A. James Mamary

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.).

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

Abstract 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.

Genome-wide association study of smoking behaviours in patients with COPD

Background Cigarette smoking is a major risk factor for chronic obstructive pulmonary disease (COPD) and COPD severity. Previous genome-wide association studies (GWAS) have identified numerous single nucleotide polymorphisms (SNPs) associated with the number of cigarettes smoked per day (CPD) and a dopamine beta-hydroxylase (DBH) locus associated with smoking cessation in multiple populations. Objective To identify SNPs associated with lifetime average and current CPD, age at smoking initiation, and smoking cessation in patients with COPD. Methods GWAS were conducted in four independent cohorts encompassing 3441 ever-smoking patients with COPD (Global Initiative for Obstructive Lung Disease stage II or higher). Untyped SNPs were imputed using the HapMap (phase II) panel. Results from all cohorts were meta-analysed. Results Several SNPs near the HLA region on chromosome 6p21 and in an intergenic region on chromosome 2q21 showed associations with age at smoking initiation, both with the lowest p=2×10−7. No SNPs were associated with lifetime average CPD, current CPD or smoking cessation with p<10−6. Nominally significant associations with candidate SNPs within cholinergic receptors, nicotinic, alpha 3/5 (CHRNA3/CHRNA5; eg, p=0.00011 for SNP rs1051730) and cytochrome P450, family 2, subfamily A, polypeptide 6 (CYP2A6; eg, p=2.78×10−5 for a non-synonymous SNP rs1801272) regions were observed for lifetime average CPD, however only CYP2A6 showed evidence of significant association with current CPD. A candidate SNP (rs3025343) in DBH was significantly (p=0.015) associated with smoking cessation. Conclusion The authors identified two candidate regions associated with age at smoking initiation in patients with COPD. Associations of CHRNA3/CHRNA5 and CYP2A6 loci with CPD and DBH with smoking cessation are also likely of importance in the smoking behaviours of patients with COPD.

Home non-invasive ventilation use following acute hypercapnic respiratory failure in COPD

RATIONALE Patients with COPD and hypercapnic respiratory failure have a worse prognosis and experience a faster deterioration in their pulmonary function. The benefit of home NPPV following an acute exacerbation of COPD with hypercapnic respiratory failure is not well understood. OBJECTIVES To evaluate the effect of home NPPV use in patients following a hospitalization for AECOPD with acute hypercapnic respiratory failure on event-free survival after an index admission. METHODS We conducted a retrospective, single-center, chart review on patients hospitalized in 2011 with a diagnosis of AECOPD, hypercapnia, and used NPPV during hospitalization. 166 patients were included and were divided into two groups: patients who used NPPV post discharge and patients who did not. RESULTS Patients in the NPPV post discharge group demonstrated superior event-free survival compared to the no-NPPV post discharge group (y2 = 23.8, p < 0.0001). The NPPV post discharge group had a statistically significant reduction in hospital readmissions (40% versus 75%, p < 0.0001) through 180 days from the index admission. CONCLUSIONS Patients who used NPPV following an admission for AECOPD with hypercapnic respiratory failure had lower readmission rates and improved event-free survival after 180 days from an index admission compared to patients who did not use NPPV post discharge.

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, M1 and M3, 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.

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.

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.

Outcomes of COPD Exacerbations Treated with Corticosteroids, Antibiotics, or Both

Background. The outcomes for outpatient treatment of acute exacerbations of COPD (AECOPD) are poorly described. Design. The results of a daily diary recording symptoms and peak flows were compiled into a severity score to trigger algorithm-based treatments and a symptom index to follow treatment response. Treatment failure (symptom index failing to return to baseline for 2 consecutive days or hospitalization within 21 days) was the main outcome. Results. Twenty-two patients (FEV1 0.81 ± 0.26 L) were treated for 115 AECOPDs (corticosteroids = 36, antibiotics = 41, corticosteroids/antibiotics = 38). Treatment failure was 50% for the corticosteroid/antibiotic compared to 28% (𝑃=0.006) for the corticosteroid and 34% (𝑃<0.0001) for the antibiotic group. Patients suffering from AECOPDs treated with corticosteroids had dyspnea, wheezing, and decreased peak flow; those treated with antibiotics had sputum symptoms; those treated with corticosteroids/antibiotics had dyspnea, wheezing, sputum symptoms, and decreased peak flows. Conclusions. AECOPDs with both dyspnea and sputum symptoms are more refractory to standard treatment and likely require closer monitoring.