Effect of the Timing of Amubarvimab/Romlusevimab (BRII-196/198) Administration on Progression to Severe Disease in Elderly Patients with COVID-19 Infection: A Retrospective Cohort Study

Objective Early intervention with neutralizing antibodies is considered to be effective in preventing disease progression in patients with mild to moderate COVID-19 infection. Elderly patients are the most susceptible and at a higher risk of COVID-19 infection. The present study aimed to assess the necessity and possible clinical benefits of the early administration of Amubarvimab/Romlusevimab (BRII-196/198) in the elderly population. Methods The present study was designed as a retrospective, multi-center cohort study conducted with 90 COVID-19 patients aged over 60, who were divided into two groups based on the timing of the administration of BRII-196/198 (administration at ≤ 3 days or > 3 days from the onset of infection symptoms). Results The ≤ 3 days group exhibited a greater positive effect (HR 5.94, 95% CI, 1.42–24.83;P < 0.01), with only 2 patients among 21 patients (9.52%) exhibiting disease progression, compared to the 31 patients among the 69 patients (44.93%) of the > 3 days group who exhibited disease progression. The multivariate Cox regression analysis revealed low flow oxygen support prior to BRII-196/198 administration (HR 3.53, 95% CI 1.42–8.77, P < 0.01) and PLT class (HR 3.68, 95% CI 1.37–9.91, P < 0.01) as independent predictors of disease progression. Conclusions In elderly patients with mild or moderate COVID-19 disease, who do not require oxygen support and had the risk factors for disease progression to severe COVID-19 disease, the administration of BRII-196/198 within 3 days resulted in a beneficial trend in terms of preventing disease progression.

Recombinant human adenovirus type 5 based vaccine candidates against GIIa- and GIIb-genotype porcine epidemic diarrhea virus induce robust humoral and cellular response in mice.

Porcine epidemic diarrhea virus (PEDV) is a porcine enteropathogenic coronavirus causing severe watery diarrhea, vomiting, dehydration, and death in piglets. However, most commercial vaccines are developed based on the GI genotype strains, and have poor immune protection against the currently dominant GII genotype strains. Therefore, four novel replication-deficient human adenovirus 5-vectored vaccines expressing codon-optimized forms of the GIIa and GIIb strain spike and S1 glycoproteins were constructed, and their immunogenicity was evaluated in mice by intramuscular (IM) injection. All the recombinant adenoviruses generated robust immune responses, and the immunogenicity of recombinant adenoviruses against the GIIa strain was stronger than that of recombinant adenoviruses against the GIIb strain. Moreover, Ad-XT-tPA-Sopt-vaccinated mice elicited optimal immune effects. In contrast, mice immunized with Ad-XT-tPA-Sopt by oral gavage did not induce strong immune responses. Overall, IM administration of Ad-XT-tPA-Sopt is a promising strategy against PEDV, and this study provides useful information for developing viral vector-based vaccines.

Successful clearance of persistent SARS-CoV-2 asymptomatic infection following a single dose of Ad5-nCoV vaccine.

Persistent asymptomatic (PA) SARS-CoV-2 infections have been identified. The immune responses in these patients are unclear, and the development of effective treatments for these patients is needed. Here, we report a cohort of 23 PA cases carrying viral RNA for up to 191 days. PA cases displayed low levels of inflammatory and interferon response, weak antibody response, diminished circulating follicular helper T cells (cTfh), and inadequate specific CD4+ and CD8+ T-cell responses during infection, which is distinct from symptomatic infections and resembling impaired immune activation. Administration of a single dose of Ad5-nCoV vaccine to 10 of these PA cases elicited rapid and robust antibody responses as well as coordinated B-cell and cTfh responses, resulting in successful viral clearance. Vaccine-induced antibodies were able to neutralize various variants of concern and persisted for over 6 months, indicating long-term protection. Therefore, our study provides an insight into the immune status of PA infections and highlights vaccination as a potential treatment for prolonged SARS-CoV-2 infections.

