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COPD 2009: Assessment of the current state-of-the-art for basic and clinical research and shaping the future

Executive Summary

Purpose

The National Heart, Lung, and Blood Institute convened a meeting of investigators on June 29-30, 2009 in Bethesda, Maryland. The purpose was to discuss potential new therapeutic interventions in COPD that may improve disease progression, survival and patient quality of life. New basic research findings in disease pathogenesis were analyzed for their translational potential. Clinical research findings were assessed for their possible implications for mechanistic understanding of disease pathogenesis and progression including poly-morbidities. The group identified research needs and formulated research recommendations to foster rapid advancement in disease preemption and personalized therapy.

In the seven years since the last NHLBI workshop that broadly assessed basic and clinical research in COPD and formulated research recommendations, NHLBI has implemented a number of initiatives ranging from studies of basic mechanisms to trials of therapies. During this period, there has been substantial progress in COPD research. Studies have significantly advanced pathogenetic understanding of the disease, demonstrated effectiveness of treatments, expanded the intellectual and practical resources of the scientific community, and identified a wide range of potential therapeutic targets. Notwithstanding the enormous progress accomplished in basic and clinical research, COPD remains the fourth leading cause of death in this country and is projected to be the third by 2020. This burden of disease is paralleled by an extraordinary economic toll in direct and indirect costs to our society. The most basic questions remain unanswered and were addressed by the group: Why does 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 can they be modulated therapeutically? Why does the disease continue to progress even after smoking cessation? How can the lung injury of COPD be reversed? In addition, new questions of great importance have emerged. What is the relevance to human disease of the new pathways identified? What is the value of current animal models? What is the validity of the current phenotypic measures and their role in guiding clinical practices? Is there value in early diagnosis and treatment? What is the origin of co-morbid conditions and how are these best managed? Does the combined pharmacological-physical-nutritional-psychological intervention have a role in the management of the disease? What new therapeutic strategies should be tested? Which are the best approaches to interventions in a community setting? These represent the topics that were addressed at the meeting in order to help NHLBI to make informed decisions on how to prioritize research in the next phase of the fight against COPD.

Recommendations:

Several specific recommendations to NHLBI on priorities for future research directions were generated by the Working Group:

  1. Investigate the molecular pathogenesis of the chronic aspects of the disease, understanding in particular the pathogenesis and impact of airway remodeling and mucous production. Study the acute phases of COPD, investigating, over the range of severity, the pathogenesis, the associated markers and the response to available treatments. Investigate the molecular pathogenesis of the non-pulmonary manifestations of COPD (i.e. CVD and lung cancer).
  2. Study the association of clinical phenotypes to specific imaging, to non-pulmonary variables, to determined clinical profiles (e.g., exacerbations), and to composite variables in order to reach a better patient stratification. This will enhance early disease diagnosis and monitoring of disease activity or progression. Utilize treatment responder analyses to aid effectiveness determination and patient subtype classification.
  3. In clinical trials consider choosing among multiple endpoints like patient reported outcomes, biomarkers or surrogate endpoints, mortality in high-risk groups (e.g., hospitalized COPD, NETT high risk group, etc.). Perform clinical trials with more than one endpoint in a network or a consortium setting and do multiple trials simultaneously to maximize patient recruitment and resources utilization.
  4. Standardize the collection and storage of specimens across studies, promoting the storage of samples that could be used for gene expression, proteomic and microbiome analyses.
  5. Improve communication and collaboration among investigators funded by different initiatives. Embed funding in each initiative to provide resources that enhance collaboration between basic science and clinical trials. Report more frequently to medical and lay communities of progress made in COPD scientific endeavors.
  6. Develop and fund COPD prevention and treatment effectiveness studies and the use of implementation science. Create a consortium of patient support groups and insurers to foster patient registries for clinical research.
  7. Set up a process to establish support for novel drug development and to do preclinical work for novel molecules discovery. The information gathered would enhance and stimulate Phase I-III trials.
  8. Develop new animal models to study COPD in general and exacerbations in particular.
  9. Study the role and application of induced pluripotent stem cells in COPD pathogenesis and therapy.

Workshop Members


Chairs

  • Rubin M. Tuder, M.D., University of Colorado School of Medicine, Aurora, CO
  • Gerard J. Criner, M.D., Temple Lung Center, Philadelphia, PA

Members

  • R. Graham Barr, M.D., Dr.P.H., Columbia University, New York, NY
  • Badrul A. Chowdhury, M.D., CDER, FDA, Silver Spring, MD
  • Janet B. Croft, Ph.D., Centers for Disease Control and Prevention, Atlanta GA
  • Ronald G. Crystal, M.D., Weill Cornell Medical College, New York, NY
  • Jeanine D’Armiento, M.D., Ph.D., Columbia University, New York, NY
  • Mark T. Dransfield, M.D., University of Alabama at Birmingham, Birmingham, AL
  • Jack A. Elias, M.D., Yale University, New Haven, CT
  • MeiLan K. Han, M.D., M.S., University of Michigan, Ann Arbor, MI
  • James C. Hogg, M.D., iCAPTURE Center, Vancouver, BC
  • Michael J. Holtzman, M.D., Washington University, St. Louis, MO
  • Jerry A. Krishnan, M.D., Ph.D., University of Chicago, Chicago, IL
  • Barry J. Make, M.D., University of Colorado, Denver, CO
  • Fernando J. Martinez, M.D., M.S., University of Michigan, Ann Arbor, MI
  • Irina Petrache, M.D., Indiana University, Indianapolis, IN
  • Stephen I. Rennard, M.D., University of Nebraska, Omaha, NE
  • Frank C. Sciurba, M.D., FCCP, University of Pittsburgh, Pittsburgh, PA
  • Edwin K. Silverman, M.D., Ph.D., Harvard Medical School, Boston, MA
  • Avrum Spira, M.D., M.Sc., Boston University, Boston, MA
  • Yohannes Tesfaigzi, Ph.D., Lovelace Respiratory Research Institute, Albuquerque, NM
  • Christine H. Wendt, M.D., University of Minnesota, Minneapolis, MN

NHLBI Staff

  • Antonello Punturieri, M.D., Ph.D., Division of Lung Diseases
  • Thomas Croxton, Ph.D., M.D., Division of Lung Diseases

Last Updated June 2011

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