Lung Ultrasound in COVID-19 Patients: Characteristics and Factors Affecting its Diagnostic Accuracy (preprint)

Background: Although chest computed tomography (CT) is the gold standard for diagnosing the majority of lung conditions, its use in screening patients for coronavirus disease 2019(COVID-19) pneumonia is not recommended. Lung ultrasound (LUS) is an alternative modality. To investigate the characteristics and diagnostic accuracy (DA) of bedside ultrasound for lung lesions in patients with COVID-19 and to determine the factors influencing the DA of lung ultrasound (LUS). Methods: A total of 330 patients with COVID-19 admitted to the hospital between February and March 2020 were retrospectively recruited. The imaging characteristics of LUS and computed tomography (CT) scans were analysed and summarized. DA was calculated using a chest CT scan as the reference standard. Furthermore, a binary logistic regression analysis was conducted to investigate the factors influencing the DA of LUS for interstitial syndrome. Results: The ultrasound findings of COVID-19 patients presented mainly as B lines (195/330, 59.1%), unsmooth or interrupted pleural lines (118/330, 35.8%), consolidation lesions (74/330, 22.4%), and pleural effusion (11/330, 3.33%). Compared with the chest CT scan, the DA of LUS for interstitial syndrome, consolidation, pleural effusion, and pleural thickening were 0.821, 0.927, 0.988, and 0.863, respectively. The diagnostic coincidence rate of LUS and chest CT in the mild, common, severe, and critical groups were 93%, 68.6%, 100%, and 100%, respectively. According to the results of the binary logistic regression, sex, disease duration, experience of the doctor, and involved lobes were independent predictors of the DA for interstitial syndrome. Conclusions: LUS had good diagnostic performance for diagnosing COVID-19 pneumonia, and showed a relatively low DA for interstitial syndrome. Female sex, doctors with less experience, long disease duration, and lesions limited to the upper or lower lobes may decrease the DA.

Prognostic value of bedside lung ultrasound score in patients with COVID-19 (preprint)

Background: Bedside lung ultrasound (LUS) has emerged as a useful and noninvasive tool to detect lung involvement and monitor changes in patients with coronavirus disease 2019 (COVID-19). However, the clinical significance of the LUS score in patients with COVID-19 remains unknown. We aimed to investigate the prognostic value of the LUS score in patients with COVID-19. Methods: : The LUS protocol consisted of 12 scanning zones and was performed in 280 consecutive patients with COVID-19. The LUS score based on B-lines, lung consolidation and pleural line abnormalities was evaluated. Results: : The median time from admission to LUS examinations was 7 days (interquartile range [IQR] 3-10). Patients in the highest LUS score group were more likely to have a lower lymphocyte percentage (LYM%); higher levels of D-dimer, C-reactive protein, hypersensitive troponin I and creatine kinase muscle-brain; more invasive mechanical ventilation therapy; higher incidence of ARDS; and higher mortality than patients in the lowest LUS score group. After a median follow-up of 14 days [IQR, 10-20 days], 37 patients developed ARDS, and 13 died. Patients with adverse outcomes presented a higher rate of bilateral involvement; more involved zones and B-lines, pleural line abnormalities and consolidation; and a higher LUS score than event-free survivors. The Cox models adding the LUS score as a continuous variable (hazard ratio [HR]: 1.05, 95% confidence intervals [CI]: 1.02～1.08; P < 0.001; Akaike Information Criterion [AIC] =272; C-index = 0.903) or as a categorical variable (HR: 10.76, 95% CI: 2.75～42.05; P = 0.001; AIC =272; C-index = 0.902) were found to predict poor outcomes more accurately than the basic model (AIC =286; C-index = 0.866). An LUS score cut-off >12 predicted adverse outcomes with a specificity and sensitivity of 90.5% and 91.9%, respectively. Conclusions: : The LUS score devised by our group performs well at predicting adverse outcomes in patients with COVID-19 and is important for risk stratification in COVID-19 patients.

SARS-CoV-2 ORF9c Is a Membrane-Associated Protein that Suppresses Antiviral Responses in Cells (preprint)

Disrupted antiviral immune responses are associated with severe COVID-19, the disease caused by SAR-CoV-2. Here, we show that the 73-amino-acid protein encoded by ORF9c of the viral genome contains a putative transmembrane domain, interacts with membrane proteins in multiple cellular compartments, and impairs antiviral processes in a lung epithelial cell line. Proteomic, interactome, and transcriptomic analyses, combined with bioinformatic analysis, revealed that expression of only this highly unstable small viral protein impaired interferon signaling, antigen presentation, and complement signaling, while inducing IL-6 signaling. Furthermore, we showed that interfering with ORF9c degradation by either proteasome inhibition or inhibition of the ATPase VCP blunted the effects of ORF9c. Our study indicated that ORF9c enables immune evasion and coordinates cellular changes essential for the SARS-CoV-2 life cycle. One-sentence summarySARS-CoV-2 ORF9c is the first human coronavirus protein localized to membrane, suppressing antiviral response, resembling full viral infection.