Dynamic evaluation of the pulmonary protective effects of prone position ventilation via respiratory mechanics for patients with moderate to severe acute respiratory distress syndrome

Background Patients with moderate to severe acute respiratory distress syndrome (ARDS) have been recommended to receive prone position ventilation (PPV). However, the dynamic changes in respiratory mechanics during PPV and their relationship with the prognosis have not been sufficiently evaluated. In addition, the impact of using neuromuscular blocking agents (NMBAs) during PPV on respiratory mechanics is not clear enough. Thus, the study aims to investigate the above-mentioned issues. Methods A prospective cohort study was conducted on 22 patients with moderate to severe ARDS who received PPV in the intensive care unit (ICU) of the First Affiliated Hospital of Guangzhou Medical University. A multifunctional gastric tube was used to measure the patients’ respiratory mechanics during supine position ventilation (SPV), early PPV (PPV within 4 h of initiation), and middle/late PPV (more than 6 h after the initiation of PPV). Longitudinal data were analyzed with generalized estimating equations (GEE). Results Compared with SPV, the esophageal pressure swings (ΔPes) measured during the PPV was significantly higher (SPV 7.46 vs. early PPV 8.00 vs. middle/late PPV 8.30 cmH2O respectively;PSPVvs.middle/late PPV =0.025<0.05). A stratified analysis by patients’ outcome showed that the peak airway pressure (Ppeak), ΔPes and respiration rate (RR) in the death group were significantly higher than survival group. On the contrary, the tidal volume (Vt), diaphragmatic electromyogram (EMGdi) and PaO2/FiO2 ratio (PFR) in the death group were significantly lower than survival group. Notably, the ΔPes and transpulmonary driving pressure (DPL) were significantly lower in the patients treated with NMBAs (7.08 vs. 8.76 cmH2O ΔPes;P<0.01), (14.82 vs. 18.08 cmH2O DPL;P<0.001). Conclusions During the transition from SPV to early PPV and then to middle/late PPV, the ΔPes in the PPV were greater than SPV and it fluctuated within a normal range while oxygenation improved significantly in all patients. The Ppeak, ΔPes and RR in the death group were significantly higher than survival group. When NMBAs were used, the ΔPes, inspiratory transpulmonary pressure (PLei), driving pressure (DP) and DPL were significantly decreased, suggesting that the rational combination of NMBAs and PPV may exert a synergistic protective effect on the lungs.

Optimal Purchasing Decisions with Supplier Default in Portfolio Procurement

As global public health events and regional conflicts have greater influence on supply chains nowadays, supplier default in procurement becomes more and more common in practice. However, there is less research on portfolio procurement purchasing decisions in the case of fixed-term contract supplier default. This paper focuses on the optimal purchasing decision of buyers by using a combination of fixed-term contracts and spot transactions, which is a beneficial extension of the classical newsvendor model. When supplier default is not considered, the optimal purchase quantity in the fixed-term contract is first obtained, which maximizes the buyer’s expected profits. Research shows that supplier default has an important impact on the optimal purchasing decision making in portfolio procurement. The optimal purchase quantity of the buyer in the fixed-term contract decreases with the increase in the default rate of the contract supplier, which implies that the default from the contract supplier inhibits a larger purchase quantity in the fixed-term contract. In addition, it is proved that the buyer’s expected profits from portfolio procurement increases with the decrease in the contract supplier’s default rate. Finally, numerical experiments and sensitivity analysis are conducted to prove the result, and some management opinions on the optimal decision-making in portfolio procurement with fixed-term contracts and spot transactions are put forward.

Proteomic profiling reveals a distinctive molecular signature for critically ill COVID-19 patients compared with asthma and chronic obstructive pulmonary disease.

