Harmonization of Respiratory Data From 9 US Population-Based Cohorts: The NHLBI Pooled Cohorts Study.

Chronic lower respiratory diseases (CLRDs) are the fourth leading cause of death in the United States. To support investigations into CLRD risk determinants and new approaches to primary prevention, we aimed to harmonize and pool respiratory data from US general population-based cohorts. Data were obtained from prospective cohorts that performed prebronchodilator spirometry and were harmonized following 2005 ATS/ERS standards. In cohorts conducting follow-up for noncardiovascular events, CLRD events were defined as hospitalizations/deaths adjudicated as CLRD-related or assigned relevant administrative codes. Coding and variable names were applied uniformly. The pooled sample included 65,251 adults in 9 cohorts followed-up for CLRD-related mortality over 653,380 person-years during 1983-2016. Average baseline age was 52 years; 56% were female; 49% were never-smokers; and racial/ethnic composition was 44% white, 22% black, 28% Hispanic/Latino, and 5% American Indian. Over 96% had complete data on smoking, clinical CLRD diagnoses, and dyspnea. After excluding invalid spirometry examinations (13%), there were 105,696 valid examinations (median, 2 per participant). Of 29,351 participants followed for CLRD hospitalizations, median follow-up was 14 years; only 5% were lost to follow-up at 10 years. The NHLBI Pooled Cohorts Study provides a harmonization standard applied to a large, US population-based sample that may be used to advance epidemiologic research on CLRD.

Associations between emphysema-like lung on CT and incident airflow limitation: a general population-based cohort study.

Emphysema on CT is associated with accelerated lung function decline in heavy smokers and patients with COPD; however, in the general population, it is not known whether greater emphysema-like lung on CT is associated with incident COPD. We used data from 2045 adult participants without initial prebronchodilator airflow limitation, classified by FEV1/FVC<0.70, in the Multi-Ethnic Study of Atherosclerosis. Emphysema-like lung on baseline cardiac CT, defined as per cent low attenuation areas<-950HU>upper limit of normal, was associated with increased odds of incident airflow limitation at 5-year follow-up on both prebronchodilator (adjusted OR 2.62, 95% CI 1.47 to 4.67) and postbronchodilator (adjusted OR 4.38, 95% CI 1.63 to 11.74) spirometry, independent of smoking history. These results support investigation into whether emphysema-like lung could be informative for COPD risk stratification.

Long-Term Stability of a Portable Carbon Monoxide Single-Breath Diffusing Capacity Instrument.

BACKGROUND: The 2005 American Thoracic Society/European Respiratory Society guidelines for single-breath diffusing capacity of the lung for carbon monoxide (DLCO) recommend a weekly biological control test and/or DLCO simulator to detect instrument error drift. Very little has been published regarding the results of such a quality assurance program. Our aim was to analyze the long-term stability of a portable DLCO instrument. METHODS: We used a new EasyOne Pro system and checked its accuracy using a DLCO simulator with 2 reference gases (concentration A: carbon monoxide [CO] = 0.1% and helium = 6.52%; concentration B: CO = 0.08% and helium = 7.21%) during the first 3 y of use in our large clinical laboratory. To detect instrument drift, a healthy woman (MSC), age 43 y old at baseline, tested herself every week during this period of time. RESULTS: More than 6,000 spirometry and 5,000 DLCO maneuvers were done using this instrument for patients during these 3 y. There were no failures in the daily volume and flow checks or the CO and helium calibration checks performed automatically by the instrument. The differences between the simulator DLCO and the measured DLCO were -0.91 ± 1.33 mL/min/mm Hg and -0.61 ± 1.45 mL/min/mm Hg for concentration A and concentration B, respectively. The results of the 110 biological control tests were: mean 30.8 ± 1.7 mL/min/mm Hg (95% CI 30.5-31.1), coefficient of variation of 5.4% in DLCO, and repeatability of 2.5 mL/min/mm Hg. Only 4 measurements were outside ±3 mL/min/mm Hg (3.6%). Her mean alveolar volume was 4.2 ± 0.25 L with coefficient of variation of 6.2%; her inspired volume was 3.05 ± 0.14 L, and coefficient of variation = 4.5%. CONCLUSIONS: Measurements of DLCO were stable over the 3-y period without any need for manual recalibration of the instrument. The biological control was as good as the DLCO simulator to evaluate this kind of device in a long-term laboratory quality control program.

