Diffusing Capacity and Mortality in Chronic Obstructive Pulmonary Disease.

Rationale: Chronic obstructive pulmonary disease (COPD) mortality risk is often estimated using the BODE (body mass index, obstruction, dyspnea, exercise capacity) index, including body mass index, forced expiratory volume in 1 second, dyspnea score, and 6-minute walk distance. Diffusing capacity of the lung for carbon monoxide (DlCO) is a potential predictor of mortality that reflects physiology distinct from that in the BODE index. Objectives: This study evaluated DlCO as a predictor of mortality using participants from the COPDGene study. Methods: We performed time-to-event analyses of individuals with COPD (former or current smokers with forced expiratory volume in 1 second/forced vital capacity < 0.7) and DlCO measurements from the COPDGene phase 2 visit. Cox proportional hazard methods were used to model survival, adjusting for age, sex, pack-years, smoking status, BODE index, computed tomography (CT) percent emphysema (low attenuation areas below -950 Hounsfield units), CT airway wall thickness, and history of cardiovascular or kidney diseases. C statistics for models with DlCO and BODE scores were used to compare discriminative accuracy. Results: Of 2,329 participants, 393 (16.8%) died during the follow-up period (median = 4.9 yr). In adjusted analyses, for every 10% decrease in DlCO percent predicted, mortality increased by 28% (hazard ratio = 1.28; 95% confidence interval, 1.17-1.41, P < 0.001). When compared with other clinical predictors, DlCO percent predicted performed similarly to BODE (C statistic DlCO = 0.68; BODE = 0.70), and the addition of DlCO to BODE improved its discriminative accuracy (C statistic = 0.71). Conclusions: Diffusing capacity, a measure of gas transfer, strongly predicted all-cause mortality in individuals with COPD, independent of BODE index and CT evidence of emphysema and airway wall thickness. These findings support inclusion of DlCO in prognostic models for COPD.

Effect of barometric pressure on single-breath carbon monoxide diffusing capacity.

BACKGROUND: Single-breath diffusing capacity for carbon monoxide (DLCO) quantifies gas transfer in the lungs. DLCO measurement is affected by barometric pressure (Pb) and alveolar partial pressure of oxygen (PAO2). The current equations for adjusting DLCO for Pb and PAO2 may not be accurate given advances in test performance and technology. We quantify changes in DLCO with alterations in Pb in normal and COPD subjects, determine the accuracy of the current Pb and PAO2 adjustment equations and develop updated adjustment equations. METHODS: We measured DLCO in 13 normal and 10 COPD subjects at 1330 m altitude and in a hypobaric/hyperbaric chamber at altitudes of sea-level and 2500 m; six normal subjects were tested at 3600 m. We determined if there were significant differences in DLCO between altitudes. We developed an equation for adjusting DLCO for changes in Pb from sea-level. We compared this equation with the existing Pb adjustment equation in normal and COPD subjects. We determined the accuracy of the current PAO2 adjustment equation and developed a new PAO2 adjustment equation. RESULTS: DLCO significantly increased with decreasing Pb. We developed a Pb adjustment equation that adjusts DLCO measured at altitudes between 1330 m and 3600 m to sea-level values. This Pb adjustment equation yields DLCO results that are not significantly different than the currently recommended equation. We developed a more accurate PAO2 adjustment equation. CONCLUSION: DLCO measurement is significantly affected by altitude. We developed equations that accurately adjust DLCO for changes in Pb and PAO2 in normal and COPD subjects.

Haemoglobin as a biomarker for clinical outcomes in chronic obstructive pulmonary disease.

