Chronic obstructive pulmonary disease (COPD) is an inflammatory condition with constantly increasing mortality rates. Interleukin (IL)-33 and its decoy receptor, soluble suppression of tumorigenicity 2 (sST2), play a central role in the inflammatory response during infection. sST2 was suggested as a factor in the pathogenesis of COPD and emerged as a predictor of mortality in other non-communicable diseases. The role of sST2 as a predictor of mortality remains unclear in COPD yet. In this cohort study, we measured circulating concentrations of IL-33 and sST2 in the serum of patients with stable COPD (n = 59), patients with acute exacerbation of COPD (n = 29) and smoking (n = 20) and non-smoking controls (n = 20), using commercially available ELISAs, and investigated the prognostic role of sST2 in stable COPD. sST2 levels were significantly higher in COPD patients and smokers compared with non-smoking controls. We identified systolic blood pressure, forced expiratory volume in 1 s (FEV1% predicted), neutrophil count, lactate dehydrogenase and pack-years index as independent predictors of sST2 levels. During a median follow-up time of 10.6 years, 28 patients (47.5%) died. sST2 was an independent predictor of all-cause mortality in patients with COPD with a hazard ratio of 2.9 (95% CI 1.1–8.4, p = 0.035) per one standard deviation after adjustment for age, sex, pack-years, FEV1% predicted and C-reactive protein (CRP). sST2 concentrations are associated with severity of disease and long-term outcome in patients with COPD.

Objective:Diastolic dysfunction of the left ventricle is common in patients with chronic obstructive pulmonary disease (COPD). Dynamic hyperinflation has been suggested as a key determinant of reduced diastolic function in COPD. We aimed to investigate the effects of induced dynamic hyperinflation on left ventricular diastolic function in healthy subjects to exclude other confounding mechanisms associated with COPD.Design:In this randomized controlled crossover trial (NCT03500822,https://www.clinicaltrials.gov/), we induced dynamic hyperinflation using the validated method of expiratory resistance breathing (ERB), which combines tachypnea with expiratory resistance, and compared the results to those of tachypnea alone. Healthy male subjects (n= 14) were randomly assigned to the ERB or control group with subsequent crossover. Mild, moderate, and severe hyperinflation (i.e., ERB1, ERB2, ERB3) were confirmed by intrinsic positive end-expiratory pressure (PEEP_i) using an esophageal balloon catheter. The effects on diastolic function of the left ventricle were measured by transthoracic echocardiographic assessment of the heart rate-adjusted transmitral E/A-ratio and E/e'-ratio.Results:We randomly assigned seven participants to the ERB group and seven to the control group (age 26 [24-26] vs. 24 [24-34],p= 0.81). Severe hyperinflation decreased the E/A-ratio compared to the control condition (1.63 [1.49–1.77] vs. 1.85 [0.95–2.75],p= 0.039), and moderate and severe ERB significantly increased the septal E/e'-ratio. No changes in diastolic function were found during mild hyperinflation. PEEPi levels during ERB were inversely correlated with the E/A ratio (regression coefficient = −0.007,p= 0.001).Conclusions:Our data indicate dynamic hyperinflation as a determinant of left ventricular diastolic dysfunction in healthy subjects. Therapeutic reduction of hyperinflation might be a treatable trait to improve diastolic function in patients with COPD.

Because of the initially urgent need for treatments for COVID-19-associated acute respiratory distress syndrome (ARDS), the efficacy and tolerability of inhaled solnatide, a direct activator of the epithelial sodium channel (ENaC) under clinical investigation for the treatment of ARDS, were assessed in a pilot trial. This randomized controlled double-blind clinical trial was performed at two study centers in Vienna, Austria. Adult mechanically ventilated patients with moderate to severe ARDS (Berlin Definition) caused by COVID-19 were randomized 1:1 to inhalation of solnatide (100 mg) or placebo twice daily for seven days. The primary outcome parameter was ventilator-free days (VFDs) within 28 days; survival was assessed at 28 and 60 days as a secondary outcome. A total of 30 out of the 40 planned patients were included, 15 randomized to solnatide and 15 to placebo. Then the trial was stopped early due to slow recruitment. The median VFDs were 0 in both groups (p = 0.653). Twenty out of 30 patients (66.7%) survived until day 28 [solnatide group: n = 11 (73.3%), placebo group: n = 9 (60%)]. One additional patient per group died until day 60. In total, 41 adverse events (AEs) and 10 serious AEs occurred in the solnatide group, and 26 AEs and 14 serious AEs in the placebo group. No AE was considered to be related to the study treatment. There was no difference in VFDs or survival between the solnatide and the placebo group. Solnatide appeared safe in this limited cohort of critically ill patients with COVID-19. EU clinical trials register, EudraCT number 2020-001244-26.