key: cord-320632-369kax2m
authors: Song, Yang; Zhang, Min; Yin, Ling; Wang, Kunkun; Zhou, Yiyi; Zhou, Mi; Lu, Yun
title: COVID-19 Treatment: Close to a Cure? – A Rapid Review of Pharmacotherapies for the Novel Coronavirus
date: 2020-07-04
journal: Int J Antimicrob Agents
DOI: 10.1016/j.ijantimicag.2020.106080
sha: 
doc_id: 320632
cord_uid: 369kax2m

Currently, there is no approved therapy for COVID-19. The World Health Organization therefore endorse supportive care only. However, frontline clinicians and researchers have been experimenting with several virus-based and host-based therapeutics since the outbreak in China. China's National Health Commission has issued the first COVID-19 Treatment Guideline with therapy suggestions (7(th) edition attached) which inspired following clinical studies worldwide. Major therapeutics are evaluated in this review. Key evidence from in vitro researches, animal models and clinical researches in emerging coronaviruses are examined. Antiviral therapies remdesivir, lopinavir/ritonavir and umifenovir, if considered, could be initiated before the peak of viral replication for optimal outcomes. Ribavirin may be beneficial as an add-on therapy and is ineffective as a monotherapy. Corticosteroids use should be limited to indicating comorbidities. IVIG is not recommended due to lack of data in COVID-19. Xuebijing may benefit patients with complications of bacterial pneumonia or sepsis. The efficacy of interferon is unclear due to conflicting outcomes in coronavirus studies. Chloroquine and hydroxychloroquine have shown in vitro inhibition of SARS-CoV-2, and the studies on clinical efficacy and whether the benefits outweigh the risk of dysrhythmias remain inconclusive. For patients who developed cytokine release syndrome, interleukin-6 inhibitors may be beneficial.

On December 31st, 2019, several pneumonia cases linked to a seafood market in Wuhan, China were reported to the World Health Organization (WHO). The fast-spreading infection, now known as coronavirus disease 2019 , is caused by a novel coronavirus (SARS-CoV-2) [1] . On March 12th, 2020, WHO declared COVID-19 outbreak a pandemic *2+. According to Johns Hopkins' COVID-19 global case dashboard, by June 12 th , June 23th, 2020, there were 9,157,320 confirmed cases and 473,849 total deaths worldwide [3] . At present, there is no treatment specific for SARS-CoV-2 with efficacy proven by randomized controlled trials (RCT). However, given the scale and rapid spread of this infectious disease, it is obligatory to take a deeper look at medication therapies that have been experimented by frontline clinicians and examine the clinical and laboratory evidence behind them.

The selection of medications in this review is based the 7 th edition of COVID-19 diagnosis and treatment guideline issued by the National Health Commission (NHC) of the People's Republic of China ( Table 2) and relevant clinical studies. Although there are few published RCTs on SARS-CoV-2, the novel virus is found to share 79% genome sequence with severe acute respiratory syndrome coronavirus (SARS-CoV) and about 50% with Middle East respiratory syndrome coronavirus (MERS-CoV) while manifesting overlapping pathogenesis [4, 5] . Relevant in vitro researches, animal models and clinical evidence in all coronaviruses and reviewed by June 12 th June 23th, 2020, in order to gain insights on the potential role of these medication therapies in combating COVID-19. Data for this review were identified by searches of PubMed and references from relevant articles using the search terms "*medication name+" and "SARS-CoV-2", "coronavirus", "COVID-19". Only articles published in English and Chinese (speaking languages of the authors) were included. Patients-based clinical data, when available, were given priority over in vitro and in vivo data. Randomized controlled trials, when available, were given priority over other studies.

Remdesivir (GS-5734) is an investigational drug first developed for the treatment of Ebola [6, 7] . As an adenosine analogue prodrug, it putatively disrupts viral RNA transcription and is viewed as a broadspectrum antiviral agent [8, 9, 10, 11] . Profoundly, remdesivir has exhibited mechanisms to overcome drug resistance and genetic mutations in coronavirus [11] . Patients with severe renal impairment (eGFR< 30 mL/min/1.73) or severe liver disease are excluded from receiving remdesivir [12, 13, 14] .

