Broad neutralization of SARS-CoV-2 variants by an inhalable bispecific single-domain antibody.

The effectiveness of SARS-CoV-2 vaccines and therapeutic antibodies have been limited by the continuous emergence of viral variants and by the restricted diffusion of antibodies from circulation into the sites of respiratory virus infection. Here, we report the identification of two highly conserved regions on the Omicron variant receptor-binding domain recognized by broadly neutralizing antibodies. Furthermore, we generated a bispecific single-domain antibody that was able to simultaneously and synergistically bind these two regions on a single Omicron variant receptor-binding domain as revealed by cryo-EM structures. We demonstrated that this bispecific antibody can be effectively delivered to lung via inhalation administration and exhibits exquisite neutralization breadth and therapeutic efficacy in mouse models of SARS-CoV-2 infections. Importantly, this study also deciphered an uncommon and highly conserved cryptic epitope within the spike trimeric interface that may have implications for the design of broadly protective SARS-CoV-2 vaccines and therapeutics.

Association of Weight Loss Achieved Through Metabolic Surgery With Risk and Severity of COVID-19 Infection.

IMPORTANCE: Obesity is an established risk factor for severe COVID-19 infection. However, it is not known whether losing weight is associated with reduced adverse outcomes of COVID-19 infection. OBJECTIVE: To investigate the association between a successful weight loss intervention and improved risk and severity of COVID-19 infection in patients with obesity. DESIGN, SETTING, AND PARTICIPANTS: This cohort study involved adult patients with a body mass index of 35 or higher (calculated as weight in kilograms divided by height in meters squared) who underwent weight loss surgery between January 1, 2004, and December 31, 2017, at the Cleveland Clinic Health System (CCHS). Patients in the surgical group were matched 1:3 to patients who did not have surgical intervention for their obesity (control group). The source of data was the CCHS electronic health record. Follow-up was conducted through March 1, 2021. EXPOSURES: Weight loss surgery including Roux-en-Y gastric bypass and sleeve gastrectomy. MAIN OUTCOMES AND MEASURES: Distinct outcomes were examined before and after COVID-19 outbreak on March 1, 2020. Weight loss and all-cause mortality were assessed between the enrollment date and March 1, 2020. Four COVID-19-related outcomes were analyzed in patients with COVID-19 diagnosis between March 1, 2020, and March 1, 2021: positive SARS-CoV-2 test result, hospitalization, need for supplemental oxygen, and severe COVID-19 infection (a composite of intensive care unit admission, need for mechanical ventilation, or death). RESULTS: A total of 20 212 patients (median [IQR] age, 46 [35-57] years; 77.6% female individuals [15 690]) with a median (IQR) body mass index of 45 (41-51) were enrolled. The overall median (IQR) follow-up duration was 6.1 (3.8-9.0) years. Before the COVID-19 outbreak, patients in the surgical group compared with control patients lost more weight (mean difference at 10 years from baseline: 18.6 [95% CI, 18.4-18.7] percentage points; P < .001) and had a 53% lower 10-year cumulative incidence of all-cause non-COVID-19 mortality (4.7% [95% CI, 3.7%-5.7%] vs 9.4% [95% CI, 8.7%-10.1%]; P < .001). Of the 20 212 enrolled patients, 11 809 were available on March 1, 2020, for an assessment of COVID-19-related outcomes. The rates of positive SARS-CoV-2 test results were comparable in the surgical and control groups (9.1% [95% CI, 7.9%-10.3%] vs 8.7% [95% CI, 8.0%-9.3%]; P = .71). However, undergoing weight loss surgery was associated with a lower risk of hospitalization (adjusted hazard ratio [HR], 0.51; 95% CI, 0.35-0.76; P < .001), need for supplemental oxygen (adjusted HR, 0.37; 95% CI, 0.23-0.61; P < .001), and severe COVID-19 infection (adjusted HR, 0.40; 95% CI, 0.18-0.86; P = .02). CONCLUSIONS AND RELEVANCE: This cohort study found that, among patients with obesity, substantial weight loss achieved with surgery was associated with improved outcomes of COVID-19 infection. The findings suggest that obesity can be a modifiable risk factor for the severity of COVID-19 infection.

