Gail Weinmann

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.

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).

Eosinophil and T cell markers predict functional decline in COPD patients

BackgroundThe major marker utilized to monitor COPD patients is forced expiratory volume in one second (FEV1). However, asingle 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.MethodsBaseline 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 (ΔFEV1 % predicted = 4.7 ± 7.2; N = 34) were retrospectively compared with study participants who experienced a rapid decline in lung function (ΔFEV1 % 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 DiscussionStable 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).ConclusionThese 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.

Chronic obstructive pulmonary disease: a view from the NHLBI.

The past decade has witnessed great progress in chronic obstructive pulmonary disease (COPD) research. New drugs have been developed and tested, indications for lung volume reduction surgery (LVRS) have been determined, and a growing base of scientific evidence now documents the efficacy of various therapies for symptoms and exacerbations. This advance in knowledge shatters the old conception of COPD as a hopelessly untreatable condition (1–4). It is clear that many patients with COPD can benefit from aggressive management, with a decrease in the frequency of hospitalizations and improvements in quality of life and survival. In addition, basic and clinical scientists have now identified cells, mechanisms, and molecules that appear to play key roles in disease pathogenesis. Additional novel treatments are on the horizon. The good news about COPD is getting out as many organizations are working effectively to increase awareness of the disease (5). Despite advances in care, the COPD epidemic persists, causing more than 120,000 deaths per year in the United States alone. COPDs position as the fourth leading cause of death in the United States is ominous and the probability of the number of cases rising even further is disturbing. Population-based surveys show that as many as 24 million people in the United States have airflow limitation consistent with COPD and that half or more of these cases have not yet been diagnosed (6). Despite the availability of effective treatments for COPD, no existing therapy halts or reverses the progressive and accelerated decline in lung function that is characteristic of this condition. We are far from having a cure for COPD, and in fact, the most basic questions about this disease remain unanswered: Why do only a minority of smokers develop clinically significant COPD? Why is there great heterogeneity in the presentation of COPD? Which pathogenetic pathways are critical, and how can they be modulated therapeutically? Why does the disease continue to progress even after smoking cessation? How can the lung injury that characterizes COPD be reversed? Better means of preventing and treating COPD are urgently needed, but it is not entirely clear what studies should be done. The strategic decisions in COPD research—which investigative approaches to use, which hypotheses to test, which pathways to explore in detail, which basic findings to translate into human studies, and which therapeutic targets to test—are perhaps more difficult to make now than ever before. As opportunities for investigation in COPD have expanded, the pulmonary communitys task of choosing the most effective directions and approaches for COPD research has become even more complex, and wise choices are critical to secure future success. In this essay, we encourage the pulmonary medical community to think about needs, opportunities, and the most productive approaches for research in COPD. We summarize new research directions and findings, how the disease itself is evolving, what research activities are currently underway, and how the infrastructure and organization of the research enterprise in the United States is adapting to new biological and technological challenges and advances that offer unprecedented opportunities for COPD research. We close with a call to action that presses the pulmonary community to widen its horizons and build interdisciplinary teams to better confront the problems of COPD.

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 patients 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.

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.