The Proceedings of the American Thoracic Society 2:361-366 (2005)
© 2005 The American Thoracic Society
Mechanisms and Experimental Models of Chronic Obstructive Pulmonary Disease Exacerbations
Patrick Mallia and
Sebastian L. Johnston
Department of Respiratory Medicine, National Heart and Lung Institute, Imperial College London, London, United Kingdom
Correspondence and requests for reprints should be addressed to Sebastian L. Johnston, M.B., B.S., Ph.D., F.R.C.P., Department of Respiratory Medicine, National Heart and Lung Institute, Imperial College London, Norfolk Place, London W2 1PG, UK. E-mail: s.johnston{at}ic.ac.uk
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ABSTRACT
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Exacerbations of chronic obstructive pulmonary disease (COPD) are a major cause of morbidity, mortality, and rising health care costs. In addition, they are associated with an accelerated loss of lung function and thus have a direct effect on disease progression. There are few studies examining the cellular and molecular mechanisms of COPD exacerbations. Exacerbations are linked to increased airway inflammation and oxidative stress, but many questions remain unanswered regarding the key inflammatory cells and mediators. Current therapies for COPD exacerbations are of limited effectiveness, and a better understanding of the inflammatory events at exacerbation is required to devise new therapeutic agents. The development of experimental models of exacerbation—for example, the use of experimental rhinovirus infection in humans with COPD—would greatly facilitate studies of exacerbations.
Key Words: chronic obstructive pulmonary disease • acute exacerbations • virus infection
Chronic obstructive pulmonary disease (COPD) is a major global public health problem, but it is the most underfunded disease in relation to its global disease burden (1). Acute exacerbations are the cause of much of the morbidity, mortality, and health care costs associated with COPD, and they have a direct effect on disease progression by accelerating loss of lung function (2, 3). Despite the tremendous impact of acute exacerbations, little is known about the cellular and molecular mechanisms of exacerbation. Exacerbations are associated with increased airway inflammation, although the inflammatory response at exacerbation is variable and may depend in part on the etiologic agent. To develop new and more effective ways of preventing and treating exacerbations, a better understanding of the mechanisms is urgently needed.
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EPIDEMIOLOGY AND DEFINITIONS
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There is no universally accepted definition as to what constitutes an exacerbation of COPD. Although usually clinicians have little difficulty in diagnosing an exacerbation of COPD, establishing a universally accepted definition for epidemiologic or interventional studies has proved difficult. The two most widely used approaches have been to use symptom-based definitions or event-based definitions, but both of these approaches have potential drawbacks. Symptom-based definitions rely on the patient reporting a worsening of the typical symptoms of COPD, such as breathlessness, cough, increased sputum production and purulence, wheeze, and chest tightness. Symptoms are the primary concern of the patient and it is generally a worsening of symptoms that prompts patients to seek medical advice, but such a definition relies on a subjective assessment and there is great variability in the threshold at which patients perceive symptoms to be worse than their usual state. Event-based definitions define an exacerbation as an event that leads the patient to seek medical advice, requires hospitalization, or necessitates treatment (generally a requirement for oral steroids or antibiotics). Event-based definitions of exacerbations are widely used in interventional clinical trials; however, data from a longitudinal study of a cohort of patients with COPD have shown that up to 50% of episodes of worsening of symptoms identified by symptom diary cards were not reported to the study investigators (4). Therefore an event-based definition may miss a substantial proportion of exacerbations that do not lead to a request for medical advice or treatment. The debate regarding the definition of an acute COPD exacerbation continues and further research is required to develop physiologic or biological markers that provide a more objective means of defining an exacerbation. A consensus statement defined an exacerbation as 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 may warrant additional treatment in a patient with underlying COPD" (5).
Most epidemiologic data regarding COPD exacerbations are derived from hospital admission data or primary care physician visits, but because exacerbations may not be reported to physicians, these figures are probably a considerable underestimate of the true incidence. Exacerbations are common events with a median of 2.4 exacerbations/patient/yr reported in one study (4), and their frequency increases with increased severity of the disease (6). COPD exacerbations are a major burden to health care systems, and their impact recently has increased. In the United Kingdom, in 2000, there were 98,000 emergency hospital admissions for COPD (7), amounting to nearly 1 million hospital-bed d/yr (8). In the United States, there were more than 660,000 hospital discharges for COPD in 1998, and 78% of the health care costs of the disease were accounted for by unscheduled hospitalizations due to acute exacerbations (9). A study of patients with COPD in the United States who were hospitalized for an acute exacerbation, half of whom required intensive care, reported an in-hospital mortality rate of 11%, and 6-mo and 1-yr mortality rates of 33 and 43%, respectively. Within 6 mo of discharge, 50% of patients had been readmitted (10).