SARS-CoV-2 Induces Lymphocytopenia by Promoting Inflammation and Decimates Secondary Lymphoid Organs.

While lymphocytopenia is a common characteristic of coronavirus disease 2019 (COVID-19), the mechanisms responsible for this lymphocyte depletion are unclear. Here, we retrospectively reviewed the clinical and immunological data from 18 fatal COVID-19 cases, results showed that these patients had severe lymphocytopenia, together with high serum levels of inflammatory cytokines (IL-6, IL-8 and IL-10), and elevation of many other mediators in routine laboratory tests, including C-reactive protein, lactate dehydrogenase, α-hydroxybutyrate dehydrogenase and natriuretic peptide type B. The spleens and hilar lymph nodes (LNs) from six additional COVID-19 patients with post-mortem examinations were also collected, histopathologic detection showed that both organs manifested severe tissue damage and lymphocyte apoptosis in these six cases. In situ hybridization assays illustrated that SARS-CoV-2 viral RNA accumulates in these tissues, and transmission electronic microscopy confirmed that coronavirus-like particles were visible in the LNs. SARS-CoV-2 Spike and Nucleocapsid protein (NP) accumulated in the spleens and LNs, and the NP antigen restricted in angiotensin-converting enzyme 2 (ACE2) positive macrophages and dendritic cells (DCs). Furthermore, SARS-CoV-2 triggered the transcription of Il6, Il8 and Il1b genes in infected primary macrophages and DCs in vitro, and SARS-CoV-2-NP+ macrophages and DCs also manifested high levels of IL-6 and IL-1ß, which might directly decimate human spleens and LNs and subsequently lead to lymphocytopenia in vivo. Collectively, these results demonstrated that SARS-CoV-2 induced lymphocytopenia by promoting systemic inflammation and direct neutralization in human spleen and LNs.

The clinical course and prognostic factors of severe COVID-19 in Wuhan, China: A retrospective case-control study.

ABSTRACT: With the surge of newly diagnosed and severe cases of coronavirus disease 2019 (COVID-19), the death toll is mounting, this study is aimed to explore the prognostic factors of severe COVID-19. This retrospective study included 122 inpatients diagnosed with COVID-19 from January 13 to February 25, 2020. Univariate and multivariate analysis were used to identity the risk factors, receiver operating characteristics curve (ROC) analysis was used for risk stratification. The baseline neutrophil-to-lymphocyte ratio (NLR) (OR = 1.171, 95%CI = 1.049-1.306, P = .005) and Lactate dehydrogenase (LDH) (OR = 1.007, 95%CI = 1.002-1.011, P = .004) were identified as the independent risk factors for severe COVID-19 conditions, and the NLR-LDH grading system was developed to perform risk stratification. The baseline C-reactive protein (CRP) (OR = 1.019, 95%CI = 1.004-1.306, P = .016) and B-type natriuretic peptide (BNP) (OR = 1.018, 95%CI = 1.004-1.035, P = .007) were identified as the independent predictors for disease progression of severe patients. Accordingly, The NLR-LDH grading system was a useful prognostic tool for the early detection of severe COVID-19. And in the severe patients, CRP and BNP seemed to be helpful for predicting the disease progression or death.

Association of Bariatric Surgery with Clinical Outcomes of SARS-CoV-2 Infection: a Systematic Review and Meta-analysis in the Initial Phase of COVID-19 Pandemic.

