Firdaus A. A. Mohamed Hoesein

Lower limit of normal or FEV1/FVC <0.70 in diagnosing COPD: An evidence-based review

AIM To review the currently available literature comparing the FEV1/FVC 40 years. METHODS A structured MEDLINE, EMBASE and Cochrane search of English-language literature was conducted. Studies comparing prevalence rates according to the LLN and a fixed value were included. Attention was paid to the choice of the reference test or gold standard used. RESULTS Eighteen studies met the inclusion criteria. Sixteen studies compared the rates of subjects diagnosed with airflow obstruction by either definition of airflow obstruction without using a non-independent reference standard (level 4 studies). Using a fixed value of FEV1/FVC, an overall higher number of subjects were diagnosed with airflow obstruction that increased with age. Two studies included a follow-up phase comparing risks of either hospitalization or occurrence of respiratory symptoms and mortality (level 2b studies). Adjusted risks of hospitalization (HR 2.6) or mortality (HR 1.3) were significantly larger in subjects with an FEV1/FVC below 0.70 but above the LLN (in-between group) compared to subjects with normal lung function. CONCLUSION The prevalence of spirometry-based COPD is greater when using the fixed value of FEV1/FVC in comparison to using the LLN. Based on one longitudinal study the in-between group appears to have a higher risk of hospitalization and mortality; therefore it seems that using the LLN of FEV1/FVC underestimates COPD. In absence of a gold standard of COPD longitudinal research will be necessary to determine which criterion is better and more clinically relevant.

CT-quantified emphysema distribution is associated with lung function decline

Emphysema distribution is associated with chronic obstructive pulmonary disease. It is, however, unknown whether computed tomography (CT)-quantified emphysema distribution (upper/lower lobe) is associated with lung function decline in heavy (former) smokers. 587 male participants underwent lung CT and pulmonary function testing at baseline and after a median (interquartile range) follow-up of 2.9 (2.8–3.0) yrs. The lungs were automatically segmented based on anatomically defined lung lobes. Severity of emphysema was automatically quantified per anatomical lung lobe and was expressed as the 15th percentile (Hounsfield unit point below which 15% of the low-attenuation voxels are distributed (Perc15)). The CT-quantified emphysema distribution was based on principal component analysis. Linear mixed models were used to assess the association of emphysema distribution with forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC), FEV1 and FVC decline. Mean±sd age was 60.2±5.4 yrs, mean baseline FEV1/FVC was 71.6±9.0% and overall mean Perc15 was -908.5±20.9 HU. Participants with upper lobe-predominant CT-quantified emphysema had a lower FEV1/FVC, FEV1 and FVC after follow-up compared with participants with lower lobe-predominant CT-quantified emphysema (p=0.001), independent of the total extent of CT-quantified emphysema. Heavy (former) smokers with upper lobe-predominant CT-quantified emphysema have a more rapid decrease in lung function than those with lower lobe-predominant CT-quantified emphysema.

Genome-wide study identifies two loci associated with lung function decline in mild to moderate COPD

Accelerated lung function decline is a key COPD phenotype; however, its genetic control remains largely unknown. We performed a genome-wide association study using the Illumina Human660W-Quad v.1_A BeadChip. Generalized estimation equations were used to assess genetic contributions to lung function decline over a 5-year period in 4,048 European American Lung Health Study participants with largely mild COPD. Genotype imputation was performed using reference HapMap II data. To validate regions meeting genome-wide significance, replication of top SNPs was attempted in independent cohorts. Three genes (TMEM26, ANK3 and FOXA1) within the regions of interest were selected for tissue expression studies using immunohistochemistry. Two intergenic SNPs (rs10761570, rs7911302) on chromosome 10 and one SNP on chromosome 14 (rs177852) met genome-wide significance after Bonferroni. Further support for the chromosome 10 region was obtained by imputation, the most significantly associated imputed SNPs (rs10761571, rs7896712) being flanked by observed markers rs10761570 and rs7911302. Results were not replicated in four general population cohorts or a smaller cohort of subjects with moderate to severe COPD; however, we show novel expression of genes near regions of significantly associated SNPS, including TMEM26 and FOXA1 in airway epithelium and lung parenchyma, and ANK3 in alveolar macrophages. Levels of expression were associated with lung function and COPD status. We identified two novel regions associated with lung function decline in mild COPD. Genes within these regions were expressed in relevant lung cells and their expression related to airflow limitation suggesting they may represent novel candidate genes for COPD susceptibility.

