Background: Studies suggest that the use of race-specific pulmonary function reference equations may obscure racial inequities in respiratory health. Whether removing race from the interpretation of pulmonary function would influence analyses of HIV and pulmonary function is unknown. Setting: Pulmonary function measurements from 1,067 men (591 with HIV) in the Multicenter AIDS Cohort Study (MACS) and 1,661 women (1,175 with HIV) in the Women’s Interagency HIV Study (WIHS) were analyzed. Methods: Percent-of-predicted values for spirometry and single-breath diffusing capacity of carbon monoxide (DLCO) measurements were generated with race-specific reference equations derived from the National Health and Nutrition Examination Survey and with the race-neutral application of reference equations derived from the Global Lung Function Initiative database. Regression models were used to evaluate the association between HIV and percent-of-predicted measures of pulmonary function. Alpaydin’s F test was used to compare how well these values predicted self-reported respiratory health-related quality of life. Results: Persons with HIV were observed to have significantly lower percent-of-predicted DLCO than those without HIV but no significant differences in spirometric measures of pulmonary function, regardless of whether a race-specific or race-neutral approach was used. Among men, but not women, the race-neutral application of reference equations to generate percent-of-predicted DLCO values performed better for predicting respiratory-related quality of life. Conclusion: The race-neutral application of pulmonary function reference equations continues to identify lung function impairment in persons with or at risk for HIV and, for DLCO, may be superior to the use of race-specific reference equations in identifying clinically relevant impairments.

Rationale: Chronic Obstructive Pulmonary Disease (COPD) mortality risk is often estimated using the BODE index (including body mass index, forced expiratory volume in one second (FEV1), dyspnea score, and six-minute walk distance). Diffusing capacity (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/current smokers with FEV1/FVC <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 <-950 Hounsfield units), CT airway wall thickness, and history of cardiovascular or kidney diseases. C-statistics for models with DLCO and BODE score were used to compare discriminative accuracy. Results: Of 2329 participants, 378(16.8%) died during the follow-up period (median 4.9 years). In adjusted analyses, for every 10% decrease in DLCO %predicted, mortality increased by 29% (Hazard ratio 1.29, 95% CI 1.17 - 1.41, p<0.001). When compared to other clinical predictors, DLCO %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.

Background Parameters from maximal expiratory flow-volume curves (MEFVC) have been linked to CT-based parameters of COPD. However, the association between MEFVC shape and phenotypes like emphysema, small airways disease (SAD) and bronchial wall thickening (BWT) has not been investigated. Research question We analyzed if the shape of MEFVC can be linked to CT-determined emphysema, SAD and BWT in a large cohort of COPDGene participants. Study design and methods In the COPDGene cohort, we used principal component analysis (PCA) to extract patterns from MEFVC shape and performed multiple linear regression to assess the association of these patterns with CT parameters over the COPD spectrum, in mild and moderate-severe COPD. Results Over the entire spectrum, in mild and moderate-severe COPD, principal components of MEFVC were important predictors for the continuous CT parameters. Their contribution to the prediction of emphysema diminished when classical pulmonary function test parameters were added. For SAD, the components remained very strong predictors. The adjusted R 2 was higher in moderate-severe COPD, while in mild COPD, the adjusted R 2 for all CT outcomes was low; 0.28 for emphysema, 0.21 for SAD and 0.19 for BWT. Interpretation The shape of the maximal expiratory flow-volume curve as analyzed with PCA is not an appropriate screening tool for early disease phenotypes identified by CT scan. However, it contributes to assessing emphysema and SAD in moderate-severe COPD.

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/hy-perbaric 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.

