Carlos H. Martinez

Relationship between quantitative CT metrics and health status and BODE in chronic obstructive pulmonary disease

Background The value of quantitative CT (QCT) to identify chronic obstructive pulmonary disease (COPD) phenotypes is increasingly appreciated. The authors hypothesised that QCT-defined emphysema and airway abnormalities relate to St Georges Respiratory Questionnaire (SGRQ) and Body-Mass Index, Airflow Obstruction, Dyspnea and Exercise Capacity Index (BODE). Methods 1200 COPDGene subjects meeting Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria for COPD with QCT analysis were included. Total lung emphysema was measured using the density mask technique with a −950 Hounsfield unit threshold. An automated programme measured mean wall thickness (WT), wall area percentage (WA%) and 10u2005mm lumenal perimeter (pi10) in six segmental bronchi. Separate multivariate analyses examined the relative influence of airway measures and emphysema on SGRQ and BODE. Results In separate models predicting SGRQ score, a 1 unit SD increase in each airway measure predicted higher SGRQ scores (for WT, 1.90 points higher, p=0.002; for WA%, 1.52 points higher, p=0.02; for pi10, 2.83 points higher p<0.001). The comparable increase in SGRQ for a 1 unit SD increase in emphysema percentage in these models was relatively weaker, significant only in the pi10 model (for emphysema percentage, 1.45 points higher, p=0.01). In separate models predicting BODE, a 1 unit SD increase in each airway measure predicted higher BODE scores (for WT, 1.07-fold increase, p<0.001; for WA%, 1.20-fold increase, p<0.001; for pi10, 1.16-fold increase, p<0.001). In these models, emphysema more strongly influenced BODE (range 1.24–1.26-fold increase, p<0.001). Conclusion Emphysema and airway disease both relate to clinically important parameters. The relative influence of airway disease is greater for SGRQ; the relative influence of emphysema is greater for BODE.

An Internet-Mediated Pedometer-Based Program Improves Health-Related Quality-of-Life Domains and Daily Step Counts in COPD

BACKGROUNDnLow levels of physical activity (PA) are associated with poor outcomes in people with COPD. Interventions to increase PA could improve outcomes.nnnMETHODSnWe tested the efficacy of a novel Internet-mediated, pedometer-based exercise intervention. Veterans with COPD (N = 239) were randomized in a 2:1 ratio to the (1) intervention group (Omron HJ-720 ITC pedometer and Internet-mediated program) or (2) wait-list control group (pedometer). The primary outcome was health-related quality of life (HRQL), assessed by the St. Georges Respiratory Questionnaire (SGRQ), at 4 months. We examined the SGRQ total score (SGRQ-TS) and three domain scores: Symptoms, Activities, and Impact. The secondary outcome was daily step counts. Linear regression models assessed the effect of intervention on outcomes.nnnRESULTSnParticipants had a mean age of 67 ± 9 years, and 94% were men. There was no significant between-group difference in mean 4-month SGRQ-TS (2.3 units, P = .14). Nevertheless, a significantly greater proportion of intervention participants than control subjects had at least a 4-unit improvement in SGRQ-TS, the minimum clinically important difference (53% vs 39%, respectively, P = .05). For domain scores, the intervention group had a lower (reflecting better HRQL) mean than the control group by 4.6 units for Symptoms (P = .046) and by 3.3 units for Impact (P = .049). There was no significant difference in Activities score between the two groups. Compared with the control subjects, intervention participants walked 779 more steps per day at 4 months (P = .005).nnnCONCLUSIONSnAn Internet-mediated, pedometer-based walking program can improve domains of HRQL and daily step counts at 4 months in people with COPD.nnnTRIAL REGISTRYnClinical Trials.gov; No.: NCT01102777; URL: www.clinicaltrials.gov.

