Anti-inflammatory effects of antibacterials on human bronchial epithelial cells

<p>Abstract</p> <p>Background</p> <p>Human Bronchial epithelial cells (hu-BEC) have been claimed to play a significant role in the pathogenesis of chronic inflammatory airway diseases like COPD. In this context IL-8 and GM-CSF have been shown to be key cytokines. Some antibiotics which are routinely used to treat lower respiratory tract infections have been shown to exert additional immunomodulatory or anti-inflammatory effects. We investigated whether these effects can also be detected in hu-BEC.</p> <p>Methods</p> <p>Hu-BEC obtained from patients undergoing lung resections were transferred to air-liquid-interface (ALI) culture. These cultures were incubated with cefuroxime (CXM, 10-62.5 mg/l), azithromycin (AZM, 0.1-1.5 mg/l), levofloxacin (LVX, 1-8 mg/l) and moxifloxacin (MXF, 1-16 mg/l). The spontaneous and TNF-α (10 ng/ml) induced expression and release of IL-8 and GM-CSF were measured using PCR and ELISA in the absence or presence of these antibiotics.</p> <p>Results</p> <p>The spontaneous IL-8 and GM-CSF release was significantly reduced with MXF (8 mg/l) by 37 ± 20% and 45 ± 31%, respectively (both p < 0.01). IL-8 release in TNF-α stimulated hu-BEC decreased by 16 ± 8% (p < 0.05) with AZM (1.5 mg/l). With MXF a concentration dependent decrease of IL-8 release was noted up to 39 ± 7% (p < 0.05). GM-CSF release from TNF-α stimulated hu-BEC was maximally decreased by 35 ± 24% (p < 0.01) with MXF (4 mg/l).</p> <p>Conclusion</p> <p>Using ALI cultures of hu-BEC we observed differential effects of antibiotics on spontaneous and TNF-α induced cytokine release. Our data suggest that MXF and AZM, beyond bactericidal effects, may attenuate the inflammatory process mediated by hu-BEC.</p

Variables predicting weaning outcome in prolonged mechanically ventilated tracheotomized patients: a retrospective study

Background: Several studies have assessed predictors of weaning and extubation outcome in short-term mechanically ventilated patients, but there are only few studies on predictors of weaning from prolonged mechanical ventilation. Methods: Retrospective, single-center, observational study at a specialized national weaning center in Germany. Patients' medical records were reviewed to obtain data on demographics, comorbidities, respiratory indices, and the result of a prospectively documented, standardized spontaneous breathing trial (SBT) upon admission to the weaning center. Respiratory indices assessed were the ventilatory ratio (VR) and parameters derived from calculated mechanical power (MP). Predictors associated with failure of prolonged weaning and failure of the SBT were assessed using a binary logistic regression model. Results: A total of 263 prolonged mechanically ventilated, tracheotomized patients, treated over a 5-year period were analyzed. After 3 weeks of mechanical ventilation, patients with unsuccessful weaning failed a SBT more frequently and showed significantly increased values for inspiratory positive airway pressure, driving pressure, VR, absolute MP, and MP normalized to predicted body weight and dynamic lung-thorax compliance (LTC-MP). In the logistic regression analyses, variables independently correlated with weaning failure were female gender (adjusted odds ratio 0.532 95% CI 0.291-0.973; p = 0.040), obesity (body mass index ≥ 30 kg/m2) (2.595 1.210-5.562; p = 0.014), COPD (3.209 1.563-6.589; p = 0.002), LTC-MP (3.470 1.067-11.284; p = 0.039), PaCO2 on mechanical ventilation (1.101 95% CI 1.034-1.173; p = 0.003), and failure of the SBT (4.702 2.250-9.825; p < 0.001). In addition, female gender (0.401 0.216-0.745; p = 0.004), LTC-MP (3.017 1.027-8.862; p = 0.046), and PaCO2 on mechanical ventilation (1.157 1.083-1.235; p < 0.001) were independent risk factors for an unsuccessful SBT. Conclusions In the present study, the derived predictors of weaning point to a crucial role of the workload imposed on respiratory muscles during spontaneous breathing. Mechanical power normalized to lung-thorax compliance was independently correlated with weaning outcome and may identify patients at high risk for weaning failure

A randomized controlled trial of liposomal cyclosporine A for inhalation in the prevention of bronchiolitis obliterans syndrome following lung transplantation

