Alphabet Soup: Assessment of Dyspnea

Abstract

The purposes of this study were: to describe chest CT findings in normal non-smoking controls and cigarette smokers with and without COPD; to compare the prevalence of CT abnormalities with severity of COPD; and to evaluate concordance between visual and quantitative chest CT (QCT) scoring. Methods: Volumetric inspiratory and expiratory CT scans of 294 subjects, including normal non-smokers, smokers without COPD, and smokers with GOLD Stage I-IV COPD, were scored at a multi-reader workshop using a standardized worksheet. There were 58 observers (33 pulmonologists, 25 radiologists); each scan was scored by 9–11 observers. Interobserver agreement was calculated using kappa statistic. Median score of visual observations was compared with QCT measurements. Results: Interobserver agreement was moderate for the presence or absence of emphysema and for the presence of panlobular emphysema; fair for the presence of centrilobular, paraseptal, and bullous emphysema subtypes and for the presence of bronchial wall thickening; and poor for gas trapping, centrilobular nodularity, mosaic attenuation, and bronchial dilation. Agreement was similar for radiologists and pulmonologists. The prevalence on CT readings of most abnormalities (e.g. emphysema, bronchial wall thickening, mosaic attenuation, expiratory gas trapping) increased significantly with greater COPD severity, while the prevalence of centrilobular nodularity decreased. Concordances between visual scoring and quantitative scoring of emphysema, gas trapping and airway wall thickening were 75%, 87% and 65%, respectively. Conclusions: Despite substantial inter-observer variation, visual assessment of chest CT scans in cigarette smokers provides information regarding lung disease severity; visual scoring may be complementary to quantitative evaluation.     

Identification of Occult Parechymal Disease Such as Emphysema or Airway Disease Using Screening Computed Tomography

ABSTRACT

Rationale: Chronic obstructive pulmonary disease (COPD) is a major public health problem. This study was performed to determine whether the low attenuation area (LAA) and visual score provided by low-dose computed tomography (CT) can be used to detect occult parenchymal disease, such as insidious COPD. Methods: Each participant underwent low-dose CT scan and pulmonary function tests. The LAA% of the corresponding lung area was calculated. The cut-off level between the normal lung density area and LAA was defined as –960 HU, and the severity of emphysematous change (visual score) and LAA% were evaluated on three same chest CT slices obtained at full inspiration. Results: Forty-eight of 2,247 individuals including 1058 non-smokers and 1189 smokers were diagnosed with COPD. Chest CT findings in individuals diagnosed with COPD showed centrilobular emphysema (50%), however, 17 of the subjects diagnosed with COPD had normal screening CT findings. Thirty-one subjects diagnosed with COPD showed a positive visual score, and 27 individuals with COPD showed LAA% of more than 30. Nine of 17 subjects with a negative visual score showed LAA% of more than 30. The visual score in smokers was significantly higher than that of non-smokers. The lung function in smokers was lower than that of non-smokers. Smokers also showed higher frequencies of chest CT abnormalities. Conclusion: Low-dose CT scans detected LAA and a positive visual score before COPD associated with an impaired lung function develops. Smokers with normal spirometry had a potential to develop an airflow obstruction accompanied with abnormal CT findings.     

Pulmonary Emphysema Subtypes on Computed Tomography: The MESA COPD Study

Background

Pulmonary emphysema is divided into 3 major subtypes at autopsy: centrilobular, paraseptal, and panlobular emphysema. These subtypes can be defined by visual assessment on computed tomography (CT); however, clinical characteristics of emphysema subtypes on CT are not well defined. We developed a reliable approach to visual assessment of emphysema subtypes on CT and examined if emphysema subtypes have distinct characteristics.

Methods

The Multi-Ethnic Study of Atherosclerosis COPD Study recruited smokers with chronic obstructive pulmonary disease (COPD) and controls ages 50-79 years with ≥10 pack-years. Participants underwent CT following a standardized protocol. Definitions of centrilobular, paraseptal, and panlobular emphysema were obtained by literature review. Six-minute walk distance and pulmonary function were performed following guidelines.

