Coronaviruses (CoVs) (order Nidovirales, family Coronaviridae, subfamily Coronavirinae) are enveloped, positive single-stranded RNA viruses, and they have the largest genomes for RNA viruses as their genome sizes range from 26 to 32 kilobases (kb) in length 1 . CoVs primarily infect birds and mammals, causing a variety of lethal diseases. They can also infect humans and cause diseases to varying degrees, from upper respiratory tract infections (URTIs) resembling the common cold to lower respiratory tract infections (LRTIs) such as bronchitis, pneumonia, and even severe acute respiratory syndrome (SARS) [2] [3] [4] . The virus is believed transmitted mainly via respiratory tract, fecal-oral transmission or contact 5 . There are over 10 types of CoVs that have been already known so far.
Historically, CoVs caused two serious infectious diseases including the SARS in 2003 and the Middle-East Respiratory Syndrome (MERS) in 2012 6, 7 , with a fatality rate of approximately 10% (916/8,422) and 35% (750/2,144), respectively 8, 9 . Therefore, it is plain to see that CoVs pose a great threat to human life.
Since the outbreak of Coronavirus Disease 2019 in December 2019 in China, there were 80,303 confirmed cases by 3 March 2020, including 2,949 deaths. Meanwhile, the disease spread overseas, with 10,059 confirmed cases and 160 deaths. Although the overall mortality rate of COVID-19 is about 3.4%, which is much lower than that of SARS and MERS, COVID-19 is extremely contagious, contributing to a fairly large infection base, hence the death toll surpassed that of SARS and MERS. The most common clinical symptoms of COVID-19 sufferers are fever, dry cough, hypodynamia, while some patients develop nasal obstruction, nasal discharge and diarrhea 10 . The current therapeutic scheme has mainly focused on symptomatic treatment as no specific medicine has This article is protected by copyright. All rights reserved.
been developed up to now. Based on the therapeutic experience of SARS and MERS, we have strived to research the efficient drugs for COVID-19 in order to improve patient's cure rate and survival quality.
Arbidol (ARB) is a kind of hemagglutinin (HA) inhibitor with a high selectivity and is able to target HA fusion machinery and prevent CoVs from adsorbing cell surface and entering the cells 11 . Currently, ARB has been authorized for years in China and was reported by researchers to be a broad-spectrum and multi-target antiviral drug, which plays an inhibitory effect on influenza virus, parainfluenza virus and coxsackievirus [12] [13] [14] . Therefore, the application of ARB in SARS was reported and the result indicated that ARB could suppress SARS-CoV 14 , which provides a new orientation for the treatment of COVID-19 in our study.
In this study, we used ARB combined with adjuvant therapy for COVID-19 sufferers and set up the control group to investigate the effect of ARB on COVID-19 patients.
The study included 62 patients with COVID-19 admitted to the First Hospital of Jiaxing from January to March, 2020, including 28 females and 34 males aged from 5 to 72, with most patients ranging from 48 to 63. All of them were confirmed cases of COVID-19 by imaging examination and pathological examination upon admission. Ground-glass opacity could be seen in imaging and virus nucleic acid (nCoV-RNA) testing was positive. We divided them into 2 groups. The one who received ARB combined with adjuvant therapy was classified into the test group (n=42), while the one who didn't was classified into the control group (n=20). All clinical data of patients, including gender, hypertension, diabetes, CT, temperature, oxygen saturation, hemoglobin (HB) concentration, C-reactive protein (CRP) and so on, were listed in Table 1 Test group: ARB was additionally added on the basis of symptomatic treatment. Patients started to take ARB as soon as they were admitted to the This article is protected by copyright. All rights reserved.
hospital. Arbidol Tablets (Jiangsu Wuzhong Pharmaceutical Group Corporation) was given for adult: 2 pills (0.2 g) by oral thrice a day. β receptor antagonists such as metoprolol and propranolol were not allowed to be used together. Drug withdrawal was recommended when the heart rate (HR) was lower than 60 beats/min. Symptomatic treatment would be applied if digestive tract reaction appeared.
Patient's clinical symptoms, such as fever, dry cough, nasal obstruction, nasal discharge, sore throat, hypodynamia, diarrhea, and some laboratory indexes including blood routine indexes, CRP, procalcitonin (PCT), blood biochemical indexes as well as the virus nucleic acid testing were observed and recorded during the treatment. Curative criteria: Patient's quarantine couldn't be abolished until their temperature returned to normal for over 3 days, with marked improvement in respiratory symptoms, significant absorption of inflammation showed by pulmonary imaging, and negative nucleic acid testing for 2 consecutive times (sampling interval was at least 1 day).
All statistical analyses were performed using SPSS 26.0. Measurement data were expressed as X±s, and differences between the two groups were analyzed by Student's t test. Part of the enumeration data were represented as percentage (%).
Comparisons between the two groups were verified by means of chi-square test or Fisher's test. P<0.05 was considered statistically significant. This article is protected by copyright. All rights reserved.
