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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 FEV 1 > 50% (reference); (2) only Dlco ≤ 50%; (3) only FEV 1  ≤ 50%; and (4) both ≤ 50% predicted. Outcomes were modeled by using multivariable linear and negative binomial regression, including emphysema and FEV 1 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, FEV 1 alone, or both Dlco and FEV 1 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., (Copyright © 2019. Published by Elsevier Inc.)

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.

Background: Standardization of the measurement of single-breath diffusing capacity of the lung for carbon monoxide (DLCO) is difficult to implement in multicenter trials as differences in equipment, training, and performance guidelines have led to high variability between and within centers. The safety assessment of inhalable insulin required the standardization of measurement of single-breath DLCO in multicenter clinical trials to optimize test precision., Methods: This was an open-label, 24-week, parallel-group, outpatient study of inhaled human insulin in participants with type 1 diabetes who were randomly assigned to receive treatment with daily premeal inhaled or subcutaneous (SC) insulin for 12 weeks, followed by SC insulin for 12 weeks. Monitoring of single-breath DLCO using standardized methodology was performed. Standardization included uniform instrumentation, centrally trained study coordinators, and centralized data monitoring and review of quality control. Sites received feedback within 24 h for any tests of unacceptable quality with recommendations for improvement., Results: A total of 226 study participants at 33 sites completed 11,335 DLCO efforts during 4,797 test sessions; 3,607 (75.2%) and 4,581 (95.5%) of all testing sessions yielded two American Thoracic Society-acceptable efforts that varied by < 1 and 2 mL/min/mm Hg, respectively. Only 65 sessions produced one or fewer acceptable efforts. The root mean square intrasubject coefficient of variation in DLCO at the end of the comparative dosing phase was 6.01%., Conclusions: The standardized methodology employed in this study demonstrates the feasibility of collecting high-quality single-breath DLCO data in the setting of a multicenter clinical trial with reliability that is comparable to spirometry.

Background: Chronic obstructive pulmonary disease (COPD) is a growing cause of morbidity and mortality worldwide, and accurate estimates of the prevalence of this disease are needed to anticipate the future burden of COPD, target key risk factors, and plan for providing COPD-related health services. We aimed to measure the prevalence of COPD and its risk factors and investigate variation across countries by age, sex, and smoking status., Methods: Participants from 12 sites (n=9425) completed postbronchodilator spirometry testing plus questionnaires about respiratory symptoms, health status, and exposure to COPD risk factors. COPD prevalence estimates based on the Global Initiative for Chronic Obstructive Lung Disease staging criteria were adjusted for the target population. Logistic regression was used to estimate adjusted odds ratios (ORs) for COPD associated with 10-year age increments and 10-pack-year (defined as the number of cigarettes smoked per day divided by 20 and multiplied by the number of years that the participant smoked) increments. Meta-analyses provided pooled estimates for these risk factors., Findings: The prevalence of stage II or higher COPD was 10.1% (SE 4.8) overall, 11.8% (7.9) for men, and 8.5% (5.8) for women. The ORs for 10-year age increments were much the same across sites and for women and men. The overall pooled estimate was 1.94 (95% CI 1.80-2.10) per 10-year increment. Site-specific pack-year ORs varied significantly in women (pooled OR=1.28, 95% CI 1.15-1.42, p=0.012), but not in men (1.16, 1.12-1.21, p=0.743)., Interpretation: This worldwide study showed higher levels and more advanced staging of spirometrically confirmed COPD than have typically been reported. However, although age and smoking are strong contributors to COPD, they do not fully explain variations in disease prevalence-other factors also seem to be important. Although smoking cessation is becoming an increasingly urgent objective for an ageing worldwide population, a better understanding of other factors that contribute to COPD is crucial to assist local public-health officials in developing the best possible primary and secondary prevention policies for their regions.

