Pulmonary arterial enlargement and acute exacerbations of COPD.

BACKGROUND: Exacerbations of chronic obstructive pulmonary disease (COPD) are associated with accelerated loss of lung function and death. Identification of patients at risk for these events, particularly those requiring hospitalization, is of major importance. Severe pulmonary hypertension is an important complication of advanced COPD and predicts acute exacerbations, though pulmonary vascular abnormalities also occur early in the course of the disease. We hypothesized that a computed tomographic (CT) metric of pulmonary vascular disease (pulmonary artery enlargement, as determined by a ratio of the diameter of the pulmonary artery to the diameter of the aorta [PA:A ratio] of >1) would be associated with severe COPD exacerbations. METHODS: We conducted a multicenter, observational trial that enrolled current and former smokers with COPD. We determined the association between a PA:A ratio of more than 1 and a history at enrollment of severe exacerbations requiring hospitalization and then examined the usefulness of the ratio as a predictor of these events in a longitudinal follow-up of this cohort, as well as in an external validation cohort. We used logistic-regression and zero-inflated negative binomial regression analyses and adjusted for known risk factors for exacerbation. RESULTS: Multivariate logistic-regression analysis showed a significant association between a PA:A ratio of more than 1 and a history of severe exacerbations at the time of enrollment in the trial (odds ratio, 4.78; 95% confidence interval [CI], 3.43 to 6.65; P<0.001). A PA:A ratio of more than 1 was also independently associated with an increased risk of future severe exacerbations in both the trial cohort (odds ratio, 3.44; 95% CI, 2.78 to 4.25; P<0.001) and the external validation cohort (odds ratio, 2.80; 95% CI, 2.11 to 3.71; P<0.001). In both cohorts, among all the variables analyzed, a PA:A ratio of more than 1 had the strongest association with severe exacerbations. CONCLUSIONS: Pulmonary artery enlargement (a PA:A ratio of >1), as detected by CT, was associated with severe exacerbations of COPD. (Funded by the National Heart, Lung, and Blood Institute; ClinicalTrials.gov numbers, NCT00608764 and NCT00292552.).

Lung Transplantation Waitlist Mortality Among Sarcoidosis Patients by Lung Allocation Score Grouping.

BACKGROUND: The Lung Allocation Score (LAS) system was designed to equalize and minimize waitlist mortality among candidiates for lung transplantation. The LAS stratifies sarcoidosis patients by mean pulmonary arterial pressure (mPAP) into group A (mPAP ≤30 mm Hg) and group D (mPAP >30 mm Hg). In this study, we aimed to analyze the effect of diagnostic grouping and patient characteristics on waitlist mortality among sarcoidosis patients. METHODS: This was a retrospective review of sarcoidosis lung transplantation candidates since LAS implementation in May 2005 through May 2019 in the Scientific Registry of Transplant Recipients database. We compared baseline characteristics, LAS variables, and waitlist outcomes between sarcoidosis groups A and D. We performed Kaplan-Meier survival analysis and multivariable regression to determine associations with waitlist mortality. RESULTS: We identified 1027 sarcoidosis candidates since LAS implementation. Of these, 385 had mPAP ≤30 mm Hg and 642 had mPAP >30 mm Hg. Waitlist mortality was 18% in sarcoidosis group D and 14% in sarcoidosis group A. Kaplan-Meier curve showed lower waitlist survival probability for sarcoidosis group D than group A (log-rank P = .0049). Functional status, oxygen requirement, and sarcoidosis group D were associated with increased waitlist mortality. Cardiac output ≥4 L/min was associated with decreased waitlist mortality. CONCLUSION: Sarcoidosis group D had lower waitlist survival than group A. Decreased survival appears driven by mPAP; sarcoidosis group D, functional status, oxygen requirement, and cardiac output had significant associations with waitlist mortality. These findings suggest that the current LAS grouping does not adequately reflect the risk for waitlist mortality among sarcoidosis group D patients.

Sarcoidosis lung transplantation waitlist mortality, a national registry database study.

