David Parr

Outcomes for COPD pharmacological trials: from lung function to biomarkers

The American Thoracic Society/European Respiratory Society jointly created a Task Force on “Outcomes for COPD pharmacological trials: from lung function to biomarkers” to inform the chronic obstructive pulmonary disease research community about the possible use and limitations of current outcomes and markers when evaluating the impact of a pharmacological therapy. Based on their review of the published literature, the following document has been prepared with individual sections that address specific outcomes and markers, and a final section that summarises their recommendations.

Exploring the role of CT densitometry: a randomised study of augmentation therapy in alpha-1 antitrypsin deficiency

Assessment of emphysema-modifying therapy is difficult, but newer outcome measures offer advantages over traditional methods. The EXAcerbations and Computed Tomography scan as Lung End-points (EXACTLE) trial explored the use of computed tomography (CT) densitometry and exacerbations for the assessment of the therapeutic effect of augmentation therapy in subjects with α1-antitrypsin (α1-AT) deficiency. In total, 77 subjects (protease inhibitor type Z) were randomised to weekly infusions of 60 mg·kg−1 human α1-AT (Prolastin®) or placebo for 2–2.5 yrs. The primary end-point was change in CT lung density, and an exploratory approach was adopted to identify optimal methodology, including two methods of adjustment for lung volume variability and two statistical approaches. Other end-points were exacerbations, health status and physiological indices. CT was more sensitive than other measures of emphysema progression, and the changes in CT and forced expiratory volume in 1 s were correlated. All methods of densitometric analysis concordantly showed a trend suggestive of treatment benefit (p-values for Prolastin® versus placebo ranged 0.049–0.084). Exacerbation frequency was unaltered by treatment, but a reduction in exacerbation severity was observed. In patients with α1-AT deficiency, CT is a more sensitive outcome measure of emphysema-modifying therapy than physiology and health status, and demonstrates a trend of treatment benefit from α1-AT augmentation.

Validation of computed tomographic lung densitometry for monitoring emphysema in α1-antitrypsin deficiency

Background: Lung densitometry derived from computed tomographic images offers an opportunity to quantify emphysema non-invasively, but a pathological standard cannot be applied to validate its use in longitudinal monitoring studies. Consequently, forced expiratory volume in 1 second (FEV1) remains the standard against which new methods must be judged. We related progression of densitometry (15th percentile point and voxel index, threshold −950 Hounsfield units) to disease stage and FEV1 decline in two studies of subjects with α1-antitrypsin deficiency (PiZ). Methods: Consistency of progression, measured using densitometry and FEV1, was assessed in relation to disease stage in a 2 year study of 74 subjects grouped according to the FEV1 criteria employed in the GOLD guidelines. In the second study of a subgroup of subjects with extended data (n = 34), summary statistics were applied to measurements performed annually over 3 years and the rate of progression of densitometry was related to FEV1 decline. Results: The progression of percentile point was consistent across a wide spectrum of disease severity, but voxel index progression varied in association with disease stage (p = 0.004). In the second study, FEV1 decline correlated with progression of lung densitometry (percentile point: rS = 0.527, p = 0.001; voxel index: rS = −0.398, p = 0.012). Conclusions: 15th percentile point is a more consistent measure of lung density loss across a wide range of physiological impairment than voxel index. However, both methods are valid for use in longitudinal and interventional studies in which emphysema is the major outcome target.

Variability in Densitometric Assessment of Pulmonary Emphysema With Computed Tomography.

Objectives:The objectives of this study were to investigate whether computed tomography (CT) densitometry can be applied consistently in different centers; and to evaluate the reproducibility of densitometric quantification of emphysema by assessment of different sources of variation, ie, intersite, interscan and inter- and intraobserver variability, in comparison with intersubject variability. Materials and Methods:In 5 different hospitals, 119 patients with emphysema were scanned using standardized protocols. In each site, an observer performed a quantitative densitometric analysis (including blood recalibration) on the corresponding patient group (n = 23–25) and one observer analyzed the entire group of 119 patients. After several months, the latter observer analyzed all data for a second time. Subsequently, different sources of variation were assessed by variance component analysis with and without volume correction of the data. Results:Inter- and intraobserver variability marginally contributes to the total variability (<0.001%). The interscan variability was 0.02% of the total variation after application of volume correction. The intersite variability was 48% as a result of one deviating CT scanner. Air recalibration normalized deviating air densities in CT scanners. Within sites, the intersubject variability ranged between 93% and 99% based on the analysis of 2 subsequent CT scans of the patients. Conclusions:Almost all variability in the density measurement of emphysema originates from differences between scanners and from differences in severity of emphysema between patients. Lung densitometry with multislice CT scanners is a highly reproducible measurement, especially if corrected for lung volume, because this reduces interscan variability.

