Enhancing Insights into Pulmonary Vascular Disease through a Precision Medicine Approach. A Joint NHLBI-Cardiovascular Medical Research and Education Fund Workshop Report.

The Division of Lung Diseases of the NHLBI and the Cardiovascular Medical Education and Research Fund held a workshop to discuss how to leverage the anticipated scientific output from the recently launched "Redefining Pulmonary Hypertension through Pulmonary Vascular Disease Phenomics" (PVDOMICS) program to develop newer approaches to pulmonary vascular disease. PVDOMICS is a collaborative, protocol-driven network to analyze all patient populations with pulmonary hypertension to define novel pulmonary vascular disease (PVD) phenotypes. Stakeholders, including basic, translational, and clinical investigators; clinicians; patient advocacy organizations; regulatory agencies; and pharmaceutical industry experts, joined to discuss the application of precision medicine to PVD clinical trials. Recommendations were generated for discussion of research priorities in line with NHLBI Strategic Vision Goals that include: (1) A national effort, involving all the stakeholders, should seek to coordinate biosamples and biodata from all funded programs to a web-based repository so that information can be shared and correlated with other research projects. Example programs sponsored by NHLBI include PVDOMICS, Pulmonary Hypertension Breakthrough Initiative, the National Biological Sample and Data Repository for PAH, and the National Precision Medicine Initiative. (2) A task force to develop a master clinical trials protocol for PVD to apply precision medicine principles to future clinical trials. Specific features include: (a) adoption of smaller clinical trials that incorporate biomarker-guided enrichment strategies, using adaptive and innovative statistical designs; and (b) development of newer endpoints that reflect well-defined and clinically meaningful changes. (3) Development of updated and systematic variables in imaging, hemodynamic, cellular, genomic, and metabolic tests that will help precisely identify individual and shared features of PVD and serve as the basis of novel phenotypes for therapeutic interventions.

Eosinophil and T cell markers predict functional decline in COPD patients.

BACKGROUND: The major marker utilized to monitor COPD patients is forced expiratory volume in one second (FEV1). However, a single measurement of FEV1 cannot reliably predict subsequent decline. Recent studies indicate that T lymphocytes and eosinophils are important determinants of disease stability in COPD. We therefore measured cytokine levels in the lung lavage fluid and plasma of COPD patients in order to determine if the levels of T cell or eosinophil related cytokines were predictive of the future course of the disease. METHODS: Baseline lung lavage and plasma samples were collected from COPD subjects with moderately severe airway obstruction and emphysematous changes on chest CT. The study participants were former smokers who had not had a disease exacerbation within the past six months or used steroids within the past two months. Those subjects who demonstrated stable disease over the following six months (DeltaFEV1 % predicted = 4.7 +/- 7.2; N = 34) were retrospectively compared with study participants who experienced a rapid decline in lung function (DeltaFEV1 % predicted = -16.0 +/- 6.0; N = 16) during the same time period and with normal controls (N = 11). Plasma and lung lavage cytokines were measured from clinical samples using the Luminex multiplex kit which enabled the simultaneous measurement of several T cell and eosinophil related cytokines. RESULTS AND DISCUSSION: Stable COPD participants had significantly higher plasma IL-2 levels compared to participants with rapidly progressive COPD (p = 0.04). In contrast, plasma eotaxin-1 levels were significantly lower in stable COPD subjects compared to normal controls (p < 0.03). In addition, lung lavage eotaxin-1 levels were significantly higher in rapidly progressive COPD participants compared to both normal controls (p < 0.02) and stable COPD participants (p < 0.05). CONCLUSION: These findings indicate that IL-2 and eotaxin-1 levels may be important markers of disease stability in advanced emphysema patients. Prospective studies will need to confirm whether measuring IL-2 or eotaxin-1 can identify patients at risk for rapid disease progression.

Longitudinal change in the BODE index predicts mortality in severe emphysema.

