Endobronchial valve therapy for severe emphysema:an overview of valve-related complications and its management

Introduction Bronchoscopic lung volume reduction treatment with one-way valves is an effective guideline treatment option for patients with severe emphysema. However, important challenges and adverse reactions may occur after treatment. Areas covered This review summarizes the complications after endobronchial and intrabronchial valve treatment that have been described by the currently published randomized controlled trials and other relevant papers regarding the complications and its management. In case there was no relevant literature regarding these subjects, recommendations are based on expert opinion. Complications include pneumothorax, post-obstruction pneumonia and hemoptysis. Also, the treatment may not be effective due to the presence of collateral ventilation or misplaced valves. Furthermore, an initial beneficial effect may vanish due to granulation tissue formation, valve dysfunction or valve migration. Careful follow-up after treatment with valves is important. Evaluation with a CT-scan and/or bronchoscopy is needed if there is no improvement after treatment, loss of benefit, or occurrence of important adverse events during follow-up. Expert opinion Treating severe emphysema patients with one-way valves requires continuous dedication and expertise, especially to achieve an optimal outcome and elegantly deal with the various complications after treatment

Change in Dynamic Hyperinflation After Bronchoscopic Lung Volume Reduction in Patients with Emphysema

Background and Purpose In patients with severe emphysema, dynamic hyperinflation is superimposed on top of already existing static hyperinflation. Static hyperinflation reduces significantly after bronchoscopic lung volume reduction (BLVR). In this study, we investigated the effect of BLVR compared to standard of care (SoC) on dynamic hyperinflation. Methods Dynamic hyperinflation was induced by a manually paced tachypnea test (MPT) and was defined by change in inspiratory capacity (IC) measured before and after MPT. Static and dynamic hyperinflation measurements were performed both at baseline and 6 months after BLVR with endobronchial valves or coils (treatment group) or SoC (control group). Results Eighteen patients underwent BLVR (78% female, 57 (43-67) years, FEV(1)25(18-37) %predicted, residual volume 231 (182-376) %predicted). Thirteen patients received SoC (100% female, 59 (44-74) years, FEV(1)25 (19-37) %predicted, residual volume 225 (152-279) %predicted. The 6 months median change in dynamic hyperinflation in the treatment group was: + 225 ml (range - 113 to + 803) (p <0.01) vs 0 ml (- 1067 to + 500) in the control group (p = 0.422). An increase in dynamic hyperinflation was significantly associated with a decrease in residual volume (r = - 0.439,p <0.01). Conclusion Bronchoscopic lung volume reduction increases the ability for dynamic hyperinflation in patients with severe emphysema. We propose this is a consequence of improved static hyperinflation

The Safety and Feasibility of Re-treating Patients with Severe Emphysema with Endobronchial Coils:A Pilot Study

Severe emphysema patients who have been treated with endobronchial coils have been shown to initially benefit, but slowly decline in the years thereafter. Re-treating a patient with endobronchial coils could potentially lead to new improvements and may again reduce the rate of further decline. To our knowledge, until now, no results are published about patients who are re-treated. The primary aim of this study is to investigate the safety and feasibility of re-treating severe emphysema patients with endobronchial coils, using the PneumRx coil system. Furthermore, as secondary aim, we will evaluate the efficacy of re-treating these patients. Patients who at least 2 years ago were treated with endobronchial coils and responded clinically meaningful to this treatment were included in the study and re-treated. Safety was evaluated by the number of reported adverse events. Efficacy was evaluated 6 months after re-treatment, and measured by the change in quality of life, exercise capacity and pulmonary function testing. Eight patients were re-treated at a median of 1382 days (range 849-1545) after initial coil treatment with a median additional of 12 (10-15) coils per patient. During treatment, and until 6 months of follow-up, no unexpected adverse events occurred. Quality of life, exercise capacity and lung function did not change significantly 6 months after re-treatment. The results of this pilot study suggest that re-treating patients with endobronchial coils is feasible and safe. However, larger studies are needed to confirm these results and to investigate the efficacy and thus the clinical relevance

Affimers as an Alternative to Antibodies in an Affinity LC-MS Assay for Quantification of the Soluble Receptor of Advanced Glycation End-Products (sRAGE) in Human Serum

Antibodies are indispensable tools in biomedical research, but their size, complexity, and sometimes lack of reproducibility created a need for the development of alternative binders to overcome these limitations. Affimers are a novel class of affinity binders based on a structurally robust protease inhibitor scaffold (i.e. Cystatin A), which are selected by phage display and produced in a rapid and simple E. coli protein expression system. These binders have a defined amino acid sequence with defined binding regions and are versatile thereby allowing for easy engineering. Here we present an affimer-based liquid chromatography-mass spectrometry (LC-MS) method for quantification of the soluble Receptor of Advanced Glycation End-products (sRAGE), a promising biomarker for chronic obstructive pulmonary disease (COPD). The method was validated according to European Medicines Agency and U.S. Food and Drug Administration guidelines and enabled quantitation of serum sRAGE between 0.2 and 10 ng/mL. Comparison between the affimer-based method and a previously developed, validated antibody-based method showed good correlation (R2 = 0.88), and indicated that 25% lower sRAGE levels are reported by the affimer-based assay. In conclusion, we show the first-time application of affimers in a quantitative LC-MS method, which supports the potential of affimers as robust alternatives to antibodies

AGER expression and alternative splicing in bronchial biopsies of smokers and never smokers

