Low DLCO Research Articles

Progressive Decline of Lung Function in Rheumatoid Arthritis-Associated Interstitial Lung Disease.

Interstitial lung disease (ILD) is associated with substantial morbidity in rheumatoid arthritis (RA), but very little is known about its long-term progression. This study was undertaken to investigate the progression of pulmonary disease using a large single-center cohort of patients with RA-associated ILD. Records of all patients with RA-associated ILD seen at Mayo Clinic between 1998 and 2014, with at least 4 weeks follow-up and at least 1 pulmonary function test, were identified and manually screened for study inclusion. Progression was defined as a diffusing capacity for carbon monoxide (DLco) <40% predicted (or patients whose illness was too advanced to undergo screening) or a forced vital capacity (FVC) <50% predicted. Time to progression was analyzed using the Kaplan-Meier method. Of the 167 patients included in the study, 81 (49%) were female, with a mean ± SD age of 67 ± 10 years at diagnosis of ILD. Median follow-up time from diagnosis of ILD was 3.3 years (range 0.01-14.8). One-third of the patients required supplemental oxygen, 40% developed DLco <40% predicted, and 22% developed FVC <50% predicted within 5 years after ILD diagnosis. Usual interstitial pneumonia (UIP) versus nonspecific interstitial pneumonia (NSIP) was a risk factor for DLco progression (hazard ratio 3.29 [95% confidence interval 1.28-8.41]). Lower DLco and FVC at baseline increased the risk for progression to DLco <40% predicted and FVC <50% predicted, and higher rates of change in the first 6 months also increased the risk of progression. Progressive loss of pulmonary function is common in RA-associated ILD and is worse in patients with UIP than in those with NSIP. Predictors of progression in patients with RA-associated ILD may aid clinicians in identifying patients at highest risk for progression of ILD.

Risk for pulmonary late effects in childhood Hodgkin lymphoma survivors.

112 Background: Survivors of Hodgkin lymphoma (HL) are at risk for pulmonary late effects, including pulmonary fibrosis (PF). Established risk factors such as younger age at diagnosis and specific therapeutic exposures explain a fraction of the risk for these outcomes. Notably, systemic inflammation and impaired telomere maintenance are associated with adverse pulmonary outcomes in adult populations, but have not been explored in cancer survivors. Our aim was to identify pulmonary diffusion defects in HL survivors, and evaluate the impact of short lymphocyte telomere length (LTL) and systemic inflammation on these outcomes. Methods: Blood samples, demographic and treatment data, and lung carbon monoxide diffusion capacity corrected for hemoglobin and alveolar volume (DLCO) were obtained from HL survivors ≥6 months off therapy and without history of relapse or transplant. LTL was measured by telomere flow FISH (Repeat Diagnostics), and age-based percentiles determined from population controls. Plasma elevations in pro-inflammatory cytokines (HCYTMAG panel, EMD Millipore) were detected on a Luminex platform. Associations between clinical features and most recent DLCO were determined by linear regression, adjusted for age, sex, radiation, and race/ethnicity. In a subset of subjects, cytokine levels and LTL were compared in survivors with DLCO above or below the mean using a Student t-test or Fisher’s Exact test, respectively. Results: Seventy-two HL survivors met inclusion criteria (mean age at diagnosis=14 years, range: 3-18 years). Mean off-therapy DLCO was 75% (range: 52-98%), below the lower limit of normal (76%) in healthy populations. DLCO was inversely associated with female sex (p = 0.002). Five of 24 survivors (21%) had LTL ≤10th percentile for age, but there was no difference in LTL relative to DLCO. Survivors with DLCO ≤75% had higher IL1α and IL1β levels (n = 30, p = 0.07). Conclusions: HL survivors had lower than expected DLCO, with females at highest risk for impaired pulmonary diffusion. Twice as many survivors as expected had LTL ≤10th percentile, and PF-related cytokine profiles were observed in survivors with lower DLCO, suggesting inflammation and telomere maintenance defects may contribute to late effects in HL survivors.

A Low Peripheral Blood CD4/CD8 Ratio Is Associated with Pulmonary Emphysema in HIV.