We recorded patient's temperature at the beginning of and during hospitalization as basically all of them had fever. The highest temperature of each patient was recorded every day. The results suggested that compared with the control group, the temperature in the test group dropped more significantly than that in the control group, and the time for back to normal was much shorter (4.98 ± 1.79 vs. 6.01 ± 1.80, p=0.021, Fig. 1) . Additionally, symptoms like dry cough of patients in the test group recovered faster than that of patients in the control group (4.39 ± 1.30 vs. 5.08 ± 1.42, p=0.040). While for other symptoms, such as nasal obstruction, nasal discharge, sore throat, hypodynamia and diarrhea, there was no marked difference in recovery time between the two groups (p>0.05). The details were listed in Table 2 .
In view of the fact that a number of patients had inflammation, we observed the changes of patient's blood routine indexes, CRP, PCT and biochemical indexes and recorded the indexes which were higher or lower than the normal range. The percentage of patients with abnormal CRP and PCT in the test group were lower than those in the control group, yet the percentage of patients who developed abnormal lymphocytes in the test group was increased than that in the control group. In addition, there was no significant difference between the 2 groups with regard to the percentage of patients with abnormal blood routine indexes, including white blood cell (WBC), HB, platelet (PLT) and so on (p>0.05). As for blood biochemical indexes, we mainly recorded alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in order to observe whether the medication This article is protected by copyright. All rights reserved.
would damage patient's liver. The result indicated that from admission to discharge, there was no significant difference between the 2 groups concerning the percentage of patients with abnormal ALT and AST (p>0.05), which validated that adding ARB to the therapeutic scheme would cause no new damage to patient's liver. The detailed results for above were seen in Fig. 2-3. 
Patient's virus nucleic acid was tested every day starting from their admission. We recorded every patient's time to achieve negative nucleic acid testing (including the 1 st , 2 nd and 3 rd time to achieve negative result, that is, the time for two consecutive negative nucleic acid tests was recorded) and their hospitalization period. The results revealed that compared with the control group, the time for patient's nucleic acid turning negative in the test group was shorter than that in the control group, especially the time to achieve 2 nd and the 3 rd negative result (Fig. 4) . The hospitalization period of the patients in the two groups were (16.5 ± 7.14) d (test group) and (18.55 ± 7.52 ) d (control group), respectively. Relatively, the hospitalization period in the test group was shorter, but there was no marked difference between the 2 groups in this aspect (p>0.05).
During the treatment, patient's principal adverse drug reactions in the 2 groups included slowed HR (test group: n=5, control group: n=2), nausea (test group: n=7, control group: n=3), diarrhea (test group: n=2, control group: n=1) and dizziness (test group: n=2, control group: n=1). There was no significant difference between the 2 groups regarding the number of patients with adverse drug reactions (p>0.05), which demonstrated that the application of ARB in COVID-2019 is safe and would cause no marked adverse drug reactions. This article is protected by copyright. All rights reserved.
Currently, antiviral, anti-infection and supportive treatment are mainly applied in COVID-19 sufferers clinically. Previously, a MERS-related systematic review and meta-analysis unveiled that the application of antiviral treatment at an early stage and a low age was able to reduce the mortality rate of MERS patients 15 . Conducting antiviral treatment has always been thought of as the key to curation of MERS-CoV infected sufferers. Consistently, the key to the treatment of COVID-19 patients also lies in antiviral treatment. In this study, we mainly found that ARB combined with common systematic therapy could relieve patient's symptoms faster, including fever, cough, nasal obstruction, nasal discharge, hypodynamia, diarrhea and so on, and accelerate patient's cure time without producing new toxic reaction and side effect. Subsequently, it was proved to demonstrate inhibitory activity against a number of DNA/RNA viruses and enveloped/nonenveloped viruses 17 . ARB plays its antiviral role mainly by suppressing virus-mediated fusion with the target membrane and consequently preventing virus from entering into target cells 18 . It has been found that ARB can interact with haemagglutinin (HA) to stabilize it against the low pH transition to its fusogenic state and therefore prevent HA-mediated membrane fusion during influenza virus infection 19 . In the treatment of Hepatitis C virus (HCV), ARB interacts with HCV envelope protein and is capable of inhibiting membrane fusion to various extent 13, 20 . Besides, the immunoregulation effect of ARB is able to interfere with macrophage activation 21 . ARB has become the This article is protected by copyright. All rights reserved.
candidate drug for treatment of human virus infection due to its broad-spectrum antiviral activity. Consistent with the prior researches, ARB combined with systematic therapy in the treatment of COVID-19 sufferers was able to relieve symptoms and shorten the course of many symptoms, and accelerate patient's nucleic acid turning negative. It could be seen that ARB played a positive role in the treatment of COVID-19. However, the results of this study are likely to be affected by other drugs as COVID-19 patients applied extensive and messy medications during treatment. Consequently, more researches need to be done in the future so as to obtain more reliable results.
In conclusion, the application of ARB in the treatment of COVID-19 sufferers is likely to shorten the course of the disease and is able to quicken patient's recovery. Hence, it's recommended that more studies should be further done clinically. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. 