| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
1 Department of Respiratory Medicine, National Heart and Lung Institute and Wright Fleming Institute of Infection and Immunity, Imperial College London, London, United Kingdom
Correspondence and requests for reprints should be addressed to Professor S. L. Johnston, MB. B.S., Ph.D., Department of Respiratory Medicine, National Heart and Lung Institute and Wright Fleming Institute Infection and Immunity, Imperial College London, Norfolk Place, London, W2 1PG, UK. E-mail: s.johnston{at}imperial.ac.uk
ABSTRACT
Chronic obstructive pulmonary disease (COPD) is increasing in prevalence. Acute exacerbations of COPD are the major cause worldwide of morbidity, mortality, and health care costs as well as decreased quality of life for the individual. The majority of exacerbations are infectious in etiology. Bacteria are detected in 50% of exacerbations and polymerase chain reaction techniques have established that, in half to two-thirds of exacerbations, viruses are causative pathogens. Combined bacterial and viral infection can be identified in 25% of exacerbations and these dual infections are often more severe. Despite occurring frequently, the mechanisms by which infection with these pathogens causes exacerbations are incompletely understood. This highlights the need for continued research, because a greater understanding of the mechanism of COPD exacerbations may lead to identification of potential targets for the development of therapeutic options for this increasingly common condition.
Key Words: chronic obstructive pulmonary disease • bacterial infection • viral infection
Chronic obstructive pulmonary disease (COPD) is an important health care burden. It affects over 5% of adults, is the fourth leading cause of death worldwide, and is the only major cause of death that is still rising (1). Its prevalence is increasing steadily, and it has been predicted that COPD will be the third leading cause of death worldwide by 2020 (2).
Exacerbations of COPD are common; they result in increased health care utilization and impair quality of life for the individual. In addition, exacerbations have a significant effect on morbidity, mortality, and disease progression. Although there is a wide variation in pattern of exacerbations between individuals, several studies have shown that the number and severity of exacerbations increase with worsening disease (3) and exacerbations result in faster decline in lung function (4). Despite the enormous impact of COPD, the treatment options currently available for prevention and management of exacerbations are inadequate and new therapies are urgently needed.
Infection is detected in up to 78% of exacerbations (5) but is likely to be implicated in most, if not all, exacerbations. The use of newer diagnostic techniques for bacteria and viruses has led to increased recognition of the importance of viral and combined bacterial and viral infection in exacerbations. This presents clinicians with further challenges in COPD management and highlights the lack of effective treatments and urgent need for further research. A greater understanding of the pathophysiology of exacerbations may identify areas from which new treatment strategies may emerge.
PATHOGEN IDENTIFICATION
Historically, sputum culture has been the mainstay of bacterial pathogen identification in COPD exacerbations. Sputum is expectorated and then subjected to microscopy and culture. A direct causal relationship between bacteria isolated from sputum and exacerbation remains unproven because this technique is limited by difficulty in expectoration, potential contamination with upper airway secretions, and presence of lower airway cells, which can lead a pathologist to consider a good sample contaminated.
A further complication is that approximately 20 to 40% of patients with COPD will have positive cultures when clinically stable (6); thus, identification of a bacterial pathogen on standard sputum culture does not distinguish between preexisting colonization or new infective agent. In the research setting, airway bacteria can be identified from samples obtained by protected brush at bronchoscopy. A protected specimen brush can obtain sterile microbial cultures and is considered the gold standard for determining infection in pneumonia; it is increasingly used in COPD research (7).The use of a brush, however, is impractical in the clinical setting. Strain-specific antibodies can be identified in patients after exacerbation because they are produced as part of the host immune response to the bacteria. These identify the particular strain and organism, potentially enabling researchers to distinguish between colonizing bacteria or new infection (8).
The classical techniques to identify viral infection by culture, serology, or immunofluorescence have now been replaced, in the research setting, by detection of viral genomic sequences by polymerase chain reaction (PCR). PCR is rapid and highly sensitive and its use has confirmed the importance of viral infections. PCR can be reliably performed on respiratory secretions, sputum, nasopharyngeal aspirates, or samples obtained at bronchoscopy. It is the only reliable method for detecting rhinoviruses, which are difficult to culture, and serology is impractical because there are over 100 serotypes. PCR for bacterial antigens in sputum samples has also been shown to be a sensitive technique (9).
