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1 Academic Unit of Respiratory Medicine, Royal Free and University College Medical School University College London, London, United Kingdom
Correspondence and requests for reprints should be addressed to Prof. J.A. Wedzicha, M.D., F.R.C.P., Academic Unit of Respiratory Medicine, Royal Free and University College Medical School, University College London, Rowland Hill Street, Hampstead, London NW3 2PF, UK. E-mail: j.a.wedzicha{at}medsch.ucl.ac.uk
ABSTRACT
Chronic obstructive pulmonary disease (COPD) exacerbations have a major impact on patients with COPD, yet they are complex events that are associated with a number of triggers and affected by the underlying disease process. A number of conditions can mimic the symptoms of an exacerbation and require evaluation. Airway and systemic inflammatory changes at exacerbation are modulated by infective factors (viruses and bacteria) and lead to the pathophysiologic effects seen at exacerbations with increase in airflow obstruction. Although bacteria or viruses can be isolated at exacerbation, often these organisms act in combination and lead to greater inflammatory changes and more severe exacerbation. Underlying structural changes such as radiologic changes of bronchiectasis that can be found in COPD can also modulate exacerbation severity and contribute to morbidity associated with exacerbations.
Key Words: chronic obstructive pulmonary disease • COPD exacerbations • infection • inflammation
A considerable amount of the morbidity and mortality in chronic obstructive pulmonary disease (COPD) is caused by exacerbations (i.e., episodes of worsening respiratory symptoms). Exacerbations are associated with demonstrable physiologic changes and increases in airway and systemic inflammation (1–3). Most COPD exacerbations last from 7 to 10 days and resolve spontaneously or after therapy. However, some may be more complex in nature and show a prolonged recovery or never recover to stable preexacerbation levels.
Exacerbations of COPD have a considerable impact on the individual with COPD. They are an important determinant of health status (4), and patients with a history of frequent exacerbations show faster disease progression (5), increased hospital admission, and increased mortality (6). Because exacerbations are such an important outcome measure in COPD, there has been considerable interest in understanding their pathophysiologic mechanisms and triggers. Although airway infection is the most important trigger of an exacerbation, a number of noninfective "conspirators" may modulate the underlying inflammatory processes.
Although COPD exacerbations are defined on the basis of increased respiratory symptoms, other conditions that cause dyspnea, such as heart failure or pulmonary embolus, may be present in patients with COPD. By increasing symptoms, these conditions mimic exacerbations (7). However, these other conditions (e.g., heart failure) do not lead to increases in airway inflammation or other consequences of exacerbations such as disease progression and thus must be differentiated from true exacerbations.
INTERACTIONS OF PATHOPHYSIOLOGIC CHANGES AT EXACERBATIONS
COPD exacerbations are associated with increased upper and lower airway (pan-airway) and systemic inflammation (3), and generally this inflammatory response increases in severity with disease progression. Studies performed using endobronchial biopsies, mainly from intubated patients, have indicated that airway neutrophils are increased at exacerbation (8), although eosinophilia may also be found in patients with milder symptoms (9). However, most of these pathologic studies were performed once the exacerbation had developed and caused symptoms, and it is likely that early pathologic changes produced by exacerbation triggers while a patient was asymptomatic have not been reported. Patients with a history of frequent exacerbations show increased airway inflammation even in the stable state (10), and this increased inflammatory response may lead to the faster disease progression seen in frequent exacerbators (5). Oxidative stress is also a feature of COPD and a key factor in the development of airway inflammation in COPD. Markers of oxidative stress, such as hydrogen peroxide and 8-isoprostane, have been shown to rise in the airways with exacerbation and follow the time course of the exacerbation (11).
In addition to inflammation within the lung, there is considerable upper airway inflammation in patients with COPD (12). Upper airway inflammation increases further at exacerbation (3), is related to nasal symptoms, and is increased in the presence of viral infection at exacerbation. Upper airway inflammatory changes are also related to the lower airway inflammatory changes, and this suggests that respiratory viruses such as human rhinovirus, the most common exacerbation trigger, may enter the upper airway and cause lower airway inflammatory changes and symptoms directly and via interactions between the upper and lower airways.
