[Show abstract][Hide abstract] ABSTRACT: Abstract Background: Whether or not antibiotic stewardship protocols based on procalcitonin levels results in cost savings remains unclear. Herein, our objective was to assess the economic impact of adopting procalcitonin testing among patients with suspected acute respiratory tract infection (ARI) from the perspective of a typical US integrated delivery network (IDN) with a 1,000,000 member catchment area or enrollment. Methods: To conduct an economic evaluation of procalcitonin testing versus usual care we built a cost-impact model based on patient-level meta-analysis data of randomized trials. The meta-analytic data was adapted to the US setting by applying the meta-analytic results to US lengths of stay, costs, and practice patterns. We estimated the annual ARI visit rate for the one million member cohort, by setting (inpatient, ICU, outpatient) and ARI diagnosis. Results: In the inpatient setting, the costs of procalcitonin-guided compared to usual care for the one million member cohort was $2,083,545, compared to $2,780,322, resulting in net savings of nearly $700,000 to the IDN for 2014. In the ICU and outpatient settings, savings were $73,326 and $5,329,824, respectively, summing up to overall net savings of $6,099,927 for the cohort. Results were robust for all ARI diagnoses. For the whole US insured population, procalcitonin-guided care would result in $1.6 billion in savings annually. Conclusions: Our results show substantial savings associated with procalcitonin protocols of ARI across common US treatment settings mainly by direct reduction in unnecessary antibiotic utilization. These results are robust to changes in key parameters, and the savings can be achieved without any negative impact on treatment outcomes.
Clinical Chemistry and Laboratory Medicine 01/2015; · 2.96 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background
Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease with poor prognosis. The kinase inhibitor nintedanib specific for vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR) and fibroblast growth factor receptor (FGFR) significantly reduced the rate of decline of forced vital capacity versus placebo.AimTo determine the in vitro effect of nintedanib on primary human lung fibroblasts. Methods: Fibroblasts were isolated from lungs of IPF patients and from non-fibrotic controls. We assessed the effect of VEGF, PDGF-BB and basic FGF (bFGF)¿±¿nintedanib on: (i) expression/activation of VEGFR, PDGFR, and FGFR, (ii) cell proliferation, secretion of (iii) matrix metalloproteinases (MMP), (iv) tissue inhibitor of metalloproteinase (TIMP), and (v) collagen.ResultsIPF fibroblasts expressed higher levels of PDGFR and FGFR than controls. PDGF-BB, bFGF, and VEGF caused a pro-proliferative effect which was prevented by nintedanib. Nintedanib enhanced the expression of pro-MMP-2, and inhibited the expression of TIMP-2. Transforming growth factor-beta-induced secretion of collagens was inhibited by nintedanib.Conclusion
Our data demonstrate a significant anti-fibrotic effect of nintedanib in IPF fibroblasts. This effect consists of the drug¿s anti-proliferative capacity, and on its effect on the extracellular matrix, the degradation of which seems to be enhanced.
Respiratory Research 12/2014; · 3.13 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The 6-Minute Walk Test (6MWT) is representative of daily-life activities and reflects the functional capacity of patients. The change of oxygen uptake (VO2) in the initial phase of low-intensity exercise (VO2 kinetics) can be used to assess submaximal exercise performance of patients.The objective of the following study was to analyse VO2 kinetics in patients with different pulmonary and cardiovascular diseases. In addition, we investigated the extent to which VO2 kinetics at the onset of the 6MWT were associated with exercise capacity, morbidity and mortality.
BMC Pulmonary Medicine 10/2014; 14(1):167. · 2.49 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: This is the experience with the Stratos system in two surgical centres for the management of two types of rib fractures: flail chest and multiple dislocated rib fractures with significant chest wall deformity.
