Promoting Participation in Pulmonary Rehabilitation after Hospitalization for Chronic Obstructive Pulmonary Disease, Strategies of Top-performing Systems: A Qualitative Study.

Rationale: Pulmonary rehabilitation (PR) after hospitalization for chronic obstructive pulmonary disease (COPD) is recommended by guidelines; however, few patients participate, and rates vary between hospitals. Objectives: To identify contextual factors and strategies that may promote participation in PR after hospitalization for COPD. Methods: Using a positive-deviance approach, we calculated hospital-specific rates of PR after hospitalization for COPD among a cohort of Medicare beneficiaries. At a purposive sample of high-performing and innovative hospitals in the United States, we conducted in-depth interviews with key stakeholders. We defined high-performing hospitals as having a PR rate above the 95th percentile, at least 6.58%. To learn from hospitals that demonstrated a commitment to improving rates of PR, regardless of PR rates after discharge, we identified innovative hospitals on the basis of a review of American Thoracic Society conference research presentations from prior years. Interviews were audio-recorded and transcribed verbatim. Using a directed content analysis approach, transcripts were coded iteratively to identify themes. Results: Interviews were conducted with 38 stakeholders at nine hospitals (seven high-performers and two innovators). Hospitals were diverse regarding size, teaching status, PR program characteristics, and geographic location. Participants included PR medical directors, PR managers, respiratory therapists, inpatient and outpatient providers, and others. We found that high-performing hospitals were broadly focused on improving care for patients with COPD, and several had recently implemented new initiatives to reduce rehospitalizations after admission for COPD in response to the Centers for Medicare and Medicaid Services/Medicare's Hospital Readmission Reduction Program. Innovative and high-performing hospitals had systems in place to identify patients with COPD that enabled them to provide patient education and targeted discharge planning. Strategies took several forms, including the use of a COPD navigator or educator. In addition, we found that high-performing hospitals reported effective interprofessional and patient communication, had clinical champions or external change agents, and received support from hospital leadership. Specific strategies to promote PR included education of referring providers, education of patients to increase awareness of PR and its benefits, and direct assistance in overcoming barriers. Conclusions: Our findings suggest that successful efforts to increase participation in PR may be most effective when part of a larger strategy to improve outcomes for patients with COPD. Further research is necessary to test the generalizability of our findings.

Comorbidities and mortality risk in adults younger than 50 years of age with chronic obstructive pulmonary disease.

RATIONALE AND OBJECTIVE: Patients with chronic obstructive pulmonary disease (COPD), usually diagnosed after the 6th decade, frequently suffer from comorbidities. Whether COPD patients 50 years or younger (Young COPD) have similar comorbidities with the same frequency and mortality impact as aged-matched controls or older COPD patients is unknown. METHODS: We compared comorbidity number, prevalence and type in 3 groups of individuals with ≥ 10 pack-years of smoking: A Young (≤ 50 years) COPD group (n = 160), an age-balanced control group without airflow obstruction (n = 125), and Old (> 50 years) COPD group (n = 1860). We also compared survival between the young COPD and control subjects. Using Cox proportional model, we determined the comorbidities associated with mortality risk and generated Comorbidomes for the "Young" and "Old" COPD groups. RESULTS: The severity distribution by GOLD spirometric stages and BODE quartiles were similar between Young and Old COPD groups. After adjusting for age, sex, and pack-years, the prevalence of subjects with at least one comorbidity was 31% for controls, 77% for the Young, and 86% for older COPD patients. Compared to controls, "Young" COPDs' had a nine-fold increased mortality risk (p < 0.0001). "Comorbidomes" differed between Young and Old COPD groups, with tuberculosis, substance use, and bipolar disorders being distinct comorbidities associated with increased mortality risk in the Young COPD group. CONCLUSIONS: Young COPD patients carry a higher comorbidity prevalence and mortality risk compared to non-obstructed control subjects. Young COPD differed from older COPD patients by the behavioral-related comorbidities that increase their risk of premature death.

Caribbean Latinx with moderate-severe asthma bear greater asthma morbidity than other Latinx.