In COPD, anaemia is associated with increased morbidity, but the relationship between haemoglobin over its entire observed range and morbidity is poorly understood. Such an understanding could guide future therapeutic targeting of haemoglobin in COPD management. Leveraging the COPDGene study, we conducted a cross-sectional analysis of haemoglobin from COPD participants, examining symptoms, quality of life, functional performance, and acute exacerbations of COPD (AECOPD). Haemoglobin was analysed both as a continuous variable and categorised into anaemia, normal haemoglobin, and polycythaemia groups. Fractional polynomial modelling was used for continuous analyses; categorical models were multivariable linear or negative binomial regressions. Covariates included demographics, comorbidities, emphysema, diffusing capacity, and airflow obstruction. From 2539 participants, 366 (14%) were identified as anaemic and 125 (5%) as polycythaemic. Compared with normal haemoglobin, anaemia was significantly associated with increased symptoms (COPD Assessment Test score: p=0.006, modified Medical Research Council (mMRC) Dyspnoea Score: p=0.001); worse quality of life (St. George's Respiratory Questionnaire (SGRQ) score: p<0.001; Medical Outcomes Study Short Form 36-item Questionnaire (SF-36) General Health: p=0.002; SF-36 Physical Health: p<0.001), decreased functional performance (6-min walk distance (6MWD): p<0.001), and severe AECOPD (p=0.01), while polycythaemia was not. Continuous models, however, demonstrated increased morbidity at both ends of the haemoglobin distribution (p<0.01 for mMRC, SGRQ, SF-36 Physical Health, 6MWD, and severe AECOPD). Evaluating interactions, both diffusing capacity and haemoglobin were independently associated with morbidity. We present novel findings that haemoglobin derangements towards either extreme of the observed range are associated with increased morbidity in COPD. Further investigation is necessary to determine whether haemoglobin derangement drives morbidity or merely reflects systemic inflammation, and whether correcting haemoglobin towards the normal range improves morbidity.

Lung function in men with and without HIV.

OBJECTIVES: Initial studies suggest HIV-positive persons may be at increased risk for chronic lung diseases such as chronic obstructive pulmonary disease, but have commonly relied on single-center designs, lacked HIV-negative controls, or assessed lung function with only spirometry. We tested differences in spirometry and single-breath diffusing capacity for carbon monoxide (DLCO) in persons with and without HIV. DESIGN: Cross-sectional, observational study. METHODS: Participants were enrolled from the Multicenter AIDS Cohort Study, a longitudinal cohort study of men who have sex with men (both HIV-positive and HIV-negative) at four sites in the United States. Standardized spirometry and DLCO testing were performed in all eligible, consenting participants at routine study visits. We tested associations between HIV status and spirometry and DLCO results, using linear and logistic regression. RESULTS: Among 1067 men, median age was 57 years, prevalence of current marijuana (30%), and cigarette (24%) use was high, and another 45% were former cigarette smokers. Median forced expiratory volume in 1 s was 97% of predicted normal and DLCO was 85% of predicted normal. HIV-positive persons demonstrated no statistical difference in forced expiratory volume in 1 s compared with HIV-negative persons, but had worse DLCO (adjusted difference -2.6% of predicted; 95% confidence interval: -4.7 to -0.6%) and a higher risk of DLCO impairment (odds ratio for DLCO < 60% of predicted 2.97; 95% confidence interval: 1.36-6.47). Lower DLCO was associated with lower nadir CD4 cell counts. CONCLUSION: HIV-positive men are at increased risk of abnormal gas exchange, indicated by low DLCO, compared with men without HIV.

Diffusing Capacity of Carbon Monoxide in Assessment of COPD.

BACKGROUND: Diffusing capacity of the lung for carbon monoxide (Dlco) is inconsistently obtained in patients with COPD, and the added benefit of Dlco testing beyond that of more common tools is unknown. OBJECTIVE: The goal of this study was to determine whether lower Dlco is associated with increased COPD morbidity independent of emphysema assessed via spirometry and CT imaging. METHODS: Data for 1,806 participants with COPD from the Genetic Epidemiology of COPD (COPDGene) study 5-year visit were analyzed, including pulmonary function testing, quality of life, symptoms, exercise performance, and exacerbation rates. Dlco percent predicted was primarily analyzed as a continuous variable and additionally categorized into four groups: (1) Dlco and FEV1 > 50% (reference); (2) only Dlco ≤ 50%; (3) only FEV1 ≤ 50%; and (4) both ≤ 50% predicted. Outcomes were modeled by using multivariable linear and negative binomial regression, including emphysema and FEV1 percent predicted among other confounders. RESULTS: In multivariable analyses, every 10% predicted decrease in Dlco was associated with symptoms and quality of life (COPD Assessment Test, 0.53 [P < .001]; St. George's Respiratory Questionnaire, 1.67 [P < .001]; Medical Outcomes Study Short Form 36 Physical Function, -0.89 [P < .001]), exercise performance (6-min walk distance, -45.35 feet; P < .001), and severe exacerbation rate (rate ratio, 1.14; P < .001). When categorized, severe impairment in Dlco alone, FEV1 alone, or both Dlco and FEV1 were associated with significantly worse morbidity compared with the reference group (P < .05 for all outcomes). CONCLUSIONS: Impairment in Dlco was associated with increased COPD symptoms, reduced exercise performance, and severe exacerbation risk even after accounting for spirometry and CT evidence of emphysema. These findings suggest that Dlco should be considered for inclusion in future multidimensional tools assessing COPD.

