Performance monitoring of EBUS for the staging and diagnosis of lung cancer: auditing the Greater Manchester EBUS service against new national standards.

INTRODUCTION: Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is a pivotal test in lung cancer staging and diagnosis, mandating robust audit and performance monitoring of EBUS services. We present the first regional cancer alliance EBUS performance audit against the new National EBUS specification. METHODS: Across the five EBUS centres in the Greater Manchester Cancer Alliance, data are recorded at the point of procedure, when pathological results are available and at 6 months postprocedure to review any further pathological sampling (eg, at surgical resection) and the outcome of clinical-radiological follow-up. Outcomes across all five centres were compared with national standards for all lung cancer EBUS procedures from 01 January 2017 to 31 December 2018. RESULTS: 1899 lung cancer staging or diagnostic EBUS procedures were performed across the five centres during the study period; 1309 staging EBUS procedures and 590 diagnostic EBUS procedures. Major complications were seen in six cases (<1%). All five trusts demonstrated performance above that set national standards in key metrics for both staging and diagnostic EBUS, however the provision of adequate tissue for predictive marker testing was below national standards at one trust. Across Greater Manchester, 72% and 64% of patients had their EBUS procedure performed within 7 days of referral in 2017 and 2018, respectively. Only one out of five trusts met the national targets of >85% of procedures performed within 7 days of referral. CONCLUSION: The National EBUS service specification is an important framework to drive the quality of EBUS services across the UK. Our data provide assurance of appropriate performance and safety while also highlighting specific areas for attention that can be addressed with the support of the cancer alliance.

EBUS-guided mediastinal lung cancer staging: monitoring of quality standards improves performance.

This audit examined key performance indices related to endobronchial ultrasound (EBUS)-guided mediastinal lung cancer staging before and after the introduction of defined quality standards, at four independent EBUS centres in one cancer network. Data from 642 procedures were prospectively collected and analysed. The introduction of standards was associated with a significant increase (p<0.001) in sampling of key mediastinal lymph node stations (4R, 4L and 7) and a reduction in the variability of staging sensitivity between centres. These data reinforce the requirement for an appropriate regulatory framework for EBUS-transbronchial needle aspiration provision that includes quality assurance and performance monitoring.

A randomized, placebo-controlled study of the effects of the p38 MAPK inhibitor SB-681323 on blood biomarkers of inflammation in COPD patients.

The p38 mitogen-activated protein kinase (MAPK) signaling upregulates inflammation and is known to be increased in chronic obstructive pulmonary disease (COPD). The authors assessed the pharmacology of the novel p38 MAPK inhibitor SB-681323 using blood biomarkers in COPD. Seventeen COPD patients (forced expiratory volume in 1 second 50%-80% predicted) using short-acting bronchodilators participated in a double-blind, double-dummy, randomized, crossover study. Patients received single oral doses of SB-681323 7.5 mg and 25 mg, prednisolone 10 mg and 30 mg, and placebo. Blood was obtained predose and at 1, 2, 6, and 24 hours postdose. Whole-blood sorbitol-induced phosphorylated (p) heat shock protein (HSP) 27 levels as a marker of p38 pathway activation and lipopolysaccharide-induced tumor necrosis factor (TNF)-alpha production were assessed. Both doses of SB-681323, but not prednisolone, significantly (P < .0001) reduced weighted mean (WM) pHSP27 (0-6 hours) by 58% compared with placebo. WM TNF-alpha production (0-24 hours) was significantly reduced compared with placebo by SB-681323 25 mg (40%, P = .005) and 7.5 mg (33.4%, P = .02), while prednisolone 30 mg and 10 mg caused 81.5% and 58.2% suppression, respectively (both P < .0001). SB-681323 inhibited the p38 MAPK pathway to a greater degree than prednisolone did. SB-681323 inhibited TNF-alpha production. SB-681323 is a potent p38 MAPK inhibitor that potentially suppresses inflammation in COPD.

COPD phenotype description using principal components analysis.

