Effect of twice daily inhaled albuterol on cardiopulmonary exercise outcomes, dynamic hyperinflation, and symptoms in secondhand tobacco-exposed persons with preserved spirometry and air trapping: a randomized controlled trial.

BACKGROUND: In tobacco-exposed persons with preserved spirometry (active smoking or secondhand smoke [SHS] exposure), air trapping can identify a subset with worse symptoms and exercise capacity. The physiologic nature of air trapping in the absence of spirometric airflow obstruction remains unclear. The aim of this study was to examine the underlying pathophysiology of air trapping in the context of preserved spirometry and to determine the utility of bronchodilators in SHS tobacco-exposed persons with preserved spirometry and air trapping. METHODS: We performed a double-blinded placebo-controlled crossover randomized clinical trial in nonsmoking individuals at risk for COPD due to exposure to occupational SHS who had preserved spirometry and air trapping defined as either a residual volume-to-total lung capacity ratio (RV/TLC) > 0.35 or presence of expiratory flow limitation (EFL, overlap of tidal breathing on maximum expiratory flow-volume loop) on spirometry at rest or during cardiopulmonary exercise testing (CPET). Those with asthma or obesity were excluded. Participants underwent CPET at baseline and after 4-week trials of twice daily inhalation of 180 mcg of albuterol or placebo separated by a 2-week washout period. The primary outcome was peak oxygen consumption (VO2) on CPET. Data was analyzed by both intention-to-treat and per-protocol based on adherence to treatment prescribed. RESULTS: Overall, 42 participants completed the entire study (66 ± 8 years old, 91% female; forced expiratory volume in 1 s [FEV1] = 103 ± 16% predicted; FEV1 to forced vital capacity [FVC] ratio = 0.75 ± 0.05; RV/TLC = 0.39 ± 0.07; 85.7% with EFL). Adherence was high with 87% and 93% of prescribed doses taken in the treatment and placebo arms of the study, respectively (P = 0.349 for comparison between the two arms). There was no significant improvement in the primary or secondary outcomes by intention-to-treat or per-protocol analysis. In per-protocol subgroup analysis of those with RV/TLC > 0.35 and ≥ 90% adherence (n = 27), albuterol caused an improvement in peak VO2 (parameter estimate [95% confidence interval] = 0.108 [0.014, 0.202]; P = 0.037), tidal volume, minute ventilation, dynamic hyperinflation, and oxygen-pulse (all P < 0.05), but no change in symptoms or physical activity. CONCLUSIONS: Albuterol may improve exercise capacity in the subgroup of SHS tobacco-exposed persons with preserved spirometry and substantial air trapping. These findings suggest that air trapping in pre-COPD may be related to small airway disease that is not considered significant by spirometric indices of airflow obstruction.

Effect of a single one-hour teaching session about environmental pollutants and climate change on the understanding and behavioral choices of adolescents: The BREATHE pilot randomized controlled trial.

BACKGROUND: Despite the wealth of scientific information on the health effects of air pollution, the adult public's lifestyle continues to be largely detrimental towards the environment. OBJECTIVE: The purpose of the study was to determine whether a short interactive teaching session on air pollution could shift reported behavioral choices of adolescents towards environmentally friendlier options. METHODS: We performed a pilot randomized control trial in which eighth-grade students were randomized to receive a one-hour script-based teaching on either the effects of air pollution on lung health (intervention group) or the role of vaccination in public health (active control group). The enrolled students completed a survey (15 multiple-choice questions; five targeting understanding (score range 5 to 20); ten targeting behavioral choices (score range 10 to 38) newly designed for this study to evaluate their understanding and predict their future behavior towards air pollution immediately before, immediately after, and one month after the teaching sessions. RESULTS: Seventy-seven students (age = 13.5±0.6 years; 50.4% female; median annual family income = $25K-$50K with 70.1% <$50K; 39 assigned to intervention group) were enrolled in the study. The teaching sessions did not result in any significant change in the participants' understanding domain scores in either the intervention or the control groups. However, the intervention (air pollution) teaching session resulted in a statistically significant increase in behavior domain score from baseline to immediately post-teaching, which continued to be present at one-month follow-up (mean ± standard deviation of score change immediately after = 1.7±3.3; score change 1-month after = 2.5±3.2; P<0.001; minimally important difference = 1.0). DISCUSSION: This pilot study highlights the potential of a short one-time teaching session in promoting environmentally friendly behavior choices among adolescents.

