Characterization of a mouse-adapted strain of bat severe acute respiratory syndrome-related coronavirus.

Bats carry genetically diverse severe acute respiratory syndrome-related coronaviruses (SARSr-CoVs). Some of them utilize human angiotensin-converting enzyme 2 (hACE2) as a receptor and cannot efficiently replicate in wild-type mice. Our previous study demonstrated that the bat SARSr-CoV rRsSHC014S induces respiratory infection and lung damage in hACE2 transgenic mice but not wild-type mice. In this study, we generated a mouse-adapted strain of rRsSHC014S, which we named SMA1901, by serial passaging of wild-type virus in BALB/c mice. SMA1901 showed increased infectivity in mouse lungs and induced interstitial lung pneumonia in both young and aged mice after intranasal inoculation. Genome sequencing revealed mutations in not only the spike protein but the whole genome, which may be responsible for the enhanced pathogenicity of SMA1901 in wild-type BALB/c mice. SMA1901 induced age-related mortality similar to that observed in SARS and COVID-19. Drug testing using antibodies and antiviral molecules indicated that this mouse-adapted virus strain can be used to test prophylactic and therapeutic drug candidates against SARSr-CoVs. IMPORTANCE The genetic diversity of SARSr-CoVs in wildlife and their potential risk of cross-species infection highlights the importance of developing a powerful animal model to evaluate the antibodies and antiviral drugs. We acquired the mouse-adapted strain of a bat-origin coronavirus named SMA1901 by natural serial passaging of rRsSHC014S in BALB/c mice. The SMA1901 infection caused interstitial pneumonia and inflammatory immune responses in both young and aged BALB/c mice after intranasal inoculation. Our model exhibited age-related mortality similar to SARS and COVID-19. Therefore, our model will be of high value for investigating the pathogenesis of bat SARSr-CoVs and could serve as a prospective test platform for prophylactic and therapeutic candidates.

Interferon therapy in patients with SARS, MERS, and COVID-19: A systematic review and meta-analysis of clinical studies.

Concern regarding coronavirus (CoV) outbreaks has stayed relevant to global health in the last decades. Emerging COVID-19 infection, caused by the novel SARS-CoV2, is now a pandemic, bringing a substantial burden to human health. Interferon (IFN), combined with other antivirals and various treatments, has been used to treat and prevent MERS-CoV, SARS-CoV, and SARS-CoV2 infections. We aimed to assess the clinical efficacy of IFN-based treatments and combinational therapy with antivirals, corticosteroids, traditional medicine, and other treatments. Major healthcare databases and grey literature were investigated. A three-stage screening was utilized, and included studies were checked against the protocol eligibility criteria. Risk of bias assessment and data extraction were performed, followed by narrative data synthesis. Fifty-five distinct studies of SARS-CoV2, MERS-CoV, and SARS-CoV were spotted. Our narrative synthesis showed a possible benefit in the use of IFN. A good quality cohort showed lower CRP levels in Arbidol (ARB) + IFN group vs. IFN only group. Another study reported a significantly shorter chest X-ray (CXR) resolution in IFN-Alfacon-1 + corticosteroid group compared with the corticosteroid only group in SARS-CoV patients. In a COVID-19 trial, total adverse drug events (ADEs) were much lower in the Favipiravir (FPV) + IFN-α group compared with the LPV/RTV arm (P = 0.001). Also, nausea in patients receiving FPV + IFN-α regimen was significantly lower (P = 0.03). Quantitative analysis of mortality did not show a conclusive effect for IFN/RBV treatment in six moderately heterogeneous MERS-CoV studies (log OR = -0.05, 95% CI: (-0.71,0.62), I2 = 44.71%). A meta-analysis of three COVID-19 studies did not show a conclusive nor meaningful relation between receiving IFN and COVID-19 severity (log OR = -0.44, 95% CI: (-1.13,0.25), I2 = 31.42%). A lack of high-quality cohorts and controlled trials was observed. Evidence suggests the potential efficacy of several combination IFN therapies such as lower ADEs, quicker resolution of CXR, or a decrease in inflammatory cytokines; Still, these options must possibly be further explored before being recommended in public guidelines. For all major CoVs, our results may indicate a lack of a definitive effect of IFN treatment on mortality. We recommend such therapeutics be administered with extreme caution until further investigation uncovers high-quality evidence in favor of IFN or combination therapy with IFN.

Treatment of severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), and coronavirus disease 2019 (COVID-19): a systematic review of in vitro, in vivo, and clinical trials.

