Reliability and validity of the Brief Pain Inventory in individuals with chronic obstructive pulmonary disease.

BACKGROUND: Pain is prevalent in chronic obstructive pulmonary disease (COPD) and the Brief Pain Inventory (BPI) appears to be a feasible questionnaire to assess this symptom. However, the reliability and validity of the BPI have not been determined in individuals with COPD. This study aimed to determine the internal consistency, test-retest reliability and validity (construct, convergent, divergent and discriminant) of the BPI in individuals with COPD. METHODS: In order to examine the test-retest reliability, individuals with COPD were recruited from pulmonary rehabilitation programmes to complete the BPI twice 1 week apart. In order to investigate validity, de-identified data was retrieved from two previous studies, including forced expiratory volume in 1-s, age, sex and data from four questionnaires: the BPI, short-form McGill Pain Questionnaire (SF-MPQ), 36-Item Short Form Survey (SF-36) and Community Health Activities Model Program for Seniors (CHAMPS) questionnaire. RESULTS: In total, 123 participants were included in the analyses (eligible data were retrieved from 86 participants and additional 37 participants were recruited). The BPI demonstrated excellent internal consistency and test-retest reliability. It also showed convergent validity with the SF-MPQ and divergent validity with the SF-36. The factor analysis yielded two factors of the BPI, which demonstrated that the two domains of the BPI measure the intended constructs. The BPI can also discriminate pain levels among COPD patients with varied levels of quality of life (SF-36) and physical activity (CHAMPS). CONCLUSION: The BPI is a reliable and valid pain questionnaire that can be used to evaluate pain in COPD. SIGNIFICANCE: This study formally established the reliability and validity of the BPI in individuals with COPD, which have not been determined in this patient group. The results of this study provide strong evidence that assessment results from this pain questionnaire are reliable and valid.

A genome-wide analysis of the response to inhaled ß2-agonists in chronic obstructive pulmonary disease.

Short-acting ß2-agonist bronchodilators are the most common medications used in treating chronic obstructive pulmonary disease (COPD). Genetic variants determining bronchodilator responsiveness (BDR) in COPD have not been identified. We performed a genome-wide association study (GWAS) of BDR in 5789 current or former smokers with COPD in one African-American and four white populations. BDR was defined as the quantitative spirometric response to inhaled ß2-agonists. We combined results in a meta-analysis. In the meta-analysis, single-nucleotide polymorphisms (SNPs) in the genes KCNK1 (P=2.02 × 10(-7)) and KCNJ2 (P=1.79 × 10(-7)) were the top associations with BDR. Among African Americans, SNPs in CDH13 were significantly associated with BDR (P=5.1 × 10(-9)). A nominal association with CDH13 was identified in a gene-based analysis in all subjects. We identified suggestive association with BDR among COPD subjects for variants near two potassium channel genes (KCNK1 and KCNJ2). SNPs in CDH13 were significantly associated with BDR in African Americans.The Pharmacogenomics Journal advance online publication, 27 October 2015; doi:10.1038/tpj.2015.65.

Polymorphisms in the superoxide dismutase-3 gene are associated with emphysema in COPD.

Superoxide dismutase-3 (SOD3) is a major extracellular antioxidant enzyme, and previous studies have indicated a possible role of this gene in chronic obstructive pulmonary disease (COPD). We hypothesized that polymorphisms in the SOD3 gene would be associated with COPD and COPD-related phenotypes. We genotyped three SOD3 polymorphisms (rs8192287 (E1), rs8192288 (I1), and rs1799895 (R213G)) in a case-control cohort, with severe COPD cases from the National Emphysema Treatment Trial (NETT, n = 389) and smoking controls from the Normative Aging Study (NAS, n = 472). We examined whether the single nucleotide polymorphisms (SNPs) were associated with COPD status, lung function variables, and quantitative computed tomography (CT) measurements of emphysema and airway wall thickness. Furthermore, we tried to replicate our initial findings in two family-based studies, the International COPD Genetics Network (ICGN, n = 3061) and the Boston Early-Onset COPD Study (EOCOPD, n = 949). In NETT COPD cases, the minor alleles of SNPs E1 and I1 were associated with a higher percentage of emphysema (%LAA950) on chest CT scan (p = .029 and p = .0058). The association with E1 was replicated in the ICGN family study, where the minor allele was associated with more emphysema (p = .048). Airway wall thickness was positively associated with the E1 SNP in ICGN; however, this finding was not confirmed in NETT. Quantitative CT data were not available in EOCOPD. The SNPs were not associated with lung function variables or COPD status in any of the populations. In conclusion, polymorphisms in the SOD3 gene were associated with CT emphysema but not COPD susceptibility, highlighting the importance of phenotype definition in COPD genetics studies.