Lung volumes differentiate the predominance of emphysema versus airway disease phenotype in early COPD: an observational study of the COPDGene cohort.

Rationale: Lung volumes identify the "susceptible smokers" who progress to develop spirometric COPD. However, among susceptible smokers, development of spirometric COPD seems to be heterogeneous, suggesting the presence of different pathological mechanisms during early establishment of spirometric COPD. The objective of the present study was to determine the differential patterns of radiographic pathologies among susceptible smokers. Methods: We categorised smokers with preserved spirometry (Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage 0) in the Genetic Epidemiology of COPD (COPDGene) cohort based on tertiles (low, intermediate and high) of lung volumes (either total lung capacity (TLC), functional residual capacity FRC or FRC/TLC) at baseline visit. We then examined the differential patterns of change in spirometry and the associated prevalence of computed tomography measured pathologies of emphysema and airway disease with those categories of lung volumes. Results: The pattern of spirometric change differed when participants were categorised by TLC versus FRC/TLC: those in the high TLC tertile showed stable forced expiratory volume in 1 s (FEV1), but enlarging forced vital capacity (FVC), while those in the high FRC/TLC tertile showed decline in both FEV1 and FVC. When participants from the high TLC and high FRC/TLC tertiles were partitioned into mutually exclusive groups, compared to those with high TLC, those with high FRC/TLC had lesser emphysema, but greater air trapping, more self-reported respiratory symptoms and exacerbation episodes and higher likelihood of progressing to more severe spirometric disease (GOLD stages 2-4 versus GOLD stage 1). Conclusions: Lung volumes identify distinct physiological and radiographic phenotypes in early disease among susceptible smokers and predict the rate of spirometric disease progression and the severity of symptoms in early COPD.

Changes in Lung Volumes with Spirometric Disease Progression in COPD.

Background: Abnormal lung volumes representing air trapping identify the subset of smokers with preserved spirometry who develop spirometric chronic obstructive pulmonary disease (COPD) and adverse outcomes. However, how lung volumes evolve in early COPD as airflow obstruction develops remains unclear. Methods: To establish how lung volumes change with the development of spirometric COPD, we examined lung volumes from the pulmonary function data (seated posture) available in the U.S. Department of Veterans Affairs electronic health records (n=71,356) and lung volumes measured by computed tomography (supine posture) available from the COPD Genetic Epidemiology (COPDGene®) study (n=7969) and the SubPopulations and InterMediate Outcome Measures In COPD Study (SPIROMICS) (n=2552) cohorts, and studied their cross-sectional distributions and longitudinal changes across the airflow obstruction spectrum. Patients with preserved ratio-impaired spirometry (PRISm) were excluded from this analysis. Results: Lung volumes from all 3 cohorts showed similar patterns of distributions and longitudinal changes with worsening airflow obstruction. The distributions for total lung capacity (TLC), vital capacity (VC), and inspiratory capacity (IC) and their patterns of change were nonlinear and included different phases. When stratified by airflow obstruction using Global initiative for chronic Obstructive Lung Disease (GOLD) stages, patients with GOLD 1 (mild) COPD had larger lung volumes (TLC, VC, IC) compared to patients with GOLD 0 (smokers with preserved spirometry) or GOLD 2 (moderate) disease. In longitudinal follow-up of baseline GOLD 0 patients who progressed to spirometric COPD, those with an initially higher TLC and VC developed mild obstruction (GOLD 1) while those with an initially lower TLC and VC developed moderate obstruction (GOLD 2). Conclusions: In COPD, TLC, and VC have biphasic distributions, change in nonlinear fashions as obstruction worsens, and could differentiate those GOLD 0 patients at risk for more rapid spirometric disease progression.

Elastin Degradation and Lung Function Deterioration with Remote Secondhand Tobacco Smoke Exposure in Never-smokers.