OBJECTIVE People living with HIV (PLWH) have a higher prevalence of respiratory symptoms than people without HIV. Antiretroviral therapy (ART) has been associated with worsened airflow limitation. This study assessed respiratory health impairment among PLWH and its association with protease inhibitor (PI) use. DESIGN Cross-sectional study of Multicenter AIDS Cohort Study (MACS) study visits from 04/01/2017 to 03/31/2018. METHODS Participants completed the St. George's Respiratory Questionnaire (SGRQ), modified Medical Research Council (mMRC) dyspnea scale, spirometry, and diffusion capacity measurement. Visit data were compared among PI users, non-PI users, and men without HIV. Binary and ordinal logistic models were used to determine the associations between HIV status, PI use, and covariates with primary outcomes of dichotomized SGRQ and mMRC dyspnea scores. RESULTS 57/177 (32.2%) of PI users self-reported pulmonary disease compared with 132/501 (26.4%) of non-PI users and 105/547 (19.2%) men without HIV. 77/177 (45.3%) of PI users had SGRQ scores ≥ 10 while 171/501 (34.7%) of non-PI users and 162/549 (29.9%) of people living without HIV had SGRQ scores ≥ 10 (p=0.001). Adjusted models found an association between PI use and SGRQ score ≥ 10 [OR 1.91 (95% CI 1.29-2.82), ref: HIV negative and OR 1.50 (95% CI 1.01-2.22) ref: non-PI users]. A similar association was found with mMRC scores and PI use [OR 1.79 (95% CI 1.21-2.64), ref: HIV negative and OR 1.53 (95% CI 1.04-2.25), ref: non-PI users]. CONCLUSIONS PI use is associated with worse respiratory health status, increased dyspnea, and an increased prevalence of self-reported pulmonary disease.

Introduction: Accurate diffusing capacity for carbon monoxide (DLCO) devices are required for clinical use and research studes; however, 25% of instruments do not meet accuracy standards (Jensen, R. et al. Eur Resp J 2009; 33:828-34). Objectives: We aimed to determine long-term accuracy of DLCO devices used in the COPDGene study. Methods: DLCO measurement was performed at all 18 COPDGene study sites from 2013 to 2020 using a ndd EasyOne Pro instrument (Zurich, Switzerland) that incorporates automated calibration and linearization of gas sensors and a flow sensor that does not require calibration. Each instrument was tested with a DLCO simulator (Hans Rudolph, Kansas City, MO) at three different simulated DLCO levels to verify and validate each instrument’s accuracy in 2013 and again in 2020. Comparisons were made between each instrument’s measured DLCO and the "targets" set by the DLCO simulator with acceptable accuracy defined as a difference < 2.0 mL/min/mmHg. Statistical comparisons between the 2013 simulation results and the 2020 simulations were done with t-tests. Results: Mean differences between the three simulated targets and measured DLCO from 2013 were 0.561, 1.122 and -0.400 mL/min/mmHg. In 2020 these differences were 0.922, -0.416 and -0.378 mL/min/mmHg. No statistically significant difference was found between 2013 and 2020 in the average of the differences from simulator targets: Mean differences and drift reported as mL/min/mmHg for 2013 was 0.180 and for 2020 was 0.069; seven year drift was 0.112. Concluison: The 18 DLCO devices used in the COPDGene study using automated calibration and linearization of gas sensors and a calibration-free flow sensor produced consistently accurate, stable measurements in DLCO over seven years.

Background: The ATS/ERS Task Force (Eur Respir J 2005; 26:948-968) recommends an increase of both 12% and 200 mL in FEV1 or FVC to define a positive bronchodilator (+BD) response. These criteria are based largely on expert opinion. We aimed to describe the BD response response characteristics of the COPDGene non-smoking, healthy cohort. Methods: We evaluated 422 non-smoking, healthy adult patients with acceptable and repeatable spirograms obtained before and after (pre- and post-BD) two inhalations of albuterol (200 mcg) at 21 COPDGene sites. The same equipment (ndd, Zucih, Switzerland) and methodologies were used at each site. We determeined the mean, SD and 95th percentile for absolute (mL) and percent (%) differences between pre-BD and post-BD for FEV1, FVC and FEV6. We also determined the number of subjects that met current ATS/ERS Task Force recommendations for +BD response. Results: The mean, SD and 95th percentile for absolute and percent differences between pre-BD and post-BD mean are shown (Table). The percent of subjects that met ATS/ERS Task Force recommendations for +BD response for FEV1 was 5.7% and for FVC was 5.2%. Conclusion: Our results indicate that in a healthy adult population, a significant BD response for FEV1 is approximately 200 mL and 9%; corresponding values for FVC are 200 mL and 6%. Our results are in agreement with the ATS/ERS Task Force recommendation for an absolute increase in FEV1 and FVC (200 mL) to define a +BD response but suggest that the 12% increase criteria for FEV1 and FVC is too large.