BACKGROUND: Airway inflammation in COPD can be measured using biomarkers such as induced sputum and Fe(NO). This study set out to explore the heterogeneity of COPD using biomarkers of airway and systemic inflammation and pulmonary function by principal components analysis (PCA). SUBJECTS AND METHODS: In 127 COPD patients (mean FEV1 61%), pulmonary function, Fe(NO), plasma CRP and TNF-alpha, sputum differential cell counts and sputum IL8 (pg/ml) were measured. Principal components analysis as well as multivariate analysis was performed. RESULTS: PCA identified four main components (% variance): (1) sputum neutrophil cell count and supernatant IL8 and plasma TNF-alpha (20.2%), (2) Sputum eosinophils % and Fe(NO) (18.2%), (3) Bronchodilator reversibility, FEV1 and IC (15.1%) and (4) CRP (11.4%). These results were confirmed by linear regression multivariate analyses which showed strong associations between the variables within components 1 and 2. CONCLUSION: COPD is a multi dimensional disease. Unrelated components of disease were identified, including neutrophilic airway inflammation which was associated with systemic inflammation, and sputum eosinophils which were related to increased Fe(NO). We confirm dissociation between airway inflammation and lung function in this cohort of patients.

The repeatability of interleukin-6, tumor necrosis factor-alpha, and C-reactive protein in COPD patients over one year.

BACKGROUND: Many of the systemic manifestations of chronic obstructive pulmonary disease (COPD) are mediated through increased systemic levels of inflammatory proteins. We assessed the long term repeatability of interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), and C-reactive protein (CRP) over one year and examined the relationships between these systemic markers in COPD. METHODS: Fifty-eight stable COPD patients completed a baseline and one-year visit. Serum IL-6, plasma CRP, and plasma TNF-alpha were measured. Repeatability was expressed by intraclass correlation coefficient (R(i)) and the Bland-Altman method. Pearson correlations were used to determine the relationships between the systemic markers at both visits. RESULTS: There was moderate repeatability with a very high degree of statistical significance (p

Reduced exhaled breath condensate pH in asthmatic smokers using inhaled corticosteroids.

BACKGROUND AND OBJECTIVES: Exhaled breath condensate (EBC) pH has been proposed as a biomarker of airway inflammation and oxidative stress in asthma. Cigarette smoking reduces EBC pH in mild asthma. The effects of smoking on EBC pH in more symptomatic asthmatic patients using inhaled corticosteroids (ICS) are unknown. We aimed to compare EBC pH in asthmatic smokers (AS) and non-smokers (ANS) with moderate to severe disease, who were taking ICS. We also investigated the relationship between EBC pH and biomarkers of airway inflammation and oxidative stress. METHODS: AS (n = 18) and ANS (n = 17), who were using ICS, were recruited and EBC pH, sputum inflammatory cell counts and sputum supernatant 8-isoprostane concentrations were measured. Full lung function testing was performed. RESULTS: EBC pH was significantly lower in AS than in ANS (6.91 vs 7.41). In AS there was a significant inverse correlation between EBC pH and 8-isoprostane levels (r = -0.54, P = 0.03). There was no correlation between EBC pH and sputum neutrophil counts. CONCLUSIONS: EBC pH appears to be a biomarker of the level of oxidative stress in smokers with moderate to severe asthma. EBC pH may have applications for the longitudinal monitoring of the effects of smoking on the airways of asthmatic patients.

Non-invasive biomarkers and pulmonary function in smokers.

Limited information exists regarding measurement, reproducibility and interrelationships of non-invasive biomarkers in smokers. We compared exhaled breath condensate (EBC) leukotriene B4 (LTB4) and 8-isoprostane, exhaled nitric oxide, induced sputum, spirometry, plethysmography, impulse oscillometry and methacholine reactivity in 18 smokers and 10 non-smokers. We assessed the relationships between these measurements and within-subject reproducibility of EBC biomarkers in smokers. Compared to non-smokers, smokers had significantly lower MMEF % predicted (mean 64.1 vs 77.7, p = 0.003), FEV1/FVC (mean 76.2 vs 79.8 p = 0.05), specific conductance (geometric mean 1.2 vs 1.6, p = 0.02), higher resonant frequency (mean 15.5 vs 9.9, p = 0.01) and higher EBC 8-isoprostane (geometric mean 49.9 vs 8.9 pg/ml p = 0.001). Median EBC pH values were similar, but a subgroup of smokers had airway acidification (pH < 7.2) not observed in non-smokers. Smokers had predominant sputum neutrophilia (mean 68.5%). Repeated EBC measurements showed no significant differences between group means, but Bland Altman analysis showed large individual variability. EBC 8-isoprostane correlated with EBC LTB4 (r = 0.78, p = 0.0001). Sputum supernatant IL-8 correlated with total neutrophil count per gram of sputum (r = 0.52, p = 0.04) and with EBC pH (r = -0.59, p = 0.02). In conclusion, smokers had evidence of small airway dysfunction, increased airway resistance, reduced lung compliance, airway neutrophilia and oxidative stress.