Volume Correction in Computed Tomography Densitometry for Follow-up Studies on Pulmonary Emphysema

Lung densitometry in drug evaluation trials can be confounded by changes in inspiration levels between computed tomography (CT) scans, limiting its sensitivity to detect changes over time. Therefore our aim was to explore whether the sensitivity of lung densitometry could be improved by correcting the measurements for changes in lung volume, based on the estimated relation between density (as measured with the 15th percentile point) and lung volume. We compared four correction methods, using CT data of 143 patients from five European countries. Patients were scanned, generally twice per visit, at baseline and after 2.5 years. The methods included one physiological model and three linear mixed-effects models using a volume-density relation: (1) estimated over the entire population with one scan per visit (model A) and two scans per visit (model B); and (2) estimated for each patient individually (model C). Both log-transformed and original volume and density values were evaluated and the differences in goodness-of-fit between methods were tested. Model C fitted best (P < 0.0001, P < 0.0001, and P = 0.064), when two scans were available. The most consistent progression estimation was obtained between sites, when both volume and density were log-transformed. Sensitivity was improved using repeated CT scans by applying volume correction to individual patient data. Volume correction reduces the variability in progression estimation by a factor of two, and is therefore recommended.

Inflammation in sputum relates to progression of disease in subjects with COPD: a prospective descriptive study

BackgroundInflammation is considered to be of primary pathogenic importance in COPD but the evidence on which current understanding is based does not distinguish between cause and effect, and no single mechanism can account for the complex pathology. We performed a prospective longitudinal study of subjects with COPD that related markers of sputum inflammation at baseline to subsequent disease progression.MethodsA cohort of 56 patients with chronic bronchitis was characterized in the stable state at baseline and after an interval of four years, using physiological measures and CT densitometry. Sputum markers of airway inflammation were quantified at baseline from spontaneously produced sputum in a sub-group (n = 38), and inflammation severity was related to subsequent disease progression.ResultsPhysiological and CT measures indicated disease progression in the whole group. In the sub-group, sputum myeloperoxidase correlated with decline in FEV1 (rs = -0.344, p = 0.019, n = 37). LTB4 and albumin leakage correlated with TLCO decline (rs = -0.310, p = 0.033, rs = -0.401, p = 0.008, respectively, n = 35) and IL-8 correlated with progression of lung densitometric indices (rs = -0.464, p = 0.005, n = 38).ConclusionThe data support a principal causative role for neutrophilic inflammation in the pathogenesis of COPD and suggest that the measurement of sputum inflammatory markers may have a predictive role in clinical practice.

Detection of emphysema progression in alpha 1-antitrypsin deficiency using CT densitometry; methodological advances.

BackgroundComputer tomography (CT) densitometry is a potential tool for detecting the progression of emphysema but the optimum methodology is uncertain. The level of inspiration affects reproducibility but the ability to adjust for this variable is facilitated by whole lung scanning methods. However, emphysema is frequently localised to sub-regions of the lung and targeted densitometric sampling may be more informative than whole lung assessment.MethodsEmphysema progression over a 2-year interval was assessed in 71 patients (alpha 1-antitrypsin deficiency with PiZ phenotype) with CT densitometry, using the 15th percentile point (Perc15) and voxel index (VI) -950 Hounsfield Units (HU) and -910 HU (VI -950 and -910) on whole lung, limited single slices, and apical, central and basal thirds. The relationship between whole lung densitometric progression (ΔCT) and change in CT-derived lung volume (ΔCTVol) was characterised, and adjustment for lung volume using statistical modelling was evaluated.ResultsCT densitometric progression was statistically significant for all methods. ΔCT correlated with ΔCTVol and linear regression indicated that nearly one half of lung density loss was secondary to apparent hyperinflation. The most accurate measure was obtained using a random coefficient model to adjust for lung volume and the greatest progression was detected by targeted sampling of the middle third of the lung.ConclusionProgressive hyperinflation may contribute significantly to loss of lung density, but volume effects and absolute tissue loss can be identified by statistical modelling. Targeted sampling of the middle lung region using Perc15 appears to be the most robust measure of emphysema progression.