RATIONALE: The predictive value of longitudinal change in BODE (Body mass index, airflow Obstruction, Dyspnea, and Exercise capacity) index has received limited attention. We hypothesized that decrease in a modified BODE (mBODE) would predict survival in National Emphysema Treatment Trial (NETT) patients. OBJECTIVES: To determine how the mBODE score changes in patients with lung volume reduction surgery versus medical therapy and correlations with survival. METHODS: Clinical data were recorded using standardized instruments. The mBODE was calculated and patient-specific mBODE trajectories during 6, 12, and 24 months of follow-up were estimated using separate regressions for each patient. Patients were classified as having decreasing, stable, increasing, or missing mBODE based on their absolute change from baseline. The predictive ability of mBODE change on survival was assessed using multivariate Cox regression models. The index of concordance was used to directly compare the predictive ability of mBODE and its separate components. MEASUREMENTS AND MAIN RESULTS: The entire cohort (610 treated medically and 608 treated surgically) was characterized by severe airflow obstruction, moderate breathlessness, and increased mBODE at baseline. A wide distribution of change in mBODE was seen at follow-up. An increase in mBODE of more than 1 point was associated with increased mortality in surgically and medically treated patients. Surgically treated patients were less likely to experience death or an increase greater than 1 in mBODE. Indices of concordance showed that mBODE change predicted survival better than its separate components. CONCLUSIONS: The mBODE demonstrates short- and intermediate-term responsiveness to intervention in severe chronic obstructive pulmonary disease. Increase in mBODE of more than 1 point from baseline to 6, 12, and 24 months of follow-up was predictive of subsequent mortality. Change in mBODE may prove a good surrogate measure of survival in therapeutic trials in severe chronic obstructive pulmonary disease. Clinical trial registered with www.clinicaltrials.gov (NCT 00000606).

A randomized trial comparing lung-volume-reduction surgery with medical therapy for severe emphysema.

BACKGROUND: Lung-volume-reduction surgery has been proposed as a palliative treatment for severe emphysema. Effects on mortality, the magnitude and durability of benefits, and criteria for the selection of patients have not been established. METHODS: A total of 1218 patients with severe emphysema underwent pulmonary rehabilitation and were randomly assigned to undergo lung-volume-reduction surgery or to receive continued medical treatment. RESULTS: Overall mortality was 0.11 death per person-year in both treatment groups (risk ratio for death in the surgery group, 1.01; P=0.90). After 24 months, exercise capacity had improved by more than 10 W in 15 percent of the patients in the surgery group, as compared with 3 percent of patients in the medical-therapy group (P<0.001). With the exclusion of a subgroup of 140 patients at high risk for death from surgery according to an interim analysis, overall mortality in the surgery group was 0.09 death per person-year, as compared with 0.10 death per person-year in the medical-therapy group (risk ratio, 0.89; P=0.31); exercise capacity after 24 months had improved by more than 10 W in 16 percent of patients in the surgery group, as compared with 3 percent of patients in the medical-therapy group (P<0.001). Among patients with predominantly upper-lobe emphysema and low exercise capacity, mortality was lower in the surgery group than in the medical-therapy group (risk ratio for death, 0.47; P=0.005). Among patients with non-upper-lobe emphysema and high exercise capacity, mortality was higher in the surgery group than in the medical-therapy group (risk ratio, 2.06; P=0.02). CONCLUSIONS: Overall, lung-volume-reduction surgery increases the chance of improved exercise capacity but does not confer a survival advantage over medical therapy. It does yield a survival advantage for patients with both predominantly upper-lobe emphysema and low base-line exercise capacity. Patients previously reported to be at high risk and those with non-upper-lobe emphysema and high base-line exercise capacity are poor candidates for lung-volume-reduction surgery, because of increased mortality and negligible functional gain.

NHLBI viewpoint: Lung health and disease prevention research starting in childhood.

Lung health begins in utero when the complex structure of the airway, alveolar, and vascular structures are formed. To really impact the United States and global burden of chronic lung diseases in both adults and children, we must understand normal and abnormal development, the outcomes of disrupted development, and the effects of in utero and postnatal exposures on lung health. With increasing recognition of early life origins of adult diseases,(1) it is important to know what early events and interventions can alter the trajectory of lung development, growth, and decline to help promote lung health and reduce chronic lung disease.

A Decade of National Heart, Lung, and Blood Institute Programs Supporting COPD Research and Education .