Bronchiolitis obliterans; Clinical research; Lung transplantationBronquiolitis obliterante; Investigación clínica; Trasplante de pulmónBronquiolitis obliterant; Recerca clínica; Trasplantament de pulmóLong-term survival after lung transplantation is limited by chronic allograft dysfunction. The aim of this study was to investigate the effect of locally augmented immunosuppression with liposomal cyclosporine A for inhalation (L-CsA-i) for the prevention of bronchiolitis obliterans syndrome (BOS). In a randomized, double-blind, placebo-controlled, multi-center Phase 3 study, 180 LT recipients in BOS grade 0 were planned to receive L-CsA-i or placebo in addition to triple-drug immunosuppression. L-CsA-i was administered twice daily via an Investigational eFlow nebulizer to recipients of single (SLT) and bilateral lung transplants (BLT) within 6–32 weeks posttransplant, and continued for 2 years. The primary endpoint was BOS-free survival. 130 patients were enrolled before the study was prematurely terminated for business reasons. Despite a 2-year actuarial difference in BOS-free survival of 14.1% in favor of L-CsA-i in the overall study population, the primary endpoint was not met (p = .243). The pre-defined per protocol analysis of SLT recipients (n = 24) resulted in a treatment difference of 58.2% (p = .053). No difference was observed in the BLT (n = 48) subpopulation (p = .973). L-CsA-i inhalation was well tolerated. Although this study failed to meet its primary endpoint, the results warrant additional investigation of L-CsA-i in lung transplant recipients.The study was funded by PARI Pharma GmbH. Open access funding enabled and organized by ProjektDEAL

Residual pulmonary vasodilative reserve predicts outcome in idiopathic pulmonary hypertension

Objective: Idiopathic pulmonary arterial hypertension (IPAH) remains a devastating and incurable, albeit treatable condition. Treatment response is not uniform and parameters that help to anticipate a rather benign or a malignant course of the disease are warranted. Acute pulmonary vasoreactivity testing during right heart catheterisation is recommended to identify a minority of patients with IPAH with sustained response to calcium channel blocker therapy. This study aimed to evaluate the prognostic significance of a residual pulmonary vasodilative reserve in patients with IPAH not meeting current vasoresponder criteria. Design: Observational right heart catheter study in 66 (n=66) patients with IPAH not meeting current vasoresponse criteria. Pulmonary vasodilative reserve was assessed by inhalation of 5 µg iloprost-aerosol. Results: Sixty-six (n=66) of 72 (n=72) patients with IPAH did not meet current definition criteria assessed during vasodilator testing to assess pulmonary vasodilatory reserve. In those, iloprost-aerosol caused a reduction of mean pulmonary artery pressure (Δ pulmonary artery pressure—11.4%; p<0.001) and increased cardiac output (Δ cardiac output +16.7%; p<0.001), resulting in a reduction of pulmonary vascular resistance (Δ pulmonary vascular resistance—25%; p<0.001). The magnitude of this response was pronounced in surviving patients. A pulmonary vascular resistance reduction of ≥30% turned out to predict outcome in patients with IPAH. Conclusions: Residual pulmonary vasodilative reserve during acute vasodilator testing is of prognostic relevance in patients with IPAH not meeting current definitions of acute vasoreactivity. Therefore vasoreactivity testing holds more information than currently used

Residual pulmonary vasodilative reserve predicts outcome in idiopathic pulmonary hypertension

Objective: Idiopathic pulmonary arterial hypertension (IPAH) remains a devastating and incurable, albeit treatable condition. Treatment response is not uniform and parameters that help to anticipate a rather benign or a malignant course of the disease are warranted. Acute pulmonary vasoreactivity testing during right heart catheterisation is recommended to identify a minority of patients with IPAH with sustained response to calcium channel blocker therapy. This study aimed to evaluate the prognostic significance of a residual pulmonary vasodilative reserve in patients with IPAH not meeting current vasoresponder criteria. Design: Observational right heart catheter study in 66 (n=66) patients with IPAH not meeting current vasoresponse criteria. Pulmonary vasodilative reserve was assessed by inhalation of 5 µg iloprost-aerosol. Results: Sixty-six (n=66) of 72 (n=72) patients with IPAH did not meet current definition criteria assessed during vasodilator testing to assess pulmonary vasodilatory reserve. In those, iloprost-aerosol caused a reduction of mean pulmonary artery pressure (Δ pulmonary artery pressure—11.4%; p<0.001) and increased cardiac output (Δ cardiac output +16.7%; p<0.001), resulting in a reduction of pulmonary vascular resistance (Δ pulmonary vascular resistance—25%; p<0.001). The magnitude of this response was pronounced in surviving patients. A pulmonary vascular resistance reduction of ≥30% turned out to predict outcome in patients with IPAH. Conclusions: Residual pulmonary vasodilative reserve during acute vasodilator testing is of prognostic relevance in patients with IPAH not meeting current definitions of acute vasoreactivity. Therefore vasoreactivity testing holds more information than currently used

Insights from the German Compassionate Use Program of Nintedanib for the Treatment of Idiopathic Pulmonary Fibrosis