Prediction of the rate of decline in FEV(1) in smokers using quantitative Computed Tomography.

BACKGROUND: A study was undertaken to determine if quantitative CT estimates of lung parenchymal overinflation and airway dimensions in smokers with a normal forced expiratory volume in 1 s (FEV(1)) can predict the rapid decline in FEV(1) that leads to chronic obstructive pulmonary disease (COPD). METHODS: Study participants (n = 143; age 45-72 years; 54% male) were part of a lung cancer screening trial, had a smoking history of >30 pack years and a normal FEV(1) and FEV(1)/forced vital capacity (FVC) at baseline (mean (SD) FEV(1) 99.4 (12.8)%, range 80.2-140.7%; mean (SD) FEV(1)/FVC 77.9 (4.4), range 70.0-88.0%). An inspiratory multislice CT scan was acquired for each subject at baseline. Custom software was used to measure airway lumen and wall dimensions; the percentage of the lung inflated beyond a predicted maximal lung inflation, the low attenuation lung area with an x ray attenuation lower than -950 HU and the size distribution of the overinflated lung areas and the low attenuation area were described using a cluster analysis. Multiple regression analysis was used to test the hypothesis that these CT measurements combined with other baseline characteristics might identify those who would develop an excessive annual decline in FEV(1). RESULTS: The mean (SD) annual change in FEV(1) was -2.3 (4.7)% predicted (range -23.0% to +8.3%). Multiple regression analysis revealed that the annual change in FEV(1)%predicted was significantly associated with baseline percentage overinflated lung area measured on quantitative CT, FEV(1)% predicted, FEV(1)/FVC and gender. CONCLUSION: Quantitative CT scan evidence of overinflation of the lung predicts a rapid annual decline in FEV(1) in smokers with normal FEV(1).

Quantitative computed tomography: emphysema and airway wall thickness by sex, age and smoking.

We investigated how quantitative high-resolution computed tomography (HRCT) measures of emphysema and airway wall thickness (AWT) vary with sex, age and smoking history. We included 463 chronic obstructive pulmonary disease (COPD) cases and 431 controls. All included subjects were current or ex-smokers aged > or = 40 yrs, and all underwent spirometry and HRCT examination. The HRCT images were quantitatively assessed, providing indices on lung density and airway dimensions. The median (25-75th percentile) %LAA950 (% low-attenuation area < -950 HU) was 8.9 (3-19) and 4.7 (1-16) in male and female COPD cases, respectively, and 0.71 (0.3-1.6) and 0.32 (0.1-0.8) in male and female controls, respectively. %LAA950 was higher in ex-smokers and increased with increasing age and with increasing number of pack-years. The mean+/-SD standardised AWT was 0.504+/-0.030 and 0.474+/-0.031 in male and female COPD cases, respectively, and 0.488+/-0.028 and 0.463+/-0.025 in male and female controls, respectively. AWT decreased with increasing age in cases, and increased with the degree of current smoking in all subjects. We found significant differences in quantitative HRCT measures of emphysema and AWT between varying sex, age and smoking groups of both control and COPD subjects.

Airway wall geometry in asthma and nonasthmatic eosinophilic bronchitis.