European journal of cardio-thoracic surgery: official journal of the European Association for Cardio-thoracic Surgery 09/2014; · 2.40 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Long acting β2-agonists (LABA) have been reported to modify the extracellular matrix (ECM) composition in the airway wall. Based on our earlier studies we here investigated the mechanism underlying the control of ECM modification by LABA in primary human airway smooth muscle cells. Cells were treated with formoterol or salmeterol (30minutes) before TGF-β1 stimulation (2-3 days) Using RT-PCT, immuno-blotting and ELISA the de novo synthesis and deposition of collagen type-I, -III, -IV and fibronectin were determined. Matrix metalloproteinases (MMP)-2 and -9 were analyzed by zymography. Both LABA activated cAMP and its corresponding transcription factor CREB within 60minutes and thus partly reduced TGF-β1-induced gene transcription of collagen type-I, -III, fibronectin and connective tissue growth factor (CTGF). The inhibitory effect of both LABA on collagen type-I and -III deposition involved a cAMP dependent mechanism, while the inhibitory effect of the two drugs on TGF-β1-induced fibronectin deposition and on CTGF secretion was independent of cAMP. Interestingly, none of the two LABA reduced CTGF-induced synthesis of collagen type-I or type-III deposition. In addition, none of the two LABA modified collagen type-IV deposition or the expression and activity of MMP-2 or MMP-9. Our results show that LABA can prevent de novo deposition of specific ECM components through cAMP dependent and independent signaling. However, they do not reduce all ECM components by the same mechanism and they do not reduce existing collagen deposits. This might explain some of the controversial reports on the anti-remodeling effect of LABA in chronic inflammatory lung diseases.
[Show abstract][Hide abstract] ABSTRACT: Chronic obstructive pulmonary disease (COPD) is a complex disease with various phenotypes. The simultaneous determination of multiple biomarkers reflecting different pathobiological pathways could be useful in identifying individuals with an increased risk of death. We derived and validated a combination of three biomarkers (adrenomedullin, arginine vasopressin and atrial natriuretic peptide), assessed in plasma samples of 385 patients, to estimate mortality risk in stable COPD. Biomarkers were analysed in combination and defined as high or low. In the derivation cohort (n = 142), there were 73 deaths during the 5-year follow-up. Crude hazard ratios for mortality were 3.0 (95% CI 1.8-5.1) for one high biomarker, 4.8 (95% CI 2.4-9.5) for two biomarkers and 9.6 (95% CI 3.3-28.3) for three high biomarkers compared with no elevated biomarkers. In the validation cohort (n = 243), 87 individuals died. Corresponding hazard ratios were 1.9 (95% CI 1.1-3.3), 3.1 (95% CI 1.8-5.4) and 5.4 (95% CI 2.5-11.4). Multivariable adjustment for clinical variables as well as the BODE (body mass index, airflow obstruction, dyspnoea, exercise capacity) index and stratification by the Global Initiative for Chronic Obstructive Lung Disease stages provided consistent results. The addition of the panel of three biomarkers to the BODE index generated a net reclassification improvement of 57.9% (95% CI 21.7-92.4%) and 45.9% (95% CI 13.9-75.7%) at 3 and 5 years, respectively. Simultaneously elevated levels of adrenomedullin, arginine vasopressin and atrial natriuretic peptide are associated with increased risk of death in patients with stable COPD.
European Respiratory Journal 07/2014; · 7.13 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Rationale: Invasive fungal disease (IFD) is a significant cause of morbidity and mortality in immunocompromised patients. Objectives: We hypothesize that galactomannan, a component of fungal cell wall, as measured in the bronchoalveolar lavage (BAL-GM) might be a diagnostic adjunct in hematological malignancies. Methods: 568 hematological cases undergoing diagnostic bronchoscopy due to respiratory symptoms and/or suspected IFD between 2009 and 2013 at a tertiary care center in Switzerland were included in this prospective, observational cohort study. We compared accuracy of the BAL-GM ELISA determination in predicting IFD as classified by the EORTC/MSG definition. Measurements and Main Results: BAL-GM was positive in 155 cases (29.2%). According to the EORTC/MSG criteria, IFD was classified as possible in 182 (34.3%), probable in 45 (8.5%) and proven 6 (1.1%). BAL-GM provided 50% sensitivity, 73.0% specificity, 16% PPV, and 93% NPV for diagnosing proven+probable IFD. Results were similar when antifungal treatment and radiologic suspicion of IFD were used as the gold standard. The AUC of the ROC curve (AUC) for the diagnosis of proven+probable IFD was 0.716 (95%CI 0.638-0.794, p<0.001). Conclusions: Galactomannan in the BAL had modest agreement with EORTC/MSG criteria for diagnosing invasive fungal disease in immunocompromised patients with a high degree of antifungal exposure.
