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).

Research progress with the severe acute respiratory syndrome coronavirus 2 Delta variant

The global outbreak of coronavirus disease 2019 (COVID-19) has affected more than 200 million people worldwide, caused millions of deaths, and has threatened global economic stability. Vaccines against severe acute respiratory syndrome coronavirus 2, the causative agent of COVID-19, have been developed, and the rollout of widespread vaccination has curbed the epidemic in many countries. However, variants of the virus, including the Delta variant, have emerged that have triggered new rounds of infection. In this review, we discuss the epidemiological characteristics, pathogenicity, clinical symptoms, laboratory tests, and imaging manifestations of the Delta variant, with the aim of offering new insight into strategies for the early detection, diagnosis, and treatment of disease caused by this coronavirus variant.

Implementation of emergency general practitioner management of patients during the complete lockdown consequent to the COVID-19 Omicron outbreak in Shanghai.

The outbreak of the Omicron strain of COVID-19 led to the most restrictive lockdowns ever implemented in Shanghai.

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.

Chinese Consensus Report on Family-Based Helicobacter pylori Infection Control and Management (2021 Edition).

OBJECTIVE: Helicobacter pylori infection is mostly a family-based infectious disease. To facilitate its prevention and management, a national consensus meeting was held to review current evidence and propose strategies for population-wide and family-based H. pylori infection control and management to reduce the related disease burden. METHODS: Fifty-seven experts from 41 major universities and institutions in 20 provinces/regions of mainland China were invited to review evidence and modify statements using Delphi process and grading of recommendations assessment, development and evaluation system. The consensus level was defined as ≥80% for agreement on the proposed statements. RESULTS: Experts discussed and modified the original 23 statements on family-based H. pylori infection transmission, control and management, and reached consensus on 16 statements. The final report consists of three parts: (1) H. pylori infection and transmission among family members, (2) prevention and management of H. pylori infection in children and elderly people within households, and (3) strategies for prevention and management of H. pylori infection for family members. In addition to the 'test-and-treat' and 'screen-and-treat' strategies, this consensus also introduced a novel third 'family-based H. pylori infection control and management' strategy to prevent its intrafamilial transmission and development of related diseases. CONCLUSION: H. pylori is transmissible from person to person, and among family members. A family-based H. pylori prevention and eradication strategy would be a suitable approach to prevent its intra-familial transmission and related diseases. The notion and practice would be beneficial not only for Chinese residents but also valuable as a reference for other highly infected areas.

Helicobacter pylori diagnosis and therapy in the era of antimicrobial stewardship.

The diagnosis and therapy of Helicobacter pylori infection have undergone major changes based on the use the principles of antimicrobial stewardship and increased availability of susceptibility profiling. H. pylori gastritis now recognized as an infectious disease, as such there is no placebo response allowing outcome to be assessed in relation to the theoretically obtainable cure rate of 100%. The recent recognition of H. pylori as an infectious disease has changed the focus to therapies optimized to reliably achieve high cure rates. Increasing antimicrobial resistance has also led to restriction of clarithromycin, levofloxacin, or metronidazole to susceptibility-based therapies. Covid-19 resulted in the almost universal availability of polymerase chain reaction testing in hospitals which can be repurposed to utilize readily available kits to provide rapid and inexpensive detection of clarithromycin resistance. In the United States, major diagnostic laboratories now offer H. pylori culture and susceptibility testing and American Molecular Laboratories offers next-generation sequencing susceptibility profiling of gastric biopsies or stools for the six commonly used antibiotics without need for endoscopy. Current treatment recommendations include (a) only use therapies that are reliably highly effective locally, (b) always perform a test-of-cure, and (c) use that data to confirm local effectiveness and share the results to inform the community regarding which therapies are effective and which are not. Empiric therapy should be restricted to those proven highly effective locally. The most common choices are 14-day bismuth quadruple therapy and rifabutin triple therapy. Prior guidelines and treatment recommendations should only be used if proven locally highly effective.

Identify potential treatments of COVID-19 from Tibetan medicine Hippophae Fructus using a network pharmacological approach

OBJECTIVE Since the coronavirus disease 2019(COVID-19) outbreak in December 2019, the search for a potential treatment for COVID-19 has been a constant focus. Therefore, we identified potential treatments for COVID-19 from Hippophae Fructus, a Tibetan medicine that may act on COVID-19, using a network pharmacology approach.METHODS We collected the chemical constituents and corresponding targets of Hippophae Fructus from traditional Chinese medicine system pharmacology(TCMSP). COVID-19 related genes were predicted in pubmed-Gene, OMIM and GeneCards databases. Then, protein-protein interactions(PPIs) of key genes were analyzed by STRING database.Compound-target-diseases network was constructed using Cytoscape software. The potential pathways were determined by Gene Ontology(GO) and Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway analyses. Additionally,molecular docking was used to verify the binding effect between the active component and the target. RESULTS A total of 33 components and 192 corresponding targets in Hippophae Fructus were found. 50 genes were obtained from the intersection of component targets and disease targets. These genes include IL-6, TNF, MAPK8 and PTGS2, which regulate several pathways associated with COVID-19, involving Hepatitis B, Influenza A, TNF signaling pathway and Tuberculosis. More importantly, high-node compounds such as quercetin and beta-sitosterol can well bind to key targets.CONCLUSION Some components in Hippophae Fructus can act on COVID-19 related genes and regulate multiple pathways. Perhaps Hippophae Fructus has the effect in treating COVID-19.