Airflow Obstruction Categorization Methods and Mortality.

RATIONALE: Current guidelines recommend using forced expiratory volume in 1 second (FEV1) % predicted to categorize the severity of airflow obstruction. There are limitations to using FEV1 % predicted for this purpose, including bias associated with demographic factors and the inability to correct for "lung size." Other methods for grading the severity of airflow obstruction have been proposed to address these limitations. OBJECTIVES: Our objectives were to categorize airflow obstruction severity using these methods and then determine which method results in a categorization most closely associated with mortality. METHODS: Study subjects were patients aged 40-80 years tested in our pulmonary function test laboratories in the period 2002 to 2013 with airflow obstruction based on an FEV1/forced vital capacity (FVC) less than the lower limit of normal. Categorization of airflow obstruction severity was determined using four methods: FEV1 % predicted; FEV1 % predicted adjusted by FVC % predicted; FEV1/FVC confidence interval approach; and FEV1 z-scores. Receiver operating characteristic curve analysis was used to determine which categorization method best predicts 5-year survival. RESULTS: We identified 2,000 patients with airflow obstruction. Important differences in the categorization of airflow obstruction severity were observed using the different methods. More patients were categorized as having severe obstruction using FEV1 % predicted and FEV1 z-scores compared with FEV1 % predicted adjusted by FVC % predicted and FEV1/FVC confidence interval approach. FEV1 % predicted was the best predictor of 5-year survival among the four methods studied. CONCLUSIONS: In our study, categorizing airflow obstruction severity using FEV1 % predicted best predicted 5-year survival. This validates the current guideline recommendation that FEV1 % predicted be used to categorize the severity of airflow obstruction.

Exposure to Oil Spill Chemicals and Lung Function in Deepwater Horizon Disaster Response Workers.

OBJECTIVE: The aim of this study was to assess the relationship between total hydrocarbon (THC) exposures attributed to oil spill clean-up work and lung function 1 to 3 years after the Deepwater Horizon (DWH) disaster. METHODS: We used data from the GuLF STUDY, a large cohort of adults who worked on response to the DWH disaster and others who were safety trained but did not work. We analyzed data from 6288 workers with two acceptable spirometry tests. We estimated THC exposure levels with a job exposure matrix. We evaluated lung function using the forced expiratory volume in 1 second (FEV1; mL), the forced vital capacity (FVC; mL), and the FEV1/FVC ratio (%). RESULTS: Lung function measures did not differ by THC exposure levels among clean-up workers. CONCLUSION: We did not observe an association between THC exposure and lung function among clean-up workers 1 to 3 years following the DWH disaster.

Lung Function in Oil Spill Response Workers 1-3 Years After the Deepwater Horizon Disaster.