American Journal of Respiratory and Critical Care Medicine 07/2014; · 11.99 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Reactive oxygen species (ROS) have been implemented in the etiology of pulmonary fibrosis (PF) in systemic sclerosis. In the bleomycin model, we evaluated the role of acquired mutations in mitochondrial DNA (mtDNA) and respiratory chain defects as a trigger of ROS formation and fibrogenesis. Adult male Wistar rats received a single intratracheal instillation of bleomycin and their lungs were examined at different time points. Ashcroft scores, collagen and TGFβ1 levels documented a delayed onset of PF by day 14. In contrast, increased malon dialdehyde as a marker of ROS formation was detectable as early as 24 hours after bleomycin instillation and continued to increase. At day 7, lung tissue acquired significant amounts of mtDNA deletions, translating into a significant dysfunction of mtDNA-encoded, but not nucleus-encoded respiratory chain subunits. mtDNA deletions and markers of mtDNA-encoded respiratory chain dysfunction significantly correlated with pulmonary TGFβ1 concentrations and predicted PF in a multivariate model.
[Show abstract][Hide abstract] ABSTRACT: IntroductionRapid and accurate risk stratification in patients with community-acquired pneumonia (CAP) is an unmet clinical need. Cortisol to dehydroepiandrosterone (DHEA) ratio was put forward as a prognostic marker in sepsis. We herein validated the prognostic value of the adrenal hormones DHEA, DHEA-Sulfate (DHEAS), cortisol/DHEA-, cortisol/DHEAS- and DHEA/DHEAS – ratios in patients with CAP.MethodsWe assessed severity of illness using the pneumonia severity index (PSI) and measured adrenal hormone concentrations in 179 serum samples of prospectively recruited patients hospitalized with CAP. We calculated spearman rank correlation, logistic regression analysis and Kaplan Meier curves to study associations of adrenal hormones and outcomes.ResultsThere was a significant correlation between PSI score and total cortisol (r = 0.24, p = 0.001), DHEAS (r = −0.23, p = 0.002), cortisol/DHEA (r = 0.23, p = 0.003), cortisol/DHEAS (r = 0.32, p = <0.0001) and DHEA/DHEAS (r = 0.20, p = 0.009). In age and gender adjusted logistic regression analysis, cortisol (OR: 2.8, 95% CI: 1.48–5.28) and DHEA (OR: 2.62, 95% CI: 1.28–5.34), but not DHEAS and the different ratios were associated with all-cause mortality. The discriminatory accuracy of cortisol and DHEA in ROC analysis (area under the curve) was 0.74 and 0.61. In Kaplan Meier analysis, patients in the highest deciles of cortisol and DHEA (p = 0.005 and p = 0.015), and to a lesser extent of cortisol/DHEAS ratio (p = 0.081) had a higher risk of death.ConclusionCortisol, DHEAS and their ratios correlate with CAP severity, and cortisol and DHEA predict mortality. Adrenal function in severe pneumonia may be an important factor for CAP outcomes.
