Future Research Directions in Chronic Obstructive Pulmonary

Disease
Published in Am J Respir Crit Care Med Vol 165. pp 838 -844, 2002 Internet address:
www.atsjournals.org
THOMAS L. CROXTON, GAIL G. WEINMANN, ROBERT M. SENIOR, and JOHN R. HOIDAL

Division of Lung Diseases, National Heart, Lung, and Blood Institute, Bethesda,
Maryland; Division of Pulmonary and Critical Care Medicine, Department of Medicine,
Barnes-Jewish Hospital, St. Louis, Missouri; and Department of Medicine, University of
Utah Medical Center, Salt Lake City, Utah
Between 3 and 7 million Americans are currently diagnosed with chronic obstructive
pulmonary disease (COPD), and the true prevalence is probably greater than 16 million
(1). Many of these individuals suffer years of progressive discomfort and disability. With
the number of deaths per year attributed to this disease at approximately 100,000 and
increasing, COPD is now the fourth leading cause of death in this country (2) and is
expected to be third by the year 2020. Cigarette smoking is firmly established as the
major cause of COPD, but approximately one-quarter of Americans continue to smoke,
despite aggressive smoking prevention and cessation efforts. Better means are clearly
needed for the prevention and treatment of COPD, and more scientific research is
needed to enable improvements in its clinical management.
Unfortunately, research progress in this field has been slow. Most basic scientific
research over the past 35 years has focused on the pathogenetic roles of cigarette
smoke, inflammation, and protease/antiprotease balance, based on the association of
COPD with cigarette smoking and the early discovery that a subgroup of patients with
emphysema is genetically deficient in an inhibitor of a neutrophil protease (3). Although
the cigarette-inflammation-protease theory captures key features of COPD
epidemiology and pathology, this approach has not yet led to a reduction in COPD
prevalence or morbidity, to the development of any therapy proven to modify the
disease process itself, or to an adequate understanding of how risk factors other than
cigarette smoking may contribute to COPD pathogenesis.
However, there are encouraging indications for future COPD research. Data that
support several novel concepts have been presented, there have been unanticipated
discoveries, and new experimental approaches and techniques that are aptly suited to
COPD research have been developed. Furthermore, elucidation of cellular pathways
that are critically involved in COPD pathogenesis may lead rapidly to clinical trials of
potential therapeutics, given the improving capabilities of the pharmaceutical industry
for development of mechanism-specific drugs.
Because of the enormous public health burden imposed by COPD and the urgent need
for research progress in this area, the National Heart, Lung, and Blood Institute (NHLBI,
Bethesda, MD) convened a Working Group to discuss potential directions for future
investigations. This group was charged with evaluating the current state of knowledge,

identifying critical gaps in our knowledge, and understanding, recognizing the most
promising opportunities, and developing specific recommendations to be used by the
NHLBI in planning its promotion of future COPD research. This article is a summary of
that Working Group meeting. Specific recommendations for future research directions in
COPD follow a discussion of several intriguing clinical and epidemiological
characteristics of COPD that must be accounted for in a more complete theory of
disease pathogenesis and a review of research advances that may foreshadow
important new areas of investigation.
ENIGMA OF COPD PATHOGENESIS
COPD is a collection of conditions, including emphysema and chronic obstructive
bronchitis, which are characterized by persistent airflow limitation that is not
substantially reversed by bronchodilators. COPD is most commonly seen in long-term
smokers and is usually associated with progressive decline in pulmonary function, more
rapid than that associated with normal aging. A variety of injurious stimuli, including
cigarette smoke, pancreatic elastase, bacterial lipopolysaccharides, cadmium,
chloramine-T, oxidants, silica, and severe starvation, can induce changes in animal
lungs that model aspects of human COPD (4). Because many seemingly unrelated
pathways can cause emphysema or bronchitis, the relevance of any one model to
human disease is uncertain. Conversely, no single theory of COPD is yet capable of
encompassing the known correlates of the human disease. Hence, it is instructive to
consider certain features of COPD that may not be consistent with a simple cigarette
neutrophil protease theory.
Variation in Susceptibility to COPD and Disease Progression
Cigarette smoking is by far the most important causative factor for COPD; and in
population studies the amount of smoking correlates with loss of lung function.
Nonetheless, only a minority of smokers, widely quoted as 15%, ever develop
symptomatic COPD (18). Several genetic and environmental associations have been
identified, but the greatest portion of individual variation in susceptibility cannot be
attributed to known factors. Understanding why only certain smokers develop COPD is
important not only for understanding the true mechanisms of disease development, but
also because such knowledge might allow targeting of intensive smoking interventions
to individuals at highest risk and might enhance the effectiveness of those interventions.
Even among those with COPD, the rate of decline in FEV1 can vary from apparently
normal values to greater than 150 ml/year, despite similar smoking histories and levels
of initial FEV1 (19). Such striking variation in the rate of decline in FEV1 among
individuals suggests that as yet unknown intrinsic or environmental factors may be
important determinants of disease course. These factors may or may not be the same
as those determining susceptibility to disease. There is also remarkable unexplained
variation in the manifestations of COPD with regard to the severity of bronchitic
symptoms, the extent of emphysema, and the distribution of emphysematous changes
in the lung (centrilobular vs. panlobular patterns).

Other Lung Diseases Associated with Cigarette Smoking

Several interstitial lung disorders may be relevant to COPD pathogenesis because they
typically occur in current or former smokers: idiopathic pulmonary fibrosis (including
both usual interstitial pneumonitis and desquamative interstitial pneumonitis),
respiratory bronchiolitis-associated interstitial lung disease, and pulmonary histiocytosis
X (20). Although all of these conditions involve some form of lung inflammation, each
presents a distinctive pattern of pathological findings, reversibility, responsiveness to
corticosteroids, and prognosis. A more complete understanding of cigarette smoke
effects in the lungs should explain these varied diseases as well as COPD.
NEW RESULTS, CONCEPTS, AND OPPORTUNITIES IN COPD RESEARCH
COPD researchers have presented a number of unexpected results, novel ideas, and
promising approaches for further research. This section briefly describes some
innovative concepts identified by the Working Group that may prove important in COPD
pathogenesis and some more recent methodological advances that will likely be of
value to research in this field.
RECOMMENDATIONS FOR FUTURE RESEARCH
There was consensus among members of the Working Group that the following
objectives are important to COPD research and are feasible within approximately five
years. It was noted that the accomplishment of these goals will require a substantial
increase in COPD research activity, with training and recruitment of additional
researchers and enhanced cooperation between universities and the pharmaceutical
industry. In many cases, the need has long been recognized, but the opportunity to
accomplish the research has come about as a result of the development of new
experimental tools and techniques.