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Rationale: Limited data on sex differences in advanced COPD are available.
Objectives: To compare male and female emphysema patients with severe disease.
Methods: One thousand fifty-three patients (38.8% female) evaluated for lung volume reduction surgery as part of the National Emphysema Treatment Trial were analyzed.
Measurements and Main Results: Detailed clinical, physiological, and radiological assessment, including quantitation of emphysema severity and distribution from helical chest computed tomography, was completed. In a subgroup (n = 101), airway size and thickness was determined by histological analyses of resected tissue. Women were younger and exhibited a lower body mass index (BMI), shorter smoking history, less severe airflow obstruction, lower Dlco and arterial Po2, higher arterial Pco2, shorter six-minute walk distance, and lower maximal wattage during oxygen-supplemented cycle ergometry. For a given FEV1% predicted, age, number of pack-years, and proportion of emphysema, women experienced greater dyspnea, higher modified BODE, more depression, lower SF-36 mental component score, and lower quality of well-being. Overall emphysema was less severe in women, with the difference from men most evident in the outer peel of the lung. Females had thicker small airway walls relative to luminal perimeters.
Conclusions: In patients with severe COPD, women, relative to men, exhibit anatomically smaller airway lumens with disproportionately thicker airway walls, and emphysema that is less extensive and characterized by smaller hole size and less peripheral involvement.
Sex differences in chronic obstructive pulmonary disease are increasingly recognized.
In patients with severe COPD, women, relative to men, exhibit anatomically smaller airway lumens with disproportionately thicker airway walls, and emphysema that is less extensive and characterized by smaller hole size and less peripheral involvement.
The prevalence and mortality of chronic obstructive pulmonary disease (COPD) in female smokers is rapidly increasing (1). Female smokers are more likely than men to report respiratory symptoms (2–4) and exhibit greater baseline airway responsiveness to methacholine (5). Indirect evidence suggests that women may be more predisposed to develop smoking-induced lung function impairment (4, 6, 7) and experience greater mortality (8). Despite these compelling data, COPD continues to be underdiagnosed in women (9), and research into sex differences in advanced COPD remains limited (4, 10, 11). Using carefully characterized patients from the National Emphysema Treatment Trial (NETT), we hypothesized that differences in disease expression in severe emphysema would be identified between males and females. Specifically, we sought to examine differences in the symptomatic, physiological, radiological, and histological expression of emphysema.
The study group consisted of 1,053 patients randomized at 17 NETT clinics (12) in whom baseline high resolution computed chest tomographs (HRCT) were available for analysis at the Imaging Analysis Center of the University of Iowa (see below). The design and methods of the trial have been detailed previously (12, 13); major enrollment criteria are enumerated in the online supplement.
Demographic data and medical history were collected using standardized instruments. Health status was assessed using general and disease-specific instruments. Dyspnea was quantified using the University of California, San Diego Shortness of Breath Questionnaire (UCSD SOBQ) (14). Depression was assessed using the Beck Depression Inventory (15).
Patients underwent spirometry before and after albuterol administration, while plethysmographic lung volumes were measured after albuterol administration. Diffusing capacity and arterial blood gases were also measured. The protocol for 6-minute walk testing (6MWT) has been described (16). Maximal exercise capacity was measured using a cycle ergometer. A multidimensional index, the BODE, was modified using previously described methodology (mBODE) (17).
Emphysema severity and distribution was determined from chest computed tomography (CT) scans obtained at full inspiration. After segmenting and dividing the lung according to previously described protocols (18), images were analyzed using custom-built software, the Pulmonary Analysis Software Suite (PASS). The density histogram was plotted, with values less than −950 HU corresponding to severe emphysema and regions with values of −910 HU and −850 HU roughly equating to moderate and mild emphysema, respectively. The alpha value (inverse slope) was determined from the log–log relationship of hole size versus number of holes (19). Lungs with greater proportions of small lesions have a steep negative slope and a large alpha.
Lung tissue was available for analysis in 101 subjects from five centers (Baylor, Colorado, Michigan, Pittsburgh, and Temple). Previous reports have described the methods used to process the tissue and to estimate airways remodeling and luminal occlusion by inflammatory exudates containing mucus (20). We examined cross sections of airways < 2 mm in diameter. Maximal lumen area was calculated (18, 21). Wall thickness included the area between the epithelial luminal surface and the connective tissue at the outer limit of the adventitia. The fractional areas (Vv) taken up by epithelium, lamina propria, the smooth muscle itself, and the adventitia were also measured. The ratio of tissue area to basement membrane length was used to express the volume to surface (V/S) ratio or thickness of the airway wall and its compartments.
Continuous data were compared using t tests. Multivariate linear regression models were used to assess the relationships between sex and dependent variables of FEV1% predicted, mBODE, dyspnea, depression, health status scores, whole-lung emphysema, and whole-lung alpha. Potential confounders included age, number of pack-years, whole-lung emphysema proportions, and FEV1% predicted (confounder excluded when it was the dependent variable in the model). mBODE or inspiratory capacity (IC)/TLC were also explored as confounders when appropriate. All sex comparisons of airway wall and its compartments were performed using a mixed hierarchical model, which accounted for the clustering of airway analysis within subjects (Proc Mixed, version 9.1; SAS, Carey, NC).
