Efficacy and safety of interleukin-6 receptor antagonists in adult patients admitted to intensive care unit with COVID-19: A systematic review and meta-analysis of randomized controlled trials.

The purpose of the systematic review was to evaluate the efficacy and safety of interleukin-6 receptor (IL-6) antagonists (tocilizumab, sarilumab) in adult patients with severe or critical COVID-19. A systematic review of the literature was conducted in Medline, Cochrane and Embase databases, and World Health Organization International Clinical Trials Registry Platform (WHO ICTRP) and ClinicalTrials.gov from the inception dates to10 January 2023. Randomized clinical trials comparing IL-6 receptor antagonists (tocilizumab, sarilumab) with a placebo or usual care treatment for adult patients with severe or critical COVID-19 were identified. Two independent reviewers performed the assessment and selection of eligible studies, assessed study quality and extracted data. Relative risk (RR), mean difference (MD), and 95% confidence interval (CI) with random-effects models was performed in meta-analysis. The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology was used to assess the quality of the evidence. The search retrieved a total of 11 RCTs involving 5028 participants were eligible for meta-analysis. Our findings suggest that as the new drug used in adult patients with severe or critical COVID-19, IL-6 antagonists (tocilizumab, sarilumab) may reduce the length of ICU stay and hospital stay. However, they did not significantly increase the risks of serious adverse events and did not reduce all-cause mortality (28-day, 14-day, and 7-day).

Long COVID brain fog and muscle pain are associated with longer time to clearance of SARS-CoV-2 RNA from the upper respiratory tract during acute infection (preprint)

The incidence of long COVID is substantial, even in people who did not require hospitalization for acute COVID-19. The pathobiological mechanisms of long COVID and the role of early viral kinetics in its development are largely unknown. Seventy-three non-hospitalized adult participants were enrolled within approximately 48 hours of their first positive SARS-CoV-2 RT-PCR test, and mid-turbinate nasal and saliva samples were collected up to 9 times within the first 45 days after enrollment. Samples were assayed for SARS-CoV-2 using RT-PCR and additional test results were abstracted from the clinical record. Each participant indicated the presence and severity of 49 long COVID symptoms at 1, 3, 6, 12, and 18 months post-COVID-19 diagnosis. Time from acute COVID-19 illness onset to SARS-CoV-2 RNA clearance greater or less than 28 days was tested for association with the presence or absence of each of 49 long COVID symptoms at 90 or more days from acute COVID-19 symptom onset. Brain fog and muscle pain at 90 or more days after acute COVID-19 onset were negatively associated with viral RNA clearance within 28 days of acute COVID-19 onset with adjustment for age, sex, BMI over 25, and COVID vaccination status prior to COVID-19 (brain fog: aRR 0.46, 95% CI 0.22 - 0.95; muscle pain: aRR 0.28, 95% CI 0.08 - 0.94). This work indicates that at least two long COVID symptoms, brain fog and muscle pain, at 90 or more days from acute COVID-19 onset are specifically associated with longer time to clearance of SARS-CoV-2 RNA from the upper respiratory tract.

Post-acute sequelae of SARS-CoV-2 (PASC) impact quality of life at 6, 12 and 18 months post-infection (preprint)

Little data exist on long COVID outcomes beyond one year. In a cohort enrolled with mild-moderate acute COVID-19, a wide range of symptoms manifest at 6, 12, and 18 months. Endorsing over 3 symptoms associates with poorer quality of life in 5 domains: physical, social, fatigue, pain, and general health.

Tea and tea drinking: China's outstanding contributions to the mankind.