High attenuation areas on chest computed tomography in community-dwelling adults: the MESA study.

Evidence suggests that lung injury, inflammation and extracellular matrix remodelling precede lung fibrosis in interstitial lung disease (ILD). We examined whether a quantitative measure of increased lung attenuation on computed tomography (CT) detects lung injury, inflammation and extracellular matrix remodelling in community-dwelling adults sampled without regard to respiratory symptoms or smoking.We measured high attenuation areas (HAA; percentage of lung voxels between -600 and -250 Hounsfield Units) on cardiac CT scans of adults enrolled in the Multi-Ethnic Study of Atherosclerosis.HAA was associated with higher serum matrix metalloproteinase-7 (mean adjusted difference 6.3% per HAA doubling, 95% CI 1.3-11.5), higher interleukin-6 (mean adjusted difference 8.8%, 95% CI 4.8-13.0), lower forced vital capacity (FVC) (mean adjusted difference -82 mL, 95% CI -119--44), lower 6-min walk distance (mean adjusted difference -40 m, 95% CI -1--80), higher odds of interstitial lung abnormalities at 9.5 years (adjusted OR 1.95, 95% CI 1.43-2.65), and higher all cause-mortality rate over 12.2 years (HR 1.58, 95% CI 1.39-1.79).High attenuation areas are associated with biomarkers of inflammation and extracellular matrix remodelling, reduced lung function, interstitial lung abnormalities, and a higher risk of death among community-dwelling adults.

Per cent emphysema is associated with respiratory and lung cancer mortality in the general population: a cohort study.

BACKGROUND: Emphysema on CT is a risk factor for all-cause mortality in persons with and without airflow obstruction; however, causes of death associated with emphysema remain uncertain, particularly in the general population. AIMS: To test associations between quantitatively assessed emphysema on CT and cause of death in persons with and without a substantial smoking history. METHODS: The Multi-Ethnic Study of Atherosclerosis recruited 6814 participants, aged 45-84 years and without clinical cardiovascular disease, in 2000-2002. Per cent emphysema was defined on cardiac CT as per cent of lung voxels less than -950 Hounsfield units; emphysema on CT was defined as per cent emphysema above the upper limit of normal. Cause of death was classified by administrative codes. Proportional-hazards models were adjusted for age, race/ethnicity, gender, body mass index, smoking status, pack-years, coronary artery calcium, site and education. Additional adjustment for lung function was made in a subset with spirometry from 2004 to 2006. RESULTS: There were 1091 deaths over 12 years median follow-up. Emphysema on CT was strongly associated with increased mortality due to respiratory diseases (adjusted HR 2.94, 95% CI 1.68 to 5.15), particularly chronic lower respiratory diseases (adjusted HR 9.54, 95% CI 4.70 to 19.35), and lung cancer (adjusted HR 1.84, 95% CI 1.09 to 3.12), but not cardiovascular disease. Associations persisted among participants with fewer than 10 pack-years and those without physician-diagnosed respiratory disease, and were similar after adjustment for airflow measures and in persons without airflow limitation. CONCLUSIONS: Quantitatively assessed emphysema on CT is associated with greater respiratory disease and lung cancer mortality, even among persons without traditional risk factors.

Classifying Chronic Lower Respiratory Disease Events in Epidemiologic Cohort Studies.