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ETIOLOGY
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A number of factors have been associated with acute exacerbations of COPD, including changes in air temperature and increased levels of airway pollutants, but most exacerbations are associated with symptoms of respiratory infection. Bacteria have been considered the main infectious cause of exacerbations, but their precise role remains controversial because patients with COPD are often colonized with bacteria even when they are clinically stable. Studies using bronchoscopic sampling have isolated bacteria from 50% of patients during an exacerbation and from 25 to 30% of stable patients (11). The most common bacteria isolated are Haemophilus influenzae, Streptococcus pneumoniae, and Moraxella catarrhalis. Exacerbations in patients with more severe COPD are more likely to be associated with recovery of gram-negative organisms, such as Pseudomonas aeruginosa. Acquisition of a new strain of colonizing H. influenzae is also associated with exacerbation (12). The relative contribution of bacteria to exacerbations varies with disease severity, with a higher isolation rate of pathogenic organisms (especially gram-negative organisms) in patients with an FEV1 of less than 50% compared with those with milder disease (13).
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VIRUSES AND COPD EXACERBATIONS
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It is only more recently that viruses have been considered a significant cause of COPD exacerbations. Older studies detected a virus in only approximately 20% of exacerbations (14, 15), suggesting a minor role in exacerbation etiology. However, these studies used diagnostic methods that have a low sensitivity for common respiratory viruses such as rhinoviruses and coronaviruses. These viruses are optimally detected by polymerase chain reaction (PCR)-based methods, and studies comparing PCR with standard virologic methods have shown that virus detection rates are significantly higher with PCR (16). In a study of patients with moderate to severe COPD from the East London COPD cohort, rhinoviruses were detected in 23% of patients at exacerbation (17). A further report from this group detected a respiratory virus in 39.2% of exacerbations, the most common being rhinoviruses, accounting for 58% of viruses (18). Sixty-four percent of the exacerbations were preceded by symptoms of a cold, so this figure likely underestimates the true frequency of viral infection. This underestimate could be attributable to a number of reasons, such as the following:- Samples were taken within 48 h of the onset of lower respiratory tract symptoms. Upper respiratory tract infection may precede the exacerbation by several days and, therefore, the virus may no longer be detectable at the time of exacerbation.
- Only nasal aspirate samples were taken, but in studies in which both nasal and sputum samples were taken, there was a higher detection rate in sputum compared with nasal samples.
Respiratory viruses have also been detected in more severe exacerbations necessitating hospital admission. A respiratory virus was detected in 56% of patients with COPD admitted to a hospital in Germany with an acute exacerbation, with rhinoviruses being the most common viruses detected (19). Viruses were found in 64% of patients with COPD in Singapore (20). In patients with COPD intubated and mechanically ventilated for a severe COPD exacerbation, virus was identified in 47% of patients (21). Therefore, these studies suggest that as many as 40 to 60% of acute exacerbations of COPD are associated with respiratory virus infection.
Most studies to date have focused solely on either bacteria or viruses as causative agents of exacerbation, and the effect of possible coinfection has not been evaluated. Data from two older studies of patients with chronic bronchitis have given conflicting results, with one study suggesting an association between viruses and bacteria (22) whereas the other found no association (23). As these studies did not use PCR methods for virus detection it is likely that they underestimated the true prevalence of virus infection and therefore it is difficult to draw any conclusions from them. Viral respiratory tract infection is known to predispose to bacterial infection in both the upper (otitis media) and lower (pneumonia) respiratory tracts. In view of the high prevalence of bacterial colonization in patients with COPD, there is potential for interaction between viruses and bacteria, but the contribution of this interaction to exacerbations remains to be ascertained.
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MECHANISMS
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COPD is associated with an inflammatory infiltrate in all lung compartments. The Global Initiative for Chronic Obstructive Lung Disease definition of COPD recognizes the central role of airway inflammation in the pathogenesis of the disease (24). Detailed studies into the key inflammatory cells and mediators in COPD have been carried out. In stable COPD there is infiltration of macrophages, neutrophils, and CD8+ T lymphocytes into the airway and increased expression of cytokines, chemokines, and adhesion molecules. Few studies have been carried out during exacerbations and consequently much less is known about the inflammatory cells and mediators of acute exacerbations.