BACKGROUND: Hispanic/Latinx (HL) ethnicity encompasses racially and culturally diverse subgroups. Studies suggest that Puerto Ricans (PR) may bear greater asthma-related morbidity than Mexicans, but these were conducted in children or had limited clinical characterization. OBJECTIVES: This study sought to determine whether disparities in asthma morbidity exist among HL adult subgroups. METHODS: Adults with moderate-severe asthma were recruited from US clinics, including from Puerto Rico, for the Person Empowered Asthma Relief (PREPARE) trial. Considering the shared heritage between PR and other Caribbean HL (Cubans and Dominicans [C&D]), the investigators compared baseline self-reported clinical characteristics between Caribbean HL (CHL) (PR and C&D: n = 457) and other HLs (OHL) (Mexicans, Spaniards, Central/South Americans; n = 141), and between CHL subgroups (C&D [n = 56] and PR [n = 401]). This study compared asthma morbidity measures (self-reported exacerbations requiring systemic corticosteroids, emergency department/urgent care (ED/UC) visits, hospitalizations, health care utilization) through negative binomial regression. RESULTS: CHL compared to OHL were similar in age, body mass index, poverty status, blood eosinophils, and fractional exhaled nitric oxide but were prescribed more asthma controller therapies. Relative to OHL, CHL had significantly increased odds of asthma exacerbations (odds ratio [OR]: 1.84; 95% CI: 1.4-2.4), ED/UC visits (OR: 1.88; 95% CI: 1.4-2.5), hospitalization (OR: 1.98; 95% CI: 1.06-3.7), and health care utilization (OR: 1.91; 95% CI: 1.44-2.53). Of the CHL subgroups, PR had significantly increased odds of asthma exacerbations, ED/UC visits, hospitalizations, and health care utilization compared to OHL, whereas C&D only had increased odds of exacerbations compared to OHL. PR compared to C&D had greater odds of ED/UC and health care utilization. CONCLUSIONS: CHL adults, compared with OHL, adults reported nearly twice the asthma morbidity; these differences are primarily driven by PR. Novel interventions are needed to reduce morbidity in this highly impacted population.

Uncertainty as a critical determinant of antibiotic prescribing in patients with an asthma exacerbation: a qualitative study.

OBJECTIVE: To identify factors that influence providers' decisions to prescribe antibiotics in patients presenting to the hospital with an asthma exacerbation. METHODS: We performed semi-structured interviews with a purposive sample of providers including sixteen hospitalists, emergency room providers, or pulmonologists, and one focus group with internal medicine residents recruited from one large, urban, teaching hospital and one small, rural, community hospital. Questions were informed by the Theoretical Domains Framework to determine factors that may influence behaviors. Directed content analysis was used to code and analyze transcripts of the interviews. RESULTS: Uncertainty regarding the diagnostic (asthma vs. COPD) and the cause of exacerbation (bacterial vs. viral infection) emerged as the main driver for prescribing behavior. Provider response to uncertainty included: "watchful waiting" or immediate antibiotic prescribing. The following factors played important roles in providers' prescribing decision: 1) awareness/agreement with existing guidelines 2) confidence in their ability to apply the guidelines in challenging cases; 3) perceived risk of patient deterioration without antibiotics; 4) fear of litigation; 5) habit and clinical inertia 6) prescribing within the group 7) lack of information of antibiotic prescribing rates and 8) lack of time and/or resources. CONCLUSIONS: We identified diagnostic uncertainty as the primary determinant of antibiotic prescribing in asthma exacerbations and developed a conceptual model to explain provider responses and factors that influenced their responses. These results enhance our understanding of the factors that can contribute to low-value and wasteful practices like superfluous antibiotic prescribing and will support the development of interventions to de-implement such practices.

Association between Initiation of Pulmonary Rehabilitation and Rehospitalizations in Patients Hospitalized with Chronic Obstructive Pulmonary Disease.

Rationale: Although clinical trials have found that pulmonary rehabilitation (PR) can reduce the risk of readmissions after hospitalization for a chronic obstructive pulmonary disease (COPD) exacerbation, less is known about PR's impact in routine clinical practice. Objectives: To evaluate the association between initiation of PR within 90 days of discharge and rehospitalization(s). Methods: We analyzed a retrospective cohort of Medicare beneficiaries (66 years of age or older) hospitalized for COPD in 2014 who survived at least 30 days after discharge. Measurements and Main Results: We used propensity score matching and estimated the risk of recurrent all-cause rehospitalizations at 1 year using a multistate model to account for the competing risk of death. Of 197,376 total patients hospitalized in 4,446 hospitals, 2,721 patients (1.5%) initiated PR within 90 days of discharge. Overall, 1,534 (56.4%) patients who initiated PR and 125,720 (64.6%) who did not were rehospitalized one or more times within 1 year of discharge. In the propensity-score-matched analysis, PR initiation was associated with a lower risk of readmission in the year after PR initiation (hazard ratio, 0.83; 95% confidence interval, 0.77-0.90). The mean cumulative number of rehospitalizations at 1 year was 0.95 for those who initiated PR within 90 days and 1.15 for those who did not (P < 0.001). Conclusions: After hospitalization for COPD, Medicare beneficiaries who initiated PR within 90 days of discharge experienced fewer rehospitalizations over 1 year. These results support findings from randomized controlled clinical trials and highlight the need to identify effective strategies to increase PR participation.

