Efficacy and safety of Lianhua Qingwen capsules combined with standard of care in the treatment of adult patients with mild to moderate COVID-19 (FLOSAN): protocol for a randomized, double-blind, international multicenter clinical trial.

Background: Effective anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) drugs are not only the next defense after vaccines but also the key part of establishing a multi-tiered coronavirus disease 2019 (COVID-19) prevention and control system. Previous studies had indicated that Lianhua Qingwen (LHQW) capsules could be an efficacious Chinese patent drug for treating mild to moderate COVID-19. However, pharmacoeconomic evaluations are lacking, and few trials have been conducted in other countries or regions to evaluate the efficacy and safety of LHQW treatment. So, this study aims to explore the clinical efficacy, safety, and economy of LHQW for treating adult patients with mild to moderate COVID-19. Methods: This is a randomized, double-blind, placebo-controlled, international multicenter clinical trial protocol. A total of 860 eligible subjects are randomized at a 1:1 ratio into the LHQW or placebo group to receive two-week treatment and follow-up visits on days 0, 3, 7, 10, and 14. Clinical symptoms, patient compliance, adverse effects, cost scale, and other indicators are recorded. The primary outcomes will be the measured median time to sustained improvement or resolution of the nine major symptoms during the 14-day observation period. Secondary outcomes regarding clinical efficacy will be evaluated in detail on the basis of clinical symptoms (especially body temperature, gastrointestinal symptoms, smell loss, and taste loss), viral nucleic acid, imaging (CT/chest X-ray), the incidence of severe/critical illness, mortality, and inflammatory factors. Moreover, we will assess health care cost, health utility, and incremental cost-effectiveness ratio (ICER) for economic evaluation. Discussion: This is the first international multicenter randomized controlled trial (RCT) of Chinese patent medicine for the treatment of early COVID-19 in accordance with WHO guidelines on COVID-19 management. This study will help clarify the potential efficacy and cost-effectiveness of LHQW in the treatment of mild to moderate COVID-19, facilitating decision-making by healthcare workers. Registration: This study is registered at the Chinese Clinical Trial Registry, with registration number: ChiCTR2200056727 (date of first registration: 11/02/2022).

Persistence and clearance of viral RNA in 2019 novel coronavirus disease rehabilitation patients.

BACKGROUND: A patient's infectivity is determined by the presence of the virus in different body fluids, secretions, and excreta. The persistence and clearance of viral RNA from different specimens of patients with 2019 novel coronavirus disease (COVID-19) remain unclear. This study analyzed the clearance time and factors influencing 2019 novel coronavirus (2019-nCoV) RNA in different samples from patients with COVID-19, providing further evidence to improve the management of patients during convalescence. METHODS: The clinical data and laboratory test results of convalescent patients with COVID-19 who were admitted to from January 20, 2020 to February 10, 2020 were collected retrospectively. The reverse transcription polymerase chain reaction (RT-PCR) results for patients' oropharyngeal swab, stool, urine, and serum samples were collected and analyzed. Convalescent patients refer to recovered non-febrile patients without respiratory symptoms who had two successive (minimum 24 h sampling interval) negative RT-PCR results for viral RNA from oropharyngeal swabs. The effects of cluster of differentiation 4 (CD4)+ T lymphocytes, inflammatory indicators, and glucocorticoid treatment on viral nucleic acid clearance were analyzed. RESULTS: In the 292 confirmed cases, 66 patients recovered after treatment and were included in our study. In total, 28 (42.4%) women and 38 men (57.6%) with a median age of 44.0 (34.0-62.0) years were analyzed. After in-hospital treatment, patients' inflammatory indicators decreased with improved clinical condition. The median time from the onset of symptoms to first negative RT-PCR results for oropharyngeal swabs in convalescent patients was 9.5 (6.0-11.0) days. By February 10, 2020, 11 convalescent patients (16.7%) still tested positive for viral RNA from stool specimens and the other 55 patients' stool specimens were negative for 2019-nCoV following a median duration of 11.0 (9.0-16.0) days after symptom onset. Among these 55 patients, 43 had a longer duration until stool specimens were negative for viral RNA than for throat swabs, with a median delay of 2.0 (1.0-4.0) days. Results for only four (6.9%) urine samples were positive for viral nucleic acid out of 58 cases; viral RNA was still present in three patients' urine specimens after throat swabs were negative. Using a multiple linear regression model (F = 2.669, P = 0.044, and adjusted R = 0.122), the analysis showed that the CD4+ T lymphocyte count may help predict the duration of viral RNA detection in patients' stools (t = -2.699, P = 0.010). The duration of viral RNA detection from oropharyngeal swabs and fecal samples in the glucocorticoid treatment group was longer than that in the non-glucocorticoid treatment group (15 days vs. 8.0 days, respectively; t = 2.550, P = 0.013) and the duration of viral RNA detection in fecal samples in the glucocorticoid treatment group was longer than that in the non-glucocorticoid treatment group (20 days vs. 11 days, respectively; t = 4.631, P < 0.001). There was no statistically significant difference in inflammatory indicators between patients with positive fecal viral RNA test results and those with negative results (P > 0.05). CONCLUSIONS: In brief, as the clearance of viral RNA in patients' stools was delayed compared to that in oropharyngeal swabs, it is important to identify viral RNA in feces during convalescence. Because of the delayed clearance of viral RNA in the glucocorticoid treatment group, glucocorticoids are not recommended in the treatment of COVID-19, especially for mild disease. The duration of RNA detection may relate to host cell immunity.