BACKGROUND: Tea trees originated in southwest China 60 million or 70 million years ago. Written records show that Chinese ancestors had begun drinking tea over 3000 years ago. Nowadays, with the aging of populations worldwide and more people suffering from non-communicable diseases or poor health, tea beverages have become an inexpensive and fine complementary and alternative medicine (CAM) therapy. At present, there are 3 billion people who like to drink tea in the world, but few of them actually understand tea, especially on its development process and the spiritual and cultural connotations. METHODS: We searched PubMed, Google Scholar, Web of Science, CNKI, and other relevant platforms with the key word "tea", and reviewed and analyzed tea-related literatures and pictures in the past 40 years about tea's history, culture, customs, experimental studies, and markets. RESULTS: China is the hometown of tea, tea trees, tea drinking, and tea culture. China has the oldest wild and planted tea trees in the world, fossil of a tea leaf from 35,400,000 years ago, and abundant tea-related literatures and art works. Moreover, tea may be the first Chinese herbal medicine (CHM) used by Chinese people in ancient times. Tea drinking has many benefits to our physical health via its antioxidant, anti-inflammatory, immuno-regulatory, anticancer, cardiovascular-protective, anti-diabetic, and anti-obesity activities. At the moment, COVID-19 is wreaking havoc across the globe and causing severe damages to people's health and lives. Tea has anti-COVID-19 functions via the enhancement of the innate immune response and inhibition of viral growth. Besides, drinking tea can allow people to acquire a peaceful, relaxed, refreshed and cheerful enjoyment, and even longevity. According to the meridian theory of traditional Chinese medicine, different kinds of tea can activate different meridian systems in the human body. At present, black tea (fermented tea) and green tea (non-fermented tea) are the most popular in the world. Black tea accounts for over 90% of all teas sold in western countries. The world's top-grade black teas include Qi Men black in China, Darjeeling and Assam black tea in India, and Uva black tea in Sri Lanka. However, all top ten famous green teas in the world are produced in China, and Xi Hu Long Jing tea is the most famous among all green teas. More than 700 different kinds of components and 27 mineral elements can be found in tea. Tea polyphenols and theaflavin/thearubigins are considered to be the major bioactive components of black tea and green tea, respectively. Overly strong or overheated tea liquid should be avoided when drinking tea. CONCLUSIONS: Today, CAM provides an array of treatment modalities for the health promotion in both developed and developing countries all over the world. Tea drinking, a simple herb-based CAM therapy, has become a popular man-made non-alcoholic beverage widely consumed worldwide, and it can improve the growth of economy as well. Tea can improve our physical and mental health and promote the harmonious development of society through its chemical and cultural elements.

Limitations of molecular and antigen test performance for SARS-CoV-2 in symptomatic and asymptomatic COVID-19 contacts (preprint)

Objectives: COVID-19 has brought unprecedented attention to the crucial role of diagnostics in pandemic control. We compared SARS-CoV-2 test performance by sample type and modality in close contacts of SARS-CoV-2 cases. Methods: Close contacts of SARS-CoV-2 positive individuals were enrolled after informed consent. Clinician-collected nasopharyngeal (NP) swabs in viral transport media (VTM) were tested with a nucleic acid test (NAT). NP VTM and self-collected passive drool were tested using the PerkinElmer real-time reverse transcription PCR (RT-PCR) assay. For the first 4 months of study, mid-turbinate swabs were tested using the BD Veritor rapid antigen test. NAT positive NP samples were tested for infectivity using a VeroE6TMPRSS2 cell culture model. Results: Between November 17, 2020, and October 1, 2021, 235 close contacts of SARS-CoV-2 cases were recruited, including 95 with symptoms (82% symptomatic for <5 days) and 140 asymptomatic individuals. NP swab reference tests were positive for 53 (22.6%) participants; 24/50 (48%) were culture positive. PerkinElmer testing of NP and saliva samples identified an additional 28 (11.9%) SARS-CoV-2 cases who tested negative by clinical NAT. Antigen tests performed for 99 close contacts showed 83% positive percent agreement (PPA) with reference NAT among early symptomatic persons, but 18% PPA in others; antigen tests in 8 of 11 (72.7%) culture-positive participants were positive. Conclusions: Contacts of SARS-CoV-2 cases may be falsely negative early after contact, which more sensitive platforms may identify. Repeat or serial SARS-CoV-2 testing with both antigen and molecular assays may be warranted for individuals with high pretest probability for infection.