Somatotypes trajectories during adulthood and their association with COPD phenotypes.

RATIONALE: Chronic obstructive pulmonary disease (COPD) comprises distinct phenotypes, all characterised by airflow limitation. OBJECTIVES: We hypothesised that somatotype changes - as a surrogate of adiposity - from early adulthood follow different trajectories to reach distinct phenotypes. METHODS: Using the validated Stunkard's Pictogram, 356 COPD patients chose the somatotype that best reflects their current body build and those at ages 18, 30, 40 and 50 years. An unbiased group-based trajectory modelling was used to determine somatotype trajectories. We then compared the current COPD-related clinical and phenotypic characteristics of subjects belonging to each trajectory. MEASUREMENTS AND MAIN RESULTS: At 18 years of age, 88% of the participants described having a lean or medium somatotype (estimated body mass index (BMI) between 19 and 23 kg·m-2) while the other 12% a heavier somatotype (estimated BMI between 25 and 27 kg·m-2). From age 18 onwards, five distinct trajectories were observed. Four of them demonstrating a continuous increase in adiposity throughout adulthood with the exception of one, where the initial increase was followed by loss of adiposity after age 40. Patients with this trajectory were primarily females with low BMI and D LCO (diffusing capacity of the lung for carbon monoxide). A persistently lean trajectory was seen in 14% of the cohort. This group had significantly lower forced expiratory volume in 1 s (FEV1), D LCO, more emphysema and a worse BODE (BMI, airflow obstruction, dyspnoea and exercise capacity) score thus resembling the multiple organ loss of tissue (MOLT) phenotype. CONCLUSIONS: COPD patients have distinct somatotype trajectories throughout adulthood. Those with the MOLT phenotype maintain a lean trajectory throughout life. Smoking subjects with this lean phenotype in early adulthood deserve particular attention as they seem to develop more severe COPD.

Association Between Initiation of Pulmonary Rehabilitation After Hospitalization for COPD and 1-Year Survival Among Medicare Beneficiaries.

Importance: Meta-analyses have suggested that initiating pulmonary rehabilitation after an exacerbation of chronic obstructive pulmonary disease (COPD) was associated with improved survival, although the number of patients studied was small and heterogeneity was high. Current guidelines recommend that patients enroll in pulmonary rehabilitation after hospital discharge. Objective: To determine the association between the initiation of pulmonary rehabilitation within 90 days of hospital discharge and 1-year survival. Design, Setting, and Patients: This retrospective, inception cohort study used claims data from fee-for-service Medicare beneficiaries hospitalized for COPD in 2014, at 4446 acute care hospitals in the US. The final date of follow-up was December 31, 2015. Exposures: Initiation of pulmonary rehabilitation within 90 days of hospital discharge. Main Outcomes and Measures: The primary outcome was all-cause mortality at 1 year. Time from discharge to death was modeled using Cox regression with time-varying exposure to pulmonary rehabilitation, adjusting for mortality and for unbalanced characteristics and propensity to initiate pulmonary rehabilitation. Additional analyses evaluated the association between timing of pulmonary rehabilitation and mortality and between number of sessions completed and mortality. Results: Of 197 376 patients (mean age, 76.9 years; 115 690 [58.6%] women), 2721 (1.5%) initiated pulmonary rehabilitation within 90 days of discharge. A total of 38 302 (19.4%) died within 1 year of discharge, including 7.3% of patients who initiated pulmonary rehabilitation within 90 days and 19.6% of patients who initiated pulmonary rehabilitation after 90 days or not at all. Initiation within 90 days was significantly associated with lower risk of death over 1 year (absolute risk difference [ARD], -6.7% [95% CI, -7.9% to -5.6%]; hazard ratio [HR], 0.63 [95% CI, 0.57 to 0.69]; P < .001). Initiation of pulmonary rehabilitation was significantly associated with lower mortality across start dates ranging from 30 days or less (ARD, -4.6% [95% CI, -5.9% to -3.2%]; HR, 0.74 [95% CI, 0.67 to 0.82]; P < .001) to 61 to 90 days after discharge (ARD, -11.1% [95% CI, -13.2% to -8.4%]; HR, 0.40 [95% CI, 0.30 to 0.54]; P < .001). Every 3 additional sessions was significantly associated with lower risk of death (HR, 0.91 [95% CI, 0.85 to 0.98]; P = .01). Conclusions and Relevance: Among fee-for-service Medicare beneficiaries hospitalized for COPD, initiation of pulmonary rehabilitation within 3 months of discharge was significantly associated with lower risk of mortality at 1 year. These findings support current guideline recommendations for pulmonary rehabilitation after hospitalization for COPD, although the potential for residual confounding exists and further research is needed.