Compared with males, female subjects were slightly younger, had a slightly lower mean Body Mass Index (BMI), and reported significantly shorter smoking histories and an older age at the time of smoking onset (Table 1). Women exhibited slightly less severe airflow obstruction but a similar TLC, slightly lower diffusing capacity (DlCO), IC/TLC, PaO2, and higher PaCO2. The difference in PaO2 persisted when adjusted for differences in PaCO2 (difference −2.21 mm Hg; 95% confidence interval [95% CI], −3.44, −0.98; P = 0.0004). The 6MWT and maximal exercise capacity were lower in women. Men exhibited slightly lower α1-antitrypsin levels than women (Table 1), although the distribution of α1 genotypes was not different (P = 0.44, data not shown). In the cohort there were only 16 patients felt to be α1-deficient; in this group, only two were females.
After adjusting for age, pack-years of smoking, and whole-lung emphysema proportion, women showed a higher prebronchodilator FEV1% predicted than men (mean FEV1% predicted 2.98% greater; 95% CI, 2.19, 3.78; P < 0.0001). Although the results were not statistically confirmed when predicted values of Hankinson and coworkers (22) were substituted for those of Crapo and colleagues (23–25), the direction remained suggestive (mean FEV1% predicted 0.69% greater; 95% CI, −0.14, 1.51; P = 0.10). All interactions involving sex and other predictors in the model were investigated; none were found to be significant. Results were similar when postbronchodilator FEV1 was examined (data not shown). Lower DlCO in females remained significant (−2.79% pred; 95% CI, −3.99, −1.58) after adjustment for whole lung emphysema proportion, age, and pack-years of smoking.
Female patients noted greater breathlessness (UCSD SOBQ) and depression (Beck total score), and lower SF-36 mental component score (MCS) (Table 1). Increased breathlessness in women (average adjusted UCSD SOBQ score 5.03 higher; 95% CI, 2.57–7.49) remained significant (P < 0.0001) after adjusting for age, FEV1% predicted, whole-lung emphysema proportion, and pack-years (Table 2). Results were similar when postbronchodilator FEV1 was used in the models (data not shown), although they were less evident when the IC/TLC was included in the model (see Table E1 in the online supplement).
In separate multivariate models predicting total Beck score (Table 2) and SF-36 MCS (Table 2), significant interactions between age and sex were found after adjusting for FEV1% predicted, whole-lung emphysema proportion, and pack-years. These sex interactions remained when the FEV1 was replaced by the IC/TLC score or the mBODE (Tables E1 and E2). Based on these interaction analyses, our data suggest that women under the age of 79.2 years tended to have a higher total Beck score than men, but as age increased, the total Beck score tended to decrease more rapidly in women than in men (Figure 1A). Similarly, women under the age of 73.5 years tended to have a lower SF-36 MCS than men of the same age, with the disparity between sexes decreasing with age (Figure 1B). These strong sex interactions remained evident after adjustment for mBODE scores (Figure E1). No other interactions with sex were found to be significant in Table 2.
Few differences were noted between sexes in health status, as assessed by the SF-36 physical component score or the SGRQ, in either univariate or multivariate analyses (Table 2). In univariate analysis, QWB was marginally lower in women than men (P = 0.05). In the multivariate setting (Table 2), the statistical significance of the association of QWB with female sex increased after adjusting for confounders (on average females lower by 0.02; 95% CI, −0.003, 0.036 lower; P = 0.02). Results were quantitatively similar using both sets of predicted values for FEV1. When postbronchodilator FEV1 was used in modeling the association of QWB and sex, it became marginally significant (0.001; 95% CI, −0.00001, 0.0002; P = 0.05).
The proportion of whole-lung emphysema in women was lower using a threshold that identifies moderate emphysema (−910 HU, P < 0.0001), and marginally lower using a threshold for severe emphysema (−950 HU, P = 0.07) (Table 1). These associations were maintained in multivariate models (Table 3) (on average 3% less moderate emphysema; 95% CI, 1.4–4.6% less; P = 0.0002, on average 16.4% less severe emphysema; 95% CI, 0.2–30.5% less; P = 0.02). Postbronchodilator FEV1 was significant when included in the model identifying severe emphysema (−950 HU) (−0.001; 95% CI, −0.002, −0.0002, P = 0.01), while other differences were unchanged. These results remained qualitatively similar when the FEV1 was replaced by the IC/TLC (Table E3) and the mBODE (Table E4). Similarly, women exhibited significantly higher whole-lung alpha value using either emphysema threshold (Tables 1 and and3).3). No significant interactions of other covariates with sex were found in any of the multivariate models in Table 3. When the analyses were adjusted for IC/TLC (Table E3) and mBODE (Table E4) in place of FEV1, the direction of these differences was similar.
Emphysema distribution also differed between sexes (Table 1). Women showed a similar proportion of emphysema in the core of the lung (P = 0.93) but a lower proportion in the peel (P = 0.002). Results were quantitatively similar using both sets of predicted values for FEV1.
The small airways of the female lung had a reduced basement membrane length (PI) compared with male lungs, but only marginally lower total wall area (Table 4). This disparity resulted in clear sex differences (P < 0.05) in estimates of thickness obtained from the ratio of wall area/PI for the total wall and its epithelial and adventitial compartments.