Combating the SARS-CoV-2 Omicron variant with non-Omicron neutralizing antibodies (preprint)

The highly mutated and transmissible Omicron variant has provoked serious concerns over its decreased sensitivity to the current coronavirus disease 2019 (COVID-19) vaccines and evasion from most anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) neutralizing antibodies (NAbs). In this study, we explored the possibility of combatting the Omicron variant by constructing bispecific antibodies based on non-Omicron NAbs. We engineered ten IgG-like bispecific antibodies with non-Omicron NAbs named GW01, 16L9, 4L12, and REGN10987 by fusing the single-chain variable fragments (scFvs) of two antibodies through a linker and then connecting them to the Fc region of IgG1. Surprisingly, eight out of ten bispecific antibodies showed high binding affinity to the Omicron receptor-binding domain (RBD) and exhibited extreme breadth and potency against pseudotyped SARS-CoV-2 variants of concern (VOCs) including Omicron, as well as authentic Omicron(+R346K) variants. Six bispecific antibodies containing the cross-NAb GW01 neutralized Omicron variant and retained their abilities to neutralize other sarbecoviruses. Bispecific antibodies inhibited Omicron infection by binding to the ACE2 binding site. A cryo-electron microscopy (cryo-EM) structure study of the representative bispecific antibody FD01 in complex with the Omicron spike (S) revealed 5 distinct trimers and one unique bi-trimer conformation. The structure and mapping analyses of 34 Omicron S variant single mutants elucidated that two scFvs of the bispecific antibody synergistically induced the RBD-down conformation into 3-RBD-up conformation, enlarged the interface area, accommodated the S371L mutation, improved the affinity between a single IgG and the Omicron RBD, and hindered ACE2 binding by forming bi-trimer conformation. Our study offers an important foundation for anti-Omicron NAb design. Engineering bispecific antibodies based on non-Omicron NAbs may provide an efficient solution to combat the Omicron variant.

Identifying the Risk of SARS-CoV-2 Infection and Environmental Monitoring in Airborne Infectious Isolation Rooms (AIIRs).

Healthcare workers (HCWs) are at high risk of occupational exposure to the new pandemic human coronavirus, SARS-CoV-2, and are a source of nosocomial transmission in airborne infectious isolation rooms (AIIRs). Here, we performed comprehensive environmental contamination surveillance to evaluate the risk of viral transmission in AIIRs with 115 rooms in three buildings at the Shanghai Public Health Clinical Center, Shanghai, during the treatment of 334 patients infected with SARS-CoV-2. The results showed that the risk of airborne transmission of SARS-CoV-2 in AIIRs was low (1.62%, 25/1544) due to the directional airflow and strong environmental hygiene procedures. However, we detected viral RNA on the surface of foot-operated openers and bathroom sinks in AIIRs (viral load: 55.00-3154.50 copies/mL). This might be a source of contamination to connecting corridors and object surfaces through the footwear and gloves used by HCWs. The risk of infection was eliminated by the use of disposable footwear covers and the application of more effective environmental and personal hygiene measures. With the help of effective infection control procedures, none of 290 HCWs was infected when working in the AIIRs at this hospital. This study has provided information pertinent for infection control in AIIRs during the treatment of COVID-19 patients.

Gamma-Glutamyltransferase Elevation Is Frequent in Patients With COVID-19: A Clinical Epidemiologic Study.

