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.

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.

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.

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.

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.