OBJECTIVE: The mortality rate for critically ill COVID-19 cases was more than 80%. Nonetheless, research about the effect of common respiratory diseases on critically ill COVID-19 expression and outcomes is scarce. DESIGN: We performed proteomic analyses on airway mucus obtained by bronchoscopy from patients with severe COVID-19, or induced sputum from patients with chronic obstructive pulmonary disease (COPD), asthma, and healthy controls. RESULTS: Of the total identified and quantified proteins, 445 differentially expressed proteins (DEPs) were found in different comparison groups. In comparison with COPD, asthma, and controls, 11 proteins were uniquely present in COVID-19 patients. Apart from DEPs associated with COPD versus controls and asthma versus controls, there was a total of 59 DEPs specific to COVID-19 patients. Finally, the findings revealed that there were 8 overlapping proteins in COVID-19 patients, including C9, FGB, FGG, PRTN3, HBB, HBA1, IGLV3-19, and COTL1. Functional analyses revealed that most of them were associated with complement and coagulation cascades, platelet activation, or iron metabolism, and anemia-related pathways. CONCLUSIONS: This study provides fundamental data for identifying COVID-19-specific proteomic changes in comparison with COPD and asthma, which may suggest molecular targets for specialized therapy.

Ribavirin Treatment for Critically Ill COVID-19 Patients: An Observational Study.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic has spread all over the world resulting in high mortality, yet no specific antiviral treatment has been recommended. METHODS: A retrospective descriptive study was conducted involving 19 consecutive critically ill patients during January 27, 2020 to April 18, 2020. Ribavirin was given at 0.15g q8h orally upon ICU admission for 7 to 21 days. Here, 28-day mortality, lower respiratory tract specimens (ETA), and ribavirin side effect on the day of ICU admission (Day 1), Day 7, Day 14 and Day 21 were analyzed. RESULTS: All the nineteen critically ill COVID-19 patients (14 males and 5 females, median age 56yr) survived through to the 28th day of observations with 6 patients (31.58%) being discharged from the ICU. The SARS-CoV-2 viral positivity in sputum/ETA was 100% (19/19) on Day 1, 73.68% (14/19) on Day 7, 57.89% (11/19) on Day 14 and 36.84% (7/19) on Day 21. Ribavirin side effect was not observed in these patients. CONCLUSION: Ribavirin is well tolerated in critically ill patients with COVID-19 and may benefit COVID-19 patients through increasing the virus clearance.

Current Status of Cell-Based Therapies for COVID-19: Evidence From Mesenchymal Stromal Cells in Sepsis and ARDS.

The severe respiratory consequences of the coronavirus disease 2019 (COVID-19) pandemic have prompted the urgent need for novel therapies. Cell-based therapies, primarily using mesenchymal stromal cells (MSCs), have demonstrated safety and potential efficacy in the treatment of critical illness, particularly sepsis and acute respiratory distress syndrome (ARDS). However, there are limited preclinical data for MSCs in COVID-19. Recent studies have shown that MSCs could decrease inflammation, improve lung permeability, enhance microbe and alveolar fluid clearance, and promote lung epithelial and endothelial repair. In addition, MSC-based therapy has shown promising effects in preclinical studies and phase 1 clinical trials in sepsis and ARDS. Here, we review recent advances related to MSC-based therapy in the context of sepsis and ARDS and evaluate the potential value of MSCs as a therapeutic strategy for COVID-19.

Visualization of Vaccine Dynamics with Quantum Dots for Immunotherapy

The direct visualization of vaccine fate is important to investigate its immunoactivation process in order to elucidate the detailed molecular reaction process at single-molecular level. Yet, visualization of the spatiotemporal trafficking of vaccines remains poorly explored. Here, we show that quantum dot (QD) nanomaterials allow for monitoring vaccine dynamics and for amplified immune response. Synthetic QDs enable efficient conjugation of antigen and adjuvants to target tissues and cells, and non-invasive imaging the trafficking dynamics to lymph nodes and cellular compartments. The nanoparticle vaccine elicits potent immune responses and anti-tumor efficacy alone or in combination with programmed cell death protein 1 blockade. The synthetic QDs showed high fluorescence quantum yield and superior photostability, and the reliable and long-term spatiotemporal tracking of vaccine dynamics was realized for the first time by using the synthetic QDs, providing a powerful strategy for studying the immune response and for evaluating the vaccine efficacy.

Case Report: Prolonged VV-ECMO (111 Days) Support in a Patient With Severe COVID-19.