Results

Twenty-seven percent of 318 smokers had emphysema on CT. Interrater reliability of emphysema subtype was substantial (K: 0.70). Compared with participants without emphysema, individuals with centrilobular or panlobular emphysema had greater dyspnea, reduced walk distance, greater hyperinflation, and lower diffusing capacity. In contrast, individuals with paraseptal emphysema were similar to controls, except for male predominance. Centrilobular, but not panlobular or paraseptal, emphysema was associated with greater smoking history (+21 pack-years P <.001). Panlobular, but not other types of emphysema, was associated with reduced body mass index (−5 kg/m²; P = .01). Other than for dyspnea, these findings were independent of the forced expiratory volume in 1 second. Seventeen percent of smokers without COPD on spirometry had emphysema, which was independently associated with reduced walk distance.

Conclusions

Emphysema subtypes on CT are common in smokers with and without COPD. Centrilobular and panlobular emphysema, but not paraseptal emphysema, have considerable symptomatic and physiological consequences.     

Lobar distribution of non-emphysematous gas trapping and lung hyperinflation in chronic obstructive pulmonary disease

BackgroundLung hyperinflation in chronic obstructive pulmonary disease (COPD) is closely associated with emphysema and non-emphysematous gas trapping, termed functional small airway disease (fSAD), on inspiratory and expiratory computed tomography (CT). Because the cranial-caudal emphysema distribution affects pulmonary function and fSAD may precede emphysema on CT, we tested the hypothesis that lobar fSAD distribution would affect lung hyperinflation differently in COPD with minimal and established emphysema.MethodsThe volume percentages of fSAD and emphysema (fSAD% and Emph%) over the upper and lower lobes were measured using inspiratory and expiratory CT in 70 subjects with COPD. Subjects were divided into those with minimal and established emphysema (n = 36 and 34) using a threshold of 10% Emph% in the whole lung.ResultsIn the minimal emphysema group, fSAD% in the upper and lower lobes was positively correlated with functional residual capacity (FRC) and residual volume to total lung capacity ratio (RV/TLC), and the correlation of fSAD% with RV/TLC was greater in the lower lobes. Conversely, in the established emphysema group, fSAD% in the upper and lower lobes was correlated with RV/TLC, but not with FRC. In multivariate analysis, fSAD% in the lower lobes, but not in the upper lobes, was associated with RV/TLC in subjects with minimal emphysema after adjusting for age, smoking status, and bronchodilator use.ConclusionNon-emphysematous gas trapping in the upper and lower lobes has a distinct physiological effect, especially in COPD with minimal emphysema. This local evaluation might allow sensitive detection of changes in lung hyperinflation in COPD.     

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

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.     

Imaging of pulmonary emphysema: A pictorial review

The term ‘emphysema’ is generally used in a morphological sense, and therefore imaging modalities have an important role in diagnosing this disease. In particular, high resolution computed tomography (HRCT) is a reliable tool for demonstrating the pathology of emphysema, even in subtle changes within secondary pulmonary lobules. Generally, pulmonary emphysema is classified into three types related to the lobular anatomy: centrilobular emphysema, panlobular emphysema, and paraseptal emphysema. In this pictorial review, we discuss the radiological – pathological correlation in each type of pulmonary emphysema. HRCT of early centrilobular emphysema shows an evenly distributed centrilobular tiny areas of low attenuation with ill-defined borders. With enlargement of the dilated airspace, the surrounding lung parenchyma is compressed, which enables observation of a clear border between the emphysematous area and the normal lung. Because the disease progresses from the centrilobular portion, normal lung parenchyma in the perilobular portion tends to be preserved, even in a case of far-advanced pulmonary emphysema. In panlobular emphysema, HRCT shows either panlobular low attenuation or ill-defined diffuse low attenuation of the lung. Paraseptal emphysema is characterized by subpleural well-defined cystic spaces. Recent topics related to imaging of pulmonary emphysema will also be discussed, including morphometry of the airway in cases of chronic obstructive pulmonary disease, combined pulmonary fibrosis and pulmonary emphysema, and bronchogenic carcinoma associated with bullous lung disease.     

