In patients with COPD, an acute worsening of respiratory symptoms is often described as an exacerbation. Exacerbations are associated with a significant increase in mortality, hospitalization, and health-care utilization, but there is currently no widely accepted definition of what constitutes an exacerbation of COPD. This paper summarizes the discussions of the workshop, "COPD: Working Towards a Greater Understanding," in which the participants proposed the following working definition of an exacerbation of COPD: a sustained worsening of the patient's condition, from the stable state and beyond normal day-to-day variations, that is acute in onset and necessitates a change in regular medication in a patient with underlying COPD.

Air pollution as a trigger for exacerbations of COPD has been recognized for > 50 years, and has led to the development of air quality standards in many countries that substantially decreased the levels of air pollutants derived from the burning of fossil fuels, such as black smoke and sulfur dioxide. However, the recent dramatic increase in motor vehicle traffic has produced a relative increase in the levels of newer pollutants, such as ozone and fine-particulate air pollution < 10 microm in diameter. Numerous epidemiologic studies have shown associations between the levels of these air pollutants and adverse health effects, such as exacerbations of airways diseases and even deaths from respiratory and cardiovascular causes. Elucidation of the mechanism of the harmful effects of these pollutants should allow improved risk assessment for patients with airways diseases who are be susceptible to the effects of these air pollutants.

A common feature of COPD and other chronic lung diseases is hypersecretion of mucus into the airways, causing peripheral airway plugging and further airflow obstruction. The mucus is secreted by goblet cells, which are present in excessive numbers in COPD. This review describes how neutrophils in the airways of COPD patients stimulate the goblet cells to secrete their products. Recent findings on the mechanisms of neutrophil stimulation of goblet cell degranulation are discussed. These implicate the proteolytic enzyme elastase and cell surface adhesion molecules, and provide a basis for the investigation of potential novel therapies.

Infectious agents are a major cause of acute exacerbations of chronic bronchitis (AECB) and COPD. Several respiratory viruses are associated with 30% of exacerbations, with or without a superimposed bacterial infection. Atypical bacteria, mostly Chlamydia pneumoniae, have been implicated in < 10% of AECB. The role of bacterial pathogens when isolated from the respiratory tract during AECB has become better defined by application of several newer investigative techniques. Bacterial pathogens can be isolated in significant concentrations from distal airways in 50% of AECB. Specific immune responses to surface exposed antigens of the infecting pathogen have been shown to develop after an exacerbation. Emerging evidence from molecular epidemiology and measurement of airway inflammation further support the role of bacteria in AECB. When properly defined, 80% of AECB are likely to be infectious in origin.

A renewed interest in the clinical and pathogenic aspects of COPD exacerbation is timely in view of national and global COPD initiatives. The three big problems regarding COPD continue to be the following: prevention of the disease; slowing progression of the disease once diagnosis has been established; and prevention and more effective treatment of the so-called exacerbation. The following assessment will raise more questions than answers and will review some of the past and current concepts and contexts.

COPD is a major cause of mortality and a significant drain on health-care resources but is widely underdiagnosed in the primary-care setting. There is an urgent need to raise the profile of the disease among both primary-care physicians and patients. At the workshop "COPD: Working Towards a Greater Understanding," a panel of COPD experts from Europe and the United States discussed ways in which awareness of COPD could be raised. Access to spirometry, and education in its use and relevance, was identified as a major goal for primary-care physicians. Simple questionnaires can promote patient awareness and provide feedback to physicians. COPD needs to be identified as not just a disease of smokers.

The compelling evidence for the increasing economic and social burden of COPD, resulting from its rising prevalence and significant morbidity, has been reviewed in other sections of this supplement. The impact of this disease within the United States and globally is projected to increase irrespective of short-term medical action, but developing successful strategies to identify the illness and reduce its impact is essential if this growing problem is to be managed successfully. In this article, some of the important concepts relevant to this process are considered, and some of the present techniques used to intervene in established COPD are reviewed.

Cessation of cigarette smoking is the single most important therapeutic intervention that is effective in reducing the symptoms of COPD and in preventing its onset. Smoking cessation is, therefore, a major goal in efforts to mitigate the burden of this disease. This review will consider the pharmacologic and behavioral therapies that have been used to assist smokers in overcoming their addiction. These strategies assist a significant minority of smokers to stop smoking and, thus, they can have an important positive impact on COPD as well as on other health outcomes.