BACKGROUND: Little is known about the effects of inhalation exposures on lung function among workers involved in the mitigation of oil spills. Our objective was to determine the relationship between oil spill response work and lung function 1-3 years after the Deepwater Horizon (DWH) disaster. METHODS: We evaluated spirometry for 7,775 adults living in the Gulf states who either participated in DWH response efforts (workers) or received safety training but were not hired (nonworkers). At an enrollment interview, we collected detailed work histories including information on potential exposure to dispersants and burning oil/gas. We assessed forced expiratory volume in 1 second (FEV1; mL), forced vital capacity (FVC; mL), and the ratio (FEV1/FVC%) for differences by broad job classes and exposure to dispersants or burning oil/gas using multivariable linear and modified Poisson regression. RESULTS: We found no differences between workers and nonworkers. Among workers, we observed a small decrement in FEV1 (Beta, -71 mL; 95% confidence interval [CI], -127 to -14) in decontamination workers compared with support workers. Workers with high potential exposure to burning oil/gas had reduced lung function compared with unexposed workers: FEV1 (Beta, -183 mL; 95% CI, -316 to -49) and FEV1/FVC (Beta, -1.93%; 95% CI, -3.50 to -0.36), and an elevated risk of having a FEV1/FVC in the lowest tertile (prevalence ratio, 1.38; 95% CI, 0.99 to 1.92). CONCLUSIONS: While no differences in lung function were found between workers and nonworkers, lung function was reduced among decontamination workers and workers with high exposure to burning oil/gas compared with unexposed workers.

The association of tidal EFL with exercise performance, exacerbations, and death in COPD.

BACKGROUND: Tidal expiratory flow limitation (EFLT) is frequently found in patients with COPD and can be detected by forced oscillations when within-breath reactance of a single-breath is ≥0.28 kPa·s·L-1. The present study explored the association of within-breath reactance measured over multiple breaths and EFLT with 6-minute walk distance (6MWD), exacerbations, and mortality. METHODS: In 425 patients, spirometry and forced oscillation technique measurements were obtained on eight occasions over 3 years. 6MWD was assessed at baseline and at the 3-year visit. Respiratory symptoms, exacerbations, and hospitalizations were recorded. A total of 5-year mortality statistics were retrieved retrospectively. We grouped patients according to the mean within-breath reactance [Formula: see text], measured over several breaths at baseline, calculated as mean inspiratory-mean expiratory reactance over the sampling period. In addition to the established threshold of EFLT, an upper limit of normal (ULN) was defined using the 97.5th percentile of [Formula: see text], of the healthy controls in the study; 6MWDs were compared according to [Formula: see text], as normal, ≥ ULN < EFLT, or ≥ EFLT. Annual exacerbation rates were analyzed using a negative binomial model in the three groups, supplemented by time to first exacerbation analysis, and dichotomizing patients at the ULN. RESULTS: In patients with COPD and baseline [Formula: see text] below the ULN (0.09 kPa·s·L-1), 6MWD was stable. 6MWD declined significantly in patients with [Formula: see text]. Worse lung function and more exacerbations were found in patients with COPD with [Formula: see text], and patients with [Formula: see text] had shorter time to first exacerbation and hospitalization. A significantly higher mortality was found in patients with [Formula: see text] and FEV1 >50%. CONCLUSION: Patients with baseline [Formula: see text] had a deterioration in exercise performance, more exacerbations, and greater hospitalizations, and, among those with moderate airway obstruction, a higher mortality. [Formula: see text] is a novel independent marker of outcome in COPD.

Comparison of NHANES III and ERS/GLI 12 for airway obstruction classification and severity.

The diagnosis and severity categorisation of obstructive lung disease is determined using reference values. The American Thoracic Society/European Respiratory Society in 2005 recommended the National Health and Nutrition Examination Survey (NHANES) III spirometry prediction equations for patients in USA aged 8-80 years. The Global Lung Initiative 2012 (GLI 12) provided spirometry prediction equations for patients aged 3-95 years. Comparison of the NHANES III and GLI 12 prediction equations for diagnosing and categorising airway obstruction in patients in USA has not been made.We aimed to quantify the differences between NHANES III and GLI 12 predicted values in Caucasians aged 18-95 years, using both mathematical simulation and clinical data. We compared predicted forced expiratory volume in 1 s (FEV1) and lower limit of normal (LLN) FEV1/forced vital capacity (FVC) % for NHANES III and GLI 12 prediction equations by applying both a simulation model and clinical spirometry data to quantify differences in the diagnosis and categorisation of airway obstruction.Mathematical simulation revealed significant similarities and differences between prediction equations for both LLN FEV1/FVC % and predicted FEV1 There are significant differences when using GLI 12 and NHANES III to diagnose airway obstruction and severity in Caucasian patients aged 18-95 years.Similarities and differences exist between NHANES III and GLI 12 for some age and height combinations. The differences in LLN FEV1/FVC % and predicted FEV1 are most prominent in older taller/shorter individuals. The magnitude of the differences can be large and may result in differences in clinical management.

