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.

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.

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.

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.

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, airflow obstruction, and impaired left ventricular filling.

BACKGROUND: Very severe chronic obstructive pulmonary disease causes cor pulmonale with elevated pulmonary vascular resistance and secondary reductions in left ventricular filling, stroke volume, and cardiac output. We hypothesized that emphysema, as detected on computed tomography (CT), and airflow obstruction are inversely related to left ventricular end-diastolic volume, stroke volume, and cardiac output among persons without very severe lung disease. METHODS: We measured left ventricular structure and function with the use of magnetic resonance imaging in 2816 persons who were 45 to 84 years of age. The extent of emphysema (expressed as percent emphysema) was defined as the percentage of voxels below -910 Hounsfield units in the lung windows on cardiac computed tomographic scans. Spirometry was performed according to American Thoracic Society guidelines. Generalized additive models were used to test for threshold effects. RESULTS: Of the study participants, 13% were current smokers, 38% were former smokers, and 49% had never smoked. A 10-point increase in percent emphysema was linearly related to reductions in left ventricular end-diastolic volume (-4.1 ml; 95% confidence interval [CI], -3.3 to -4.9; P<0.001), stroke volume (-2.7 ml; 95% CI, -2.2 to -3.3; P<0.001), and cardiac output (-0.19 liters per minute; 95% CI, -0.14 to -0.23; P<0.001). These associations were of greater magnitude among current smokers than among former smokers and those who had never smoked. The extent of airflow obstruction was similarly associated with left ventricular structure and function, and smoking status had similar modifying effects on these associations. Percent emphysema and airflow obstruction were not associated with the left ventricular ejection fraction. CONCLUSIONS: In a population-based study, a greater extent of emphysema on CT scanning and more severe airflow obstruction were linearly related to impaired left ventricular filling, reduced stroke volume, and lower cardiac output without changes in the ejection fraction.

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.

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.

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.

Pulmonary function testing.

Pulmonary function testing is often considered the basis for diagnosis in many categories of pulmonary disease. Although most of the testing methodologies are well established and widely employed, there are still many questions regarding how tests should be performed, how to ensure that reliable data are produced, what reference values and rules should be used, and how pulmonary function tests (PFTs) should be interpreted to best support clinical decision making. This conference was organized around a set of questions aimed at many of these issues. Each presenter was asked to address a specific topic regarding what tests should be done, how those test should be performed to answer a particular clinical question, and to relate test results to an accurate diagnosis and appropriate treatment of the patient. These topics included testing of adults and children, with concentration on important disease entities such as COPD, asthma, and unexplained dyspnea. Special emphasis was given to discussing reference values, lower limits of normal, interpretive strategies to optimize disease classification, and those factors directly affecting data quality. Established techniques for spirometry, lung volumes, diffusing capacity, exercise testing, and bronchial challenges were compared and contrasted with new technologies, and with technologies that might be part of pulmonary function laboratories in the near future.

Longitudinal lung function declines among California flavoring manufacturing workers.

BACKGROUND: The California Department of Public Health received serial spirometry data for flavoring manufacturing workers at 20 companies at risk of bronchiolitis obliterans. METHODS: We graded spirometry quality; identified individual workers with excessive decline in forced expiratory volume in 1 s (FEV(1)) using relative longitudinal limits of decline based on 4% average within-person variability; and analyzed declines by occupational risk factors. RESULTS: The quality of 1,696 spirometry tests from 724 workers varied by 17 providers, with poorer quality from commercial providers. Of 416 workers with at least two tests, 40 (9.6%) had abnormal FEV(1) decline. Of 289 workers with high quality spirometry, 21 (7.3%) had abnormal decline. Only one of the 21 had airways obstruction. Abnormal FEV(1) decline rates (per person-month) were greater among workers at companies using ≥800 lbs/year diacetyl than at companies using lesser amounts. Abnormal FEV(1) decline rates were greater at companies previously having four-person clusters of spirometric obstruction than at companies with no or only one worker with obstruction. CONCLUSIONS: Spirometric surveillance of flavoring workers can identify individual workers with an abnormal FEV(1) decline for preventive intervention, even when the FEV(1) itself remains within the normal range. Good quality spirometry and classification of abnormal with relative longitudinal limit of decline minimize misclassification of possible work-related health effects.

Cigarette smoking is associated with subclinical parenchymal lung disease: the Multi-Ethnic Study of Atherosclerosis (MESA)-lung study.

RATIONALE: Cigarette smoking is a risk factor for diffuse parenchymal lung disease. Risk factors for subclinical parenchymal lung disease have not been described. OBJECTIVES: To determine if cigarette smoking is associated with subclinical parenchymal lung disease, as measured by spirometric restriction and regions of high attenuation on computed tomography (CT) imaging. METHODS: We examined 2,563 adults without airflow obstruction or clinical cardiovascular disease in the Multi-Ethnic Study of Atherosclerosis, a population-based cohort sampled from six communities in the United States. Cumulative and current cigarette smoking were assessed by pack-years and urine cotinine, respectively. Spirometric restriction was defined as a forced vital capacity less than the lower limit of normal. High attenuation areas on the lung fields of cardiac CT scans were defined as regions having an attenuation between -600 and -250 Hounsfield units, reflecting ground-glass and reticular abnormalities. Generalized additive models were used to adjust for age, gender, race/ethnicity, smoking status, anthropometrics, center, and CT scan parameters. MEASUREMENTS AND MAIN RESULTS: The prevalence of spirometric restriction was 10.0% (95% confidence interval [CI], 8.9-11.2%) and increased relatively by 8% (95% CI, 3-12%) for each 10 cigarette pack-years in multivariate analysis. The median volume of high attenuation areas was 119 cm(3) (interquartile range, 100-143 cm(3)). The volume of high attenuation areas increased by 1.6 cm(3) (95% CI, 0.9-2.4 cm(3)) for each 10 cigarette pack-years in multivariate analysis. CONCLUSIONS: Smoking may cause subclinical parenchymal lung disease detectable by spirometry and CT imaging, even among a generally healthy cohort.