Early predicting indicators of conversion from mild to moderate in overseas-imported COVID-19 cases.

BACKGROUND: Due to the ongoing pandemic of coronavirus disease 2019 (COVID-19) in foreign countries and regions, many overseas people arrive in China by air. Currently, most of the new cases of COVID-19 were imported from overseas. Here, we evaluated the predictive effect of the level of blood albumin (ALB) and serum prealbumin (PA) level in overseas-imported cases on the conversion of mild COVID-19 to moderate and its value in guiding nutritional support for these travelers. METHODS: We retrospectively analyzed serum levels of ALB and PA of 193 patients with imported COVID-19 admitted to the Shanghai Public Health Clinical Center at the time of admission on April 8, 2020. RESULTS: Since the first overseas-imported case was admitted to Shanghai on March 5, 2020, 195 overseas-imported cases have been treated in the Shanghai Public Health Clinical Center. The disease was mild or moderate. A total of 193 patients (111 males and 82 females) entered our analysis and the disease was moderate in 108 patients and mild in 85 patients. Patients were aged 6 to 66 years (mean: 28 years). There was a strong negative correlation between the proportion of moderate type and ALB (P=0.0073); thus, patients with a lower level of ALB were more likely to be diagnosed with moderate type. The correlation coefficient was close to 0 in the scatter plot, indicating that there was no linear correlation between PA and the diagnosis of moderate type (P>0.05). There was a strong negative correlation between age and ALB level (P<0.001), while length of hospital stay did not show a linear correlation with ALB or PB levels (both P>0.05). Therefore, older patients had lower levels of ALB and were more likely to develop moderate COVID-19. CONCLUSIONS: The serum ALB level can be an early predictive indicator for the conversion of mild COVID-19 to moderate in cases imported overseas and may guide nutritional support.

Dynamic anti-spike protein antibody profiles in COVID-19 patients.

OBJECTIVES: This study intended to investigate the dynamics of anti-spike (S) IgG and IgM antibodies in COVID-19 patients. METHODS: Anti-S IgG/IgM was determined by a semi-quantitative fluorescence immunoassay in the plasma of COVID-19 patients at the manifestation and rehabilitation stages. The immunoreactivity to full-length S proteins, C-terminal domain (CTD), and N-terminal domain (NTD) of S1 fragments were determined by an ELISA assay. Clinical properties at admission and discharge were collected simultaneously. RESULTS: The positive rates of anti-S IgG/IgM in COVID-19 patients were elevated after rehabilitation compared to the in-patients. Anti-S IgG and IgM were not apparent until day 14 and day ten, respectively, according to Simple Moving Average analysis with five days' slide window deduction. More than 90% of the rehabilitation patients exhibited IgG and IgM responses targeting CTD-S1 fragments. Decreased total peripheral lymphocytes, CD4+ and CD8+ T cell counts were seen in COVID-19 patients at admission and recovered after the rehabilitation. CONCLUSIONS: Anti-S IgG and IgM do not appear at the onset with the decrease in T cells, making early serological screening less significant. However, the presence of high IgG and IgM to S1-CTD in the recovered patients highlights humoral responses after SARS-CoV-2 infection, which might be associated with efficient immune protection in COVID-19 patients.