COPD is the only leading cause of death that is increasing in prevalence worldwide. The lack of international standardization in the diagnosis of COPD means that intercountry comparisons are difficult. This review highlights the Global Initiative for Obstructive Lung Disease, a program aimed at focusing attention on the importance of COPD as a global health problem, and designing and implementing consistent international strategies for effective prevention, diagnosis, and treatment.

In 1995, the European Respiratory Society published a European Consensus Statement on the optimal assessment and management of COPD. In the document, several important areas for future research are identified that may help to increase knowledge of the current situation of COPD within Europe; these include pathophysiology, epidemiology, and the clinical benefits of treatment. This article reviews a selection of important data that have become available since the consensus statement was published, with a specific focus on epidemiology and treatment.

COPD is a common disease that is often not diagnosed in the primary-care setting. This review highlights the findings of studies ranging from the early 1960s to the third National Health and Nutrition Examination Survey (NHANES III) study, undertaken to try and accurately estimate the prevalence of COPD in the US population. Results of the NHANES III indicate that COPD remains frequently underdiagnosed, and that spirometry should be more widely used in the primary-care setting to identify asymptomatic disease. Early intervention, in particular smoking cessation, could alter the course and outcome of disease in patients with COPD.

Oxidative stress results from an oxidant/antioxidant imbalance, an excess of oxidants and/or a depletion of antioxidants. Oxidative stress is thought to play an important role in the pathogenesis of a number of lung diseases, not only through direct injurious effects, but by involvement in the molecular mechanisms that control lung inflammation. A number of studies have shown an increased oxidant burden and consequently increased markers of oxidative stress in the airspaces, breath, blood, and urine in smokers and in patients with COPD. The presence of oxidative stress has important consequences for the pathogenesis of COPD. These include oxidative inactivation of antiproteinases, airspace epithelial injury, increased sequestration of neutrophils in the pulmonary microvasculature, and gene expression of proinflammatory mediators. With regard to the latter, oxidative stress has a role in enhancing the inflammation that occurs in smokers and patients with COPD, through the activation of redox-sensitive transcriptions factors such as nuclear factor-kappaB and activator protein-1, which regulate the genes for proinflammatory mediators and protective antioxidant gene expression. The sources of the increased oxidative stress in patients with COPD are derived from the increased burden of oxidants present in cigarette smoke, or from the increased amounts of reactive oxygen species released from leukocytes, both in the airspaces and in the blood. Antioxidant depletion or deficiency in antioxidants may contribute to oxidative stress. The development of airflow limitation is related to dietary deficiency of antioxidants, and hence dietary supplementation may be a beneficial therapeutic intervention in this condition. Antioxidants that have good bioavailability or molecules that have antioxidant enzyme activity may be therapies that not only protect against the direct injurious effects of oxidants, but may fundamentally alter the inflammatory events that play an important part in the pathogenesis of COPD.

Bacterial infection of the lower respiratory tract can impact on the etiology, pathogenesis, and the clinical course of COPD in several ways. Several recent cohort studies suggest that lung growth is impaired by childhood lower respiratory tract infection, making these individuals more vulnerable to developing COPD on exposure to additional injurious agents. Impairment of mucociliary clearance and local immune defense in smokers allows bacterial pathogens to gain a foothold in the lower respiratory tract. These pathogens and their products can cause further impairment of mucociliary clearance due to enhanced mucus secretion, disruption of normal ciliary activity, and airway epithelial injury, and thus persist in the lower respiratory tract. This chronic colonization of the lower respiratory tract by bacterial pathogens could induce a chronic inflammatory response with lung damage. Nontypeable Haemophilus influenzae, usually regarded as an extracellular mucosal pathogen, has been demonstrated to cause intracellular infections of the upper and lower respiratory tract respiratory tissue. Increased incidence of chronic Chlamydia pneumoniae infection of the respiratory tract has been associated with COPD. These chronic infections of respiratory tissues could contribute to the pathogenesis of COPD by altering the host response to cigarette smoke or by inducing a chronic inflammatory response. Application of newer molecular and immunologic research techniques is helping us define precisely the role of bacterial infection in COPD.

Few effective therapies exist for patients with COPD. Rehabilitative therapy aimed at curing dysfunction of the peripheral muscles may be an appropriate addition to this short list. This review does the following: (1) presents evidence that skeletal muscle dysfunction is present in COPD patients; (2) considers the mechanisms of this dysfunction; (3) describes the role of exercise training in correcting this disorder; and (4) speculates that anabolic hormone supplementation may find a place in COPD therapy. Further research will be necessary to refine these concepts.