This retrospective analysis of a large, prospectively studied cohort of patients with severe COPD enrolled in a clinical trial of lung volume reduction surgery documents sex-specific disparities in symptom severity, health status, and distribution of pathologic changes assessed using both radiological and histological techniques. For a given age, FEV1% predicted, smoking history, and proportion of emphysema, women experienced greater dyspnea, higher mBODE scores, higher depression scores, a lower SF-36 MCS, and a lower quality of well-being than men. Women also showed less severe overall emphysema than men, particularly in the lung peel, and smaller emphysema hole size, even with adjustment for FEV1% predicted, age, and smoking history. The small (< 2 mm diameter) airways of women had relatively thicker walls and disproportionately reduced airway lumens. By simultaneously correlating symptoms with carefully standardized physiological, radiological, and histological data, these results for the first time unite several previously separate lines of investigation in women's health and COPD.
These data showing greater breathlessness in women relative to men at similar degrees of airflow obstruction and emphysema severity are important because they imply that sex-specific anatomic differences must be considered in models of COPD pathogenesis. Interestingly, this difference was less evident after adjustment in IC/TLC, suggesting that part of this difference may relate to differences in lung volume. Our data agree with population-based studies in which women reported greater respiratory symptoms (3, 26–31), with two multinational studies based on physician-reported COPD, in which women were more likely to report severe dyspnea (2, 32), and with two case-control studies (33, 34). The magnitude of difference in breathlessness in multivariate modeling in our data was above the level felt to be a minimal clinically important difference with this instrument (35). When the dyspnea score was incorporated in a validated multidimensional index (36), the mBODE (17), we also found that women exhibited higher scores than men. Extending these findings using state-of-the-art quantitative CT imaging and histological techniques, our results lay the groundwork to integrate population-based COPD research with current concepts on the neuropsychological responses to stress and the molecular pathogenesis of inflammation.
The significant differences in the amount and distribution of emphysema in women compared with men are novel findings that encompass both severe (< −950 HU) and less severe (< −910 HU) emphysema. Few studies have examined the severity or distribution of emphysema in women with severe COPD. In a population-based study, patients with clinically defined emphysema were primarily male, whereas patients with chronic asthmatic bronchitis were predominantly female (37). Using state-of-the-art CT imaging, we confirm that emphysema is less severe in women, especially distally, and when present, is characterized by smaller hole size. Although the absolute differences between the sexes were modest, all analyses were remarkably consistent in their direction. Furthermore, in multivariate analysis adjusting for FEV1, IC/TLC, mBODE, smoking history, and age, the proportion of severe emphysema was significantly lower in women, suggesting distinct differences in emphysema severity and distribution.
Whether comparable degrees of cigarette smoking induce greater reductions in lung function in female smokers is controversial, with data for (6, 26, 38–40) and against (41–43) that premise. Based on the ability to adjust for the proportion of emphysema, we noted a higher FEV1% predicted in women at a given duration of cigarette smoking, and no significant interaction between sex and smoking history. Women in our cohort initiated smoking at a later age than men. Given their lower mean age at the time of randomization, these changes are consistent with those reported by other investigators (http://www.cdc.gov/tobacco/sgr/sgr_forwomen/pdfs/chp2.pdf), and may explain the lesser total pack-years of cigarette smoke exposure. Because our patients were selected for severe chronic airflow obstruction and an emphysematous phenotype, our data do not exclude the possibility that lung function deteriorates faster in female smokers during earlier stages of COPD (6, 26, 38–40, 44, 45). We noted a lower DlCO in women despite lesser anatomic emphysema. This finding may relate to the complex contributions of lung mechanics and gas exchange which contribute to DlCO. Interestingly, previous studies have identified a differential impact of central relative to distal emphysema on DlCO (46). Thus, differences in emphysema distribution identified in women in the current study may help explain the differences in DlCO.
The similarity between the sexes seen in FEV1% predicted implies that women should have a greater degree of peripheral airway pathology (20). Indeed, using validated morphometric techniques to analyze airway histology in a subset of our patients with similar airflow obstruction and smoking history to the entire cohort, we confirm that women have smaller airway lumens and disproportionately thicker airway walls than men. This change would be anticipated to alter airway compliance and increase airways resistance. Theoretical analysis of the effect of airway wall thickness on resistance indicates that in proportion to the change in lumen radius even a minor thickening of the airway wall amplifies the effect of muscle shortening on lumen caliber and increases resistance of the airways (47).
Women in our study had worse health status, reflected in a lower QWB, although SF-36 PCS and SGRQ scores were similar in both sexes. These data are congruent with the limited data on sex differences in health status in COPD (48), which found that women expressed greater dissatisfaction with their lives (49), and were more likely to categorize their global self-reported health as “not very well” than as “well” (30). Recently, a small case control study suggested worse SGRQ in women (33), although this finding was not supported by others (34, 50). Women might report greater respiratory symptoms and worse health status because they perceive a given physiological perturbation differently (51).