Rationale: Coronavirus disease 2019 (COVID-19) has spread worldwide and poses a threat to humanity. However, no specific therapy has been established for this disease yet. We conducted a systematic review to highlight therapeutic agents that might be effective in treating COVID-19. Methods: We searched Medline, Medrxiv.org, and reference lists of relevant publications to identify articles of in vitro, in vivo, and clinical studies on treatments for severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), and COVID-19 published in English until the last update on October 11, 2020. Results: We included 36 studies on SARS, 30 studies on MERS, and 10 meta-analyses on SARS and MERS in this study. Through 12,200 title and 830 full-text screenings for COVID-19, eight in vitro studies, 46 randomized controlled trials (RCTs) on 6,886 patients, and 29 meta-analyses were obtained and investigated. There was no therapeutic agent that consistently resulted in positive outcomes across SARS, MERS, and COVID-19. Remdesivir showed a therapeutic effect for COVID-19 in two RCTs involving the largest number of total participants (n = 1,461). Other therapies that showed an effect in at least two RCTs for COVID-19 were sofosbuvir/daclatasvir (n = 114), colchicine (n = 140), IFN-ß1b (n = 193), and convalescent plasma therapy (n = 126). Conclusions: This review provides information to help establish treatment and research directions for COVID-19 based on currently available evidence. Further RCTs are required.

A systematic review and meta-analysis of the efficacy and safety of western medicine routine treatment combined with Chinese herbal medicine in the treatment of COVID-19.

BACKGROUND: COVID-19 is a global public health emergency. At present, there is no highly effective medicine for the prevention and treatment of 2019-nCoV. Western medicine for COVID-19 is mainly based on symptomatic support therapy. Chinese herbal medicine has been used to prevent infectious diseases for thousands of years in China. Western medicine routine treatment combined with Chinese herbal medicine is an alternative clinical option but lacks evidence-based medical evidence. The systematic review protocol aims to formulate a research plan that can evaluate the efficacy and safety of western medicine routine treatment combined with Chinese herbal medicine for COVID-19. METHODS: We will search the following eight databases: Cochrane Library, PubMed, Embase, Medline, CNKI, Wanfang, VIP, and CBM. The search time is up to the end of July 2020. Two authors will independently complete literature screening, data extraction, and risk of bias assessment. In case of disagreement, the third author will assist in the judgment. The primary outcome will be the clinical cure rate. The secondary outcome will be accounting symptoms, fever time, time of virus nucleic acid turning negative, check the condition by drawing blood, pneumonia absorption rate, patient hospitalization time, severe conversion rate and case fatality rate, adverse reactions, and adverse events. Revman 5.3 will be used for systematic reviews and meta-analysis. The report of the protocol will follow the PRISMA-P statement, and the report of the systematic review and meta-analysis will follow the PRISMA statement. RESULTS: We will provide evidence-based medical evidence of the efficacy and safety of western medicine routine treatment combined with Chinese herbal medicine for COVID-19. The findings will be published in peer-reviewed journals. REGISTRATION DETAILS: CRD42020190106.

Efficacy and safety of Shufeng Jiedu capsule for coronavirus disease 2019 (COVID-19): A protocol for systematic review and meta-analysis.

BACKGROUND: From the end of 2019 to the present, coronavirus disease 2019 (COVID-19) has put considerable pressure on the worlds medical system and caused significant mortality and economic losses around the world. In China, the Shufeng Jiedu capsule has been widely used in the treatment of COVID-19, but there is still a lack of evidence-based medical evaluation. METHODS: According to the retrieval strategies, randomized controlled trials (RCTs) on the Shufeng Jiedu capsule for COVID-19 were obtained from CNKI, WanFang, VIP, PubMed, Embase and Cochrane Library, regardless of publication date, or language. Studies were screened based on inclusion and exclusion criteria, and the Cochrane risk bias assessment tool was used to evaluate the quality of the studies. The meta-analysis was performed using RevMan 5.3 and STATA 14.2 software. Ultimately, the evidentiary grade for the results will be evaluated. RESULTS: This study will evaluate the efficacy and safety of the Shufeng Jiedu capsule in the treatment of COVID-19 and provide a more reasonable choice of medication in clinical practice. CONCLUSION: Our findings will provide references for future clinical decision and guidance development. REGISTRATION: INPLASY registration number: INPLASY202070024.

Exploring an Integrative Therapy for Treating COVID-19: A Randomized Controlled Trial.

