key: cord-0965278-dvfcxenz authors: Li, Xuan; Liyang, Zhou; Zhang, Lina; Zheng, Shuo; Huang, Fang; Pan, Xingfei; Fang, Wang title: The combined regimens of antiviral therapy might not be useful for the viral clearance of severe COVID-19 cases date: 2021-10-01 journal: J Infect Public Health DOI: 10.1016/j.jiph.2021.09.020 sha: 706797cd2f70018d7e336241d983f974edb0e1cf doc_id: 965278 cord_uid: dvfcxenz BACKGROUND: Severe COVID-19 caused by SARS-CoV-2 should closely be cared because of the relatively high mortality rate. If SARS-CoV-2 could be cleared as soon as possible, the mortality rate might lower. In the present study, we analyzed factors which might be related to the clearance of SARS-CoV-2. METHODS: One hundred and twenty-eight severe COVID-19 cases were enrolled. All of them had been isolated and treated at the Third People’s Hospital of Shenzhen because they were positive for nucleic acid of SARS-CoV-2 tested by qRT-PCR. Their baseline clinical characteristics and antiviral regimens were collected and analyzed, respectively. RESULTS: Of the 128 enrolled severe COVID-19 cases, unfortunately 3 died. The mean viral duration of all patients was 23.5 (range 17-32) days. All patients achieved viral clearance during 9 weeks. 13.4 % of patients achieved viral clearance within 2 weeks, and 63.0% of patients achieved viral clearance within 4 weeks. The combined regimens of three or more antiviral drugs, the use of invasive mechanical ventilation, and late admission might be related to the delay of viral clearance within 2 weeks. The use of arbidol, the use of invasive mechanical ventilation, and late admission might be related to the delay of viral clearance within 4 weeks. Patients often had a prolonged course of COVID-19 and hospitalization, and were more likely transferred to intensive care unit (ICU) for treatment, if they could not clear SARS-CoV-2 during 23 days. CONCLUSION: Severe COVID-19 cases should be admitted to hospital as soon as possible. The combined regimens of three or more antiviral drugs might not be useful for viral clearance, and should be performed carefully and cautiously. The outbreak of corona virus disease 2019 (COVID-19) caused by severe acute respiratory syndrome corona virus-2 (SARS-CoV-2) has posed a serious impact on the health system worldwide. The number of confirmed COVID-19 cases and deaths dramatically increases in the world. The mortality rate of severe COVID-19 cases is relatively high because severe COVID-19 cases easily progress to life-threatening fatal clinical outcomes such as ARDS, respiratory failure, sepsis, septic shock, etc. It was reported that the median viral duration of survivors of SARS-CoV-2 infection is about 20.0 days (IQR 17.0-24.0). However, SARS-CoV-2 could be continuously detected in patients who unfortunately died of COVID-19 before they died [1] . Another study found that the viral clearance of patients in ICU is slower compared with that of non-ICU patients [2] . For patients with COVID-19, the viral duration is closely related to the disease progression and the severity of the disease. Therefore, controlling SARS-CoV-2 replication and clearing it as soon as possible might improve the prognosis of patients with COVID-19. Various antiviral drugs, such as interferon alpha, ribavirin, arbidol, chloroquine phosphate, lopinavir/ ritonavir, etc., could be recommended to treat patients and might improve the prognosis of patients by the World Health J o u r n a l P r e -p r o o f Organization (WHO) and National Health Commission of China [3] [4] [5] . However, the use of these drugs is mostly based on data collected from treatment of SARS or MERS or the experimental results in vitro. Furthermore, their efficacy and safety still need further researching. For example, some researchers even believe that the use of lopinavir/ ritonavir could hinder viral clearance [6] . Others report that [7] the use of glucocorticoids might be related to the delay of viral clearance. The viral duration varies with the severity of the disease. Therefore, there might be a difference in factors-related to viral clearance between mild and severe COVID-19 patients. In the present study, we enrolled 128 severe COVID-19 patients from the Third People's Hospital of Shenzhen, and analyzed factors-related to the viral clearance. The retrospective study was approved by the Ethics Committee of the Third People's Hospital of Shenzhen. All patients were isolated and treated at the Third People's Hospital of Shenzhen which was the only designated hospital for treatment of COVID-19 cases in Shenzhen by local