INTRODUCTION: Obesity worsens clinical outcomes of coronavirus disease 2019 (COVID-19). The aim of this study was to measure the association between history of bariatric surgery and the severity of COVID-19. METHODS: Data source included PubMed/MEDLINE, Scopus, Google Scholar, and pre-print servers between January and November 1, 2020. Literature was screened and selected to extract the relevant data. The two outcomes of this meta-analysis were the difference in mortality and hospitalization rates in patients with SARS-CoV-2 infection with and without history of bariatric surgery. Random-effect models were used to estimate the pooled effects. RESULTS: The systematic review yielded 3 retrospective studies on 9022 patients. The risk of mortality without previous bariatric surgery was 133 per 1000 cases and its risk with previous bariatric surgery was 33 per 1000 (summary OR 0.22, 95% CI 0.19-0.26). No heterogeneity was observed between the included studies (I2 = 0%, P = 0.98 for heterogeneity). In the pooled analysis, the hospitalization rate in patients without previous bariatric surgery was 412 per 1000 cases and its rate in patients with previous bariatric surgery was 164 per 1000 (summary OR 0.28, 95% CI 0.12-0.65). No heterogeneity was observed between the included studies (I2 = 0%, P = 0.71 for heterogeneity). There was a substantial risk of bias across the studies for confounding and selection bias. CONCLUSION: Findings of this meta-analysis of observational studies suggest that prior bariatric surgery is associated with a lower rate of mortality and hospital admission in patients with obesity who become infected with SARS-CoV-2. Confirmation of these findings will require larger studies with better quality data.

Association of prior metabolic and bariatric surgery with severity of coronavirus disease 2019 (COVID-19) in patients with obesity.

BACKGROUND: Obesity is a risk factor for poor clinical outcomes in patients with coronavirus disease 2019 (COVID-19). OBJECTIVES: To investigate the relationship between prior metabolic surgery and the severity of COVID-19 in patients with severe obesity. SETTING: Cleveland Clinic Health System in the United States. METHODS: Among 4365 patients who tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) between March 8, 2020 and July 22, 2020 in the Cleveland Clinic Health System, 33 patients were identified who had a prior history of metabolic surgery. The surgical patients were propensity matched 1:10 to nonsurgical patients to assemble a cohort of control patients (n = 330) with a body mass index (BMI) ≥ 40 kg/m2 at the time of SARS-CoV-2 testing. The primary endpoint was the rate of hospital admission. The exploratory endpoints included admission to the intensive care unit (ICU), need for mechanical ventilation and dialysis during index hospitalization, and mortality. After propensity score matching, outcomes were compared in univariate and multivariate regression models. RESULTS: The average BMI of the surgical group was 49.1 ± 8.8 kg/m2 before metabolic surgery and was down to 37.2 ± 7.1 at the time of SARS-CoV-2 testing, compared with the control group's BMI of 46.7 ± 6.4 kg/m2. In the univariate analysis, 6 (18.2%) patients in the metabolic surgery group and 139 (42.1%) patients in the control group were admitted to the hospital (P = .013). In the multivariate analysis, a prior history of metabolic surgery was associated with a lower hospital admission rate compared with control patients with obesity (odds ratio, 0.31; 95% confidence interval, 0.11-0.88; P = .028). While none of the 4 exploratory outcomes occurred in the metabolic surgery group, 43 (13.0%) patients in the control group required ICU admission (P = .021), 22 (6.7%) required mechanical ventilation, 5 (1.5%) required dialysis, and 8 (2.4%) patients died. CONCLUSION: Prior metabolic surgery with subsequent weight loss and improvement of metabolic abnormalities was associated with lower rates of hospital and ICU admission in patients with obesity who became infected with SARS-CoV-2. Confirmation of these findings will require larger studies.

Myocardial injury and risk factors for mortality in patients with COVID-19 pneumonia.