Phenotype of Spirometric Impairment in an Aging Population.

RATIONALE: The Global Lung Initiative (GLI) provides age-appropriate criteria for establishing spirometric impairment, including mild, moderate, and severe chronic obstructive pulmonary disease (COPD) and restrictive pattern, but its association with respiratory-related phenotypes has not been evaluated. OBJECTIVES: To evaluate respiratory-related phenotypes in GLI-defined spirometric impairment. METHODS: In COPDGene (N = 10,131 patients; age range, 45-81 yr; average smoking history, 44.3 pack-years), we evaluated spirometry, dyspnea (modified Medical Research Council grade, ≥2), poor respiratory health-related quality of life (St. George's Respiratory Questionnaire total score, ≥25), poor exercise performance (6-minute-walk distance, <391 m), bronchodilator reversibility (FEV1 change, >12% and ≥200 ml), and computed tomography-diagnosed emphysema and gas trapping (>5% and >15% of lung, respectively). MEASUREMENTS AND MAIN RESULTS: GLI established normal spirometry in 5,100 patients (50.3%), mild COPD in 669 (6.6%), moderate COPD in 865 (8.5%), severe COPD in 2,522 (24.9%), and restrictive pattern in 975 (9.6%). Relative to normal spirometry, graded associations with respiratory-related phenotypes were found for mild, moderate, and severe COPD, with respective adjusted odds ratios (95% confidence intervals) as follows: dyspnea-1.31 (1.10-1.56), 2.20 (1.81-2.68), and 10.73 (8.04-14.33); poor respiratory health-related quality of life-1.49 (1.28-1.75), 2.69 (2.08-3.47), and 14.61 (10.09-21.17); poor exercise performance-1.11 (0.94-1.31), 1.58 (1.33-1.88), and 4.58 (3.42-6.12); bronchodilator reversibility-2.76 (2.24-3.40), 5.18 (4.29-6.27), and 6.21 (5.06-7.62); emphysema-4.86 (3.16-7.47), 6.41 (4.09-10.05), and 17.79 (10.79-29.32); and gas trapping-3.92 (3.12-4.93), 5.20 (3.82-7.07), and 16.28 (9.71-27.30). Restrictive pattern was also associated with multiple respiratory-related phenotypes at a level similar to moderate COPD, but it was otherwise not associated with emphysema (0.89 [0.60-1.32]) or gas trapping (1.15 [0.92-1.42]). CONCLUSIONS: GLI-defined spirometric impairment establishes clinically meaningful respiratory disease, as validated by graded associations with respiratory-related phenotypes.

A genome-wide association study identifies risk loci for spirometric measures among smokers of European and African ancestry.

BACKGROUND: Pulmonary function decline is a major contributor to morbidity and mortality among smokers. Post bronchodilator FEV1 and FEV1/FVC ratio are considered the standard assessment of airflow obstruction. We performed a genome-wide association study (GWAS) in 9919 current and former smokers in the COPDGene study (6659 non-Hispanic Whites [NHW] and 3260 African Americans [AA]) to identify associations with spirometric measures (post-bronchodilator FEV1 and FEV1/FVC). We also conducted meta-analysis of FEV1 and FEV1/FVC GWAS in the COPDGene, ECLIPSE, and GenKOLS cohorts (total n = 13,532). RESULTS: Among NHW in the COPDGene cohort, both measures of pulmonary function were significantly associated with SNPs at the 15q25 locus [containing CHRNA3/5, AGPHD1, IREB2, CHRNB4] (lowest p-value = 2.17 × 10(-11)), and FEV1/FVC was associated with a genomic region on chromosome 4 [upstream of HHIP] (lowest p-value = 5.94 × 10(-10)); both regions have been previously associated with COPD. For the meta-analysis, in addition to confirming associations to the regions near CHRNA3/5 and HHIP, genome-wide significant associations were identified for FEV1 on chromosome 1 [TGFB2] (p-value = 8.99 × 10(-9)), 9 [DBH] (p-value = 9.69 × 10(-9)) and 19 [CYP2A6/7] (p-value = 3.49 × 10(-8)) and for FEV1/FVC on chromosome 1 [TGFB2] (p-value = 8.99 × 10(-9)), 4 [FAM13A] (p-value = 3.88 × 10(-12)), 11 [MMP3/12] (p-value = 3.29 × 10(-10)) and 14 [RIN3] (p-value = 5.64 × 10(-9)). CONCLUSIONS: In a large genome-wide association study of lung function in smokers, we found genome-wide significant associations at several previously described loci with lung function or COPD. We additionally identified a novel genome-wide significant locus with FEV1 on chromosome 9 [DBH] in a meta-analysis of three study populations.