The past decade of research in chronic obstructive pulmonary disease (COPD) has seen a new age of understanding both pathogenic mechanisms and clinical manifestations of the disease. The National Heart, Lung, and Blood Institute (NHLBI) has helped guide this progress with a series of initiatives to stimulate COPD research in various ways. These initiatives were designed to promote a precision medicine approach to treating COPD, one that takes advantage of targeting particular molecular pathways and the individual pathobiologies of the diversity of COPD patients. This review describes the strategic objectives of these initiatives, as well as some of their observed and anticipated outcomes. In addition, we address parallel steps NHLBI has taken to promote COPD awareness among the public. As we look toward the immediate future of COPD research and education, we see a time of great progress in terms of understanding and treatment. Furthermore, while this remains a debilitating and disturbingly prevalent disease, as NHLBI looks even farther ahead, we envision emerging efforts toward COPD prevention.

Strategic plan for pediatric respiratory diseases research: an NHLBI working group report.

The Division of Lung Diseases of the National Heart, Lung and Blood Institute (NHLBI) recently held a workshop to identify gaps in our understanding and treatment of childhood lung diseases and to define strategies to enhance translational research in this field. Leading experts with diverse experience in both laboratory and patient-oriented research reviewed selected areas of pediatric lung diseases, including perinatal programming and epigenetic influences; mechanisms of lung injury, repair, and regeneration; pulmonary vascular disease (PVD); sleep and control of breathing; and the application of novel translational methods to enhance personalized medicine. This report summarizes the proceedings of this workshop and provides recommendations for emphasis on targeted areas for future investigation. The priority areas identified for research in pediatric pulmonary diseases included: (1) epigenetic and environmental influences on lung development that program pediatric lung diseases, (2) injury, regeneration, and repair in the developing lung, (3) PVD in children, (4) development and adaptation of ventilatory responses to postnatal life, (5) nonatopic wheezing: aberrant large airway development or injury? (6) strategies to improve assessment, diagnosis, and treatment of pediatric respiratory diseases, and (7) predictive and personalized medicine for children.

The National Emphysema Treatment Trial (NETT): a study in agency collaboration.

The National Emphysema Treatment Trial (NETT) was a multicenter, randomized, controlled clinical trial, comparing the efficacy of lung volume reduction surgery (LVRS) plus medical management with rehabilitation to medical management with rehabilitation in 1,218 patients with severe emphysema. The NETT was a precedent-setting collaborative effort of three government agencies: the Centers for Medicare and Medicaid Services (CMS); the National Heart, Lung, and Blood Institute of the National Institutes of Health (NIH); and the Agency for Healthcare Research and Quality (AHRQ). NETT provided Medicare beneficiaries with controlled access to a promising but unproven procedure, while scientifically valid data on the efficacy and costs were collected to guide future use, coverage decisions, and policy. NETT demonstrates that collaboration among federal agencies and among health plans, researchers, and providers can successfully fulfill their differing missions simultaneously and is a productive approach to evaluating new treatments of mutual interest.

Sex differences in severe pulmonary emphysema.

RATIONALE: Limited data on sex differences in advanced COPD are available. OBJECTIVES: To compare male and female emphysema patients with severe disease. METHODS: One thousand fifty-three patients (38.8% female) evaluated for lung volume reduction surgery as part of the National Emphysema Treatment Trial were analyzed. MEASUREMENTS AND MAIN RESULTS: Detailed clinical, physiological, and radiological assessment, including quantitation of emphysema severity and distribution from helical chest computed tomography, was completed. In a subgroup (n = 101), airway size and thickness was determined by histological analyses of resected tissue. Women were younger and exhibited a lower body mass index (BMI), shorter smoking history, less severe airflow obstruction, lower Dl(co) and arterial Po(2), higher arterial Pco(2), shorter six-minute walk distance, and lower maximal wattage during oxygen-supplemented cycle ergometry. For a given FEV(1)% predicted, age, number of pack-years, and proportion of emphysema, women experienced greater dyspnea, higher modified BODE, more depression, lower SF-36 mental component score, and lower quality of well-being. Overall emphysema was less severe in women, with the difference from men most evident in the outer peel of the lung. Females had thicker small airway walls relative to luminal perimeters. CONCLUSIONS: In patients with severe COPD, women, relative to men, exhibit anatomically smaller airway lumens with disproportionately thicker airway walls, and emphysema that is less extensive and characterized by smaller hole size and less peripheral involvement.

Predictors of mortality in patients with emphysema and severe airflow obstruction.