Remdesivir is generally well tolerated with possible adverse effects of nausea, liver enzyme elevation, hypotension and respiratory failure [6, 7, 13, 14] .

In a mouse SARS-CoV model, remdesivir reduced viral burden and lung pathology efficiently.

Notably, when remdesivir was given after the peak of viral replication and airway epithelium damage, it no longer increased survival or reserved pulmonary function significantly [15] . In February 2020, results of remdesivir in the first nonhuman primate model of MERS became available, revealing successful reduction of clinical signs, lung lesions, and viral replication [16] . The regimen was started 12 hours postinoculation, again signaling the importance of early initiation of therapy [16] .

In February 2020, remdesivir produced high efficacy against SARS-CoV-2 in vitro (half maximal effective concentration EC 50 = 0.77 μM; the 50% cytotoxic concentration CC 50 > 100 μM; the selectivity index SI > 129.87) *9+. The first COVID-19 case in the United States was treated with remdesivir intravenously (IV) [17] . Within 24 hours of remdesivir initiation, the patient became afebrile, off nasal cannulae, with chest rales resolved. However, the viral loads had been downward trending even before remdesivir treatment. It therefore cannot be determined if further viral load decrease and clinical improvement were a direct result of remdesivir. A case series of remdesivir compassionate use (N=53) reported 68% improved oxygenation, 47% discharge and 13% death. The study was weakened by many factors, including most significantly the lack of a paired control group [12] . A double-blinded RCT in China (N=237) revealed no superiority of remdesivir over placebo in time to clinical recovery, 28-day mortality and viral clearance [13] . On average, remdesivir was initiated 11 days post symptom onset, likely past the peak of viral replication. As COVID-19 surge passed in China, the trial only recruited 50% of target sample size, reducing statistical power. SIMPLE, a phase 3 open-label RCT, revealed that remdesivir 5-day vs. 10-day regimens of 200 mg once followed by 100 mg IV daily produced similar outcomes. The group that started remdesivir early (<10 days of symptoms onset) had a higher discharge rate on day 14 (62% vs 49%). The National Institutes of Health (NIH) recently released preliminary result analysis of the Adaptive COVID-19 Treatment Trial (ACTT, N=1063) [18] . In this RCT, remdesivir arm had 31% faster time to recovery than the placebo group (P<0.001). Mortality rate was also reduced in remdesivir group but not statistically significant (8% vs. 11.6%, P=0.059). The forthcoming full publication might reveal whether the promising outcomes were associated with early administration of remdesivir, as suggested by previous studies.

By far, remdesivir has not shown significant mortality benefit. When initiated early, remdesivir appears to expedite recovery. As an investigative drug on incomplete trials, remdesivir is neither recommended nor disapproved by China's NHC and WHO [19, 20] . Currently, remdesivir is recommended by the NIH for hospitalized severe COVID-19 cases as defined by oxygenation needs [21] .

Lopinavir/ritonavir (LPV/r) is a combination protease inhibitor approved for the treatment of human immunodeficiency virus (HIV) infection [22] . Lopinavir binds to viral protease and prevents cleavage of the Gag-Pol polyprotein, resulting in the production of immature, non-infectious viral particles. Ritonavir increases the plasma concentration of lopinavir by inhibiting cytochrome P450 3A (CYP3A) metabolism.

Short-term side effects of LPV/r include nausea, diarrhea, abdominal pain, elevation of liver enzyme and prolongation of QT and PR interval [22] .

Lopinavir showed in vitro cytopathic effect against SARS-CoV at 4 μg/mL *23+. Although the trough (5.5 μg/mL) concentration of lopinavir was above 4 μg/mL, the free drug concentration would likely be below the inhibitory threshold in the setting of high protein binding (98-99%). The unfavorable pharmacodynamics are likely to limit the efficacy of LPV/r in COVID-19 as well.