Identification of potential key genes for SARS-CoV-2 infected human bronchial organoids based on bioinformatics analysis (preprint)

There is an urgent need to understand the pathogenesis of the severe acute respiratory syndrome coronavirus clade 2 (SARS-CoV-2) that leads to COVID-19 and respiratory failure. Our study is to discover differentially expressed genes (DEGs) and biological signaling pathways by using a bioinformatics approach to elucidate their potential pathogenesis. The gene expression profiles of the GSE150819 datasets were originally produced using an Illumina NextSeq 500 (Homo sapiens). KEGG (Kyoto Encyclopedia of Genes and Genomes) and GO (Gene Ontology) were utilized to identify functional categories and significant pathways. KEGG and GO results suggested that the Cytokine-cytokine receptor interaction, P53 signaling pathway, and Apoptosis are the main signaling pathways in SARS-CoV-2 infected human bronchial organoids (hBOs). Furthermore, NFKBIA, C3, and CCL20 may be key genes in SARS-CoV-2 infected hBOs. Therefore, our study provides further insights into the therapy of COVID-19.

Multi-organ Proteomic Landscape of COVID-19 Autopsies (preprint)

The molecular pathology of multi-organ injuries in COVID-19 patients remains unclear, preventing effective therapeutics development. Here, we report an in-depth multi-organ proteomic landscape of COVID-19 patient autopsy samples. By integrative analysis of proteomes of seven organs, namely lung, spleen, liver, heart, kidney, thyroid and testis, we characterized 11,394 proteins, in which 5336 were perturbed in COVID-19 patients compared to controls. Our data showed that CTSL, rather than ACE2, was significantly upregulated in the lung from COVID-19 patients. Dysregulation of protein translation, glucose metabolism, fatty acid metabolism was detected in multiple organs. Our data suggested upon SARS-CoV-2 infection, hyperinflammation might be triggered which in turn induces damage of gas exchange barrier in the lung, leading to hypoxia, angiogenesis, coagulation and fibrosis in the lung, kidney, spleen, liver, heart and thyroid. Evidence for testicular injuries included reduced Leydig cells, suppressed cholesterol biosynthesis and sperm mobility. In summary, this study depicts the multi-organ proteomic landscape of COVID-19 autopsies, and uncovered dysregulated proteins and biological processes, offering novel therapeutic clues. HIGHLIGHTSO_LICharacterization of 5336 regulated proteins out of 11,394 quantified proteins in the lung, spleen, liver, kidney, heart, thyroid and testis autopsies from 19 patients died from COVID-19. C_LIO_LICTSL, rather than ACE2, was significantly upregulated in the lung from COVID-19 patients. C_LIO_LIEvidence for suppression of glucose metabolism in the spleen, liver and kidney; suppression of fatty acid metabolism in the kidney; enhanced fatty acid metabolism in the lung, spleen, liver, heart and thyroid from COVID-19 patients; enhanced protein translation initiation in the lung, liver, renal medulla and thyroid. C_LIO_LITentative model for multi-organ injuries in patients died from COVID-19: SARS-CoV-2 infection triggers hyperinflammatory which in turn induces damage of gas exchange barrier in the lung, leading to hypoxia, angiogenesis, coagulation and fibrosis in the lung, kidney, spleen, liver, heart, kidney and thyroid. C_LIO_LITesticular injuries in COVID-19 patients included reduced Leydig cells, suppressed cholesterol biosynthesis and sperm mobility. C_LI

NVX-CoV2373 vaccine protects cynomolgus macaque upper and lower airways against SARS-CoV-2 challenge (preprint)