ROLE OF SPUTUM ANALYSIS
Despite its limitations, sputum culture remains the predominant investigation performed in the clinical setting. Sputum inspection at the bedside is a widely performed and useful observation. The traditional association of sputum purulence with bacterial infection is supported by the higher rate of isolation of bacterial pathogens in individuals with purulent sputum at presentation, with one group identifying a positive bacterial culture in 84% of purulent sputum compared with 38% if sputum was mucoid (10). Self-reported assessment of sputum purulence has also been investigated in a group of 40 patients requiring hospitalization for exacerbations of COPD. Results of sputum samples and protected brush specimens showed that self-reported sputum purulence was associated with a high yield of potentially pathogenic microorganisms with a positive predictive value of 77% (11).
Purulence and darkening of the sputum are associated with increased sputum neutrophils and neutrophil myeloperoxidase. Interestingly, raised sputum neutrophil counts are not limited to bacterial infections: they have been reported in all infectious exacerbations and numbers were related to the exacerbation severity regardless of whether a viral or bacterial pathogen was detected (12). Although raised sputum neutrophils were seen in both bacterial and viral infection, sputum eosinophils were shown to be increased only during virus-associated exacerbations (12). This raises the possibility that clinicians could use a sputum cell count to obtain etiological information and potentially guide treatment. Further studies are required to confirm and further investigate this potentially clinically important observation.
COPD EXACERBATIONS ASSOCIATED WITH BACTERIAL PATHOGENS
The predominant bacteria isolated from sputum samples in COPD exacerbations are noncapsulated Haemophilus influenzae, Moraxella catarrhalis, and Streptococcus pneumoniae. In patients with more severe exacerbations who required mechanical ventilation, Pseudomonas aeruginosa and gram-negative bacilli are also recognized (5). Bacteria are associated with 50% of exacerbations (13) and have been shown to enhance pulmonary inflammation, induce mucus hypersecretion (14), and reduce ciliary beat frequency (15) in vitro. Isolation of these pathogenic bacteria in sputum is associated with higher sputum neutrophil counts (16), and inflammatory mediator levels increase in proportion to bacterial load (17).
MECHANISMS OF BACTERIUM-INDUCED COPD EXACERBATION
Identification of bacteria during exacerbation has been associated with higher levels of inflammatory mediators, such as IL-8, tumor necrosis factor (TNF)-
, and neutrophil elastase (18), which, combined with increased airway neutrophilia, supports the concept that the isolated bacteria have a causative role in the exacerbation.
Despite bacteria being detected in at least 50% of exacerbations (13), controlled trials have shown surprisingly limited benefit of antibiotic therapy in COPD exacerbations (19), and their role remains controversial. A meta-analysis of relevant trials demonstrated a small, but statistically significant, benefit with antibiotics (20). It is possible that disagreement among different trials may be a result of varying degrees of selection of exacerbations. If all cases of bacterial infection were identified, antibiotics would only be expected to be effective in 50% of exacerbations, and in published studies, it is possible that they may not produce a significant clinical response in exacerbations caused by a combined bacterial and viral infection. Furthermore, larger, placebo-controlled trials in patients with more severe COPD, with selection criteria designed to include exacerbations likely to be caused by bacteria, have confirmed some benefit with antibiotic therapy (21).
Underestimation of the importance of viral infections in the etiology of exacerbations may also have contributed to the poor outcomes in earlier trials with antibiotics. Recent evidence from patients with severe COPD who were hospitalized with acute exacerbation and were then reviewed in convalescence when stable demonstrated evidence of infection in 78% of patients, with bacterial infection alone in 29%, combined bacterial and viral infection in a further 25%, and viral infection alone in 23% of patients (12). Thus, even in severe exacerbations, the etiological importance of viral infections is similar to that of bacteria. This pathogen detection rate is higher than in previous studies and this is likely to be due to the use of improved detection techniques. The investigators used sputum sampling and both quantitative bacteriology and a PCR panel for all common respiratory viruses for the first time. This high level of combined infections further highlights the clinical need for treatments other than antibiotics.
ROLE OF BACTERIAL COLONIZATION
Approximately 20 to 30% of patients with COPD have positive bacterial cultures when clinically stable. The presence of bacteria in the lower airways suggests impaired host defense mechanisms and is associated with a higher inflammatory burden (17). Colonization with monocultures of S. pneumoniae has been shown to predispose patients to increased risk of exacerbations (22). The species and strain of bacteria colonizing the airway can vary over time and acquisition of new strains of bacteria exposes the patient to a twofold increased risk of exacerbation (23). As expected, increasing variability in colonizing bacteria is associated with a faster decline in lung function, as are higher bacterial load and IL-8 levels (24).