During the severe acute respiratory syndrome (SARS) outbreak, it appeared that LPV/r conferred clinical benefit in an early phase of the disease to reduce peak viral load before progression to acute respiratory distress syndrome (ARDS). When LPV/r was added to ribavirin and corticosteroids as initial treatment, the mortality and intubation rates were lower than among those who received it as rescue therapy (2.3% vs. 15.6%, 0% vs. 110% respectively, p<0.05) in a multicenter retrospective cohort study [24] . A Hong Kong study retrospectively evaluated the efficacy of LPV/r in 152 patients with SARS.

Patients from the historical control arm received ribavirin while those in the second arm received LPV/r in addition to ribavirin. The second group showed lower rates of 21 days adverse outcomes (ARDS or death) when compared to the historical controls (2.4% vs. 28.8%, p<0.001) [23] .

In a cohort study describing 18 patients with COVID-19 in Singapore, five of 6 patients with hypoxemia started lopinavir/ritonavir (200 mg/100 mg BID). Two patients deteriorated and required admission to intensive care units (ICU). Both patients had persistent nasopharyngeal viral loads during their ICU stay. Limitations of the study include statistical underpowering, suboptimal dose of lopinavir/ritonavir, and delay on initiation of therapy or absence of combination therapy with ribavirin [25] . The ELACOI trial, a single-blind RCT (preprint), included 44 patients with mild to moderate COVID-19 symptoms. There were no differences in the primary outcome of time to negative pharyngeal PCR test between the LPV/r, umifenovir and control groups (8.5, 7 and 4 days, respectively). There were no differences in pyrexia, cough or lung CT findings at day 7 and 14. Five patients in the LPV/r group experienced adverse events including gastrointestinal symptoms and worsening liver function [26] .

On March 18th, the results of the first COVID-19 clinical trial of LPV/r were published.

Unfortunately, LPV/r did not show superiority over standard care for time to achieve clinical improvement, 28-day mortality and viral clearance [27] . In the trial, LPV/r shortened ICU stay by a median of 5 days (95% CI, −9 to 0). The authors made valuable points that the study size is small and the antiviral medication might have been initiated too late in the course of infection.

recommended against by the NIH due to unfavorable pharmacodynamics and lack of proven clinical efficacy [21] .

Ribavirin is a nucleoside analog which has antiviral activity against multiple RNA viruses, including respiratory syncytial virus, SARS-CoV and MERS-CoV by interfering with RNA polymerase and viral protein synthesis [28, 29] . The most severe adverse effects are hemolytic anemia and leukopenia. Other adverse effects include fatigue, pruritus, rash, and gout. Ribavirin is a notorious teratogenic drug and is contraindicated in pregnancy [28, 29] .

Ribavirin, with or without the concomitant use of steroids, was used extensively during the 2013 SARS outbreak. In vitro tests showed that ribavirin inhibited a β coronavirus at relatively high concentration [30] . However, when using ribavirin with interferon-α2b combined, lower concentrations of ribavirin inhibited viral replication in Vero cell lines [30] .

A prospective, uncontrolled study evaluated clinical outcomes of ribavirin and corticosteroids in 132 patients with suspected SARS when fever was not resolved after 48 hours of hospital admission. Twentyfive patients (18.1%) responded to ribavirin and corticosteroids and two of those patients received ribavirin IV [31] . Approximately 49% to 59% of patients treated with ribavirin had a reduction in hemoglobin of more than 2 g/dL from baseline, 36% to 76% had evidence of hemolytic anemia and 40% experienced elevation of transaminases [31, 32] .

In a phase 2 open-label COVID-19 trial, which enrolled 127 patients from 6 Hong Kong hospitals, Hung and his colleagues compared triple therapy (lopinavir/ritonavir 400/100 mg PO every 12 hours, ribavirin 400 mg PO every 12 hours, and interferon β-1b 8 million IU SQ on alternative days) with a control group of LPV/r [33] . Median time from symptom onset to start of treatment was 5 days. In an intent-to-treat analysis, the triple therapy group had a significantly shorter median time to negative PCR test (HR 4.37, 95% CI 1.86-10.24, P=0.0010), shorter clinical improvement and time to complete symptoms (4 days vs. 8 days, respectively) and shorter median hospital stay (9 days vs. 14.5 days). There was no difference in the incidence of adverse events, serious adverse events or duration of nausea/vomiting. Limitations of study include the open-label study design, absence of critically ill patients, and the confounding factor of a subgroup omitting concurrent interferon β -1b if time of symptom onset was 7 days or more.