Airway dimensions and pulmonary function in chronic obstructive pulmonary disease and bronchial asthma

Background and objective: COPD and bronchial asthma are chronic airway diseases with a different pathogenesis. Comparisons of differences in airway calibre by bronchial generation between these diseases and their importance to pulmonary function have not been fully studied. We investigated airway calibre and wall thickness in relation to pulmonary function in patients with asthma, COPD, asthma plus emphysema and normal subjects using CT. Methods: Sixty‐three asthmatic patients, 46 COPD, 23 patients with asthma plus emphysema and 61 control subjects were studied cross‐sectionally. We used a software with curved multiplanar reconstruction to measure airway dimensions from 3rd‐ to 6th‐generation bronchi of the right lower posterior bronchus. Results: Patients with COPD had increased wall thickness, but the airway was not narrow from the 3rd‐(subsegmental) to 6th‐generation bronchi. Mean bronchial inner diameter (Di) of 3rd‐ to 6th‐generation bronchi in patients with asthma or asthma plus emphysema was smaller than that of COPD patients and normal subjects. Airway luminal area (Ai) of 5th‐generation bronchi most closely correlated with pulmonary function in patients with stable asthma. Although Di was similar in patients with asthma and asthma plus emphysema, the Ai of 6th‐generation bronchi correlated significantly with pulmonary function in patients with asthma plus emphysema. Conclusions: Airway calibre in asthma may be smaller than in COPD. Airflow limitations correlated more closely with peripheral Ai in patients with asthma plus emphysema than in patients with asthma alone.     

Recent findings in chronic obstructive pulmonary disease by using quantitative computed tomography

Chronic obstructive pulmonary disease (COPD) is characterized by an incompletely reversible airflow limitation that results from a combination of airway wall remodeling and emphysematous lung destruction. Forced expiratory volume in 1 s (FEV₁) has been considered the gold standard for diagnosis, classification, and follow-up in patients with COPD, but it has certain limitations and it is still necessary to find other noninvasive modalities to complement FEV₁ to evaluate the effect of therapeutic interventions and the pathogenesis of COPD. Quantitative computed tomography (CT) has partly met this demand. The extent of emphysema and airway dimensions measured using quantitative CT are associated with morphological and functional changes and clinical symptoms in patients with COPD. Phenotyping COPD based on quantitative CT has facilitated interventional and genotypic studies. Recent advances in COPD findings with quantitative CT are discussed in this review.     

The EvA study: aims and strategy

The EvA study is a European Union-funded project under the Seventh Framework Programme (FP7), which aims at defining new markers for chronic obstructive pulmonary disease (COPD) and its subtypes. The acronym is derived from emphysema versus airway disease, indicating that the project targets these two main phenotypes of the disease. The EvA study is based on the concept that emphysema and airway disease are governed by different pathophysiological processes, are driven by different genes and have differential gene expression in the lung. To define these genes, patients and non-COPD controls are recruited for clinical examination, lung function analysis and computed tomography (CT) of the lung. CT scans are used to define the phenotypes based on lung density and airway wall thickness. This is followed by bronchoscopy in order to obtain samples from the airways and the alveoli. These tissue samples, along with blood samples, are then subjected to genome-wide expression and association analysis and markers linked to the phenotypes are identified. The population of the EvA study is different from other COPD study populations, since patients with current oral glucocorticoids, antibiotics and exacerbations or current smokers are excluded, such that the signals detected in the molecular analysis are due to the distinct inflammatory process of emphysema and airway disease in COPD.     

CT assessment of subtypes of pulmonary emphysema in smokers

OBJECTIVE: To determine the incidence of subtypes of pulmonary emphysema (PE) identified by CT imaging in male patients who have a significant smoking history. Patients and setting: We reviewed 945 subjects (619 men and 326 women) who had undergone CT scanning. However, only the data for male subjects were analyzed due to there being too few female subjects. The male subjects were divided into the following two age groups: group A (age, 50 years). There were two subtypes of PE found: centrilobular emphysema (CLE) and paraseptal emphysema (PSE). Based on these subtypes, PE was divided into the following three categories: I (CLE or CLE-predominant); II (CLE and PSE of equal extent); and III (PSE or PSE-predominant). RESULTS: PE was found in 270 of 516 male smokers (10 of 38 female smokers had PE). Among male subjects, in age group A there were 53 subjects with some degree of PE (category I, 12 subjects [22.6%]; category II, 7 subjects [13.2%]; and category III, 34 subjects [64.2%]). Among men in age group B, there were 217 subjects with some degree of PE (category I, 109 subjects [50.2%]; category II, 23 subjects [10.6%]; and category III, 85 subjects [39.2%]). CONCLUSION: In age group A, men < 50 years of age who were in category III (PSE or PSE-predominant PE) predominated (34 of 53 subjects; 64.2%). In age group B, men > 50 years of age who were in category I (CLE or CLE-predominant PE) predominated (109 of 217 subjects; 50.2%).     