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CELLULAR MECHANISMS
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Although it is assumed that exacerbations are associated with an inflammatory infiltrate, the inflammatory cells recruited to the lung during COPD exacerbations are not well defined. The few studies that are available have had significant confounding factors that may limit their relevance concerning the majority of COPD exacerbations (Table 1). Bronchial biopsies taken during exacerbations of chronic bronchitis showed a prominent airway eosinophilia with a 30-fold increase in the number of eosinophils, together with smaller increases in neutrophils, T lymphocytes, and tumor necrosis factor (TNF)-
–positive cells (25). In another study using bronchoalveolar lavage fluid from patients with exacerbated chronic bronchitis, there were increased numbers of neutrophils and eosinophils, but the increase in neutrophils was more marked than that of eosinophils (26). In patients intubated with a severe COPD exacerbation, bronchial biopsies showed increased numbers of neutrophils compared with patients with stable COPD, but other cell types were not reported (21). Studies of induced sputum from patients with moderate to severe COPD reported no differences in either total cell numbers or relative percentages of eosinophils, lymphocytes, macrophages, or neutrophils in sputum at exacerbation compared with the stable state (27, 28). Markers of neutrophil activation such as myeloperoxidase are increased in serum of patients with exacerbations compared with stable COPD (29), but sputum myeloperoxidase levels at exacerbation are not significantly higher (30). Because of differences in patient selection, severity of disease, and methods of airway sampling, the results of these studies are not directly comparable. However, the variability in the results highlights the need for further studies investigating the inflammatory cells recruited to the lung at exacerbation.
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TABLE 1. Limitations of published studies of the inflammatory response in acute exacerbations of chronic obstructive pulmonary disease
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INFLAMMATORY MEDIATORS
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COPD is associated with the presence of inflammatory mediators in induced sputum and bronchoalveolar lavage fluid. During acute exacerbations, levels of these mediators are further increased compared with the stable state, suggesting that by amplifying airway inflammation, exacerbations augment smoking-induced inflammation. A number of proinflammatory mediators have been detected at exacerbation and are potential targets for new therapeutic agents.- TNF-: TNF- is a proinflammatory cytokine, the main source of which, in the lung, is the macrophage. It has multiple proinflammatory actions, including neutrophil degranulation and stimulation of the respiratory burst, upregulation of adhesion molecules, stimulation of interleukin (IL)-8 production, and induction of airway hyperresponsiveness. TNF- is elevated in the sputum of patients with COPD compared with healthy smokers (31) and in patients with COPD who are colonized with H. influenzae (32). TNF- is further elevated in sputum from patients with COPD during an exacerbation, compared with the stable state (30), and during bacterial exacerbations of chronic bronchitis (33). In view of its effect on the recruitment and activation of neutrophils, TNF- may be a central mediator of neutrophilic inflammation in COPD exacerbation.
- IL-8: IL-8 is a CXC chemokine that is a chemoattractant for neutrophils and CD8+ T lymphocytes. It is secreted by numerous cell types, including bronchial epithelial cells, macrophages, and neutrophils, and its expression is upregulated in response to cigarette smoke. IL-8 levels in sputum are significantly higher in patients with COPD compared with healthy smokers (31), and levels correlate with the rate of decline in FEV1 (34). In some studies, IL-8 has been reported to be increased in both sputum (31, 35) and serum (36) during COPD exacerbations, but other studies have not found significant differences in IL-8 at exacerbation (27, 28). Patients with COPD who have more frequent exacerbations have higher sputum levels of IL-8 when stable, suggesting there may be proinflammatory effects of exacerbations that persist after the acute episode has resolved (27). There were significantly higher numbers of IL-8 mRNA–positive cells in the subepithelium in biopsies taken from patients with exacerbated COPD compared with patients with stable COPD. However, in this study the dominant neutrophil chemoattractant was epithelium-derived neutrophil attractant-78 and not IL-8 (21). Further work is needed to define the role of the IL-8 and other neutrophil chemoattractants in COPD exacerbations.
- Leukotriene B4: Leukotriene B4 (LTB4) is a member of the leukotriene family of biologically active fatty acids produced by activated macrophages and neutrophils. Its production is increased by various stimuli, including TNF-, neutrophil elastase, and LTB4 itself. LTB4 results in increased adherence of neutrophils to endothelial surfaces and stimulates neutrophils to release lysosomal enzymes, generate superoxide radicals, and produce IL-8. LTB4 levels in exhaled breath condensate are significantly elevated in subjects with COPD compared with control smokers (37) and in the sputum in patients with chronic bronchitis colonized with bacteria compared with noncolonized patients (38). LTB4 in sputum and exhaled breath (39) is increased further at exacerbation, and levels fall in response to treatment (35).