Background: The Lung Allocation Score (LAS) prioritises lung transplantation candidates, balancing waitlist mortality and post-transplant survival. The score groups sarcoidosis candidates based on mean pulmonary artery pressure: those with ≤30 mmHg (sarcoidosis A) are grouped with COPD and those with >30 mmHg (sarcoidosis D) with idiopathic pulmonary fibrosis (IPF). We hypothesise that sarcoidosis candidates have a higher waitlist mortality than other candidates within their LAS grouping. Methods: This is a retrospective cohort study of consecutive lung transplantation candidates from the Scientific Registry of Transplant Recipients database from May 2005 to May 2019. We included candidates aged ≥18 years diagnosed with sarcoidosis, COPD or IPF. Univariate, multivariate and survival estimate analyses were performed. Results: We identified 385 sarcoidosis A, 642 sarcoidosis D, 7081 COPD and 10 639 IPF lung transplantation candidates. 17.3% of sarcoidosis D, 14.8% of IPF, 14.3% of sarcoidosis A and 9.8% of COPD candidates died awaiting transplant. Sarcoidosis A was an independent risk factor for waitlist mortality. Sarcoidosis A had a lower waitlist survival probability compared to COPD. Sarcoidosis D had the highest waitlist mortality. IPF candidates had lower waitlist survival probability than sarcoidosis D in the first 60 days after listing. Conclusion: Based on our results, the grouping of candidates with sarcoidosis in allocation systems should be revised to mitigate waitlist mortality disparity.

Prevalence of abnormal spirometry in individuals with a smoking history and no known obstructive lung disease.

INTRODUCTION: Recent evidence suggests a high prevalence of undiagnosed chronic obstructive pulmonary disease (COPD). These individuals are at risk of exacerbations and delayed treatment. We analyzed an at-risk population for the prevalence of abnormal spirometry to provide clarity into who should undergo early spirometry. METHODS: We analyzed data from the COPDGene study. Participants with ≥10 pack-years of smoking were included. Individuals with self-reported or physician-diagnosed COPD, asthma, chronic bronchitis, emphysema and/or were on inhalers were excluded. Parsimonious multivariable logistic regression models identified factors associated with abnormal spirometry, defined as either airflow obstruction (AFO) or preserved ratio impaired spirometry. Variables were selected for the final model using a stepwise backward variable elimination process which minimized Akaike information criterion (AIC). Similarly, during the 5-year follow-up period, we assessed factors associated with incident diagnosis of COPD. RESULTS: Of 5055 individuals, 1064 (21%) had undiagnosed AFO. Age, pack-years, current smoking and a history of acute bronchitis were associated with AFO while body mass index, female sex, and Black race were inversely associated. Among 2800 participants with 5-year follow-up, 532 (19%) had an incident diagnosis of COPD. Associated risk factors included mMRC ≥2, chronic productive cough, respiratory exacerbations during the follow-up period, and abnormal spirometry. Age was inversely associated. CONCLUSIONS: The prevalence of undiagnosed COPD is high in at-risk populations. We found multiple factors associated with undiagnosed COPD and incident diagnosis of COPD at follow up. These results can be used to identify those at risk for undiagnosed COPD to facilitate earlier diagnosis and treatment.

A combined pulmonary-radiology workshop for visual evaluation of COPD: study design, chest CT findings and concordance with quantitative evaluation.

UNLABELLED: The purposes of this study were: to describe chest CT findings in normal non-smoking controls and cigarette smokers with and without COPD; to compare the prevalence of CT abnormalities with severity of COPD; and to evaluate concordance between visual and quantitative chest CT (QCT) scoring. METHODS: Volumetric inspiratory and expiratory CT scans of 294 subjects, including normal non-smokers, smokers without COPD, and smokers with GOLD Stage I-IV COPD, were scored at a multi-reader workshop using a standardized worksheet. There were 58 observers (33 pulmonologists, 25 radiologists); each scan was scored by 9-11 observers. Interobserver agreement was calculated using kappa statistic. Median score of visual observations was compared with QCT measurements. RESULTS: Interobserver agreement was moderate for the presence or absence of emphysema and for the presence of panlobular emphysema; fair for the presence of centrilobular, paraseptal, and bullous emphysema subtypes and for the presence of bronchial wall thickening; and poor for gas trapping, centrilobular nodularity, mosaic attenuation, and bronchial dilation. Agreement was similar for radiologists and pulmonologists. The prevalence on CT readings of most abnormalities (e.g. emphysema, bronchial wall thickening, mosaic attenuation, expiratory gas trapping) increased significantly with greater COPD severity, while the prevalence of centrilobular nodularity decreased. Concordances between visual scoring and quantitative scoring of emphysema, gas trapping and airway wall thickening were 75%, 87% and 65%, respectively. CONCLUSIONS: Despite substantial inter-observer variation, visual assessment of chest CT scans in cigarette smokers provides information regarding lung disease severity; visual scoring may be complementary to quantitative evaluation.

