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.

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.

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.

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.

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.

Questionnaires and pocket spirometers provide an alternative approach for COPD screening in the general population.

BACKGROUND: In response to the Agency for Healthcare Research and Quality statement questioning the usefulness of "screening spirometry," the National Heart, Lung, and Blood Institute and the COPD Foundation held a consensus conference in June 2008 to establish a procedure to detect cases of COPD in the general population. Conference participants developed a three-stage approach, using a brief questionnaire, peak flow measurement with a pocket spirometer, and diagnostic quality spirometry. The overall objective of this study was to examine the usefulness of a simple questionnaire and peak flow measurement in screening for COPD in a self-selected population. We hypothesized that this combination would efficiently screen for clinically relevant COPD. METHODS: We queried individuals attending public events regarding the presence of wheeze and/or asthma, mucus production, dyspnea, exposure to irritants, and tobacco use. Peak expiratory flow (PEF) was then measured with a pocket spirometer. If PEF was < 70% predicted, spirometry was performed. In order to estimate the false-negative rate, a random sample of every 10th participant was also selected for spirometry. RESULTS: Between June 2008 and December 2009, 5,761 adults completed the risk assessment questionnaire. The mean age of the respondents was 54 years, 58% were women, and 88% were white. Of these, 5,638 participants completed pocket spirometry, and 315 (5.6%) had PEF < 70% predicted. Of 5,323 with normal PEF, 651 underwent spirometry. The performance of PEF was assessed via positive and negative predictive values relative to a diagnosis of clinically significant airflow obstruction, defined as FEV(1)/FEV(6) < the lower limit of normal and FEV(1) < 60% predicted. Of 4,238 subjects with at least two risk factors, 267 (6.3%) had PEF < 70%, compared with 48 of the 1,400 subjects (3.4%) with fewer than two risk factors (P < .001). Based on 729 participants with acceptable spirometry, 63.1% (113 of 179) of those with abnormal PEF tested positive for clinically significant airflow obstruction, compared with 5.5% (30 of 550) with normal PEF (P < .001). The estimated prevalence of significant COPD among the 5,638 screened was 8.7%, and sensitivity and specificity were 40.7% and 97.7%, respectively. CONCLUSIONS: A staged approach to COPD screening in adults is useful for detecting clinically significant airflow obstruction in our study population.

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.

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.

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.

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.

Longitudinal assessment of spirometry in the World Trade Center medical monitoring program.

BACKGROUND: Multiple studies have demonstrated an initial high prevalence of spirometric abnormalities following World Trade Center (WTC) disaster exposure. We assessed prevalence of spirometric abnormalities and changes in spirometry between baseline and first follow-up evaluation in participants in the WTC Worker and Volunteer Medical Monitoring Program. We also determined the predictors of spirometric change between the two examinations. METHODS: Prebronchodilator and postbronchodilator spirometry, demographics, occupational history, smoking status, and respiratory symptoms and exposure onset were obtained at both examinations (about 3 years apart). RESULTS: At the second examination, 24.1% of individuals had abnormal spirometry findings. The predominant defect was a low FVC without obstruction (16.1%). Between examinations, the majority of individuals did not have a greater-than-expected decline in lung function. The mean declines in prebronchodilator FEV(1) and FVC were 13 mL/yr and 2 mL/yr, respectively (postbronchodilator results were similar and not reported). Significant predictors of greater average decline between examinations were lack of bronchodilator responsiveness at examination 1 and weight gain [corrected]. CONCLUSIONS: Elevated rates of spirometric abnormalities were present at both examinations, with reduced FVC most common. Although the majority had a normal decline in lung function, lack of bronchodilator response at examination 1 and weight gain were significantly associated with greater-than-normal lung function declines [corrected]. Due to the presence of spirometric abnormalities > 5 years after the disaster in many exposed individuals, longer-term monitoring of WTC responders is essential.

Making the diagnosis of asthma.

Diagnostic tests can only increase or decrease the probability of the asthma diagnosis, so a thorough history is very important. In patients with asthma-like symptoms, spirometric evidence of airway obstruction plus a large bronchodilator response makes asthma much more likely. However, normal spirometry is common in patients with mild asthma who are not symptomatic at the time of testing, and patients with poorly controlled asthma may lack substantial bronchodilator response. Inhalation challenge test often helps confirm asthma in patients with normal spirometry. Adult smokers with intermittent respiratory symptoms may have either asthma or chronic obstructive pulmonary disease (COPD). Normal post-bronchodilator spirometry rules out COPD. In patients with airway obstruction, a low diffusing capacity of the lung for carbon monoxide increases the probability of COPD and makes asthma much less likely. A high exhaled nitric oxide level makes allergic asthma more likely. Response to inhaled corticosteroids makes asthma more likely and COPD less likely.