Large airway bacterial load correlates with increased exacerbation frequency and inflammation (25); however, it is debated whether carrying asymptomatic bacteria increases exacerbations with the colonizing bacteria or if it increases host susceptibility to infection with other bacterial strains. Before the demonstration of the relationship between exacerbations and new strain acquisition, the widely held view of exacerbation mechanism was that an increase in colonizing bacterial load in the airways leads to increased airway inflammation and therefore increased respiratory symptoms. This is supported by studies that have confirmed increased bacterial load during exacerbations compared with stable disease (10); however, specific strains of bacteria were not analyzed. Whether an increase in airway-colonizing bacterial load is an independent cause of COPD exacerbations was addressed in a recent, prospective, longitudinal cohort study. The investigators identified that concentrations of preexisting bacterial strains in sputum were not higher during exacerbations than when colonized in the stable state (24). However, there were small increases in sputum concentrations of newly acquired strains during exacerbations. This led the investigators to suggest that acquisition of new strains rather than changes in colonizing bacterial load is likely to be an important mechanism for COPD exacerbations (26).
ROLE OF VIRAL INFECTIONS IN ACUTE EXACERBATIONS OF COPD
Many viruses are implicated in acute exacerbations of COPD, including influenza, parainfluenza, respiratory syncytial virus (RSV), and rhinovirus. Human rhinovirus is the dominant viral pathogen. Newly emerging viruses, such as human metapneumoviruses, may also be important, because in 10 to 15% of acute respiratory illness, no pathogen can be detected despite PCR (48). It is possible that new and as yet unknown viruses may account for these illnesses.
Until recently, the role of viral infections in acute exacerbations of COPD had been underestimated. Traditional virological techniques have reported rates of viral detection up to 20% (27). More recently, studies using PCR of nasal aspirates during acute exacerbation identified infection rates of 39% and reported that exacerbations associated with a positive viral pathogen were more severe and required longer recovery periods (28). PCR analysis of sputum in patients with severe COPD, with exacerbations requiring hospitalization, detected viruses in 48.4% compared with 6.2% of these patients at follow-up when stable (12). These data are further supported by a study that detected viruses in 56% of patients hospitalized with acute exacerbations (29) and another identified viral infection in 47% of patients who had clinically more severe exacerbations requiring intensive care unit admission and mechanical ventilation (30). A study in Singapore had a detection rate of 64% (31).
Although these studies confirm the importance of viruses during exacerbations, this may still be an underestimation of the true importance of viral infections. Most studies investigate patients presenting to physicians with COPD exacerbations. This presentation can potentially occur after the peak viral load has passed, and sampling at presentation may fail to identify viruses and so underestimate true numbers of virus-induced exacerbations. A study using prospective diary card recordings indicated that coldlike symptoms preceded 65% of COPD exacerbations; however, in the same study, viruses were only detected in 39% of patients (28). It is a potential explanation that, in this study, viral pathogens were missed, and if so, this would suggest that viral infection may be related to as many as two-thirds of all infectious COPD exacerbations.
MECHANISMS OF VIRUS-INDUCED COPD EXACERBATION
The mechanisms by which viruses cause exacerbations are incompletely understood, and the majority of information comes from experimental rhinovirus studies in patients with asthma. This is not an ideal population because the mechanism of airway inflammation is likely to be largely distinct in the two respiratory diseases; it is therefore essential to perform similar investigations in COPD. Greater understanding of the mechanism by which viruses cause exacerbations of COPD could identify targets for development of future therapeutic interventions.
Inflammation is believed to be central to the pathogenesis of exacerbations, but a clear picture of the inflammatory changes during an exacerbation of COPD is yet to emerge. This is mainly due to the practical issues of performing bronchoscopy during acute exacerbations, and means that the majority of information on airway inflammation in COPD comes from measurement of mediators and cellular information from patients with stable COPD. Bronchoscopic sampling in stable patients has shown that inflammation in COPD is characterized by increased macrophages and CD8 T lymphocytes and airway neutrophils. Induced sputum is an important, less invasive technique and more practical for repeated or multiple measurements.
It has been hypothesized that this inflammation may be an exaggerated form of the normal inflammatory response to inhaled stimuli because there is increased IL-8, Gro, and matrix metalloproteinase-9 (32). Airway eosinophilia (33) and neutrophilic inflammation (30) have also been reported.
Exacerbations associated with viral infections cause an increase in inflammation, and increased levels of many inflammatory mediators can be measured during an exacerbation. These include TNF-, IL-8 (34), epithelium-derived neutrophil attractant (ENA)-78 (30), RANTES (regulated upon activation, normal T-cell expressed and secreted) (35), endothelin–1 (36), and leukotriene B4 (37). During an exacerbation, neutrophils and eosinophils predominate (34). IL-8 is a neutrophil chemoattractant and activator that has been suggested to have a major role in the inflammatory response to viral infection. The literature on the importance of IL-8 in COPD exacerbations is contradictory, however, as some studies have reported increased levels (35), whereas others do not report this finding (36).