OBJECTIVES: To develop a new Chinese medicine (CM)-based drug and to evaluate its safety and effect for suppressing acute respiratory distress syndrome (ARDS) in COVID-19 patients. METHODS: A putative ARDS-suppressing drug Keguan-1 was first developed and then evaluated by a randomized, controlled two-arm trial. The two arms of the trial consist of a control therapy (alpha interferon inhalation, 50 µg twice daily; and lopinavir/ritonavir, 400 and 100 mg twice daily, respectively) and a testing therapy (control therapy plus Keguan-1 19.4 g twice daily) by random number table at 1:1 ratio with 24 cases each group. After 2-week treatment, adverse events, time to fever resolution, ARDS development, and lung injury on newly diagnosed COVID-19 patients were assessed. RESULTS: An analysis of the data from the first 30 participants showed that the control arm and the testing arm did not exhibit any significant differences in terms of adverse events. Based on this result, the study was expanded to include a total of 48 participants (24 cases each arm). The results show that compared with the control arm, the testing arm exhibited a significant improvement in time to fever resolution (P=0.035), and a significant reduction in the development of ARDS (P=0.048). CONCLUSIONS: Keguan-1-based integrative therapy was safe and superior to the standard therapy in suppressing the development of ARDS in COVID-19 patients. (Trial registration No. NCT04251871 at www.clinicaltrials.gov ).

Chinese herbs combined with Western medicine for severe acute respiratory syndrome (SARS).

BACKGROUND: Severe acute respiratory syndrome (SARS) is an acute respiratory disease caused by a novel coronavirus, which first appeared in Foshan City, China on 22 December 2002. Chinese herbs were used in its treatment. OBJECTIVES: To evaluate the possible effectiveness and safety of Chinese herbs combined with Western medicines versus Western medicines alone for SARS patients. SEARCH METHODS: We searched CENTRAL 2012, Issue 3, MEDLINE (1966 to February Week 4, 2012), EMBASE (1990 to March 2012) and the Chinese Biomedical Literature (Issue 3, 2012). SELECTION CRITERIA: Randomised controlled trials (RCTs) and quasi-RCTs of Chinese herbs combined with Western medicines versus Western medicines alone for patients diagnosed with SARS. DATA COLLECTION AND ANALYSIS: Two review authors (XL, MZ) independently extracted trial data. We extracted dichotomous and continuous data with 95% confidence intervals (CI). For dichotomous data, we used risk ratio (RR). For continuous data, we calculated mean differences (MD). We calculated overall results based on the random-effects model if heterogeneity existed between studies. If no heterogeneity was detected between the studies, we used the fixed-effect model. We used the Z score and the Chi(2) test with significance being set at P < 0.05 to test heterogeneity. No severe adverse events were reported. MAIN RESULTS: We included 12 RCTs and one quasi-RCT. A total of 640 SARS patients and 12 Chinese herbs were identified. We did not find Chinese herbs combined with Western medicines decreased mortality versus Western medicines alone. Two herbs may improve symptoms. Five herbs may improve lung infiltrate absorption. Four herbs may decrease the dosage of corticosteroids. Three herbs may improve the quality of life of SARS patients. One herb may shorten the length of hospital stay. AUTHORS' CONCLUSIONS: Chinese herbs combined with Western medicines made no difference in decreasing mortality versus Western medicines alone. It is possible that Chinese herbs combined with Western medicines may improve symptoms, quality of life and absorption of pulmonary infiltration, and decrease the corticosteroid dosage for SARS patients. The evidence is weak because of the poor quality of the included trials. Long-term follow-up of these included trials is needed.

Symptom combinations associated with outcome and therapeutic effects in a cohort of cases with SARS.

Severe acute respiratory syndrome (SARS) is an infectious disease and some of its symptoms were clinically indistinguishable of those from similar diseases. This study aimed to find the symptom combinations associated with adverse outcome and the therapeutic effects in a cohort of patients with probable SARS retrospectively. In 2003, 123 SARS cases in Beijing were subjected to a strictly western medicine (WM) treatment, or a combined treatment (WM plus Herba houttuyniae injection, addition of individualized herbal treatments when necessary), of which 115 were followed till death or discharge; 8 were transferred and lost to follow-up. In both treatment groups, clinical manifestations were evaluated daily; development of signs and symptoms, and their possible relationship with outcome, were assessed. The relationships between these sign/symptom complexes and outcome under two treatment protocols were evaluated and differences were noted. Dynamic symptom combinations, dividing into the early, the medium-term and the durational symptom clusters, were identified as likely being related to the adverse outcomes of SARS (p < 0.05, p < 0.01). Compared with a strictly WM treatment, the combined treatment resulted in a longer hospital stay (p = 0.028), a non-statistically significant mortality rate decrease (combined treatment: 9.6% versus WM: 11.1%), and a significant improvement of arthralgia and myalgia (p < 0.05) in the early symptom cluster. Additionally, the combined protocol improved arterial oxyhemoglobin saturation significantly at day 22 (p < 0.05). In conclusion, the progress and outcome of SARS may be associated with specific temporal patterns of development in combination of several non-specific signs and symptom complexes, which are also helpful for evaluating the therapeutic effects on SARS patients.

