen MF Bangdiwala AS Pastick KA Lofgren SM Okafor EC Skipper CP Nascene AA Nicol MR Abassi M Engen NW Cheng MP LaBar D Lother SA MacKenzie LJ Drobot G Marten N Zarychanski R Kelly LE Schwartz IS McDonald EG Rajasingham R Lee TC Hullsiek KH A Randomized Trial of Hydroxychloroquine as Postexposure Prophylaxis for Covid-19 N Engl J Med 2020 383 517 525 32492293 10.1056/NEJMoa2016638 PMC7289276

111 Bakheit AH Al-Hadiya BM Abd-Elgalil AA Azithromycin Profiles Drug Subst Excip Relat Methodol 2014 39 1 40 24794904 10.1016/B978-0-12-800173-8.00001-5

112 Piscitelli SC Danziger LH Rodvold KA Clarithromycin and azithromycin: new macrolide antibiotics Clin Pharm 1992 11 137 152 1312921

113 Amsden GW Erythromycin, clarithromycin, and azithromycin: are the differences real? Clin Ther 1996 18 56 72; discussion 55 8851453 10.1016/s0149-2918(96)80179-2

114 Poschet JF Perkett EA Timmins GS Deretic V Azithromycin and ciprofloxacin have a chloroquine-like effect on respiratory epithelial cells. bioRxiv. 2020.

115 Damle B Vourvahis M Wang E Leaney J Corrigan B Clinical Pharmacology Perspectives on the Antiviral Activity of Azithromycin and Use in COVID-19 Clin Pharmacol Ther 2020 108 201 211 32302411 10.1002/cpt.1857 PMC7262099

116 Singlas E [Clinical pharmacokinetics of azithromycin] Pathol Biol (Paris) 1995 43 505 511 8539072

117 Schlossberg D Azithromycin and clarithromycin Med Clin North Am 1995 79 803 815 7791424 10.1016/s0025-7125(16)30040-2

118 Ben-Chetrit E Colchicine. Textbook of Autoinflammation. 2019: 729-749

119 Cocco G Chu DC Pandolfi S Colchicine in clinical medicine. A guide for internists Eur J Intern Med 2010 21 503 508 21111934 10.1016/j.ejim.2010.09.010

120 Deftereos SG Siasos G Giannopoulos G Vrachatis DA Angelidis C Giotaki SG Gargalianos P Giamarellou H Gogos C Daikos G Lazanas M Lagiou P Saroglou G Sipsas N Tsiodras S Chatzigeorgiou D Moussas N Kotanidou A Koulouris N Oikonomou E Kaoukis A Kossyvakis C Raisakis K Fountoulaki K Comis M Tsiachris D Sarri E Theodorakis A Martinez-Dolz L Sanz-Sánchez J Reimers B Stefanini GG Cleman M Filippou D Olympios CD Pyrgakis VN Goudevenos J Hahalis G Kolettis TM Iliodromitis E Tousoulis D Stefanadis C The Greek study in the effects of colchicine in COvid-19 complications prevention (GRECCO-19 study): Rationale and study design Hellenic J Cardiol 2020 61 42 45 32251729 10.1016/j.hjc.2020.03.002 PMC7194546

121 Niel E Scherrmann JM Colchicine today Joint Bone Spine 2006 73 672 678 17067838 10.1016/j.jbspin.2006.03.006

122 Achtert G Scherrmann JM Christen MO Pharmacokinetics/bioavailability of colchicine in healthy male volunteers Eur J Drug Metab Pharmacokinet 1989 14 317 322 2633927 10.1007/BF03190118

123 Gendelman O Amital H Bragazzi NL Watad A Chodick G Continuous hydroxychloroquine or colchicine therapy does not prevent infection with SARS-CoV-2: Insights from a large healthcare database analysis Autoimmun Rev 2020 19 102566 32380315 10.1016/j.autrev.2020.102566 PMC7198406

124 Feinberg SM Feinberg AR Pruzansky J Fisherman EW Methylprednisolone (medrol), a potent new anti-inflammatory steroid; therapeutic results in allergic diseases J Am Med Assoc 1957 165 1560 1562 13475063 10.1001/jama.1957.72980300006009b

