Proteomic determinants of disease, mortality and sequelae in COVID-19 patients requiring invasive mechanical ventilation

Introduction: The molecular mechanisms linked to the pathology of severe COVID-19 and its outcomes are poorly described. Aim(s): To analyze the proteomic profile of bronchial aspirates (BAS) samples from critically ill COVID-19 patients in order to identify factors associated with the disease and its prognosis. Method(s): Multicenter study including 74 critically ill non-COVID-19 and COVID-19 patients. BAS was obtained by bronchoaspiration after invasive mechanical ventilation (IMV) initiation. Proximity extension assay (PEA) technology was used for proteomic profiling. Random forest (RF) statistical models were used to predict the variable importance. Result(s): After adjusting for confounding factors, CST5, NADK, SRPK2 and TGF-alpha showed differences between COVID-19 and non-COVID-19 patients. Reduced levels of ENTPD2 and PTN were observed in non-survivors, even after adjustment. AGR2, NQO2, IL-1alpha, OSM and TRAIL, were the top five strongest predictors for ICU mortality and were used to build a prediction model. PTN (HR=4.00) ENTPD2 (HR=2.14) and the prediction model (HR=6.25) were associated with higher risk of death. In survivors, FCRL1, NTF4 and THOP1 correlated with lung function (DLCO levels) 3-months after hospital discharge. Similar findings were observed for Flt3L and THOP1 and radiological features (TSS). The proteins identified are expressed in immune and non-immune lung cells. A poor control of viral infectivity and an inappropriate reparative response seems to be linked to the disease and fatal outcomes, respectively. Conclusion(s): In critically ill COVID-19 patients, specific proteomic profiles are associated with the pathology, mortality and lung sequelae.

One year overview of follow-up in a post-covid consultation of critical patients with covid-19

Introduction: Long-term clinical management and evolution of a cohort of critical COVID-19 survivors has not been well described. Method(s): We report a prospective observational study of COVID-19 patients admitted to ICU between March to August 2020. The follow-up comprised symptoms, pulmonary function test, 6-minute walking test (6MWT, and chest computed tomography (CT). Additionally, questionnaires to evaluate the prevalence of post-covid19 syndrome was performed at 1-year. Result(s) and Conclusion(s): A total of 181 patients were admitted at the ICU during the study period. They were predominantly middle-aged (median [IQR] of 61 [52;67] years old) male (66.9%) with a median of ICU stay of 9 (5- 24.2) days. Twenty percent of them died in the hospital and 39 were not able to be included, a final cohort of 105 patients initiated the follow-up. At one year, 32.2% persist with respiratory alterations and needed to continue the follow-up. 10% still had severe lung diffusing (DLCO) involvement (<60%) and 53.7% had a fibrotic pattern on CT. Moreover, patients had a mean (SD) of symptoms of 5.77 (4.66) and 61.3% meet criteria for post-covid syndrome at one-year. During the follow-up 46 patients were discharge and 16 were transfer to others consultations. Other conditions such as emphysema (21.6%), COPD (8.2%), severe neurocognitive disorders (4.1%) and lung cancer (1%) have been identified. A high use of healthcare resources is observed in the first year of these critical survivors after hospital discharge.

Proteomic profiling of severe lung diffusion impairment in the recovery stage of COVID-19-induced ARDS