Systemic inflammation is an important feature of COPD and leads to considerable comorbidity associated with the condition (13). These systemic inflammatory markers, (e.g., C-reactive protein [CRP], IL-6, or plasma fibrinogen) increase at exacerbation (14), are greater in the presence of airway infection at exacerbation, and usually fall with resolution of the episode. When patients with COPD are stable, there is little direct relation between airway and systemic inflammation; however, at exacerbation, inflammation in the two compartments is related, suggesting that one of the causes of a systemic inflammatory response at exacerbation may be "spill over" from the airways (3). In addition, respiratory viral infections and other infective agents may increase systemic inflammation directly. Some of these systemic inflammatory markers (e.g., plasma fibrinogen and CRP) have been linked to increased cardiovascular risk. Respiratory infections have been associated with increased cardiac events (15), and thus a COPD exacerbation, especially when triggered by an infection, may also be associated with increased cardiovascular morbidity, although further research is required to evaluate these relationships.
The fact that exacerbation of COPD remains a clinical diagnosis of exclusion and the difficulties inherent in assessing airway inflammatory markers in clinical practice have led to the idea that systemic biomarkers may have clinical utility at exacerbation of COPD. We have recently reported on a study examining the utility of 36 plasma biomarkers in confirming exacerbation or predicting exacerbation severity (14). The acute phase response was related, independently, to markers of lymphocyte–neutrophil and monocyte function (Figure 1). The best biomarker for confirming a COPD exacerbation was CRP, but even this was neither sufficiently sensitive nor specific to be useful in the absence of an assessment of symptoms. In addition, none of the biomarkers when measured at exacerbation onset could reliably predict the clinical course of the episode. However, there are data to suggest that systemic biomarkers assessed during the time course of an exacerbation, at 2 weeks after exacerbation onset, may predict the likelihood of subsequent exacerbation (16).
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Changes in airflow limitation at exacerbation result in changes in peak expiratory flow rate. However, these changes in peak flow are too small to be useful in assessing individual patients (1). This may be because peak flow is predominantly an assessment of larger airway obstruction, whereas in COPD the majority of the airflow limitation occurs in the smaller airways. Peak flow measurements are useful in monitoring changes due to asthma exacerbations where the peak flow changes are much greater.
CAUSES OF COPD EXACERBATIONS
Most COPD exacerbations are caused by episodes of tracheobronchial infection or pollutants. The apparent contributions of individual agents vary by the methodology of the study selected and the severity of the underlying COPD and the exacerbation. Broadly speaking, airway bacteria and viruses may each be detected in around 50% of samples from the lower airways in patients at exacerbation of COPD. However, the presence of an organism in sputum does not imply causation, and exacerbations are heterogenous events that are considered to be caused by complex interactions between the host, airway pathogens, and environmental pollution, resulting in an increase in the inflammatory burden (16).
Bacterial Infection
The importance of bacteria as a cause of exacerbation is controversial. The same species isolated from lower airway specimens at the time of exacerbation may be found in the stable state, a phenomenon termed "lower airway bacterial colonization." More recently it has been reported that exacerbation may result from a change in the colonizing strain (17), although not all exacerbations are associated with strain change, and not all strain changes cause exacerbation. Further evidence that bacteria cause exacerbations may be drawn from the benefit observed in trials of antibiotics (18) and the demonstration of new strain-specific local and systemic antibody responses to organisms acquired at the time of these events. In general, the bacterial load and the proportion of patients with detectable bacteria increase at exacerbations. In one study in patients with moderate to severe COPD, bacteria were found in 48.2% of patients in the stable state, whereas at exacerbation bacterial detection rose to 69.6%, with an associated rise in airway bacterial load (19). Sputum purulence is a reliable indicator for the presence of bacteria. The most commonly identified species are Haemophilus influenzae, Moraxella catarrhalis, and Streptococcus pneumoniae. It is not uncommon to find Pseudomonas aeruginosa and other gram-negative bacilli in more severe disease. There is ongoing controversy about the role of atypical organisms such as chlamydia and mycoplasma.
Viral Infection
Respiratory viruses, especially rhinoviruses, are an important cause of exacerbation, with viruses detected in up to 50% of exacerbations depending on diagnostic techniques (21). In an analysis of 85 hospitalizations for exacerbation (median FEV1 49% predicted) (22), 56% of episodes were associated with the isolation of a respiratory virus. These were more commonly rhinovirus (36% of isolations) than any of the other viruses detected, which included influenza A (25%), respiratory syncytial virus (22%), parainfluenza-3 (10%), and influenza B (7%).
