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.

Clinical consequences of health measures and lock down for covid-19 in exacerbations in patients with chronic obstructive pulmonary disease (COPD)

Introduction: Covid-19 pandemic has meant that measures such as social distance, self protection measures and lock down can have an impact on exacerbations in patients with COPD. The aim of our study is to evaluate the impact about these measures on exacerbations in COPD patients. Material(s) and Method(s): Retrospective observational study of COPD patients visited at two public hospitals in Lleida in 2019. Several clinical variables and the number and type of exacerbations from March 2019 to December 2021 were collected from their electronic history. The mean number of exacerbations from March to May 2020 (period of lock down) was analyzed and compared with the same period of the previous year (March-May 2019). The behavior of exacerbations after progressive ending of lock down period (June 2020-December 2021) was observed. Result(s): A total of 310 patients were included with a mean (SD) age of 66.8+/-8.34 years. Patients had a FEV1 of 48.5+/-18.8% and 19.7% of them belong to group D according to GOLD guidelines. In lock down period between March and May 2020 there was a reduction in the mean number of exacerbations compared to the same period of the previous year (0.13+/-0.34 vs. 0.36+/-0.55;p<0.001). An increase in exacerbations was observed in the subsequent periods from June 2020 to February 2021 (0.3+/-0.56) and from June 2021 to December 2021 (0.43+/-0.68), coinciding with the relaxation of health measures. Conclusion(s): The results of our study suggest that measures such as lock down, social distance and self-protection have an impact on exacerbations in patients with COPD.

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.

Risk factors for mortality in COPD patients with COVID19 admitted to Intensive Care Unit

Background and aim: Patients with Chronic obstructive pulmonary disease (COPD) and COVID-19 have increased risk of hospitalization and Instensive Care Unit (ICU) admission (1). Aims and objectives: To indentify risk factors for intrahospital mortality in COPD patients with COVID-19 admitted to Spanish ICUs. Method(s): Demographic and clinical data during ICU admission were recorded using REDCap on all patients hospitalized for COVID-19 in 70 Spanish ICUs (2). We described the baseline clinical characteristics of COPD compared to other chronic respiratory disease (CRD) and to the overall population. We identified the risk factors for intrahospital mortality of COPD patients receiving invasive mechanical ventilation (IMV) and for those COPD receiving noninvasive respiratory support (NIRS). Result(s): Two hundred and sixty-eight ICU patients (5%) had COPD out of 5196 included. No differences were found between COPD, CRD or the overall population in the rates of IMV (76-78%) vs NIRS (22-24%). COPD intrahospital mortality was much higher in the IMV subgroup (58%). Independent risk factors for intrahospital mortality in the COPD+IMV or COPD+NIRS were: age and chronic Kidney disease or hypertension, respectively. Previous NIRS in COPD+IMV group was protective for intrahospital mortality (Figure). Conclusion(s): New strategies are needed to reduce the high intrahospital and 90-days mortality of COPD COVID-19 patients admitted to ICU.

Risk factors associated with mortality among elderly patients with COVID-19: Data from 55 intensive care units in Spain.

INTRODUCTION AND OBJECTIVES: Critically-ill elderly ICU patients with COVID-19 have poor outcomes. We aimed to compare the rates of in-hospital mortality between non-elderly and elderly critically-ill COVID-19 ventilated patients, as well as to analyze the characteristics, secondary outcomes and independent risk factors associated with in-hospital mortality of elderly ventilated patients. PATIENTS AND METHODS: We conducted a multicentre, observational cohort study including consecutive critically-ill patients admitted to 55 Spanish ICUs due to severe COVID-19 requiring mechanical ventilation (non-invasive respiratory support [NIRS; include non-invasive mechanical ventilation and high-flow nasal cannula] and invasive mechanical ventilation [IMV]) between February 2020 and October 2021. RESULTS: Out of 5,090 critically-ill ventilated patients, 1,525 (27%) were aged ≥70 years (554 [36%] received NIRS and 971 [64%] received IMV. In the elderly group, median age was 74 years (interquartile range 72-77) and 68% were male. Overall in-hospital mortality was 31% (23% in patients <70 years and 50% in those ≥70 years; p<0.001). In-hospital mortality in the group ≥70 years significantly varied according to the modality of ventilation (40% in NIRS vs. 55% in IMV group; p<0.001). Factors independently associated with in-hospital mortality in elderly ventilated patients were age (sHR 1.07 [95%CI 1.05-1.10], p<0.001); previous admission within the last 30 days (sHR 1.40 [95%CI 1.04-1.89], p = 0.027); chronic heart disease (sHR 1.21 [95%CI 1.01-1.44], p = 0.041); chronic renal failure (sHR 1.43 [95%CI 1.12- 1.82], p = 0.005); platelet count (sHR 0.98 [95% CI 0.98-0.99], p<0.001); IMV at ICU admission (sHR 1.41 [95% CI 1.16- 1.73], p<0.001); and systemic steroids (sHR 0.61 [95%CI 0.48- 0.77], p<0.001). CONCLUSIONS: Amongst critically-ill COVID-19 ventilated patients, those aged ≥70 years presented significantly higher rates of in-hospital mortality than younger patients. Increasing age, previous admission within the last 30 days, chronic heart disease, chronic renal failure, platelet count, IMV at ICU admission and systemic steroids (protective) all comprised independent factors for in-hospital mortality in elderly patients.

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.