Women in our study exhibited greater depression and significantly worse SF-36 MCS scores. In addition, age and sex interacted, with younger women exhibiting significantly greater Beck and lower SF-36 MCS scores than older women; this trend was much less evident in males. The magnitude of the difference in multivariate modeling is within the range identified for mild depression (15). Sex differences in depressive symptoms have recently been reported in COPD (34, 52). Furthermore, depression may potentiate the sensation of breathlessness (34, 53). Similar interactions between age and sex on depression have been reported previously in healthy subjects (54). Several explanations have been proposed for age and sex differences in depression, including differences in defensiveness and rumination, respectively (54). Older adults exhibit greater defensiveness (55) and an increased ability to regulate emotions (56). Importantly, women show greater defensiveness than men with increasing age. Rumination is associated with increased depression, is more common in women, and among women is inversely related to age (57). Younger women's tendencies to feel less control over emotions and negative events, and feel a greater responsibility for the emotional tone of relationships, may mediate the relationship between rumination and depression (58). However, in another recent study (59) rumination and depression were positively associated with peripheral blood lymphocyte, leukocyte, and B cell counts, as well as health care utilization, in healthy older adults but not in younger adults. Our data cannot provide a mechanistic explanation for the reported differences, but suggest that additional investigation in this area is required.
Why cigarette smoking differentially affects the airways and lung parenchyma of men versus women is unclear. Potential explanations include greater baseline airway hyperresponsiveness in women (5, 60–62) and differences in particulate deposition within the airways (2, 4). The magnitude and character of the inflammatory response to cigarette smoke is likely to be affected by sex hormones, for which several leukocyte subsets have receptors. Progesterone induces cyclical changes in IL-8 production (63) and promotes a Th2 cytokine response (64). Cyclical changes in estradiol concentrations in women have been associated with changes in lung adrenergic receptor density and in concentrations of mucus, acetylcholine, and prostaglandin (4). Estradiol also increases T cell expression of receptors for CC chemokines and alters T cell homing patterns (65). Interestingly, analysis of bronchoalveolar fluid in healthy individuals showed a significantly increased percentage of CD4+ T cells in women over age 43, compared with men and with younger women (66). Idiopathic cough, associated with lymphocytic inflammation manifest as bronchoalveolar lymphocytosis, is seen predominately in older women (67). However, even though human innate and adaptive immune responses show complex degrees of sexual dimorphism that vary with the specific pathogen and over the life of the individual (68), current understandings of this dimorphism do not fully explain sex-based differences in COPD pathogenesis or phenotype, and most importantly, do not yet suggest opportunities for prevention or treatment.
Limitations of this study come from its highly selective sample population. All subjects were enrolled in NETT, a randomized trial of lung volume reduction surgery for patients with a predominantly emphysematous phenotype. As such, selection bias was imposed by requirements for sustained smoking cessation and absence of comorbidities or significant sputum production. Similarly, the requirement for severe emphysema limits generalizability to all patients with COPD, as does the potential of a referral bias varying by sex. On the other hand, no specific sex-related factors were included in the evaluation process or in the inclusion/exclusion criteria, which should minimize bias in the current analyses. The cross-sectional nature of the analyses also limits the ability to define mechanisms and distinct phenotypes. Nevertheless, the results of our study should be considered as hypothesis generating. It is possible that our findings on emphysema characteristics and airway abnormalities result principally from the greater size of the adult male lung. Importantly, sex differences in emphysema distribution and proportion persisted after extensive analyses adjusting for lung volume.
In summary, this study shows that women with severe COPD exhibit distinct disease manifestations than men. Relative to men, advanced COPD in women is characterized anatomically by smaller airway lumens and disproportionately thick airway walls, and by emphysema that is less extensive, manifest by smaller hole size and less peripheral involvement. These anatomic differences are accompanied by distinctive symptomatology. At a given FEV1% predicted, age, and proportion of emphysema, female patients with COPD report greater breathlessness and depression, despite similar health status. Our data should motivate future studies to determine the complex interactions between biological and sociocultural factors (4) that contribute to these differences, and thus to provide a foundation for novel therapies to reduce the increasingly disproportionate burden of this common disease in women.
The National Emphysema Treatment Trial (NETT) was supported by contracts with the National Heart, Lung, and Blood Institute (N01HR76101, N01HR76102, N01HR76103, N01HR76104, N01HR76105, N01HR76106, N01HR76107, N01HR76108, N01HR76109, N01HR76110, N01HR76111, N01HR76112, N01HR76113, N01HR76114, N01HR76115, N01HR76116, N01HR76118, and N01HR76119); the Centers for Medicare and Medicaid Services (CMS; formerly the Health Care Financing Administration); and the Agency for Healthcare Research and Quality (AHRQ). J.L.C. is supported by funding from a Research Enhancement Award Program (REAP) from the Biomedical Laboratory Research & Development Service, Department of Veterans Affairs.