Assessment of pulmonary neutrophilic inflammation in emphysema by quantitative positron emission tomography

RATIONALE Neutrophilic inflammation is understood to be of pathogenetic importance in chronic obstructive pulmonary disease (COPD) and may be quantified using 18-fluorodeoxyglucose positron emission tomography-computed tomography ((18)FDG PET-CT) as a noninvasive, spatially informative biomarker. OBJECTIVES To assess the potential usefulness of (18)FDG PET-CT as a surrogate measure of pulmonary neutrophilic inflammation in patients with usual COPD and α(1)-antitrypsin deficiency (AATD). METHODS (18)FDG PET-CT imaging was performed in 10 patients with usual COPD, 10 patients with AATD, and 10 healthy control subjects. Pulmonary (18)FDG uptake was estimated by three-dimensional Patlak graphical analysis as an indicator of pulmonary neutrophilic glycolytic activity. Patients with AATD were treated with 12 weekly intravenous infusions of AAT augmentation therapy before repeat imaging. (18)FDG uptake, lung physiology, lung density, and systemic markers of inflammation were compared for all groups at baseline and, in patients with AATD, at baseline and on treatment. MEASUREMENTS AND MAIN RESULTS (18)FDG uptake in the upper lung of patients with usual COPD was greater compared with the healthy control group (P = 0.009) and correlated with measures of disease severity (FEV(1)% predicted, r = -0.848, P = 0.001; FEV(1)/FVC, r = -0.918, P < 0.001; Kco% predicted, r = -0.624, P = 0.027; 15th percentile point, r = -0.709, P = 0.011). No significant difference was observed between measurements at baseline and on treatment in patients with AATD. CONCLUSIONS Quantitative (18)FDG PET-CT has a potential role as an imaging biomarker in mechanistic and interventional studies in patients with usual COPD. The data support previous evidence of distinct functional characteristics of neutrophils in COPD. Clinical trial registered with https://eudract.ema.europa.eu/index.html (EudraCT 2007-004869-18).

Influence of lung CT changes in chronic obstructive pulmonary disease (COPD) on the human lung microbiome

Background Changes in microbial community composition in the lung of patients suffering from moderate to severe COPD have been well documented. However, knowledge about specific microbiome structures in the human lung associated with CT defined abnormalities is limited. Methods Bacterial community composition derived from brush samples from lungs of 16 patients suffering from different CT defined subtypes of COPD and 9 healthy subjects was analyzed using a cultivation independent barcoding approach applying 454-pyrosequencing of 16S rRNA gene fragment amplicons. Results We could show that bacterial community composition in patients with changes in CT (either airway or emphysema type changes, designated as severe subtypes) was different from community composition in lungs of patients without visible changes in CT as well as from healthy subjects (designated as mild COPD subtype and control group) (PC1, Padj = 0.002). Higher abundance of Prevotella in samples from patients with mild COPD subtype and from controls and of Streptococcus in the severe subtype cases mainly contributed to the separation of bacterial communities of subjects. No significant effects of treatment with inhaled glucocorticoids on bacterial community composition were detected within COPD cases with and without abnormalities in CT in PCoA. Co-occurrence analysis suggests the presence of networks of co-occurring bacteria. Four communities of positively correlated bacteria were revealed. The microbial communities can clearly be distinguished by their associations with the CT defined disease phenotype. Conclusion Our findings indicate that CT detectable structural changes in the lung of COPD patients, which we termed severe subtypes, are associated with alterations in bacterial communities, which may induce further changes in the interaction between microbes and host cells. This might result in a changed interplay with the host immune system.

European Respiratory Society statement: diagnosis and treatment of pulmonary disease in α1-antitrypsin deficiency

α1-antitrypsin deficiency (AATD) is the most common hereditary disorder in adults. It is associated with an increased risk of developing pulmonary emphysema and liver disease. The pulmonary emphysema in AATD is strongly linked to smoking, but even a proportion of never-smokers develop progressive lung disease. A large proportion of individuals affected remain undiagnosed and therefore without access to appropriate care and treatment. The most recent international statement on AATD was published by the American Thoracic Society and the European Respiratory Society in 2003. Since then there has been a continuous development of novel, more accurate and less expensive genetic diagnostic methods. Furthermore, new outcome parameters have been developed and validated for use in clinical trials and a new series of observational and randomised clinical trials have provided more evidence concerning the efficacy and safety of augmentation therapy, the only specific treatment available for the pulmonary disease associated with AATD. As AATD is a rare disease, it is crucial to organise national and international registries and collect information prospectively about the natural history of the disease. Management of AATD patients must be supervised by national or regional expert centres and inequalities in access to therapies across Europe should be addressed. Description of the best practice in diagnosis and treatment of pulmonary disease in alpha-1 antitrypsin deficiency http://ow.ly/fD3S30fuy4H