The extent of emphysema in patients with COPD

Background and Aims: The global initiative for COPD (GOLD) adopted the degree of airway obstruction as a measure of the severity of the disease. The objective of this study was to apply CT to assess the extent of emphysema in patients with chronic obstructive pulmonary disease (COPD) and relate this extent to the GOLD stage of airway obstruction. Materials and Methods: We included 209 patients with COPD. COPD was defined as FEV₁/FVC < 0.70 and no reversibility to β₂‐agonists. All patients were current smokers with a smoking history of ≥20 pack‐years. Patients were assessed by lung function measurement and visual and quantitative assessment of CT, from which the relative area of emphysema below ?910 Hounsfield units (RA‐910) was extracted. Results: Mean RA‐910 was 7.4% (n = 5) in patients with GOLD stage I, 17.0% (n = 119) in stage II, 24.2% (n = 79) in stage III and 33.9% (n = 6) in stage IV. Regression analysis showed a change in RA‐910 of 7.8% with increasing severity according to GOLD stage (P < 0.001). Combined visual and quantitative assessment of CT showed that 184 patients had radiological evidence of emphysema, whereas 25 patients had no emphysema. Conclusion: The extent of emphysema increases with increasing severity of COPD and most patients with COPD have emphysema. Tissue destruction by emphysema is therefore an important determinant of disease severity in COPD. Please cite this paper as: Shaker SB, Stavngaard T, Hestad M, Bach KS, Tonnesen P and Dirksen A. The extent of emphysema in patients with COPD. The Clinical Respiratory Journal 2009; 3: 15–21.     

Combined pulmonary fibrosis and emphysema (CPFE): an entity different from emphysema or pulmonary fibrosis alone

Chronic obstructive pulmonary disease (COPD) and idiopathic interstitial pneumonias (IIP), with different radiological, pathological, functional and prognostic characteristics, have been regarded as separate entities for a long time. However, there is an increasing recognition of the coexistence of emphysema and pulmonary fibrosis in individuals. The association was first described as a syndrome by Cottin in 2005, named “combined pulmonary fibrosis and emphysema (CPFE)”, which is characterized by exertional dyspnea, upper-lobe emphysema and lower-lobe fibrosis, preserved lung volume and severely diminished capacity of gas exchange. CPFE is frequently complicated by pulmonary hypertension, acute lung injury and lung cancer and prognosis of it is poor. Treatments for CPFE patients with severe pulmonary hypertension are less effective other than lung transplantation. However, CPFE has not yet attracted wide attention of clinicians and there is no research systematically contrasting the differences among CPFE, emphysema/COPD and IIP at the same time. The authors will review the existing knowledge of CPFE and compare them to either entity alone for the first time, with the purpose of improving the awareness of this syndrome and exploring novel effective therapeutic strategies in clinical practice.     

New concepts in the radiological assessment of COPD

Chronic obstructive pulmonary disease (COPD) is a complex genetic disorder in which environmental factors, such as tobacco smoke, interact with genetic susceptibility to cause disease. Airway obstruction in COPD is due to an exaggerated inflammatory response that ultimately destroys the lung parenchyma (emphysema) and increases airway resistance by remodeling the airway wall. Until recently, assessment of these disease processes required the examination of resected tissue. However, computed tomography (CT) now allows researchers to measure the structure of the lung parenchyma and airway wall without having to remove the tissue. This review describes some of the new CT techniques for quantitative assessment of lung structure. These techniques are extremely important to study the pathogenesis of COPD as well as differentiate patients with predominantly emphysema disease from those with airway wall remodeling, and to assess the effects of therapeutic interventions.     