Lung volume reduction surgery and lung volume reduction in advanced emphysema: who and why?

Emphysema is a disabling and progressive disease that is hallmarked by decreased exercise tolerance and impaired quality of life. Hyperinflation is the sentinel physiological characteristic of emphysema that has been shown to be responsible for exercise intolerance, dyspnea, impaired quality of life, and mortality. Surgical interventions that reduce lung volume have been the focus of multiple proposed interventions over the past century; however, evidence documenting their effectiveness has been lacking. Recently, lung volume reduction surgery (LVRS) has undergone rigorous study in the National Emphysema Treatment Trial (NETT) that documented its short and long-term effectiveness, associated morbidity and mortality, and essential characteristics that predict success or failure. Additional recent investigation has examined the use of less invasive techniques, predominantly bronchoscopic techniques that reduce lung volume without open thoracotomy. This article summarizes the major results of the NETT and briefly reviews some preliminary results of studies examining new techniques of bronchoscopic lung volume reduction.

Clinical predictors and explant lung pathology of acute exacerbation of idiopathic pulmonary fibrosis.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is characterised by constant threat of acute exacerbation of IPF (AE-IPF). It would be significant to identify risk factors of AE-IPF. We sought to determine the prognostic value of lung transplantation candidacy testing for AE-IPF and describe explant pathology of recipients with and without AE-IPF before lung transplantation. METHODS: Retrospective cohort study of 89 IPF patients listed for lung transplantation. Data included pulmonary function testing, echocardiography, right heart catheterisation, imaging, oesophageal pH/manometry and blood tests. Explanted tissue was evaluated by pulmonary pathologists and correlated to computed tomography (CT) findings. RESULTS: Out of 89 patients with IPF, 52 were transplanted during stable IPF and 37 had AE-IPF before transplantation (n=28) or death (n=9). There were no substantial differences in candidacy testing with and without AE-IPF. AE-IPF had higher rate of decline of forced vital capacity (FVC) (21±22% versus 4.8±14%, p=0.00019). FVC decline of >15% had a hazard ratio of 7.2 for developing AE-IPF compared to FVC decline of <5% (p=0.004). AE-IPF had more secondary diverse histopathology (82% versus 29%, p<0.0001) beyond diffuse alveolar damage. There was no correlation between ground-glass opacities (GGO) on chest CT at any point to development of AE-IPF (p=0.077), but GGO during AE-IPF predicted secondary pathological process beyond diffuse alveolar damage. CONCLUSIONS: Lung transplantation candidacy testing including reflux studies did not predict AE-IPF besides FVC absolute decline. CT did not predict clinical or pathological AE-IPF. Secondary diverse lung pathology beyond diffuse alveolar damage was present in most AE-IPF, but not in stable IPF.

Acute Hypoxemic Respiratory Failure and Native Lung Idiopathic Pulmonary Fibrosis Exacerbation in Single-lung Transplant Patients with Cytomegalovirus Disease: A Case Series.

BACKGROUND: Our case series describes three patients who have received single-lung transplantations for idiopathic pulmonary fibrosis (IPF) that develop cytomegalovirus (CMV) disease and hypoxemic respiratory failure with radiographic opacification of the native lung and sparing of the allograft. RESULTS: Hypoxemia resolved with treatment and with resolution of CMV viremia. Viral infections causing IPF exacerbations have been described in the literature, however, pulmonary CMV disease in single-lung transplant recipients has typically been observed as pneumonitis of the allograft. CONCLUSIONS: These clinical scenarios are consistent with acute exacerbation of native-lung IPF and subradiographic pneumonitis of the allograft caused by CMV disease.

Mortality for sarcoidosis patients on the transplant wait list in the Lung Allocation Score era: Experience from a high volume center.