BACKGROUND: Coronavirus disease 2019 (COVID-19) pneumonia tends to affect cardiovascular system and cause cardiovascular damage. This study aimed to explore the prevalence of myocardial injury and risk factors for mortality in patients with COVID-19 pneumonia. METHOD: Two hundred and twenty-four consecutive patients with confirmed diagnosis of SARS-CoV-2 infection and definite outcomes (discharge or death) were retrospectively analyzed. Laboratory results including myocardial biomarkers, oxygen saturation, inflammatory indicators and coagulation function were compared between survivors and non-survivors. Univariate and multivariate logistic regression model were used to explore risk factors for in-hospital mortality, and a chart with different combinations of risk factors was constructed to predict mortality. RESULTS: Two hundred and three patients were included in the final analysis, consisting of 145 patients who recovered and 58 patients who died. Compared with survivors, non-survivors were older, with more comorbidities, more severe inflammation and active coagulation function, higher levels of myocardial biomarkers and lower SaO2. 28 (50%) non-survivors and 9 (6%) survivors developed myocardial injury, which was associated with disease severity at admission. Elevated d-dimer (OR = 9.51, 95% CI [3.61-25.0], P < 0.001), creatinine kinase-myocardial band (OR = 6.93, 95% CI [1.83-26.2], P = 0.004), Troponin I (OR = 10.1, 95% CI [3.1-32.8], P < 0.001) and C-reactive protein (OR = 15.1, 95% CI [1.7-129.3], P = 0.013) were risk factors for mortality. Patients with abnormal levels of d-dimer, Troponin I and CRP were predicted to have significantly higher probability of death. CONCLUSIONS: Our results suggest that SARS-CoV-2 infection may induce myocardial injury and consequently exacerbate the clinical course and worsen prognosis. Abnormal d-dimer, CK-MB, Troponin I and CRP are risk factors for short-term mortality.

COVID-19 patients with hypertension have more severe disease: a multicenter retrospective observational study.

This study aims to explore the effect of hypertension on disease progression and prognosis in patients with coronavirus disease 2019 (COVID-19). A total of 310 patients diagnosed with COVID-19 were studied. A comparison was made between two groups of patients, those with hypertension and those without hypertension. Their demographic data, clinical manifestations, laboratory indicators, and treatment methods were collected and analyzed. A total of 310 patients, including 113 patients with hypertension and 197 patients without hypertension, were included in the analysis. Compared with patients without hypertension, patients with hypertension were older, were more likely to have diabetes and cerebrovascular disease, and were more likely to be transferred to the intensive care unit. The neutrophil count and lactate dehydrogenase, fibrinogen, and D-dimer levels in hypertensive patients were significantly higher than those in nonhypertensive patients (P < 0.05). However, multivariate analysis (adjusted for age and sex) failed to show that hypertension was an independent risk factor for COVID-19 mortality or severity. COVID-19 patients with hypertension were more likely than patients without hypertension to have severe pneumonia, excessive inflammatory reactions, organ and tissue damage, and deterioration of the disease. Patients with hypertension should be given additional attention to prevent worsening of their condition.

Factors associated with duration of viral shedding in adults with COVID-19 outside of Wuhan, China: A retrospective cohort study

Objectives To investigate factors associated with the duration of viral shedding in patients with COVID-19 outside of Wuhan. Methods In this retrospective cohort study, patients with laboratory-confirmed COVID-19 in Changsha, China were included. Clinical characteristics, laboratory findings, treatment and outcome were retrieved. Univariable and multivariable analysis were performed to explore potential factors. Results Totally 147 patients with COVID-19 were included. The median duration of viral shedding (the number of days from symptoms onset till the successive negative detection of SARS-CoV-2 RNA) was 17 days (interquartile range [IQR], 12 to 21). Multivariable Logistic regression analysis indicated that the highest temperature at admission (odds ratio [OR], 5.200;95% confidence interval [CI]: 1.190-22.726;p = 0.028) and time from symptom onset to admission (OR, 1.740;95% CI: 1.296-2.337;p < 0.001) and hospital length of stay (OR, 1.604;95% CI: 1.262-2.040;p < 0.001) were risk factors for prolonged duration of viral shedding. Conclusions This is the study with relatively large sample size that mainly focused on the duration of viral shedding and relevant factors in patients with COVID-19 outside of Wuhan, China. Potential risk factors were identified and should be taken into consideration for the strategy of quarantine of infected patients.