BACKGROUND: Variable airflow obstruction and airway hyperresponsiveness (AHR) are features of asthma, which are absent in nonasthmatic eosinophilic bronchitis (EB). Airway remodelling is characteristic of both conditions suggesting that remodelling and airway dysfunction are disassociated, but whether the airway geometry differs between asthma and nonasthmatic EB is uncertain. METHODS: We assessed airway geometry by computed tomography (CT) imaging in asthma vs EB. A total of 12 subjects with mild-moderate asthma, 14 subjects with refractory asthma, 10 subjects with EB and 11 healthy volunteers were recruited. Subjects had a narrow collimation (0.75 mm) CT scan from the aortic arch to the carina to capture the right upper lobe apical segmental bronchus (RB1). In subjects with asthma and EB, CT scans were performed before and after a 2-week course of oral prednisolone (0.5 mg/kg). RESULTS: Mild-moderate and refractory asthma were associated with RB1 wall thickening in contrast to subjects with nonasthmatic EB who had maintained RB1 patency without wall thickening [mean (SD) % wall area and luminal area mild-t0-moderate asthma 67.7 (7.3)% and 6.6 (2.8) mm(2)/m(2), refractory asthma 67.3 (5.6)% and 6.7 (3.4) mm(2)/m(2), healthy control group 59.7 (6.3)% and 8.7 (3.8) mm(2)/m(2), EB 61.4 (7.8)% and 11.1 (4.6) mm(2)/m(2) respectively; P < 0.05]. Airway wall thickening of non-RB1 airways generation three to six was a feature of asthma only. There was no change in airway geometry of RB1 after prednisolone. Proximal airway wall thickening was associated with AHR in asthma (r = -0.56; P = 0.02). CONCLUSIONS: Maintained airway patency in EB may protect against the development of AHR, whereas airway wall thickening may promote AHR in asthma.

Lung structure and function of infants with recurrent wheeze when asymptomatic.

Infants with recurrent wheeze have repeated episodes of airways obstruction; however, relatively little is known about the structure and function of their lungs when not symptomatic. The current authors evaluated whether infants with recurrent wheeze have smaller airway lumens or thickened airway walls, as well as decreased airway function. High-resolution computed tomography images 1 mm thick were obtained at three anatomic locations at an elevated lung volume and at functional residual capacity. Forced expiratory flows were also measured in subjects with recurrent wheeze. Airway lumen, wall areas and lung tissue density were not significantly different for recurrent wheeze (n = 17) and control (n = 14) subjects; however, subjects with recurrent wheeze had lower forced expiratory flows than predicted. Similar findings were obtained when subjects were grouped by exposure to tobacco smoke. These findings indicate that infants with recurrent wheeze, as well as exposure to tobacco smoke, have lower airway function when not symptomatic. The lower forced expiratory flows may result from a degree of airway narrowing that could not be resolved with the methodology employed or from other mechanisms, such as more collapsible airways or decreased pulmonary elastic recoil.

Evaluation of serum CC-16 as a biomarker for COPD in the ECLIPSE cohort.

BACKGROUND: Circulating levels of Clara cell secretory protein-16 (CC-16) have been linked to Clara cell toxicity. It has therefore been suggested that this protein may be a useful marker of chronic obstructive pulmonary disease (COPD). METHODS: Serum CC-16 levels were measured in 2083 individuals aged 40-75 years with COPD and a smoking history of >or=10 pack-years, 332 controls with a smoking history of >or=10 pack-years and normal lung function and 237 non-smoking controls. RESULTS: Serum CC-16 had a coefficient of repeatability of 2.90 over 3 months in a pilot study of 267 individuals. The median serum CC-16 level was significantly reduced in a replication group of 1888 current and former smokers with COPD compared with 296 current and former smokers without airflow obstruction (4.9 and 5.6 ng/ml, respectively; p<0.001) and 201 non-smokers (6.4 ng/ml; p<0.001). Serum levels of CC-16 were lower in current than in former smokers with GOLD stage II and III COPD but were not different in individuals with stage IV disease. Former, but not current smokers, with COPD had lower serum CC-16 levels with increasing severity of COPD (GOLD II vs GOLD IV COPD: 5.5 and 5.0 ng/ml, p = 0.006; r = 0.11 with forced expiratory volume in 1 s, p<0.001) and had significantly higher levels if they also had reversible airflow obstruction (p = 0.034). Serum CC-16 was affected by gender and age (r = 0.35; p<0.001) in subjects with COPD but not by body mass index or the presence of either chronic bronchitis or emphysema. CONCLUSIONS: Serum CC-16 levels are reduced in individuals with COPD and there is a weak correlation with disease severity in former smokers.