SARS in Singapore: surveillance strategies in a globalising city.

Public health measures employed to fight against the spread of SARS need to be guided by biomedical knowledge as well as an understanding of the social science aspects of the disease. Using Singapore as a case study, we explore how the state constructs the disease and implements measures targeted at creating a ring of defense around the island and using surveillance to monitor and prevent its spread. While there is support, there is also resentment among some Singaporeans who complain that their right to privacy has been invaded and that over surveillance may have actually occurred. Marginalisation and discrimination have not only affected the local population but in this open economy which is striving to achieve global city status, businesses, tourism, foreign talent, foreign contract workers and foreign students studying in Singapore have also been negatively affected. While Singapore has been applauded by WHO and used as an example of quick and effective response, a holistic approach to the management of infectious disease must address the social implications of strategies that are drawn from medical knowledge alone because it impinges on the social lives of people and how people interact with each other under stressful circumstances.

[Effect of glucocorticoid with traditional Chinese medicine in severe acute aespiratory syndrome (SARS)].

OBJECTIVE: To evaluate the effects of traditional Chinese medicine in 461 cases of severe acute respiratory syndrome(SARS) on glucocorticoid's dosage. METHOD: By using the polycentric nonrandomized concurrent controled trial and under the condition of glucocorticoid use, the patierts were divided into two groups: the integrated traditional Chinese and western mendicine(ITCWM) and simplicity western mendicine alone(WM). The observation indexes were time in hospital, pneumonia duration, mortality, glucocorticoid's gross dosage, glucocorticoid's average dosage of days and glucocorticoid use time. RESULT: In the ITCWM group, average time in hospital was shortened (P = 0.058), pneumonia duration was shortened (P = 0.057), mortality fell (P = -0.001). The median of glucocorticoid' s gross dosage was 1,277.0 mg x d(-1) in the ITCWM group, and that was 1,680.0 mg x d(-1) in the WM group (P = 0.083). The median of glucocorticoid's average dosage of days was 84.40 mg x d(-1) in the ITCWM group, and that was 115.33 mg x d(-1) in the WM group (P = 0.025). According to the analysis of 461 cases divided by stages and different ponderance, within 7 days after illness, in the ITCWM group, the glucocorticoid' s average dosage decreased. In the common type, the dosage in the ITCWM and in the WM was 146.43 mg x d(-1), and 183.64 mg x d(-1), respectively (P = 0.057), in the severe type, that was 137.71 and 177.86 mg x d(-1), respectively (P = 0.001). CONCLUSION: Compared with the group of simplicity western mendicine, in the group of integratived Chinese and western mendicine, time in hospital shorten, pneumonia duration shorten, mortality fall, simultaneity, glucocorticoid's average dosage is decreased. The use of TCM in the forepart of treatment can be capable of decreasing glucocorticoid's dosage.

Effect of integrated traditional Chinese and Western medicine on SARS: a review of clinical evidence.