PLoS ONE 06/2014; 9(6):e99518. · 3.53 Impact Factor
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[Show abstract][Hide abstract] ABSTRACT: The fully human anti-lipopolysaccharide (LPS) immunoglobulin M (IgM) monoclonal antibody panobacumab was developed as an adjunctive immunotherapy for the treatment of O11 serotype Pseudomonas aeruginosa infections. We evaluated the potential clinical efficacy of panobacumab in the treatment of nosocomial pneumonia. We performed a post-hoc analysis of a multicenter phase IIa trial (NCT00851435) designed to prospectively evaluate the safety and pharmacokinetics of panobacumab. Patients treated with panobacumab (n = 17), including 13 patients receiving the full treatment (three doses of 1.2 mg/kg), were compared to 14 patients who did not receive the antibody. Overall, the 17 patients receiving panobacumab were more ill. They were an average of 72 years old [interquartile range (IQR): 64-79] versus an average of 50 years old (IQR: 30-73) (p = 0.024) and had Acute Physiology and Chronic Health Evaluation II (APACHE II) scores of 17 (IQR: 16-22) versus 15 (IQR: 10-19) (p = 0.043). Adjunctive immunotherapy resulted in an improved clinical outcome in the group receiving the full three-course panobacumab treatment, with a resolution rate of 85 % (11/13) versus 64 % (9/14) (p = 0.048). The Kaplan-Meier survival curve showed a statistically significantly shorter time to clinical resolution in this group of patients (8.0 [IQR: 7.0-11.5] versus 18.5 [IQR: 8-30] days in those who did not receive the antibody; p = 0.004). Panobacumab adjunctive immunotherapy may improve clinical outcome in a shorter time if patients receive the full treatment (three doses). These preliminary results suggest that passive immunotherapy targeting LPS may be a complementary strategy for the treatment of nosocomial O11 P. aeruginosa pneumonia.
European Journal of Clinical Microbiology 05/2014; 33(10). · 2.54 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background. Bronchial smooth muscle cells (BSMC) are a major source of proinflammatory and proangiogenic cytokines and chemokines, including VEGF and CXC-chemokines. CXC-chemokines act primarily on neutrophils, mediating their recruitment to and activation at the site of inflammation. In humans, house-dust mite (HDM) allergens can cause asthmatic exacerbations and trigger an inflammatory response through protease-dependent mechanisms. Objective. We investigated the effect HDM extract on the release of pro-angiogenic and proinflammatory cytokines from BSMC.
Methods. Human primary BSMC were stimulated with HDM extract in the absence or presence of fetal calf serum (FCS). Twenty angiogenic cytokines were detected by a specific antibody array and modified protein levels were confirmed by ELISA. Neutrophil migration was measured using a 96-well Boyden chamber.
Results. ENA-78/CXCL5 protein levels in conditioned medium of BSMC stimulated with HDM extract were significantly reduced (n = 10, P < 0.05) but restored in the presence of 5% FCS. HDM extracts did not affect ENA-78/CXCL5 mRNA levels. Recombinant ENA-78/CXCL5 was degraded after incubation with HDM extracts (n = 7, P < 0.05) but restored after the addition of the serine protease AEBSF. Neutrophil migration towards recombinant ENA-78/CXCL5 was also reduced in the presence of HDM extract. Conclusion. HDM proteases degrade ENA-78/CXCL5. Thus exposure to HDM allergens may alter ENA-78/CXCL5 levels in the lungs and may affect angiogenesis and the inflammatory response in the airways of asthma patients.
Journal of Allergy 05/2014; 2014:673673.
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[Show abstract][Hide abstract] ABSTRACT: The major impetus for structured follow-up after primary treatment of localized non-small-cell lung cancer is both early detection and re-treatment of recurrent disease with a curative intent, and early detection and treatment of a secondary primary tumor. In patients with lung cancer, the significance of intensive follow-up is still under debate.
memo - Magazine of European Medical Oncology 05/2014; 7(2):97-101.
[Show abstract][Hide abstract] ABSTRACT: The prevalence of exertional hypoxemia in unselected COPD patients is unknown. Intermittent hypoxia leads to adrenomedullin (ADM) up regulation through the HIF-1 pathway. We aimed to assess the prevalence and the annual probability to develop exertional hypoxemia in stable COPD. We also hypothesized that increased ADM might be associated with exertional hypoxemia and envisioned that adding ADM to clinical variables might improve its prediction in COPD.
1233 6-minute walking tests and circulating proadrenomedullin levels from 574 patients with clinically stable, moderate to very severe COPD enrolled in a multinational cohort study and followed-up for 2 years were concomitantly analyzed.
