Anand S. Iyer

CT Scan-Measured Pulmonary Artery to Aorta Ratio and Echocardiography for Detecting Pulmonary Hypertension in Severe COPD

BACKGROUND COPD is associated with significant morbidity primarily driven by acute exacerbations. Relative pulmonary artery (PA) enlargement, defined as a PA to ascending aorta (A) diameter ratio greater than one (PA:A>1) identifies patients at increased risk for exacerbations. However, little is known about the correlation between PA:A, echocardiography, and invasive hemodynamics in COPD. METHODS A retrospective observational study of patients with severe COPD being evaluated for lung transplantation at a single center between 2007 and 2011 was conducted. Clinical characteristics, CT scans, echocardiograms, and right-sided heart catheterizations were reviewed. The PA diameter at the bifurcation and A diameter from the same CT image were measured. Linear and logistic regression were used to examine the relationships between PA:A ratio by CT scan and PA systolic pressure (PASP) by echocardiogram with invasive hemodynamics. Receiver operating characteristic analysis assessed the usefulness of the PA:A ratio and PASP in predicting resting pulmonary hypertension (PH) (mean pulmonary artery pressure [mPAP]>25 mm Hg). RESULTS Sixty patients with a mean predicted FEV1 of 27%±12% were evaluated. CT scan-measured PA:A correlated linearly with mPAP after adjustment for multiple covariates (r=0.30, P=.03), a finding not observed with PASP. In a multivariate logistic model, mPAP was independently associated with PA:A>1 (OR, 1.44; 95% CI, 1.02-2.04; P=.04). PA:A>1 was 73% sensitive and 84% specific for identifying patients with resting PH (area under the curve, 0.83; 95% CI, 0.72-0.93; P<.001), whereas PASP was not useful. CONCLUSIONS A PA:A ratio>1 on CT scan outperforms echocardiography for diagnosing resting PH in patients with severe COPD.

Uncontrolled hypertension and increased risk for incident heart failure in older adults with hypertension: findings from a propensity-matched prospective population study.

Hypertension is a risk factor for incident heart failure (HF). However, the effect of uncontrolled blood pressure (BP) on incident HF in older adults with hypertension has not been prospectively examined in propensity-matched studies. Of the 5795 Cardiovascular Health Study participants, > or =65 years, 2562 with self-reported physician-diagnosed hypertension had no baseline HF. Of these, 1391 had uncontrolled hypertension, defined as systolic BP (SBP) > or =140 (n = 1373) or diastolic BP > or =90 mm Hg (n = 18). Propensity scores for uncontrolled hypertension, calculated for each participant, were used to assemble a cohort of 1021 pairs of participants with controlled and uncontrolled hypertension who were balanced on 31 baseline characteristics. Centrally adjudicated incident HF developed in 23% and 26% of participants with controlled and uncontrolled hypertension respectively during 13 years of follow-up (matched hazard ratio [HR] when uncontrolled hypertension was compared with controlled hypertension, 1.39; 95% confidence interval [CI], 1.12 to 1.73; P = .003). HRs (95% CI) for incident HF for those with (n = 503) and without (n = 1539) chronic kidney disease (CKD) were 1.73 (95% CI, 1.26 to 2.38; P = .001) and 1.08 (95% CI, 0.87 to 1.34; P = .486) respectively (P for interaction, .012). Compared with participants with controlled hypertension, HRs for incident HF associated with SBP 140 to 159 and > or =160 mm Hg were 1.06 (95% CI, 0.86 to 1.31; P = .572) and 1.58 (95% CI, 1.27 to 1.96; P < .0001), respectively. In community-dwelling older adults with hypertension, those with uncontrolled (versus controlled) BP have increased risk of new-onset HF, which is more pronounced in those with SBP > or =160 mm Hg and with CKD.

Pulmonary artery enlargement is associated with right ventricular dysfunction and loss of blood volume in small pulmonary vessels in chronic obstructive pulmonary disease.

