Impact of surgical and of bronchoscopic lung volume reductions in patients with emphysema and hyperinflation on lung structure, function and inflammation

Background – A robust biomarker for predicting and evaluating the response to lung volume reduction (LVR) interventions remains elusive. We investigated the hypothesis that LVR will be accompanied by measurable changes in novel indices of lung structure, function, and inflammation that can be correlated with changes to the conventional clinical parameters and that reliable identifiers of baseline predictors of therapeutic response (minimal clinically important difference, MCID, of at least 10% reduction of residual volume) will be identified. Methods – 72 consecutive subjects with severe emphysema and hyperinflation scheduled for lung volume reductions were recruited: lung volume reduction surgery (LVRS) – 15; Endobronchial valve (EBV) – 29, Endobronchial coil (EBC) – 28. All underwent detailed clinical phenotyping comprising demographics, symptom scores, computed tomography imaging, exercise capacity and lung function measurements during exacerbation-free periods at baseline and at three months after intervention. Novel techniques including quantitative computed tomography (qCT), impulse oscillometry (IOS) and multiple breath nitrogen washout (MBNW), and microvesicle quantification were employed to assess changes in lung structure, function and inflammation, respectively. Results – Surgery achieved the greatest lung volume reductions, △residual volume (RV) of -1.26 ± 0.58 litres (p<0.01), and more than 90% of recipients met the MCID of ≥10% RV reduction. It was the only intervention to be accompanied by improvements in functional gas trapping on CT, IOS expiratory airways resistance at 5Hz, expiratory and within-breath reactance at 5Hz, and peripheral resonant frequency, attributable to recovery of small airways function. Valve implantations reduced residual volume by -0.91 ± 0.66 litres (p<0.01) and 62% of recipients attained the MCID of ≥10% RV reduction. This was in addition to a smaller reduction in IOS expiratory and within-breath reactance at 5Hz without an accompanying signal in resistance, resonant frequency, or functional gas trapping on CT. Modest improvements to alveolar gas mixing (AME) and small airways function (Sacin) were measured using MBNW in a subset of patients. These data suggest the impact of valves on the peripheral airway compartment was less pronounced than with surgery and was achieved predominantly by deflation of emphysematous lung tissue and restoration of the mechanical pump. Coil implantations resulted in modest volume reductions, △residual volume of -0.31 ± 0.60L (p=0.01): Only 35% of subjects achieved the MCID of ≥10% RV reduction. Three-month physiological outcomes were similarly disappointing with improvements limited to CT-intraparenchymal blood vessel volume (perhaps due to greater radial traction exerted by the coils on the surrounding parenchyma) and the area under reactance during expiration (AXex) on IOS. The comparatively minor degree of volume reduction achieved (and the fall in gas transfer) using this technique may explain the relatively small impact on peripheral airways function. An inflammatory sub-study identified a variety of microvesicle (MV) populations in bronchoalveolar lavage fluid (BALF) and in the plasma of patients with mild to very severe COPD. Of these, polymorphouclear (neutrophil)-derived MVs were found to be substantially increased in BALF and their numbers correlated with airflow limitation, reduced exercise capacity, impaired of quality of life, and the BODE index. BALF neutrophil-derived MVs correlated with BALF neutrophil cell numbers but not with circulating neutrophil MV numbers, implying local alveolar release rather than translocation from the circulation. BALF neutrophil-derived MVs were also shown to be a more robust biomarker of disease severity than BALF neutrophil cell and cytokine levels. In a subset of valve and coil recipients, BALF-neutrophil derived MV levels were evaluated before and after intervention. Mean volume reduction in the coil recipients was exceeded threefold by that of the valve beneficiaries. Unexpectedly there was no statistically significant change in MV numbers at three months in the valve arm. Possible explanations include contamination from more proximal airway sampling / spill over from the ipsilateral lobe(s) or induction of a localised inflammatory response to biofilm formation overlying the nitinol-silicone implants. In contrast, a statistically significant fall in MV numbers was observed in the coil cohort in the absence of clinically meaningful volume reduction. It must however be borne in mind that despite the thin profile of the nitinol endobronchial coil, the surface area of the airway epithelium exposed to sampling is reduced. There were no identifiable predictors of therapeutic response among the novel indices of lung structure, function, and inflammation analysed. Conclusions – The degree of lung volume reduction achieved is critical in determining favourable clinical outcomes for patients with severe emphysema and hyperinflation. Similarly, the structural and functional impacts of lung volume reduction on the small airways compartment, the principal site of airflow obstruction, are proportional to the degree of volume reduction achieved (surgery > valves > coils). The impact of these therapies on airways inflammation requires further scrutiny. qCT and IOS qualify as structural and functional biomarkers, respectively, for evaluating volume reduction – however, their predictive value for therapeutic response is not established from this small dataset. BALF neutrophil-derived MV observations are potentially useful contributors to disease phenotyping alongside lung function tests and qCT imaging – their role as biomarkers for predicting and assessing therapeutic response remains to be seen. Larger randomised controlled trial designs are recommended to further investigate these preliminary findings.Open Acces