Background: Prolonged past exposure to secondhand tobacco smoke (SHS) in never-smokers is associated with abnormal lung function and reduced diffusing capacity suggestive of an associated lung tissue injury and damage. The mechanisms by which past SHS exposure may contribute to lung tissue damage are unknown. Elastin is a major constituent of extracellular matrix in lung parenchyma. Objective: To determine whether past exposure to SHS is associated with ongoing lung tissue damage as indicated by elevated elastin degradation products that are linked to lung function. Methods: We measured the plasma levels of elastin degradation markers (EDM) from 193 never-smoking flight attendants with a history of remote SHS exposure in aircraft cabins and 103 nonsmoking flight attendants or sea-level control participants without such history of cabin SHS exposure and examined those levels versus their lung function with adjustment for covariates. The cabin SHS exposure was estimated based on airline employment history and years of the smoking ban enactment. Results: The median [interquartile range] plasma EDM level for all participants was 0.30 [0.24-0.36] ng/mL with a total range of 0.16-0.65 ng/mL. Plasma EDM levels were elevated in those with a history of exposure to cabin SHS compared to those not exposed (0.33±0.08 versus 0.26±0.06 ng/mL; age- and sex-adjusted P<0.001). In those with a history of cabin SHS exposure, higher EDM levels were associated with a lower diffusing capacity (parameter estimate [PE] 95% [confidence interval(CI)]=4.2 [0.4-8.0] %predicted decrease per 0.1 ng/mL increase in EDM; P=0.030). Furthermore, EDM levels were inversely associated with forced expiratory volume in 1 second (FEV1), FEV1 to forced vital capacity (FVC) ratio , and forced expiratory flow rate between 25% and 75% ( FEF25%-75%) (PE [95%CI]=5.8 [2.1-9.4], 4.0 [2.2-5.7], and 12.5 [5.8-19.2] %predicted decrease per 0.1 ng/mL increase in EDM, respectively; P<0.001). Plasma EDM mediated a substantial fraction of the association of SHS with FEV1, FVC, and FEF25%-75% (P<0.05). Conclusions: Long after past exposure to SHS, there is ongoing elastin degradation beyond what is expected from the aging process, which likely contributes to lower lung function and a reduced pulmonary capillary bed as seen in chronic obstructive pulmonary disease (COPD).

Remote exposure to secondhand tobacco smoke is associated with lower exercise capacity through effects on oxygen pulse, a proxy of cardiac stroke volume.

BACKGROUND: Past exposure to secondhand tobacco smoke (SHS) is associated with exercise limitation. Pulmonary factors including air trapping contribute to this limitation but the contribution of cardiovascular factors is unclear. OBJECTIVE: To determine the contribution of cardiovascular mechanisms to SHS-associated exercise limitation. METHODS: We examined the cardiovascular responses to maximum-effort exercise in 245 never-smokers with remote, prolonged occupational exposure to SHS and no known history of cardiovascular disease. We estimated the contribution of oxygen-pulse (proxy for cardiac stroke volume) and changes in systolic blood pressures (SBP), diastolic blood pressures and heart rate (HR) towards exercise capacity, and examined whether the association of SHS with exercise capacity was mediated through these variables. RESULTS: At peak exercise (highest workload completed (WattsPeak)=156±46 watts (135±33 %predicted)), oxygen consumption and oxygen-pulse (O2-PulsePeak) were 1557±476 mL/min (100±24 %predicted) and 11.0±3.0 mL/beat (116±25 %predicted), respectively, with 29% and 3% participants not achieving their predicted normal range. Oxygen saturation at peak exercise was 98%±1% and remained >93% in all participants. Sixty-six per cent showed hypertensive response to exercise. In models adjusted for covariates, WattsPeak was associated directly with O2-PulsePeak, HRPeak and SBPPeak and inversely with SHS, air trapping (residual volume/total lung capacity) and rise of SBP over workload (all p<0.01). Moreover, SHS exposure association with WattsPeak was substantially (41%) mediated through its effect on O2-PulsePeak (p=0.038). Although not statistically significant, a considerable proportion (36%) of air trapping effect on WattsPeak seemed to be mediated through O2-PulsePeak (p=0.078). The likelihood of having baseline respiratory symptoms (modified Medical Research Council score ≥1) was associated with steeper rise in SBP over workload (p<0.01). CONCLUSION: In a never-smoker population with remote exposure to SHS, abnormal escalation of blood pressure and an SHS-associated reduction in cardiac output contributed to lower exercise capacity.