Ribavirin IV is suggested by China's NHC for COVID-19 as only an add-on therapy to lopinavir/ritonavir or interferon (table 2) [19]. It is not evaluated by the NIH [21] .

Interferon (IFN) induces several parallel antiviral pathways by triggering viral RNA degradation, RNA transcription alteration, protein synthesis inhibition, and apoptosis [34] . The common side effects include flu-like symptoms and mood changes [35] . It is contraindicated in patients with decompensated liver disease, severe autoimmune disease, worsening psychiatric conditions, cytopenia and uncontrolled seizures [35] . During the SARS and MERS outbreaks, interferon was widely used for its antiviral effects after

showing in vitro efficacy [42, 43] . An open-label uncontrolled retrospective study on SARS showed that the addition of Alfacon-1® (IFN-α) to corticosteroids was associated with faster lung recovery and shorter intubation time compared to corticosteroids alone [36] . Similarly, a randomized, 4-arm, openlabel, retrospective study on SARS in Guangzhou, China demonstrated that IFN plus high dose steroid therapy achieved respiratory improvement, faster resolution of pulmonary infiltrates, and less need for MV [37] . Moreover, IFN combined with ribavirin was correlated with neither a faster viral clearance, nor an improved survival rate in older (>50 years old) critically-ill patients with comorbidities [38, 39, 41] .

In vitro data of interferon activity against SARS-CoV-2 suggested that the EC50 in Vero cells of [21] .

Corticosteroids are a type of anti-inflammatory medication that is effective in treatment of a variety of conditions such as asthma, allergic conditions, autoimmune diseases, septic shock, and cancers [45] .

Corticosteroids are a double-edged sword since while these agents inhibit inflammation, they also impair immune response and increase the risk of infection. The adverse effects vary depending on the dosage and duration of therapy. These side effects include hyperglycemia, abdominal obesity, infection, mood swing, osteoporosis, growth retardation, glaucoma and hypertension [45] .

A systematic review of steroids administered to patients with SARS reported no survival benefit and possible harm including avascular necrosis, psychosis, diabetes, and delayed viral clearance [46] .

Another study of patients receiving corticosteroids for MERS found no benefit in mortality but delayed lower respiratory tract clearance of the virus [47] .

Since the outbreak of COVID-19, corticosteroid treatment has been used in up to 45% of infected patients in China [48, 49] . One retrospective observational study showed 72% of the ICU patients with COVID-19 received glucocorticoid therapy [48] . In COVID-19 patients with ARDS, treatment with steroids is associated with decreased risk of death compared to the patients who did not receive steroids (46% vs 61.8%) [50] . However, the existing evidence regarding the use of steroids in this specific patient population remains inconclusive due to methodological limitations. [53] .

As of now, the use of corticosteroids to reduce cytokine-related pulmonary damage in patients with COVID-19 pneumonia is controversial. Robust evidence from well-designed clinical trials is needed for the recommendation of corticosteroid treatment in COVID-19 patients who developed different complications.

Intravenous immunoglobulin (IVIG) is a product of human immunoglobulins derived from plasma, indicated for various immunodeficiencies, autoimmune and inflammatory disorders [54, 55] . IVIG has potent immune replacement and immune modulating effects via complex pathways [55] . In addition, IVIG has anti-inflammatory properties and can neutralize bacterial toxins [56] . The most common adverse reactions of IVIG are headache, fever and tachycardia [55] .