Venovenous extracorporeal membrane oxygenation (VV-ECMO) may be a lifesaving rescue therapy for patients with severe coronavirus disease 2019 (COVID-19). However, little is known regarding the efficacy of prolonged ECMO (duration longer than 14 days) in patients with COVID-19. In this case report, we report the successful use of prolonged VV-ECMO (111 days) in a 61-year-old man with severe COVID-19. Given the high mortality rate of severe COVID-19, this case provided evidence for use of prolonged VV-ECMO as supportive care in patients with severe COVID-19.

Secondary infection in severe and critical COVID-19 patients in China: a multicenter retrospective study.

BACKGROUND: Since 2020 COVID-19 pandemic became an emergent public sanitary incident. The epidemiology data and the impact on prognosis of secondary infection in severe and critical COVID-19 patients in China remained largely unclear. METHODS: We retrospectively reviewed medical records of all adult patients with laboratory-confirmed COVID-19 who were admitted to ICUs from January 18th 2020 to April 26th 2020 at two hospitals in Wuhan, China and one hospital in Guangzhou, China. We measured the frequency of bacteria and fungi cultured from respiratory tract, blood and other body fluid specimens. The risk factors for and impact of secondary infection on clinical outcomes were also assessed. RESULTS: Secondary infections were very common (86.6%) when patients were admitted to ICU for >72 hours. The majority of infections were respiratory, with the most common organisms being Klebsiella pneumoniae (24.5%), Acinetobacter baumannii (21.8%), Stenotrophomonas maltophilia (9.9%), Candida albicans (6.8%), and Pseudomonas spp. (4.8%). Furthermore, the proportions of multidrug resistant (MDR) bacteria and carbapenem resistant Enterobacteriaceae (CRE) were high. We also found that age ≥60 years and mechanical ventilation ≥13 days independently increased the likelihood of secondary infection. Finally, patients with positive cultures had reduced ventilator free days in 28 days and patients with CRE and/or MDR bacteria positivity showed lower 28-day survival rate. CONCLUSIONS: In a retrospective cohort of severe and critical COVID-19 patients admitted to ICUs in China, the prevalence of secondary infection was high, especially with CRE and MDR bacteria, resulting in poor clinical outcomes.

Earlier diagnosis improves COVID-19 prognosis: a nationwide retrospective cohort analysis.

BACKGROUND: Risk of adverse outcomes in COVID-19 patients by stratifying by the time from symptom onset to confirmed diagnosis status is still uncertain. METHODS: We included 1,590 hospitalized COVID-19 patients confirmed by real-time RT-PCR assay or high-throughput sequencing of pharyngeal and nasal swab specimens from 575 hospitals across China between 11 December 2019 and 31 January 2020. Times from symptom onset to confirmed diagnosis, from symptom onset to first medical visit and from first medical visit to confirmed diagnosis were described and turned into binary variables by the maximally selected rank statistics method. Then, survival analysis, including a log-rank test, Cox regression, and conditional inference tree (CTREE) was conducted, regarding whether patients progressed to a severe disease level during the observational period (assessed as severe pneumonia according to the Chinese Expert Consensus on Clinical Practice for Emergency Severe Pneumonia, admission to an intensive care unit, administration of invasive ventilation, or death) as the prognosis outcome, the dependent variable. Independent factors included whether the time from symptom onset to confirmed diagnosis was longer than 5 days (the exposure) and other demographic and clinical factors as multivariate adjustments. The clinical characteristics of the patients with different times from symptom onset to confirmed diagnosis were also compared. RESULTS: The medians of the times from symptom onset to confirmed diagnosis, from symptom onset to first medical visit, and from first medical visit to confirmed diagnosis were 6, 3, and 2 days. After adjusting for age, sex, smoking status, and comorbidity status, age [hazard ratio (HR): 1.03; 95% CI: 1.01-1.04], comorbidity (HR: 1.84; 95% CI: 1.23-2.73), and a duration from symptom onset to confirmed diagnosis of >5 days (HR: 1.69; 95% CI: 1.10-2.60) were independent predictors of COVID-19 prognosis, which echoed the CTREE models, with significant nodes such as time from symptom onset to confirmed diagnosis, age, and comorbidities. Males, older patients with symptoms such as dry cough/productive cough/shortness of breath, and prior COPD were observed more often in the patients who procrastinated before initiating the first medical consultation. CONCLUSIONS: A longer time from symptom onset to confirmed diagnosis yielded a worse COVID-19 prognosis.