New bronchoscopic treatment modalities for patients with chronic bronchitis

Chronic bronchitis is a chronic, progressive disease that is difficult to treat. Despite much effort, patients remain highly symptomatic. Currently, a number of innovative bronchoscopic treatments for this disease are under investigation. Liquid nitrogen metered cryospray, bronchial rheoplasty and balloon desobstruction all aim to destroy the hyperplastic goblet cells and excess submucous glands using different strategies. These therapies are in an early phase of clinical research and larger randomised controlled trials are needed to confirm the pilot data available and to evaluate the treatment durability. The fourth technique, targeted lung denervation (TLD), aims to decrease the release of acetylcholine, which regulates smooth muscle tone and mucus production by ablating the parasympathetic nerves running alongside the main bronchi. Evaluation of this treatment is at a more advanced stage and promising effects on exacerbation frequency have been shown. However, confirmation of the benefit in improvement in chronic bronchitis symptoms is still needed

Knowledge, attitudes, and practices regarding ticks, tick-borne pathogens, and tick prevention among beef producers in Oklahoma

Tick-borne diseases are increasing in the United States, with regional need to understand how knowledge of ticks translates into preventative behavior among specific occupational groups. Little is known regarding what livestock producers know about ticks and their perceived personal and herd-based risk despite being one of the largest agro-industries in the United States. Using a nonprobability convenience sampling protocol, 183 beef producers representing 65% of the counties in Oklahoma completed a 15-question survey focused on knowledge of ticks and perceived risks ticks pose to their cattle and themselves, their methods of prevention (personal and their cattle), and sources of information. Most producers thought ticks were not a major problem for their cattle (58%), themselves, their families, and those who worked for them (66%). Most were personally concerned about spotted fever group rickettsiosis (79%) but had never heard of ehrlichiosis (9%). Eighty-five percent used at least one type of personal protective behavior, and 86% used at least one source of information for issues with ticks on their cattle. As the first published tick-focused survey involving livestock producers in the United States, it is apparent that beef producers in the central region are cognizant of ticks on their cattle and perceive ticks to be a risk on some level. However, increasing their knowledge of all areas of ticks and tick-borne pathogens, especially preventative measures for humans and cattle, is needed.Peer reviewedEntomology and Plant PathologyAnimal and Food Science

Domains within RbpA serve specific functional roles that regulate the expression of distinct mycobacterial gene subsets

The RNA polymerase (RNAP) binding protein A (RbpA) contributes to the formation of stable RNAP-promoter open complexes (R

A prospective safety and feasibility study of metered cryospray for patients with chronic bronchitis in COPD

BACKGROUND: No currently approved intervention counteracts airway metaplasia and mucus hypersecretion of Chronic Bronchitis (CB) in COPD. Metered Cryospray (MCS) delivering liquid nitrogen (LN2) to the tracheobronchial airways ablates abnormal epithelium and facilitates healthy mucosal regeneration. The objective of this study was to evaluate the feasibility, efficacy and safety of MCS in CB. METHODS: Patients with a FEV1, 30-80% of expected, taking optimal medication were recruited. Primary outcomes: feasibility - completion of treatments; efficacy - 3-month change in St George's Respiratory Questionnaire (SGRQ); safety - incidence of adverse events (AEs). SECONDARY OUTCOMES: lung function, exercise capacity, additional patient-reported outcomes (PROs). RESULTS: 35 patients, 19 male/16 female, aged 47-76 years, GOLD grade I (3), II (10) and III (22), underwent staggered LN2 treatments to the tracheobronchial tree.34 patients completed three treatments, each lasting 34·3±12·1 min, separated by 4-6 weeks: one withdrew after the first treatment. Approximately 1800 doses of MCS were delivered.Clinically meaningful improvements in PROs were observed at 3-months; ΔSGRQ -6·4 [95% CI -11.4, -1.3; p=0·01], COPD Assessment Test (CAT) -3·8 [95% CI -6.4, -1.3; p<0·01] and Leicester Cough Questionnaire (LCQ) 21·6 [95% CI 7.3, 35.9; p<0·01]. CAT changes were durable to 6-months (-3·4 [95% CI -5.9, -0.9; p=0·01]), SGRQ and LCQ to 9-months (-6·9 [95% CI -13.0, -0.9; p=0·03] and 13·4 [95% 2.1, 24.6; p=0·02], respectively).At 12-months, 14 serious AEs were recorded in 11 (31·4%) subjects, 6 moderate (43%) and 8 severe (57%). 9 were respiratory-related: 6 exacerbations of COPD, 2 pneumonias, and 1, increased coughing, recovered without sequelae. None were serious device or procedure-related AEs. CONCLUSION: MCS is safe, feasible and associated with clinically meaningful improvements in multidimensional PROs

