The roles of critical pro-inflammatory cytokines in the drive of cytokine storm during SARS-CoV-2 infection.

In patients with severe COVID-19, acute respiratory distress syndrome (ARDS), multiple organ dysfunction syndrome (MODS), and even mortality can result from cytokine storm, which is a hyperinflammatory medical condition caused by the excessive and uncontrolled release of pro-inflammatory cytokines. High levels of numerous crucial pro-inflammatory cytokines, such as interleukin-1 (IL-1), IL-2, IL-6, tumor necrosis factor-α, interferon (IFN)-γ, IFN-induced protein 10 kDa, granulocyte-macrophage colony-stimulating factor, monocyte chemoattractant protein-1, and IL-10 and so on, have been found in severe COVID-19. They participate in cascade amplification pathways of pro-inflammatory responses through complex inflammatory networks. Here, we review the involvements of these critical inflammatory cytokines in SARS-CoV-2 infection and discuss their potential roles in triggering or regulating cytokine storm, which can help to understand the pathogenesis of severe COVID-19. So far, there is rarely effective therapeutic strategy for patients with cytokine storm besides using glucocorticoids, which is proved to result in fatal side effects. Clarifying the roles of key involved cytokines in the complex inflammatory network of cytokine storm will help to develop an ideal therapeutic intervention, such as neutralizing antibody of certain cytokine or inhibitor of some inflammatory signal pathways.

Omicsynin B4 potently blocks coronavirus infection by inhibiting host proteases cathepsin L and TMPRSS2.

The emergence of SARS-CoV-2 variants represents a major threat to public health and requires identification of novel therapeutic agents to address the unmet medical needs. Small molecules impeding viral entry through inhibition of spike protein priming proteases could have potent antiviral effects against SARS-CoV-2 infection. Omicsynin B4, a pseudo-tetrapeptides identified from Streptomyces sp. 1647, has potent antiviral activity against influenza A viruses in our previous study. Here, we found omicsynin B4 exhibited broad-spectrum anti-coronavirus activity against HCoV-229E, HCoV-OC43 and SARS-CoV-2 prototype and its variants in multiple cell lines. Further investigations revealed omicsynin B4 blocked the viral entry and might be related to the inhibition of host proteases. SARS-CoV-2 spike protein mediated pseudovirus assay supported the inhibitory activity on viral entry of omicsynin B4 with a more potent inhibition of Omicron variant, especially when overexpression of human TMPRSS2. Moreover, omicsynin B4 exhibited superior inhibitory activity in the sub-nanomolar range against CTSL, and a sub-micromolar inhibition against TMPRSS2 in biochemical assays. The molecular docking analysis confirmed that omicsynin B4 fits well in the substrate binding sites and forms a covalent bond to Cys25 and Ser441 in CTSL and TMPRSS2, respectively. In conclusion, we found that omicsynin B4 may serve as a natural protease inhibitor for CTSL and TMPRSS2, blocking various coronavirus S protein-driven entry into cells. These results further highlight the potential of omicsynin B4 as an attractive candidate for broad-spectrum antiviral therapy that could rapidly respond to emerging variants of SARS-CoV-2.

Susceptibility and infectiousness of SARS-CoV-2 in children versus adults, by variant (wild-type, Alpha, Delta): a systematic review and meta-analysis of household contact studies (preprint)

