Studying the pathophysiology of coronavirus disease 2019: a protocol for the Berlin prospective COVID-19 patient cohort (Pa-COVID-19).

PURPOSE: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread worldwide causing a global health emergency. Pa-COVID-19 aims to provide comprehensive data on clinical course, pathophysiology, immunology and outcome of COVID-19, to identify prognostic biomarkers, clinical scores, and therapeutic targets for improved clinical management and preventive interventions. METHODS: Pa-COVID-19 is a prospective observational cohort study of patients with confirmed SARS-CoV-2 infection treated at Charité - Universitätsmedizin Berlin. We collect data on epidemiology, demography, medical history, symptoms, clinical course, and pathogen testing and treatment. Systematic, serial blood sampling will allow deep molecular and immunological phenotyping, transcriptomic profiling, and comprehensive biobanking. Longitudinal data and sample collection during hospitalization will be supplemented by long-term follow-up. RESULTS: Outcome measures include the WHO clinical ordinal scale on day 15 and clinical, functional, and health-related quality-of-life assessments at discharge and during follow-up. We developed a scalable dataset to (i) suit national standards of care, (ii) facilitate comprehensive data collection in medical care facilities with varying resources, and (iii) allow for rapid implementation of interventional trials based on the standardized study design and data collection. We propose this scalable protocol as blueprint for harmonized data collection and deep phenotyping in COVID-19 in Germany. CONCLUSION: We established a basic platform for harmonized, scalable data collection, pathophysiological analysis, and deep phenotyping of COVID-19, which enables rapid generation of evidence for improved medical care and identification of candidate therapeutic and preventive strategies. The electronic database accredited for interventional trials allows fast trial implementation for candidate therapeutic agents. TRIAL REGISTRATION: Registered at the German registry for clinical studies (DRKS00021688).

When Treatment of Pulmonary Emphysema with Endobronchial Valves Did Not Work: Evaluation of Quantitative CT Analysis and Pulmonary Function Tests Before and After Valve Explantation.

Purpose: To investigate changes in quantitative CT analysis (QCT) and pulmonary function tests (PFT) in pulmonary emphysema patients who required premature removal of endobronchial valves (EBV). Patients and Methods: Our hospital's medical records listed 274 patients with high-grade COPD (GOLD stages 3 and 4) and pulmonary emphysema who were treated with EBV to reduce lung volume. Prior to intervention, a complete evaluation was performed that included quantitative computed tomography analysis (QCT) of scans acquired at full inspiration and full expiration, pulmonary function tests (PFT), and paraclinical findings (6-minute walking distance test (6MWDT) and quality of life questionnaires). In 41 of these 274 patients, EBV treatment was unsuccessful and the valves had to be removed for various reasons. A total of 10 of these 41 patients ventured a second attempt at EBV therapy and underwent complete reevaluation. In our retrospective study, results from three time points were compared: Before EBV implantation (BL), after EBV implantation (TP2), and after EBV explantation (TP3). QCT parameters included lung volume, total emphysema score (TES, ie, the emphysema index) and the 15th percentile of lung attenuation (P15) for the whole lung and each lobe separately. Differences in these parameters between inspiration and expiration were calculated (Vol. Diff (%), TES Diff (%), P15 Diff (%)). The results of PFT and further clinical tests were taken from the patient's records. Results: We found persistent therapy effect in the target lobe even after valve explantation together with a compensatory hyperinflation of the rest of the lung. As a result of these two divergent effects, the volume of the total lung remained rather constant. Furthermore, there was a slight deterioration of the emphysema score for the whole lung, whereas the TES of the target lobe persistently improved. Conclusion: Interestingly, we found evidence that, contrary to our expectations, unsuccessful EBV therapy can have a persistent positive effect on target lobe QCT scores.

Quantitative CT Analysis in Patients with Pulmonary Emphysema: Do Calculated Differences Between Full Inspiration and Expiration Correlate with Lung Function?

Purpose: The aim of this retrospective study was to evaluate correlations between parameters of quantitative computed tomography (QCT) analysis, especially the 15th percentile of lung attenuation (P15), and parameters of clinical tests in a large group of patients with pulmonary emphysema. Patients and Methods: One hundred and seventy-two patients with pulmonary emphysema and chronic obstructive pulmonary disease (COPD) global initiative for chronic obstructive lung disease (GOLD) stage 3 or 4 were assessed by nonenhanced thin-section CT scans in full inspiratory and expiratory breath-hold, pulmonary function test (PFT), a 6-minute walk test (6MWT), and quality of life questionnaires (SGRQ and CAT). QCT parameters included total lung volume (TLV), total emphysema score (TES), and P15, all measured at inspiration (IN) and expiration (EX). Differences between inspiration and expiration were calculated for TLV (TLVDiff), TES (TESDiff), and P15 (P15Diff). Spearman correlation analysis was performed. Results: CT-measured lung volume in inspiration (TLVIN) correlated strongly with spirometry-measured total lung capacity (TLC) (r=0.81, p<0.001) and moderately to strongly with residual volume (RV), forced vital capacity (FVC), and forced expiratory volume in 1 second (FEV1)/FVC (r=0.60, 0.56, and -0.49, each p<0.001). Lung volume in expiration (TLVEX) correlated moderately to strongly with TLC, RV and FEV1/FVC ratio (r=0.75, 0.66, and -0.43, each p<0.001). TES and P15 showed stronger correlations with the carbon monoxide transfer coefficient (KCO%) (r= -0.42, 0.44, both p<0.001), when measured during expiration. P15Diff correlated moderately with KCO% and carbon monoxide diffusing capacity (DLCO%) (r= 0.41, 0.40, both p<0.001). The 6MWT and most QCT parameters showed significant differences between COPD GOLD 3 and 4 groups. Conclusion: Our results suggest that QCT can help predict the severity of lung function decrease in patients with pulmonary emphysema and COPD GOLD 3 or 4. Some QCT parameters, including P15EX and P15Diff, correlated moderately to strongly with parameters of pulmonary function tests.

Dysfunctional glycogen storage in a mouse model of alpha1-antitrypsin deficiency.

Autophagy is an intracellular pathway that contributes to the degradation and recycling of unfolded proteins. Based on the knowledge that autophagy affects glycogen metabolism and that alpha(1)-antitrypsin (AAT) deficiency is associated with an autophagic response in the liver, we hypothesized that the conformational abnormalities of the Z-AAT protein interfere with hepatocyte glycogen storage and/or metabolism. Compared with wild-type mice (WT), the Z-AAT mice had lower liver glycogen stores (P < 0.001) and abnormal activities of glycogen-related enzymes, including acid alpha-glucosidase (P < 0.05) and the total glycogen synthase (P < 0.05). As metabolic consequences, PiZ mice demonstrated lower blood glucose levels (P < 0.05), lower body weights (P < 0.001), and lower fat pad weights (P < 0.001) compared with WT. After the stress of fasting or partial hepatectomy, PiZ mice had further reduced liver glycogen and lower blood glucose levels (both P < 0.05 compared WT). Finally, PiZ mice exhibited decreased survival after partial hepatectomy (P < 0.01 compared with WT), but this was normalized with postoperative dextrose supplementation. In conclusion, these observations are consistent with the general concept that abnormal protein conformation and degradation affects other cellular functions, suggesting that diseases in the liver might benefit from metabolic compensation if glycogen metabolism is affected.