This article has an online supplement, which is accessible from this issue's table of contents at www.atsjournals.org
Originally Published in Press as DOI: 10.1164/rccm.200606-828OC on April 12, 2007
Conflict of Interest Statement: F.J.M. is a consultant for Altana Pharma and has received compensation greater than $10K. He has been a member of several Advisory Boards, CME committees and the Speaker's Bureau for Boehringer Ingelheim (BI), Pfizer, and GlaxoSmithKline (GSK). Total compensation per company is greater than $10K. In addition, he is on the advisory board for Novartis and speaker's bureau for Sepracor and Astra, receiving less than $10K per company. He has been an investigator for industry-sponsored studies for GSK, BI, and Actelion. J.L.C. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. F.S. does not have a financial relationship with a commercial entity that has aninterest in the subject of this manuscript. J.M. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. N.D.G. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. G.W. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. E.K. is a member of the GERRAF board, for which she receives $2,500 annually, and serves on the advisory board for GE, CT, and GE Healthcare, for which she has received less than $3,000 annually. S.M. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. G.J.C. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. D.D.S. has received honoraria for speaking engagements from Astra Zeneca (AZ) in 2004 ($3,000) and in 2005 ($11,000), and from GSK in 2004 ($8,000), in 2005 ($6,000), and in 2006 ($12,000). He has also received unrestricted research funding as either the principal investigator or co-principal investigator from GSK in 2004 for $1.5 million and from AZ in 2007 ($100,000). He has also received $1,500 from GSK for consultancy work in 2006. J.H. has acted as an advisor to Altana in February 2006, GSK in September 2006, and Sepicor in October 2006. He has served as a consultant for GSK and Bronchus Technologies in 2006. He has received grants through a peer reviewed Canadian Institutes of Health Research-industry sponsored program in which Merck and GSK have served as the industrial partners. He has received less than Can $20,000 as compensation for this work. A.L.R. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. M.H. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. A.P.F. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. B.M. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. E.A.H. is a founder and shareholder in VIDA Diagnostics, a company commercializing image analysis software used in this study. Z.M. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. R.W. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript.
The members of the National Emphysema Treatment Trial Research Group were as follows: Office of the Chair of the Steering Committee, University of Pennsylvania, Philadelphia, PA: Alfred P. Fishman, M.D. (Chair); Betsy Ann Bozzarello; Ameena Al-Amin. Clinical Centers: Baylor College of Medicine, Houston, TX: Marcia Katz, M.D. (Principal Investigator); Carolyn Wheeler, R.N., B.S.N. (Principal Clinic Coordinator); Elaine Baker, R.R.T., R.P.F.T.; Peter Barnard, Ph.D., R.P.F.T.; Phil Cagle, M.D.; James Carter, M.D.; Sophia Chatziioannou, M.D.; Karla Conejo-Gonzales; Kimberly Dubose, R.R.T.; John Haddad, M.D.; David Hicks, R.R.T., R.P.F.T.; Neal Kleiman, M.D.; Mary Milburn-Barnes, C.R.T.T.; Chinh Nguyen, R.P.F.T.; Michael Reardon, M.D.; Joseph Reeves-Viets, M.D.; Steven Sax, M.D.; Amir Sharafkhaneh, M.D.; Owen Wilson, Ph.D.; Christine Young, P.T.; Rafael Espada, M.D. (Principal Investigator 1996–2002); Rose Butanda (1999–2001); Minnie Ellisor (2002); Pamela Fox, M.D. (1999–2001); Katherine Hale, M.D. (1998–2000); Everett Hood, R.P.F.T. (1998–2000); Amy Jahn (1998–2000); Satish Jhingran, M.D. (1998–2001); Karen King, R.P.F.T. (1998–1999); Charles Miller III, Ph.D. (1996–1999); Imran Nizami, M.D. (Co-Principal Investigator, 2000–2001); Todd Officer (1998–2000); Jeannie Ricketts (1998–2000); Joe Rodarte, M.D. (Co-Principal Investigator 1996–2000); Robert Teague, M.D. (Co-Principal Investigator 