Computed tomography assessment of lung volume changes after bronchial valve treatment.

The aim of the present study was to correlate clinical outcome measures following treatment with bronchial valves with regional lung volume. Computed tomography (CT) scan data from 57 subjects with severe emphysema were obtained from nine North American clinical trial sites. IBV(R) Valves (Spiration, Inc., Redmond, WA, USA) were placed to occlude segmental and subsegmental bronchi in right and left upper lobes using a flexible bronchoscope. Subjects completed a St George's Respiratory Questionnaire (SGRQ), pulmonary function test (PFT) and exercise capacity test. CT scans were analysed at baseline and at 1, 3 or 6 months after treatment to measure total and lobar lung density, volume and mass. Total lung volumes measured using CT were strongly correlated with PFT and did not change with treatment. However, the treated upper lobes significantly decreased in volume in 88% of the observations, by mean+/-sd 335+/-444 mL, or a decrease of 10.2% in the 6 month data. The untreated lobes had an 11.6% increase in volume. Changes in regional lung volume were associated with clinically meaningful improvements in SGRQ (-8.95+/-16.22), but not clinically meaningful PFT changes. The significant health status improvements reported by subjects following bilateral bronchial valve treatment are associated with regional lung volume changes and interlobar shift measured using computed tomography.

Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-points (ECLIPSE).

Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease and not well understood. The forced expiratory volume in one second is used for the diagnosis and staging of COPD, but there is wide acceptance that it is a crude measure and insensitive to change over shorter periods of time. Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-points (ECLIPSE) is a 3-yr longitudinal study with four specific aims: 1) definition of clinically relevant COPD subtypes; 2) identification of parameters that predict disease progression in these subtypes; 3) examination of biomarkers that correlate with COPD subtypes and may predict disease progression; and 4) identification of novel genetic factors and/or biomarkers that both correlate with clinically relevant COPD subtypes and predict disease progression. ECLIPSE plans to recruit 2,180 COPD subjects in Global Initiative for Chronic Obstructive Lung Disease categories II-IV and 343 smoking and 223 nonsmoking control subjects. Study procedures are to be performed at baseline, 3 months, 6 months and every 6 months thereafter. Assessments include pulmonary function measurements (spirometry, impulse oscillometry and plethysmography), chest computed tomography, biomarker measurement (in blood, sputum, urine and exhaled breath condensate), health outcomes, body impedance, resting oxygen saturation and 6-min walking distance. Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-points is the largest study attempting to better describe the subtypes of chronic obstructive pulmonary disease, as well as defining predictive markers of its progression.

Bronchiolitis obliterans following lung transplantation: early detection using computed tomographic scanning.

BACKGROUND: Computed tomographic (CT) scanning may enable earlier diagnosis of chronic lung allograft dysfunction than forced expiratory volume in 1 second (FEV1). A study was undertaken to determine intra-observer and inter-observer agreement of composite and air trapping CT scores, to examine the association of FEV1 with the composite and air trapping CT score, and to relate the baseline composite CT score to changes in FEV1 and changes in the composite CT score over 1 year. METHODS: Lung function and baseline CT scans following transplantation and at subsequent annual follow ups were analysed in 38 lung transplant recipients. Scans were randomly scored by two observers for bronchiectasis, mucus plugging, airway wall thickening, consolidation, mosaic pattern, and air trapping, and re-scored after 1 month. CT scores were expressed on a scale of 0-100 and correlated with FEV1 as a percentage of the post-transplant baseline value. RESULTS: The mean (SD) interval between baseline and follow up CT scans was 11.2 (4.7) months. Inter-observer and intra-observer agreement was good for both the composite and air trapping CT scores. There was a significant association between FEV1 and the composite CT score, with each unit of worsening in the baseline composite CT score predicting a 1.55% and 1.37% worsening in FEV1 over the following year (p<0.0001) and a 1.25 and 1.12 unit worsening in the composite CT score (p<0.0001) for observers 1 and 2, respectively. CONCLUSION: These findings indicate a potential role for a composite CT scoring system in the early detection of bronchiolitis obliterans.