Detection and Quantification by Deformation Imaging of the Functional Impact of Septal Compared to Free Wall Preexcitation in the Wolff-Parkinson-White Syndrome

Pacing experiments in healthy animal hearts have suggested a larger detrimental effect of septal compared to free wall preexcitation. We investigated the intrinsic relation among the site of electrical preexcitation, mechanical dyssynchrony, and dysfunction in human patients. In 33 patients with Wolff-Parkinson-White (WPW) syndrome and 18 controls, regional myocardial deformation was assessed by speckle tracking mapping (ST-Map) to assess the preexcitation site, shortening sequences and dyssynchrony, and the extent of local and global ejecting shortening. The ST-Map data in patients with accessory atrioventricular pathways correctly diagnosed as located in the interventricular septum (IVS) (n = 11) or left ventricular free wall (LFW) (n = 12) were compared to the corresponding control values. A local ejecting shortening of <2 SD of the control values identified hypokinetic segments. The localization of the atrioventricular pathways by ST-Map matched with the invasive electrophysiology findings in 23 of 33 patients and was one segment different in 5 of 33 patients. In both WPW-IVS and WPW-LFW, local ejecting shortening was impaired at the preexcitation site (p <0.01). However, at similar electrical and mechanical dyssynchrony, WPW-IVS had more extensive hypokinesia than did WPW-LFW (3.6 +/- 0.9 vs 1.8 +/- 1.3 segments, p <0.01). Compared to controls, the left ventricular function was significantly reduced only in WPW-IVS (global ejecting shortening 17 +/- 2% vs 19 +/- 2%, p = 0.01; ejection fraction 55 +/- 5% vs 59 +/- 3%, p = 0.02). In conclusion, preexcitation is associated with local hypokinesia, which at comparable preexcitation is more extensive in WPW-IVS than in WPW-LFW and could adversely affect ventricular function. ST-Map might have a future role in detecting and guiding treatment of septal pathways with significant mechanical effects.

Contribution of CT Quantified Emphysema, Air Trapping and Airway Wall Thickness on Pulmonary Function in Male Smokers With and Without COPD

Abstract Emphysema, airway wall thickening and air trapping are associated with chronic obstructive pulmonary disease (COPD). All three can be quantified by computed tomography (CT) of the chest. The goal of the current study is to determine the relative contribution of CT derived parameters on spirometry, lung volume and lung diffusion testing. Emphysema, airway wall thickening and air trapping were quantified automatically on CT in 1,138 male smokers with and without COPD. Emphysema was quantified by the percentage of voxels below –950 Hounsfield Units (HU), airway wall thickness by the square root of wall area for a theoretical airway with 10 mm lumen perimeter (Pi10) and air trapping by the ratio of mean lung density at expiration and inspiration (E/I-ratio). Spirometry, residual volume to total lung capacity (RV/TLC) and diffusion capacity (Kco) were obtained. Standardized regression coefficients (β) were used to analyze the relative contribution of CT changes to pulmonary function measures. The independent contribution of the three CT measures differed per lung function parameter. For the FEV1 airway wall thickness was the most contributing structural lung change (β = –0.46), while for the FEV1/FVC this was emphysema (β = –0.55). For the residual volume (RV) air trapping was most contributing (β = –0.35). Lung diffusion capacity was most influenced by emphysema (β = –0.42). In a cohort of smokers with and without COPD the effect of different CT changes varies per lung function measure and therefore emphysema, airway wall thickness and air trapping need to be taken in account.