Background: Nintedanib is approved for the treatment of idiopathic pulmonary fibrosis(IPF) and has been shown to slow disease progression by reducing annual lung function decline. Objective: To evaluate the results of a large cohort of IPF patients treated with nintedanib within a compassionate use program(CUP) in Germany(9 centers). Methods: Patients ( >= 40 years) were required to have a confirmed diagnosis of IPF, a forced vital capacity(FVC) >= 50% predicted ( pred.) and a carbon monoxide diffusing capacity(DLCO) 30-79% pred. and not to be eligible for pirfenidone treatment. Clinical data, pulmonary function tests and adverse events were recorded up to July 2015. Results: Sixty-two patients (48 male/14 female) with moderate IPF (FVC 64 +/- 17% pred. and DLCO 40 +/- 10% pred.) were treated with nintedanib. 77% of patients switched from pirfenidone (mean treatment duration 14 +/- 2 months) mostly due to disease progression (mean decline in FVC 7.4 +/- 3% pred. in the 6 months prior to nintedanib intake). Initiation of nintedanib treatment occurred 69 +/- 29 months after IPF diagnosis, and mean treatment duration was 8 +/- 4 months. Most patients (63%) stabilized 6 months after treatment start (mean FVC decline 3 +/- 1 vs. -17 +/- 2% in patients with disease progression;p < 0.01). The most common adverse events were diarrhea (63%) and weight loss (50%). Dose reduction occurred in 34% of cases and treatment discontinuation in 10%. Conclusion: Nintedanib treatment was generally well tolerated and was associated with FVC stabilization in the majority of IPF patients in this CUP setting where most patients were not treatment naive. Our data are in agreement with the previously published data. (C) 2016 The Author(s) Published by S. Karger AG, Base

Self-Report Daily Life Activity as a Prognostic Marker of Idiopathic Pulmonary Fibrosis

BACKGROUND Idiopathic pulmonary fibrosis (IPF) is a progressive disease, leading to substantial physical impairment. The distance walked in 6 min (6MWD) is a measure of exercise tolerance and is of prognostic relevance in IPF. While 6MWD is a punctual measurement which may not be representative, self-reported daily life activity may represent the patients' functional capacity more globally even in less severe affected patients. OBJECTIVES We evaluated and characterized a simple classification system based on the patients' self-reported daily activity and analyzed if this would add significantly to the prognostic information of the 6MWD alone in IPF patients. METHODS Daily life activity was assessed in IPF (n = 156) patients with standardized questions and categorized in activity classes (AC I-IV), comprising the less severe impaired in AC I and II. The 6MWD was also assessed. RESULTS ACs were related to the lung functional impairment and inversely correlated to the 6MWD. Thirty-two patients were in AC I/II, 98 in AC III and 26 patients in AC IV. Thirty-seven (23.7%) patients died during a median follow-up of 14.9 months, comprising 1 patient in AC I/II. In addition, a 6MWD \textless470 m predicted mortality. Combining AC I/II and a 6MWD \textgreater470 m identified a subgroup of patients with favorable outcome. CONCLUSIONS AC is a novel scoring system which can easily be obtained and correlates with lung functional and physical impairments as well as mortality. Moreover, AC adds prognostic information to the 6MWD

Clinical Impact of Physical Activity and Cough on Disease Progression in Fibrotic Interstitial Lung Disease

Physical activity limitations and cough are common in patients with interstitial lung disease (ILD), potentially leading to reduced health-related quality of life. We aimed to compare physical activity and cough between patients with subjective, progressive idiopathic pulmonary fibrosis (IPF) and fibrotic non-IPF ILD. In this prospective observational study, wrist accelerometers were worn for seven consecutive days to track steps per day (SPD). Cough was evaluated using a visual analog scale (VAScough) at baseline and weekly for six months. We included 35 patients (IPF: n = 13; non-IPF: n = 22; mean ± SD age 61.8 ± 10.8 years; FVC 65.3 ± 21.7% predicted). Baseline mean ± SD SPD was 5008 ± 4234, with no differences between IPF and non-IPF ILD. At baseline, cough was reported by 94.3% patients (mean ± SD VAScough 3.3 ± 2.6). Compared to non-IPF ILD, patients with IPF had significantly higher burden of cough (p = 0.020), and experienced a greater increase in cough over six months (p = 0.009). Patients who died or underwent lung transplantation (n = 5), had significantly lower SPD (p = 0.007) and higher VAScough (p = 0.047). Long-term follow up identified VAScough (HR: 1.387; 95%-CI 1.081–1.781; p = 0.010) and SPD (per 1000 SPD: HR 0.606; 95%-CI: 0.412–0.892; p = 0.011) as significant predictors for transplant-free survival. In conclusion, although activity didn’t differ between IPF and non-IPF ILD, cough burden was significantly greater in IPF. SPD and VAScough differed significantly in patients who subsequently experienced disease progression and were associated with long-term transplant-free survival, calling for better acknowledgement of both parameters in disease management