health authorities. Three hundred and ninety-five COVID-19 patients were included and selected. One hundred and twenty-eight patients with severe COVID-19 were enrolled ( Figure 1 ). All patients were positive for nucleic acid of SARS-COV-2 tested by qRT-PCR before they were admitted to the Third People's Hospital of Shenzhen. The definition of severe COVID-19, viral clearance, viral duration and discharge (http://www.nhc.gov.cn/xcs/zhengcwj/202003/4856d5b0458141fa9f376853224d41d7. shtml). Clinical data of the enrolled patients were all extracted from the electronic medical records and collected by two doctors who were responsible for the following-up of COVID-19 cases in the Third People's Hospital of Shenzhen. Data of continuous variables in this study were expressed by median (interquartile range) or mean±SD, and data of categorical variables were expressed by absolute numbers (%). Mann-Whitney U test was used to compare differences between continuous variables. Chi-square test or Fisher exact test was used to compare differences between categorical variables. Logistic regression was used to analyze favorable factors-related to viral clearance. Differences were considered statistically significant at a P value < 0.05. All data were analyzed using SPSS v22.00 statistical analysis software (SPSS Inc, Chicago, IL). The baseline clinical characteristics of 128 severe COVID-19 patients were shown in Table 1 It took 9 weeks for all patients to achieve viral clearance. As shown in Table 2 , the viral clearance rates of severe COVID-19 patients within 1, 2, 3, 4, 5, 6, 7, 8, 9 weeks were 0.8, 13.3, 37.5, 62.5, 82.8, 95.3, 98.4, 99.2, 100%, respectively. It took 7 weeks or 9 weeks for serious cases or critical cases to completely achieve viral clearance, respectively. There were statistically significant differences in the viral clearance rate between serious cases and critical cases within 3, 4, 5, 6 and 7 weeks, respectively. However, there was not a statistically significant difference in the viral clearance rate between serious cases and critical cases at the other time points ( Figure 2 ). Then patients were divided into two groups according to age. Sixty-nine patients were included in Group A (age ≤ 60 years), and 59 patients in Group B (age > 60 years). Three patients in Group B did not survive from COVID-19. The recovery rate was 100% (69/69) in Group A, and 94.92% (56/59) in Group B ( Figure 3 ). The cumulative viral clearance rate in different aged subjects was shown in Figure 4 . It took 7 weeks or 9 weeks for younger patients or old patients to completely achieve viral clearance. In order to clarify factors-related to viral clearance in severe patients, logistics regression analysis was used to analyze factors-related to early viral clearance (within 2 weeks) and late viral clearance (within 4 weeks). Table 3 , univariate logistics regression analysis showed that having underlying pulmonary diseases, the use of intravenous immunoglobulin therapy, the use of glucocorticoids, the combined regimens of three or more antiviral drugs, the use of invasive mechanical ventilation, and time from onset of symptoms to admission were related to viral clearance within 2 weeks. Then the above variables were included in the multivariate logistics regression analysis. The results showed that the combined regimens of three or more antiviral drugs (OR=3.896, P=0.033), the use of invasive mechanical ventilation (OR=8.208, P=0.013) were risk factors for early viral clearance, respectively. Time from onset of symptoms to admission was associated with viral clearance, and late admission was an unfavorable factor for early viral clearance (OR=1.850, P=0.003). Table 4 , univariate logistics regression analysis showed that fever, PCT, the use of intravenous immunoglobulin therapy, the use of glucocorticoids, the use of arbidol, the use of invasive mechanical ventilation, and time from onset of symptoms to admission were related to viral clearance within 4weeks. Then the above J o u r n a l P r e -p r o o f variables were included in the multivariate logistics regression analysis. The results showed that the use of arbidor (OR=3.338, P=0.006), the use of invasive mechanical ventilation (OR=3.820, P=0.001) were risk factors for late viral clearance. Time from onset of symptoms to admission was associated with viral clearance, and late admission was a risk factor for late viral clearance (OR=1.188, P=0.003). According to the average viral duration, severe COVID-19 patients were divided into two groups: patients with long viral duration (> 23 