An official American Thoracic Society/European Respiratory Society statement: asthma control and exacerbations: standardizing endpoints for clinical asthma trials and clinical practice.

BACKGROUND: The assessment of asthma control is pivotal to the evaluation of treatment response in individuals and in clinical trials. Previously, asthma control, severity, and exacerbations were defined and assessed in many different ways. PURPOSE: The Task Force was established to provide recommendations about standardization of outcomes relating to asthma control, severity, and exacerbations in clinical trials and clinical practice, for adults and children aged 6 years or older. METHODS: A narrative literature review was conducted to evaluate the measurement properties and strengths/weaknesses of outcome measures relevant to asthma control and exacerbations. The review focused on diary variables, physiologic measurements, composite scores, biomarkers, quality of life questionnaires, and indirect measures. RESULTS: The Task Force developed new definitions for asthma control, severity, and exacerbations, based on current treatment principles and clinical and research relevance. In view of current knowledge about the multiple domains of asthma and asthma control, no single outcome measure can adequately assess asthma control. Its assessment in clinical trials and in clinical practice should include components relevant to both of the goals of asthma treatment, namely achievement of best possible clinical control and reduction of future risk of adverse outcomes. Recommendations are provided for the assessment of asthma control in clinical trials and clinical practice, both at baseline and in the assessment of treatment response. CONCLUSIONS: The Task Force recommendations provide a basis for a multicomponent assessment of asthma by clinicians, researchers, and other relevant groups in the design, conduct, and evaluation of clinical trials, and in clinical practice.

Four-year calibration stability of the EasyOne portable spirometer.

BACKGROUND: Clinical practice guidelines recommend daily spirometer calibration checks and weekly linearity checks. The long-term stability of the volume and flow accuracy of a specific model of spirometer should be carefully characterized before modification of the frequency of calibration checks is considered for that model of spirometer. METHODS: The EasyOne ultrasonic flow-sensing spirometer was chosen for use by the clinical centers at the 2002 inception of the World Trade Center Worker and Volunteer Medical Screening Program. The screening program quality-control procedure required that the expiratory and inspiratory volume accuracy of each spirometer be checked every day of testing, and the flow accuracy (linearity) checked every week. The calibration check results were transferred to a central database for summary. RESULTS: Over 5,000 calibration-check results (4,109 single-speed and 1,189 three-speed) were accumulated from a total of 34 spirometers during the period February 2003 through March 2007. The mean single-speed calibration errors (and 5th-95th percentiles) were -2 mL (-80 to 70 mL) for exhalation and -10 mL (-80 to 60 mL) for inhalation. 98% of the exhalation and 97% of the inhalation calibration checks were accurate within 3.0%. There was no evidence of significant non-linearity according to the results of the 3-speed calibration checks (mean errors of -3, -5, and -6 mL at each speed). CONCLUSIONS: The EasyOne retained inhalation and exhalation volume accuracy of better than 3% for at least 4 years. Routine multiple-speed volume calibration checks may not be necessary with the EasyOne. The acceptability and repeatability of patient efforts should be the primary focus of quality-assurance programs with spirometers that have been demonstrated to remain accurate for long periods.

Quality of spirometry performed by 13,599 participants in the World Trade Center Worker and Volunteer Medical Screening Program.

OBJECTIVE: To determine the ability of spirometry technicians in the World Trade Center Worker and Volunteer Medical Screening Program to meet American Thoracic Society spirometry quality goals. METHODS: Spirometry technicians were trained centrally and performed spirometry sessions at 6 sites in the greater New York City area. We reviewed and graded the spirometry results for quality every month. RESULTS: About 80% (range 70-88%) of the spirometry sessions met the American Thoracic Society spirometry goals. In general, the spirometry technicians with the most experience were more successful in meeting the quality goals. Participant characteristics explained very little of the quality variability. CONCLUSIONS: The overall spirometry quality in this multicenter program was very good. Efforts to improve spirometry quality should focus on the performance of individual spirometry technicians.

Industry-wide medical surveillance of California flavor manufacturing workers: Cross-sectional results.

BACKGROUND: Two cases of bronchiolitis obliterans in flavor manufacturing workers prompted California health and labor agencies to initiate industry-wide surveillance. METHODS: Companies' physicians submitted cross-sectional questionnaire and spirometry data for 467 workers in 16 workplaces. We compared prevalence ratios of respiratory symptoms, diagnoses, and abnormal spirometry to a general population sample. We calculated odds ratios for risk factors for spirometric obstructive abnormality. RESULTS: Flavoring workers were 2.7 times more likely than the general population to have severe airways obstruction. Risk factors identified for 18 cases with obstruction from six companies included younger age, Hispanic ethnicity, liquid and powder production work, greater company diacetyl usage, and having a coworker with obstruction. Severity of obstruction was related to tenure. At least 12 workers had probable occupational fixed airways obstruction. CONCLUSIONS: The flavoring industry risk of severe lung disease justifies lowering flavoring exposures and medical screening for secondary prevention until worker safety is demonstrated.