Background: Around 80% of patients who developed COVID-19-driven ARDS present lung ailment. There is a lack of knowledge of the mechanisms that mediate the pulmonary outcomes. Aim(s): To characterize the factors linked to diffusion impairment in survivors of severe COVID-19. Method(s): Prospective cohort study including 87 COVID-19-induced ARDS survivors. A complete pulmonary evaluation was performed 3 months after hospital discharge. 364 proteins were quantified using the proximity extension assay (PEA). Partial least square-discriminant analysis (PLS-DA) and random forest (RF) were used for multivariable analyses. Result(s): Moderate to severe diffusion impairment (DLCO<60% predicted) was observed in the 30% of the cohort. 15 proteins were differentially detected [false discovery rate (FDR)<0.05] in the univariate analysis. Pleiotrophin showed the highest differences (fold change=2.22 and FDR=0.001). In continuous analysis, proteins were inversely and independently associated with DLCO, and in some cases showed a robust dose-response relationship. PLS-DA and RF identified proteomic profiles related to the severity of diffusion capacity. Clusters identified were enriched in mediators of cell proliferation and differentiation, tissue remodeling, angiogenesis, coagulation, inflammation, immune response and fibrosis. Proteins are expressed in immune and non-immune lung cells. Conclusion(s): In survivors of COVID-19-driven ARDS, lung dysfunction is linked to plasma factors involved in injury and repair mechanisms. The host proteomic profile provides a novel understanding of post-acute sequelae and may be source of therapeutic strategies and biomarkers.

School Community Remote Education Readiness Assessment Framework

The continuity of education services during the Covid-19 pandemic has made clear that ICT (Information and Communication Technologies) is essential to achieve (even if partially) curricular goals with continuing isolation and confinement. Schools administrators need information on capability gaps regarding access, technology know-how, connectivity, and infrastructure, not just for each school but also for the community that it serves. Several models have been proposed to evaluate ICT impact on remote education, but none assess readiness and find gaps at specific schools and communities. This article describes School Community Remote Education Readiness Assessment Framework (SCRE-RAF), structured as a capability maturity model, geared to identify and measure capability gaps and derive improvement roadmaps for specific school communities. It defines four maturity levels (Emerging, Application, Integration, Transformation);eight Domain Areas (KDA), namely ICT skills, Instructional Design, Infrastructure, Connectivity, Teaching Processes, Innovation Policies, Administration and Resources, and Learner-Oriented Services;and 17 Key Process Indicators (KPI) with their capability levels. SCRE-RAF's structure and KPIs have been assessed though a survey to grade school teachers at a Chilean school network;all proposed KPI's had relevance agreement of 80% or higher from surveyed teachers, with highest agreement for ICT skills and the lowest for Student-Teacher Ratio. SCRE-RAF will now be deployed in a broader pilot to assess a small number of schools, and its results will be incorporated before deploying to larger school districts.

Circulating micrornas as biomarkers of COVID-19 severity

RATIONALE: The identification of minimally invasive and easily-accessible biomarkers to support the management of coronavirus disease 2019 (COVID-19) in hospitalized patients constitutes a hot topic in clinical research. MicroRNAs (miRNAs) have been proposed as clinical indicators to assist in medical decision-making. Here, we aimed to examine the circulating miRNA profile of hospitalized COVID-19 patients and to evaluate its potential as a source of biomarkers for the management of the disease. METHODS: Observational, prospective and multicenter study which included 84 patients with a positive nasopharyngeal swab PCR test for SARS-CoV-2, recruited during the first pandemic wave in Spain (March-May 2020). Patients were stratified according to disease severity: hospitalized patients admitted to the clinical wards without requiring critical care (n = 47) and hospitalized patients admitted to the ICU (n = 37). An additional study considering ICU non-survivors (n=17) and survivors (n = 20) was performed. Expression profiling of 41 miRNAs was performed in plasma samples using RT-qPCR. The panel included miRNAs associated with: i) immune/inflammatory response;ii) lung damage;iii) respiratory viral infections;iv) myocardial damage;v) coagulation. Quality control was performed using spike-ins and hemolysis tests. Predictive models were constructed using a variable selection process based on LASSO regression. RESULTS: Ten circulating miRNAs were deregulated in ICU compared to ward patients. LASSO analysis identified a signature of three miRNAs that displayed an optimal discrimination ability to distinguish between ICU and ward patients (AUC = 0.88) (Figure 1A). Among ICU patients, six miRNAs were downregulated when comparing nonsurvivors to survivors. A signature based on two miRNAs was found to be a relevant predictor of mortality during ICU stay (AUC = 0.84) (Figure 1B). The discrimination potential of the miRNA signature was higher than the observed for clinical laboratory parameters such as leukocyte counts (including neutrophil count, lymphocyte count and the neutrophil-tolymphocyte ratio), CRP or D-dimer (maximum AUC for these variables = 0.76). CONCLUSIONS: The severity of COVID-19 impacts on the circulating miRNA profile. The results suggest the potential usefulness of the circulating miRNA signature for the management of the disease over contemporaneous tests, at least in ICU patients.