Background—Chronic obstructive pulmonary disease causes significant morbidity and concomitant pulmonary vascular disease and cardiac dysfunction are associated with poor prognosis. Computed tomography–detected relative pulmonary artery (PA) enlargement defined as a PA to ascending aorta diameter ratio >1 (PA:A>1) is a marker for pulmonary hypertension and predicts chronic obstructive pulmonary disease exacerbations. However, little is known about the relationship between the PA:A ratio, pulmonary blood volume, and cardiac function. Methods and Results—A single-center prospective cohort study of patients with chronic obstructive pulmonary disease was conducted. Clinical characteristics and computed tomography metrics, including the PA:A and pulmonary blood vessel volume, were measured. Ventricular functions, volumes, and dimensions were measured by cine cardiac MRI with 3-dimensional analysis. Linear regression examined the relationships between clinical characteristics, computed tomography and cardiac MRI metrics, and 6-minute walk distance. Twenty-four patients were evaluated and those with PA:A>1 had higher right ventricular (RV) end-diastolic and end-systolic volume indices accompanied by lower RV ejection fraction (52±7% versus 60±9%; P=0.04). The PA:A correlated inversely with total intraparenchymal pulmonary blood vessel volume and the volume of distal vessels with a cross-sectional area of <5 mm2. Lower forced expiratory volume, PA:A>1, and hyperinflation correlated with reduced RV ejection fraction. Both PA diameter and reduced RV ejection fraction were independently associated with reduced 6-minute walk distance. Conclusions—The loss of blood volume in distal pulmonary vessels is associated with PA enlargement on computed tomography. Cardiac MRI detects early RV dysfunction and remodeling in nonsevere chronic obstructive pulmonary disease patients with a PA:A>1. Both RV dysfunction and PA enlargement are independently associated with reduced walk distance. Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT00608764.

Results of a Medicare Bundled Payments for Care Improvement Initiative for Chronic Obstructive Pulmonary Disease Readmissions

Rationale: Approximately 20% of Medicare beneficiaries hospitalized for acute exacerbations of chronic obstructive pulmonary disease (COPD) are readmitted within 30 days of discharge. In addition to implementing penalties for excess readmissions, the U.S. Centers for Medicare and Medicaid Services has developed Bundled Payments for Care Improvement (BPCI) initiatives to improve outcomes and control costs. Objectives: To evaluate whether a comprehensive COPD multidisciplinary intervention focusing on inpatient, transitional, and outpatient care as part of our institutions BPCI participation would reduce 30‐day all‐cause readmission rates for COPD exacerbations and reduce overall costs. Methods: We performed a pre‐postintervention study comparing all‐cause readmissions and costs after index hospitalization for Medicare‐only patients with acute exacerbation of COPD. The primary outcome was the difference in 30‐day all‐cause readmission rate compared with historical control subjects; secondary outcomes included the 90‐day all‐cause readmission rate and also health care costs compared with BPCI target prices. Results: Seventy‐eight consecutive Medicare patients were prospectively enrolled in the BPCI intervention in 2014 and compared with 109 patients in the historical group from 2012. Patients in BPCI were more likely to receive regular follow‐up phone calls, pneumococcal and influenza vaccines, home health care, durable medical equipment, and pulmonary rehabilitation, and to attend pulmonary clinic. There was no difference in all‐cause readmission rates at 30 days (BPCI, 12 events [15.4%] vs. non‐BPCI, 19 events [17.4%]; P = 0.711), and 90 days (21 [26.9%] vs. 37 [33.9%]; P = 0.306). Compared with BPCI target prices, we incurred 4.3% lower 90‐day costs before accounting for significant investment from the health system. Conclusions: A Medicare BPCI intervention did not reduce 30‐day all‐cause readmission rates or overall costs after hospitalization for acute exacerbation of COPD. Although additional studies enrolling larger numbers of patients at multiple centers may demonstrate the efficacy of our BPCI initiative for COPD readmissions, this is unlikely to be cost effective at any single center.

Serum eosinophils as a COPD biomarker: ready for prime time?

Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease with many sub-phenotypes that are probably driven by diff erent biological mechanisms. Although this complexity is poorly understood, defi ning COPD phenotypes based not only on the severity of airfl ow obstruction but also by imaging characteristics, the presence or absence of cardinal symptoms, or frequent exacerbations has led to a better understanding of disease expression and has helped target treatments. However, there are no serum biomarkers that reliably predict treatment response, that are available in almost all clinical settings, and that can dramatically change the treatment paradigm for millions of people. In The Lancet Respiratory Medicine, Henrik Watz and colleagues present their secondary analysis of the WISDOM trial with fi ndings showing a robust association between the withdrawal of inhaled corticosteroids (ICS) and an increased risk of moderateto-severe acute exacerbations of COPD in patients with relatively high baseline serum eosinophil counts. Moderate or severe exacerbation rate was higher in the ICS-withdrawal group versus the ICS-continuation group in patients with eosinophil counts of at least 2% (rate ratio 1·22 [95% CI 1·02–1·48]), with the treatmentby-subgroup interaction becoming signifi cant in patients with eosinophil counts of at least 4% (1·63 [1·19–2·24]) and at least 5% (1·82 [1·20–2·76]). When combined with similar fi ndings from other recent reports, we believe this biomarker is ready for prime time use. Data supporting a role for serum eosinophil counts to identify steroid-responsive COPD populations are remarkably consistent. The prevalence of relatively elevated serum eosinophils has been repeatedly reported to range from 50–70% of patients, similar to the 54% in the present study. Also, irrespective of study design (observational or secondary analysis of a randomised trial; initiation or withdrawal of ICS therapy), sponsor (including rival large pharmaceutical companies), and patient population (moderate or severe airfl ow limitation), there seems to remain a clear association between a relative increase in serum eosinophils and exacerbation risk, as well as mitigation of that risk with ICS. The results of the current analysis are also entirely consistent with the fi ndings of Bafadhel and colleagues who reported that systemic steroids improve outcomes in exacerbations associated with serum eosinophil counts of more than 2%, while perhaps being detrimental in those with a lower eosinophil count. We expect that some of our colleagues in the fi eld of respiratory medicine will respond with skepticism and highlight some shortcomings of the biomarker. Firstly, the underlying mechanism remains unknown, given that Watz and colleagues found no association between RAST positivity or immunoglobulin E concentrations and the relative benefi ts of ICS, suggesting this is not atopy-mediated. Second, since the correlation between serum and sputum eosinophils is not reliable in asthma and is poorly described in COPD, and ICS are known to target sputum eosinophils, the relevance of this serum biomarker could be questioned. Finally, there was no benefi t on time to fi rst exacerbation between eosinophil groups. We agree that more work is needed. However, induced sputum is impractical for widespread clinical use and serum eosinophils seem accurate enough. We also feel that the time-to-event endpoint is statistically less useful for capturing the impact of repeated events. The fact that ICS responsiveness could not be predicted by any clinical parameter other than this biomarker underscores its immediate usefulness. Watz and colleagues should be commended for their heroic eff orts to defi ne the precise absolute Lancet Respir Med 2016

GWAS and systems biology analysis of depressive symptoms among smokers from the COPDGene cohort

BACKGROUND Large sample GWAS is needed to identify genetic factors associated with depression. This study used genome-wide genotypic and phenotypic data from the COPDGene study to identify genetic risk factors for depression. METHODS Data were from 9716 COPDGene subjects with ≥10 pack-year history. Depression was defined as antidepressant use and/or a HADS depression subscale score ≥8. Non-Hispanic White (6576) and African-American (3140) subsets were analyzed. A GWAS pipeline identified SNPs associated with depression in each group. Network analysis software analyzed gene interactions through common biological pathways, genetic interactions, and tissue-specific gene expression. RESULTS The mean age was 59.4 years (SD 9.0) with 46.5% female subjects. Depression was in 24.7% of the NHW group (1622) and 12.5% of the AA group (391). No SNPs had genome-wide significance. One of the top SNPs, rs12036147 (p = 1.28 × 10-6), is near CHRM3. Another SNP was near MDGA2 (rs17118176, p = 3.52 × 10-6). Top genes formed networks for synaptic transmission with a statistically significant level of more co-expression in brain than other tissues, particularly in the basal ganglia (p = 1.00 × 10-4). LIMITATIONS Limitations included a depression definition based on antidepressant use and a limited HADS score subgroup, which could increase false negatives in depressed patients not on antidepressants. Antidepressants used for smoking cessation in non-depressed patients could lead to false positives. CONCLUSIONS Systems biology analysis identified statistically significant pathways whereby multiple genes influence depression. The gene set pathway analysis and COPDGene data can help investigate depression in future studies.