RATIONALE: One in 12 adults has chronic obstructive pulmonary disease or asthma. Acute exacerbations of these chronic lower respiratory diseases (CLRDs) are a major cause of morbidity and mortality. Valid approaches to classifying cases and exacerbations in the general population are needed to facilitate prevention research. OBJECTIVES: To assess the feasibility, reproducibility, and performance of a protocol to identify CLRD cases and exacerbations triggering emergency department (ED) visits or hospitalizations in cohorts of patients derived from general populations of adults. METHODS: A protocol was developed to classify CLRD cases and severe exacerbations on the basis of review of medical records. ED and inpatient medical records were ascertained prospectively in the Hispanic Community Health Study/Study of Latinos, and inpatient records were retrospectively identified by administrative codes in the Multi-Ethnic Study of Atherosclerosis. "Probable" exacerbations were defined as a physician's diagnosis of CLRD with acute respiratory symptoms. "Highly probable" exacerbations additionally required systemic corticosteroid therapy, and "definite" exacerbations required airflow limitation or evidence of CLRD on imaging studies. Adjudicated results were compared with CLRD cases identified by spirometry and self-report, and with an administrative definition of exacerbations. MEASUREMENTS AND MAIN RESULTS: Protocol-based classification was completed independently by two physicians for 216 medical records (56 ED visits and 61 hospitalizations in the Hispanic Community Health Study/Study of Latinos; 99 hospitalizations in the Multi-Ethnic Study of Atherosclerosis). Reviewer disagreement occurred in 2-5% of cases and 4-8% of exacerbations. Eighty-nine percent of records were confirmed as at least probable CLRD cases. Fifty-six percent of confirmed CLRD cases had airflow limitation on the basis of baseline study spirometry. Of records that described CLRD as the primary discharge diagnosis code, an acute exacerbation was confirmed as at least probable for 96% and as highly probable or definite for 77%. Only 50% of records with CLRD as a secondary code were confirmed, although such records accounted for over half of all confirmed exacerbations. CONCLUSIONS: CLRD cases and severe exacerbations without preceding documentation of airflow limitation are identified frequently in population-based cohorts of persons. A primary discharge diagnosis of CLRD is specific but insensitive for defining exacerbations. Protocol-based classification of medical records may be appropriate to supplement and to validate identification of CLRD cases and exacerbations in general population studies. Clinical trials registered with www.clinicaltrials.gov (NCT00005487 and NCT02060344).

A genome-wide association study of chronic obstructive pulmonary disease in Hispanics.

RATIONALE: Genome-wide association studies (GWAS) of chronic obstructive pulmonary disease (COPD) have identified disease-susceptibility loci, mostly in subjects of European descent. OBJECTIVES: We hypothesized that by studying Hispanic populations we would be able to identify unique loci that contribute to COPD pathogenesis in Hispanics but remain undetected in GWAS of non-Hispanic populations. METHODS: We conducted a metaanalysis of two GWAS of COPD in independent cohorts of Hispanics in Costa Rica and the United States (Multi-Ethnic Study of Atherosclerosis [MESA]). We performed a replication study of the top single-nucleotide polymorphisms in an independent Hispanic cohort in New Mexico (the Lovelace Smokers Cohort). We also attempted to replicate prior findings from genome-wide studies in non-Hispanic populations in Hispanic cohorts. MEASUREMENTS AND MAIN RESULTS: We found no genome-wide significant association with COPD in our metaanalysis of Costa Rica and MESA. After combining the top results from this metaanalysis with those from our replication study in the Lovelace Smokers Cohort, we identified two single-nucleotide polymorphisms approaching genome-wide significance for an association with COPD. The first (rs858249, combined P value = 6.1 × 10(-8)) is near the genes KLHL7 and NUPL2 on chromosome 7. The second (rs286499, combined P value = 8.4 × 10(-8)) is located in an intron of DLG2. The two most significant single-nucleotide polymorphisms in FAM13A from a previous genome-wide study in non-Hispanics were associated with COPD in Hispanics. CONCLUSIONS: We have identified two novel loci (in or near the genes KLHL7/NUPL2 and DLG2) that may play a role in COPD pathogenesis in Hispanic populations.

Noninvasive tests for the diagnostic evaluation of dyspnea among outpatients: the Multi-Ethnic Study of Atherosclerosis lung study.