PURPOSE: Limited data exist describing risk factors for mortality in patients having predominantly emphysema. SUBJECTS AND METHODS: A total of 609 patients with severe emphysema (ages 40-83 yr; 64.2% male) randomized to the medical therapy arm of the National Emphysema Treatment Trial formed the study group. Cox proportional hazards regression analysis was used to investigate risk factors for all-cause mortality. Risk factors examined included demographics, body mass index, physiologic data, quality of life, dyspnea, oxygen utilization, hemoglobin, smoking history, quantitative emphysema markers on computed tomography, and a modification of a recently described multifunctional index (modified BODE). RESULTS: Overall, high mortality was seen in this cohort (12.7 deaths per 100 person-years; 292 total deaths). In multivariate analyses, increasing age (p=0.001), oxygen utilization (p=0.04), lower total lung capacity % predicted (p=0.05), higher residual volume % predicted (p=0.04), lower maximal cardiopulmonary exercise testing workload (p=0.002), greater proportion of emphysema in the lower lung zone versus the upper lung zone (p=0.005), and lower upper-to-lower-lung perfusion ratio (p=0.007), and modified BODE (p=0.02) were predictive of mortality. FEV1 was a significant predictor of mortality in univariate analysis (p=0.005), but not in multivariate analysis (p=0.21). CONCLUSION: Although patients with advanced emphysema experience significant mortality, subgroups based on age, oxygen utilization, physiologic measures, exercise capacity, and emphysema distribution identify those at increased risk of death.

Challenges associated with estimating minimal clinically important differences in COPD-the NHLBI perspective.

Chronic Obstructive Pulmonary Disease (COPD) is a common lung disease that exemplifies the value, as well as the difficulties and challenges, of using minimal clinically important differences (MCID) in clinical research. Development and validation of better endpoints for clinical studies is critical to research progress in COPD. However, the clinical, genetic, and pharmacological heterogeneity of the COPD patient population complicates attempts to define and validate MCIDs for COPD. It is difficult to identify a single measurable outcome that reflects the many components of the COPD patient's health state. Acute exacerbations of symptoms, which COPD patients often experience, present another challenge in the development of MCIDs for this disease. Consequently, the NHLBI does not require the use of MCIDs in clinical research. This allows research on the causes, prevention and diagnosis of COPD and use of endpoints for which an MCID is not yet known. It is important for the scientific community to reach agreement on what is a meaningful MCID in therapeutic trials for COPD. Further research into the concept of the MCID and its application should enable therapeutic trials in COPD to yield knowledge that is more effectively translated into improved public health.

Effect of inhaled triamcinolone on the decline in pulmonary function in chronic obstructive pulmonary disease.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) results from a progressive decline in lung function, which is thought to be the consequence of airway inflammation. We hypothesized that antiinflammatory therapy with inhaled corticosteroids would slow this decline. METHODS: We enrolled 1116 persons with COPD whose forced expiratory volume in one second (FEV1) was 30 to 90 percent of the predicted value in a 10-center, placebo-controlled, randomized trial of inhaled triamcinolone acetonide administered at a dose of 600 microg twice daily. The primary outcome measure was the rate of decline in FEV1 after the administration of a bronchodilator. The secondary outcome measures included respiratory symptoms, use of health care services, and airway reactivity. In a substudy of 412 participants, we measured bone density in the lumbar spine and femur at base line and one and three years after the beginning of treatment. RESULTS: The mean duration of follow-up was 40 months. The rate of decline in the FEV1 after bronchodilator use was similar in the 559 participants in the triamcinolone group and the 557 participants in the placebo group (44.2+/-2.9 vs. 47.0+/-3.0 ml per year, P= 0.50). Members of the triamcinolone group had fewer respiratory symptoms during the course of the study (21.1 per 100 person-years vs. 28.2 per 100 person-years, P=0.005) and had fewer visits to a physician because of a respiratory illness (1.2 per 100 person-years vs. 2.1 per 100 person-years, P=0.03). Those taking triamcinolone also had lower airway reactivity in response to methacholine challenge at 9 months and 33 months (P=0.02 for both comparisons). After three years, the bone density of the lumbar spine and the femur was significantly lower in the triamcinolone group (P < or = 0.007). CONCLUSIONS: Inhaled triamcinolone does not slow the rate of decline in lung function in people with COPD, but it improves airway reactivity and respiratory symptoms and decreases the use of health care services for respiratory problems. These benefits should be weighed against the potential long-term adverse effects of triamcinolone on bone mineral density.