ObjectivesThe prevalence of emphysema is higher among HIV-infected (HIV+) individuals compared to HIV-uninfected persons. While greater tobacco use contributes, HIV-related effects on immunity likely confer additional risk. Low peripheral blood CD4+ to CD8+ T-lymphocyte (CD4/CD8) ratio may reflect chronic inflammation in HIV and may be a marker of chronic lung disease in this population. Therefore, we sought to determine whether the CD4/CD8 ratio was associated with chronic obstructive pulmonary disease (COPD), particularly the emphysema subtype, in a cohort of HIV+ subjects.MethodsWe performed a cross-sectional analysis of 190 HIV+ subjects enrolled in the Examinations of HIV Associated Lung Emphysema (EXHALE) study. Subjects underwent baseline laboratory assessments, pulmonary function testing and chest computed tomography (CT) analyzed for emphysema severity and distribution. We determined the association between CD4/CD8 ratio and emphysema, and the association between CD4/CD8 ratio and pulmonary function markers of COPD.ResultsMild or greater emphysema (>10% lung involvement) was present in 31% of subjects. Low CD4/CD8 ratio was associated with >10% emphysema in multivariable models, adjusting for risk factors including smoking, current and nadir CD4 count and HIV RNA level. Those with CD4/CD8 ratio <0.4 had 6.3 (1.1–39) times the odds of >10% emphysema compared to those with a ratio >1.0 in fully adjusted models. A low CD4/CD8 ratio was also associated with reduced diffusion capacity (DLCO).ConclusionsA low CD4/CD8 ratio was associated with emphysema and low DLCO in HIV+ subjects, independent of other risk factors and clinical markers of HIV. The CD4/CD8 ratio may be a useful, clinically available, marker for risk of emphysema in HIV+ subjects in the antiretroviral therapy (ART) era.

The importance of PET/CT findings and hematological parameters in prediction of progression in sarcoidosis cases.

Aim: We aimed to reveal the correlation of NLR rate, RDW and MPV values and with the findings of PET/CT regarding the prediction of disease progression and the clinical characteristics. Materials and methods: The treatment naive sarcoidosis cases, of whose PET/CT have been taken due to mediastinal lymphadenopathy of whose diagnosis have been confirmed by biopsy, were included in the study. Hematological parameters, clinical, radiological and PET/CT findings are evaluated. Results: 40 sarcoidosis and 40 healthy control cases were included in the study. NLR, RDW, MPV and the sedimentation values in the sarcoidosis group were determined statistically significantly higher. In patients having parenchymal involvement in PET/CT, the values of FVC%, DLCO, DLCO%, DLCO/VA and DLCO/VA% were determined significantly lower. High NLR and PET/CT LAP SUVmax values and low DLCO% values are statistically significantly correlated with one-year disease progression. For predicting the progression, for the NLR cut-off value 3.20, the area under the curve was determined as 0.79 (CI 62.2-96.5), sensitivity as 80.0%, specificity as 76.7% and for the PET/CT SUVmax cut-off value 9.5, the area under the curve was determined as 0.71 (CI 46.6-95.9), sensitivity as 70.0%, specificity as 82.1%. Conclusion: We determined that the values observed in routine hematologic examinations such as NLR, RDW and MPV, were high in sarcoidosis cases. In addition, the values of NLR, DLCO% and PET/CT SUVmax might be used in predicting the progression. At the same, once again we showed that the lung parenchyma involvement in PET/CT correlates with many pulmonary function parameters. (Sarcoidosis Vasc Diffuse Lung Dis 2017; 34: 242-250)

SC08.01 Impact and Management of Co-Morbidities

SC08.01 Impact and Management of Co-Morbidities

Emphysema Distribution and Diffusion Capacity Predict Emphysema Progression in Human Immunodeficiency Virus Infection