1999–2000); Kedren Williams (1998–1999). Brigham and Women's Hospital, Boston, MA: John Reilly, M.D. (Principal Investigator); David Sugarbaker, M.D. (Co-Principal Investigator); Carol Fanning, R.R.T. (Principal Clinic Coordinator); Simon Body, M.D.; Sabine Duffy, M.D.; Vladmir Formanek, M.D.; Anne Fuhlbrigge, M.D.; Philip Hartigan, M.D.; Sarah Hooper, E.P.; Andetta Hunsaker, M.D.; Francine Jacobson, M.D.; Marilyn Moy, M.D.; Susan Peterson, R.R.T.; Roger Russell, M.D.; Diane Saunders; Scott Swanson, M.D. (Co-Principal Investigator, 1996–2001). Cedars-Sinai Medical Center, Los Angeles, CA: Rob McKenna, M.D. (Principal Investigator); Zab Mohsenifar, M.D. (Co-Principal Investigator); Carol Geaga, R.N. (Principal Clinic Coordinator); Manmohan Biring, M.D.; Susan Clark, R.N., M.N.; Jennifer Cutler, M.D.; Robert Frantz, M.D.; Peter Julien, M.D.; Michael Lewis, M.D.; Jennifer Minkoff-Rau, M.S.W.; Valentina Yegyan, B.S., C.P.F.T.; Milton Joyner, B.A. (1996–2002). Cleveland Clinic Foundation, Cleveland, OH: Malcolm DeCamp, M.D. (Principal Investigator); James Stoller, MD (Co-Principal Investigator); Yvonne Meli, R.N., (Principal Clinic Coordinator); John Apostolakis, M.D.; Darryl Atwell, M.D.; Jeffrey Chapman, M.D.; Pierre DeVilliers, M.D.; Raed Dweik, M.D.; Erik Kraenzler, M.D.; Rosemary Lann, L.I.S.W.; Nancy Kurokawa, R.R.T., C.P.F.T.; Scott Marlow, R.R.T.; Kevin McCarthy, R.C.P.T.; Pricilla McCreight, R.R.T., C.P.F.T.; Atul Mehta, M.D.; Moulay Meziane, M.D.; Omar Minai, M.D.; Mindi Steiger, R.R.T.; Kenneth White, R.P.F.T.; Janet Maurer, M.D. (Principal Investigator, 1996–2001); Terri Durr, RN (2000–2001); Charles Hearn, D.O. (1998–2001); Susan Lubell, P.A.-C. (1999–-2000); Peter O'Donovan, M.D. (1998–2003); Robert Schilz, D.O. (1998–2002). Columbia University, New York, NY in consortium with Long Island Jewish Medical Center, New Hyde Park, NY: Mark Ginsburg, M.D. (Principal Investigator); Byron Thomashow, M.D. (Co-Principal Investigator); Patricia Jellen, M.S.N., R.N. (Principal Clinic Coordinator); John Austin, M.D.; Matthew Bartels, M.D.; Yahya Berkmen, M.D.; Patricia Berkoski, M.S., R.R.T. (Site coordinator, L.I.J.); Frances Brogan, M.S.N., R.N.; Amy Chong, B.S., C.R.T.; Glenda DeMercado, B.S.N.; Angela DiMango, M.D.; Sandy Do, M.S., P.T.; Bessie Kachulis, M.D.; Arfa Khan, M.D.; Berend Mets, M.D.; Mitchell O'Shea, B.S., R.T., C.P.F.T.; Gregory Pearson, M.D.; Leonard Rossoff, M.D.; Steven Scharf, M.D., Ph.D. (Co-Principal Investigator, 1998–2002); Maria Shiau, M.D.; Paul Simonelli, M.D.; Kim Stavrolakes, M.S., P.T.; Donna Tsang, B.S.; Denise Vilotijevic, M.S., P.T.; Chun Yip, M.D.; Mike Mantinaos, M.D. (1998–2001); Kerri McKeon, B.S., R.R.T., R.N. (1998–1999); Jacqueline Pfeffer, M.P.H., P.T. (1997–2002). Duke University Medical Center, Durham, NC: Neil MacIntyre, M.D. (Principal Investigator); R. Duane Davis, M.D. (Co-Principal Investigator); John Howe, R.N. (Principal Clinic Coordinator); R. Edward Coleman, M.D.; Rebecca Crouch, R.P.T.; Dora Greene; Katherine Grichnik, M.D.; David Harpole, Jr., M.D.; Abby Krichman, R.R.T.; Brian Lawlor, R.R.T.; Holman McAdams, M.D.; John Plankeel, M.D.; Susan Rinaldo-Gallo, M.E.D.; Sheila Shearer, R.R.T.; Jeanne Smith, A.C.S.W.; Mark Stafford-Smith, M.D.; Victor Tapson, M.D.; Mark Steele, M.D. (1998–1999); Jennifer Norten, MD (1998–1999). Mayo Foundation, Rochester, MN: James Utz, M.D. (Principal Investigator); Claude Deschamps, M.D. (Co-Principal Investigator); Kathy Mieras, C.C.R.P. (Principal Clinic Coordinator); Martin Abel, M.D.; Mark Allen, M.D.; Deb Andrist, R.N.; Gregory Aughenbaugh, M.D.; Sharon Bendel, R.N.; Eric Edell, M.D.; Marlene Edgar; Bonnie Edwards; Beth Elliot, M.D.; James Garrett, R.R.T.; Delmar Gillespie, M.D.; Judd Gurney, M.D.; Boleyn Hammel; Karen Hanson, R.R.T.; Lori Hanson, R.R.T.; Gordon Harms, M.D.; June Hart; Thomas Hartman, M.D.; Robert Hyatt, M.D.; Eric Jensen, M.D.; Nicole Jenson, R.R.T.; Sanjay Kalra, M.D.; Philip Karsell, M.D.; Jennifer Lamb; David Midthun, M.D.; Carl Mottram, R.R.T.; Stephen Swensen, M.D.; Anne-Marie Sykes, M.D.; Karen Taylor; Norman Torres, M.D.; Rolf Hubmayr, M.D. (1998–2000); Daniel Miller, M.D. (1999–2002); Sara