Computed tomographic estimation of lung dimensions throughout the growth period.

The aim of the current study was to use computed tomography (CT) to estimate airway wall and lumen, and arterial and parenchyma dimensions in children throughout the growth period, and to provide normative data to study alterations caused by pulmonary disease. Clinical CT scans reported as normal that were performed in children for nonpulmonary and noncardiac reasons were analysed for lung weight, gas volume, lung expansion, lung surface/volume ratio, airway wall area, airway lumen area, airway lumen perimeter, arterial area and airway surface length/area ratio. The age range of the 50 subjects was 0-17.2 yrs. The data showed only little increase in lung expansion throughout childhood (n = 32). There was substantial variability in lung expansion between subjects. Airway wall and lumen and arterial area were exponentially associated with subjects' height (n = 50). Airway surface length/area ratio was linearly associated to alveolar surface/volume ratio. The data from the current study provide normative computed tomography estimates of airway wall and lumen, and arterial and parenchyma dimensions throughout the growth period that may be useful for the study of alterations in disease.

Computed tomographic imaging of the airways: relationship to structure and function.

Alterations in the structure of the airways, collectively termed airway remodelling, contribute to airflow obstruction in a variety of chronic lung diseases. While histology has provided valuable insights into the structure of airway wall remodelling, this technique is invasive and does not allow the longitudinal analysis of airway wall dimensions. Technical advances in computed tomography allow the assessment of airway wall dimensions, and are ideally suited for the noninvasive investigation of the pathogenesis of airway wall remodelling and the evaluation of new therapeutic interventions. The aim of this article is to review the use of computed tomography in the investigation of airway structure and function in health and disease.

Estimation of lung growth using computed tomography.

Anatomical studies suggest that normal lungs grow by rapid alveolar addition until about 2 yrs of age followed by a gradual increase in alveolar dimensions. The aim of this study was to examine the hypothesis that normal lung growth can be monitored by computed tomography (CT). Therefore, the gas volume per gram of lung tissue was estimated from measurements of lung density obtained from CT scans performed on children throughout the growth period. CT scans were performed on 17 males and 18 females, ranging in age from 15 days-17.6 yrs. CT-measured lung weight was correlated with predicted post mortem values and CT measured gas volume with predicted values of functional residual capacity. The median value for lung expansion was 1.86 mL x g(-1) at 15 days, decreased to 0.79 mL x g(-1) by 2 yrs and then increased steadily to 5.07 mL x g(-1) at 17 yrs. Computed tomography scans can be used to estimate lung weight, gas volume and expansion of normal lungs during the growth period. The increase in the lung expansion after the age of 2 yrs suggests progressive alveolar expansion with increasing lung volume.

Selection of patients for lung volume reduction surgery using a power law analysis of the computed tomographic scan.

BACKGROUND: A study was undertaken to test the hypothesis that patients respond better to lung volume reduction surgery (LVRS) if their emphysema is confluent and predominantly located in the upper lobes. METHODS: A density mask analysis was used to identify voxels inflated beyond 10.2 ml gas/g tissue (-910 HU) on preoperative and postoperative CT scans from patients receiving LVRS. These hyperinflated regions were considered to represent emphysematous lesions. A power law analysis was used to determine the relationship between the number (K) and size (A) of the emphysematous lesions in the whole lung and two anatomical regions using the power law equation Y=KA(-D). RESULTS: The analysis showed a positive correlation between the change in the power law exponent (D) and the change in exercise (Watts) after surgery (r=0.47, p=0.03). There was also a negative correlation between the power law exponent D in the upper region of the lung preoperatively and the change in exercise following surgery (r=-0.60, p<0.05). CONCLUSIONS: These results confirm that patients with large upper lobe lesions respond better to LVRS than patients with small uniformly distributed disease. Power law analysis of lung CT scans provides a quantitative method for determining the extent and location of emphysema within the lungs of patients with COPD.