Automatically Explaining Machine Learning Predictions on Severe Chronic Obstructive Pulmonary Disease Exacerbations: Retrospective Cohort Study.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a major cause of death and places a heavy burden on health care. To optimize the allocation of precious preventive care management resources and improve the outcomes for high-risk patients with COPD, we recently built the most accurate model to date to predict severe COPD exacerbations, which need inpatient stays or emergency department visits, in the following 12 months. Our model is a machine learning model. As is the case with most machine learning models, our model does not explain its predictions, forming a barrier for clinical use. Previously, we designed a method to automatically provide rule-type explanations for machine learning predictions and suggest tailored interventions with no loss of model performance. This method has been tested before for asthma outcome prediction but not for COPD outcome prediction. OBJECTIVE: This study aims to assess the generalizability of our automatic explanation method for predicting severe COPD exacerbations. METHODS: The patient cohort included all patients with COPD who visited the University of Washington Medicine facilities between 2011 and 2019. In a secondary analysis of 43,576 data instances, we used our formerly developed automatic explanation method to automatically explain our model's predictions and suggest tailored interventions. RESULTS: Our method explained the predictions for 97.1% (100/103) of the patients with COPD whom our model correctly predicted to have severe COPD exacerbations in the following 12 months and the predictions for 73.6% (134/182) of the patients with COPD who had ≥1 severe COPD exacerbation in the following 12 months. CONCLUSIONS: Our automatic explanation method worked well for predicting severe COPD exacerbations. After further improving our method, we hope to use it to facilitate future clinical use of our model. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.2196/13783.

Developing a Machine Learning Model to Predict Severe Chronic Obstructive Pulmonary Disease Exacerbations: Retrospective Cohort Study.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) poses a large burden on health care. Severe COPD exacerbations require emergency department visits or inpatient stays, often cause an irreversible decline in lung function and health status, and account for 90.3% of the total medical cost related to COPD. Many severe COPD exacerbations are deemed preventable with appropriate outpatient care. Current models for predicting severe COPD exacerbations lack accuracy, making it difficult to effectively target patients at high risk for preventive care management to reduce severe COPD exacerbations and improve outcomes. OBJECTIVE: The aim of this study is to develop a more accurate model to predict severe COPD exacerbations. METHODS: We examined all patients with COPD who visited the University of Washington Medicine facilities between 2011 and 2019 and identified 278 candidate features. By performing secondary analysis on 43,576 University of Washington Medicine data instances from 2011 to 2019, we created a machine learning model to predict severe COPD exacerbations in the next year for patients with COPD. RESULTS: The final model had an area under the receiver operating characteristic curve of 0.866. When using the top 9.99% (752/7529) of the patients with the largest predicted risk to set the cutoff threshold for binary classification, the model gained an accuracy of 90.33% (6801/7529), a sensitivity of 56.6% (103/182), and a specificity of 91.17% (6698/7347). CONCLUSIONS: Our model provided a more accurate prediction of severe COPD exacerbations in the next year compared with prior published models. After further improvement of its performance measures (eg, by adding features extracted from clinical notes), our model could be used in a decision support tool to guide the identification of patients with COPD and at high risk for care management to improve outcomes. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.2196/13783.

Performance of a Computational Phenotyping Algorithm for Sarcoidosis Using Diagnostic Codes in Electronic Medical Records: Case Validation Study From 2 Veterans Affairs Medical Centers.