Bartling, R.N. (1998–2000); Kris Bradt (1998–2002). National Jewish Medical and Research Center, Denver, CO: Barry Make, M.D. (Principal Investigator); Marvin Pomerantz, M.D. (Co-Principal Investigator); Mary Gilmartin, R.N., R.R.T. (Principal Clinic Coordinator); Joyce Canterbury; Martin Carlos; Phyllis Dibbern, P.T.; Enrique Fernandez, M.D.; Lisa Geyman, M.S.P.T.; Connie Hudson; David Lynch, M.D.; John Newell, M.D.; Robert Quaife, M.D.; Jennifer Propst, R.N.; Cynthia Raymond, M.S.; Jane Whalen-Price, P.T.; Kathy Winner, O.T.R.; Martin Zamora, M.D.; Reuben Cherniack, M.D. (Principal Investigator, 1997–2000). Ohio State University, Columbus, OH: Philip Diaz, M.D. (Principal Investigator); Patrick Ross, M.D. (Co-Principal Investigator); Tina Bees (Principal Clinic Coordinator); Jan Drake; Charles Emery, Ph.D.; Mark Gerhardt, M.D., Ph.D.; Mark King, M.D.; David Rittinger; Mahasti Rittinger. Saint Louis University, Saint Louis, MO: Keith Naunheim, M.D. (Principal Investigator); Robert Gerber, M.D. (Co-Principal Investigator); Joan Osterloh, R.N., M.S.N. (Principal Clinic Coordinator); Susan Borosh; Willard Chamberlain, D.O.; Sally Frese; Alan Hibbit; Mary Ellen Kleinhenz, M.D.; Gregg Ruppel; Cary Stolar, M.D.; Janice Willey; Francisco Alvarez, M.D. (Co-Principal Investigator, 1999–2002); Cesar Keller, M.D. (Co-Principal Investigator, 1996–2000). Temple University, Philadelphia, PA: Gerard Criner, M.D. (Principal Investigator); Satoshi Furukawa, M.D. (Co-Principal Investigator); Anne Marie Kuzma, R.N., M.S.N. (Principal Clinic Coordinator); Roger Barnette, M.D.; Neil Brister, M.D.; Kevin Carney, R.N., C.C.T.C.; Wissam Chatila, M.D.; Francis Cordova, M.D.; Gilbert D'Alonzo, D.O.; Michael Keresztury, M.D.; Karen Kirsch; Chul Kwak, M.D.; Kathy Lautensack, R.N., B.S.N.; Madelina Lorenzon, C.P.F.T.; Ubaldo Martin, M.D.; Peter Rising, M.S.; Scott Schartel, M.D.; John Travaline, M.D.; Gwendolyn Vance, R.N., C.C.T.C.; Phillip Boiselle, M.D. (1997–2000); Gerald O'Brien, M.D. (1997–2000). University of California, San Diego, San Diego, CA: Andrew Ries, M.D., M.P.H. (Principal Investigator); Robert Kaplan, Ph.D. (Co-Principal Investigator); Catherine Ramirez, B.S., R.C.P. (Principal Clinic Coordinator); David Frankville, M.D.; Paul Friedman, M.D.; James Harrell, M.D.; Jeffery Johnson; David Kapelanski, M.D.; David Kupferberg, M.D., M.P.H.; Catherine Larsen, M.P.H.; Trina Limberg, R.R.T.; Michael Magliocca, R.N., C.N.P.; Frank J. Papatheofanis, M.D., Ph.D.; Dawn Sassi-Dambron, R.N.; Melissa Weeks. University of Maryland at Baltimore, Baltimore, MD in consortium with Johns Hopkins Hospital, Baltimore, MD: Mark Krasna, M.D. (Principal Investigator); Henry Fessler, M.D. (Co-Principal Investigator); Iris Moskowitz (Principal Clinic Coordinator); Timothy Gilbert, M.D.; Jonathan Orens, M.D.; Steven Scharf, M.D., Ph.D.; David Shade; Stanley Siegelman, M.D.; Kenneth Silver, M.D.; Clarence Weir; Charles White, M.D. University of Michigan, Ann Arbor, MI: Fernando Martinez, M.D. (Principal Investigator); Mark Iannettoni, M.D. (Co-Principal Investigator); Catherine Meldrum, B.S.N., R.N., C.C.R.N. (Principal Clinic Coordinator); William Bria, M.D.; Kelly Campbell; Paul Christensen, M.D.; Kevin Flaherty, M.D.; Steven Gay, M.D.; Paramjit Gill, R.N.; Paul Kazanjian, M.D.; Ella Kazerooni, M.D.; Vivian Knieper; Tammy Ojo, M.D.; Lewis Poole; Leslie Quint, M.D.; Paul Rysso; Thomas Sisson, M.D.; Mercedes True; Brian Woodcock, M.D.; Lori Zaremba, R.N. University of Pennsylvania, Philadelphia, PA: Larry Kaiser, M.D. (Principal Investigator); John Hansen-Flaschen, M.D. (Co-Principal Investigator); Mary Louise Dempsey, B.S.N., R.N. (Principal Clinic Coordinator); Abass Alavi, M.D.; Theresa Alcorn, Selim Arcasoy, M.D.; Judith Aronchick, M.D.; Stanley Aukberg, M.D.; Bryan Benedict, RRT; Susan Craemer, BS, RRT, C.P.F.T.; Ron Daniele, M.D.; Jeffrey Edelman, M.D.; Warren Gefter, M.D.; Laura Kotler-Klein, M.S.S.; Robert Kotloff, M.D.; David Lipson, M.D.; Wallace Miller, Jr., M.D.; Richard O'Connell, R.P.F.T.; Staci Opelman, M.S.W.; Harold Palevsky, M.D.; William Russell, R.P.F.T.; Heather Sheaffer, M.S.W.; Rodney Simcox, B.S.R.T., R.R.T.; Susanne Snedeker, RRT, C.P.F.T.; Jennifer