Functional single nucleotide polymorphisms of the CCL5 gene and nonemphysematous phenotype in COPD patients

It was previously reported that the gain-of-function -28 guanine allele of the promoter single nucleotide polymorphism (SNP; cytosine to guanine substitution of nucleotide -28 (-28C>G)) in the CC chemokine ligand 5 gene (CCL5) was associated with susceptibility to late-onset asthma in patients who developed asthma at age > or =40 yrs. The clinical diagnosis of chronic obstructive pulmonary disease (COPD) includes emphysema and small airway disease, and upregulation of CCL5 has been described in the airways of patients with COPD. It was hypothesised that CCL5 has a genetic impact upon the variable expression of emphysema in patients with COPD. Patients with COPD were studied (n = 267). All of the patients underwent pulmonary high-resolution computed tomography (CT), and visual scoring (CT score) was performed to determine emphysema severity. Three SNPs of CCL5 were genotyped, including -403G>A, -28C>G and 375T>C. A significant difference was found in CT score according to CCL5 genotype; the -28G allele was inversely associated with CT score. When the analysis was confined to 180 patients with bronchial reversibility of <15%, even stronger evidence for this association was noted. Functional single nucleotide polymorphisms in the CC chemokine ligand 5 gene were associated with milder emphysema. Together with previous findings, the present study may identify the CC chemokine ligand 5 gene as part of a common pathway in the pathogenesis of late-onset asthma and chronic obstructive pulmonary disease with milder emphysema.     

CT Emphysema Predicts Thoracic Aortic Calcification in Smokers with and Without COPD

ABSTRACT

COPD patients are at increased risk for cardiovascular morbidity and mortality independent of smoking habits. Recent studies suggest CT emphysema is an independent predictor of cardiovascular risk as evidenced by its association with arterial stiffness and impaired endothelial function. We examined the relationship between demographics, lung function, CT emphysema and airway wall thickness and thoracic aortic calcification, another marker of cardiovascular risk, in the National Lung Screening Trial. We hypothesized that CT emphysema would be independently associated with thoracic aortic calcification. Two hundred forty current and former smokers were enrolled. After CT examination, we recorded subjects’ demographics and they performed spirometry. Subjects were classified into COPD and non-COPD subgroups. CT emphysema was quantified as a percentage of lung volume and measurements of the right upper lobe airway were performed using standard methods and expressed as wall area (%). Total calcification scores for the thoracic aorta were computed using TeraRecon image analysis. Univariate and multivariate analyses were performed to determine the associations between calcium score and subject characteristics. Subjects with COPD were older, more often male, heavier smokers and had more CT emphysema and greater aortic calcification than those without COPD. Calcium score was associated with age, pack-years, CT emphysema, wall area%, and lung function on univariate testing but only with age and CT emphysema on multivariate analysis. We conclude that CT emphysema is independently associated with thoracic calcification and thus may be used to assess cardiovascular risk in smokers with and without COPD.     

Polymorphisms in the Superoxide Dismutase-3 Gene Are Associated with Emphysema in COPD

ABSTRACT

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.     

Pathophysiology of airflow limitation in chronic obstructive pulmonary disease

The airflow limitation that defines chronic obstructive pulmonary disease (COPD) is the result of a prolonged time constant for lung emptying, caused by increased resistance of the small conducting airways and increased compliance of the lung as a result of emphysematous destruction. These lesions are associated with a chronic innate and adaptive inflammatory immune response of the host to a lifetime exposure to inhaled toxic gases and particles. Processes contributing to obstruction in the small conducting airways include disruption of the epithelial barrier, interference with mucociliary clearance apparatus that results in accumulation of inflammatory mucous exudates in the small airway lumen, infiltration of the airway walls by inflammatory cells, and deposition of connective tissue in the airway wall. This remodelling and repair thickens the airway walls, reduces lumen calibre, and restricts the normal increase in calibre produced by lung inflation. Emphysematous lung destruction is associated with an infiltration of the same type of inflammatory cells found in the airways. The centrilobular pattern of emphysematous destruction is most closely associated with cigarette smoking, and although it is initially focused on respiratory bronchioles, separate lesions coalesce to destroy large volumes of lung tissue. The panacinar pattern of emphysema is characterised by a more even involvement of the acinus and is associated with alpha1 antitrypsin deficiency. The technology needed to diagnose and quantitate the individual small airway and emphysema phenotypes present in people with COPD is being developed, and should prove helpful in the assessment of therapeutic interventions designed to modify the progress of either phenotype.     