Clinical research in chronic obstructive pulmonary disease: needs and opportunities.

Chronic obstructive pulmonary disease (COPD) is a common condition, and one difficult to manage. Available treatments, other than smoking cessation, are only minimally effective, and the knowledge basis for clinical decision making is limited. To identify areas in which further clinical research may lead to significant improvements in the care of patients with COPD, the National Heart, Lung, and Blood Institute convened a Working Group, entitled "Clinical Research in COPD: Needs and Opportunities," on March 21-22, 2002. This group of experts identified important questions in the field and made the following recommendations: (1) establish a multicenter Clinical Research Network to perform multiple, short-term clinical trials of treatments in patients with moderate-to-severe COPD; (2) create a system for the standardized collection, processing, and distribution of lung tissue specimens and associated clinical and laboratory data; (3) develop standards for the classification and staging of COPD; (4) characterize the development and progression of COPD using measures and biomarkers that relate to current concepts of pathogenesis; and (5) evaluate indications for long-term oxygen therapy for patients with COPD.

Patients at high risk of death after lung-volume-reduction surgery.

BACKGROUND: Lung-volume-reduction surgery is a proposed treatment for emphysema, but optimal selection criteria have not been defined. The National Emphysema Treatment Trial is a randomized, multicenter clinical trial comparing lung-volume-reduction surgery with medical treatment. METHODS: After evaluation and pulmonary rehabilitation, we randomly assigned patients to undergo lung-volume-reduction surgery or receive medical treatment. Outcomes were monitored by an independent data and safety monitoring board. RESULTS: A total of 1033 patients had been randomized by June 2001. For 69 patients who had a forced expiratory volume in one second (FEV1) that was no more than 20 percent of their predicted value and either a homogeneous distribution of emphysema on computed tomography or a carbon monoxide diffusing capacity that was no more than 20 percent of their predicted value, the 30-day mortality rate after surgery was 16 percent (95 percent confidence interval, 8.2 to 26.7 percent), as compared with a rate of 0 percent among 70 medically treated patients (P<0.001). Among these high-risk patients, the overall mortality rate was higher in surgical patients than medical patients (0.43 deaths per person-year vs. 0.11 deaths per person-year; relative risk, 3.9; 95 percent confidence interval, 1.9 to 9.0). As compared with medically treated patients, survivors of surgery had small improvements at six months in the maximal workload (P= 0.06), the distance walked in six minutes (P=0.03), and FEV1 (P<0.001), but a similar health-related quality of life. The results of the analysis of functional outcomes for all patients, which accounted for deaths and missing data, did not favor either treatment. CONCLUSIONS: Caution is warranted in the use of lung-volume-reduction surgery in patients with emphysema who have a low FEV1 and either homogeneous emphysema or a very low carbon monoxide diffusing capacity. These patients are at high risk for death after surgery and also are unlikely to benefit from the surgery.

Loss of bone density with inhaled triamcinolone in Lung Health Study II.

Inhaled glucocorticosteroids (ICS) are commonly prescribed for chronic obstructive pulmonary disease. No adverse effect on bone mineral density (BMD) has been proven. In a randomized double-blind, placebo-controlled trial at seven centers in North America, we recruited 412 current smokers or recent quitters with mild to moderate chronic obstructive pulmonary disease. They used inhaled triamcinolone acetonide, 600 mcg, or placebo, twice daily. We measured femoral neck and lumbar spine BMD at baseline and after 1 and 3 years, and serum osteocalcin at baseline, 3 months, 1 year, and 3 years. After 3 years, BMD at the femoral neck decreased 1.78% more with ICS than with placebo (p < 0.001). More participants in the ICS group experienced 6% or more loss of femoral neck BMD (p = 0.002). Lumbar spine BMD increased in the placebo group by 0.98% but decreased by 0.35% in the ICS group (a difference of 1.33%, p = 0.007). Changes in osteocalcin did not correlate with changes in BMD. Fractures, lost height, or osteoporosis diagnoses were not increased among ICS users compared with placebo users. In summary, the use of inhaled triamcinolone acetonide was associated with loss of BMD at the femoral neck and lumbar spine after 3 years of treatment.