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.

Diabetes patients with comorbidities had unfavorable outcomes following COVID-19: A retrospective study.

BACKGROUND: Previous studies have shown that diabetes mellitus is a common comorbidity of coronavirus disease 2019 (COVID-19), but the effects of diabetes or anti-diabetic medication on the mortality of COVID-19 have not been well described. AIM: To investigate the outcome of different statuses (with or without comorbidity) and anti-diabetic medication use before admission of diabetic after COVID-19. METHODS: In this multicenter and retrospective study, we enrolled 1422 consecutive hospitalized patients from January 21, 2020, to March 25, 2020, at six hospitals in Hubei Province, China. The primary endpoint was in-hospital mortality. Epidemiological material, demographic information, clinical data, laboratory parameters, radiographic characteristics, treatment and outcome were extracted from electronic medical records using a standardized data collection form. Most of the laboratory data except fasting plasma glucose (FPG) were obtained in first hospitalization, and FPG was collected in the next day morning. Major clinical symptoms, vital signs at admission and comorbidities were collected. The treatment data included not only COVID-19 but also diabetes mellitus. The duration from the onset of symptoms to admission, illness severity, intensive care unit (ICU) admission, and length of hospital stay were also recorded. All data were checked by a team of sophisticated physicians. RESULTS: Patients with diabetes were 10 years older than non-diabetic patients [(39 - 64) vs (56 - 70), P < 0.001] and had a higher prevalence of comorbidities such as hypertension (55.5% vs 21.4%, P < 0.001), coronary heart disease (CHD) (9.9% vs 3.5%, P < 0.001), cerebrovascular disease (CVD) (3% vs 2.2%, P < 0.001), and chronic kidney disease (CKD) (4.7% vs 1.5%, P = 0.007). Mortality (13.6% vs 7.2%, P = 0.003) was more prevalent among the diabetes group. Further analysis revealed that patients with diabetes who took acarbose had a lower mortality rate (2.2% vs 26.1, P < 0.01). Multivariable Cox regression showed that male sex [hazard ratio (HR) 2.59 (1.68 - 3.99), P < 0.001], hypertension [HR 1.75 (1.18 - 2.60), P = 0.006), CKD [HR 4.55 (2.52-8.20), P < 0.001], CVD [HR 2.35 (1.27 - 4.33), P = 0.006], and age were risk factors for the COVID-19 mortality. Higher HRs were noted in those aged ≥ 65 (HR 11.8 [4.6 - 30.2], P < 0.001) vs 50-64 years (HR 5.86 [2.27 - 15.12], P < 0.001). The survival curve revealed that, compared with the diabetes only group, the mortality was increased in the diabetes with comorbidities group (P = 0.009) but was not significantly different from the non-comorbidity group (P = 0.59). CONCLUSION: Patients with diabetes had worse outcomes when suffering from COVID-19; however, the outcome was not associated with diabetes itself but with comorbidities. Furthermore, acarbose could reduce the mortality in diabetic.

Optimization of outpatient protection and CVC maintenance for tumor patients during a new COVID - 19 outbreak

Since December 2019, corona virus disease 2019 epidemic is severe, contagious, concealed, and spreads rapidly, so prevention and control are extremely difficult in China. As a cancer specialist hospital, patients need to travel to and from the hospital multiple times for chemoradiation, reexamination and maintenance, and repeated treatments lead to low immunity. Cancer patients become susceptible to the new type of COVID-19. Improper protection can easily cause nosocomial infections. In this regard, our hospital's catheter clinic established a new set of coronavirus protection measures and optimized the maintenance process. From February 3 to February 28, 2020, a total of 758 patients with tumors were maintained, including 159 patients returning from overseas (except for Hubei) and 8 patients returning from Hubei. There was no case of cross-infection for the coronavirus in the hospital. The experience is described as below.

Dynamic changes in monocytes subsets in COVID-19 patients.

BACKGROUND: Coronavirus disease 2019 (COVID-19) is affecting the whole world and threatening human health. We aim to investigate the immunological characteristics of monocytes in critical patients with COVID-19. METHODS: The number and immune status of monocytes were detected by flow cytometry in 32 COVID-19 patients and 18 healthy individuals. RESULTS: In critical patients with COVID-19, the absolute number of total monocytes and CD16- monocytes was significantly decreased but CD16+ pro-inflammatory monocytes was increased compared to healthy controls. Antigen presentation potential of monocytes, as measured by HLA-DR expression, was suppressed, while their inflammatory phenotype (CD38 expression) was enhanced. Cytokine levels showed sustained increases in critical patients. And the levels of IL-6 were positively correlated with CD16+ monocytes number. IL-6 and IL-10 levels were negatively correlated with HLA-DR expression of monocytes. During the recovery of COVID-19 patients, the count and immune status of monocyte subsets were restored by degrees. HLA-DR+ monocytes possessed good sensitivity and specificity for predicting the incidence of critical patients with COVID-19. CONCLUSIONS: In critical patients with COVID-19, decline in number and HLA-DR expression of monocytes might lead to decreased antigen presentation potential and thus immunosuppression, while increased CD16+ pro-inflammatory monocytes might mediate hyperinflammation. HLA-DR+ monocytes might be a meaningful assisted indicator to predict the incidence of critical patients with COVID-19.