A Geographic Analysis of Racial Disparities in Use of Pulmonary Rehabilitation After Hospitalization for COPD Exacerbation.

BACKGROUND: Guidelines recommend pulmonary rehabilitation (PR) after hospitalization for an exacerbation of COPD, but few patients enroll in PR. We explored whether density of PR programs explained regional variation and racial disparities in receipt of PR. METHODS: We used Centers for Medicare & Medicaid Services data from 223,832 Medicare beneficiaries hospitalized for COPD during 2012 who were eligible for PR postdischarge. We used Hospital-Referral Regions (HRR) as the unit of analysis. For each HRR, we calculated the density of PR programs as a measure of program access and estimated risk-standardized rates of PR within 6 months of discharge overall, and for non-Hispanic, white, and black beneficiaries. We used linear regression to examine the relationship between access to PR and HRR PR rates. We tested for racial disparity in PR rates among non-Hispanic white and black beneficiaries living in the same HRRs. RESULTS: Across 306 HRRs, the median number of PR programs per 1,000 Medicare beneficiaries was 0.06 (interquartile range [IQR], 0.04-0.10). Risk-standardized rates of PR ranged from 0.53% to 6.67% (median, 1.93%). Density of PR programs was positively associated with PR rates overall and among non-Hispanic white beneficiaries (P < .001), but this relationship was not observed among black beneficiaries. Rates were higher among non-Hispanic white beneficiaries (median, 2.08%; IQR, 1.54%-2.87%) compared with black beneficiaries (median, 1.19%; IQR, 1.15%-1.20%). CONCLUSIONS: Greater PR program density was associated with higher rates of PR for non-Hispanic white but not black beneficiaries. Further research is needed to identify reasons for this discrepancy and strategies to increase receipt of PR for black patients.

Participation in Pulmonary Rehabilitation after Hospitalization for Chronic Obstructive Pulmonary Disease among Medicare Beneficiaries.

RATIONALE: Current guidelines recommend pulmonary rehabilitation (PR) after hospitalization for a chronic obstructive pulmonary disease (COPD) exacerbation, but little is known about its adoption or factors associated with participation. OBJECTIVES: To evaluate receipt of PR after a hospitalization for COPD exacerbation among Medicare beneficiaries and identify individual- and hospital-level predictors of PR receipt and adherence. METHODS: We identified individuals hospitalized for COPD during 2012 and recorded receipt, timing, and number of PR visits. We used generalized estimating equation models to identify factors associated with initiation of PR within 6 months of discharge and examined factors associated with number of PR sessions completed. RESULTS: Of 223,832 individuals hospitalized for COPD, 4,225 (1.9%) received PR within 6 months of their index hospitalization, and 6,111 (2.7%) did so within 12 months. Median time from discharge until first PR session was 95 days (interquartile range, 44-190 d), and median number of sessions completed was 16 (interquartile range, 6-25). The strongest factor associated with initiating PR within 6 months was prior home oxygen use (odds ratio [OR], 1.49; 95% confidence interval [CI], 1.39-1.59). Individuals aged 75-84 years and those aged 85 years and older (respectively, OR, 0.70; 95% CI, 0.66-0.75; and OR, 0.25; 95% CI 0.22-0.28), those living over 10 miles from a PR facility (OR, 0.42; 95% CI, 0.39-0.46), and those with lower socioeconomic status (OR, 0.42; 95% CI, 0.38-0.46) were less likely to receive PR. CONCLUSIONS: Two years after Medicare began providing coverage for PR, participation rates after hospitalization were extremely low. This highlights the need for strategies to increase participation.