Importance: Understanding the susceptibility and infectiousness of children and adolescents in comparison to adults is important to appreciate their role in the COVID-19 pandemic. Objective: To determine SARS-CoV-2 susceptibility and infectiousness of children and adolescents with adults as comparator for three variants (wild-type, Alpha, Delta) in the household setting. We aimed to identify the effects independent of vaccination. Data Sources: We searched EMBASE, PubMed and medRxiv up to January 2022. Additional studies were identified through contacting subject experts. Study Selection: Two reviewers independently identified studies providing secondary attack rates (SAR) for SARS-CoV-2 infection in children (0-9 years), adolescents (10-19 years) or both compared with adults (20 years and older) derived from household data. Data Extraction and Synthesis: Two reviewers independently performed data extraction. We assessed risk of bias of included studies using a critical appraisal checklist and a random-effects meta-analysis model to pool association estimates. Main Outcomes and Measures: Odds ratio (OR) for SARS-CoV-2 infection comparing children and adolescents with adults stratified by wild-type, Alpha, and Delta variant, respectively. Susceptibility was defined as the secondary attack rate (SAR) among susceptible household contacts irrespective of the age of the index case. Infectiousness was defined as the SAR irrespective of the age of household contacts when children/adolescents/adults were the index case. Results: Twenty-eight studies (308,857 contacts) were included in the susceptibility analysis, for Delta only one (large) study was available. Compared to adults children and adolescents were less susceptible to the wild-type and Delta variant, but equally susceptible to the Alpha variant. In the infectiousness analysis, 21 studies (201,199 index cases) were included. Compared to adults, children and adolescents were less infectious when infected with the wild-type and Delta variant. Alpha variant-related infectiousness remained unclear, 0-9 year old children were at least as infectious as adults. SAR among household contacts was highest during circulation of the Alpha variant, lowest during wild-type circulation and intermediate during Delta circulation. Conclusions and Relevance: When considering the potential role of children and adolescents, for each variant susceptibility, infectiousness, age group and overall transmissibility need to be assessed to guide public health policy.

Transmission roles of symptomatic and asymptomatic COVID-19 cases: a modeling study (preprint)

ObjectiveAge-dependent asymptomatic and symptomatic transmission dynamics of COVID-19 have not been well quantified due to limited data. MethodsThrough a population-based surveillance network, we collected data on 1342 confirmed cases with a 90-days follow-up for all asymptomatic cases. ResultsThe difference in transmissibility of a symptomatic and asymptomatic case depended on age and was most distinct for the middle-age groups. The asymptomatic cases had a 66.72% lower transmissibility rate than symptomatic cases, and 74.10% (95%CI: 65.85% - 80.72%) of all asymptomatic cases were missed in detection. The average proportion of asymptomatic cases was 28.22% (95%CI: 22.97% - 34.56%). Simulation showed that the burden of asymptomatic transmission increased as the epidemic continued and could potentially dominate the spreading. ConclusionAsymptomatic COVID-19 cases play a significant role in transmission. Vaccine Strategies prioritizing the population between 30-60 years old are likely to have the most population-level benefits.

The risk factors for severe patients with COVID-19 in China: A systematic review and meta-analysis

COVID-19 is spreading exponentially. In order to optimize medical resources allocation and reduce mortality, biomarkers are needed to differentiate between COVID-19 patients with or without severe diseases early as possible. We searched Ovid MEDLINE(R), Ovid EMBASE, CNKI, Wanfang, VIP databases, the Cochrane Library, and medRxiv for primary articles in English or Chinese up to March 30, 2020 to systematically evaluate the risk factors for severe patients in China. Mean difference or standardize mean difference and odds ratio with 95% confidence intervals were performed by random-effect or fixed models in cases of significant heterogeneity between studies. We used I 2 to evaluate the magnitude of heterogeneity. A total of 54 articles involving about 7000 patients were eligible for this meta-analysis. In total, 52 of 67 parameters between severe and non-severe cases were significantly different. Elderly male patients with comorbidities including hypertension, diabetes, chronic obstructive pulmonary disease (COPD) cardiovascular disease, cerebrovascular disease, chronic kidney disease, or cancer were more common in severe COVID-19 patients. Regarding the clinical manifestations on admission, fever, cough, expectoration, dyspnea, chest distress, fatigue, headache, chills, anorexia, or abdominal pain were more prevalent in severe COVID-19 patients. The results of the clinical examination showed that high C-reactive protein (CRP), high lactate dehydrogenase (LDH), high D-dimer, and decreased T lymphocytes cells subsets, decreased lymphocyte may help clinicians predict the progression of severe illness in patients with COVID-19. Our findings will be conducive for clinician to stratify the COVID-19 patients to reduce mortality under the relative shortage of medical resources. [ABSTRACT FROM AUTHOR] Copyright of European Journal of Inflammation (Sage Publications, Ltd.) is the property of Sage Publications, Ltd. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Modeling the use of SARS-CoV-2 vaccination to safely relax non-pharmaceutical interventions (preprint)