A newly identified coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes the infectious coronavirus disease 2019 (COVID-19), emerged in December 2019 in Wuhan, Hubei Province, China, and now poses a major threat to global public health. Previous studies have observed highly variable alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels in patients with COVID-19. However, circulating levels of the cholangiocyte injury biomarker gamma-glutamyltransferase (GGT) have yet to be reported in the existing COVID-19 case studies. Herein, we describe the relationship between GGT levels and clinical and biochemical characteristics of patients with COVID-19. Our study is a retrospective case series of 98 consecutive hospitalized patients with confirmed COVID-19 at Wenzhou Central Hospital in Wenzhou, China, from January 17 to February 5, 2020. Clinical data were collected using a standardized case report form. Diagnosis of COVID-19 was assessed by symptomatology, reverse-transcription polymerase chain reaction (RT-PCR), and computed tomography scan. The medical records of patients were analyzed by the research team. Of the 98 patients evaluated, elevated GGT levels were observed in 32.7%; increased C-reactive protein (CRP) and elevated ALT and AST levels were observed in 22.5%, 13.3%, and 20.4%, respectively; and elevated alkaline phosphatase (ALP) and triglycerides (TGs) were found in 2% and 21.4%, respectively. Initially, in the 82 patients without chronic liver disease and alcohol history, age older than 40 years (P = 0.027); male sex (P = 0.0145); elevated CRP (P = 0.0366), ALT (P < 0.0001), and ALP (P = 0.0003); and increased TGs (P = 0.0002) were found to be associated with elevated GGT levels. Elevated GGT (P = 0.0086) and CRP (P = 0.0162) levels had a longer length of hospital stay. Conclusion: A sizable number of patients with COVID-19 infection have elevated serum GGT levels. This elevation supports involvement of the liver in persons with COVID-19.

Delayed rise of oral fluid antibodies, elevated BMI, and absence of early fever correlate with longer time to SARS-CoV-2 RNA clearance in an longitudinally sampled cohort of COVID-19 outpatients (preprint)

BackgroundSustained molecular detection of SARS-CoV-2 RNA in the upper respiratory tract (URT) in mild to moderate COVID-19 is common. We sought to identify host and immune determinants of prolonged SARS-CoV-2 RNA detection. MethodsNinety-five outpatients self-collected mid-turbinate nasal, oropharyngeal (OP), and gingival crevicular fluid (oral fluid) samples at home and in a research clinic a median of 6 times over 1-3 months. Samples were tested for viral RNA, virus culture, and SARS-CoV-2 and other human coronavirus antibodies, and associations were estimated using Cox proportional hazards models. ResultsViral RNA clearance, as measured by SARS-CoV-2 RT-PCR, in 507 URT samples occurred a median (IQR) 33.5 (17-63.5) days post-symptom onset. Sixteen nasal-OP samples collected 2-11 days post-symptom onset were virus culture positive out of 183 RT-PCR positive samples tested. All participants but one with positive virus culture were negative for concomitant oral fluid anti-SARS-CoV-2 antibodies. The mean time to first antibody detection in oral fluid was 8-13 days post-symptom onset. A longer time to first detection of oral fluid anti-SARS-CoV-2 S antibodies (aHR 0.96, 95% CI 0.92-0.99, p=0.020) and BMI [≥] 25kg/m2 (aHR 0.37, 95% CI 0.18-0.78, p=0.009) were independently associated with a longer time to SARS-CoV-2 viral RNA clearance. Fever as one of first three COVID-19 symptoms correlated with shorter time to viral RNA clearance (aHR 2.06, 95% CI 1.02-4.18, p=0.044). ConclusionsWe demonstrate that delayed rise of oral fluid SARS-CoV-2-specific antibodies, elevated BMI, and absence of early fever are independently associated with delayed URT viral RNA clearance.

Blood molecular markers associated with COVID-19 immunopathology and multi-organ damage.