Vertical P-wave axis: the electrocardiographic synonym for pulmonary emphysema and its severity

Background

The correlation between vertical P-wave axis (P-axis > 60°) and pulmonary emphysema was investigated on a very large controlled series to see if P-axis verticalisation as lone criterion can be effectively used to screen emphysema in general population. Correlation between degrees of P-axis verticalisation and the severity of the obstructive lung disease (as per global initiative for chronic obstructive lung disease [GOLD] criteria) was also studied to see if this criterion can be used for gross quantification of the chronic obstructive pulmonary disease (COPD) in routine clinical practice.

Materials and methods

Around 6500 unselected, routine electrocardiograms (ECGs) were reviewed which yielded 600 ECGs with vertical P-axis in sinus rhythm. 635 ECGs from the same continuum were selected with P-axis ≤60° matched for patient''s age and sex serving as controls. Charts were reviewed for the diagnosis of COPD and emphysema based on medical history, pulmonary function tests, and imaging studies.

Results

Prevalence of emphysema in patients with vertical P-axis was strikingly higher than in the control group: 85% vs 4.4%. The sensitivity and specificity of vertical P-axis for diagnosing emphysema was 94.76% and 86.47%, respectively. Vertical P-axis and forced expiratory volume (FEV1) were inversely correlated (Pearson correlation coefficient=−0.683). Prevalence of severe COPD was strikingly higher in patients with P-axis > 75° as compared to the group with P-axis 60°–75°: 96.3% vs 4.6%. Close to 80% of the emphysema patients with P-axis > 85° had very severe disease (FEV1 < 30%).

Conclusion

P-axis verticalisation is highly effective for screening emphysema and degree of verticalisation provides a gross quantification of the disease.     

Journal Club

Systemic Steroid Exposure is Associated with Differential Methylation in Chronic Obstructive Pulmonary Disease. E.S. Wan, W. Qiu, A. Baccarelli, V.J. Carey, H. Bacherman, S.I. Rennard, A. Agusti, W.H. Anderson, D.A. Lomas, D.L. Demeo. Am J Respir Crit Care Med. 2012 Oct 11. [Epub ahead of print].

RATIONALE: Systemic glucocorticoids are used therapeutically to treat a variety of medical conditions. Epigenetic processes such as DNA methylation may reflect exposure to and may be involved in mediating the responses and side effects associated with these medications.

OBJECTIVE: To test the hypothesis that differences in DNA methylation are associated with current systemic steroid use.

METHODS: We obtained DNA methylation data at 27,578 CpG sites in 14,475 genes throughout the genome in two large, independent cohorts: the International COPD Genetics Network (ndiscovery = 1085) and the Boston Early Onset COPD study (nreplication = 369). Sites were tested for association with current systemic steroid use using generalized linear mixed models.

MAIN RESULTS: 511 sites demonstrated significant differential methylation by systemic corticosteroid use in all 3 of our primary models. Pyrosequencing validation confirmed robust differential methylation at CpG sites annotated to genes such as SLC22A18, LRP3, HIPK3, SCNN1A, FXYD1, IRF7, AZU1, SIT1, GPR97, ABHD16B, and RABGEF1. Functional annotation clustering demonstrated significant enrichment in intrinsic membrane components, hemostasis and coagulation, cellular ion homeostasis, leukocyte and lymphocyte activation and chemotaxis, protein transport, and responses to nutrients.

CONCLUSIONS: Our analyses suggest systemic steroid use is associated with site-specific differential methylation throughout the genome. Differentially methylated CpG sites were found in both biologically plausible and previously unsuspected pathways; these genes and pathways may be relevant in the development of novel targeted therapies.