In response to the COVID-19 pandemic, widespread non-pharmaceutical interventions (NPIs), including physical distancing, mask wearing, and enhanced hygiene, have been implemented. As of March 2021, three effective vaccines have been approved for emergency use in the United States, with several other vaccines in the pipeline. We use a transmission model to study when and how NPIs could be relaxed in the United States with relative safety as vaccination becomes more widespread. We compare different relaxation scenarios where NPIs begin to relax 0-9 months after vaccination begins for both a one dose and two dose strategy, with historical levels of social interactions being reached within 1 month to 1 year. In our model, vaccination can allow widespread relaxation of NPIs to begin safely within 2 to 9 months, greatly reducing deaths and peak health system burden compared to relaxing NPIs without vaccination. Vaccinated individuals can safely begin to relax NPIs sooner than unvaccinated individuals. The extent of delay needed to safely reopen depends primarily on the rate of vaccine rollout, with the degree of protection against asymptomatic infection playing a secondary role. If a vaccination rate of 3 million doses/day can be achieved, similar to the typical rollout speed of seasonal influenza vaccination, NPIs could begin to be safely relaxed in 2-3 months. With a vaccination rate of 1 million doses/day, a 6–9-month delay is needed. A one dose strategy is preferred if relative efficacy is similar to a two-dose series, but the relative benefit of this strategy is minimal when vaccine rollout is fast. Due to the urgent need to pursue strategies that enable safe relaxation of NPIs, we recommend a two-dose strategy with an initial delay of at least 3 months in relaxing restrictions further, and that the speed of vaccine rollout be given immediate priority.

Estimation of case-fatality rate in COVID-19 patients with hypertension and diabetes mellitus in the New York State (preprint)

We estimated the case-fatality rate (CFR) and ratios (RR) in adult COVID-19 cases with hypertension and diabetes mellitus in the New York State. We found that the elderly population had a higher CFR, but the elevated CFR ratios associated with comorbidities are more pronounced for the younger population.

Different cardiac perfoemance in patients with COVID-19 in ICU and general ward by standard and strain echocardiography (preprint)

Background: The initial mechanism of COVID-19 is the binding of the virus to ACE2. Since the heart and the vessels also express ACE2, they both could become targets of the virus. However, cardiac performance of patients in ICU and general ward may be different, requested individualized treatment. The aim of this study is to explore the global and segmental myocardial performance of the severe and mild COVID-19 patients.Methods: 45 patients, including 25 mild and 20 severe patients in intensive care unit (ICU) with COVID-19 infection were included in this study. The clinical history, laboratory test and standard and strain echocardiography were performed at admission. Of them, 13 severe patients received serial echocardiography, especially, 10 patients received echocardiographic examinations more than 7 times.  Results: 1. Both mild and severe COVID-19 infected patients showed reduced cardiac diastolic function; 2. Severe patients in ICU exhibited exacerbated right ventricular systolic function; 3. Both mild and severe patients with COVID-19 showed impaired left ventricular strain, worse strain in severe patient. 4. The apical longitudinal strain of mild patients was higher than basal and middle segment. No difference among apical, middle and basal segments in severe patients. 5. There was a negative correlation between LV GLS and log TnT-hs, as well as NT-pro BNP. 6. The EF value and strain of left atrium of mild and severe patients decreased; 7. LV GLS, LV GCS and LA GLS area under the ROC curve to predict the disease severity were 0.698, 0.758 and 0.782 respectively. 8. In the follow-up of severe patients, left atrial and ventricular strain showed an increased trend.Conclusions: These findings suggested that left ventricular performance was subclinically impaired during COVID-9 infection irrespective of infection severity and the strain of LV and LA may predict the disease severity. The cardiac function had an increasing trend for severe patients treated in ICU. 

If containment is not possible, how do we minimize mortality for COVID-19 and other emerging infectious disease outbreaks? (preprint)

If COVID-19 containment policies fail and social distancing measures cannot be sustained until vaccines becomes available, the next best approach is to use interventions that reduce mortality and prevent excess infections while allowing low-risk individuals to acquire immunity through natural infection until population level immunity is achieved. In such a situation, allowing some infections to occur in lower-risk groups might lead to an overall greater reduction in mortality than trying to protect everyone equally.

Assessing the impact of a symptom-based mass screening and testing intervention during a novel infectious disease outbreak: The case of COVID-19 (preprint)

A symptom-based mass screening and testing intervention (MSTI) can identify a large fraction of infected individuals during an infectious disease outbreak. China is currently using this strategy for the COVID-19 outbreak. However, MSTI might lead to increased transmission if not properly implemented. We investigate under which conditions MSTI is beneficial.