The Proceedings of the American Thoracic Society 1:71-72 (2004)
© 2004 The American Thoracic Society
Introduction
Stephen I. Rennard and
Paul M. O'Byrne
University of Nebraska Medical Center, Omaha, Nebraska; and Firestone Institute for Respiratory Health, Hamilton, Ontario, Canada
Correspondence and requests for reprints should be addressed to Stephen I. Rennard, M.D., University of Nebraska Medical Center, 985885 Nebraska Medical Center, Omaha, NE 68198–5885. E-mail: srennard{at}unmc.edu
Over the past 20 years, it has become practice to treat hospitalized COPD exacerbation patients with corticosteroids. The rationale for this practice is not entirely clear, but the reasoning may have been that what is good for the treatment of an asthma attack may also work for COPD exacerbations. (1)
This sentiment arguably applies, even nowadays, to the not uncommon view in respiratory medicine that chronic obstructive pulmonary disease (COPD) is a poor second cousin of asthma. COPD has often been misdiagnosed as asthma, and its therapy continues to be provided by drugs that, by and large, were developed for asthma: that is, oral and inhaled corticosteroids and inhaled bronchodilators such as ß2-adrenoceptor agonists and muscarinic receptor antagonists (2) (see Buhl and Farmer in the present volume). Furthermore, it is reasonable to say that in the field of respiratory disorders, until less than 10 years ago, the primary foci of academic research and the pharmaceutical industry were in asthma, both from the perspectives of elucidating the underlying disease mechanisms, as well as in pursuing new drug targets for its treatment. In contrast, during the same period, COPD was virtually ignored by most pharmaceutical companies and basic researchers alike as an attractive disease "target," likely as a result of several factors. These include (1) a conviction that COPD is "self-inflicted" as a result of a lifestyle choice to smoke, (2) its pathophysiology is very poorly understood, (3) there was (and is) justified concern, at least in the industry, that clinically meaningful endpoints for drug registration are poorly classified, and (4) because COPD is a slowly progressive disease, clinical trials can be protracted and, consequently, may be prohibitively expensive. In the case of exacerbation of COPD, the definition(s), cause(s), measurement endpoint(s), and therapy are equally unclear and controversial.
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DEFINITIONS OF EXACERBATION
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Although there is no commonly agreed specific definition of what constitutes an exacerbation of COPD, most investigators use some measure(s) of increased symptoms. Such can vary from relatively mild to severe, leading to a requirement for increased therapy, hospitalization, and even death from acute respiratory failure. Exacerbations in COPD probably are heterogeneous, the nature of how they manifest varying with the level of underlying disease severity as well as the initiating stimulus of the exacerbation. Such stimuli can include viral or bacterial infection, pollution, physical stress, and other unknown factors. In asthma, the term "exacerbation" is often used to define an "attack" that is relatively more severe, often rapidly life threatening, and/or prolonged than the "everyday" episodes of wheezing, dyspnea, cough, and other symptoms in many patients with asthma despite "effective" maintenance therapy (2). In particular, life-threatening exacerbations are common and frequent in those patients with a history of severe, persistent asthma, many of whom are children. Such exacerbations occur with disquieting frequency despite aggressive therapy with high-dose oral and inhaled corticosteroids. The etiology of such exacerbation in severe asthma is still unclear (3). Indeed, a recent study in small numbers of children with asthma experiencing severe exacerbation reported little evidence of ongoing inflammation, likely as a consequence of steroid therapy, and even relatively normal lung function (4).
Although relatively few asthma exacerbations result in the death of the patient as compared with COPD, the numbers of deaths annually due to acute exacerbation in asthma and COPD remain alarmingly high (5, 6). Clearly, therefore, there remain significant unmet medical needs as well as poor understanding of the etiology, pathophysiology, and management of exacerbation in these chronic respiratory disorders (7).
