Sex Differences in Emphysema and Airway Diseases in Smokers. P.G. Camp, H.O. Coxson, R. D. Levy, S. Pillai, W. Anderson, J. Vestbo, S.M. Kennedy, E.K. Silverman, D.A. Lomas, P.D. Paré (Chest 2009; Jul 17. Epub ahead of print).
Background. Recent reports suggest that women are more susceptible to cigarette smoke and to an airway-predominant rather than emphysema-predominant COPD phenotype. The study purpose was to test for sex differences in COPD phenotypes using high resolution CT (HRCT) in male and female smokers with and without COPD.
Methods. All subjects completed spirometry and an epidemiologic respiratory questionnaire. Inspiratory HRCT scans were obtained on 688 smokers enrolled in a family-based study of COPD. Emphysema was assessed using a density mask with a Hounsfield Unit (HU) cutoff of −950 to calculate the percentage low attenuation area (LAA%) and by the fractal value D, which is the slope of a power law analysis defining the relationship between the number and size of the emphysematous lesions. Airway wall thickness was assessed by calculating the square root of airway wall area (SQRTWA) and the wall area (WA) % relative to internal perimeter.
Results. Women had similar FEV(1) % predicted (women 65.5 ± 31.9%; men 62.1 ± 30.4%; p = 0.16) but fewer pack years of cigarettes (women 37.8 ± 19.7; men 47.8 ± 27.4; p < 0.0001). Men had a greater LAA% (24 + 12% vs 20 + 11%; p < 0.0001) and larger emphysematous spaces than women and these differences persisted after adjusting for covariates (weight, pack years, current smoking status, center of enrollment and FEV(1)% predicted p = 0.0006). Women had a smaller SQRTWA and WA% after adjusting for covariates (p < 0.0001).
Conclusions. Male smokers have more emphysema than female smokers, but female smokers do not show increased wall thickness compared to men.
Comments: It is interesting that this study did not necessarily suggest that women are more affected than males as males had more emphysema and women did not have evidence of increased wall thickness. These women had lower pack-year histories and this may influence the degree of lung damage. While the authors say that they adjusted for pack-years as a covariate, it would be interesting to match women and men with similar pack-year histories to see if women have more damage. Given that women may have more bronchial hyper reactivity (BHR), this may also be important to evaluate in this cohort and determine whether or not a greater BHR influences the assessment of the airway component of COPD in women.
Temporal Clustering of Exacerbations in Chronic Obstructive Pulmonary Disease. J.R. Hurst, G.C. Donaldson, J.K. Quint, J.J. Goldring, R. Baghai-Ravary, J.A. Wedzicha. (Am J Respir Crit Care Med 2009 Mar 1;179(5):369–374).
Rationale. Exacerbations are important events in chronic obstructive pulmonary disease. Preventing exacerbations is a key treatment goal. Observational data suggest that after a first exacerbation, patients may be at increased risk of a second exacerbation, but this has not been specifically studied. We hypothesized that exacerbations may cluster together in time, a finding that would have important implications for targeting preventative interventions and the analysis of clinical trial data.
Objectives. To assess whether exacerbations are random events, or cluster in time.
Methods. A total of 297 patients in the London chronic obstructive pulmonary disease cohort recorded daily symptoms and were assessed for a total of 904 patient-years. The observed timing of second exacerbations after an initial exacerbation was compared with that expected should exacerbations occur randomly.
Measurements and Main Results. The observed timing distribution of second exacerbations differed significantly (p < 0.001) from the expected exponential function (shape parameter of the fitted Weibull function, 0.966 [95% confidence interval, 0.948–0.985]), suggesting that more second exacerbations occurred sooner than later and that exacerbations cluster together in time. Twenty-seven percent of first exacerbations were followed by a second recurrent event within 8 weeks. Approximately one third of exacerbations were recurrent exacerbations. Although initial exacerbations were milder than isolated events, they were not less likely to receive treatment, and under-treatment of initial events is not a plausible explanation for exacerbation recurrence. Recurrent exacerbations contribute significantly to overall exacerbation frequency (ρ = 0.81; p < 0.0001).
Conclusions. Exacerbations are not random events but cluster together in time such that there is a high-risk period for recurrent exacerbation in the 8-week period after an initial exacerbation.
Comment: Many of us in clinical practice see patients that just don't seem to return to baseline after an exacerbation and may very well have a repeat exacerbation within 8 to 12 weeks. This study raises important questions that need to be further addressed. Perhaps there is something distinct about the exacerbator group or something that may predict who they are. Perhaps they have aspiration problems or underlying bronchiectatic changes. The fact that the group identified as having these frequent exacerbations were significantly younger seems counterintuitive to what one might have expected. Is it possible they were more of an asthma phenotype than COPD (although there was no difference in pulmonary function between this group and others)? The fact that they were younger but seemed to have similar lung function suggests that they may be so-called “rapid decliners,” a feature that does seem to predict frequent exacerbators. This study is very instructive and further highlights the heterogeneity of COPD.
PTEN identified as Important Risk Factor of Chronic Obstructive Pulmonary Disease. H.D. Hosgood 3rd, I. Menashe, X. He, S. Chanock, Q. Lan. (Respir Med 2009 Jul 20. Epub ahead of print).
Common genetic variation may play an important role in altering chronic obstructive pulmonary disease (COPD) risk. In Xuanwei, China, the COPD rate is more than twice the Chinese national average, and COPD is strongly associated with in-home coal use. To identify genetic variation that may be associated with COPD in a population with substantial in-home coal smoke exposures, we evaluated 1261 single nucleotide polymorphisms (SNPs) in 380 candidate genes potentially relevant for cancer and other human diseases in a population-based case-control study in Xuanwei (53 cases; 107 controls). PTEN was the most significantly associated gene with COPD in a minP analysis using 20,000 permutations (p = 0.00005). SNP-based analyses found that homozygote variant carriers of PTEN rs 701848 (OR(TT) = 0.12, 95% CI = 0.03–0.47) had a significant decreased risk of COPD. PTEN, or phosphatase and tensin homolog, is an important regulator of cell cycle progression and cellular survival via the AKT signaling pathway. Our exploratory analysis suggests that genetic variation in PTEN may be an important risk factor of COPD in Xuanwei. However, due to the small sample size, additional studies are needed to evaluate these associations within Xuanwei and other populations with coal smoke exposures.
Comments: We are gaining greater appreciation for the heterogeneity of COPD in terms of both biology and etiology. It will be interesting to see if PTEN is more relevant in this population in China where the major etiology may very well be in-home coal use rather than tobacco smoke. It will also be instructive to evaluate PTEN in COPD cohorts that are more ethnically/racially diverse, and perhaps with a more significant smoking history to determine if this SNP has a general association with increased COPD prevalence or if it confers only risks in particular populations and/or with particular exposures, hence demonstrating the complexity of the study of epi-genetics in COPD.
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