125 Villar J Belda J Añón JM Blanco J Pérez-Méndez L Ferrando C Martínez D Soler JA Ambrós A Muñoz T Rivas R Corpas R Díaz-Dominguez FJ Soro M García-Bello MA Fernández RL Kacmarek RM DEXA-ARDS Network Evaluating the efficacy of dexamethasone in the treatment of patients with persistent acute respiratory distress syndrome: study protocol for a randomized controlled trial Trials 2016 17 342 27449641 10.1186/s13063-016-1456-4 PMC4957909

126 Russell CD Millar JE Baillie JK Clinical evidence does not support corticosteroid treatment for 2019-nCoV lung injury Lancet 2020 395 473 475 32043983 10.1016/S0140-6736(20)30317-2 PMC7134694

127 Yasir M Goyal A Bansal P Sonthalia S Corticosteroid Adverse Effects 2020 30285357

128 Garg DC Wagner JG Sakmar E Weidler DJ Albert KS Rectal and oral absorption of methylprednisolone acetate Clin Pharmacol Ther 1979 26 232 239 455892 10.1002/cpt1979262232

129 Szefler SJ Ebling WF Georgitis JW Jusko WJ Methylprednisolone versus prednisolone pharmacokinetics in relation to dose in adults Eur J Clin Pharmacol 1986 30 323 329 3732369 10.1007/BF00541537

130 Buhler DR Thomas RC Jr Schlagel CA Absorption, metabolism and excretion of 6-Alpha-Methyl-Prednisolone-3h,21-Acetate following oral and intramuscular administrations in the dog Endocrinology 1965 76 852 864 14294877 10.1210/endo-76-5-852

131 Miura M Ohki H Yoshiba S Ueda H Sugaya A Satoh M Yamagishi H Adverse effects of methylprednisolone pulse therapy in refractory Kawasaki disease Arch Dis Child 2005 90 1096 1097 16177169 10.1136/adc.2004.062299 PMC1720131

132 Joseph RM Hunter AL Ray DW Dixon WG Systemic glucocorticoid therapy and adrenal insufficiency in adults: A systematic review Semin Arthritis Rheum 2016 46 133 141 27105755 10.1016/j.semarthrit.2016.03.001 PMC4987145

133 Wang Y Jiang W He Q Wang C Liu B Zhou P Dong N Tong Q Early, low-dose and short-term application of corticosteroid treatment in patients with severe COVID-19 pneumonia: single-center experience from Wuhan, China. medRxiv. 2020.

134 Peking Union Medical College Hospital Glucocorticoid Therapy for COVID-19 Critically Ill Patients With Severe Acute Respiratory Failure. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000 [cited 2020 April 21]. Available from: https://clinicaltrials.gov/ct2/show/NCT04244591

135 Wu C Chen X Cai Y Xia J Zhou X Xu S Huang H Zhang L Zhou X Du C Zhang Y Song J Wang S Chao Y Yang Z Xu J Zhou X Chen D Xiong W Xu L Zhou F Jiang J Bai C Zheng J Song Y Risk Factors Associated With Acute Respiratory Distress Syndrome and Death in Patients With Coronavirus Disease 2019 Pneumonia in Wuhan, China JAMA Intern Med 2020 180 934 943 32167524 10.1001/jamainternmed.2020.0994 PMC7070509

136 RECOVERY Collaborative Group Horby P Lim WS Emberson JR Mafham M Bell JL Linsell L Staplin N Brightling C Ustianowski A Elmahi E Prudon B Green C Felton T Chadwick D Rege K Fegan C Chappell LC Faust SN Jaki T Jeffery K Montgomery A Rowan K Juszczak E Baillie JK Haynes R Landray MJ Dexamethasone in Hospitalized Patients with Covid-19 - Preliminary Report N Engl J Med 2020 10.1056/NEJMoa2021436 PMC7383595 32678530