Easing the Tension Between Palliative Care and Intensive Care in Chronic Obstructive Pulmonary Disease

Integrating early palliative care for the millions of adults with serious illnesses has received increasing national attention. However, efforts to improve palliative care access across the continuum for all serious illnesses have not been uniform. This is due in part to perceptions that nonmalignant progressive illnesses, such as chronic obstructive pulmonary disease (COPD), are not as serious or as potentially fatal. Progressive COPD is the third leading cause of death in the United States, and patients have a host of unmet palliative care needs equal to or more severe than most types of cancerrefractory dyspnea, untreated anxiety and depressive symptoms, social isolation, and an unpredictable illness trajectory that makes outlook planning exceedingly difficult. These uncertainties result in care that is frequently not concordant with the wishes of patients and their families. In this issue of the Journal of Palliative Care, Shen et al shed light on a tension that exists between providing palliative care and intensive care for patients with COPD at the end of life. Resolving this tension is possible but will require that pulmonologists make a paradigm shift away from snatching patients with COPD from the brink of death and toward advanced preparation for expected crises. Shen et al selected a cohort of adults with COPD from the Nationwide Inpatient Sample during their terminal hospitalization, a sicker population than the one Rush et al studied who were on home oxygen and admitted for an acute exacerbation. In the current study of patients dying with COPD, Shen et al found that 39% received palliative care consultation at the end of life compared to only 2% in the study by Rush et al. Other reassuring trends included a significant increase in do-notresuscitate status (compound annual growth rate [CAGR]: 36%, P <.001) and a small increase in palliative care consultation over the study period (CAGR: 5.3%, P <.001). However, this reassurance was short lived. From 2010 to 2014, the authors also discovered a significant interval increase in the frequency of invasive, life-sustaining procedures at the end of life for patients dying with COPD (CAGR: 7%, P <.001). By study end, nearly half had received mechanical ventilation in their last days, 1 in 8 had received dialysis, 1 in 10 had received vasopressors, and 1 in 4 had received more than 1 procedure at the end of life. This is the first observational study on the use of lifesustaining procedures and inpatient palliative care consultation for patients dying with COPD. The authors are to be commended for raising awareness of the tension that exists between providing life-sustaining procedures versus delivering palliative care at the end of life in COPD, though a few study limitations are notable. First, use of the V66.7 palliative care consultation code inadequately identifies patients who actually receive these services and does not allow for exploration into the quality of the consultation or services offered. This was a critical factor in the only study that did not find positive outcomes following palliative consultation in the intensive care unit. Second, demonstration of an interval increase in palliative care consultation during the study period may simply represent the temporal trend of a nationwide increase in inpatient palliative care services and not something particularly unique to COPD. Most hospitals in the United States with more than 300 beds now have inpatient palliative care. Third, expert end-of-life care is but a drop in the ocean of what palliative care can offer for patients with COPD and their caregivers. Consulting palliative care at the end of life for a mechanically ventilated patient with COPD is too late. The continuum of care model instead teaches us that palliative care should be instituted early in serious illness to provide

Life-Space mobility and clinical outcomes in COPD

Background Social isolation is a common experience in patients with COPD but is not captured by existing patient-reported outcomes, and its association with clinical outcomes is unknown. Methods We prospectively enrolled adults with stable COPD who completed the University of Alabama at Birmingham Life Space Assessment (LSA) (range: 0–120, restricted Life-Space mobility: ≤60 and a marker of social isolation in older adults); six-minute walk test (6MWT), and the University of California at San Diego Shortness of Breath Questionnaire, COPD Assessment Test, and Hospital Anxiety and Depression Scale. The occurrence of severe exacerbations (emergency room visit or hospitalization) was recorded by review of the electronic record up to 1 year after enrollment. We determined associations between Life-Space mobility and clinical outcomes using regression analyses. Results Fifty subjects had a mean ± SD %-predicted FEV1 of 42.9±15.5, and 23 (46%) had restricted Life-Space mobility. After adjusting for age, gender, %-predicted FEV1, comorbidity count, inhaled corticosteroid/long-acting beta2-agonist use, and prior cardiopulmonary rehabilitation, subjects with restricted Life-Space had an increased risk for severe exacerbations (adjusted incidence rate ratio 4.65, 95% CI 1.19–18.23, P=0.03). LSA scores were associated with 6MWD (R=0.50, P<0.001), dyspnea (R=−0.58, P<0.001), quality of life (R=−0.34, P=0.02), and depressive symptoms (R=−0.39, P=0.005). Conclusion Restricted Life-Space mobility predicts severe exacerbations and is associated with reduced exercise tolerance, more severe dyspnea, reduced quality of life, and greater depressive symptoms.