days) and patients with short viral duration (≤23 days). As shown in Table 5 , compared with patients with short viral duration, patients with long viral duration had longer hospitalization and longer disease course of the disease. Furthermore, patients with long viral duration were more likely transferred to ICU for treatment [22 (33.8%) VS 4 (6.3%)]. Some studies reported [6] [7] [8] that late admission is a risk factor for viral clearance of patients with COVID-19. In the present study, we found that for severe COVID-19 patients, late admission was also a risk factor for viral clearance. So patients with severe COVID-19 should be treated as soon as possible. However, it was still unclear which of regimens such as antiviral therapy or adjuvant therapy could accelerate the viral clearance of COVID-19 patients. Arbidol, an antiviral drug to influenza, could specifically inhibit the fusion of J o u r n a l P r e -p r o o f virus to the host cell membrane, and the synthesis of viral RNA [9] . Previous studies found that arbidol could inhibit the replication of SARS-CoV [10] . As a result, arbidol is recommended to try to treat COVID-19 by National Health Commission of China. Recently, a study [11] found that the viral clearance rate of patients treated with arbidol (16 patients) is 100% after 2 weeks of treatment course, while the viral clearance rate of those treated with lopinavir/ ritonavir (34 patients) is only 55.9%. However, another study [12] found that the median viral duration of patients treated with arbidol is 18 days, while the viral duration of the control group is 16 days. So arbidol could not helpfully accelerate viral clearance. This was in accordance with our results. Our results found that arbidol was a negative factor-related to viral clearance for patients with severe COVID-19. However, the sample size of our study was relatively small which could be lead to different results. We think that the role of abidor in viral clearance of patients with severe COVID-19 should be further evaluated In the present study, we also found that the use of interferon alpha inhalation, lopinavir/ritonavir, favipiravir, ribavirin, and oseltamivir could not helpfully accelerate viral clearance. Previous studies also reported that the drugs above could We also found that the use of invasive mechanical ventilation was an independent risk factor for viral clearance which was in accordance with the results of Chen et al [6] . Patients with invasive mechanical ventilation had usually prolonged hospitalization which could cause them re-infection, and the delay of viral clearance. In the present study, we also found that compared with patients with short viral duration, patients with long viral duration had a longer hospitalization and longer disease course, and were more likely to be transferred to ICU for treatment. Therefore, it was necessary to find a favorable regimen to achieve viral clearance as soon as possible in order to shorten hospitalization, the disease course and hinder the disease progression. Our study also had some limitations. Firstly, the present study was a retrospective study and lacked an effective control group. Secondly, the present study J o u r n a l P r e -p r o o f J o u r n a l P r e -p r o o f Abbreviations: BMI, body mass index; WBC, white blood cell; NEUT, Neutrop hils; NS, not significant. a P value indicated differences between two group. P<0.05 was considered statistically significant. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study Clinical progression of patients with COVID-19 in Shanghai Clinical management of 2019 nCoV guidelines by National Health Commission of the People Republic of China WHO: Clinical management of severe acute respiratory infection when novel coronavirus (nCoV) infection is suspected A rapid advice guideline for the diagnosis and treatment of 2019 novel coronavirus (2019-nCoV) infected pneumonia (standard version) Associations of clinical characteristics and antiviral drugs with viral RNA clearance in patients with COVID-19 in Guangzhou, China: a retrospective cohort study Persistence and clearance of viral RNA in 2019 novel coronavirus disease rehabilitation patients Factors Associated With Prolonged Viral RNA Shedding in Patients with Coronavirus Disease 2019 (COVID-19) Arbidol: A potential antiviral drug for the treatment of SARS-CoV-2 by blocking trimerization of the spike glycoprotein Arbidol monotherapy is superior to lopinavir/ritonavir in treating COVID-19. Days of fever,median(IQR) Days of ICU, median(IQR),d 13 Disease course, median(IQR),d 23 Not applicable.