137 González Canga A Sahagún Prieto AM Diez Liébana MJ Fernández Martínez N Sierra Vega M García Vieitez JJ The pharmacokinetics and interactions of ivermectin in humans--a mini-review AAPS J 2008 10 42 46 18446504 10.1208/s12248-007-9000-9 PMC2751445

138 U S. Food and Drug Administration Stromectol (Ivermectin). [cited 2020 August 3]. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/Label/2008/050742s022Lbl.pdf

139 Drugbank ca. Ivermectin. [cited 2020 August 3]. Available from: https://www.drugbank.ca/drugs/DB00602

140 Xu TL Han Y Liu W Pang XY Zheng B Zhang Y Zhou XN Antivirus effectiveness of ivermectin on dengue virus type 2 in Aedes albopictus PLoS Negl Trop Dis 2018 12 e0006934 30452439 10.1371/journal.pntd.0006934 PMC6277121

141 Mastrangelo E Pezzullo M De Burghgraeve T Kaptein S Pastorino B Dallmeier K de Lamballerie X Neyts J Hanson AM Frick DN Bolognesi M Milani M Ivermectin is a potent inhibitor of flavivirus replication specifically targeting NS3 helicase activity: new prospects for an old drug J Antimicrob Chemother 2012 67 1884 1894 22535622 10.1093/jac/dks147 PMC3888155

142 Wagstaff KM Sivakumaran H Heaton SM Harrich D Jans DA Ivermectin is a specific inhibitor of importin α/β-mediated nuclear import able to inhibit replication of HIV-1 and dengue virus Biochem J 2012 443 851 856 22417684 10.1042/BJ20120150 PMC3327999

143 Caly L Druce JD Catton MG Jans DA Wagstaff KM The FDA-approved drug ivermectin inhibits the replication of SARS-CoV-2 in vitro Antiviral Res 2020 178 104787 32251768 10.1016/j.antiviral.2020.104787 PMC7129059

144 Cheng Y Wong R Soo YO Wong WS Lee CK Ng MH Chan P Wong KC Leung CB Cheng G Use of convalescent plasma therapy in SARS patients in Hong Kong Eur J Clin Microbiol Infect Dis 2005 24 44 46 15616839 10.1007/s10096-004-1271-9 PMC7088355

145 Arabi Y Balkhy H Hajeer AH Bouchama A Hayden FG Al-Omari A Al-Hameed FM Taha Y Shindo N Whitehead J Merson L AlJohani S Al-Khairy K Carson G Luke TC Hensley L Al-Dawood A Al-Qahtani S Modjarrad K Sadat M Rohde G Leport C Fowler R Feasibility, safety, clinical, and laboratory effects of convalescent plasma therapy for patients with Middle East respiratory syndrome coronavirus infection: a study protocol Springerplus 2015 4 709 26618098 10.1186/s40064-015-1490-9 PMC4653124

146 van Griensven J Edwards T de Lamballerie X Semple MG Gallian P Baize S Horby PW Raoul H Magassouba N Antierens A Lomas C Faye O Sall AA Fransen K Buyze J Ravinetto R Tiberghien P Claeys Y De Crop M Lynen L Bah EI Smith PG Delamou A De Weggheleire A Haba N Ebola-Tx Consortium Evaluation of Convalescent Plasma for Ebola Virus Disease in Guinea N Engl J Med 2016 374 33 42 26735992 10.1056/NEJMoa1511812 PMC5856332

147 Hung IF To KK Lee CK Lee KL Chan K Yan WW Liu R Watt CL Chan WM Lai KY Koo CK Buckley T Chow FL Wong KK Chan HS Ching CK Tang BS Lau CC Li IW Liu SH Chan KH Lin CK Yuen KY Convalescent plasma treatment reduced mortality in patients with severe pandemic influenza A (H1N1) 2009 virus infection Clin Infect Dis 2011 52 447 456 21248066 10.1093/cid/ciq106 PMC7531589