Comments: For many COPD patients oral steroids seem to be more effective than inhaled steroids even at very low doses. The reasons for this are likely multifactorial but may include systemic steroids having effects on certain extrapulmonary manifestations of COPD that nonetheless effect their symptoms and propensity for exacerbations. The ability of this research to identify potential systemic therapeutic targets that may provide benefits without the adverse consequences of long term systemic steroids would be a significant advance.

The Effect of Emphysema on Computed Tomographic Measures of Airway Dimensions in Smokers. A.A. Diaz, M.K. Han, C.E. Come, R.S. Estepar, J.C. Ross, V. Kim, M.T. Dransfield, D. Curran-Everett, J.D. Schroeder, D.A. Lynch, J. Tschirren, E.K. Silverman, G.R. Washko. Chest. 2012 Oct 8. [Epub ahead of print]

BACKGROUND: In CT scans of smokers with COPD, the subsegmental airway wall area percent (WA%) is greater and more strongly correlated with FEV1% predicted than WA% obtained in the segmental airways. Since emphysema is linked to loss of airway tethering and may limit airway expansion, increases in WA% may be related to emphysema and not solely due to remodeling. We aimed to first determine if the stronger association of subsegmental vs. segmental WA% with FEV1% predicted is mitigated by emphysema; and second, to assess the relationships between emphysema, WA%, and total bronchial area (TBA).

METHODS: We analyzed CT segmental and subsegmental WA% (WA% = 100*wall area/TBA) of six bronchial paths and corresponding lobar emphysema, lung function, and clinical data in 983 smokers with COPD.

RESULTS: Compared to segmental, the subsegmental WA% had a greater effect on FEV1% predicted (–0.8 to –1.7% vs. –1.9 to –2.6% per 1-unit increase in WA%, respectively; P<0.05 for most bronchial paths). After adjusting for emphysema, the association between subsegmental WA% and FEV1% predicted was weakened in two bronchial paths. Increases in WA% between bronchial segments correlated directly with emphysema in all bronchial paths (P<0.05). In multivariate regression models, emphysema was directly related to subsegmental WA% in most bronchial paths and inversely related to subsegmental TBA in all bronchial paths.

CONCLUSION: The greater effect of subsegmental WA% on airflow obstruction is mitigated by emphysema. Part of the emphysema effect might be due to loss of airway tethering leading to reduction in TBA and increase in WA%.

Comments: Several studies have identified the central role of small airway damage in the pathophysiology of COPD. The role of alveolar destruction from emphysema and loss of smaller airway tethering has been proposed in past and is supported by this study. While it is typically proposed that only 20–30% of COPD patients have significant emphysema it is possible that we underestimate the presence of emphysema in patients typically considered to be purely chronic bronchitis that do not have CT performed. It is possible also that CT scan may underestimate emphysematous changes that may be only appreciated on direct tissue examination. Further studies are needed to elucidate the importance of these findings.

Chronic obstructive pulmonary disease as a cardiovascular risk factor. Results of a case-control study (CONSISTE study). P. de Lucas-Ramos, J.L. Izquierdo-Alonso, J.M. Moro, J.F. Frances, P.V. Lozano, J.M. Bellon-Cano; CONSISTE study group. Int J Chron Obstruct Pulmon Dis. 2012;7:679-86. Epub 2012 Oct 1.

INTRODUCTION: Chronic obstructive pulmonary disease (COPD) patients present a high prevalence of cardiovascular disease. This excess of comorbidity could be related to a common pathogenic mechanism, but it could also be explained by the existence of common risk factors. The objective of this study was to determine whether COPD patients present greater cardiovascular comorbidity than control subjects and whether COPD can be considered a risk factor per se.

METHODS: 1200 COPD patients and 300 control subjects were recruited for this multicenter, cross-sectional, case-control study.

RESULTS: Compared with the control group, the COPD group showed a significantly higher prevalence of ischemic heart disease (12.5% versus 4.7%; P < 0.0001), cerebrovascular disease (10% versus 2%; P < 0.0001), and peripheral vascular disease (16.4% versus 4.1%; P < 0.001). In the univariate risk analysis, COPD, hypertension, diabetes, obesity, and dyslipidemia were risk factors for ischemic heart disease. In the multivariate analysis adjusted for the remaining factors, COPD was still an independent risk factor (odds ratio: 2.23; 95% confidence interval: 1.18–4.24; P = 0.014).