Diagnosis of chronic obstructive pulmonary disease in lung cancer screening Computed Tomography scans: independent contribution of emphysema, air trapping and bronchial wall thickening

BackgroundBeyond lung cancer, screening CT contains additional information on other smoking related diseases (e.g. chronic obstructive pulmonary disease, COPD). Since pulmonary function testing is not regularly incorporated in lung cancer screening, imaging biomarkers for COPD are likely to provide important surrogate measures for disease evaluation. Therefore, this study aims to determine the independent diagnostic value of CT emphysema, CT air trapping and CT bronchial wall thickness for COPD in low-dose screening CT scans.MethodsPrebronchodilator spirometry and volumetric inspiratory and expiratory chest CT were obtained on the same day in 1140 male lung cancer screening participants. Emphysema, air trapping and bronchial wall thickness were automatically quantified in the CT scans. Logistic regression analysis was performed to derivate a model to diagnose COPD. The model was internally validated using bootstrapping techniques.ResultsEach of the three CT biomarkers independently contributed diagnostic value for COPD, additional to age, body mass index, smoking history and smoking status. The diagnostic model that included all three CT biomarkers had a sensitivity and specificity of 73.2% and 88.%, respectively. The positive and negative predictive value were 80.2% and 84.2%, respectively. Of all participants, 82.8% was assigned the correct status. The C-statistic was 0.87, and the Net Reclassification Index compared to a model without any CT biomarkers was 44.4%. However, the added value of the expiratory CT data was limited, with an increase in Net Reclassification Index of 4.5% compared to a model with only inspiratory CT data.ConclusionQuantitatively assessed CT emphysema, air trapping and bronchial wall thickness each contain independent diagnostic information for COPD, and these imaging biomarkers might prove useful in the absence of lung function testing and may influence lung cancer screening strategy. Inspiratory CT biomarkers alone may be sufficient to identify patients with COPD in lung cancer screening setting.

Low-dose CT measurements of airway dimensions and emphysema associated with airflow limitation in heavy smokers: a cross sectional study

BackgroundIncreased airway wall thickness (AWT) and parenchymal lung destruction bothcontribute to airflow limitation. Advances in computed tomography (CT)post-processing imaging allow to quantify these features. The aim of thisDutch population study is to assess the relationships between AWT, lungfunction, emphysema and respiratory symptoms.MethodsAWT and emphysema were assessed by low-dose CT in 500 male heavy smokers,randomly selected from a lung cancer screening population. AWT was measuredin each lung lobe in cross-sectionally reformatted images with an automatedimaging program at locations with an internal diameter of 3.5 mm, andvalidated in smaller cohorts of patients. The 15th percentilemethod (Perc15) was used to assess the severity of emphysema. Informationabout respiratory symptoms and smoking behavior was collected byquestionnaires and lung function by spirometry.ResultsMedian AWT in airways with an internal diameter of 3.5 mm(AWT3.5) was 0.57 (0.44 - 0.74) mm. Median AWT in subjectswithout symptoms was 0.52 (0.41-0.66) and in those with dyspnea and/orwheezing 0.65 (0.52-0.81) mm (p<0.001). In the multivariate analysisonly AWT3.5 and emphysema independently explained 31.1%and9.5%of the variance in FEV1%predicted, respectively,after adjustment for smoking behavior.ConclusionsPost processing standardization of airway wall measurements provides areliable and useful method to assess airway wall thickness. Increased airwaywall thickness contributes more to airflow limitation than emphysema in asmoking male population even after adjustment for smoking behavior.

Association of chronic obstructive pulmonary disease and smoking status with bone density and vertebral fractures in male lung cancer screening participants.