Phenotype of normal spirometry in an aging population.

RATIONALE: In aging populations, the commonly used Global Initiative for Chronic Obstructive Lung Disease (GOLD) may misclassify normal spirometry as respiratory impairment (airflow obstruction and restrictive pattern), including the presumption of respiratory disease (chronic obstructive pulmonary disease [COPD]). OBJECTIVES: To evaluate the phenotype of normal spirometry as defined by a new approach from the Global Lung Initiative (GLI), overall and across GOLD spirometric categories. METHODS: Using data from COPDGene (n = 10,131; ages 45-81; smoking history, ≥10 pack-years), we evaluated spirometry and multiple phenotypes, including dyspnea severity (Modified Medical Research Council grade 0-4), health-related quality of life (St. George's Respiratory Questionnaire total score), 6-minute-walk distance, bronchodilator reversibility (FEV1 % change), computed tomography-measured percentage of lung with emphysema (% emphysema) and gas trapping (% gas trapping), and small airway dimensions (square root of the wall area for a standardized airway with an internal perimeter of 10 mm). MEASUREMENTS AND MAIN RESULTS: Among 5,100 participants with GLI-defined normal spirometry, GOLD identified respiratory impairment in 1,146 (22.5%), including a restrictive pattern in 464 (9.1%), mild COPD in 380 (7.5%), moderate COPD in 302 (5.9%), and severe COPD in none. Overall, the phenotype of GLI-defined normal spirometry included normal adjusted mean values for dyspnea grade (0.8), St. George's Respiratory Questionnaire (15.9), 6-minute-walk distance (1,424 ft [434 m]), bronchodilator reversibility (2.7%), % emphysema (0.9%), % gas trapping (10.7%), and square root of the wall area for a standardized airway with an internal perimeter of 10 mm (3.65 mm); corresponding 95% confidence intervals were similarly normal. These phenotypes remained normal for GLI-defined normal spirometry across GOLD spirometric categories. CONCLUSIONS: GLI-defined normal spirometry, even when classified as respiratory impairment by GOLD, included adjusted mean values in the normal range for multiple phenotypes. These results suggest that among adults with GLI-defined normal spirometry, GOLD may misclassify normal phenotypes as having respiratory impairment.

Variability of within-breath reactance in COPD patients and its association with dyspnoea.

The forced oscillation technique can identify expiratory flow limitation (EFL) when a large difference in inspiratory and expiratory reactance (ΔXrs) occurs. However, flow limitation can vary from breath to breath, and so we compared a multiple-breath ΔXrs approach to the traditional breath-by-breath assessment of EFL. We investigated the within- and between-day reproducibility and the factors that affect the size of ΔXrs when used as a continuous measurement over multiple breaths. In addition, we examined how multiple-breath ΔXrs relates to the sensation of breathlessness. 425 moderate to very severe chronic obstructive pulmonary disease (COPD) patients and 229 controls were included. Spirometry and impedance measurements were performed on a MasterScope CT Impulse Oscillation System. Median ΔXrs approached zero in healthy controls with little variation between measurements. COPD patients generally had higher ΔXrs and higher variability. The COPD patients with ΔXrs >0.1 kPa · L(-1) · s(-1) were prone to be more breathless and had a higher modified Medical Research Council dyspnoea scale score. In controls, the 95th percentile of ΔXrs was as low as 0.07 kPa · L(-1) · s(-1). We describe a new method to assess EFL at a patient level and propose a cut-off, mean ΔXrs >0.1 kPa · L(-1) · s(-1), as a way to identify COPD patients who are more likely to report dyspnoea.