Background: The objective of the study was to characterize the biological and technical components of variability associated with longitudinal measurements of FEV(1) and carbon monoxide diffusing capacity (Dlco). Variability was apportioned to subject and instrument for five commercially available pulmonary function testing (PFT) systems: Collins CPL (Ferraris Respiratory; Louisville, CO); Morgan Transflow Test PFT System (Morgan Scientific; Haverhill, MA); SensorMedics Vmax 22D (VIASYS Healthcare; Yorba Linda, CA); Jaeger USA Masterscreen Diffusion TP (VIASYS Healthcare; Yorba Linda, CA); and Medical Graphics Profiler DX System (Medical Graphics Corporation; St. Paul, MN)., Methods: This was a randomized, replicated cross-over, single-center methodology study in 11 healthy subjects aged 20 to 65 years. Spirometry and Dlco measurements were performed at baseline, 3 months, and 6 months. Repetitive simulations of FEV(1) and Dlco were performed on the same instruments on four occasions over a 90-day period using a spirometry waveform generator and a Dlco simulator., Results: The coefficient of variation associated with repetitive measurements of FEV(1) or Dlco in subjects was consistently larger than that associated with repetitive simulated waveforms across the five instruments. Instrumentation accounted for 13 to 58% of the total FEV(1) and 36 to 70% of the total Dlco variability observed in subjects. Sample size estimates of hypothetical studies designed to detect treatment group differences of 0.050 L in FEV(1) and 0.5 mL/min/mm Hg in Dlco varied as much as four times depending on the instrument utilized., Conclusions: These results provide a semiquantitative assessment of the biological and technical components of PFT variability in a highly standardized setting. They illustrate how instrument choice and test variability can impact sample size determinations in clinical studies that use FEV(1) and Dlco as end points.

Background: The objective of the study was to quantify the accuracy and reproducibility of five commercially available pulmonary function test (PFT) instruments (Collins CPL [Ferraris Respiratory; Louisville, CO]; Morgan Transflow Test PFT System [Morgan Scientific; Haverhill, MA]; SensorMedics Vmax 22D [VIASYS Healthcare; Yorba Linda, CA]; Jaeger USA Masterscreen Diffusion TP [VIASYS Healthcare]; and Medical Graphics Profiler DX System [Medical Graphics Corp; St. Paul, MN]) that are associated with spirometry and the measurement of pulmonary diffusing capacity., Methods: In a multifactor, single-center, repeated-measures, full factorial 90-day study, a pulmonary waveform generator and a single-breath simulator of diffusing capacity of the lung for carbon monoxide (Dlco) were used to perform simulations of FVC and Dlco maneuvers. Accuracy was assessed as the difference between the observed and simulated values. Reproducibility was determined as the coefficient of variation of all measurements made during the study., Results: All instruments demonstrated a high degree of accuracy in the measurement of FVC and FEV(1). Overall, the accuracies associated with the measurement of peak flow, forced expiratory flow, mid-expiratory phase, and diffusing capacity were generally lower and more variable among the instruments tested. The coefficients of variation of Dlco measurements over 90 days were higher than those observed for spirometry., Conclusions: This study demonstrates the feasibility of assessing the accuracy and reproducibility of modern PFT instruments using simulation testing. Our results provide an assessment of the component of PFT accuracy and reproducibility that is due to instrumentation alone.

Background: Peak forced expiratory flow (PEF) and FEV(1) are spirometry measures used in diagnosing and monitoring lung diseases. We tested the premise that within-test variability in PEF is associated with corresponding variability in FEV(1) during a single test session., Methods: A total of 2,464 healthy adults from the Health, Aging, and Body Composition Study whose spirometry results met American Thoracic Society acceptability criteria were screened and analyzed. The three "best" test results (highest sum of FVC and FEV(1)) were selected for each subject. For those with acceptable spirometry results, two groups were created: group 1, normal FEV(1)/FVC ratio; group 2, reduced FEV(1)/FVC ratio. For each subject, the difference between the highest and lowest PEF (DeltaPEF) and the associated difference between the highest and lowest FEV(1) (DeltaFEV(1)) were calculated. Regression analysis was performed using the largest PEF and best FEV(1), and the percentage of DeltaPEF (%DeltaPEF) and percentage of DeltaFEV(1) (%DeltaFEV(1)) were calculated in both groups., Results: Regression analysis for group 1 and group 2 showed an insignificant association between %DeltaPEF and %DeltaFEV(1) (r(2) = 0.0001, p = 0.59, and r(2) = 0.040, p = 0.15, respectively). For both groups, a 29% DeltaPEF was associated with a 1% DeltaFEV(1)., Conclusion: Within a single spirometry test session, %DeltaPEF and %DeltaFEV(1) contain independent information. PEF has a higher degree of intrinsic variability than FEV(1). Changes in PEF do not have a significant effect on FEV(1). Spirometry maneuvers should not be excluded based on peak flow variability.