Currently, there is no solid clinical evidence to support the use of IVIG in coronaviruses. Several animal studies found that equine and bovine-produced human immune antibodies can reduce viral titers and accelerate viral clearance of MERS-CoV in mouse models [57] . During the 2013 SARS epidemic, observational studies and case reports described IVIG for the treatment of critically ill patients in combination with antiviral therapies. In a clinical review on SARS, IVIG was used with interferon in all critically ill patients (n=120). The authors concluded that there was no significant benefit [36] . In another prospective observational study, IVIG was used in SARS patients with severe leukopenia or thrombocytopenia, and it appeared to be effective for controlling cytopenia by increasing leukocyte and platelet counts. However, without a control group, IVIG's role in SARS treatment remains undetermined [58] .

Since the outbreak of COVID-19 in China, clinicians have used IVIG in patients infected with SARS-CoV-2 based on extrapolated IVIG data from SARS and MERS. In a descriptive study of COVID-19, 27% of 99 patients received IVIG, but the efficacy and safety of IVIG in was not addressed in this study [47] . Several observational case reports suggest that high dose IVIG at the early stage of clinical deterioration may improve clinical outcomes in patients with severe symptoms [59, 60] . 

Xuebijing (XBJ) is a widely used traditional herbal medicine in China for its anti-inflammatory and antiendotoxin effects [61, 62] . It is a five-herbal combination (carthamus tinctorius, radix paeoniae rubra, ligusticum wallichii, salvia miltirrhiza and angelica sinensis). The common side effects include infusion reactions of rash, tachycardia, hypotension and GI discomforts including nausea, vomiting, abdominal pain and/or diarrhea [61, 62] .

In a meta-analysis of case-control studies on sepsis, XBJ significantly reduced 28-day mortality and improved clinical parameters including the Acute Physiology and Chronic Health Evaluation II score (APACHE II), WBC, C-reactive protein (CRP), procalcitonin and body temperature [61] . That being said, the efficacy of XBJ in sepsis needs to be confirmed in a RCT. The current clinical data on XBJ in ARDS are inconsistent. One RCT showed reduction in duration of MV, ICU stay and Murray score, while the other RCT revealed no difference in these clinical outcomes [63, 64] . However, neither of the ARDS studies proved significant 28-day mortality benefit. Further well-designed RCT with larger sample size is warranted to conclude on XBJ in ARDS. In a multicenter RCT on critically-ill patients with severe community-acquired pneumonia (CAP), XBJ significantly improved pneumonia severity index, 28-day mortality, duration of MV, and ICU stay [65] . 

Umifenovir is a synthetic antiviral drug marketed in Russia and China for treating seasonal influenza. It has shown broad-spectrum antiviral activity against other viruses including SARS-CoV [66] . It is generally well tolerated.

Umifenovir is used alone or in combination with other antiviral treatment in a few clinical studies. In one trial, a total of 81 COVID-19 non-ICU patients were assigned to either umifenovir group or control group. The median times from onset of symptoms to SARS-CoV-2 RT-PCR negative were similar. No clinical differences were reported and the umifenovir group had slightly longer hospital stay (13d vs. 11d) [67] . In a COVID-19 case series study, the combination of umifenovir, lopinavir/ritonavir and traditional Chinese medicine alleviated pneumonia symptoms in all four patients and decreased viral load to undetectable in two [68] . A retrospective cohort study on non-ventilated COVID-19 patients (N=33) compared LPV/r plus umifenovir and LPV/r monotherapy over treatment of 5-21 days [69] . The LPV/r plus umifenovir combination group had a higher negative viral detection rate on day 7 and day 14, with significantly improved chest CT scans on day 7. However, inflammation markers were not compared at baseline. The LPV/r monotherapy group had significantly higher corticosteroids usage, which could delay viral clearance.

All available clinical studies on umifenovir are with significant limitations in study designs and sample sizes. It appears that umifenovir monotherapy is ineffective. The combination of umifenovir with other antivirals might benefit viral clearance and chest CT improvement. Whether the positive outcome is achieved by using antiviral combination strategy or by adding umifenovir remains to be studied. All these studies should be treated as hypothesis generating and should be interpreted with great caution.