BackgroundChronic obstructive pulmonary disease (COPD) and emphysema are common amongst patients with human immunodeficiency virus (HIV). We sought to determine the clinical factors that are associated with emphysema progression in HIV.Methods345 HIV-infected patients enrolled in an outpatient HIV metabolic clinic with ≥2 chest computed tomography scans made up the study cohort. Images were qualitatively scored for emphysema based on percentage involvement of the lung. Emphysema progression was defined as any increase in emphysema score over the study period. Univariate analyses of clinical, respiratory, and laboratory data, as well as multivariable logistic regression models, were performed to determine clinical features significantly associated with emphysema progression.Results17.4% of the cohort were emphysema progressors. Emphysema progression was most strongly associated with having a low baseline diffusion capacity of carbon monoxide (DLCO) and having combination centrilobular and paraseptal emphysema distribution. In adjusted models, the odds ratio (OR) for emphysema progression for every 10% increase in DLCO percent predicted was 0.58 (95% confidence interval [CI] 0.41–0.81). The equivalent OR (95% CI) for centrilobular and paraseptal emphysema distribution was 10.60 (2.93–48.98). Together, these variables had an area under the curve (AUC) statistic of 0.85 for predicting emphysema progression. This was an improvement over the performance of spirometry (forced expiratory volume in 1 second to forced vital capacity ratio), which predicted emphysema progression with an AUC of only 0.65.ConclusionCombined paraseptal and centrilobular emphysema distribution and low DLCO could identify HIV patients who may experience emphysema progression.

Effect of gastroesophageal reflux disease on spirometry, lung diffusion, and impulse oscillometry

Gastroesophageal reflux disease (GERD) is known to be associated with many forms of respiratory diseases, including asthma, pulmonary fibrosis, cystic fibrosis, and obstructive sleep apnea syndrome. It is frequently coexistent, and may be causative or may exacerbate pre-existing lung disease. The main purpose of this study was to assess the effects of GERD on spirometry, lung diffusion, and impulse oscillometry. This study included 48 consecutive newly endoscopically diagnosed GERD patients with no pulmonary symptoms or previous smoking history who attended the Gastrointestinal Clinic at Ain Shams Hospital and Misr University for Science and Technology with complaints of reflux symptoms. Spirometry, lung diffusion, and oscillometry were performed in all included patients. There were statistically significant differences between cases with different grades of reflux as regards age. Most of the patients were included within grade B GERD with the highest mean age being 46.33±11.51. However, there was no significant difference as regards sex. There were statistically significant differences between cases with different grades of reflux as regards forced expiratory volume at the first second/forced vital capacity, maximum expiratory flow 25–75, and diffusing capacity of the lung for carbon monoxide (DLCO), but there was a highly statistically significant difference regarding residual volume/total lung capacity and residual volume. The grade of reflux was the only independent factor affecting DLCO, and grade B patients showed lower DLCO compared with grade A patients. There was a statistically significant positive correlation between grades of reflux and forced expiratory volume at the first second/forced vital capacity, maximum expiratory flow 25–75, and maximum mid-expiratory flow/peak expiratory flow, and a statistically significant negative correlation between grades of reflux and R20. There was a negative correlation between grades of reflux and DLCO, but it was not significant. GERD severity is associated with impairment of gas exchange (DLCO) and central airway affection (R20) on impulse oscillometry. This may be due to microaspiration of gastric acid or fluid into the airways.

Lower diffusing capacity with chronic bronchitis predicts higher risk of acute exacerbation in chronic obstructive lung disease.

This study was designed to evaluate the effect of chronic bronchitis (CB) symptoms and degree of emphysema in a multicenter Korean cohort. From April 2012 to May 2015, patients diagnosed with chronic obstructive lung disease (COPD) who were aged above 40 years at 46 hospitals throughout Korea were enrolled. All of the patients were classified according to CB symptoms and the diffusing capacity of the lung for carbon monoxide (DLCO); demographic data, symptom scores, and the result of lung function tests and exacerbations were then analyzed. A total of 812 patients were enrolled. Among these patients, 285 (35.1%) had CB symptoms. A total of 51% of patients had high DLCO without CB symptoms [CB (-) high DLCO], 24.9% had CB symptoms only [CB (+) high DLCO], 14.2% had low DLCO only [CB (-) low DLCO], and 10.2% had both low DLCO and CB [CB (+) low DLCO]. Patients with CB (+) low DLCO showed a significantly lower post-bronchodilator (BD) forced expiratory volume for 1 second (FEV1) and more severe dyspnea than patients with CB (-) high DLCO. On multivariate analysis, the risk of acute exacerbation was two times higher [odds ratio (OR) 2.06; 95% confidence interval (CI): 1.18-3.62; P=0.01] in the CB (+) low DLCO group than in the CB (-) high DLCO group. In this COPD cohort, patients showed distinct clinical characteristics and outcomes according to the presence of CB and degree of DLCO. CB and low DLCO were associated with the risk of acute exacerbation.