BACKGROUND: Electronic medical records (EMRs) offer the promise of computationally identifying sarcoidosis cases. However, the accuracy of identifying these cases in the EMR is unknown. OBJECTIVE: The aim of this study is to determine the statistical performance of using the International Classification of Diseases (ICD) diagnostic codes to identify patients with sarcoidosis in the EMR. METHODS: We used the ICD diagnostic codes to identify sarcoidosis cases by searching the EMRs of the San Francisco and Palo Alto Veterans Affairs medical centers and randomly selecting 200 patients. To improve the diagnostic accuracy of the computational algorithm in cases where histopathological data are unavailable, we developed an index of suspicion to identify cases with a high index of suspicion for sarcoidosis (confirmed and probable) based on clinical and radiographic features alone using the American Thoracic Society practice guideline. Through medical record review, we determined the positive predictive value (PPV) of diagnosing sarcoidosis by two computational methods: using ICD codes alone and using ICD codes plus the high index of suspicion. RESULTS: Among the 200 patients, 158 (79%) had a high index of suspicion for sarcoidosis. Of these 158 patients, 142 (89.9%) had documentation of nonnecrotizing granuloma, confirming biopsy-proven sarcoidosis. The PPV of using ICD codes alone was 79% (95% CI 78.6%-80.5%) for identifying sarcoidosis cases and 71% (95% CI 64.7%-77.3%) for identifying histopathologically confirmed sarcoidosis in the EMRs. The inclusion of the generated high index of suspicion to identify confirmed sarcoidosis cases increased the PPV significantly to 100% (95% CI 96.5%-100%). Histopathology documentation alone was 90% sensitive compared with high index of suspicion. CONCLUSIONS: ICD codes are reasonable classifiers for identifying sarcoidosis cases within EMRs with a PPV of 79%. Using a computational algorithm to capture index of suspicion data elements could significantly improve the case-identification accuracy.

Actigraphy informs distinct patient-centered outcomes in Pre-COPD.

BACKGROUND: Actigraphy can provide useful patient-centered outcomes for quantification of physical activity in the "real-world" setting. METHODS: To characterize the relationship of actigraphy outputs with "in-laboratory" measures of cardiopulmonary function and respiratory symptoms in pre-COPD, we obtained actigraphy data for 8 h/day for 5 consecutive days a week before in-laboratory administration of respiratory questionnaires, PFT, and CPET to a subgroup of subjects participating in the larger study of the health effects of exposure to secondhand tobacco smoke who had air trapping but no spirometric obstruction (pre-COPD). Using machine learning approaches, we identified the most relevant actigraphy predictors and examined their associations with symptoms, lung function, and exercise outcomes. RESULTS: Sixty-one subjects (age = 66±7 years; BMI = 24±3 kg/m2; FEV1/FVC = 0.75 ± 0.05; FEV1 = 103 ± 17 %predicted) completed the nested study. In the hierarchical cluster analysis, the activity, distance, and energy domains of actigraphy, including moderate to vigorous physical activity, were closely correlated with each other, but were only loosely associated with spirometric and peak exercise measures of oxygen consumption, ventilation, oxygen-pulse, and anaerobic threshold (VO2AT), and were divergent from symptom measures. Conversely, the sedentary domain clustered with respiratory symptoms, air trapping, airflow indices, and ventilatory efficiency. In Regression modeling, sedentary domain was inversely associated with baseline lung volumes and tidal breathing at peak exercise, while the activity domains were associated with VO2AT. Respiratory symptoms and PFT data were not associated with actigraphy outcomes. DISCUSSION: Outpatient actigraphy can provide information for "real-world" patient-centered outcomes that are not captured by standardized respiratory questionnaires, lung function, or exercise testing. Actigraphy activity and sedentary domains inform of distinct outcomes.

Lower PDL1, PDL2, and AXL Expression on Lung Myeloid Cells Suggests Inflammatory Bias in Smoking and Chronic Obstructive Pulmonary Disease.

Lung myeloid cells are important in pulmonary immune homeostasis and in the pathogenesis of chronic obstructive pulmonary disease (COPD). Multiparameter immunophenotypic characterization of these cells is challenging because of their autofluorescence and diversity. We evaluated the immunophenotypic landscape of airway myeloid cells in COPD using time of flight mass cytometry. Cells from BAL, which were obtained from never-smokers (n = 8) and smokers with (n = 20) and without (n = 4) spirometric COPD, were examined using a 44-parameter time of flight mass cytometry panel. Unsupervised cluster analysis was used to identify cellular subtypes that were confirmed by manual gating. We identified major populations of CD68+ and CD68- cells with 22 distinct phenotypic clusters, of which 18 were myeloid cells. We found a higher abundance of putative recruited myeloid cells (CD68+ classical monocytes) in BAL from patients with COPD. CD68+ classical monocyte population had distinct responses to smoking and COPD that were potentially related to their recruitment from the interstitium and vasculature. We demonstrate that BAL cells from smokers and subjects with COPD have lower AXL expression. Also, among subjects with COPD, we report significant differences in the abundance of PDL1high and PDL2high clusters and in the expression of PDL1 and PDL2 across several macrophage subtypes suggesting modulation of inflammatory responses. In addition, several phenotypic differences in BAL cells from subjects with history of COPD exacerbation were identified that could inform potential disease mechanisms. Overall, we report several changes to the immunophenotypic landscape that occur with smoking, COPD, and past exacerbations that are consistent with decreased regulation and increased activation of inflammatory pathways.