Chronic Obstructive Pulmonary Disease (COPD) as a disease of early aging: Evidence from the EpiChron Cohort.

BACKGROUND: Aging is an important risk factor for most chronic diseases. Patients with COPD develop more comorbidities than non-COPD subjects. We hypothesized that the development of comorbidities characteristically affecting the elderly occur at an earlier age in subjects with the diagnosis of COPD. METHODS AND FINDINGS: We included all subjects carrying the diagnosis of COPD (n = 27,617), and a similar number of age and sex matched individuals without the diagnosis, extracted from the 727,241 records of individuals 40 years and older included in the EpiChron Cohort (Aragon, Spain). We compared the cumulative number of comorbidities, their prevalence and the mortality risk between both groups. Using network analysis, we explored the connectivity between comorbidities and the most influential comorbidities in both groups. We divided the groups into 5 incremental age categories and compared their comorbidity networks. We then selected those comorbidities known to affect primarily the elderly and compared their prevalence across the 5 age groups. In addition, we replicated the analysis in the smokers' subgroup to correct for the confounding effect of cigarette smoking. Subjects with COPD had more comorbidities and died at a younger age compared to controls. Comparison of both cohorts across 5 incremental age groups showed that the number of comorbidities, the prevalence of diseases characteristic of aging and network's density for the COPD group aged 56-65 were similar to those of non-COPD 15 to 20 years older. The findings persisted after adjusting for smoking. CONCLUSION: Multimorbidity increases with age but in patients carrying the diagnosis of COPD, these comorbidities are seen at an earlier age.

Prospective comparison of non-invasive risk markers of major cardiovascular events in COPD patients.

BACKGROUND: Chronic Obstructive Pulmonary Disease (COPD) is an independent risk factor for cardiovascular (CV) disease, one of the most frequent causes of death in COPD patients. The goal of the present study was to evaluate the prognostic value of non-invasive CV risk markers in COPD patients. METHODS: CV risk was prospectively evaluated in 287 COPD patients using non-invasive markers including the Framingham score, the Systematic Coronary Risk Evaluation (SCORE) charts, coronary arterial calcium (CAC), epicardial adipose tissue (EAT), as well as clinical, biochemical and physiological variables. The predictive power of each parameter was explored using CV events as the main outcome. RESULTS: During a median follow up of 65 months (ICR: 36-100), 44 CV events were recorded, 12 acute myocardial infarctions (27.3%), 10 ischemic heart disease/angina (22.7%), 12 peripheral artery disease events requiring surgery (27.3%) and 10 strokes (22.7%). A total of 35 CV deaths occurred during that period. Univariable analysis determined that age, hypertension, CRP, total Cholesterol, LDL-Cholesterol, Framingham score and CAC were independently associated with CV events. Multivariable analysis identified CAC as the best predictor of CV events (HR; 95%CI: 1.32; 1.19-1.46, p < 001). CONCLUSIONS: In COPD patients attending pulmonary clinics, CAC was the best independent non-invasive predictor of CV events. This tool may help evaluate the risk for a CV event in patients with COPD. Larger studies should reproduce and validate these findings.

Determinants of exercise-induced oxygen desaturation including pulmonary emphysema in COPD: Results from the ECLIPSE study.

Exercise-induced oxygen desaturation (EID) is related to mortality in patients with chronic obstructive pulmonary disease (COPD). We investigated: (1) the prevalence of EID; (2) the relative-weight of several physiological determinants of EID including pulmonary emphysema, and (3) the relationship of EID with certain patients' clinical characteristics. Data from 2050 COPD patients (age: 63.3 ± 7.1years; FEV1: 48.7 ± 15.7%pred.) were analyzed. The occurrence of EID (SpO2post ≤88%) at the six-minute walking test (6MWT) was investigated in association with emphysema quantified by computed-tomography (QCT), and several clinical characteristics. 435 patients (21%) exhibited EID. Subjects with EID had more QCT-emphysema, lower exercise capacity and worse health-status (BODE, ADO indexes) compared to non-EID. Determinant of EID were obesity (BMI≥30 kg/m2), impaired FEV1 (≤44%pred.), moderate or worse emphysema, and low SpO2 at rest (≤93%). Linear regression indicated that each 1-point increase on the ADO-score independently elevates odds ratio (≤1.5fold) for EID. About one in five COPD patients in the ECLIPSE cohort present EID. Advanced emphysema is associated with EID. In addition, obesity, severe airflow limitation, and low resting oxygen saturation increase the risk for EID. Patients with EID in GOLD stage II have higher odds to have moderate or worse emphysema compared those with EID in GOLD stage III-IV. Emphysematous patients with high ADO-score should be monitored for EID.