Background: COPD is projected to be the third leading cause of death worldwide by 2020. The Burden of Obstructive Lung Disease initiative was started to measure the prevalence of COPD in a standardized way and to provide estimates of the social and economic burden of disease., Methods: We surveyed a gender-stratified, population-based sample of 2,200 adults >or= 40 years of age. The findings of prebronchodilator and postbronchodilator spirometry, as well as information on smoking and reported respiratory disease was recorded. Irreversible airflow obstruction was defined as a postbronchodilator FEV(1)/FVC ratio of < 0.70., Results: For 1,258 participants with good-quality postbronchodilator spirometry findings, the overall prevalence of COPD at stage I or higher was 26.1%, and was equal in men and women. The prevalence of COPD stage II or higher (FEV(1)/FVC ratio, < 0.7; FEV(1), < 80% predicted) was 10.7%. The prevalence of COPD stage I+, and COPD stage II+, increased with age and cigarette smoking. A doctor diagnosis of COPD was reported by only 5.6% of participants., Conclusion: One quarter of residents of Salzburg County (Austria) who were >or= 40 years of age had at least mild irreversible airflow obstruction. The high prevalence of COPD highlights the impending health-care crisis that will affect many countries as a result of this greatly underappreciated condition.

The purpose of the study was to determine the best surrogate for FVC when performing spirometry to detect obstruction or restriction. Volume-time curves from 3,539 participants in the Family Heart Study with acceptable quality test sessions were analyzed. An index of the variability of each timed volume (FEVx) from 1 to 12 s was determined for each subject. The least within-test session variability was seen for forced expired volume in 6 s (FEV(6)) and forced expired volume in 7 s (for both, mean range was 95 mL). The sensitivity and specificity for detecting obstruction and restriction when substituting the FEV(6) for the FVC were then determined before and after allowing for measurement errors of 50 mL (approximately the lower limit of spirometers ability to detect volume). Sensitivity was 76% before the 50-mL error analysis and 95% after. Specificity was 98% before the 50-mL error analysis and 99.5% after. We conclude that use of FEV(6) to replace the FVC for spirometry testing will result in improved reproducibility, with no significant loss of sensitivity or specificity, after allowing a 50-mL measurement error, for detecting obstruction or restriction.

Purposes: To investigate delays in the diagnosis of deep vein thrombosis (DVT) and pulmonary embolism (PE)., Subjects and Methods: We prospectively identified 1,152 patients in whom DVT or PE had been diagnosed at 70 North American medical centers. We recorded demographic characteristics and dates of symptom onset, initial medical evaluation, and confirmatory diagnostic tests., Results: We identified substantial numbers of patients for whom there were delays in the diagnosis of DVT, PE, or both. For acute DVT, 170 of 808 patients (21%) received diagnoses > 1 week after symptom onset, and 40 of 808 patients (5%) received diagnoses > 3 weeks after symptom onset. On average, 80% of the delay in diagnosis of DVT occurred between symptom onset and medical evaluation. Acute PE was diagnosed in 59 of 344 patients (17%) > 1 week after symptom onset, and in 17 of 344 patients (5%) > 3 weeks after the onset of symptoms. Delays in the diagnosis of PE represented both delays in seeking medical attention (mean, 3 days; upper limit of 95% confidence interval [CI], 12 days); and delays from the first medical evaluation to diagnosis (mean, 2 days; upper limit of 95% CI, 9 days)., Conclusions: Although the majority of patients with DVT and PE seek medical attention and receive diagnoses promptly after symptom onset, substantial delays exist in the diagnosis of DVT and PE for many patients. There is a need to develop and test strategies that reduce delays in diagnosis.

Objectives: (1) To compare the performance of three spirometric algorithms developed to predict whether the total lung capacity (TLC) is reduced vs normal or increased, (2) to determine if forced expiratory volume at 6 s (FEV(6)) can be substituted for FVC in these algorithms, and (3) to determine if ascertainment bias was present in patients referred for the measurement of spirometry and TLC compared to patients referred for spirometry only., Methods: We analyzed the results of 219 consenting consecutive patients referred to a New Zealand tertiary hospital respiratory laboratory for spirometry and TLC measurements. Spirometry results from 370 patients referred for spirometry but not lung volumes were used to test for potential ascertainment bias. Spirometry results were analyzed using the lower limit of normal (LLN) values from the third National Health and Nutrition Examination Study reference equations. The equations of Goldman and Becklake, and Crapo were used to classify TLC as normal or abnormal. Receiver operator characteristic curves were used to produce an algorithm using the LLN for FVC and FEV(6). The performances of previous algorithms and our own algorithms were analyzed for predicting a reduced lung volume against the "gold standard," plethysmographic TLC., Results: All three algorithms predicted a reduced TLC with an accuracy of approximately 50%. In contrast, all algorithms predicted TLC was either normal or increased with an accuracy of > or = 99% regardless of the reference set used. The algorithms based on FEV(6) performed equally as well as the FVC algorithms. No ascertainment bias was found., Conclusions: This study provides evidence that spirometry-based algorithms can accurately predict when TLC is either normal or increased, and can also increase the a priori probability that TLC is reduced to approximately 50%. FEV(6) is equivalent to FVC in these predictions.