Single-breath diffusing capacity for carbon monoxide instrument accuracy across 3 health systems.

BACKGROUND: Measuring diffusing capacity of the lung for carbon monoxide (DLCO) is complex and associated with wide intra- and inter-laboratory variability. Increased D(LCO) variability may have important clinical consequences. The objective of the study was to assess instrument performance across hospital pulmonary function testing laboratories using a D(LCO) simulator that produces precise and repeatable D(LCO) values. METHODS: D(LCO) instruments were tested with CO gas concentrations representing medium and high range D(LCO) values. The absolute difference between observed and target D(LCO) value was used to determine measurement accuracy; accuracy was defined as an average deviation from the target value of < 2.0 mL/min/mm Hg. Accuracy of inspired volume measurement and gas sensors were also determined. RESULTS: Twenty-three instruments were tested across 3 healthcare systems. The mean absolute deviation from the target value was 1.80 mL/min/mm Hg (range 0.24-4.23) with 10 of 23 instruments (43%) being inaccurate. High volume laboratories performed better than low volume laboratories, although the difference was not significant. There was no significant difference among the instruments by manufacturers. Inspired volume was not accurate in 48% of devices; mean absolute deviation from target value was 3.7%. Instrument gas analyzers performed adequately in all instruments. CONCLUSIONS: D(LCO) instrument accuracy was unacceptable in 43% of devices. Instrument inaccuracy can be primarily attributed to errors in inspired volume measurement and not gas analyzer performance. D(LCO) instrument performance may be improved by regular testing with a simulator. Caution should be used when comparing D(LCO) results reported from different laboratories.

Spirometric reference values for Malagasy adults aged 18-73 years.

The American Thoracic Society (ATS) and European Respiratory Society (ERS) recommend that spirometry prediction equations be derived from samples of similar race/ethnicity. Malagasy prediction equations do not exist. The objectives of this study were to establish prediction equations for healthy Malagasy adults, and then compare Malagasy measurements with published prediction equations. We enrolled 2491 healthy Malagasy subjects aged 18-73 years (1428 males) from June 2006 to April 2008. The subjects attempted to meet the ATS/ERS 2005 guidelines when performing forced expiratory spirograms. We compared Malagasy measurements of forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC) and FEV1/FVC with predictions from the European Community for Steel and Coal (ECSC), the third National Health and Nutrition Examination Survey (NHANES III) and the ERS Global Lung Function Initiative (GLI) 2012 study. A linear model for the entire population, using age and height as independent variables, best predicted all spirometry parameters for sea level and highland subjects. FEV1, FVC and FEV1/FVC were most accurately predicted by NHANES III African-American male and female, and by GLI 2012 black male and black and South East Asian female equations. ECSC-predicted FEV1, FVC and FEV1/FVC were poorly matched to Malagasy measurements. We provide the first spirometry reference equations for a healthy adult Malagasy population, and the first comparison of Malagasy population measurements with ECSC, NHANES III and GLI 2012 prediction equations.

FEV(1)/FEV(6) to diagnose airflow obstruction. Comparisons with computed tomography and morbidity indices.

