key: cord-327028-dbvucvy3 authors: Zhang, Cantong; Huang, Shaoying; Zheng, Fengping; Dai, Yong title: Controversial treatments: An updated understanding of the coronavirus disease 2019 date: 2020-04-10 journal: J Med Virol DOI: 10.1002/jmv.25788 sha: doc_id: 327028 cord_uid: dbvucvy3 An outbreak of severe acute respiratory syndrome‐related coronavirus 2 infection has posed significant threats to international health and the economy. In the absence of specific treatment for this virus, there is an urgent need to learn from the experience and lessons in China. To reduce the case‐fatality rate among coronavirus disease 2019 patients, we should not ignore the complications, such as RNAaemia, acute respiratory distress syndrome, and multiple organ dysfunction. To help understand the advantages and limitations of differential treatments, we provide a timely review and discuss the complications and corresponding major treatments, especially controversial ones such as antiviral therapy (remdesivir, ribavirin, and chloroquine), glucocorticoid therapy, extracorporeal support including an artificial liver system, and extracorporeal membrane oxygenation based on available evidence. As a result, we suggest that antiviral therapy and organ function support are vital to reduce mortality for mild patients and critical patients, respectively. To reduce the case-fatality rate and complication rate without registered treatment or a vaccine, there is an urgent need for health care workers worldwide to review and propose experience and lessons from critical COVID-19 patients in a timely manner. Given the treatments mentioned above, we will discuss antiviral therapy, glucocorticoid therapy, and extracorporeal support, including ECMO and artificial liver system (ALS) available for the treatment of COVID-19 based on current published evidence. Furthermore, we list a table to conclude the mechanism, advantages, and limitations for different treatments mentioned in this review (Table 2) The mechanism of remdesivir against the virus showed that the drug effectively inhibited the Ebola virus RNA-dependent RNA polymerase (RdRp) complex. 12, 13 The remdesivir could form remdesivir triphosphate (remdesivir-TP) in vivo, which was incorporated into the newly synthesized RNA chain of the virus as the substrate of the virus RdRp, thereby interrupting the transcription of the virus. 12 Another study showed that remdesivir-TP could compete with adenosine triphosphate (ATP). 14 After entering the cells, a monophosphoramidate prodrug of remdesivir transformed into triphosphate metabolite (NTP) in three steps, and NTP and ATP competed to bind viral RdRp. NTP was incorporated into the RNA synthesis chain, contributing to the termination of viral RNA synthesis and inhibiting RdRp enzyme activity. 12 In addition, remdesivir was used against a case of 2019 novel coronavirus, reported in N Engl J Med, leading to widespread interest. 15 In this case report, a patient with COVID-19 was treated by intravenous remdesivir without apparent adverse reactions on the evening of the seventh day of hospitalization. The patient's clinical symptoms improved on the eighth day after hospitalization (the 12th day after onset). Phase III clinical trials of remdesivir had been completed for the treatment of Ebola virus infection with complete data on human pharmacokinetics and safety. 16 Recently, phase III randomized controlled trials were carried out to evaluate intravenous remdesivir for COVID-19 (NCT04252664 and NCT04257656), which will be completed in April 2020 and May 2020, respectively. 17, 18 Remdesivir (100 mg except for the first day of 200 mg) for 10 days with placebo in the phase III trials, which were initiated in China, is worthy of concern about adverse reactions at this dose due to differences in ethnicity. Ribavirin is a broad-spectrum nucleoside antiviral drug that is phosphorylated in virus-infected cells, and its product acts as a competitive inhibitor of virus synthetase, interfering with early viral transcription events and hindering the synthesis of ribonucleoproteins, thereby hindering virus replication and spread. In vitro, four studies observed antiviral effects against SARS, [19] [20] [21] [22] but the results from Cinatl et al 23 During the COVID-19 epidemic, ribavirin was indicated for the general treatment of COVID-19 in Chinese treatment guidelines, 31 and it is recommended that ribavirin is combined with interferon as not be ignored. 38 The contraindications, relative contraindications, and pharmaceutical precautions are listed in Table S1 . 39 (Table 1) . 38 Corticosteroids have been widely used in the treatment of past coronavirus infections (such as SARS and MERS), and corticosteroids are also one of the methods for treating COVID-19. 31, 4, 40, 41 However, no evidence was found on the antiviral effect of corticosteroids alone in resisting SARS-CoV in vitro. 25 48 and a similar cytokine storm reported by Huang et al. 40 Hence, it was suggested to use appropriate corticosteroids for patients suffering from ARDS. 49 Furthermore, pathological studies of COVID-19 observed pulmonary edema and hyaline membrane formation, implying that timely use of corticosteroids is necessary for severe patients, 48 which was also supported by retrospective pathologic examinations showing edema, and proteinaceous exudate with globules in the lungs of two patients with COVID-19. 50 4 | SUPPORT THERAPY The ALS is one of an effective method for treating liver failure, 51 and its treatment mechanism is based on liver cell regeneration ability. Through a extracorporeal equipment, ALS removes all kinds of harmful substances, supplements necessary material, improves the internal environment, and temporarily replaces part of liver function, to create good conditions for the regeneration of liver cells or while waiting for an opportunity for liver transplantation. 52 Among the three types (nonbiological, biological, and hybrid) of artificial liver support systems, artificial extracorporeal liver support therapy has been widely used in acute liver failure and has been proven to improve survival. 53 As mentioned above, cytokine storm was associated with disease severity reported by a study, which illustrated that GCSF, IP10, MCP1, MIP1A, and TNF-α were found to be higher in patients who require ICU admission. 40 Moreover, a retrospective study including 99 patients with COVID-19 showed that 17 patients suffered ARDS, and among them, 11 patients progressed rapidly and eventually died of multiple organ failure. 