key: cord-0911004-iq1bxo0s authors: Lian, Ningfang; Xie, Hansheng; Lin, Su; Huang, Jiefeng; Zhao, Jianming; Lin, Qichang title: Umifenovir treatment is not associated with improved outcomes in patients with coronavirus disease 2019: A retrospective study date: 2020-04-25 journal: Clin Microbiol Infect DOI: 10.1016/j.cmi.2020.04.026 sha: e781af3c526535129e3aaeefab6c1090fecbbcb9 doc_id: 911004 cord_uid: iq1bxo0s Abstract Objectives Coronavirus disease 2019 (COVID-19) is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Umifenovir (Arbidol®) is an antiviral drug being used to treat influenza in Russia and China. This study aimed to investigate the effectiveness and safety of umifenovir for COVID-19. Methods A retrospective study was performed in non-ICU Ward in Jinyintan Hospital from February 2, 2020 to March 20, 2020. COVID-19 was confirmed by real-time reverse-transcriptase polymerase-chain-reaction (RT-PCR) assay for pharyngeal swab specimens. The confirmed patients were divided into umifenovir group and control group according to the use of umifenovir. The main outcomes were the negative rate of pharyngeal swab’s test for SARS-CoV-2 within 1 week after admission, as well as the duration for virus turning negative. The negativity time of SARS-CoV-2 was defined as the first day of a negative test if the nucleid acid of SARS-CoV-2 was negative for 2 consecutive tests. Results A total of 81 COVID-19 patients were included, with 45 in umifenovir group and 36 in control group. Baseline clinical, laboratory characteristics were comparable between two groups. 33/45 (73.3%) patients in umifenovir group were tested negative in SARS-CoV-2 within 7 days after admission, the number was 28/36 (77.8%) in control group (p=0.19). The median time from onset of symtoms to SARS-CoV-2 turning negative were 18 days (interquartile range [IQR] 12-21) in umifenovir group and 16 days (IQR, 11-21) in control group (p= 0.42). Patients in umifenovir group had longer hospital stay than patients in control group (13 days [IQR, 9-17] vs 11 days [IQR, 9-14], p=0.04). No deaths or severe adverse reaction were found in both groups. Conclusions Umifenovir might not improve the prognosis or accelerate the SARS-CoV-2 clearance in non-ICU patients. A randomized control clinical trial is needed to assess the efficacy of umifenovir. Coronavirus Disease 2019 (COVID-19) is a new form of respiratory disorder caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) 1, 2 . There is no specific vaccine or treatment for COVID-19. As of now, symptomatic and supportive treatment are the main medical approach for those patients. SARS-CoV-2 is enveloped, positive-sense RNA virus belonging Human Coronaviruses (hCoVs). The other two members of hCoVs, namely severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS), have already caused several epidemics worldwide 3 . Previous studies have shown that the SARS-CoV-2 and SARS-CoV genome sequences are highly homologous 4, 5 . Umifenovir (C 22 6 . Previous clinical and basic researches showed that umifenovir could reduce the reproduction of the SARS virus in vitro 7, 8 . However, the use of umifenovir for COVID-19 remains unclear 8, 9 . It is important to evaluate the effectiveness and safety of umifenovir in COVID-19 due to the lack of antiviral treatment for this novel disease. The present retrospective study aimed to compare the clinical characteristics and outcomes between COVID-19 patients with or without umifenovir treatment. Exclusion criteria were patients using other medications with potential antiviral activity. The following data were collected from electronic medical records: age, sex, chronic medical illness, symptoms, laboratory findings, chest computed tomographic (CT) scans, main treatment, time of symptom onset, time of first negative result of pharyngeal swab and the length of hospital stay. Onset of disease was defined as the first day of the symptoms occurred. The negativity time of SARS-CoV-2 was defined as the first day of a negative test if the nucleid acid of SARS-CoV-2 was negative for 2 consecutive pharyngeal swab tests by RT-PCR. The data were collected and reviewed by a trained team of designated physicians. Baseline data referred to the clinical data on the time of admission and laboratory data within the first 24 hours after admission, as some biochemical indexes were tested and reported at the second day during hospitalization. The images of CT scans within 2 days after admission and 7 days after treatment were collected. CT scans were reviewed and scored by two physicians majored in Respiratory medicine. The scores of CT scans were assessed based on previous reports (Table S1 , Supplementary Information) 11 . There was a score of 0-5 for each lobe, with a total possible score of 0-25. The main outcomes were the negative rate of pharyngeal swab's test for SARS-CoV-2 within 1 week after admission, as well as the duration for virus turning negative. The second outcome was the changes in the CT scores after treatment. All patients received symptomatic treatment, including appropriate supportive care and regular clinical and laboratory monitoring. A standard protocol for the monitoring COVID-19 patients in this hospital were as follows: The pharyngeal swab nucleic acid test of SARS-CoV-2 was done every 2 days in patients with normal body temperature and improved symptoms after admission. The chest CT examination was performed within 2 days of admission and at the 7th day after hospitalization. According to with or without umifenovir treatment, patients were divided into umifenovir group and control group. Patients in umifenovir group received umifenovir at 0.2 gram three times a day. The levels of ALT (alanine transaminase), AST (aspartate aminotransferase) and creatinine after treatment were collected at the 10th day after hospitalization. In