RATIONALE: FVC is a difficult maneuver for many patients, and forced expiratory volume in 6 seconds (FEV6) has been proposed as a surrogate for FVC for the diagnosis of chronic obstructive pulmonary disease (COPD). Previous studies have performed head-to-head comparisons of these thresholds but did not examine their relationships with structural lung disease, symptoms, or exacerbations. OBJECTIVES: To compare FEV1/FEV6 with FEV1/FVC in the diagnosis of COPD-related morbidity and structural lung disease as assessed by CT. METHODS: We analyzed data from a large multicenter cohort study (COPDGene) that included current and former smokers (age 45-80 yr). Accuracy and concordance between the two ratios in diagnosing structural COPD was compared using CT measures of emphysema and airway disease and COPD-related morbidity to assess how the two ratios compare in defining disease. RESULTS: A total of 10,018 subjects were included. FEV1/FEV6 showed excellent accuracy in diagnosing airflow obstruction using FEV1/FVC < 0.70 as a reference (area under curve, 0.99; 95% confidence interval [CI], 0.989-0.992; P < 0.001). FEV1/FEV6 < 0.73 had the best sum of sensitivity (92.1%; 95% CI, 90.8-92.4) and specificity (97.3%; 95% CI, 97.3-98.1). There was excellent agreement between the two diagnostic cutoffs (κ = 0.90; 95% CI, 0.80-0.91; P < 0.001). In comparison with control subjects and those positive by FEV1/FVC alone, subjects positive by FEV1/FEV6 alone had greater gas trapping and airway wall thickness, worse functional capacity, and a greater number of exacerbations on follow-up. These relationships held true when disease definitions were made using the lower limits of normal. CONCLUSIONS: FEV1/FEV6 can be substituted for FEV1/FVC in diagnosing airflow obstruction and may better predict COPD-related pathology and morbidity.

Long-term intersession variability for single-breath diffusing capacity.

BACKGROUND: Characterizing long-term diffusing capacity (DL(CO)) variability is important in assessing quality control for DL(CO) equipment and patient management. Long-term DL(CO) variability has not been reported. OBJECTIVES: It was the aim of this study to characterize long-term variability of DL(CO) in a cohort of biocontrols and to compare different methods of selecting a target value. METHODS: Longitudinal DL(CO) monitoring of biocontrols was performed as part of the inhaled insulin development program; 288 biocontrols were tested twice monthly for up to 5 years using a standardized technique. Variability, expressed either as percent change or DL(CO) units, was assessed using three different target values. RESULTS: The 90th percentile for mean intersession change in DL(CO) was between 10.9 and 15.8% (2.6-4.1 units) depending on the target value. Variability was lowest when the mean of all DL(CO) tests was used as the target value and highest when the baseline DL(CO) was used. The average of the first six DL(CO) tests provided an accurate estimate of the mean DL(CO) value. Using this target, the 90th percentile for mean intersession change was 12.3% and 3.0 units. Variability was stable over time and there were no meaningful associations between variability and demographic factors. CONCLUSIONS: DL(CO) biocontrol deviations >12% or >3.0 units, from the average of the first six tests, indicate that the instrument is not within quality control limits and should be carefully evaluated before further patient testing.

Prevalence of airway obstruction in recreational SCUBA divers.

OBJECTIVE: The prevalence of airflow obstruction in recreational self-contained underwater breathing apparatus (SCUBA) divers is unknown. Since airflow obstruction is a relative contraindication for diving, we conducted a study to determine its prevalence and magnitude in a cohort of recreational divers in Saba, Netherlands Antilles. METHODS: Prior to diving, divers were asked to complete a diving/health questionnaire and then to perform spirometry administered by trained dive store personnel. Spirometry instrumentation provided immediate feedback regarding test quality. RESULTS: Of 8365 eligible divers during the study period (November 1997-March 1999), 668 enrolled and completed questionnaires. Of those completing questionnaires, 46% reported a history of smoking, 13% were current smokers, 15% wheezed, 6% had asthma, 4% used bronchodilators, and 3% took oral steroids. Of 654 completing spirometry, 231 had acceptable spirometry quality and complete questionnaires. By forced expiratory volume in 1 second/forced vital capacity, 10% had mild, 1.7% had moderate, and 0.4% had severe airflow obstruction. CONCLUSIONS: The prevalence of airflow obstruction was 6% to 15% by report and 12% by spirometry, approximating the combined prevalence of asthma and chronic obstructive pulmonary disease in the general population. Study limitations include possible self-selection and low enrollment rate. Prospective lung function testing can be conducted at remote sites using nonmedical personnel as "testers." This study could guide future investigations to determine if asthma is a risk factor for decompression illness.