Stone-Wynne, M.S.W.; Gregory Tino, M.D.; Peter Wahl; James Walter, RPFT; Patricia Ward; David Zisman, M.D.; James Mendez, M.S.N., C.R.N.P. (1997–2001); Angela Wurster, MSN, CRNP (1997–1999). University of Pittsburgh, Pittsburgh, PA: Frank Sciurba, M.D. (Principal Investigator); James Luketich, M.D. (Co-Principal Investigator); Colleen Witt, M.S. (Principal Clinic Coordinator); Gerald Ayres; Michael Donahoe, M.D.; Carl Fuhrman, M.D.; Robert Hoffman, M.D.; Joan Lacomis, M.D.; Joan Sexton; William Slivka; Diane Strollo, M.D.; Erin Sullivan, M.D.; Tomeka Simon; Catherine Wrona, R.N., B.S.N.; Gerene Bauldoff, R.N., M.S.N. (1997–2000); Manuel Brown, M.D. (1997–2002); Elisabeth George, R.N., M.S.N. (Principal Clinic Coordinator 1997–2001); Robert Keenan, M.D. (Co-Principal Investigator 1997–2000); Theodore Kopp, M.S. (1997–1999); Laurie Silfies (1997–2001). University of Washington, Seattle, WA: Joshua Benditt, M.D. (Principal Investigator), Douglas Wood, M.D. (Co-Principal Investigator); Margaret Snyder, M.N. (Principal Clinic Coordinator); Kymberley Anable; Nancy Battaglia; Louie Boitano; Andrew Bowdle, M.D.; Leighton Chan, M.D.; Cindy Chwalik; Bruce Culver, M.D.; Thurman Gillespy, M.D.; David Godwin, M.D.; Jeanne Hoffman; Andra Ibrahim, M.D.; Diane Lockhart; Stephen Marglin, M.D.; Kenneth Martay, M.D.; Patricia McDowell; Donald Oxorn, M.D.; Liz Roessler; Michelle Toshima; Susan Golden (1998–2000). Other Participants: Agency for Healthcare Research and Quality, Rockville, MD: Lynn Bosco, M.D., M.P.H.; Yen-Pin Chiang, Ph.D.; Carolyn Clancy, M.D.; Harry Handelsman, D.O. Centers for Medicare and Medicaid Services, Baltimore, MD: Steven M. Berkowitz, Ph.D.; Tanisha Carino, Ph.D.; Joe Chin, M.D.; JoAnna Baldwin; Karen McVearry; Anthony Norris; Sarah Shirey; Claudette Sikora; Steven Sheingold, Ph.D. (1997–2004). Coordinating Center, The Johns Hopkins University, Baltimore, MD: Steven Piantadosi, M.D., Ph.D. (Principal Investigator); James Tonascia, Ph.D (Co-Principal Investigator); Patricia Belt; Amanda Blackford, Sc.M.; Karen Collins; Betty Collison; Ryan Colvin, M.P.H.; John Dodge; Michele Donithan, M.H.S.; Vera Edmonds; Gregory L. Foster, M.A.; Julie Fuller; Judith Harle; Rosetta Jackson; Shing Lee, Sc.M.; Charlene Levine; Hope Livingston; Jill Meinert; Jennifer Meyers; Deborah Nowakowski; Kapreena Owens; Shangqian Qi, M.D.; Michael Smith; Brett Simon, M.D.; Paul Smith; Alice Sternberg, ScM; Mark Van Natta, M.H.S.; Laura Wilson, Sc.M.; Robert Wise, M.D. Cost Effectiveness Subcommittee: Robert M. Kaplan, Ph.D. (Chair); J. Sanford Schwartz, M.D. (Co-Chair); Yen-Pin Chiang, Ph.D.; Marianne C. Fahs, Ph.D.; A. Mark Fendrick, M.D.; Alan J. Moskowitz, M.D.; Dev Pathak, Ph.D.; Scott Ramsey, M.D., Ph.D.; Steven Sheingold, Ph.D.; A. Laurie Shroyer, Ph.D.; Judith Wagner, Ph.D.; Roger Yusen, M.D. Cost Effectiveness Data Center, Fred Hutchinson Cancer Research Center, Seattle, WA: Scott Ramsey, M.D., Ph.D. (Principal Investigator); Ruth Etzioni, Ph.D.; Sean Sullivan, Ph.D.; Douglas Wood, M.D.; Thomas Schroeder, M.A.; Karma Kreizenbeck; Kristin Berry, M.S.; Nadia Howlader, M.S. CT Scan Image Storage and Analysis Center, University of Iowa, Iowa City, IA: Eric Hoffman, Ph.D. (Principal Investigator); Janice Cook-Granroth, B.S.; Angela Delsing, R.T.; Junfeng Guo, Ph.D.; Geoffrey McLennan, M.D.; Brian Mullan, M.D.; Chris Piker, B.S.; Joseph Reinhardt, Ph.D.; Blake Robinswood; Jered Sieren, R.T.R.; William Stanford, M.D. Data and Safety Monitoring Board: John A. Waldhausen, M.D. (Chair); Gordon Bernard, M.D.; David DeMets, Ph.D.; Mark Ferguson, M.D.; Eddie Hoover, M.D.; Robert Levine, M.D.; Donald Mahler, M.D.; A. John McSweeny, Ph.D.; Jeanine Wiener-Kronish, M.D.; O. Dale Williams, Ph.D.; Magdy Younes, M.D. Marketing Center, Temple University, Philadelphia, PA: Gerard Criner, M.D. (Principal Investigator); Charles Soltoff, M.B.A. Project Office, National Heart, Lung, and Blood Institute, Bethesda, MD: Gail Weinmann, M.D. (Project Officer); Joanne Deshler (Contracting Officer); Dean Follmann, Ph.D.; James Kiley, Ph.D.; Margaret Wu, Ph.D. (1996–2001). Other acknowledgments: Arthur Gelb, M.D., Lakewood Regional Medical Center, Lakewood, CA.