RATIONALE: Sarcoidosis progresses to end stage fibrotic lung disease in 10% of patients and may necessitate lung transplantation. Organ allocation is currently determined by the Lung Allocation Score (LAS), but its performance in a sarcoidosis population has not been evaluated. OBJECTIVES: To determine sarcoidosis-specific wait list mortality and identify predictive factors of death on the transplantation wait list. METHODS: This was a single-center retrospective study of all sarcoidosis patients listed for lung transplant from March 2012 to February 2019. We compared patients who were transplanted to those who died awaiting organs. We collected baseline listing characteristics, physiologic testing, and outcomes data. Statistical analysis was performed by 2-tailed Student's t-test, Mann-Whitney U test, and Chi-Square analysis (where appropriate). Receiver-operating characteristic curves were constructed for variables reaching statistical significance. RESULTS: Twenty eight sarcoidosis patients were included in analysis. Mortality among wait listed patients was 18%, which exceeded the mortality of COPD and IPF. LAS scores did not differ at initial listing (41 vs. 46, p = 0.35) or at transplant/death (41 vs. 41, p = 0.91); wait list times also did not statistically differ (307 days vs. 177 days, p = 0.19). We identified bilirubin (AUC = 0.92), DLCO (AUC = 0.84), FEV1/FVC at transplant/death (AUC = 0.85), and composite physiologic index (AUC = 0.86) as predictors of death on the transplant list. Pulmonary hypertension was not associated with death. CONCLUSION: Unexpected sudden death was common in our cohort and was associated with markers of advanced fibrotic disease, not pulmonary hypertension.

Race and Gender Disparities are Evident in COPD Underdiagnoses Across all Severities of Measured Airflow Obstruction.

The COPD Genetic Epidemiology (COPDGene®) study provides a rich cross-sectional dataset of patients with substantial tobacco smoke exposure, varied by race, gender, chronic obstructive pulmonary disease (COPD) diagnosis, and disease. We aimed to determine the influence of race, gender and Global initiative for chronic Obstructive Lung Disease (GOLD) stage on prevalence of prior COPD diagnosis at COPDGene® enrollment. Data from the complete phase 1 cohort of 10,192 participants were analyzed. Participants were non-Hispanic white and African-American, ≥45 years of age with a minimum of 10 pack years of cigarette smoking. Characterization upon enrollment included spirometry, demographics and history of COPD diagnosis determined by questionnaire. We evaluated the effects of race and gender on the likelihood of prior diagnosis of COPD and the interaction of race and GOLD stage, and gender and GOLD stage, as determined at study enrollment, on likelihood of prior diagnosis of COPD. We evaluated the 3-way interaction of race, gender and GOLD stage on prior diagnosis. African-Americans had higher odds of not having a prior COPD diagnosis at all GOLD stages of airflow obstruction versus non-Hispanic whites (p<0.0001). Women had higher odds of having a prior COPD diagnosis at all GOLD stages versus men (p<0.0001). Three-way interaction of race, gender and GOLD stage was not significant. African-Americans were less likely to have prior COPD regardless of the severity of airflow obstruction determined at study enrollment. Women were more likely to have a prior COPD diagnosis regardless of the severity of measured airflow obstruction. Race and gender are associated with significant disparities in COPD diagnosis.

Effect of Acute Exacerbation of Idiopathic Pulmonary Fibrosis on Lung Transplantation Outcome.

BACKGROUND: Acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) has an expected median survival of 3 months. Lung transplantation is a potentially lifesaving therapy for AE-IPF. However, the current knowledge of transplantation outcomes during AE-IPF is limited to a few small retrospective studies, reporting only 1-year post-transplantation survival. METHODS: Study population included patients with IPF consecutively listed for lung transplantation at a single institution between the years 2012 and 2016. We collected lung allocation score (LAS), hospitalization, and survival data. The primary outcome was survival among patients transplanted during stable IPF vs during AE-IPF. RESULTS: Of 89 patients with IPF listed for lung transplantation, 52 were transplanted during stable IPF and 37 were hospitalized due to AE-IPF. Of these 37 patients, nine died before transplantation, and 28 were transplanted during AE-IPF. Fifty percent of patients transplanted during AE-IPF died in a mean follow-up of 1.6 ± 1.2 years compared with 12% of patients transplanted during stable IPF who died in a mean follow-up of 2.6 ± 1.2 years. The Kaplan-Meier survival curves post-transplantation after 1 and 3 years for patients who were transplanted during stable IPF were 94% and 90% vs 71% and 60% in patients who were transplanted during AE-IPF (P = .0001). LAS above 80 conferred a 3-year hazard ratio for mortality of 5.7 vs LAS lower than 80 (95% CI, 2.33-14.0; P < .0005). CONCLUSIONS: Patients with IPF transplanted during AE-IPF had significantly worse short-term and long-term survival compared with patients transplanted during stable IPF. Patients with AE-IPF and very high LAS may not experience the survival advantage expected from lung transplantation.

Risk of Death by Comorbidity Prompting Rehospitalization Following the Initial COPD Hospitalization.