Background: Essential hypertension and symptoms of depression such as unexplained fatigue and tiredness are frequently encountered in primary medical care clinics. Although, exhaustive evaluation rarely detects unsuspected underlying disorders, obstructive sleep apnea (OSA) is commonly associated with each of these conditions. We tested the hypothesis that therapy with antihypertensive and antidepressant medications predicts the increased likelihood of OSA., Methods: We analyzed the computer archive of 212,972 patients for prescriptions for antihypertensive medications, antidepressant medications, and International Classification of Diseases, Ninth Revision codes for OSA. Prevalence, prevalence odds ratio (POR), and confidence intervals (CIs) were calculated correcting for gender and age group., Results: The prevalence rates of OSA were 0.8%, 2.8%, and 3.2% for men and 0.4%, 1.4%, and 1.8% for women aged 20 to 39 years, 40 to 59 years, and >or= 60 years, respectively. Compared to groups of corresponding age and gender who had not received prescriptions for either hypertension or depression, the highest PORs were found in patients receiving medications from both categories: 18.30 (95% CI, 10.69 to 25.66), 5.72 (95% CI, 4.10 to 6.70), and 4.47 (95% CI, 2.45 to 7.01) for men, and 17.43 (95% CI, 9.54 to 28.67), 7.29 (95% CI, 5.20 to 9.29), and 2.72 (95% CI, 1.48 to 4.73) for women., Conclusions: We found that the likelihood of having a diagnosis of OSA increases when either antihypertensive or antidepressant medications have been prescribed. The probability is highest in the young and middle-age groups receiving prescriptions for both medications. The possibility of OSA should be considered in any patient with hypertension and depression or unexplained fatigue who is receiving antihypertensive and antidepressant medications.

Study Objectives: The guidelines of the National Lung Health Education Program for COPD screening proposed a shorter FVC maneuver (forced expiratory volume at 6 s of exhalation [FEV(6)]). Although reference values for FEV(6) are available from the third National Health and Nutrition Examination Survey, forced expiratory flow between 25% and 75% of FVC (FEF(25-75%)) reference values for the shorter 6-s maneuver are not available and are needed. In particular, calculation of largest observed volume during the first 6 s of an FVC maneuver (FVC(6)), from a shortened FVC maneuver, is necessary because the FEF(25-75%) measurement is based on a percentage of FVC or, for a shorter maneuver, FVC(6)., Design: We reanalyzed the raw volume-time curves from the third National Health and Nutrition Examination Survey to calculate FVC(6), forced expiratory volume at 0.5 s of exhalation, forced expiratory volume at 3 s of exhalation, ratio of the FEV(1) to largest observed volume during the first 6 s of an FVC maneuver expressed as a percentage (FEV(1)/FEV(6)%), and forced expiratory flow between 25% and 75% of the largest observed volume during the first 6 s of an FVC maneuver (FEF(25-75%6)) in addition to the previously reported values for FEV(1), FEV(6), and FEV(1)/FEV(6)%., Patients or Participants: Using the same normal, asymptomatic, nonsmoking reference population from a previous study, reference values for these parameters were derived from best values., Results: A total of 2,261 white, 2,564 African-American, and 2,666 Mexican-American subjects aged 8 to 80 years were included in the analysis. Fifty-four subjects from the previous study were not included due to missing raw volume-time curves., Conclusions: These reference values, utilizing the FVC(6), provide investigators with the means of evaluating the relative merits of using the shorter FVC maneuver as a surrogate for the traditional FVC. They are needed particularly for calculating FEF(25-75%), as statistically significant differences were observed between the FEF(25-75%) and FEF(25-75%6).