Laboratory-based Intermountain Validated Exacerbation (LIVE) Score stability in patients with chronic obstructive pulmonary disease.

BACKGROUND: The Laboratory-based Intermountain Validated Exacerbation (LIVE) Score is associated with mortality and chronic obstructive pulmonary disease (COPD) exacerbation risk across multiple health systems. However, whether the LIVE Score and its associated risk is a stable patient characteristic is unknown. METHODS: We validated the LIVE Score in a fourth health system. Then we determined the LIVE Score stability in a retrospective cohort of 98 766 patients with COPD in four health systems where it was previously validated. We assessed whether LIVE Scores changed or remained the same over time. Stability was defined as a majority of surviving patients having the same LIVE Score 4 years later. RESULTS: The LIVE Score separated patients into three LIVE Score risk groups of low, medium, and high mortality and LIVE Score stability. Mortality ranged from 6.2% for low-risk LIVE to 45.8% for high-risk LIVE (p<0.001). We found that low-risk LIVE groups were stable and high-risk LIVE groups were unstable. Low-risk LIVE group patients remained low risk, but few high-risk LIVE group patients remained high risk (79.0% high vs 48.1% medium vs 8.8% low, p<0.001 for all pairwise comparisons). CONCLUSION: The LIVE Score identifies three major clinically actionable cohorts: a stable low-risk LIVE group, an unstable high-risk LIVE group with high mortality rates, and a medium-risk LIVE group. These observations further our understanding of how existing data used to calculate the LIVE Score may target interventions across risk cohorts of patients with COPD in a health system.

Radiographic lung volumes predict progression to COPD in smokers with preserved spirometry in SPIROMICS.

The characteristics that predict progression to overt chronic obstructive pulmonary disease (COPD) in smokers without spirometric airflow obstruction are not clearly defined.We conducted a post hoc analysis of 849 current and former smokers (≥20 pack-years) with preserved spirometry from the Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS) cohort who had baseline computed tomography (CT) scans of lungs and serial spirometry. We examined whether CT-derived lung volumes representing air trapping could predict adverse respiratory outcomes and more rapid decline in spirometry to overt COPD using mixed-effect linear modelling.Among these subjects with normal forced expiratory volume in 1 s (FEV1) to forced vital capacity (FVC) ratio, CT-measured residual volume (RVCT) to total lung capacity (TLCCT) ratio varied widely, from 21% to 59%. Over 2.5±0.7 years of follow-up, subjects with higher RVCT/TLCCT had a greater differential rate of decline in FEV1/FVC; those in the upper RVCT/TLCCT tertile had a 0.66% (95% CI 0.06%-1.27%) faster rate of decline per year compared with those in the lower tertile (p=0.015) regardless of demographics, baseline spirometry, respiratory symptoms score, smoking status (former versus current) or smoking burden (pack-years). Accordingly, subjects with higher RVCT/TLCCT were more likely to develop spirometric COPD (OR 5.7 (95% CI 2.4-13.2) in upper versus lower RVCT/TLCCT tertile; p<0.001). Other CT indices of air trapping showed similar patterns of association with lung function decline; however, when all CT indices of air trapping, emphysema, and airway disease were included in the same model, only RVCT/TLCCT retained its significance.Increased air trapping based on radiographic lung volumes predicts accelerated spirometry decline and progression to COPD in smokers without obstruction.

Lung volume indices predict morbidity in smokers with preserved spirometry.