Core to rind distribution of severe emphysema predicts outcome of lung volume reduction surgery.

Computed tomography (CT) has shown that emphysema is more extensive in the inner (core) region than in the outer (rind) region of the lung. It has been suggested that the concentration of emphysematous lesions in the outer rind leads to a better outcome following lung volume reduction surgery (LVRS) because these regions tend to be more surgically accessible. The present study used a recently described, computer-based CT scan analysis to quantify severe emphysema (lung inflation > 10.2 ml gas/g tissue), mild/moderate emphysema (lung inflation = 10.2 to 6.0 ml gas/g tissue), and normal lung tissue (lung inflation < 6.0 ml gas/g tissue) present in the core and rind of the lung in 21 LVRS patients. The results show that the quantification of severe emphysema independently predicts change in maximal exercise response and FEV(1). We conclude that a greater extent of severe emphysema in the rind of the upper lung predicts greater benefit from LVRS because it identifies the lesions most accessible to removal by LVRS.

Bullae, bronchiectasis and nutritional emphysema in severe anorexia nervosa.

STUDY OBJECTIVES: Pulmonary complications of anorexia nervosa are rarely documented. The case of a patient with anorexia nervosa and pulmonary disease is presented, a new quantitative computed tomography (CT) method for the detection of emphysema is employed, the literature is reviewed and the concept of 'nutritional' emphysema is discussed. RESULTS: The case of a 34-year-old, nonsmoking woman with long-standing severe anorexia nervosa who was evaluated for cough and progressive shortness of breath is reported. Pulmonary function testing showed a predominant restrictive pattern with a marked reduction in carbon monoxide transfer and respiratory muscle strength, and an elevated residual volume. Imaging revealed bullae and bronchiectasis, and quantitative analysis of the CT scan was consistent with mild, generalized emphysema. Bronchial washings grew Pseudomonas aeruginosa. Known causes for bronchiectasis were excluded. A literature review disclosed few reported noninfectious pulmonary complications of anorexia nervosa. CONCLUSIONS: To the authors' knowledge, this is the first report of bullae and bronchiectasis in a patient with anorexia nervosa, and the CT analysis was consistent with mild emphysema. Malnutrition has been associated with emphysematous changes in animals and may be the primary insult in the development of emphysema, bullae and bronchiectasis in the present patient.

Amplification of inflammation in emphysema and its association with latent adenoviral infection.

This study examines the hypothesis that the cigarette smoke-induced inflammatory process is amplified in severe emphysema and explores the association of this response with latent adenoviral infection. Lung tissue from patients with similar smoking histories and either no (n = 7), mild (n = 7), or severe emphysema (n = 7) was obtained by lung resection. Numbers of polymorphonuclear cells (PMN), macrophages, B cells, CD4, CD8 lymphocytes, and eosinophils present in tissue and airspaces and of epithelial cells expressing adenoviral E1A protein were determined using quantitative techniques. Severe emphysema was associated with an absolute increase in the total number of inflammatory cells in the lung tissue and airspaces. The computed tomography (CT) determined extent of lung destruction was related to the number of cells/m(2) surface area by R(2) values that ranged from 0.858 (CD8 cells) to 0.483 (B cells) in the tissue and 0.630 (CD4 cells) to 0.198 (B cells) in the airspaces. These changes were associated with a 5- to 40-fold increase in the number of alveolar epithelial cells expressing adenoviral E1A protein in mild and severe disease, respectively. We conclude that cigarette smoke-induced lung inflammation is amplified in severe emphysema and that latent expression of the adenoviral E1A protein expressed by alveolar epithelial cells influenced this amplification process.