order to further clarify the impact of umifenovir on patients with different severity, we divided the patients into moderate subgroup and severe subgroup according to the criteria of the diagnosis and treatment program of COVID-19 (Trial seventh Edition) 12 . Patients were defined as in severe COVID-19 if they met any of the following criteria: (1) Respiratory distress, breathing frequency ≥ 30 breaths / min; (2) In resting state, means oxygen saturation ≤ 93%; (3) Arterial blood oxygen partial pressure / oxygen concentration ≤ 300 mmHg (1 mmHg = 0.133 kPa), Others were included in moderate group. Patients who needed mechanical ventilation or vasopressor were defined as critical ill patients. All statistical analyses were performed by using SPSS 22.0. Categorical variables were described as percentages, and continuous variables were described using mean±SD or median (interquartile range) value. Means for continuous variables were compared using independent group t tests when the data were normally distributed; otherwise, the Mann-Whitney test was used. Categorical variables were compared using the χ2 test; Fisher exact test was used when the data were limited. The significance was recognized at a P value less than 0.05. A total of 108 patients with COVID-19 were hospitalized in the ward between February 2, 2020 to March 20, 2020. The reasons for 27 subjects being excluded from the final analysis were as follows: treatment with Lopinavir ritonavir (11); treatment with Redcive (8) Table 1 ). The majority were given umifenovir upon admission, the others were given within the first 24 hours after admission, as the nucleid acid of SARS-CoV-2 was tested upon admission and reported at the second day during hospitalization. 8 [9] [10] [11] [12] [13] [14] days, p=0.04) ( Table 2) . Patients with severe disease given umifenovir did not fare better than severe patients in the control group (Table 3) (Table 1 ). This retrospective study found that umifenovir treatment did not shorten the negativity time of SARS-CoV-2, or the length of hospital stay in non-ICU hospitalized patients with COVID-19. No severe side effect was found in umifenovir treatment. No vaccine is available for COVID-19 for now, so it is urgent to find an effective medicine against COVID-19 8 . Umifenovir as a broad-spectrum antiviral agent has been proposed as a potential medication for COVID-19 12 . An in vitro study showed that umifenovir can significantly inhibit the China's prevention and treatment guidelines and widely used in clinical treatment of COVID-19, its effectiveness has been questioned 12, 14, 15 . In this study, the median time from onset of the disease to first negative result of pharyngeal swab for SARS-CoV was not different between two groups, suggesting umifenovir cannot accelerate viral clearance. As the baseline CT scores were higher in umifenovir group, stratified analysis based on CT scores were performed to correct this bias between two groups. The results of stratified analysis supported that umifenovir therapy was not superior over supportive therapy treatment in terms of radiology improvement. The results were consistent with a previous study which found that 5 days' umifenovir treatment did not increase the negative rate of pharyngeal swab's test within 1 week 15 . In our study, even the patients who had longer treatment duration There are several limitations in the study. First of all, this is a single center, retrospective study with a small sample size. Observational studies have bias and the conclusion could be subjective. Second, pharyngeal swabs were not collected every day due to the limited medical resources, and pathogenic nucleic acids were not quantified as well. Third, this study only included patients with moderate and severe COVID-19, so the effectiveness of umifenovir in mild and critical patients cannot be confirmed in this study. In conclusions, compared with symptomatic and supportive treatment, additional umifenovir has not been found to shorten the duration of SARS-CoV-2 negativity time and improve the prognosis in non-ICU patients. This conclusion needs to be further verified in randomized control clinical trials. The authors disclose no conflicts of interest. Qichang Lin design study and revised the manuscript, Ningfang Lian and Xie Hansheng analysis data and prepare the manuscript, Jianming Zhao collect data and perform manuscript drafting, Jiefeng Huang search the literature and analysis data, Su Lin reviewed the results and made critical comments on the manuscript. From SARS to COVID-19: A previously unknown SARSrelated coronavirus (SARS-CoV-2) of pandemic potential infecting humans -Call for a One Health approach. One health Coronavirus disease 2019: What we know Overview of Current Therapeutics and Novel Candidates Against Influenza, Respiratory Syncytial Virus, and Middle East Respiratory Syndrome Coronavirus Infections Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China Clinical characteristics of 50466 hospitalized patients with 2019-nCoV infection Drug treatment options for the 2019-new coronavirus (2019-nCoV) Arbidol combined with LPV/r versus LPV/r alone against Corona Virus Disease 2019: A retrospective cohort study Clinical management of severe acute respiratory infection when novel coronavirus (nCoV) infection is suspected: interim guidance Pulmonary sequelae in convalescent patients after severe acute respiratory syndrome: evaluation with thin-section CT Novel coronavirus pneumonia prevention and control program Recent developments in anti-severe acute respiratory syndrome coronavirus chemotherapy Discovering drugs to treat coronavirus disease 2019 (COVID-19) Efficacy of lopinavir, ritonavir and abidol for the treatment of new coronavirus pneumonia This work was supported by the Natural Science Foundation of Fujian Province, China (No.