COVID-19 is characterized by dysregulated immune responses, metabolic dysfunction and adverse effects on the function of multiple organs. To understand host responses to COVID-19 pathophysiology, we combined transcriptomics, proteomics, and metabolomics to identify molecular markers in peripheral blood and plasma samples of 66 COVID-19-infected patients experiencing a range of disease severities and 17 healthy controls. A large number of expressed genes, proteins, metabolites, and extracellular RNAs (exRNAs) exhibit strong associations with various clinical parameters. Multiple sets of tissue-specific proteins and exRNAs varied significantly in both mild and severe patients suggesting a potential impact on tissue function. Chronic activation of neutrophils, IFN-I signaling, and a high level of inflammatory cytokines were observed in patients with severe disease progression. In contrast, COVID-19-infected patients experiencing milder disease symptoms showed robust T-cell responses. Finally, we identified genes, proteins, and exRNAs as potential biomarkers that might assist in predicting the prognosis of SARS-CoV-2 infection. These data refine our understanding of the pathophysiology and clinical progress of COVID-19.

Variability of Salivary and Nasal Specimens for SARS-CoV-2 Detection (preprint)

In a large cohort of ambulatory confirmed COVID-19 patients with multiple self-collected sample time points, we compared 202 matched nasal-oropharyngeal swabs and oral salivary fluid sample pairs by RT-PCR. Nasal-oropharyngeal swabs were more sensitive than this salivary sample type (oral crevicular fluid) suggesting that not all saliva sample types have equivalent sensitivity. However, all samples that were Vero E6-TMPRSS2 cell culture positive (e.g., infectious virus) were also oral fluid RT-PCR positive suggesting that oral fluid may find the patients most likely to transmit disease to others.

Analysis of similarities and differences between coronavirus disease 2019 and severe acute respiratory syndrome

Both coronavirus disease 2019 (COVID-19) and severe acute respiratory syndrome (SARS) are epidemic, contagious, sudden, and publicly harmful diseases. The whole-genome nucleotide identity of the pathogens causing the two diseases reached 79.5%. The mechanism and treatment of COVID-19 are still under investigation. Combining the experiences of SARS prevention and treatment in 2003, and the case data and literature of COVID-19, the similarities and differences between the two diseases in terms of causes, susceptible people, characteristics, dialectical mode, and treatment were analyzed. The two diseases are both plagues in terms of Chinese medicine. The cause of SARS was 'heat poison,' and its pathogenesis was 'heat poison, stasis, and qi and yin deficiency.' Therefore the treatment regimen was mainly to clear away heat, detoxicate, and expel evil. While the cause of COVID-19 was 'wet poison,' and its pathogenesis was 'wet, poison, heat, stasis, close, syncope, and yang collapse.' Hence the basic treatment strategy was to declare lung and remove dampness. Treatment of COVID-19 was clearing away evil qi as soon as possible, with the basic treatment regimen, which was declaring lung, removing dampness, and dispelling the evil. Combined with Traditional Chinese medicine's (TCM's) understanding and experience in SARS prevention and treatment, and Chinese clinical cured cases, we try to provide strategies for people all over the world to understand and respond to COVID-19, through the analysis and comparison. To improve COVID-19 prevention and treatment regimen and give full play to the advantages of TCM.

COVID-19 severity is associated with immunopathology and multi-organ damage (preprint)

COVID-19 is characterised by dysregulated immune responses, metabolic dysfunction and adverse effects on the function of multiple organs. To understand how host responses contribute to COVID-19 pathophysiology, we used a multi-omics approach to identify molecular markers in peripheral blood and plasma samples that distinguish COVID-19 patients experiencing a range of disease severities. A large number of expressed genes, proteins, metabolites and extracellular RNAs (exRNAs) were identified that exhibited strong associations with various clinical parameters. Multiple sets of tissue-specific proteins and exRNAs varied significantly in both mild and severe patients, indicative of multi-organ damage. The continuous activation of IFN-I signalling and neutrophils, as well as a high level of inflammatory cytokines, were observed in severe disease patients. In contrast, COVID-19 in mild patients was characterised by robust T cell responses. Finally, we show that some of expressed genes, proteins and exRNAs can be used as biomarkers to predict the clinical outcomes of SARS-CoV-2 infection. These data refine our understanding of the pathophysiology and clinical progress of COVID-19 and will help guide future studies in this area.