Exhaled nitric oxide measurement in workers in a microwave popcorn production plant.

Airways obstruction in microwave-popcorn workers has been attributed to inhalation of flavoring agents. Two former workers at a microwave-popcorn plant were found by lung biopsy to have bronchiolitis obliterans. The study's aim was to determine whether exhaled nitric oxide (FENO) levels were associated with exposure levels, respiratory symptoms, or airways obstruction. A questionnaire, spirometry, and FENO measurements were completed by 135 workers. The FENO levels of workers with high flavoring exposures (n = 107) were compared with those of workers with low exposures (n = 28) and healthy external controls (n = 31). FENO levels were significantly lower in the high-exposure group (p < 0.05). There is no indication that FENO is useful as a marker of lung injury in a flavoring-exposed worker population with a substantial lung disease burden, but the finding of low FENO in the high-exposure group should not be dismissed.

Induction of asthma and the environment: what we know and need to know.

The prevalence of asthma has increased dramatically over the last 25 years in the United States and in other nations as a result of ill-defined changes in living conditions in modern society. On 18 and 19 October 2004 the U.S. Environmental Protection Agency and the National Institute of Environmental Health Sciences sponsored the workshop "Environmental Influences on the Induction and Incidence of Asthma" to review current scientific evidence with respect to factors that may contribute to the induction of asthma. Participants addressed two broad questions: a) What does the science suggest that regulatory and public health agencies could do now to reduce the incidence of asthma? and b) What research is needed to improve our understanding of the factors that contribute to the induction of asthma and our ability to manage this problem? In this article (one of four articles resulting from the workshop), we briefly characterize asthma and its public health and economic impacts, and intervention strategies that have been successfully used to prevent induction of asthma in the workplace. We conclude with the findings of seven working groups that focus on ambient air, indoor pollutants (biologics), occupational exposures, early life stages, older adults, intrinsic susceptibility, and lifestyle. These groups found strong scientific support for public health efforts to limit in utero and postnatal exposure to cigarette smoke. However, with respect to other potential types of interventions, participants noted many scientific questions, which are summarized in this article. Research to address these questions could have a significant public health and economic impact that would be well worth the investment.

Induced sputum evaluation in microwave popcorn production workers.

OBJECTIVE: Severe airways obstruction and bronchiolitis obliterans have been reported in microwave popcorn production workers and attributed to inhalation of flavoring agents. We investigated whether exposure to flavoring agents is associated with airways inflammation in popcorn production workers. METHODS: Fifty-nine workers with high exposures and 22 patients with low exposures to flavoring vapors completed a questionnaire, spirometry, and sputum induction. Sputum cell counts were categorized as "high" if greater than (and "low" if less than or equal to) the median cell counts of a healthy external control group (n = 24). We compared high- and low-exposure groups as well as all workers with control subjects. RESULTS: Neutrophil concentrations in nonsmoking workers were significantly higher than those of the healthy nonsmoking control group (p < 0.05). The smoking-adjusted odds ratio for high neutrophil count (> 1.63 x 10(5)/mL) was 3.8 (95% confidence interval, 1.3 to 11.5) in the high-exposure group compared with the low-exposure group. Sputum interleukin-8 and eosinophil cationic protein levels were higher in high-exposure workers than in low-exposure workers (p < 0.05). For the worker group, mean values of FEV1 percentage of predicted and FEV1/FVC percentage of predicted were > 95%. There were no relationships between sputum characteristics and the presence of airways obstruction. CONCLUSIONS: High exposure to popcorn flavoring agents is associated with neutrophilic airway inflammation in popcorn production workers. These data provide further evidence that popcorn production workers face a significant occupational hazard through exposure to flavoring agents.

Repeatability of spirometry in 18,000 adult patients.

The objective of this study was to determine the limits for repeatability of FEV1, FVC, and PEF during spirometry test sessions in adult outpatients. A retrospective chart review of 18,000 consecutive patients, aged 20 to 90 years, referred to a large outpatient pulmonary function laboratory for testing was performed. Measurements included the differences between the highest and second-highest FVC (dFVC), FEV1 (dFEV1), and PEF (dPEF), from prebronchodilator spirometry, and anthropometric factors. Ninety percent of the patients were able to reproduce FEV1 within 120 ml (6.1%), FVC within 150 ml (5.3%), and PEF within 0.80 L (12%). Patient characteristics, such as sex, age, height, smoking status, and FEV1 (% predicted), had very little effect on repeatability, explaining only 2 to 4% of the variation in repeatability (expressed in milliliters). We conclude that the ability of patients to meet or exceed spirometry repeatability goals does not depend on patient characteristics when testing is performed by experienced personnel. The current American Thoracic Society repeatability goal of 200 ml for FEV1 and FVC may be too lenient.