BACKGROUND: Abnormal lung volumes that reflect air trapping are common in COPD. However, their significance in smokers with preserved spirometry (normal FEV1 to FVC ratio) is unclear. METHODS: Using the Veterans Administration Informatics and Computing Infrastructure database, we identified 7479 patients at risk for COPD (ever smokers >40 years of age without restrictive lung disease) who had preserved spirometry and concomitant lung volume measurements, and examined their subsequent health records for clinical diagnoses of COPD, healthcare utilisation, follow-up spirometry and mortality. RESULTS: Air trapping was prevalent, with 31% of patients having residual volume to total lung capacity ratio (RV:TLC) greater than the upper limit of normal (ULN). RV:TLC varied widely from 14% to 77% (51% to 204% of predicted) across the normal ranges of FEV1:FVC and FEV1. Patients with RV:TLC greater than the ULN were more likely to receive subsequent clinical diagnoses of COPD (HR (95% CI)=1.55 (1.42 to 1.70), p<0.001) and had higher all-cause mortality (HR (95% CI)=1.41 (1.29 to 1.54), p<0.001). They had higher rates of respiratory medication prescriptions and hospital and intensive care unit admissions. Other air trapping and static hyperinflation indices showed similar associations with health outcomes. Additionally, high-normal RV:TLC was associated with intermediate adverse health outcomes compared with low-normal and abnormal RV:TLC. Abnormal RV:TLC predicted higher likelihood of progression to spirometric COPD (OR (95% CI)=1.30 (1.03 to 1.65), p=0.027). CONCLUSION: In this study of the Veterans Affairs electronic health records, air trapping was common in smokers with preserved spirometry and predicted adverse respiratory outcomes and progression to overt COPD.

Stability of Frequency of Severe Chronic Obstructive Pulmonary Disease Exacerbations and Health Care Utilization in Clinical Populations.

Rationale: Although chronic obstructive pulmonary disease (COPD) exacerbation frequency is stable in research cohorts, whether severe COPD exacerbation frequency can be used to identify patients at high risk for future severe COPD exacerbations and/or mortality is unknown. Methods: Severe COPD exacerbation frequency stability was determined in 3 distinct clinical cohorts. A total of 17,450 patients with COPD in Intermountain Healthcare were categorized based on the number of severe COPD exacerbations per year. We determined whether exacerbation frequency was stable and whether it predicted mortality. These findings were validated in 83,134 patients from the U.S. Veterans Affairs (VA) nationwide health care system and 3326 patients from the University of Chicago Medicine health system. Results: In the Intermountain Healthcare cohort, the majority (84%, 14,706 patients) had no exacerbations in 2009 and were likely to remain non-exacerbators with a significantly lower 6-year mortality compared with frequent exacerbators (2 or more exacerbations per year) (25% versus 57%, p<0.001). Similar findings were noted in the VA health system and the University of Chicago Medicine health system. Non-exacerbators were likely to remain non-exacerbators with the lowest overall mortality. In all cohorts, frequent exacerbator was not a stable phenotype until patients had at least 2 consecutive years of frequent exacerbations. COPD exacerbation frequency predicted any cause mortality. Conclusions: In clinical datasets across different organizations, severe COPD exacerbation frequency was stable after at least 2 consecutive years of frequent exacerbations. Thus, severe COPD exacerbation frequency identifies patients across a health care system at high risk for future COPD-related health care utilization and overall mortality.

The Laboratory-Based Intermountain Validated Exacerbation (LIVE) Score Identifies Chronic Obstructive Pulmonary Disease Patients at High Mortality Risk.

Background: Identifying COPD patients at high risk for mortality or healthcare utilization remains a challenge. A robust system for identifying high-risk COPD patients using Electronic Health Record (EHR) data would empower targeting interventions aimed at ensuring guideline compliance and multimorbidity management. The purpose of this study was to empirically derive, validate, and characterize subgroups of COPD patients based on routinely collected clinical data widely available within the EHR. Methods: Cluster analysis was used in 5,006 patients with COPD at Intermountain to identify clusters based on a large collection of clinical variables. Recursive Partitioning (RP) was then used to determine a preferred tree that assigned patients to clusters based on a parsimonious variable subset. The mortality, COPD exacerbations, and comorbidity profile of the identified groups were examined. The findings were validated in an independent Intermountain cohort and in external cohorts from the United States Veterans Affairs (VA) and University of Chicago Medicine systems. Measurements and Main Results: The RP algorithm identified five LIVE Scores based on laboratory values: albumin, creatinine, chloride, potassium, and hemoglobin. The groups were characterized by increasing risk of mortality. The lowest risk, LIVE Score 5 had 8% 4-year mortality vs. 56% in the highest risk LIVE Score 1 (p < 0.001). These findings were validated in the VA cohort (n = 83,134), an expanded Intermountain cohort (n = 48,871) and in the University of Chicago system (n = 3,236). Higher mortality groups also had higher COPD exacerbation rates and comorbidity rates. Conclusions: In large clinical datasets across different organizations, the LIVE Score utilizes existing laboratory data for COPD patients, and may be used to stratify risk for mortality and COPD exacerbations.