Pulmonary function and radiological features in survivors of critical COVID-19: A 3-month prospective cohort

Background More than 20% of hospitalized patients with coronavirus disease 2019 (COVID-19) develop acute respiratory distress syndrome (ARDS) requiring intensive care unit (ICU) admission. The long-term respiratory sequelae in ICU survivors remain unclear. Aim: To perform a detailed characterization of the long-term pulmonary sequelae in critical COVID-19 survivors. Study Design and Methods Consecutive patients with COVID-19 requiring ICU admission were recruited and evaluated 3 months after hospitalization discharge. The follow-up comprised symptom and quality of life, anxiety and depression questionnaires, pulmonary function tests, exercise test (6-minute walking test (6MWT)) and chest computed tomography (CT). Results 125 ICU patients with ARDS secondary to COVID-19 were recruited between March and June 2020. At the 3-month follow-up, 62 patients were available for pulmonary evaluation. The most frequent symptoms were dyspnea (46.7%), and cough (34.4%). Eighty-two percent of patients showed a lung diffusing capacity of less than 80%. The mean distance in the 6MWT was 401±93 mts. CT scans were abnormal in 70.2% of patients, showing reticular lesions in 49.1% and fibrotic patterns in 21.1%. Patients with more severe alterations on chest CT had worse pulmonary function and presented more degrees of desaturation in the 6MWT. Factors associated with the severity of lung damage on chest CT were age and prone position during the ICU stay. Interpretation Pulmonary structural abnormalities and functional impairment are highly prevalent in surviving ICU patients with ARDS secondary to COVID-19 3 months after hospital discharge. Pulmonary evaluation should be considered for all critical COVID-19 survivors 3 months post discharge.

Neuropsychiatric symptoms and quality of life in Spanish patients with Alzheimer's disease during the COVID-19 lockdown.

BACKGROUND AND PURPOSE: The COVID-19 epidemic is affecting almost all individuals worldwide, and patients with Alzheimer's disease (AD) and amnesic mild cognitive impairment (MCI) are particularly at risk due to their characteristics and age. We analysed the impact of the pandemic on these patients' neuropsychiatric symptoms and their quality of life after 5 weeks of lockdown in Spain. METHODS: A total of 40 patients with a diagnosis of MCI (n = 20) or mild AD (n = 20) from the Cognitive Stimulation Program of the Cognitive Disorders Unit were evaluated. All patients had undergone a previous evaluation during the month before the lockdown, and were re-evaluated after 5 weeks of lockdown. The Neuropsychiatric Inventory (NPI) and EuroQol-5D questionnaire (EQ-5D) were used to assess neuropsychiatric symptoms in patients and the quality of life in patients as well in caregivers. RESULTS: The mean (SD) total baseline NPI score was 33.75 (22.28), compared with 39.05 (27.96) after confinement (P = 0.028). The most frequently affected neuropsychiatric symptoms were apathy [4.15 (3.78) vs. 5.75 (4.02); P = 0.002] and anxiety [3.95 (3.73) vs. 5.30 (4.01); P = 0.006] in patients with MCI, and apathy [2.35 (2.70) vs. 3.75 (3.78); P = 0.036], agitation [0.45 (1.14) vs. 1.50 (2.66); P = 0.029] and aberrant motor behaviour [1.25 (2.86) vs. 2.00 (2.93); P = 0.044] in patients with AD. We did not observe differences in EQ-5D scores during the re-evaluation. The 30% of patients and 40% of caregivers reported a worsening of the patients' health status during confinement. CONCLUSIONS: The results of this study show the worsening of neuropsychiatric symptoms in patients with AD and MCI during 5 weeks of lockdown, with agitation, apathy and aberrant motor activity being the most affected symptoms.