Umifenovir is a newly added antiviral option in China's NHC guide on COVID-19 ( 

Chloroquine (CQ) is a classic antimalarial drug. Its well-known effect of neutralizing acidic endosomal pH supports broad-spectrum antiviral usage by blocking endosome-mediated viral entry [70] . It also exhibits anti-inflammatory and immunomodulatory benefits in viral infections. HCQ is a less toxic metabolite of CQ. Both could be toxic and even fatal if overdosed [71, 72] . The adverse effects include retinopathy, liver enzyme elevation, blood counts change and mood change. It is important to monitor drug interactions with other QTc-prolonging agents [71, 72] .

Since the COVID-19 outbreak, CQ showed antiviral effect on SARS-CoV-2 in vitro, with the 90% effective concentration (EC 90 ) of 6.90 μM, which is clinically achievable *9+. HCQ is even more potent in vitro (EC 50 =0.72 μM) against SARS-CoV-2 and a pharmacokinetic model found that a regimen of 400 mg twice a day orally followed by 200 mg twice a day orally for four days would achieve therapeutic level [73] .

An open-label non-randomized clinical trial in France studied HCQ regimen of 200 mg three times a day orally with and without azithromycin. The study reported 100% viral clearance on day 6 in HCQ plus azithromycin group vs. 57.1% in HCQ monotherapy group vs. 12.5% in control group [74] .

However, the small-size trial (N=42) was not randomized. The HCQ group had higher viral load at baseline. The control group had younger patients. Six patients were excluded in results reporting.

Clinical outcomes were not studied.

The first published RCT assessing HCQ in COVID-19 was conducted in China (n=150) [75] . clearance is expected to happen much sooner. It is worth noting that the SOC arm is not a placebo.

More than 50% patients in both arms received other antivirals. This introduces a great confounder, especially when there are no conclusions on the effect of antivirals in COVID-19 yet. Another small-size HCQ trial in Shanghai with similar outcomes had the same issue [76] . The RCT also reports higher adverse effect in HCQ plus SOC group (30% vs. 9%). This could be due to the high-dose regimen of HCQ 800-1200 mg daily.

In June, a retrospective multicenter study (n=807) in American veterans with COVID-19 showed HCQ as ineffective and potentially harmful [77] . HCQ with or without AZM did not decrease mortality, MV rate or length of hospitalization. The HCQ group, but not HCQ + AZM group, even had higher risk of death. However, the study subjects were not randomized. Naturally, patients with severe disease were more likely to start HCQ treatment. In fact, both HCQ and HCQ + AZM groups had more patients with elevated liver enzymes and inflammation markers, which are confounders that could affect study outcomes [77] . A New York hospital reported QTc prolongation associated with HCQ + AZM (n=84) [78] .

QTc increased from a baseline of 435 ± 24 ms to a maximal value of 463 ± 32 ms (P < 0.001) on day 3.6 ± daily for 10 days in all settings due to potential toxicity [21] .

Tocilizumab (Actemra®), known as a humanized interleukin-6 (IL-6) receptor antagonist, is currently approved for rheumatoid arthritis, and cytokine release syndrome (CRS) due to chimeric antigen receptor T cell (CART) therapy [79] . The common side effects of tocilizumab include hypersensitivity reaction and infection [79] .

In COVID-19 patients with CRS, patients were found to have elevated levels of cytokines such as IL-2 receptor (IL-2R), IL-6, 8, 10 and TNFα that indicate inflammation and immunological diseases. In addition, CRS was revealed to be associated with the severity of COVID-19 [80, 81] . These data suggest that the IL-6 pathway may play an important role in the overactive inflammatory response in the lungs of COVID-19 patients. Therefore, it could be a potential target for immunotherapy of COVID-19.

A recent one single-group, multicenter study showed that within a few days of administration of tocilizumab, fever was reduced to normal temperatures and oxygen intake was lowered in 75% of patients with severe or critical COVID-19. They also observed a significant improvement in CT imaging, abnormally elevated CRP and lymphopenia. No obvious adverse reactions were identified in this study [82] . It suggests that tocilizumab may be a new therapeutic strategy for treatment of severe or critical COVID-19 patients, however, further data from large RCTs are required to justify the efficacy and safety of tocilizumab.