Although it is likely that increased production of these inflammatory mediators, chemokines, and cytokines enhances airway inflammation and contributes to increased disease activity in the absence of good experimental models of COPD exacerbations, the relative importance of these mediators and their relationship with exacerbation severity remain unknown.
IMPORTANCE OF RHINOVIRUS INFECTIONS
Most respiratory viruses have been reported in association with exacerbations of COPD; however, rhinoviruses are responsible for the majority (
66%) of these viruses (28). Rhinoviruses have been shown to replicate in the lower airways (30, 38), which is contrary to the previously widespread view that rhinoviruses were unable to infect the lower airways due to their optimal replication temperature of 33°C.
Detection of rhinovirus in sputum samples is associated with increased levels of the proinflammatory cytokine IL-6. This may contribute to increased inflammation and increased severity of exacerbation (39). Rhinovirus infection has also been shown to stimulate mucus production in vitro (40).
It has been reported that the rhinovirus major group receptor intercellular adhesion molecule (ICAM)-1 is up-regulated on the bronchial epithelium of patients with COPD (41). Although interesting, the relevance of this observation is not clear, because it is not known whether COPD is associated with increased susceptibility to major group rhinoviral infection as might be expected if this mechanism were important.
More recently, the transcription factor nuclear factor (NF)-
β has been implicated in immune responses to viral infection. Activated NF-β has been detected in macrophages from induced sputum (40) and rhinovirus-induced activation of NF-β has been demonstrated in vitro (42). What is not known is whether rhinoviruses infect macrophages in vivo.
More information is known about rhinoviral infection in asthma. Bronchial epithelial cells taken from asthmatics infected with rhinovirus showed decreased IFN-β production and increased viral replication compared with bronchial epithelial cells taken from nonasthmatics infected with rhinovirus (43). Bronchial epithelial cell IFN-
production has also been shown to be reduced in asthma and in relation to viral load (42). Cells from bronchoalveolar lavage were also deficient in IFN-, and this was related to asthma exacerbation severity in vivo (44). Prospective experimental infection studies in asthma have thus increased understanding of the mechanisms of asthma exacerbation and identified areas for further study. Similar studies in patients with COPD are urgently needed to further investigate signaling pathways important in COPD.
AN EXPERIMENTAL RHINOVIRUS INFECTION MODEL IN COPD
A recent pilot study to investigate the safety of experimental rhinovirus infection in COPD recruited patients with stable mild/moderate COPD and induced experimental infection with rhinovirus. This procedure appeared safe, it successfully induced infection, and it provided preliminary evidence for a causative role for rhinovirus infection in COPD exacerbations (45). Although it was a pilot study and only performed in a small number of patients, it raises the possibility of using this model to investigate important questions, such as the mechanism of airway inflammation in COPD exacerbations, whether there is increased susceptibility to infection in patients with COPD, and whether rhinovirus infection increases the risk of bacterial infections. Work is currently ongoing to investigate rhinovirus inoculation combined with lower airway sampling to further this research.
ATYPICAL ORGANISMS
Atypical infections have also been implicated in exacerbations of COPD. One study observed serological and molecular evidence of Chlamydia pneumoniae in 8.9% of patients during acute exacerbations (46). A causal role is far from certain, however, because another study found no association between C. pneumoniae identification and inflammatory markers (47). Whether this is a pathogen or an incidental finding is yet to be determined.
C. pneumoniae is known to be increased in stable asthma (48), and treatment of exacerbations with telithromycin enhanced recovery from acute exacerbations of asthma (49). Currently, this has not been investigated in COPD and further investigation is needed into the role of atypical bacteria in exacerbations of COPD.
CONCLUSIONS
Exacerbations of COPD have a major impact on the quality of life of patients with the condition. They are a major cause of hospital admission and health care utilization. The evidence presented above shows that the great majority of exacerbations have an infectious etiology and that bacterial, viral, and combined bacterial and viral infections are increasingly recognized to be important in the pathology of exacerbations. The role of atypical organisms is less clear and the mechanisms important in infectious exacerbations are poorly understood. It is hoped that further research using the human experimental model described above will be an important development permitting studies to investigate these mechanisms. We await results with interest to determine whether a target for therapeutic intervention can be identified.
FOOTNOTES
Supported by AstraZeneca, Centocor, GlaxoSmithKline, Pfizer, and Merck.
Conflict of Interest Statement: A.S. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. P.M. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. S.L.J. has served as a consultant to AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, MedImmune, Merck, Pfizer, Sanofi-Aventis, Schering Plough, and Synergen.
(Received in original form July 18, 2007; accepted in final form September 17, 2007)
REFERENCES
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