- Endothelin-1: Endothelin (ET)-1 is a peptide with potent vasoconstrictor and bronchoconstrictor effects. It stimulates mucus secretion and airway edema, and upregulates other inflammatory mediators, such as IL-6, IL-8, and granulocyte-macrophage colony–stimulating factor. Levels of sputum ET-1 are elevated in patients with COPD compared with normal control subjects (40), and plasma levels of ET-1 are inversely correlated with FEV1 (28). Sputum and plasma levels of ET-1 are elevated at exacerbation versus the stable state (28), and so it may be an important inflammatory mediator in COPD exacerbations.
The molecular mechanisms whereby inflammatory mediators are upregulated at exacerbation remain undetermined. In vitro studies of rhinovirus infection in cell lines have indicated that it activates transcription factors such as nuclear factor (NF)-
B and activator protein-1 that increase transcription of proinflammatory genes (41). COPD exacerbations are associated with NF-B activation in macrophages in induced sputum (42), so this transcription factor may have a central role in the upregulation of inflammatory response at exacerbation.
Few studies have evaluated whether the inflammatory response differs according to the etiologic agent of exacerbation. Exacerbations of chronic bronchitis in which H. influenzae or M. catarrhalis were identified were associated with higher levels of sputum IL-8, TNF-, and neutrophil elastase than were those in which no bacterial pathogen was isolated (33). Exacerbations associated with purulent sputum (and a high incidence of bacterial infection) were associated with significantly higher levels of IL-8, TNF-, LTB4, and myeloperoxidase compared with those associated with mucoid sputum (43). Presumably, many of the culture-negative exacerbations were caused by virus infection; therefore, these studies suggest that bacterial exacerbations are associated with more severe airway inflammation. However, a study of virus-associated exacerbations reported that they were associated with more symptoms and higher levels of sputum IL-6 compared with those in which no virus was detected (18). ET-1 in sputum was higher in patients with COPD with documented viral or chlamydial infection than in those without, although the numbers were small and the difference did not reach statistical significance (28). Others have reported that the increases in airway inflammatory markers in patients with an acute exacerbation of COPD occur independently of a demonstrable viral or bacterial infection (30) and that neutrophil numbers are not related to the presence of viral infection (21). Therefore, further studies are needed in which sampling is carried out for both bacteria and viruses to determine the effect of different etiologic agents of exacerbation severity and inflammatory mediators. A better understanding of the role of bacteria and viruses in acute exacerbations is needed to make more effective use of current and future antibacterial and antiviral agents.
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OXIDATIVE STRESS
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COPD is associated with increased oxidative stress, which is believed to play a central role in the pathogenesis of the disease. Oxidative stress can damage DNA, lipids, and proteins and activate NF-B, which switches on the genes for TNF-, IL-8, and other inflammatory proteins, and damage antiproteases, thus impairing antiprotease mechanisms. Markers of both local pulmonary and systemic oxidative stress are elevated in patients with COPD (44). Acute exacerbations result in increased oxidative stress greater than that present in stable disease. Elevated levels of markers of oxidative stress in exhaled breath condensate, including hydrogen peroxide (45) and 8-isoprostane (39), have been documented at exacerbation. Markers of oxidative stress are also elevated in plasma (46), suggesting that exacerbations induce systemic oxidative stress. Hence, induction of oxidative stress may be one mechanism whereby exacerbations enhance smoking-induced pulmonary pathology and accelerate loss of lung function in COPD.
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EXPERIMENTAL MODELS OF COPD EXACERBATION
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Need for Experimental Models
New therapeutic agents for COPD exacerbations are urgently needed, because current treatment consists primarily of supportive measures combined with drugs used in asthma and pneumonia, which have limited effectiveness in COPD (47). Further studies are needed to determine the key mediators of exacerbation and to identify new therapeutic targets. One of the reasons for the current paucity of data regarding mechanisms of exacerbations is the lack of a valid model of COPD exacerbation. The development of a model of exacerbation would be of enormous benefit to increasing our understanding of the disease.