There is an urgent need for a safe and protective vaccine to control the global spread of SARS-CoV-2 and prevent COVID-19. Here, we report the immunogenicity and protective efficacy of a SARS-CoV-2 subunit vaccine (NVX-CoV2373) produced from the full-length SARS-CoV-2 spike (S) glycoprotein stabilized in the prefusion conformation. Cynomolgus macaques (Macaca fascicularis) immunized with NVX-CoV2373 and the saponin-based Matrix-M adjuvant induced anti-S antibody that was neutralizing and blocked binding to the human angiotensin-converting enzyme 2 (hACE2) receptor. Following intranasal and intratracheal challenge with SARS-CoV-2, immunized macaques were protected against upper and lower infection and pulmonary disease. These results support ongoing phase 1/2 clinical studies of the safety and immunogenicity of NVX-CoV2327 vaccine (NCT04368988). HighlightsO_LIFull-length SARS-CoV-2 prefusion spike with Matrix-M1 (NVX-CoV2373) vaccine. C_LIO_LIInduced hACE2 receptor blocking and neutralizing antibodies in macaques. C_LIO_LIVaccine protected against SARS-CoV-2 replication in the nose and lungs. C_LIO_LIAbsence of pulmonary pathology in NVX-CoV2373 vaccinated macaques. C_LI

Prognostic value of bedside lung ultrasound-score in patients with COVID-19 (preprint)

Background: Bedside lung ultrasound (LUS) has emerged as a useful and non-invasive tool to detect lung involvement and monitor changes in patients with coronavirus disease 2019(COVID-19). While the clinical significance of LUS-score in patients with COVID-19 remains unknown. We aimed to investigate the prognostic value of LUS-score in patients with COVID-19.MethodsLUS protocol consisted of 12 scanning zones and was performed in 280 consecutive patients with COVID-19. LUS-score based on B-lines, pleural line abnormalities and lung consolidation was evaluated. The primary outcome was a combination of severe acute respiratory distress syndrome (ARDS), and mortality.ResultsCompared with patients in the lowest LUS-score group, those in the highest LUS-score group were more likely to have a lower lymphocyte%, higher levels of D-dimer, C-reactive protein, hypersensitive troponin I and creatine kinase muscle-brain, more invasive mechanical ventilation therapy, higher incidence of ARDS, and higher mortality. After a median follow-up of 14 days, 37 patients progressed to the poor outcome. Compared with event-free survivors, patients with adverse event presented higher rate of bilateral involved, more involved zones and B-lines, pleural lines abnormalities and consolidation, and higher LUS-score. The Cox models adding LUS-score as a continuous variable (hazard ratio [HR]: 1.05, 95% confidence intervals [CI]: 1.02~1.08; P < 0.001; Akaike Information Criterion [AIC] =272; C-index = 0.903) or as a categorical variable (HR: 10.76, 95% CI: 2.75~42.05; P = 0.001; AIC =272; C-index = 0.902) were found to predict poor outcome more accurately than the basic model (AIC =286; C-index = 0.866). LUS-score cutoff >12 would predict adverse events with specificity and sensitivity of 90.5% and 91.9%, respectively.ConclusionsLUS-score is a powerful predictor of adverse events in patients with COVID-19, and is important for risk stratification in COVID-19 patients.

Deep Venous Thrombosis in COVID-19 Patients: A Cohort Analysis (preprint)

BackgroundDeep venous thrombosis (DVT) is a severe complication of the coronavirus disease 2019 (COVID-19). It may interfere with COVID-19 treatment and delay the recovery, but there is less data about the anticoagulant therapy and sex difference of VTE in patients with COVID-19. The purpose of this study is to study the prevalence, risk factors, anticoagulant therapy and sex difference of deep venous thrombosis (DVT) in patients with COVID-19.MethodsThe enrolled 121 patients were confirmed positive for COVID-19. All suspected patients with a high Caprini index (≥4) or PADUA index (≥4) received color Doppler Ultrasound (US) to screen DVT in both lower extremities. Clinical characteristics of DVT-COVID-19 patients were analyzed. Multivariate logistic regression was performed to identify risk factors related to DVT in COVID-19 patients. The distribution of DVT locations, anticoagulation therapy with sex difference, and the outcomes were also analyzed.ResultsDVT was found in 48% asymptomatic COVID-19 patients with increased PAUDA index or Caprini index by US scanning. Multivariate logistic regression determined that age, CRP and baseline D-dimer were risk factors among COVDI-19 patients. Although the most common DVT location was infrapopliteal (Class I and Class II), higher mortality in DVT-COVID-19 patients was confirmed. DVT-COVID-19 patients presented significant increases in the CRP, neutrophil count and D-dimer throughout the whole inpatient period compared to non-DVT-COVID-19 patients. Although anticoagulation therapy accelerated the recovery of lymphocytopenia condition in DVT patients, men DVT-COVID-19 patients showed higher CRP and neutrophil count vs. lymphocyte count (N/L) ratio but lower lymphocyte count compared to women DVT-COVID-19 patients. ConclusionsDVT is common in COVID-19 patients with high risk factors, especially for older age, higher CRP and baseline D-dimer populations. It is important to consider sex differences in the anticoagulant therapy among DVT-COVID-19 patients.