CONCLUSION: COPD patients show a high prevalence of cardiovascular disease, higher than expected given their age and the coexistence of classic cardiovascular risk factors

Comments: In this study both cases and controls had to be over 40, minimum 10 pack year history and no other respiratory diagnoses. Controls were recruited largely from a group referred for tobacco consults and did not have pulmonary symptoms. This study showed that compared to smokers, smokers with COPD were significantly more likely to have comorbidities except for lung cancer. The rates of lung cancer were very low and the study was powered based on risk of ischemic heart disease. Ischemic heart disease was much higher in those with stage IV versus stage III but not with other groups. In multivariate analysis adjusted for smoking, age, dyslipidemia, hypertension COPD was still a risk factor for ischemic heart disease and for peripheral vascular disease and cerebral vascular disease. The relationship between atherosclerosis and COPD in smokers is compelling and may ultimately be incorporated in management guidelines with regard to screening and treatment paradigms for COPD.

Treatment of COPD by clinical phenotypes. Putting old evidence into clinical practice. M. Miravitlles, J. Jose Soler-Cataluna, M. Calle, J.B. Soriano. Eur Respir J. 2012 Oct 11. [Epub ahead of print]

Abstract: The new GOLD update has moved forward the principles of treatment of stable COPD by including the concepts of symptoms and risks into the decision of therapy; however, no mention of the concept of clinical phenotypes was included. It is recognized that COPD is a very heterogeneous disease and not all patients respond to all the drugs available for treatment. The identification of responders to therapies is crucial in chronic diseases to provide the most appropriate treatment and avoid unnecessary medications. The classically defined phenotypes of chronic bronchitis and emphysema, together with the newly described phenotypes of overlap COPD-asthma and frequent exacerbator allow a simple classification of patients that share clinical characteristics and outcomes and, more importantly, similar responses to existing treatments.These clinical phenotypes can help clinicians identify patients that respond to specific pharmacologic interventions. As an example, frequent exacerbators are the only subjects with an indication for anti-inflammatory treatment in COPD. Among them, those with chronic bronchitis are the only candidates to receive PDE4 inhibitors. Patients with overlap COPD-asthma phenotype show an enhanced response to inhaled corticosteroids and infrequent exacerbators should only receive bronchodilators. These well defined clinical phenotypes could potentially be incorporated into treatment guidelines.

Comment: This article is a very nice review of the utility of current clinical phenotypes that can be used to guide initial therapeutic strategies. While the Gold guidelines current iteration has included risks and symptoms to the treatment guideline paradigm the proposed treatment by clinical phenotypes as outlined in this article is perhaps more user friendly for the practicing clinician. Indeed many clinicians can readily assess and identify clinical phenotypes in their patient population rather than remember the criteria for each quadrant of the current Gold Guideline paradigm. Ultimately however each patient is and individual and therapy should take many factors into consideration.     

Racial Differences in CT Phenotypes in COPD

Abstract

Background: Whether African Americans (AA) are more susceptible to COPD than non-Hispanic Whites (NHW) and whether racial differences in disease phenotype exist is controversial. The objective is to determine racial differences in the extent of emphysema and airway remodeling in COPD. Methods: First, 2,500 subjects enrolled in the COPDGene study were used to evaluate racial differences in quantitative CT (QCT) parameters of% emphysema, air trapping and airway wall thickness. Independent variables studied included race, age, gender, education, BMI, pack-years, smoking status, age at smoking initiation, asthma, previous work in dusty job, CT scanner and center of recruitment. Results: Of the 1,063 subjects with GOLD Stage II-IV COPD, 200 self-reported as AA. AAs had a lower mean% emphysema (13.1% vs. 16.1%, p = 0.005) than NHW and proportionately less emphysema in the lower lung zones. After adjustment for covariates, there was no statistical difference by race in air trapping or airway wall thickness. Measured QCT parameters were more predictive of poor functional status in NHWs compared to AAs. Conclusions: AAs have less emphysema than NHWs but the same degree of airway disease. Additional factors not easily assessed by current QCT techniques may account for the poor functional status in AAs.