Subspecificities of anticentromeric protein A antibodies identify systemic sclerosis patients at higher risk of pulmonary vascular disease.

Patients with systemic sclerosis (SSc) who express autoantibodies to centromeric proteins (CENPs) are at risk of developing pulmonary vascular disease and pulmonary arterial hypertension without fibrosis. Currently no biomarkers are available to predict these complications. We previously characterized the fine specificity of anti-CENP-A antibodies in SSc by screening a phage display library (expressing random 12-mer peptides), and identified phage clones whose peptides were differentially recognized by patients’ autoantibodies. Here, we examined if subgroups of SSc patients with different anti-CENP-A antibody subspecificities also differ clinically, and if serum reactivity to phage-displayed peptides can predict pulmonary vascular disease.Clinical data and serum samples were collected from 84 anti-CENP-A-positive SSc patients. Indirect ELISAs were used to test serum reactivity. Pulmonary vascular disease was defined as high systolic pulmonary arterial pressure (sPAP) and low diffusing lung capacity for carbon monoxide (DLCO; percent of predicted values).Sera were screened for reactivity to peptides expressed by phage clones pc4.2 and pc14.1, confirming our earlier observation of differential specificities. Linear regression showed that the levels of antibodies specific for the 2 phage clones were associated with clinical features of pulmonary vascular disease, but in opposite ways: anti-pc4.2 antibodies were positively associated with sPAP and inversely associated with DLCO, whereas anti-pc14.1 antibodies were inversely associated with sPAP and positively associated with DLCO. Anti-pc4.2 and anti-pc14.1 antibody levels predicted sPAP independently of DLCO. These associations were confirmed by logistic regression using antibodies as predictors and dichotomized sPAP (cutoff, 45 mm Hg) as outcome. The ratio of the 2 antibody levels was a useful marker in predicting high sPAP.This study demonstrates that some SSc clinical features associate with subspecificities of anti-CENP-A antibodies. Moreover, it shows that a simple, inexpensive phage-based assay can predict which SSc patients have high sPAP and low DLCO, hence who are at greater risk of developing pulmonary arterial hypertension. The ability to identify these at-risk patients can contribute to clinical efficiency and effectiveness. Further research into the peptides expressed by the phage clones may reveal the molecular mechanisms that put some anti-CENP-A-positive patients at greater risk than others for pulmonary vascular disease.

Low DLCO in Idiopathic Pulmonary Arterial Hypertension—Clinical Correlates and Prognostic Significance

Introduction: Decreased diffusing capacity of the lung for carbon monoxide (DLCO) is observed in some idiopathic pulmonary arterial hypertension (IPAH) patients, but its clinical significance is uncertain. We aimed to assess clinical correlates and prognostic significance of low DLCO in IPAH patients. Material and methods: In the group of 65 IPAH patients the cut off value for low DLCO was set up based on histogram as &lt;55% of predicted value. Demographic data, exercise capacity, lung function tests, hemodynamic parameters and survival of the patients were compared depending on DLCO value. Results: Low DLCO was found in 18% of the patients, and it was associated with male sex, older age, worse functional status and exercise capacity, and higher prevalence of coronary artery disease. Low DLCO carried a 4-fold increase of death risk in 5-year perspective. Conclusions: Low DLCO was a marker of worse functional capacity and increased risk of death in studied IPAH patients.