Exome Array Analysis Identifies a Common Variant in IL27 Associated with Chronic Obstructive Pulmonary Disease.

RATIONALE: Chronic obstructive pulmonary disease (COPD) susceptibility is in part related to genetic variants. Most genetic studies have been focused on genome-wide common variants without a specific focus on coding variants, but common and rare coding variants may also affect COPD susceptibility. OBJECTIVES: To identify coding variants associated with COPD. METHODS: We tested nonsynonymous, splice, and stop variants derived from the Illumina HumanExome array for association with COPD in five study populations enriched for COPD. We evaluated single variants with a minor allele frequency greater than 0.5% using logistic regression. Results were combined using a fixed effects meta-analysis. We replicated novel single-variant associations in three additional COPD cohorts. MEASUREMENTS AND MAIN RESULTS: We included 6,004 control subjects and 6,161 COPD cases across five cohorts for analysis. Our top result was rs16969968 (P = 1.7 × 10(-14)) in CHRNA5, a locus previously associated with COPD susceptibility and nicotine dependence. Additional top results were found in AGER, MMP3, and SERPINA1. A nonsynonymous variant, rs181206, in IL27 (P = 4.7 × 10(-6)) was just below the level of exome-wide significance but attained exome-wide significance (P = 5.7 × 10(-8)) when combined with results from other cohorts. Gene expression datasets revealed an association of rs181206 and the surrounding locus with expression of multiple genes; several were differentially expressed in COPD lung tissue, including TUFM. CONCLUSIONS: In an exome array analysis of COPD, we identified nonsynonymous variants at previously described loci and a novel exome-wide significant variant in IL27. This variant is at a locus previously described in genome-wide associations with diabetes, inflammatory bowel disease, and obesity and appears to affect genes potentially related to COPD pathogenesis.

Exome Sequencing Analysis in Severe, Early-Onset Chronic Obstructive Pulmonary Disease.

RATIONALE: Genomic regions identified by genome-wide association studies explain only a small fraction of heritability for chronic obstructive pulmonary disease (COPD). Alpha-1 antitrypsin deficiency shows that rare coding variants of large effect also influence COPD susceptibility. We hypothesized that exome sequencing in families identified through a proband with severe, early-onset COPD would identify additional rare genetic determinants of large effect. OBJECTIVES: To identify rare genetic determinants of severe COPD. METHODS: We applied filtering approaches to identify potential causal variants for COPD in whole exomes from 347 subjects in 49 extended pedigrees from the Boston Early-Onset COPD Study. We assessed the power of this approach under different levels of genetic heterogeneity using simulations. We tested genes identified in these families using gene-based association tests in exomes of 204 cases with severe COPD and 195 resistant smokers from the COPDGene study. In addition, we examined previously described loci associated with COPD using these datasets. MEASUREMENTS AND MAIN RESULTS: We identified 69 genes with predicted deleterious nonsynonymous, stop, or splice variants that segregated with severe COPD in at least two pedigrees. Four genes (DNAH8, ALCAM, RARS, and GBF1) also demonstrated an increase in rare nonsynonymous, stop, and/or splice mutations in cases compared with resistant smokers from the COPDGene study; however, these results were not statistically significant. We demonstrate the limitations of the power of this approach under genetic heterogeneity through simulation. CONCLUSIONS: Rare deleterious coding variants may increase risk for COPD, but multiple genes likely contribute to COPD susceptibility.

Prognostic value of variables derived from the six-minute walk test in patients with COPD: Results from the ECLIPSE study.