We studied the vertebral fracture prevalence on low‐dose chest computed tomography (CT) in male lung cancer screening participants and the association of fractures and bone density with chronic obstructive pulmonary disease (COPD) and smoking. 1140 male current and former smokers with ≥16.5 packyears from the NELSON lung cancer screening trial were included. Age, body mass index, and smoking status were registered. CT scans and pulmonary function tests were obtained on the same day. On CT, vertebral fractures and bone density were measured. The cohort had a mean age of 62.5 years (standard deviation 5.2) old; 531 (46.6%) had quit smoking; and 437 (38.3%) had COPD. Of the group, 100 (8.8%) participants had a vertebral fracture. Fracture prevalence was higher in current compared to former smokers (11.3% versus 5.8%, p = 0.001), but similar in participants with COPD compared to those without (9.6% versus 8.3%, p = 0.430). The multivariable adjusted odds ratio for fracture presence was 1.79 (95% CI: 1.13–2.84) in current smokers and 1.08 (95% CI: 0.69–1.67) in COPD participants. Bone density was lower in current compared to former smokers (103.2HU versus 108.7HU, p = 0.006) and in participants with COPD compared to those without [100.7 Hounsfield Units (HU) versus 108.9HU, p < 0.001]. In multivariate analysis, smoking status and COPD status were independently associated with bone density, corrected for age and body mass index. In conclusion, our study shows that lung cancer screening participants have a substantial vertebral fracture burden. Fractures are more common in current smokers, who also have lower bone density. We could not confirm that COPD is independently associated with vertebral fractures.

Lung Function Decline in Male Heavy Smokers Relates to Baseline Airflow Obstruction Severity

BACKGROUND Recent evidence indicates that the rate of lung function decline is steepest in mild COPD and slower in moderate to severe COPD. The current study assessed whether lung function decline relates to baseline airflow obstruction severity in male heavy smokers. METHODS In total, 2,003 male smokers with a mean (SD) age of 59.8 (5.3) years underwent pulmonary function testing at baseline and after 3-year follow-up. Participants were classified by entry FEV1/FVC as follows: group 1, >70%; group 2, <70%, but greater than lower limit of normal (LLN); and group 3, less than LLN. Differences in lung function decline among the groups were assessed using multiple regression after adjustment for pack-years, smoking status (current or former smoker), presence or absence of mucus production, medical center, height, age, CT scan-derived emphysema severity (15th percentile), observation time (years in study), and the baseline values. RESULTS Over 3 years, the mean (SD) FEV₁/FVC, FEV₁, and maximum expiratory flow at 50% of FVC decreases in group 1 were 3.1% (1), 0.21 L (0.07), and 0.40 L/s (0.26), respectively. In group 3, these decreases were 2.4% (1.1), 0.15 L (0.08), and 0.06 L/s (0.19), respectively. All lung function parameters showed the greatest decline in group 1 (P < .001). CONCLUSIONS Diagnosing COPD based on the presence of more severe airflow obstruction (as defined by FEV₁/FVC less than LLN) means that, at the time of such a diagnosis, subjects had passed the phase of strong lung-function decline. TRIAL REGISTRY ISRCTN Register; No.: ISRCTN63545820; URL: www.trialregister.nl

Spirometric thresholds for diagnosing COPD: 0.70 or LLN, pre- or post-dilator values?

Abstract In absence of a gold standard for chronic obstructive pulmonary disease (COPD) it remains difficult to compare the true diagnostic characteristics of the forced expiratory volume in 1 second to the forced vital capacity (FEV1/FVC) <0.70 and < lower limit of normal (LLN). COPD is a clinical diagnosis, based on symptoms signs and lung function results combined, and an expert panel assessment would be an adequate reference standard. We compared the diagnostic properties of FEV1/FVC <LLN and <0.70 against this panel diagnosis: 342 participants, aged >50, consulting for persistent cough, but without physician-diagnosed COPD, were prospectively enrolled. All underwent extensive history taking, physical examination, spirometry and diffusion testing. An expert panel, including a board certified respiratory physician, assessed all diagnostic information to determine the presence or absence of COPD and served as reference standard. Then, 104 participants were diagnosed with COPD by the panel. The reproducibility of the panel diagnosis was high (kappa of 0.94). Sensitivity estimates of <0.70 were significantly higher than that of <LLN (0.73 and 0.47, respectively, p < 0.001). The fixed approach was less specific than the LLN (0.95 and 0.99, respectively, p < 0.001). There was no significant difference in diagnostic property when using pre- or post-bronchodilator FEV1/FVC (p = 0.615). In a symptomatic primary care population, the FEV1/FVC <0.70 was more accurate to detect COPD.