Office-based DLCO tests help pulmonologists to make important clinical decisions.

Measurement of diffusing capacity of the lungs for carbon monoxide (DLCO), also known as transfer factor, is the second most important pulmonary function test (PFT), after spirometry. Previously available only in hospital-based PFT labs, DLCO testing is now available at outpatient clinics using a portable device. Compared to spirometry tests, assessments with these devices require very little effort. The patient breathes quietly, inhales the test gas, holds the breath for ten seconds, and then exhales. In adult smokers with post-bronchodilator airway obstruction, a low DLCO greatly increases the probability of the emphysema phenotype of COPD due to cigarette smoking, while a normal DLCO makes chronic asthma more likely. In patients with spirometric restriction (a low FVC with a normal FEV1/FVC), a low DLCO increases the pre-test probability of an interstitial lung disease (ILD), while a normal DLCO makes a chest wall type of restriction more likely. A normal TLC (VA from the single-breath helium dilution provided by a DLCO test) rules out restriction of lung volumes without the need for a body box measurement. In patients with dyspnea of unknown cause, the pattern of a low DLCO with normal spirometry increases the likelihood of pulmonary vascular disease, but this pattern also occurs with several other diseases such as a mild ILD. Once a diagnosis is made, the percent predicted DLCO provides an objective index of disease severity and prognosis. A DLCO below 40% predicted, or a decline in DLCO of more than 4 units, is associated with increased morbidity and mortality.

Number of Ribs Resected is Associated with Respiratory Complications Following Lobectomy with en bloc Chest Wall Resection.

Pulmonary lobectomy with en bloc chest wall resection is a common strategy for treating lung cancers invading the chest wall. We hypothesized a direct relationship exists between number of ribs resected and postoperative respiratory complications. An institutional database was queried for patients with non-small cell lung cancer that underwent lobectomy with en bloc chest wall resection between 2003 and 2014. Propensity matching was used to identify a cohort of patients who underwent lobectomy via thoracotomy without chest wall resection. Patients were propensity matched on age, gender, smoking history, FEV1, and DLCO. The relationship between number of ribs resected and postoperative respiratory complications (bronchoscopy, re-intubation, pneumonia, or tracheostomy) was examined. Sixty-eight patients (34 chest wall resections; 34 without chest wall resection) were divided into 3 cohorts: cohort A=0 ribs resected (n=34), cohort B=1-3 ribs resected (n=24), and cohort C=4-6 ribs resected (n=10). Patient demographics were similar between cohorts. The 90-day mortality rate was 2.9% (2/68) and did not vary between cohorts. On multivariate analysis, having 1-3 ribs resected (OR 19.29, 95% CI (1.33, 280.72); p=0.03), 4-6 ribs resected [OR 26.66, (1.48, 481.86); p=0.03), and a lower DLCO (OR 0.91, (0.84, 0.99); p=0.02) were associated with postoperative respiratory complications. In patients undergoing lobectomy with en bloc chest wall resection for non-small cell lung cancer, the number of ribs resected is directly associated with incidence of postoperative respiratory complications.

MUC1 gene polymorphisms are associated with serum KL-6 levels and pulmonary dysfunction in pulmonary alveolar proteinosis.

BackgroundKL-6, a human MUC1 mucin, is a sensitive biomarker for interstitial lung diseases including pulmonary alveolar proteinosis (PAP). A correlation between MUC1 gene single nucleotide polymorphism (SNP) rs4072037 genotype and serum KL-6 levels has been reported. This study was aimed at investigating the correlation between MUC1 SNP genotype, severity of disease and disease outcome in PAP.MethodsTwenty four patients with PAP and 30 healthy volunteers were studied. MUC1 rs4072037 was detected by using a real-time polymerase chain reaction (RT-PCR). Genotyping was performed by pyrosequencing. KL-6 levels were measured in serum by Nanopia KL-6 assay (SEKISUI Diagnostics).ResultsThe frequency of MUC1 rs4072037 alleles was significantly different between PAP patients and healthy volunteers (PAP, A/A 46 %, A/G 54 %, G/G 0 %; healthy controls, A/A 30 %, A/G 40 %, G/G 30 %; p = 0.013). Serum KL-6 levels were significantly higher in PAP patients than in controls (p < 0.0001), and significantly higher in PAP patients with A/A genotype than in those with A/G genotype (p = 0.007). Patients with A/A genotype had higher alveolar-arterial oxygen difference (A-aDO2) and lower DLco compared to those with A/G genotype (p = 0.027 and p = 0.012, respectively). Multivariate analysis, Kaplan-Meier analysis and C statistics showed that the rs4072037 A/A genotype was associated with higher rate of disease progression (HR: 5.557, p = 0.014).ConclusionsMUC1 rs4072037 A/A genotype is associated with more severe pulmonary dysfunction and a higher rate of disease progression in PAP patients.