Ageing and the epidemiology of multimorbidity

The world’s population is ageing and an important part of this demographic shift is the development of chronic illness. In short, a person who does not die of acute illnesses, such as infections, and survives with chronic illnesses is more likely to develop additional chronic illnesses. Chronic respiratory diseases are an important component of these diseases associated with ageing. This article reviews the relationship between ageing and chronic respiratory disease, and also how certain chronic diseases cluster with others, either on the basis of underlying risk factors, complication of the primary disease or other factors, such as an increased state of inflammation. While death is inevitable, disabling chronic illnesses are not. Better understanding of how individuals can age healthily without the development of multiple chronic illnesses should lead to an improved global quality of life. Chronic respiratory diseases increase with age and are linked to many other diseases http://ow.ly/yMYZc

Impact of self-reported Gastroesophageal reflux disease in subjects from COPDGene cohort

BackgroundThe coexistence of gastroesophageal reflux disease (GERD) and COPD has been recognized, but there has been no comprehensive evaluation of the impact of GERD on COPD-related health status and patient-centered outcomes.MethodsCross-sectional and longitudinal study of 4,483 participants in the COPDGene cohort who met GOLD criteria for COPD. Physician-diagnosed GERD was ascertained by questionnaire. Clinical features, spirometry and imaging were compared between COPD subjects without versus with GERD. We evaluated the relationship between GERD and symptoms, exacerbations and markers of microaspiration in univariate and multivariate models. Associations were additionally tested for the confounding effect of covariates associated with a diagnosis of GERD and the use of proton-pump inhibitor medications (PPIs). To determine whether GERD is simply a marker for the presence of other conditions independently associated with worse COPD outcomes, we also tested models incorporating a GERD propensity score.ResultsGERD was reported by 29% of subjects with female predominance. Subjects with GERD were more likely to have chronic bronchitis symptoms, higher prevalence of prior cardiovascular events (combined myocardial infarction, coronary artery disease and stroke 21.3% vs. 13.4.0%, pu2009<u20090.0001). Subjects with GERD also had more severe dyspnea (MMRC score 2.2 vs. 1.8, pu2009<u20090.0001), and poorer quality of life (QOL) scores (St. George’s Respiratory Questionnaire (SGRQ) total score 41.8 vs. 34.9, pu2009<u20090.0001; SF36 Physical Component Score 38.2 vs. 41.4, pu2009<u20090.0001). In multivariate models, a significant relationship was detected between GERD and SGRQ (3.4 points difference, pu2009<u20090.001) and frequent exacerbations at baseline (≥2 exacerbation per annum at inclusion OR 1.40, pu2009=u20090.006). During a mean follow-up time of two years, GERD was also associated with frequent (≥2/year exacerbations OR 1.40, pu2009=u20090.006), even in models in which PPIs, GERD-PPI interactions and a GERD propensity score were included. PPI use was associated with frequent exacerbator phenotype, but did not meaningfully influence the GERD-exacerbation association.ConclusionsIn COPD the presence of physician-diagnosed GERD is associated with increased symptoms, poorer QOL and increased frequency of exacerbations at baseline and during follow-up. These associations are maintained after controlling for PPI use. The PPI-exacerbations association could result from confounding-by-indication.

Undiagnosed Obstructive Lung Disease in the United States. Associated Factors and Long-term Mortality