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 DL(CO)testing were performed in all eligible, consenting participants at routine study visits. We tested associations between HIV status and spirometry and DL(CO)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 DL(CO)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 DL(CO)impairment (odds ratio for DLCO < 60% of predicted 2.97; 95% confidence interval: 1.36-6.47). Lower DL(CO)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.

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.

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). CONCLUSION: 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.

Background: Spirometric changes due to decreases in barometric pressure (Pb) are uncertain. As Pb decreases, dynamic thoracic gas compression during forced exhalation increases and gas density decreases; both processes will variably affect spirometry with decreasing Pb (Cross, T. et al. Physiological Reports 2018; 6(6):e13576). We aimed to examine if there are changes in FVC and FEV1 in normal subjects and COPD patients across different Pb in a controlled environment. Methods: We performed spirometry on 13 normal subjects and 10 COPD patients at ambient conditions (650 mmHg) and in a hypobaric/hyperbaric chamber after 30 minutes of quiet breathing at the following Pb: 759 mmHg, 563 mmHg, and for 6 of the normals at 494 mmHg. Testing at the various Pb was performed on separate days at the same time of day. The EasyOne Pro (ndd, Zurich, Switzerland) ultrasound spirometer was used. We analyzed the largest acceptable values for FVC and FEV1 for each individual at each Pb. We used a basic linear mixed statistical model to evaluate differences in group means with changing Pb. Results: The mean (95% CI) for FVC and FEV1 for normal and COPD groups vs. Pb are shown in the Figure. There were no significant differences in either FVC or FEV1 vs. Pb for either group. Conclusion: FVC and FEV1 did not significantly change in a controlled environment across the Pb tested (759 to 494 mmHg) in either normal subjects or COPD patients.

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.

Background: The COPDGene study includes a subset of healthy, non-smoking subjects, 532 (229 Men, 303 Women) age range 45 to 88 years. PFTs were obtained using validated equipment (ndd, Zurich Switzerland). Pre- and post-bronchodilator (BD) spirometry provided an opportunity to examine BD effect and magnitude in a current well-documented study. We aimed to determine if this subset is similar to normal subjects collected in the NHANESIII study. Methods: Spirometry was collected in accordance with the 2005 ATS/ERS recommendations. All data were over-read and graded (A to F) for the parameters FVC, FEV1 and PEF. The predicted values for FEV1 and FVC were calculated from the NHANES III reference equations (Hankinson, JL. et al. Am J Respir Crit Care Med 1999; 159:179-187). We analyzed only acceptable quality post-BD spirograms (grades A, B and C) and calculated (COPDGene-NHANES III) group means and SD for FEV1% predicted and FVC% predicted, and tested histogram distributions for normality (Statistica). Results: Of the 532 subjects, 467 had acceptable quality tests. (COPDGene-NHANESIII) group means for FEV1% predicted and FVC% predicted were +2.2% and -1.5%, respectively (TABLE); there were no statistically significant differences between the COPDGene healthy, non-smoking subjects and NHANESIII. Conclusion: COPDGene healthy, non-smoking subjects spirometry data are not statistically significantly different from the NHANESIII normals, allowing detailed analysis of this pre- and post-BD dataset with confidence that the data is representative of a normal population.

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.

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 1second (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.

D.C. Johnson proposed that an adjustment of the predicted value for the diffusing capacity of the lung for carbon monoxide (DLCO) based on the measured and predicted lung volume be included in the report of DLCO test results. An interpretation algorithm is also proposed. A correction of the predicted value for DLCO based on the measured lung volume is not recommended http://ow.ly/KFn730cPJ9n