BACKGROUND: Dyspnea on exertion is a common and debilitating symptom, yet evidence for the relative value of cardiac and pulmonary tests for the evaluation of chronic dyspnea among adults without known cardiac or pulmonary disease is limited. METHODS: The Multi-Ethnic Study of Atherosclerosis (MESA) enrolled participants aged 45 to 84 years who were free of clinical cardiovascular disease from 6 communities; participants with clinical pulmonary disease were excluded from this report. Dyspnea on exertion was assessed via structured interview. Tests included electrocardiograms, cardiac computed tomography (CT) for coronary artery calcium, cardiac magnetic resonance imaging, spirometry, percent emphysema (percent of lung regions <-950 HU) on CT, inflammatory biomarkers, and N-terminal pro-brain natriuretic peptide (NT-proBNP). Logistic regression was used to identify independent correlates of dyspnea after adjustment for age, sex, body mass index, physical activity, anxiety, and leg pain. RESULTS: Among 1969 participants without known cardiopulmonary disease, 9% had dyspnea. The forced expiratory volume in 1 second (FEV1) (P < .001), NT-proBNP (P = .004), and percent emphysema on CT (P = .004) provided independent information on the probability of self-reported dyspnea. Associations with the FEV1 were stronger among smokers and participants with other recent respiratory symptoms or seasonal allergies; associations with NT-proBNP were present only among participants with coexisting symptoms of lower-extremity edema. Only the FEV1 provided a significant improvement in the receiver operating curve. CONCLUSIONS: Among adults without known cardiac or pulmonary disease reporting dyspnea on exertion, spirometry, NT-proBNP, and CT imaging for pulmonary parenchymal disease were the most informative tests.

Association between emphysema-like lung on cardiac computed tomography and mortality in persons without airflow obstruction: a cohort study.

BACKGROUND: Low lung function is known to predict mortality in the general population, but the prognostic significance of emphysema on computed tomography (CT) in persons without chronic obstructive pulmonary disease (COPD) is uncertain. OBJECTIVE: To determine whether greater emphysema-like lung on CT is associated with all-cause mortality among persons in the general population without airflow obstruction or COPD. DESIGN: Prospective cohort study. SETTING: Population-based, multiethnic sample from 6 U.S. communities. PARTICIPANTS: 2965 participants aged 45 to 84 years without airflow obstruction on spirometry. MEASUREMENTS: Emphysema-like lung was defined as the number of lung voxels with attenuation less than -950 Hounsfield units on cardiac CT and was adjusted for the number of total imaged lung voxels. RESULTS: Among 2965 participants, 50.9% of whom had never smoked, there were 186 deaths over a median of 6.2 years. Greater emphysema-like lung was independently associated with increased mortality (adjusted hazard ratio per one-half interquartile range, 1.14 [95% CI, 1.04 to 1.24]; P=0.004) after adjustment for potential confounders, including cardiovascular risk factors and FEV1. Generalized additive models supported a linear association between emphysema-like lung and mortality without evidence for a threshold. The association was of greatest magnitude among smokers, although multiplicative interaction terms did not support effect modification by smoking status. LIMITATIONS: Cardiac CT scans did not include lung apices. The number of deaths was limited among subgroup analyses. CONCLUSION: Emphysema-like lung on CT was associated with all-cause mortality among persons without airflow obstruction or COPD in a general population sample, particularly among smokers. Recognition of the independent prognostic significance of emphysema on CT among patients without COPD on spirometry is warranted. PRIMARY FUNDING SOURCE: National Heart, Lung, and Blood Institute.

Association Between 6-Minute Walk Test and All-Cause Mortality, Coronary Heart Disease-Specific Mortality, and Incident Coronary Heart Disease.

OBJECTIVE: To examine the association between 6-min walk test (6 MWT) performance and all-cause mortality, coronary heart disease mortality, and incident coronary heart disease in older adults. METHOD: We conducted a time-to-event analysis of 1,665 Cardiovascular Health Study participants without prevalent cardiovascular disease with a 6 MWT. RESULTS: During a mean follow-up of 8 years, there were 305 incident coronary heart disease events, and 504 deaths of which 100 were coronary heart disease-related deaths. The 6 MWT performance in the shortest two distance quintiles was associated with increased risk of all-cause mortality (290-338 m: hazard ratio [HR] = 1.7; 95% confidence interval [CI] = [1.2, 2.5]; <290 m: HR = 2.1; 95% CI = [1.4, 3.0]). The adjusted risk of coronary heart disease mortality incident events among those with a 6 MWT < 290 m was not significant. DISCUSSION: Performance on the 6 MWT is independently associated with all-cause mortality and is of prognostic utility in community-dwelling older adults.

Exposures and cross-shift lung function declines in wildland firefighters.