RATIONALEnUnderstanding factors associated with undiagnosed obstructive lung disease and its impact on mortality could inform the ongoing discussions about benefits and risks of screening and case finding.nnnOBJECTIVESnTo define factors associated with undiagnosed obstructive lung disease and its long-term mortality.nnnMETHODSnCross-sectional analysis of participants, aged 20 to 79 years, in two National Health and Nutritional Examination Surveys (NHANES), NHANES III (1988-1994) and NHANES 2007-2012, with longitudinal follow-up of NHANES III participants.nnnMEASUREMENTS AND MAIN RESULTSnWe classified participants with spirometry-confirmed obstructive disease, based on the fixed ratio definition (FEV1/FVC < 0.7), as diagnosed (physician diagnosis of either asthma or chronic obstructive pulmonary disease), and undiagnosed (no recorded physician diagnosis). For the longitudinal analysis of NHANES III participants, mortality was the outcome of interest. We tested the contribution of self-reported health status and comorbidity burden (exposure) to the odds of being undiagnosed using logistic models adjusted for demographics, smoking status, and lung function. We estimated hazard ratios (HRs) for all-cause mortality for diagnosed and undiagnosed subjects participating in NHANES III who had spirometry using Cox- proportional regression analysis. Among those with spirometry-defined obstruction, 71.2% (SE, 1.8) in NHANES III and 72.0% (SE, 1.9) in NHANES 2007-2012 were undiagnosed. In multivariate models, undiagnosed obstructive disease was consistently associated in both surveys with self-reported good/excellent health status, lower comorbidity burden, higher lung function, and being of racial/ethnic minority. Among NHANES III participants (median follow up, 14.5 yr), both undiagnosed (HR, 1.23; 95% confidence interval, 1.08-1.40) and correctly diagnosed participants (HR, 1.74; 95% confidence interval, 1.45-2.09) had higher risk for all-cause mortality than participants without obstruction.nnnCONCLUSIONSnUndiagnosed obstructive lung disease is common among American adults and remained unchanged over 2 decades. Although undiagnosed subjects appear healthier than those with a diagnosis, their risk of death was increased compared with subjects without obstruction. These findings need to be considered when judging the implications of case-finding programs for obstructive lung disease.

Clinical and computed tomographic predictors of chronic bronchitis in COPD: a cross sectional analysis of the COPDGene study

BackgroundChronic bronchitis (CB) has been related to poor outcomes in Chronic Obstructive Pulmonary Disease (COPD). From a clinical standpoint, we have shown that subjects with CB in a group with moderate to severe airflow obstruction were younger, more likely to be current smokers, male, Caucasian, had worse health related quality of life, more dyspnea, and increased exacerbation history compared to those without CB. We sought to further refine our clinical characterization of chronic bronchitics in a larger cohort and analyze the CT correlates of CB in COPD subjects. We hypothesized that COPD patients with CB would have thicker airways and a greater history of smoking, acute bronchitis, allergic rhinitis, and occupational exposures compared to those without CB.MethodsWe divided 2703 GOLD 1–4 subjects in the Genetic Epidemiology of COPD (COPDGene®) Study into two groups based on symptoms: chronic bronchitis (CB+, nu2009=u2009663, 24.5%) and no chronic bronchitis (CB-, nu2009=u20092040, 75.5%). Subjects underwent extensive clinical characterization, and quantitative CT analysis to calculate mean wall area percent (WA%) of 6 segmental airways was performed using VIDA PW2 (http://www.vidadiagnostics.com). Square roots of the wall areas of bronchi with internal perimeters 10xa0mm and 15xa0mm (Pi10 and Pi15, respectively), % emphysema, %gas trapping, were calculated using 3D Slicer (http://www.slicer.org).ResultsThere were no differences in % emphysema (11.4u2009±u200912.0 vs. 12.0u2009±u200912.6%, pu2009=u20090.347) or % gas trapping (35.3u2009±u200921.2 vs. 36.3u2009±u200920.6%, pu2009=u20090.272) between groups. Mean segmental WA% (63.0u2009±u20093.2 vs. 62.0u2009±u20093.1%, pu2009<u20090.0001), Pi10 (3.72u2009±u20090.15 vs. 3.69u2009±u20090.14xa0mm, pu2009<u20090.0001), and Pi15 (5.24u2009±u20090.22 vs. 5.17u2009±u20090.20, pu2009<u20090.0001) were greater in the CBu2009+u2009group. Greater percentages of gastroesophageal reflux, allergic rhinitis, histories of asthma and acute bronchitis, exposures to dusts and occupational exposures, and current smokers were seen in the CBu2009+u2009group. In multivariate binomial logistic regression, male gender, Caucasian race, a lower FEV1%, allergic rhinitis, history of acute bronchitis, current smoking, and increased airway wall thickness increased odds for having CB.ConclusionsHistories of asthma, allergic rhinitis, acute bronchitis, current smoking, a lower FEV1%, Caucasian race, male gender, and increased airway wall thickness are associated with CB. These data provide clinical and radiologic correlations to the clinical phenotype of CB.