Analysis of clinical features and related factors of coronavirus disease 2019 in Shanghai

Objective • To explore the common clinical features of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)-infected local patients in Shanghai and their related influencing factors. Methods • A total of 320 patients admitted to Shanghai Public Health Clinical Center from January to March 2020 and diagnosed as having coronavirus disease 2019(COVID-19) were selected. Clinical data of the patients were collected to analyze their characteristics. Using the statistical operation formula of R language, the correlation analysis of hospitalization days, days of increased hypersensitive C-reactive protein concentration (allergic days), days of lung CT improvement (CT days), and days required for nucleic acid turning negative with the main clinical manifestations and laboratory data was carried out. The correlation factors affecting the above four variables were analyzed. Results • Among the 320 patients, the proportions of mild type, moderate type, serious type and critical type were 6.25%, 83.44%, 6.88% and 3.44%, respectively;91.25% of them had a history of exposure to Hubei. The proportions of fever, cough, sputum and fatigue were 79.06%, 46.56%, 21.56% and 15.31%, respectively. Spearman correlation analysis showed that the concentrations of lactate dehydrogenase, interleukin-2(IL-2) and IL-6 were positively correlated with the above four variables, respectively (all P<0.05), albumin concentration was negatively correlated with allergic days (P=0.018), and CD4+ cell count was negatively correlated with CT days and days required for nucleic acid turning negative (both P<0.05). Stepwise multiple linear regression analysis showed that procalcitonin (PCT) concentration was negatively correlated with hospitalization days, CT days and allergic days (both P<0.05), and disease type was positively correlated with hospitalization days, allergic days, CT days and days required for nucleic acid turning negative (all P<0.05). Conclusion • Moderate type is common in the local patients in Shanghai;fever, cough and fatigue are common symptoms, and most of the patients are accompanied by lung CT abnormalities. The therapeutic effect and prognosis of these patients are closely related to disease type, concentrations of PCT and IL-6, as well as CD4+ cell count.

Assessing risk factors for SARS-CoV-2 infection in patients presenting with symptoms in Shanghai, China: a multicentre, observational cohort study.

Background: The outbreak of COVID-19 has led to international concern. We aimed to establish an effective screening strategy in Shanghai, China, to aid early identification of patients with COVID-19. Methods: We did a multicentre, observational cohort study in fever clinics of 25 hospitals in 16 districts of Shanghai. All patients visiting the clinics within the study period were included. A strategy for COVID-19 screening was presented and then suspected cases were monitored and analysed until they were confirmed as cases or excluded. Logistic regression was used to determine the risk factors of COVID-19. Findings: We enrolled patients visiting fever clinics from Jan 17 to Feb 16, 2020. Among 53 617 patients visiting fever clinics, 1004 (1·9%) were considered as suspected cases, with 188 (0·4% of all patients, 18·7% of suspected cases) eventually diagnosed as confirmed cases. 154 patients with missing data were excluded from the analysis. Exposure history (odds ratio [OR] 4·16, 95% CI 2·74-6·33; p<0·0001), fatigue (OR 1·56, 1·01-2·41; p=0·043), white blood cell count less than 4 × 109 per L (OR 2·44, 1·28-4·64; p=0·0066), lymphocyte count less than 0·8 × 109 per L (OR 1·82, 1·00-3·31; p=0·049), ground glass opacity (OR 1·95, 1·32-2·89; p=0·0009), and having both lungs affected (OR 1·54, 1·04-2·28; p=0·032) were independent risk factors for confirmed COVID-19. Interpretation: The screening strategy was effective for confirming or excluding COVID-19 during the spread of this contagious disease. Relevant independent risk factors identified in this study might be helpful for early recognition of the disease. Funding: National Natural Science Foundation of China.