A comparison of exhaled nitric oxide measurements performed using three different analysers.

INTRODUCTION: Exhaled nitric oxide (NO) is an established technique for monitoring airway inflammation. We have compared exhaled NO measurements from 3 different analysers; Ecomedics (E), Niox (N) and Logan (L). METHODS: Thirty subjects (10 non-smoking healthy subjects, 10 non-smoking patients with asthma and 10 ex-smoking COPD patients) performed 3 repeated measurements of exhaled NO at a flow rate of 50 ml/s on each of the 3 analysers. Within analyser variability was determined by calculating the repeatability coefficient for each analyser. Differences between analysers were assessed by (1) the differences between group means and (2) the Bland Altman method to estimate the variability expected for an individual using the 3 analysers. RESULTS: The repeatability coefficients (expressed as ratios) were 1.12, 1.19 and 1.19 for N, E and L, respectively. There were significant differences (P<0.05) between analysers; the Logan analyser gave the highest group mean values and Ecomedics gave the lowest group mean values. Differences between analysers were observed in all subject groups (healthy, asthma, COPD). Similar results were obtained in the 3 groups when analysed separately. Bland Altman analysis gave the following ratios [data are mean ratio (95% limits of agreement)]; N:E 1.59 (1.02-2.50), L:N 1.23 (0.72-2.13), L:E 1.96 (1.09-3.57). CONCLUSION: Our findings indicate that exhaled NO measurements in healthy subjects and patients with airways disease differ according to the type of analyser used.

The potential for bronchoscopic lung volume reduction using bronchial prostheses: a pilot study.

STUDY OBJECTIVES: Significant morbidity and mortality offset the benefits of lung volume reduction surgery (LVRS) for emphysema. By contributing to distal lung collapse, bronchoscopic placement of valved prostheses has the potential to noninvasively replicate the beneficial effects of LVRS. The purpose of this study was to investigate the safety and feasibility of placing valves in segmental airways of patients with emphysema. DESIGN: Case series. SETTING: Tertiary hospital, severe airways disease clinic. PATIENTS: Ten patients aged 51 to 69 years with apical emphysema and hyperinflation, otherwise suitable for standard LVRS. Mean preoperative FEV(1) was 0.72 L (19 to 46% predicted), and 6-min walk distance was 340 m (range, 245 to 425 m). INTERVENTION: Apical, bronchoscopic, segmental airway placement of one-way valves (silicone-based Nitinol bronchial stent; Emphasys Medical; Redwood City, CA) under general anesthesia. Placement was over a guidewire under bronchoscopic and fluoroscopic control. RESULTS: Four to 11 prostheses per patient took 52 to 137 min to obstruct upper-lobe segments bilaterally. Inpatient stay was 1 to 8 days. No major complications were seen in the 30-day study period. Minor complications included exacerbation of COPD (n = 3), asymptomatic localized pneumothorax (n = 1), and lower-lobe pneumonia (day 37; n = 1). Symptomatic improvement was noted in four patients. No major change in radiologic findings, lung function, or 6-min walk distance was evident at 1 month, although gas transfer improved from 7.47 +/- 2.0 to 8.26 +/- 2.6 mL/min/mm Hg (p = 0.04) and nuclear upper-lobe perfusion fell from 32 +/- 10 to 27 +/- 9% (mean +/- SD) [p = 0.02]. CONCLUSION: Bronchoscopic prostheses can be safely and reliably placed into the human lung. Further study is needed to explore patient characteristics that determine symptomatic efficacy in a larger patient cohort.