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

Abstract

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