Survival protection by bodyweight in isolated scleroderma-related pulmonary artery hypertension.

In chronic heart failure (CHF) due to systemic cardiovascular disease, obese patients have better survival. Bodyweight versus survival was analyzed post hoc in subjects with limited scleroderma (SSc) and isolated pulmonary artery hypertension (PAH), i.e. with CHF due to pulmonary vascular disease. Rheumatologists referred scleroderma subjects for evaluation, and PAH was ascertained by right heart catheterization (RHC). Forty-nine SSc-PAH subjects were stratified by body mass index (BMI): obese 7 (14.3%), overweight 11 (22.4%), normal weight 21 (42.9%), and underweight 10 (20.4%) for 24-month follow-up and pooled together for long-term 72-month follow-up. Survival was analyzed by Kaplan-Meier method. Multivariate Cox proportional hazards modeling helped to assess variables associated to survival. At 24months (17 events), survival increases with BMI across four groups (logrank for trend P=0.031). By Cox multivariate mortality, best model included: BMI (P=0.043), low lung diffusion (DLco, P=0.007), and reduced stroke volume index (SVI, P=0.017). At 72month (37 events), higher BMI values were associated with better survival but not significantly (P=0.076). By multivariate modeling BMI did not enter any model, whereas low DLco entered all (P<0.001). Also low SVI (P=0.02) and low mixed venous saturation (SvO2, P=0.009) were associated with the prognosis. From PAH diagnosis to final event, BMI had small (5.4%), but significant decline (P<0.001). This is ascribed to CHF progression, and may explain BMI predictive power weakening. The results suggest BMI decline should be contrasted, DLco is useful for screening and with SVI and SvO2 for assessing prognosis and treatment.

Widespread activation of immunity and pro-inflammatory programs in peripheral blood leukocytes of HIV-infected patients with impaired lung gas exchange.

HIV infection is associated with impaired lung gas transfer as indicated by a low diffusing capacity (DLCO), but the mechanisms are not well understood. We hypothesized that HIV‐associated gas exchange impairment is indicative of system‐wide perturbations that could be reflected by alterations in peripheral blood leukocyte (PBL) gene expression. Forty HIV‐infected (HIV +) and uninfected (HIV –) men with preserved versus low DLCO were enrolled. All subjects were current smokers and those with acute illness, lung diseases other than COPD or asthma were excluded. Total RNA was extracted from PBLs and hybridized to whole‐genome microarrays. Gene set enrichment analysis (GSEA) was performed between HIV + versus HIV – subjects with preserved DLCO and those with low DLCO to identify differentially activated pathways. Using pathway‐based analyses, we found that in subjects with preserved DLCO, HIV infection is associated with activation of processes involved in immunity, cell cycle, and apoptosis. Applying a similar analysis to subjects with low DLCO, we identified a much broader repertoire of pro‐inflammatory and immune‐related pathways in HIV + patients relative to HIV – subjects, with up‐regulation of multiple interleukin pathways, interferon signaling, and toll‐like receptor signaling. We confirmed elevated circulating levels of IL‐6 in HIV + patients with low DLCO relative to the other groups. Our findings reveal that PBLs of subjects with HIV infection and low DLCO are distinguished by widespread enrichment of immuno‐inflammatory programs. Activation of these pathways may alter the biology of circulating leukocytes and play a role in the pathogenesis of HIV‐associated gas exchange impairment.