COVID-19: Is it safe now? Study of asymptomatic infection spread and quantity risk based on SAIR model

Based on the characteristic of the COVID-19 asymptomatic infection, and due to the shortage of traditional mathematical models of transmission dynamics of infectious diseases, we propose a new SAIR model. This SAIR model fully considers the infectious characteristics of asymptomatic cases and the transformation characteristics between the four kinds case. According to the data released by the National Health Commission of P.R.C, the model parameters are calculated, and the transmission process of the COVID-19 is simulated dynamically. It is found that the SAIR model data are in good agreement with the actual data, and the time characteristics of the infection rate are particularly accurate, proving the accuracy and effectiveness of the model. Then, on the basis of the differences between the model data and the real data, the standard deviation of the error is calculated. From the standard deviation, the functional intervals of the confirmed infection rate and the asymptomatic infection rate, the interval of the total number of cases in the model, and the interval of the number of asymptomatic cases in the society are also calculated. The number of asymptomatic cases in society is of important and realistic significance for the assessment of risk and subsequent control measures. Then, according to the dynamic simulation data of the model with changed value of parameters, the remarkable effects of strict quarantines are discussed. Finally, the possible direction of further study is given.

Analysis of pathological changes in the epithelium in COVID-19 patient airways.

Severe COVID-19 patient airways plugged by MUC5AC-containing mucus exhibit hyperplasia of goblet cells, and hypoplasia of multiciliated cells and club cells, as well as significantly reduced CC16 and MUC5B levels, and increased IL-13 levels https://bit.ly/2M2NcdO.

Hematological changes in COVID- 19 patients: early indications of diagnosis and progression

Hematological changes in patients with COVID-l9 caused by SARS-Cov-2 infection are common. It is found that lymphopenia and leukopenia occur frequently in the early stage of infection, and CD4⁺ and CD8⁺ T lymphocytes decrease significantly. Thrombocylopenia and decreased hemoglobin can also he found in COVID-l9. When the disease progresses to severe stage, lymphocytopenia continues to aggravaled. Increased number of neulrophils, neutrophil-to-lymphocyte ratio (NLR) and decreased level of hemoglobin are related to the disease progression and poor prognosis. The activation of monocyte-macrophage system aggravates the, immune damage of lung and other tissues. which leads to the increase of D-dimer, prothrombin time and platelet consumption. This paper summarized the latest outcomes of corresponding study and clarified the heamtopoietic abnormality caused by COVID-19 and potential mechanism.

Lung Recruitment, Individualized PEEP, and Prone Position Ventilation for COVID-19-Associated Severe ARDS: A Single Center Observational Study.

Background: Patients with coronavirus disease 2019 (COVID-19) may develop severe acute respiratory distress syndrome (ARDS). The aim of the study was to explore the lung recruitability, individualized positive end-expiratory pressure (PEEP), and prone position in COVID-19-associated severe ARDS. Methods: Twenty patients who met the inclusion criteria were studied retrospectively (PaO2/FiO2 68.0 ± 10.3 mmHg). The patients were ventilated under volume-controlled mode with tidal volume of 6 mL/kg predicted body weight. The lung recruitability was assessed via the improvement of PaO2, PaCO2, and static respiratory system compliance (Cstat) from low to high PEEP (5-15 cmH2O). Patients were considered recruitable if two out of three parameters improved. Subsequently, PEEP was titrated according to the best Cstat. The patients were turned to prone position for further 18-20 h. Results: For recruitability assessment, average value of PaO2 was slightly improved at PEEP 15 cmH2O (68.0 ± 10.3 vs. 69.7 ± 7.9 mmHg, baseline vs. PEEP 15 cmH2O; p = 0.31). However, both PaCO2 and Cstat worsened (PaCO2: 72.5 ± 7.1 vs. 75.1 ± 9.0 mmHg; p < 0.01. Cstat: 17.5 ± 3.5 vs. 16.6 ± 3.9 ml/cmH2O; p = 0.05). Only four patients (20%) were considered lung recruitable. Individually titrated PEEP was higher than the baseline PEEP (8.0 ± 2.1 cmH2O vs. 5 cmH2O, p < 0.001). After 18-20 h of prone positioning, investigated parameters were significantly improved compared to the baseline (PaO2: 82.4 ± 15.5 mmHg. PaCO2: 67.2 ± 6.4 mmHg. Cstat: 20.6 ± 4.4 ml/cmH2O. All p < 0.001 vs. baseline). Conclusions: Lung recruitability was very low in COVID-19-associated severe ARDS. Individually titrated PEEP and prone positioning might improve lung mechanics and blood gasses.