The clinical impact of non-obstructive chronic bronchitis in current and former smokers

BACKGROUNDnAs the clinical significance of chronic bronchitis among smokers without airflow obstruction is unclear, we sought to determine morbidity associated with this disorder.nnnMETHODSnWe examined subjects from the COPDGene study and compared those with FEV1/FVC ≥ 0.70, no diagnosis of asthma and chronic bronchitis as defined as a history of cough and phlegm production for ≥ 3 months/year for ≥ 2 years (NCB) to non-obstructed subjects without chronic bronchitis (CB-). Multivariate analysis was used to determine factors associated with and impact of NCB.nnnRESULTSnWe identified 597 NCB and 4283 CB- subjects. NCB participants were younger (55.4 vs. 57.2 years, p < 0.001) with greater tobacco exposure (42.9 vs. 37.8 pack-years, p < 0.001) and more often current smokers; more frequently reported occupational exposure to fumes (52.8% vs. 42.2%, p < 0.001), dust for ≥ 1 year (55.3% vs. 42.0%, p < 0.001) and were less likely to be currently working. NCB subjects demonstrated worse quality-of-life (SGRQ 35.6 vs. 15.1, p < 0.001) and exercise capacity (walk distance 415 vs. 449 m, p < 0.001) and more frequently reported respiratory flare-ups requiring treatment with antibiotics or steroids (0.30 vs. 0.10 annual events/subject, p < 0.001) prior to enrollment and during follow-up (0.34 vs. 0.16 annual events/subject, p < 0.001). In multivariate analysis, current smoking, GERD, sleep apnea and occupational exposures were significantly associated with NCB.nnnCONCLUSIONSnWhile longitudinal data will be needed to determine whether NCB progresses to COPD, NCB patients have poorer quality-of-life, exercise capacity and frequent respiratory events. Beyond smoking cessation interventions, further research is warranted to determine the benefit of other therapeutics in this population. Clinical Trials Registration # NCT00608764 (http://clinicaltrials.gov/show/NCT00608764). Link to study protocol: http://www.copdgene.org/sites/default/files/COPDGeneProtocol-5-0_06-19-2009.pdf.

Frequency of exacerbations in patients with chronic obstructive pulmonary disease: an analysis of the SPIROMICS cohort