In addition to the six-min walk distance (6 MWD), other six-min walk test (6 MWT) derived variables, such as mean walk-speed (6MWSpeed), 6-min walk-work (6 MWW), distance-saturation product (DSP), exercise-induced oxygen desaturation (EID), and unintended stops may be useful for the prediction of mortality and hospitalization in patients with chronic obstructive pulmonary disease (COPD). We studied the association between 6 MWT-derived variables and mortality as well as hospitalization in COPD patients and compared it with the BODE index. A three-year prospective study (ECLIPSE) to evaluate the prognostic value of 6 MWT-derived variables in 2010 COPD patients. Cox's proportional-hazard regressions were performed to estimate 3-year mortality and hospitalization. During the follow-up, 193 subjects died and 622 were hospitalized. An adjusted Cox's regression model of hazard ratio [HR] for impaired 6 MWT-derived variables was significant referring to: mortality (6 MWD ≤334 m [2.30], 6MWSpeed ≤0.9 m/sec [2.15], 6 MWW ≤20000 m kg [2.17], DSP ≤290 m% [2.70], EID ≤88% [1.75], unintended stops [1.99]; and hospitalization (6 MWW ≤27000 m kg [1.23], EID ≤88% [1.25], BODE index ≥3 points [1.40]; all p ≤ 0.05). The 6 MWT-derived variables have an additional predictive value of mortality in patients with COPD. The 6 MWW, EID and the BODE index refine the prognosis of hospitalization.

COPD comorbidities network.

Multimorbidity frequently affects the ageing population and their co-existence may not occur at random. Understanding their interactions and that with clinical variables could be important for disease screening and management.In a cohort of 1969 chronic obstructive pulmonary disease (COPD) patients and 316 non-COPD controls, we applied a network-based analysis to explore the associations between multiple comorbidities. Clinical characteristics (age, degree of obstruction, walking, dyspnoea, body mass index) and 79 comorbidities were identified and their interrelationships quantified. Using network visualisation software, we represented each clinical variable and comorbidity as a node with linkages representing statistically significant associations.The resulting COPD comorbidity network had 428, 357 or 265 linkages depending on the statistical threshold used (p≤0.01, p≤0.001 or p≤0.0001). There were more nodes and links in COPD compared with controls after adjusting for age, sex and number of subjects. In COPD, a subset of nodes had a larger number of linkages representing hubs. Four sub-networks or modules were identified using an inter-linkage affinity algorithm and their display provided meaningful interactions not discernible by univariate analysis.COPD patients are affected by larger number of multiple interlinked morbidities which clustering pattern may suggest common pathobiological processes or be utilised for screening and/or therapeutic interventions.

A randomised trial of lung sealant versus medical therapy for advanced emphysema.

Uncontrolled pilot studies demonstrated promising results of endoscopic lung volume reduction using emphysematous lung sealant (ELS) in patients with advanced, upper lobe predominant emphysema. We aimed to evaluate the safety and efficacy of ELS in a randomised controlled setting.Patients were randomised to ELS plus medical treatment or medical treatment alone. Despite early termination for business reasons and inability to assess the primary 12-month end-point, 95 out of 300 patients were successfully randomised, providing sufficient data for 3- and 6-month analysis.57 patients (34 treatment and 23 control) had efficacy results at 3 months; 34 (21 treatment and 13 control) at 6 months. In the treatment group, 3-month lung function, dyspnoea, and quality of life improved significantly from baseline when compared to control. Improvements persisted at 6 months with >50% of treated patients experiencing clinically important improvements, including some whose lung function improved by >100%. 44% of treated patients experienced adverse events requiring hospitalisation (2.5-fold more than control, p=0.01), with two deaths in the treated cohort. Treatment responders tended to be those experiencing respiratory adverse events.Despite early termination, results show that minimally invasive ELS may be efficacious, yet significant risks (probably inflammatory) limit its current utility.

Comorbidity Distribution, Clinical Expression and Survival in COPD Patients with Different Body Mass Index.

Rationale: Contrary to the general population, in patients with chronic obstructive pulmonary disease (COPD) a low body mass index (BMI) is associated with excess mortality, while obesity appears protective (obesity paradox). We hypothesized that BMI is associated with a distinct number and expression of comorbidities in patients with COPD. The type of comorbidity may relate to mortality variability. Objectives and Methods: We followed 1659 COPD patients for a median of 51 months [IQR 27-77] with detailed comorbidity records and tracking pulmonary function, exercise capacity, dyspnea, health status, and cause of death. The cohort was categorized into the 5 National Heart Lung and Blood Institute (NHLBI) BMI groups with determination made about each group's relationship to specific comorbidities, clinical parameters and risk for death. Results: Whereas osteoporosis, substance abuse, abdominal aortic aneurism and peripheral arterial disease were more prevalent in patients with low BMI, metabolic and cardiac problems were more frequent in those with high BMI. The BMI was inversely related to the ratio of forced expiratory volume in 1 second (FEV1) to forced vital capacity (FVC)(FEV1 %), BODE (Body mass index, airway Obstruction, Dyspnea, Exercise capacity) index and hyperinflation, had a "U" shape with dyspnea and the St. George's Respiratory Questionaire (SGRQ) score and an inverse "U" with exercise capacity. The crude mortality rate was 60%, 43%, 37%, 36% and 28% from the lowest to highest BMI groups (p<.0001). More respiratory deaths were observed in the lowest BMI group even though they had a lower number of comorbidities. Conclusions: Different BMI categories are associated with distinct clinical expressions of COPD and comorbidity patterns. The relationship between BMI and mortality in patients with COPD remains an unresolved paradox.