Lung volumes identify an at-risk group in persons with prolonged secondhand tobacco smoke exposure but without overt airflow obstruction.

INTRODUCTION: Exposure to secondhand smoke (SHS) is associated with occult obstructive lung disease as evident by abnormal airflow indices representing small airway disease despite having preserved spirometry (normal forced expiratory volume in 1 s-to-forced vital capacity ratio, FEV1/FVC). The significance of lung volumes that reflect air trapping in the presence of preserved spirometry is unclear. METHODS: To investigate whether lung volumes representing air trapping could determine susceptibility to respiratory morbidity in people with SHS exposure but without spirometric chronic obstructive pulmonary disease, we examined a cohort of 256 subjects with prolonged occupational SHS exposure and preserved spirometry. We elicited symptom prevalence by structured questionnaires, examined functional capacity (maximum oxygen uptake, VO2max) by exercise testing, and estimated associations of those outcomes with air trapping (plethysmography-measured residual volume-to-total lung capacity ratio, RV/TLC), and progressive air trapping with exertion (increase in fraction of tidal breathing that is flow limited on expiration during exercise (per cent of expiratory flow limitation, %EFL)). RESULTS: RV/TLC was within the predicted normal limits, but was highly variable spanning 22%±13% and 16%±8% across the increments of FEV1/FVC and FEV1, respectively. Respiratory complaints were prevalent (50.4%) with the most common symptom being ≥2 episodes of cough per year (44.5%). Higher RV/TLC was associated with higher OR of reporting respiratory symptoms (n=256; r2=0.03; p=0.011) and lower VO2max (n=179; r2=0.47; p=0.013), and %EFL was negatively associated with VO2max (n=32; r2=0.40; p=0.017). CONCLUSIONS: In those at risk for obstruction due to SHS exposure but with preserved spirometry, higher RV/TLC identifies a subgroup with increased respiratory symptoms and lower exercise capacity.

Modeling vascular inflammation and atherogenicity after inhalation of ambient levels of ozone: exploratory lessons from transcriptomics.

BACKGROUND: Epidemiologic studies have linked inhalation of air pollutants such as ozone to cardiovascular mortality. Human exposure studies have shown that inhalation of ambient levels of ozone causes airway and systemic inflammation and an imbalance in sympathetic/parasympathetic tone. METHODS: To explore molecular mechanisms through which ozone inhalation contributes to cardiovascular mortality, we compared transcriptomics data previously obtained from bronchoalveolar lavage (BAL) cells obtained from healthy subjects after inhalational exposure to ozone (200 ppb for 4 h) to those of various cell samples from 11 published studies of patients with atherosclerotic disease using the Nextbio genomic data platform. Overlapping gene ontologies that may be involved in the transition from pulmonary to systemic vascular inflammation after ozone inhalation were explored. Local and systemic enzymatic activity of an overlapping upregulated gene, matrix metalloproteinase-9 (MMP-9), was measured by zymography after ozone exposure. RESULTS: A set of differentially expressed genes involved in response to stimulus, stress, and wounding were in common between the ozone and most of the atherosclerosis studies. Many of these genes contribute to biological processes such as cholesterol metabolism dysfunction, increased monocyte adherence, endothelial cell lesions, and matrix remodeling, and to diseases such as heart failure, ischemia, and atherosclerotic occlusive disease. Inhalation of ozone increased MMP-9 enzymatic activity in both BAL fluid and serum. CONCLUSIONS: Comparison of transcriptomics between BAL cells after ozone exposure and various cell types from patients with atherosclerotic disease reveals commonly regulated processes and potential mechanisms by which ozone inhalation may contribute to progression of pre-existent atherosclerotic lesions.