Respiratory problems are common among wildland firefighters. However, there are few studies directly linking occupational exposures to respiratory effects in this population. Our objective was to characterize wildland fire fighting occupational exposures and assess their associations with cross-shift changes in lung function. We studied 17 members of the Alpine Interagency Hotshot Crew with environmental sampling and pulmonary function testing during a large wildfire. We characterized particles by examining size distribution and mass concentration, and conducting elemental and morphological analyses. We examined associations between cross-shift lung function change and various analytes, including levoglucosan, an indicator of wood smoke from burning biomass. The levoglucosan component of the wildfire aerosol showed a predominantly bimodal size distribution: a coarse particle mode with a mass median aerodynamic diameter about 12 µm and a fine particle mode with a mass median aerodynamic diameter < 0.5 µm. Levoglucosan was found mainly in the respirable fraction and its concentration was higher for fire line construction operations than for mop-up operations. Larger cross-shift declines in forced expiratory volume in one second were associated with exposure to higher concentrations of respirable levoglucosan (p < 0.05). Paired analyses of real-time personal air sampling measurements indicated that higher carbon monoxide (CO) concentrations were correlated with higher particulate concentrations when examined by mean values, but not by individual data points. However, low CO concentrations did not provide reliable assurance of concomitantly low particulate concentrations. We conclude that inhalation of fine smoke particles is associated with acute lung function decline in some wildland firefighters. Based on short-term findings, it appears important to address possible long-term respiratory health issues for wildland firefighters. [Supplementary materials are available for this article. Go to the publisher's online edition of Journal of Occupational and Environmental Hygiene for the following free supplemental resources: a file containing additional information on historical studies of wildland fire exposures, a file containing the daily-exposure-severity questionnaire completed by wildland firefighter participants at the end of each day, and a file containing additional details of the investigation of correlations between carbon monoxide concentrations and other measured exposure factors in the current study.].

Percent emphysema and right ventricular structure and function: the Multi-Ethnic Study of Atherosclerosis-Lung and Multi-Ethnic Study of Atherosclerosis-Right Ventricle Studies.

BACKGROUND: Severe COPD can lead to cor pulmonale and emphysema and is associated with impaired left ventricular (LV) filling. We evaluated whether emphysema and airflow obstruction would be associated with changes in right ventricular (RV) structure and function and whether these associations would differ by smoking status. METHODS: The Multi-Ethnic Study of Atherosclerosis (MESA) performed cardiac MRI on 5,098 participants without clinical cardiovascular disease aged 45 to 84 years. RV and emphysema measures were available for 4,188 participants. Percent emphysema was defined as the percentage of voxels below -910 Hounsfield units in the lung windows on cardiac CT scans. Generalized additive models were used to control for confounders and adjust for respective LV parameters. RESULTS: Participants consisted of 13% current smokers, 36% former smokers, and 52% never smokers. Percent emphysema was inversely associated with RV end-diastolic volume, stroke volume, cardiac output, and mass prior to adjustment for LV measures. After adjustment for LV end-diastolic volume, greater percent emphysema was associated with greater RV end-diastolic volume (+1.5 mL, P=.03) among current smokers, smaller RV end-diastolic volume (-0.8 mL, P=.02) among former smokers, and similar changes among never smokers. CONCLUSIONS: Percent emphysema was associated with smaller RV volumes and lower mass. The relationship of emphysema to cardiac function is complex but likely involves increased pulmonary vascular resistance, predominantly with reduced cardiac output, pulmonary hyperinflation, and accelerated cardiopulmonary aging.

Case-finding options for COPD: results from the Burden of Obstructive Lung Disease study.

This study aimed to compare strategies for chronic obstructive pulmonary disease (COPD) case finding using data from the Burden of Obstructive Lung Disease study. Population-based samples of adults aged ≥40 yrs (n = 9,390) from 14 countries completed a questionnaire and spirometry. We compared the screening efficiency of differently staged algorithms that used questionnaire data and/or peak expiratory flow (PEF) data to identify persons at risk for COPD and, hence, needing confirmatory spirometry. Separate algorithms were fitted for moderate/severe COPD and for severe COPD. We estimated the cost of each algorithm in 1,000 people. For moderate/severe COPD, use of questionnaire data alone permitted high sensitivity (97%) but required confirmatory spirometry in 80% of participants. Use of PEF necessitated confirmatory spirometry in only 19-22% of subjects, with 83-84% sensitivity. For severe COPD, use of PEF achieved 91-93% sensitivity, requiring confirmatory spirometry in <9% of participants. Cost analysis suggested that a staged screening algorithm using only PEF initially, followed by confirmatory spirometry as needed, was the most cost-effective case-finding strategy. Our results support the use of PEF as a simple, cost-effective initial screening tool for conducting COPD case-finding in adults aged ≥40 yrs. These findings should be validated in real-world settings such as the primary care environment.