Identifying Responders and Exploring Mechanisms of Action of the Endobronchial Coil Treatment for Emphysema

Background: So far, 3 randomized controlled trials have shown that the endobronchial treatment using coils is safe and effective. However, the more exact underlying mechanism of the treatment and best predictors of response are unknown. Objectives: The aim of the study was to gain more knowledge about the underlying physiological mechanism of the lung volume reduction coil treatment and to identify potential predictors of response to this treatment. Methods: This was a prospective nonrandomized single-center study which included patients who were bilaterally treated with coils. Patients underwent an extensive number of physical tests at baseline and 3 months after treatment. Results: Twenty-four patients (29% male, mean age 62 years, forced expiratory volume in 1 s [FEV1] 26% pred, residual volume (RV) 231% pred) were included. Three months after treatment, significant improvements were found in spirometry, static hyperinflation, air trapping, airway resistance, treated lobe RV and treated lobes air trapping measured on CT scan, exercise capacity, and quality of life. The change in RV and airway resistance was significantly associated with a change in FEV1, forced vital capacity, air trapping, maximal expiratory pressure, dynamic compliance, and dynamic hyperinflation. Predictors of treatment response at baseline were a higher RV, larger air trapping, higher emphysema score in the treated lobes, and a lower physical activity level. Conclusions: Our results confirm that emphysema patients benefit from endobronchial coil treatment. The primary mechanism of action is decreasing static hyperinflation with improvement of airway resistance which consequently changes dynamic lung mechanics. However, the right patient population needs to be selected for the treatment to be beneficial which should include patients with severe lung hyperinflation, severe air trapping, and significant emphysema in target lobes

Safety of denervation following targeted lung denervation therapy for COPD:AIRFLOW-1 3-year outcomes

Background Targeted lung denervation (TLD) is a novel bronchoscopic therapy that disrupts parasympathetic pulmonary nerve input to the lung reducing clinical consequences of cholinergic hyperactivity. The AIRFLOW-1 study assessed safety and TLD dose in patients with moderate-to-severe, symptomatic COPD. This analysis evaluated the long-term impact of TLD on COPD exacerbations, pulmonary function, and quality of life over 3 years of follow up. Methods TLD was performed in a prospective, energy-level randomized (29 W vs 32 W power), multicenter study (NCT02058459). Additional patients were enrolled in an open label confirmation phase to confirm improved gastrointestinal safety after procedural modifications. Durability of TLD was evaluated at 1, 2, and 3 years post-treatment and assessed through analysis of COPD exacerbations, pulmonary lung function, and quality of life. Results Three-year follow-up data were available for 73.9% of patients (n = 34). The annualized rate of moderate to severe COPD exacerbations remained stable over the duration of the study. Lung function (FEV1, FVC, RV, and TLC) and quality of life (SGRQ-C and CAT) remained stable over 3 years of follow-up. No new gastrointestinal adverse events and no unexpected serious adverse events were observed. Conclusion TLD in COPD patients demonstrated a positive safety profile out to 3 years, with no late-onset serious adverse events related to denervation therapy. Clinical stability in lung function, quality of life, and exacerbations were observed in TLD treated patients over 3 years of follow up

Legume abundance along successional and rainfall gradients in Neotropical forests