COVID-19-associated coagulopathy: thromboembolism prophylaxis and poor prognosis in ICU.

BACKGROUND: Coronavirus disease 2019 (COVID-19) is associated with coagulation abnormalities which are indicators of higher mortality especially in severe cases. METHODS: We studied patients with proven COVID-19 disease in the intensive care unit of Jinyintan Hospital, Wuhan, China from 30 to 2019 to 31 March 2020. RESULTS: Of 180 patients, 89 (49.44 %) had died, 85 (47.22 %) had been discharged alive, and 6 (3.33 %) were still hospitalised by the end of data collection. A D-dimer concentration of > 0.5 mg/L on admission was significantly associated with 30 day mortality, and a D-dimer concentration of > 5 mg/L was found in a much higher proportion of non-survivors than survivors. Sepsis-induced coagulopathy (SIC) and disseminated intravascular coagulation (DIC) scoring systems were dichotomised as < 4 or ≥ 4 and < 5 or ≥ 5, respectively, and the mortality rate was significantly different between the two stratifications in both scoring systems. Enoxaparin was administered to 68 (37.78 %) patients for thromboembolic prophylaxis, and stratification by the D-dimer concentration and DIC score confirmed lower mortality in patients who received enoxaparin when the D-dimer concentration was > 2 than < 2 mg/L or DIC score was ≥ 5 than < 5. A low platelet count and low serum calcium concentration were also related to mortality. CONCLUSIONS: A D-dimer concentration of > 0.5 mg/L on admission is a risk factor for severe disease. A SIC score of > 4 and DIC score of > 5 may be used to predict mortality. Thromboembolic prophylaxis can reduce mortality only in patients with a D-dimer concentration of > 2 mg/L or DIC score of ≥ 5.

The proteomic characteristics of airway mucus from critical ill COVID-19 patients.

BACKGROUND: The pandemic of the coronavirus disease 2019 (COVID-19) has brought a global public health crisis. However, the pathogenesis underlying COVID-19 are barely understood. METHODS: In this study, we performed proteomic analyses of airway mucus obtained by bronchoscopy from severe COVID-19 patients. In total, 2351 and 2073 proteins were identified and quantified in COVID-19 patients and healthy controls, respectively. RESULTS: Among them, 92 differentiated expressed proteins (DEPs) (46 up-regulated and 46 down-regulated) were found with a fold change >1.5 or <0.67 and a p-value <0.05, and 375 proteins were uniquely present in airway mucus from COVID-19 patients. Pathway and network enrichment analyses revealed that the 92 DEPs were mostly associated with metabolic, complement and coagulation cascades, lysosome, and cholesterol metabolism pathways, and the 375 COVID-19 only proteins were mainly enriched in amino acid degradation (Valine, Leucine and Isoleucine degradation), amino acid metabolism (beta-Alanine, Tryptophan, Cysteine and Methionine metabolism), oxidative phosphorylation, phagosome, and cholesterol metabolism pathways. CONCLUSIONS: This study aims to provide fundamental data for elucidating proteomic changes of COVID-19, which may implicate further investigation of molecular targets directing at specific therapy.