Animal Models of COPD
A number of different animal models of emphysema exist, but the mouse provides the best choice for an animal model because reagents and tools for investigation have been most extensively developed for this species. Furthermore, the murine genome has been extensively sequenced, and similarities exist with the human genome. Three main approaches to modeling COPD in mice have been used:
- Inhalation of noxious stimuli
- Instillation of tissue-degrading enzymes such as proteinases
- Genetic manipulation
However, animal models have a number of limitations because of anatomic and physiologic differences between the respiratory tracts of mice and humans. Mice have few cilia, few submucosal glands in the trachea, no goblet cells, and less branching of the bronchial tree compared with humans. There are differences also in murine inflammatory mediators compared with those of humans, and the role of important proinflammatory cytokines found in humans such as IL-8 and LTB4 may differ in mice (48). In addition, COPD is characterized by variable pathology and severity, whereas animal models are restricted to a limited range of pathologies. These differences must be borne in mind when interpreting results from animal studies, together with the fact that currently available animal models are models of stable disease and not of exacerbations.
Experimental Model of COPD Exacerbations in Humans
Carrying out studies of naturally occurring COPD exacerbations has proved difficult for a number of reasons (Table 2). One way to overcome these obstacles is by developing a model of COPD exacerbation that would allow studies to take place under controlled conditions. Much more is known about mechanisms of asthma exacerbation. Part of the reason for this is that a model of asthma exacerbation in humans has been developed on the basis of experimental rhinovirus infection. Human rhinoviruses are the most common cause of asthma exacerbations, and experimental rhinovirus infection in carefully selected asthmatic volunteers reproduces the clinical features of naturally occurring asthma exacerbations (49). Studies using experimental rhinovirus infection in asthma have provided a number of important insights into the mechanisms linking virus infection with asthma exacerbations. Rhinovirus infections have been shown to induce nitric oxide, sputum markers of eosinophil activation, IL-8, and neutrophilia; bronchial infiltration with eosinophils and with CD4+ and CD8+ lymphocytes; and activation of prostaglandin and leukotriene synthetic pathways (50, 51). Use of experimental rhinovirus infection as a model of exacerbation has a number of advantages over studying wild-type exacerbations (Table 3).
Studies have also linked rhinovirus infection to COPD exacerbations (17, 18). Because of the role of rhinovirus as a cause of COPD exacerbation, we have carried out a pilot study to investigate whether experimental rhinovirus infection can be used to develop a model of exacerbation in COPD. Using experimental rhinovirus infection in subjects with mild COPD, we were able to induce colds together with the lower respiratory tract symptoms and changes in lung function typical of a COPD exacerbation (52). This was associated with detection of rhinovirus and the cytokines IL-8 and IL-6 in upper airway samples. For ethical and safety reasons this study was carried out in subjects with mild COPD. As it has been shown that airway inflammation at exacerbation may differ according to the severity of the underlying COPD (21, 25), it remains to be established whether this model is relevant to exacerbations in patients with more severe disease. More detailed studies in larger numbers of subjects are required to evaluate whether a pattern of inflammatory mediators and cells similar to that seen in naturally occurring exacerbations is reproduced in this model. Such studies are currently underway to validate this as a model of naturally occurring exacerbations. However, despite its limitations this model has the potential to overcome many of the problems associated with studying exacerbations and lead to valuable insights into the pathophysiologic mechanisms of exacerbations. In addition, it could be used to evaluate the effect of existing and novel therapies on COPD exacerbation.
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CONCLUSIONS
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Acute exacerbations of COPD are a major cause of morbidity, mortality, and associated health care costs; thus, new treatments are urgently needed. The rational design of new therapeutic agents is currently hampered by our limited knowledge of the cellular and molecular mechanisms of exacerbations. More studies are needed to define the key inflammatory cells and mediators involved in exacerbations, but such studies in patients with COPD remain difficult. Animal models of COPD have limitations in their applicability to human disease, and no animal models of exacerbations exist. An experimental model of COPD exacerbation would overcome the difficulties associated with studying naturally occurring exacerbations and allow investigations under controlled conditions. The development of such a model would be a major step forward in advancing our understanding of the mechanisms of COPD exacerbations.
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FOOTNOTES
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Supported by an unrestricted grant from GlaxoSmithKline and by British Lung Foundation/Severin Wunderman Family Foundation Lung Research Program grant P00/2.
Conflict of Interest Statement: Neither of the authors has a financial relationship with a commercial entity that has an interest in the subject of this manuscript.
(Received in original form April 5, 2005; accepted in final form May 19, 2005)
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ABSTRACT
EPIDEMIOLOGY AND DEFINITIONS