The nutrient demands of regrowing tropical forests are partly satisfied by nitrogen-fixing legume trees, but our understanding of the abundance of those species is biased towards wet tropical regions. Here we show how the abundance of Leguminosae is affected by both recovery from disturbance and large-scale rainfall gradients through a synthesis of forest inventory plots from a network of 42 Neotropical forest chronosequences. During the first three decades of natural forest regeneration, legume basal area is twice as high in dry compared with wet secondary forests. The tremendous ecological success of legumes in recently disturbed, water-limited forests is likely to be related to both their reduced leaflet size and ability to fix N2, which together enhance legume drought tolerance and water-use efficiency. Earth system models should incorporate these large-scale successional and climatic patterns of legume dominance to provide more accurate estimates of the maximum potential for natural nitrogen fixation across tropical forests.Additional co-authors: Rebecca J. Cole, Gabriel Dalla Colletta, Ben de Jong, Julie S. Denslow, Saara J. DeWalt, Juan Manuel Dupuy, Sandra M. Durán, Mário Marcos do Espírito Santo, G. Wilson Fernandes, Yule Roberta Ferreira Nunes, Bryan Finegan, Vanessa Granda Moser, Jefferson S. Hall, José Luis Hernández-Stefanoni, André B. Junqueira, Deborah Kennard, Edwin Lebrija-Trejos, Susan G. Letcher, Madelon Lohbeck, Erika Marín-Spiotta, Miguel Martínez-Ramos, Jorge A. Meave, Duncan N. L. Menge, Francisco Mora, Rodrigo Muñoz, Robert Muscarella, Susana Ochoa-Gaona, Edith Orihuela-Belmonte, Rebecca Ostertag, Marielos Peña-Claros, Eduardo A. Pérez-García, Daniel Piotto, Peter B. Reich, Casandra Reyes-García, Jorge Rodríguez-Velázquez, I. Eunice Romero-Pérez, Lucía Sanaphre-Villanueva, Arturo Sanchez-Azofeifa, Naomi B. Schwartz, Arlete Silva de Almeida, Jarcilene S. Almeida-Cortez, Whendee Silver, Vanessa de Souza Moreno, Benjamin W. Sullivan, Nathan G. Swenson, Maria Uriarte, Michiel van Breugel, Hans van der Wal, Maria das Dores Magalhães Veloso, Hans F. M. Vester, Ima Célia Guimarães Vieira, Jess K. Zimmerman & Jennifer S. Power

Effect of Zephyr Endobronchial Valves on Dyspnea, Activity Levels, and Quality of Life at One Year Results from a Randomized Clinical Trial

Rationale: Bronchoscopic lung volume reduction with Zephyr Valves improves lung function, exercise tolerance, and quality of life of patients with hyperinflated emphysema and little to no collateral ventilation. Objectives: Post hoc analysis of patient-reported outcomes (PROs), including multidimensional measures of dyspnea, activity, and quality of life, in the LIBERATE (Lung Function Improvement after Bronchoscopic Lung Volume Reduction with Pulmonx Endobronchial Valves used in Treatment of Emphysema) study are reported. Methods: A total of 190 patients with severe heterogeneous emphysema and little to no collateral ventilation in the target lobe were randomized 2:1 to the Zephyr Valve or standard of care. Changes in PROs at 12 months in the two groups were compared: dyspnea with the Transitional Dyspnea Index (TDI), focal score; the Chronic Obstructive Pulmonary Disease Assessment Test (CAT; breathlessness on hill/stairs); Borg; the EXAcerbations of Chronic pulmonary disease Tool-PRO, dyspnea domain; activity with the TDI, magnitude of task/effort/functional impairment, CAT (limited activities), and the St. George's Respiratory Questionnaire (SGRQ), activity domain; and psychosocial status with the SGRQ, impacts domain, and CAT (confidence and energy). Results: At 12 months, patients using the Zephyr Valve achieved statistically significant and clinically meaningful improvements in the SGRQ; CAT; and the TDI, focal score, compared with standard of care. Improvements in the SGRQ were driven by the impacts and activity domains (P, 0.05 and P, 0.001, respectively). Reduction in CAT was through improvements in breathlessness (P, 0.05), energy level (P, 0.05), activities (P, 0.001), and increased confidence when leaving home (P, 0.05). The TDI measures of effort, task, and functional impairment were uniformly improved (P, 0.001). The EXAcerbations of Chronic Pulmonary Disease Tool (EXACT)-PRO, dyspnea domain, was significantly improved in the Zephyr Valve group. Improvements correlated with changes in residual volume and residual volume/TLC ratio. Conclusions: Patients with severe hyperinflated emphysema achieving lung volume reductions with Zephyr Valves experience improvements in multidimensional scores for breathlessness, activity, and psychosocial parameters out to at least 12 months

The Power of Play: A Pediatric Role in Enhancing Development in Young Children

Children need to develop a variety of skill sets to optimize their development and manage toxic stress. Research demonstrates that developmentally appropriate play with parents and peers is a singular opportunity to promote the social-emotional, cognitive, language, and self-regulation skills that build executive function and a prosocial brain. Furthermore, play supports the formation of the safe, stable, and nurturing relationships with all caregivers that children need to thrive