Post‐exercise changes in endothelin‐1 in military veterans with respiratory complaints

Post‐9/11 veterans frequently report respiratory symptoms following deployment to Iraq and Afghanistan, which may be related to deployment‐related exposures. Work from our clinic has observed evidence of pulmonary vascular dysfunction (i.e., normal spirometry and reduced lung diffusing capacity [DLCO])as a common abnormality in this population. The goal of the present study was to evaluate changes in endothelin‐1 (ET‐1), a key vascular regulator, before and after a maximal cardiopulmonary exercise test and determine its relationship with measures of pulmonary gas‐exchange. Seven post‐9/11 veterans(34.7±4.1 years) with a median deployment length of 13 months and dyspnea onexertion (5.6±1.2 Borg Scale), completed a modified Bruce protocol on amotorized treadmill. Pre and post‐exercise venous plasma concentrations of ET‐1 were obtained using sensitive ELISA. Pulmonary gas‐exchange was assessed during exercise (VE/VCO2 slope) and at rest (DLCO). Baseline concentrations of ET‐1(1.04±0.2 pg/mL) were similar to post‐exercise levels (0.93±0.3; p=0.32), with three individuals demonstrating an exercise‐induced increase. The change in ET‐1 (−10.3±23.4%) was associated with exercise ventilatory efficiency (VE/VCO2 slope; r =0.77; p = 0.04), but was not associated with DLCO. However, we observed a mild reduction in DLCO (&lt;85% predicted) in 4 veterans and normal DLCO (&gt;85%) in the remaining group of individuals. Atrend for higher concentration of ET‐1 was observed (1.48±0.5 vs. 0.93±0.03pg/mL; p=0.08) in those with low DLCO (78.8±0.04%) versus normal DLCO (93.9±0.03%). The present study demonstrated that exercise‐induced changes in ET‐1 were associated with inefficient exercise ventilation, and individuals with reduced gas‐exchange at rest exhibit higher plasma levels of ET‐1. Future studies may consider investigating ET‐1 and pulmonary gas‐exchange in deployed veterans presenting with unexplained dyspnea.Support or Funding InformationVA RR&amp;D 1I21RX001079‐01

Low DLCO in idiopathic pulmonary arterial hypertension - clinical correlates and prognostic significance.

Decreased diffusing capacity of the lung for carbon monoxide (DLCO) is observed in some idiopathic pulmonary arterial hypertension (IPAH) patients, but its clinical significance is uncertain. We aimed to assess clinical correlates and prognostic significance of low DLCO in IPAH patients. In the group of 65 IPAH patients the cut off value for low DLCO was set up based on histogram as < 55% of predicted value. Demographic data, exercise capacity, lung function tests, hemodynamic parameters and survival of the patients were compared depending on DLCO value. Low DLCO was found in 18% of the patients, and it was associated with male sex, older age, worse functional status and exercise capacity, and higher prevalence of coronary artery disease. Low DLCO carried a 4-fold increase of death risk in 5-year perspective. Low DLCO was a marker of worse functional capacity and increased risk of death in studied IPAH patients.

Respiratory Factors Contributing to Exercise Intolerance in Breast Cancer Survivors: A Case-Control Study

ContextBreast cancer survivors often experience activity-related dyspnea and exercise intolerance, but the underlying mechanisms remain unknown. ObjectivesWe evaluated physiological contributors to reduced peak oxygen uptake (VO2), with particular attention to the role of respiratory impairment. MethodsWe compared symptom assessments, respiratory and peripheral muscle strength, pulmonary function, and ventilatory responses to symptom-limited incremental treadmill exercise in 29 women who had survived breast cancer and 29 age-matched healthy controls. ResultsPeak VO2 was reduced more than 20%, on average, in the cancer group compared with controls (P < 0.001). Slopes of dyspnea intensity ratings over ventilation or VO2 were >50% greater in the cancer group compared to controls (P < 0.05). Women with breast cancer had lower lung diffusing capacity for carbon monoxide (DLCO), respiratory and limb muscle strength, and ventilatory thresholds during exercise compared with controls (all P < 0.05). During exercise, indices of ventilatory efficiency were similar to controls, but inspiratory capacity (IC) was lower and breathing pattern was more rapid and shallow in the cancer group (P < 0.05). The lower peak VO2 in the cancer group was associated with greater dyspnea intensity, and lower DLCO, IC and ventilatory threshold (all P < 0.05). ConclusionBreast cancer survivors had greater peripheral and respiratory muscle weakness, greater reduction of IC, impaired lung diffusion, and evidence of deconditioning compared with controls. Exercise intolerance was multifactorial and correlated well with the combination of these factors as well as with exertional dyspnea. Individualized physiological testing in breast cancer survivors can identify important contributors to exercise intolerance which can be targeted for treatment.