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DRUG THERAPY OF EXACERBATIONS
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Although the etiology and pathophysiology of asthma are probably better understood than in COPD and despite all of the basic research activities therein over the years, the mainstays in the therapy of asthma are still inhaled bronchodilators, particularly ß2-adrenoceptor agonists, and the inhaled corticosteroids, which have multiple clinically beneficial effects on the inflammation of the airways in this disease. In addition, daily oral corticosteroids are often prescribed to patients with moderate to severe asthma. Recent years have witnessed and welcomed the development of long-acting ß2-agonist bronchodilators, greatly increasing convenience and disease control for patients. Also, the introduction of therapy consisting of the simultaneous administration of an inhaled corticosteroid and long-acting ß2-agonist in combination is yielding unmistakably additional benefits in treating asthma.
Regardless, in the last 30 years or so of scientific investigation, the only new drugs that have become available therapy for asthma patients are the orally active antileukotriene agents such as leukotriene D4 receptor antagonists and an injectable anti-IgE antibody, omalizumab, which was approved for human use in severe asthma in 2003 (8). Drugs used as therapy for exacerbation of asthma are essentially the same, although systemic corticosteroids and supplemental oxygen are recommended when required. Despite their side effects and questionable efficacy, methylxanthines such as theophylline are still administered by many physicians. Furthermore, the therapy of exacerbations of asthma and COPD is remarkably similar, likely reflecting in part the lack of understanding of underlying mechanisms and the limited pharmaceutical options available. The only "new" therapies in recent years for COPD are virtually the same as those described previously here for asthma: the long-acting ß2-agonist and anticholinergic bronchodilators, inhaled and oral corticosteroids, and combinations either of a short-acting ß2-agonist and an anticholinergic or of an inhaled corticosteroid and long-acting ß2-agonist. Encouragingly, several clinical studies have now indicated that inhaled corticosteroids, alone or in combination with a long-acting ß2-agonist, effectively reduce the frequency and severity of exacerbations in both asthma and COPD. These and other studies are discussed in more detail in this supplement, respectively, by Paul O'Byrne and Peter Calverley.
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AIMS OF THE SYMPOSIUM
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The goal of biomedical research, ultimately, is an increased understanding of the pathophysiology and the biochemical mechanisms underlying disease such that better drug therapies can be discovered and made available to patients. In potentially lethal and distressing conditions such as exacerbations of COPD and asthma, this goal is of pressing importance.
This supplement gathers articles that summarize the presentations at the third AstraZeneca annual COPD Symposium in April 2003 in Lund, Sweden, the first being held in 2001 (9, 10). The editors wish to specifically thank Dr. Stephen Farmer and Dr. Bertil Lindmark of AstraZeneca who provided sponsorship and logistical support while encouraging free scientific interchange without concern for commercial issues. In this context, the diverse etiology and pathophysiology of exacerbations in COPD and asthma are reviewed, compared, and contrasted. Although there are differences, there are also similarities, not only in etiology and mechanisms, but also in nosologic factors, as the definition, classification, and measurement of exacerbations are problematic in both disorders. Both the acute therapeutic management and prevention of exacerbations are increasingly recognized as important goals. The symposium reviewed our current knowledge of exacerbations and addressed key questions about definitions and basic biological mechanisms that must be answered before the problems posed can be tackled effectively by researchers and clinicians alike.
The future development of truly effective therapies for exacerbation of asthma and COPD will depend on a better comprehension of the underlying causes (microorganisms, pollution, genetic predisposition). In addition, an improved appreciation of how best to define exacerbations in COPD and asthma, including the desirable clinical and surrogate endpoints to achieve with therapy, is desirable. This symposium provided an open forum for discussion, often heated but entertaining debate and scientific collaboration.
(Received in original form August 24, 2003; accepted in final form December 11, 2003)
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REFERENCES
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DEFINITIONS OF EXACERBATION
DRUG THERAPY OF EXACERBATIONS