AIM: To assess the possible effect of integrated traditional Chinese and Western medicine on severe acute respiratory syndromes. METHODS: The current available randomized controlled trials of integrated traditional Chinese and Western medicine on SARS were identified through systematically searching literature in any languages or any types of publications. Additional studies of gray literature were also collected. The quality of studies was evaluated by two investigators independently based largely on the quality criteria specified CONSORT. Statistical analysis of the results was performed using RevMan 4.2.0 software developed by the Cochrane Collaboration. RESULTS: Six studies (n = 366) fulfilling the inclusion criteria were found, of which the quality of one study was graded as B, the remaining five were graded as C. Two studies were performed with meta-analysis, the other four studies existed some heterogeneity for which meta-analysis could not be performed, a significant effect on lung infiltrate absorption was found in the treatment groups of these two studies (RR 6.68, 95% CI (2.93, 15.24), P<0.01), there was no significant differences between the mortality (RR 0.86, 95% CI (0.22, 3.29), P = 0.82) and the average dosage of corticosteroid (WMD -39.65, 95% CI (-116.84, 37.54), P = 0.31). The other three studies also showed significant differences in infiltrate absorption, including national drug No. 2. 3. 4 in combination with Western medicine (RR 5.45, 95% CI (1.54, 19.26)), compound formulas NO. 1 combined with Western medicine (WMD 0.24, 95% CI (0.02, 0.46)), compound formulas combined with Western medicine (RR 8.06, 95% CI (0.40, 163.21)). Kangfeidian No.4 in combination with Western medicine had no significant effect on symptom improvement such as loss of dyspnea and cough (RR 1.50, 95%CI (0.41, 5.43)) and (RR 1.29, 95%CI (0.30, 5.43)). CONCLUSION: Integrated traditional Chinese and Western medicines has some positive effects on lung infiltrate absorption in SARS patients, and is recommended as an adjunct treatment for SARS. However, its effect on SARS requires further careful study due to limited available randomized control trials.

Statistical evidence for the usefulness of Chinese medicine in the treatment of SARS.

This study estimated case fatality rates in Hong Kong, Singapore and Beijing using the number of new admissions, deaths and discharges by cure. To determine the relationships between the hazard for death and that for cure, a cure--death hazard plot was developed. The daily ratios of the two hazards determine the ultimate case fatality rate. The case fatality rate was approximately 18% for Hong Kong and Singapore, while the rate for Beijing exceeded 52% until 5 May, was 16% for 5-19 May, and 4%-1% after 20 May. These results show a significant difference in the case fatality rate between Beijing and other areas, which seems to have been due to the difference in treatment methods. That is, it suggests that combining traditional Chinese medicine with Western medicine is useful in the treatment of SARS.

Chinese herbal medicine for severe acute respiratory syndrome: a systematic review and meta-analysis.

OBJECTIVES: To review randomized controlled trials (RCTs) evaluating the effects of Chinese herbal medicine for treating severe acute respiratory syndrome (SARS) systematically. DESIGN: Electronic and manual searches identified RCTs comparing Chinese medicine integrated to conventional medicine versus conventional medicine alone. Methodological quality of trials was assessed by generation of allocation sequence, allocation concealment, blinding, and intention-to-treat. RESULTS: Eight RCTs (488 patients with SARS) were included. The methodological quality was generally low. The combined therapy showed significant reduction of mortality (relative risk 0.32 [95% confidence interval {CI} 0.12 to 0.91]), shortened duration of fever, symptom relief, reductions in chest radiograph abnormalities, and reductions in secondary fungal infections among patients receiving glucocorticoids. There were no significant effects on quality of life or glucocorticoid dosage. CONCLUSION: Chinese herbal medicine combined with conventional medicine may have beneficial effects in patients with SARS. The evidence is insufficient because of the low methodological quality of the included trials.

A retrospective study on clinical features of and treatment methods for 77 severe cases of SARS.

In this retrospective study, clinical data including clinical manifestations, routine blood tests, chest radiographic imaging from 77 severe cases of SARS treated with integrated Chinese and Western medicine were collected and statistically analyzed. Twenty-nine (37.6%) patients were admitted to the intensive care unit, non-invasive ventilation was used in 40 (51.9%) cases, and invasive ventilatory procedure was performed in eight (10.3%) cases. Seventy (90.9%) patients were clinically cured and seven (9.0%) died. The duration of defervescence was 8.3 +/- 5.0 days after admission. In the early stage, normal leucocyte count was seen in 46 (75.4%) of the 61 patients tested, decreased leucocyte count in 13 (21.3%) and elevated leucocyte count in only two (3.2%) cases. A decreased lymphocyte count was also seen in 23 (37.7%) cases of the 61 patients tested on admission, and by day 14, the number of patients with decreased lymphocyte count (1.11 +/- 0.66 x 10(9)) increased to 32 (47.7%) in 67 cases examined. Neutral granulocyte count was normal or decreased in 58 (95.0%) patients on admission, but elevated from the 7th day onward and peaked on day 21 in 32 (65.3%) of the 49 cases tested. All of the blood abnormalities returned to normal in the convalescent stage. Twenty-nine (37.6%) of the 77 severe cases of SARS patients demonstrated an extensive lung involvement. In comparison with the non-severe SARS cases, this group of patients showed significantly more pneumonic air-space opacities and ground glass-like changes on the chest radiographs (p < 0.05, chi2 test). The role Chinese medicine played in the treatment of SARS was discussed.