Diffusion Capacity and Mortality in Patients With Pulmonary Hypertension Due to Heart Failure With Preserved Ejection Fraction

ObjectivesThis study sought to investigate the prognostic importance of a low diffusion capacity of the lung for carbon monoxide (DLCO) in patients with a catheter-based diagnosis of pulmonary hypertension due to heart failure with preserved ejection fraction (PH-HFpEF). BackgroundIn patients with pulmonary arterial hypertension, a low DLCO is associated with poor outcome. It is unclear whether the same is true in patients with PH-HFpEF. MethodsThis study retrospectively analyzed clinical characteristics, smoking history, lung function measurements, chest computed tomography, hemodynamics, and survival in 108 patients with PH-HFpEF. The presence of post-capillary PH was determined by right heart catheterization. Patients with moderate or severe lung function abnormalities were excluded. ResultsOn the basis of previous studies and receiver-operating characteristic curve analysis, the study cohort was divided into patients with a DLCO <45% of the predicted value (DLCO<45%, low DLCO; n = 52) and patients with a DLCO ≥45% of the predicted value (DLCO≥45%; n = 56). DLCO<45% was associated with male sex (odds ratio [OR]: 2.71; 95% confidence interval [CI]: 1.05 to 6.99; p = 0.039) and smoking history (OR: 5.01; 95% CI: 1.91 to 13.10; p < 0.001). There were no correlations between DLCO and other lung function parameters and hemodynamics. Compared with patients with DLCO≥45%, patients with DLCO<45% had a significantly worse outcome (survival rate at 3 years 36.5% vs. 87.8%, p < 0.001 by log-rank analysis). Cox proportional hazard analysis identified DLCO<45% as an independent predictor of death (hazard ratio: 6.6; 95% CI: 2.6 to 16.9; p < 0.001). ConclusionsIn patients with PH-HFpEF, a low DLCO is strongly associated with mortality.

A New Scale to Assess the Severity and Prognosis of Pulmonary Alveolar Proteinosis.

Background. Pulmonary Alveolar Proteinosis (PAP) is a syndrome characterized by pulmonary surfactant accumulation. Small proportion of PAP patients experienced spontaneous remission. Objective. The aim of this study was to assess the severity and prognosis of PAP using various indexes. Methods. Characteristics, PaO2, lung function parameters, and HRCT score of 101 patients with PAP were retrospectively analyzed. Many indexes were explored and integrated into a scale. Results. PaO2 was lower among smokers than among never-smokers. PaO2 differed between each pair of patient groups stratified according to HRCT score or DLCO, % predicted, which differed between any two groups stratified according to PaO2. The PAP patients who died presented with more symptoms, a higher HRCT score, and lower DLCO, % predicted, than survivors. Smoking status, symptoms, PaO2, HRCT score, and DLCO, % predicted, were integrated into a scale (severity and prognosis score of PAP (SPSP)). SPSP correlated positively with PaO2, FVC, % predicted, FEV1, % predicted, and DLCO, % predicted, and negatively with HRCT score. The patients who died displayed a higher SPSP than survivors. Conclusion. Smoking status, symptoms, PaO2, HRCT score, and DLCO, % predicted, were integrated into a scale (SPSP) that can be used to assess the severity and prognosis of PAP to some degree.