49 In these death cases, timely treatment of critical cases is of vital significance. 49 This review will help understand the advantages and limitations of differential treatments. In this review, we summarize and discuss Extracorporeal support (ALS and ECMO) should be considered under strict indications and contraindications; otherwise, the waste of resources and additional complications will be enormous. ECMO may be used more aggressively and many more ECMO devices could be transferred to Hubei Province in the future due to the temporary absence of effective antiviral drugs and the hope of reducing mortality. In conclusion, antiviral therapy and organ function support are most effective in reducing the mortality rate in patients with mild syndrome and patients in critical condition, respectively. Estimating the unreported number of novel coronavirus (2019-nCoV) cases in China in the first half of January 2020: a data-driven modelling analysis of the early outbreak World Health Organization. Coronavirus disease 2019 (COVID-19) situation report-39 Time to use the p-word? Coronavirus enters dangerous new phase Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a singlecentered, retrospective, observational study Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan Clinical characteristics of coronavirus disease 2019 in China Therapeutic options for the 2019 novel coronavirus (2019-nCoV) Broad-spectrum antiviral GS-5734 inhibits both epidemic and zoonotic coronaviruses Coronavirus susceptibility to the antiviral remdesivir (GS-5734) is mediated by the viral polymerase and the proofreading exoribonuclease. mBio Comparative therapeutic efficacy of remdesivir and combination lopinavir, ritonavir, and interferon beta against MERS-CoV Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro Therapeutic efficacy of the small molecule GS-5734 against Ebola virus in rhesus monkeys Treating Ebola virus infection Mechanism of inhibition of Ebola virus RNA-dependent RNA polymerase by remdesivir First case of 2019 novel coronavirus in the United States A randomized, controlled trial of Ebola virus disease therapeutics Severe 2019-nCoV Remdesivir RCT Mild/Moderate 2019-nCoV Remdesivir RCT In vitro susceptibility of 10 clinical isolates of SARS coronavirus to selected antiviral compounds Role of lopinavir/ritonavir in the treatment of SARS: initial virological and clinical findings Ribavirin and interferon-β synergistically inhibit SARS-associated coronavirus replication in animal and human cell lines Inhibition of SARS coronavirus infection in vitro with clinically approved antiviral drugs Glycyrrhizin, an active component of liquorice roots, and replication of SARS-associated coronavirus Severe acute respiratory syndromerelated coronavirus is inhibited by interferon-α SARS: systematic review of treatment effects Clinical features and short-term outcomes of 144 patients with SARS in the greater Toronto area Common adverse events associated with the use of ribavirin for severe acute respiratory syndrome in Canada Clinical features and short-term outcomes of 144 patients with SARS in the greater Toronto area Severe acute respiratory syndrome: report of treatment and outcome after a major outbreak Pre-emptive use of aerosolized ribavirin in the treatment of asymptomatic pediatric marrow transplant patients testing positive for RSV Chinese Clinical Guidance. Diagnosis & Treatment Scheme for Novel Corona Virus Pneumonia (Trial) Inhibition of novel β coronavirus replication by a combination of interferon-α2b and ribavirin New insights into the antiviral effects of chloroquine Design and synthesis of hydroxyferroquine derivatives with antimalarial and antiviral activities In vitro inhibition of severe acute respiratory syndrome coronavirus by chloroquine Effects of chloroquine on viral infections: an old drug against today's diseases? Chloroquine is a potent inhibitor of SARS coronavirus infection and spread Multicenter collaboration group of Department of Science and Technology of Guangdong Province and Health Commission of Guangdong Province for chloroquine in the treatment of novel coronavirus pneumonia. Expert consensus on chloroquine phosphate for the treatment of novel coronavirus pneumonia 关于调整试用磷酸氯喹治疗新冠肺炎用法用量的通知 Clinical features of patients infected with 2019 novel coronavirus in Wuhan Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China Clinical management of severe acute respiratory infection when novel coronavirus (nCoV) infection is suspected: interim guidance Factors of avascular necrosis of femoral head and osteoporosis in SARS patients' convalescence Factors associated with psychosis among patients with severe acute respiratory syndrome: a casecontrol study Glucocorticoid-induced diabetes in severe acute respiratory syndrome: the impact of high dosage and duration of methylprednisolone therapy Effects of early corticosteroid treatment on plasma SARS-associated coronavirus RNA concentrations in adult patients Clinical evidence does not support corticosteroid treatment for 2019-nCoV lung injury. The Lancet Pathological findings of COVID-19 associated with acute respiratory distress syndrome Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study Pulmonary pathology of early phase SARS-COV-2 pneumonia Artificial extracorporeal liver support therapy in patients with severe liver failure Systematic review and metaanalysis of survival following extracorporeal liver support Clinical findings in 111 cases of influenza A (H7N9) virus infection Evaluation of plasma exchange and continuous veno-venous hemofiltration for the treatment of severe avian influenza a (H7N9): a cohort study Application of extracorporeal membrane oxygenation in patients with severe acute respiratory distress syndrome induced by avian influenza A (H7N9) viral pneumonia: national data from the Chinese multicentre collaboration Extracorporeal membrane oxygenation for 2009 influenza A (H1N1) acute respiratory distress syndrome China: People's Medical Publishing House. 60. GBD 2016 Lower Respiratory Infections Collaborators. Estimates of the global, regional, and national morbidity, mortality, and aetiologies of lower respiratory infections in 195 countries, 1990-2016: a systematic analysis for the Global Burden of Disease Study Controversial treatments: An updated understanding of the coronavirus disease 2019 The authors declare that there is no conflict of interests. http://orcid.org/0000-0001-6315-3811Shaoying Huang http://orcid.org/0000-0002-4607-6743