Sarilumab (Kevzara®) is another fully-human monoclonal antibody that inhibits the IL-6 pathway by binding and blocking the IL-6 receptor. It has been approved for the treatment of rheumatoid arthritis [83] . The common toxicities include neutropenia, thrombocytopenia, infusion reaction and infection [83] . The global clinical trials of sarilumab in COVID-19 treatment have been initiated to evaluate the clinical outcomes such as fever, the need for supplemental oxygen, mortality, MV, ICU stay and hospitalization [84] .

Siltuximab (Sylvant®) approved in the US to treat patients with multicentric Castleman disease is the third potential IL-6 targeted therapy for COVID-19 trials [83] . Similar to other IL-6 antagonists, the common adverse effects of siltuximab are cytopenia, infection and hypersensitivity reaction [85] . ▪ Based on respiratory distress and chest imaging, may consider glucocorticoid that is equivalent to methylprednisolone 1-2 mg/kg/day for 3-5 days or less. Note that large-dose glucocorticoid suppresses immune system and could delay clearance of SARS-CoV-2.

▪ May consider Xuebijing 100ml IV twice a day.

▪ May use microecological preparation to maintain intestinal flora balance and prevent secondary infection.

▪ Provide psychotherapy for patients who develop high level of anxiety.

I. Practice syndrome differentiation and dialectics-based medicine.

General recommendations of traditional therapies are made for each stage of clinical course from initial, severe, critical to recovery stage. (Note: Please refer to the original guide for details.)

Severe case: respiratory rate ≥ 30 per minutes, oxygen saturation ≤ 93%, PaO2/FiO2 ≤ 300 mmHg, or significant disease progression in 24-48 hours per chest imaging Critical case: ARDS requiring mechanical ventilation, shock, or organ failure requiring ICU care

Currently the guidance from WHO focuses on supportive care and the management of complications per general guidelines [20] . Remdesivir is moderately recommended by the NIH for hospitalized severe cases [21] . The COVID-19 diagnosis and treatment guideline issued by China's NHC provides several medication therapy recommendations (table 2) [19]. All these therapeutics are discussed in this review.

This review does not include darunavir/cobicistat, nitazoxanide, angiotensin II receptor blockers and other medications that have been suggested for SARS-CoV-2, awaiting evidence. This review does not discuss any oral-route traditional Chinese medications, the prescribing of which follows dialecticsbased medicine.

In conclusion, supportive care remains the cornerstone of COVID-19 management.

Complications should be managed according to general guidelines. When safety is ensured, remdesivir might be considered early in the course of illness promptly prior to disease progression for potential clinical recovery. For the other medication agents discussed in the review, outcomes from case reports and case series cannot be generalized for a larger population. More well-designed RCTs in COVID-19

therapies are warranted before final conclusions on efficacy can be made.

Funding: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

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Plaquenil (hydroxychloroquine) [prescribing information

In Vitro Antiviral Activity and Projection of Optimized Dosing Design of Hydroxychloroquine for the Treatment of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2)

Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial

Hydroxychloroquine in patients with mainly mild to moderate coronavirus disease 2019: open label, randomised controlled trial

A pilot study of hydroxychloroquine in treatment of patients with common coronavirus disease-19 (COVID-19)

Outcomes of hydroxychloroquine usage in United States veterans hospitalized with Covid-19

The QT interval in patients with COVID-19 treated with hydroxychloroquine and azithromycin

Correlation Analysis Between Disease Severity and Inflammation-related Parameters in Patients with COVID-19 Pneumonia. medRxiv

Diagnostic Utility of Clinical Laboratory Data Determinations for Patients with the Severe COVID-19

Effective treatment of severe COVID-19 patients with tocilizumab

Kevzara® (sarilumab) [prescribing information

Sylvant® (siltuximab) package insert

An Observational Case-control Study of the Use of Siltuximab in ARDS Patients Diagnosed With COVID-19 Infection (SISCO)

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

Ethical Approval: Not applicable for this review article