148 Li L Zhang W Hu Y Tong X Zheng S Yang J Kong Y Ren L Wei Q Mei H Hu C Tao C Yang R Wang J Yu Y Guo Y Wu X Xu Z Zeng L Xiong N Chen L Wang J Man N Liu Y Xu H Deng E Zhang X Li C Wang C Su S Zhang L Wang J Wu Y Liu Z Effect of Convalescent Plasma Therapy on Time to Clinical Improvement in Patients With Severe and Life-threatening COVID-19: A Randomized Clinical Trial JAMA 2020 324 460 470 32492084 10.1001/jama.2020.10044 PMC7270883

149 Shen C Wang Z Zhao F Yang Y Li J Yuan J Wang F Li D Yang M Xing L Wei J Xiao H Yang Y Qu J Qing L Chen L Xu Z Peng L Li Y Zheng H Chen F Huang K Jiang Y Liu D Zhang Z Liu Y Liu L Treatment of 5 Critically Ill Patients With COVID-19 With Convalescent Plasma JAMA 2020 323 1582 1589 32219428 10.1001/jama.2020.4783 PMC7101507

150 Duan K Liu B Li C Zhang H Yu T Qu J Zhou M Chen L Meng S Hu Y Peng C Yuan M Huang J Wang Z Yu J Gao X Wang D Yu X Li L Zhang J Wu X Li B Xu Y Chen W Peng Y Hu Y Lin L Liu X Huang S Zhou Z Zhang L Wang Y Zhang Z Deng K Xia Z Gong Q Zhang W Zheng X Liu Y Yang H Zhou D Yu D Hou J Shi Z Chen S Chen Z Zhang X Yang X Effectiveness of convalescent plasma therapy in severe COVID-19 patients Proc Natl Acad Sci USA 2020 117 9490 9496 32253318 10.1073/pnas.2004168117 PMC7196837

151 Alshahrani MS Sindi A Alshamsi F Al-Omari A El Tahan M Alahmadi B Zein A Khatani N Al-Hameed F Alamri S Abdelzaher M Alghamdi A Alfousan F Tash A Tashkandi W Alraddadi R Lewis K Badawee M Arabi YM Fan E Alhazzani W Extracorporeal membrane oxygenation for severe Middle East respiratory syndrome coronavirus Ann Intensive Care 2018 8 3 29330690 10.1186/s13613-017-0350-x PMC5768582

152 Napp LC Bauersachs J Triple cannulation ECMO. In: Firstenberg M, editor. ECMO, InTech Open. 2016

153 Combes A Hajage D Capellier G Demoule A Lavoué S Guervilly C Da Silva D Zafrani L Tirot P Veber B Maury E Levy B Cohen Y Richard C Kalfon P Bouadma L Mehdaoui H Beduneau G Lebreton G Brochard L Ferguson ND Fan E Slutsky AS Brodie D Mercat A EOLIA Trial Group REVA and ECMONet Extracorporeal Membrane Oxygenation for Severe Acute Respiratory Distress Syndrome N Engl J Med 2018 378 1965 1975 29791822 10.1056/NEJMoa1800385

154 Chow J Alhussaini A Calvillo-Argüelles O Billia F Luk A Cardiovascular Collapse in COVID-19 Infection: The Role of Venoarterial Extracorporeal Membrane Oxygenation (VA-ECMO) CJC Open 2020 2 273 277 32363334 10.1016/j.cjco.2020.04.003 PMC7194983

155 Kowalewski M Fina D Słomka A Raffa GM Martucci G Lo Coco V De Piero ME Ranucci M Suwalski P Lorusso R COVID-19 and ECMO: the interplay between coagulation and inflammation-a narrative review Crit Care 2020 24 205 32384917 10.1186/s13054-020-02925-3 PMC7209766

156 Xie J Tong Z Guan X Du B Qiu H Slutsky AS Critical care crisis and some recommendations during the COVID-19 epidemic in China Intensive Care Med 2020 46 837 840 32123994 10.1007/s00134-020-05979-7 PMC7080165

157 Henry BM Lippi G Poor survival with extracorporeal membrane oxygenation in acute respiratory distress syndrome (ARDS) due to coronavirus disease 2019 (COVID-19): Pooled analysis of early reports J Crit Care 2020 58 27 28 32279018 10.1016/j.jcrc.2020.03.011 PMC7118619