BACKGROUNDnPresent treatment strategies to stratify exacerbation risk in patients with chronic obstructive pulmonary disease (COPD) rely on a history of two or more events in the previous year. We aimed to understand year to year variability in exacerbations and factors associated with consistent exacerbations over time.nnnMETHODSnIn this longitudinal, prospective analysis of exacerbations in the Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS) cohort, we analysed patients aged 40-80 years with COPD for whom 3 years of prospective data were available, identified through various means including care at academic and non-academic medical centres, word of mouth, and existing patient registries. Participants were enrolled in the study between Nov 12, 2010, and July 31, 2015. We classified patients according to yearly exacerbation frequency: no exacerbations in any year; one exacerbation in every year during 3 years of follow-up; and those with inconsistent exacerbations (individuals who had both years with exacerbations and years without during the 3 years of follow-up). Participants were characterised by the Global Initiative for Chronic Obstructive Lung Disease (GOLD) spirometric category (1-4) on the basis of post-bronchodilator FEV1. Stepwise logistic regression was used to compare factors associated with one or more acute exacerbations of COPD every year for 3 years versus no exacerbations in the same timeframe. Additionally, a stepwise zero-inflated negative binomial model was used to assess predictors of exacerbation count during follow-up in all patients with available data. Baseline symptom burden was assessed with the COPD assessment test. This trial is registered with ClinicalTrials.gov, number NCT01969344.nnnFINDINGSn2981 patients were enrolled during the study. 1843 patients had COPD, of which 1105 patients had 3 years of complete, prospective follow-up data. 538 (49%) of 1105 patients had at least one acute exacerbation during the 3 years of follow-up, whereas 567 (51%) had none. 82 (7%) of 1105 patients had at least one acute exacerbation each year, whereas only 23 (2%) had two or more acute exacerbations in each year. An inconsistent pattern (both years with and without acute exacerbations) was common (456 [41%] of the group), particularly among GOLD stages 3 and 4 patients (256 [56%] of 456). In logistic regression, consistent acute exacerbations (≥1 event per year for 3 years) were associated with higher baseline symptom burden, previous exacerbations, greater evidence of small airway abnormality on CT, lower interleukin-15 concentrations, and higher interleukin-8 concentrations, than were no acute exacerbations.nnnINTERPRETATIONnAlthough acute exacerbations are common, the exacerbation status of most individuals varies markedly from year to year. Among patients who had any acute exacerbation over 3 years, very few repeatedly had two or more events per year. In addition to symptoms and history of exacerbations in the year before study enrolment, we identified several novel biomarkers associated with consistent exacerbations, including CT-defined small airway abnormality, and interleukin-15 and interleukin-8 concentrations.nnnFUNDINGnNational Institutes of Health, and National Heart, Lung, and Blood Institute.Background Current treatment strategies to stratify exacerbation risk rely on history of ≥2 events in the previous year. To understand year-to-year variability and factors associated with consistent exacerbations over time, we present a prospective analysis of the SPIROMICS cohort. Methods We analyzed SPIROMICS participants with COPD and three years of prospective data (n=1,105). We classified participants according to yearly exacerbation frequency. Stepwise logistic regression compared factors associated with individuals experiencing ≥1 AECOPD in every year for three years versus none. Results During three years follow-up, 48·7% of participants experienced at least one AECOPD, while the majority (51·3%) experienced none. Only 2·1% had ≥2 AECOPD in each year. An inconsistent pattern (both years with and years without AECOPD) was common (41·3% of the group), particularly among GOLD stages 3 and 4 subjects (56·1%). In logistic regression, consistent AECOPD (≥1 event per year for three years) as compared to no AECOPD were associated with higher baseline symptom burden assessed with the COPD Assessment Test, previous exacerbations, greater evidence of small airway abnormality by computed tomography, lower Interleukin-15 (IL-15) and elevated Interleukin-8 (IL-8). Conclusions Although AECOPD are common, the exacerbation status of most individuals varies markedly from year to year. Among participants who experienced any AECOPD over three years, very few repeatedly experienced ≥2 events/year. In addition to symptoms and history of exacerbations in the prior year, we identified several novel biomarkers associated with consistent exacerbations, including CT-defined small airway abnormality, IL-15 and IL-8.

Gender Differences in Symptoms and Care Delivery for Chronic Obstructive Pulmonary Disease

BACKGROUNDnMorbidity and mortality for women with chronic obstructive pulmonary disease (COPD) are increasing, and little is known about gender differences in perception of COPD care.nnnMETHODSnSurveys were administered to a convenience sample of COPD patients to evaluate perceptions about symptoms, barriers to care, and sources of information about COPD.nnnRESULTSnData on 295 female and 273 male participants were analyzed. With similar frequencies, women and men reported dyspnea and rated their health as poor/very poor. Although more women than men reported annual household income <

Contribution of the Environment and Comorbidities to Chronic Obstructive Pulmonary Disease Phenotypes

30,000, no significant gender differences in frequency of health insurance, physician visits, or ever having had spirometry were detected. In adjusted models (1) women were more likely to report COPD diagnostic delay (odds ratio [OR] 1.66, 95% confidence interval [CI] 1.13-2.45, p=0.01), although anxiety (OR 1.83, 95% CI 1.10-3.06, p=0.02) and history of exacerbations (OR 1.60, 95% CI 1.08-2.37, p=0.01) were also significant predictors, (2) female gender was associated with difficulty reaching ones physician (OR 2.54, 95% CI 1.33-4.86, p=0.004), as was prior history of exacerbations (OR 2.25, 95% CI 1.21-4.20, p=0.01), and (3) female gender (OR 2.15, 95% CI 1.10-4.21, p=0.02) was the only significant predictor for finding time spent with their physician as insufficient.nnnCONCLUSIONSnSignificant gender-related differences in the perception of COPD healthcare delivery exist, revealing an opportunity to better understand what influences these attitudes and to improve care for both men and women.