Rationale: Chronic obstructive pulmonary disease (COPD) hospitalizations increase short and long-term mortality; multiple COPD hospitalizations track with even higher mortality. While comorbidities such as coronary artery disease (CAD) and congestive heart failure (CHF) are common in COPD, their contribution to mortality risk after a sentinel COPD hospitalization is unknown. Purpose: Assess the effect on mortality of comorbid conditions prompting rehospitalization following COPD exacerbation hospitalization. Methods: We performed a retrospective cohort analysis of patients hospitalized for COPD exacerbations in Pennsylvania from 1990-2010 using the Pennsylvania Health Care Cost Containment Council (PHC4) database. We included patients > 40 years old hospitalized for an acute exacerbation of COPD (AECOPD; International Classification of Diseases-Ninth Edition, [ICD-9] #491, 492, 496) by discharge diagnosis. Thirty-day mortality in patients with COPD hospitalization for acute exacerbation who were rehospitalized for COPD < 30days post-discharge was compared to those primarily readmitted for comorbid conditions. Relative risk of death after readmission was determined by diagnosis. Primary end-point was mortality 30 days post-readmission for 14 most common non-COPD diagnoses, including heart failure, pneumonia, pulmonary embolus (PE), and myocardial infarction. Results: Patients were nearly 2 times more likely to die within 30 days when readmitted for pneumonia (p<0.0001) or myocardial infarction (p<0.0001) rather than COPD. Septicemia conferred the highest mortality. Conclusions: COPD patients rehospitalized for comorbid conditions such as myocardial infarction, pneumonia, septicemia or pulmonary heart disease (includes PE) were significantly more likely to die within 30 days than patients readmitted for COPD. Great emphasis is already placed on preventing COPD rehospitalization; however, more attention should focus on preemptive risk reduction for comorbidities in COPD patients.

Survival in Patients Receiving Prolonged Ventilation: Factors that Influence Outcome.

BACKGROUND: Prolonged mechanical ventilation is increasingly common. It is expensive and associated with significant morbidity and mortality. Our objective is to comprehensively characterize patients admitted to a Ventilator Rehabilitation Unit (VRU) for weaning and identify characteristics associated with survival. METHODS: 182 consecutive patients over 3.5 years admitted to Temple University Hospital (TUH) VRU were characterized. Data were derived from comprehensive chart review and a prospectively collected computerized database. Survival was determined by hospital records and social security death index and mailed questionnaires. RESULTS: Upon admission to the VRU, patients were hypoalbuminemic (albumin 2.3 ± 0.6 g/dL), anemic (hemoglobin 9.6 ± 1.4 g/dL), with moderate severity of illness (APACHE II score 10.7 + 4.1), and multiple comorbidities (Charlson index 4.3 + 2.3). In-hospital mortality (19%) was related to a higher Charlson Index score (P = 0.006; OR 1.08-1.6), and APACHE II score (P = 0.016; OR 1.03-1.29). In-hospital mortality was inversely related to admission albumin levels (P = 0.023; OR 0.17-0.9). The presence of COPD as a comorbid illness or primary determinant of respiratory failure and higher VRU admission APACHE II score predicted higher long-term mortality. Conversely, higher VRU admission hemoglobin was associated with better long term survival (OR 0.57-0.90; P = 0.0006). CONCLUSION: Patients receiving prolonged ventilation are hypoalbuminemic, anemic, have moderate severity of illness, and multiple comorbidities. Survival relates to these factors and the underlying illness precipitating respiratory failure, especially COPD.

Tiotropium bromide for chronic obstructive pulmonary disease.

Tiotropium bromide is a long-acting, once-daily inhaled anticholinergic approved for the treatment of chronic obstructive pulmonary disease (COPD). Functional and kinetic selectivity for muscarinic (M) receptors, M(1) and M(3), in the lung permit sustained bronchodilation in moderate and severe COPD. Tiotropium is associated with increased lung function, health-related quality of life and exercise tolerance, and reduced dyspnea and acute exacerbations of COPD. It has been hypothesized that tiotropium may retard the accelerated decline in lung function associated with COPD, although a recent study does not support this notion. Tiotropium is safe and well-tolerated, with few side effects. Concerns about cardiovascular side effects and increased stroke risk have been alleviated by a recent, large, multicenter, prospective, randomized trial. Herein, we discuss the pharmacology, physiology and safety profile of tiotropium, as well as the clinical studies that have demonstrated its efficacy in COPD. Additional review of airway muscarinic receptor physiology and cholinergic pathobiology relevant to COPD and asthma provides context for future experimental and therapeutic roles for tiotropium.