The prevalence of exertional hypoxemia was 29.1%. In a matrix derived from a fitted-multi-state model, the annual probability to develop exertional hypoxemia was 21.6%. Exertional hypoxemia was associated with greater deterioration of specific domains of health-related QoL, higher severe exacerbation and death annual rates. In the logistic linear and conditional Cox-regression multivariable analyses, both FEV1% predicted and proADM proved independent predictors of exertional hypoxemia (p<0.001 for both). Adjustment for comorbidities, including cardiovascular disorders, and exacerbation-rate did not influence results. Relative to using FEV1% pred alone, adding proADM resulted in a significant improvement of the predictive properties (p=0.018). Based on the suggested non-linear nomogram, patients with moderate COPD (FEV1 predicted=50%) but high proADM levels (>2nmol/l) presented increased risk (>30%) for exertional desaturation.
Exertional desaturation is common and associated with poorer clinical outcomes in COPD. Adrenomedullin improves prediction of exertional desaturation as compared to the use of FEV1%pred alone.
[Show abstract][Hide abstract] ABSTRACT: B-cells in airways and lung parenchyma may be involved in COPD evolution. However, whether their pathogenic role is beneficial or harmful remains controversial. The objective of this study was to investigate the maturation of adenovirus-specific immunoglobulins in COPD patients in respect to clinical outcome.
The presence of adenovirus-specific immunoglobulins during acutely exacerbated COPD (AECOPD) was analyzed at exacerbation and 2-3 weeks later. Patients with detectable adenovirus-specific IgM and low IgG avidity were grouped into fast and delayed IgG maturation. The clinical outcome of both groups was evaluated.
Out of 208 patients, 43 patients (20.7%) had serologic evidence of recent adenovirus infection and were grouped into 26 patients with fast IgG maturation and 17 patients with delayed IgG maturation. Baseline characteristics, AECOPD therapy, and duration of hospitalization were similar in both groups. However, the AECOPD recurrence rate within six months was higher (p = 0.003) and there was a trend for earlier AECOPD related re-hospitalizations (p = 0.061) in patients with delayed IgG maturation. The time to re-hospitalization or death within two years was shorter in patients with delayed IgG maturation (p = 0.003). Adenovirus-specific IgG maturation was an independent predictor of both, the number of recurrent AECOPDs within six months (p = 0.001) and the occurrence of hospitalization or death within two years (p = 0.005).
Delayed immunoglobulin avidity maturation, following COPD exacerbation, is associated with worse outcome.
[Show abstract][Hide abstract] ABSTRACT: To the Editor:The course of sarcoidosis is heterogeneous, and the assessment of pulmonary and extrathoracic organ involvement is important for clinical treatment decisions (1). Whole-body imaging techniques have been evaluated to assess total disease activity (2, 3). (18)F-fluoro-2-deoxy-d-glucose positron emission tomography ((18)FDG-PET) and (18)FDG-PET/computed tomography (CT) allow a complete picture of active intra- and extrapulmonary sites (4). Whole-body magnetic resonance imaging (WB-MRI) is an established diagnostic tool for multifocal disorders such as multiple myeloma and metastatic diseases (5, 6). The role of WB-MRI in the assessment of extrathoracic organ involvement in patients with sarcoidosis has not yet been studied.We present an institutional review board-approved study including 24 patients with histologically confirmed sarcoidosis. Patients were recruited regardless of treatment, apparent extrapulmonary involvement and symptoms; written informed consent was obtained. To estimate extrapulmonary disease activity, the extrapulmonary physician organ severity tool (ePOST) was employed (7), scoring 17 organs (0: not affected; 6: very severely affected). Pulmonary function tests (PFTs) and serum levels of angiotensin-converting enzyme (ACE) and soluble interleukin-2 receptor (sIL-2R) were assessed. All subjects underwent WB-MRI on a clinical 1.5-T whole-body scanner with an 18-channel coil array system (Magnetom Avanto (Tim); Siemens Medical Solutions, Erlangen, Germany). The acquisition consisted of the following.
European Respiratory Journal 03/2014; · 7.13 Impact Factor