Rhinoviruses are also the viruses most frequently associated with the common cold, isolated in 30 to 50% of such episodes and at even greater frequency during the spring and autumn peaks. COPD exacerbations are also more common at this time. Exacerbations associated with coryzal symptoms, or those in which a virus has been isolated from the respiratory tract, are of greater severity than nonviral exacerbations when assessed by changes in symptoms, lung function, and airway and systemic inflammatory markers. This suggests that respiratory viruses are important not only in causing but also in determining the severity of exacerbations.
The pathogenesis of rhinoviral infection has been well described by numerous experimental studies in healthy human volunteers. Deposition, by aerosol or direct contact, occurs in the anterior nasal mucosa or eye (with subsequent passage down the nasolacrimal duct). Mucociliary action transports the virus posteriorly to establish initial infection in the nasopharynx. Here, after entry into the cell via the appropriate receptor, viral replication occurs. Up to 95% of subjects without strain-specific protective antibody become infected, although symptomatic colds develop in only 75% of these subjects. There is little evidence of a cytopathic effect, although there may be epithelial shedding, and symptoms are therefore predominantly due to the host immune response. In support of this, the concentration of IL-8 in nasal lavage fluid correlates with symptom severity during experimental rhinovirus colds (23). The rhinorrhea and nasal obstruction arise from vasodilatation and increased vascular permeability of the nasal mucosa. Cholinergic stimulation results in increased mucus production and sneezing. Symptoms occur as early as 12 hours after inoculation and peak by day 3. The mean duration of symptoms is between 7 and 10 days.
For many years it had been assumed that rhinovirus infection was restricted to the upper airway. In situ hybridization during experimental infection has confirmed that rhinovirus can directly infect the lower airway (24).
The more frequent isolation of respiratory viruses at exacerbation than in the stable state, the association of viruses at exacerbation with greater airway inflammation, and the high prevalence of coryzal symptoms during exacerbations have been cited as evidence in support of the concept that respiratory viruses cause exacerbation. The mechanisms by which viruses cause the deterioration in symptoms and lung function that characterize exacerbations remain poorly understood. Potential mechanisms to explain how viral infection can result in deterioration of symptoms and lung function include direct infection of the lower respiratory tract (as has been demonstrated for rhinovirus), neural reflex responses, and "cross-talk" between the upper and lower airway. The latter may occur by passage of mediators directly along the mucosal surface or via the blood stream. In addition, the virus-associated airway inflammation, with resultant increase in bronchial wall thickness and luminal exudates, is likely to be partially responsible for the clinical features of exacerbation.
Coinfection
Further complicating the interactions of airway infection and inflammation is the situation in which respiratory viruses and bacteria may be isolated. A greater systemic inflammatory response has been reported in those exacerbations associated with both H. influenzae and rhinovirus isolation, and when the isolation of Haemophilus was associated with new or worsening coryzal symptoms (a surrogate of viral infection), such infections were more severe as assessed by changes in symptoms and lung function at exacerbation onset (20).
Pollutants
The role of pollutants in causing exacerbation has been difficult to assess, but data from six European cities in the APHEA (Air Pollution and Health: a European Approach) project reported an association between increased air pollution and a rise in hospital admissions for COPD (25). Particulate matter up to 10 µm in size (PM10), largely produced by diesel exhaust, seems to be particularly important. In a separate study providing a potential mechanism, exposure of smokers with COPD to increasing PM10 concentration was associated with a reduction in FEV1 (26).
STRUCTURAL FUNCTIONAL INTERACTIONS
Given the importance of exacerbations, there is considerable interest in those patients termed "frequent exacerbators" who seem particularly prone to these events. Studies have examined the role of bacteria and viral infection in this phenotype and provide examples of interactions between structural and functional aspects of the disease. For example, with the advent of CT scanning, it is recognized that a significant proportion of patients with COPD have radiographic evidence of bronchiectasis. Moreover, the presence of bronchiectasis seems to modulate the exacerbation and affects the frequency and severity of exacerbations (25). Thus, structural features may affect outcome of the exacerbation and need to be considered in when assessing the patient. Frequent COPD exacerbators may also be more prone to the common cold (26). An explanation for this observation would be that the effect of exacerbation frequency in patients is to increase airway inflammation, causing up-regulation of intercellular adhesion molecule-1 (ICAM-1), which is the cellular receptor for the major type of rhinoviruses.
FOOTNOTES
Conflict of Interest Statement: J.A.W. has received lecture fees and a research grant for studies of COPD exacerbations from AstraZeneca. J.R.H. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript.
(Received in original form July 25, 2007; accepted in final form September 1, 2007)
REFERENCES
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