COVID-19 pneumonia: CD8+ T and NK cells are decreased in number but compensatory increased in cytotoxic potential.

BACKGROUND: Coronavirus disease 2019 (COVID-19) is posing a huge threat to human health worldwide. We aim to investigate the immune status of CD8+ T and NK cells in COVID-19 patients. METHODS: The count and immune status of lymphocytes were detected by flow cytometry in 32 COVID-19 patients and 18 healthy individuals. RESULTS: As the disease progression in COVID-19 patients, CD8+ T and NK cells were significantly decreased in absolute number but highly activated. After patients' condition improved, the count and immune status of CD8+ T and NK cells restored to some extent. GrA+CD8+ T and perforin+ NK cells had good sensitivity and specificity for assisting diagnosis of COVID-19. CONCLUSIONS: As the disease progression, the declined lymphocytes in COVID-19 patients might lead to compensatory activation of CD8+ T and NK cells. GrA+CD8+ T and perforin+ NK cells might be used as meaningful indicators for assisting diagnosis of COVID-19.

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.

Epidemiological features and viral shedding in children with SARS-CoV-2 infection.

A pandemic of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection broke out all over the world; however, epidemiological data and viral shedding in pediatric patients are limited. We conducted a retrospective, multicenter study, and followed-up with all children from the families with SARS-CoV-2 infected members in Zhejiang Province, China. All infections were confirmed by testing the SARS-CoV-2 RNA with real-time reverse transcription PCR method, and epidemiological data between children and adults in the same families were compared. Effect of antiviral therapy was evaluated observationally and fecal-viral excretion times among groups with different antiviral regiments were compared with Kaplan-Meier plot. By 29 February 2020, 1298 cases from 883 families were confirmed with SARS-CoV-2 infection and 314 of which were families with children. Incidence of infection in child close contacts was significantly lower than that in adult contacts (13.2% vs 21.2%). The mean age of 43 pediatric cases was 8.2 years and mean incubation period was 9.1 days. Forty (93.0%) were family clustering. Thirty-three children had coronavirus disease 2019 (20 pneumonia) with mild symptoms and 10 were asymptomatic. Fecal SARS-CoV-2 RNA detection was positive in 91.4% (32/35) cases and some children had viral excretion time over 70 days. Viral clearance time was not different among the groups treated with different antiviral regiments. No subsequent infection was observed in family contacts of fecal-viral-excreting children. Children have lower susceptibility of SARS-CoV-2 infection, longer incubation, and fecal-viral excretion time. Positive results of fecal SARS-CoV-2 RNA detection were not used as indication for hospitalization or quarantine.

Continuous tracking of COVID-19 patients' immune status.

BACKGROUND: COVID-19 is threating human health worldwide. We aim to investigate the dynamic changes of immune status in COVID-19 patients with clinical evolution. METHODS: Sixty-one COVID-19 patients (42 mild cases and 19 severe cases, 51 cases without secondary infection as non-infection group and 10 cases with secondary bacterial/fungal infection as infection group) and 52 healthy controls (HCs) were enrolled from our hospital. Leucocyte classification, lymphocyte subsets and cytokines were detected by full-automatic blood cell analyzer and flow cytometer, respectively. RESULTS: Upon admission, eosinophils and lymphocyte subsets decreased significantly, while neutrophils, monocytes, basophils, IL-2, IL-6, IL-10 and IFN-γ increased significantly in COVID-19 patients compared to HCs. CD3+ T and DN (CD3+CD4-CD8-) cells appeared sustained decline, leucocytes, neutrophils and IL-10 showed sustained increase in severe group compared to mild group. Compared with the non-infection group, we observed a depletion of eosinophils, CD3+ T and CD4+ T cells, but leucocytes, neutrophils, IL-6 and IL-10 on the contrary in the infection group. Besides, in severe group of COVID-19 patients, DN cells were negatively correlated with IL-10, and DP (CD3+CD4+CD8+) cells were negatively correlated with IL-6. Lymphocytes, eosinophils, CD3+ T cells, CD4+ T cells, IL-6 and IL-10 all had great diagnostic efficacy (AUC, 0.905-0.975) for COVID-19. The laboratory indicators of COVID-19 patients with improved condition also showed a recovery trend with time. CONCLUSIONS: The immune status of COVID-19 patients is different in each stage, and dynamic monitoring of related indicators can help predict the disease and may avoid cytokine storms.