Abstract Cigarette smoking is one of the major risk factors for the development of chronic obstructive pulmonary disease (COPD). Evidence is accumulating that Receptor for Advanced Glycation-End products (RAGE)-signaling is a key pathway in the pathophysiology of COPD. To date, it is unknown how smoking affects RAGE expression. In the current study, we investigated the effect of smoking on AGER, the gene encoding RAGE, expression and on alternative splicing of AGER. To this end, we conducted RNA-Seq on bronchial biopsies for asymptomatic smokers (n = 36) and never smokers (n = 40). Total AGER gene expression was accessed using DESeq2, while alternative splicing was investigated by measuring the number of specific split reads spanning exon-exon junctions and the total split reads. One of the major isoforms of RAGE is endogenous soluble (es) RAGE, an anti-inflammatory decoy receptor, making up for approximately 10% of the total amount of soluble (s)RAGE. We found that smokers show decreased total gene expression of AGER in bronchial biopsies, while the relative abundance of the esRAGE isoform is increased. Furthermore, no difference in the serum levels of total sRAGE were observed between smokers and non-smokers. Our data indicates that smoking initiates a protective anti-inflammatory mechanism with decreased expression of the pro-inflammatory gene AGER and increased relative abundance of the anti-inflammatory isoform esRAGE

Predicted values for the forced expiratory flow adjusted for forced vital capacity, a descriptive study

Background: The forced expiratory flows (FEFs) towards the end of the expiration may be more sensitive in detecting peripheral airways obstruction compared to the forced expiratory volume in 1 s and forced vital capacity (FVC). However, they are highly variable. A partial solution is to adjust the FEFs for FVC (FEF/FVC). Here we provide reference equations for these adjusted FEFs at 25%, 50%, 75% and 25-75% of FVC, which are currently lacking. Methods: We included pulmonary healthy, never-smoker adults; 14 472 subjects from Lifelines, a biobank for health research, and 338 subjects from the department's control cohorts (NORM and Fiddle). Reference equations were obtained by linear regression on 80% of the Lifelines dataset and validated on the remaining data. The best model was defined as the one with the highest adjusted R2-value. The difference in variability between adjusted and unadjusted FEFs was evaluated using the coefficient of variation. Results: For all adjusted FEFs, the best model contained age, height and weight. The adjustment improved the coefficient of variation of the FEF75 from 39% to 36% and from 43% to 40%, respectively, in males and females. The highest percentage of explained variance by the reference equation was obtained for FEF75/FVC, 32%-38% for males, and 41%-46% for females, depending on the validation set. Conclusion: We developed reference equations for FVC-adjusted FEF values. We demonstrated minimally yet significantly improved variability. Future studies in obstructive airway diseases should demonstrate whether it is worthwhile to use these (predicted) adjusted FEF values

Prioritization of COPD protein biomarkers, based on a systematic study of the literature

Chronic Obstructive Pulmonary Disease (COPD) is a chronic lung disease mostly due to smoking and until now diagnosed by spirometry (post bronchodilator FEV1/FVC <70%). However, in spite of the usefulness of FEV1 as diagnostic and prognostic tool, it has proven to be a weak indicator of future exacerbations, unable to predict lung function decline within COPD patients, as well as unable to identify the smokers “susceptible” to developing COPD at an early stage. Thus, there is an urgent need for biomarkers that address these questions and support clinical decision making in the diagnosis and treatment of (early) COPD. In this respect, considerable efforts have been devoted to identifying protein biomarkers that enable a better understanding of this complex disease and leading to better diagnostic and prognostic tools. However, in spite of the wide range of candidates that have been suggested as potentially useful COPD biomarkers, most remained at the level of the initial discovery, and only fibrinogen has been approved by the Food and Drug Administration (FDA) as predictor for all-cause mortality and COPD exacerbations. There is thus a need for future investigations of these biomarkers in large-scale and well characterized studies in order to prove their usefulness as surrogate endpoints. Based on this, the aim of the present review is to advance COPD biomarker development by providing a comprehensive overview of protein biomarker candidates which have been evaluated in clinical studies and prioritize them according to their potential of becoming valid, clinically useful COPD biomarkers

Quantification of the soluble Receptor of Advanced Glycation End-Products (sRAGE) by LC-MS after enrichment by strong cation exchange (SCX) solid-phase extraction (SPE) at the protein level

The study of low abundant proteins contributes to increasing our knowledge about (patho) physiological processes and may lead to the identification and clinical application of disease markers. However, studying these proteins is challenging as high-abundant proteins complicate their analysis. Antibodies are often used to enrich proteins from biological matrices prior to their analysis, though antibody-free approaches have been described for some proteins as well. Here we report an antibody-free workflow on the basis of strong cation exchange (SCX) enrichment and liquid chromatography-mass spectrometry (LC-MS) for quantification of the soluble Receptor of Advanced Glycation End-products (sRAGE), a promising biomarker in chronic obstructive pulmonary disease (COPD). sRAGE was quantified in serum at clinically relevant low to sub ng mL(-1) levels. The method was validated according to U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA) guidelines and was compared to an antibody-based LC-MS sRAGE method. The SCX-based method builds upon the bipolar charge distribution of sRAGE, which has a highly basic N-terminal part and an acidic C-terminal part resulting in an overall neutral isoelectric point (pI). The highly basic N-terminal part (pI(calculated) = 10.3) allowed for sRAGE to be enriched by SCX at pH 10, a pH at which most serum proteins do not bind. This study shows that ion exchange-based enrichment is a viable approach for the LC-MS analysis of several low abundant proteins following a thorough analysis of their physical-chemical properties. (C) 2018 The Authors. Published by Elsevier B.V