Differences in cardiopulmonary exercise test results by American Thoracic Society/European Respiratory Society-Global Initiative for Chronic Obstructive Lung Disease stage categories and gender.

BACKGROUND: The American Thoracic Society (ATS)/European Respiratory Society (ERS)-Global Initiative for Chronic Obstructive Lung Disease (GOLD) has developed a new staging system based on the degree of airflow obstruction. Its validity to predict exercise capacity as an outcome has not been extensively studied. We hypothesized that exercise performance measured by cardiopulmonary exercise test (CPET) results should decline significantly with each disease stage, independent of gender. METHODS: We examined 453 consecutive incremental CPET and pulmonary function tests performed in patients who had been referred to a single respiratory physiology laboratory in a tertiary care hospital. They were divided into a control group (normal lung function) and ATS/ERS-GOLD stages 1 to 4. We measured anthropometrics, peak work (in watts), peak oxygen uptake (in liters per kilogram per minute and percent predicted), breathing reserve (in percent predicted), and arterial blood gas response. We compared these results between different stages and genders. RESULTS: The mean (+/- SD) age for the entire group was 64 +/- 11 years, the mean FEV(1) was 66 +/- 28%, and the mean body mass index (BMI) was 27.2 +/- 5.82 kg/m(2). Patients in stage 4 were significantly younger (p < 0.001) and had a lower BMI (p < 0.02) compared to those in stages 1 to 3. There was a significant reduction in exercise capacity for patients at every stage except for those in stage 1, who had values similar to those of the control group. Women had better lung function and exercise capacity than men, but the difference disappeared when adjusted by COPD stages. CONCLUSIONS: The ATS/ERS-GOLD staging system can be used to indicate differences in exercise capacity in patients with COPD stages 2 to 4 and to normalize apparent gender disparities. The value of differentiating stage 1 patients requires further studies with different outcomes.

Systemic cytokines, clinical and physiological changes in patients hospitalized for exacerbation of COPD.

BACKGROUND: Systemic inflammation in patients with COPD may worsen during exacerbations, but there is limited information relating levels of systemic inflammatory markers with symptoms and physiologic changes during an exacerbation METHODS: We measured dyspnea using the visual analog scale, pulmonary function tests, hemograms, and plasma levels for interleukin (IL)-6, IL-8, leukotriene B(4) (LTB4), tumor necrosis factor-alpha, and secretory leukocyte protease inhibitor (SLPI) in 20 patients on admission to a hospital for exacerbation of COPD (ECOPD), 48 h later (interim), and 8 weeks after hospital discharge (recovery). RESULTS: Dyspnea was present in all patients. Inspiratory capacity improved faster than FEV(1). Compared to recovery, there was a significant increase in the mean (+/- SD) hospital admission plasma levels of IL-6 (6.38 +/- 0.72 to 2.80 +/- 0.79 pg/mL; p = 0.0001), IL-8 (8.18 +/- 0.85 to 3.72 +/- 0.85 pg/mL; p = 0.002), and LTB4 (8,675 +/- 1,652 to 2,534 +/- 1,813 pg/mL; p = 0.003), and the percentages of segmented neutrophils (79 to 69%; p < 0.02) and band forms (7.3 to 1.0%; p < 0.01) in peripheral blood, with no changes in TNF-alpha and SLPI. There were significant correlations between changes in IL-6 (r = 0.61; p = 0.01) and IL-8 (r = 0.56; p = 0.04) with changes in dyspnea and levels of IL-6 (r = -0.51; p = 0.04) and TNF-alpha (r = -0.71; p < 0.02) with changes in FEV(1.) CONCLUSIONS: Hospitalized patients with ECOPDs experience significant changes in systemic cytokine levels that correlate with symptoms and lung function. An ECOPD represents not only a worsening of airflow obstruction but also increased systemic demand in a host with limited ventilatory reserve.