Multi-ethnic reference values for spirometry for the 3-95-yr age range: the global lung function 2012 equations.

The aim of the Task Force was to derive continuous prediction equations and their lower limits of normal for spirometric indices, which are applicable globally. Over 160,000 data points from 72 centres in 33 countries were shared with the European Respiratory Society Global Lung Function Initiative. Eliminating data that could not be used (mostly missing ethnic group, some outliers) left 97,759 records of healthy nonsmokers (55.3% females) aged 2.5-95 yrs. Lung function data were collated and prediction equations derived using the LMS method, which allows simultaneous modelling of the mean (mu), the coefficient of variation (sigma) and skewness (lambda) of a distribution family. After discarding 23,572 records, mostly because they could not be combined with other ethnic or geographic groups, reference equations were derived for healthy individuals aged 3-95 yrs for Caucasians (n=57,395), African-Americans (n=3,545), and North (n=4,992) and South East Asians (n=8,255). Forced expiratory value in 1 s (FEV(1)) and forced vital capacity (FVC) between ethnic groups differed proportionally from that in Caucasians, such that FEV(1)/FVC remained virtually independent of ethnic group. For individuals not represented by these four groups, or of mixed ethnic origins, a composite equation taken as the average of the above equations is provided to facilitate interpretation until a more appropriate solution is developed. Spirometric prediction equations for the 3-95-age range are now available that include appropriate age-dependent lower limits of normal. They can be applied globally to different ethnic groups. Additional data from the Indian subcontinent and Arabic, Polynesian and Latin American countries, as well as Africa will further improve these equations in the future.

PFT interpretive strategies: American Thoracic Society/ European Respiratory Society 2005 guideline gaps.

All pulmonologists, including those recently completing training, should be competent in critically evaluating and interpreting pulmonary function tests (PFTs). In addition, some authorities recommend that respiratory therapists learn to provide preliminary PFT interpretations for the medical directors of PFT labs. The 2005 American Thoracic Society/European Respiratory Society guidelines for interpreting PFTs lack recommendations for the best reference equations for lung volumes and diffusing capacity of the lung for carbon monoxide (D(LCO)), and lack reference equations for non-whites. The pre-test probability of lung disease should be determined using a short questionnaire. The "nonspecific pattern" occurs in about 15% of patients referred to a PFT lab, but it has many clinical correlates and the course is usually benign. Less common PFT patterns and those resulting from comorbid conditions (such as obesity, respiratory muscle weakness, or heart failure) are not discussed by the guidelines. More than half of patients with interstitial lung disease have a normal ratio of D(LCO)/V(A) (alveolar volume), and many have a normal total lung capacity.

Should we keep pushing for a spirometer in every doctor's office?

Professional societies have encouraged primary care providers to conduct spirometry testing for the detection of chronic obstructive pulmonary disease (COPD). In spite of this effort, the success rate is unacceptably low. Simple flow-sensing spirometers have technical flaws that can cause misreadings, and they are rarely checked for accuracy. When spirometry is performed by an experienced technologist, and when payment is made on the criterion of quality, the success rate for adults and school-aged children can be as high as 90%. But testing remains a challenge for younger children and the elderly. Regular feedback for the technologist about their testing results is essential. Even with an accurate spirometer, an able patient, and a skilled technologist, the ordering physician may wrongly interpret the data. Use of spirometry in primary care will continue to be problematic unless high quality testing is tied to reimbursement. Using FEV(1) or peak flow measurements to rule out airway abnormality in the majority of patients, followed by referral for more sophisticated studies in those remaining, may be the best approach. Respiratory therapists should engage in this effort.