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Academic Unit of Respiratory Medicine, University College, London, United Kingdom
Correspondence and requests for reprints should be addressed to Jadwiga A. Wedzicha, M.D., Academic Unit of Respiratory Medicine, Royal Free and University College Medical School, Rowland Hill Street, Hampstead, London NW3 2PF, UK. E-mail: j.a.wedzicha{at}medsch.ucl.ac.uk
ABSTRACT
Chronic obstructive pulmonary disease (COPD) is not only an established major cause of mortality and morbidity but is increasing in worldwide prevalence despite current medical interventions. The natural history of COPD is punctuated by periods of acute symptomatic, physiologic, and functional deterioration or exacerbations. These events are responsible for considerable additional morbidity and mortality and impact on patients' long-term health status. Despite advances in understanding disease mechanisms and in treatment, exacerbations continue to be the major cause of COPD-associated hospitalization, and provision for their management incurs considerable health care costs. Although pharmacologic therapies may improve clinical outcomes, these benefits must be optimized by prompt diagnosis and delivery. This will require improved understanding of this complex disease by physicians and patients alike.
Key Words: chronic obstructive pulmonary disease • clinical outcomes • exacerbations
The natural history of chronic obstructive pulmonary disease (COPD) is punctuated by episodes of worsening symptoms, such as dyspnea, cough, sputum volume, and purulence. These COPD exacerbations are also associated with physiologic deterioration and increases in airway and systemic inflammation (1, 2) and have important consequences for patients and health care providers alike.
Changes in physiologic indices during exacerbations—for example, falls in peak flow or FEV1—are generally small and not useful in predicting or monitoring these events. However, larger falls in peak flow can be associated with symptoms of dyspnea and the presence of symptomatic colds as triggers of the exacerbation (3). An increased magnitude of the physiologic change at exacerbation has also been related to longer recovery time from exacerbations (3), and two recent studies have shown that changes in inspiratory capacity and dynamic hyperinflation are important relating to both exacerbation recovery and dyspnea during the exacerbation (4, 5).
Studies have shown increased airway inflammatory markers, such as increased sputum interleukin 6 (IL-6) and IL-8 at exacerbation compared with the stable state, although the magnitude of these inflammatory changes is variable (1). Patients with evidence of respiratory viral infection at exacerbation have greater increases in airway and systemic inflammatory markers, which are associated with longer and thus more severe exacerbations (6–9). Neutrophilic inflammation at COPD exacerbation has been associated with bacterial detection in the sputum (10), and thus, factors triggering the exacerbation modify the inflammatory response, explaining the heterogeneous inflammatory responses obtained at exacerbation. A recent study has shown that the combination of Haemophilus influenzae at exacerbation and the detection of rhinovirus or the presence of the common cold at exacerbation leads to even greater airway inflammation, suggesting a complex interplay between a number of different pathogenic factors may modulate the nature of any one event (11). Oxidative stress is a key factor in the development of airway inflammation in COPD and can be further increased by respiratory viral infections. A recent study has shown that patients with severe exacerbations who required hospital admission or assisted ventilation have evidence of increased large airway IL-8 levels and increased oxidative stress (12). Thus, the combination of the symptomatic, physiologic, and inflammatory effects of exacerbations have important effects on patients with COPD, and these issues are discussed in this article, mainly from the perspective of outpatient exacerbations. This review covers exacerbation severity, frequency, effects of exacerbations on disease progression, and functional effects.
EXACERBATION SEVERITY
Although the relationship between disease severity and the frequency of exacerbations is not particularly close, it can generally be observed that more severe exacerbations are found in patients with greater severity of disease. Patients with more advanced disease are also those who are most likely to develop respiratory failure with their exacerbations.
Indeed, our longitudinal study has shown that, over time, patients with exacerbations have more symptoms and take a longer time to recover as baseline disease severity worsens (13). Recent data from a study by Hogg and colleagues show that COPD is associated with progressive airway inflammation and that the inflammation is particularly marked in patients with severe COPD (14). Because airway inflammation is progressive with time, it is likely that exacerbations are associated with greater inflammatory changes as the disease progresses and thus will be more severe. In our longitudinal analysis, we have also shown that, with time, exacerbations are more likely to be associated with more purulent sputum and again this suggests there is an increased inflammatory load at exacerbation with disease progression (13). Thus, patients with more severe exacerbations are also those who are most at risk from the clinical consequences of these events due to the severity of their underlying disease.
The importance of severe exacerbations is reflected in data from health economic studies relating to COPD exacerbations. Andersson and colleagues have calculated that the costs of treating COPD exacerbations amount to 35 to 45% of the entire costs of managing COPD as a disease (15). These authors also showed that the costs of treatment increased considerably with severity of the exacerbation. Severe exacerbations that required a visit to the accident and emergency department or resulted in a hospitalization were on average 10 times more expensive than moderate exacerbations (requiring a visit to the primary care physician or outpatient clinic) and 60 times more expensive than mild–moderate exacerbations that involved telephone contact with a health care center and/or treatment with antibiotics or systemic corticosteroids. In a separate study, Oostenbrink and Rutten-van Mölken reported that exacerbations associated with a hospitalization accounted for 90% of the total costs of managing COPD exacerbations (16).
A number of risk factors for hospitalization of patients with COPD have been identified and thus these may also be proposed as risk factors for severe exacerbations. These include low body mass index, increased baseline dyspnea, lower FEV1, hypoxia, and reduced levels of physical activity (17, 18). Recent awareness of these risk factors has enabled patients at risk to be specially targeted for monitoring and intervention. However, patients with COPD are often elderly and can have high levels of anxiety and depression (19). These factors may contribute to the finding that patients with COPD often do not seek medical attention for their exacerbations (20). It is also possible that delays in seeking therapy can lead to increased hospitalization. We have reported a prospective study where we related the time between onset of exacerbation symptoms and presentation to the outcome of the exacerbation (20). Exacerbations where the patient was treated early after onset of symptoms had a faster recovery time, compared with exacerbations where there was a delay in treatment (Figure 1). Another interesting result from this study was that patients who tended not to seek treatment for their exacerbations either from the study team or from their primary care physicians were more likely to be admitted to the hospital for treatment of exacerbations than those patients who routinely reported their exacerbations for treatment. In this same study, patients who had a higher percentage of their exacerbations seen by a physician had better health status than patients who tended not to report their exacerbations for therapy.
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There is some evidence that exacerbation frequency increases with disease severity, mainly from pharmacologic studies in which subgroup analyses have been performed (21). It is also possible that there is a critical level of lung function in the natural history of COPD at which exacerbation frequency increases. However, when the East London COPD patient cohort was followed over a 6-yr period, there was no overall change found in the exacerbation frequency (13). This may be due to the fact that, over time, COPD exacerbations do not increase linearly with the fall in FEV1. Another explanation may be that therapy for COPD, which is known to reduce exacerbation frequency, may have played a part in stabilizing the exacerbation rates of the patients monitored in this cohort.
We have previously classified patients with COPD in the East London study into "frequent" and "infrequent" exacerbators, and we found that quality-of-life scores were significantly worse in the frequent, compared with the infrequent, exacerbators (22). This finding has now been confirmed in other studies (21). Furthermore, a recent Spanish study has shown that patients with frequent hospitalization for exacerbations are at risk of earlier mortality (23). Therefore, exacerbation frequency is an important determinant of health status in COPD and is now regarded as one of the important outcome measures for this disease. Patients who were frequent exacerbators in one year were likely to have a higher exacerbation frequency in following years. An earlier study of acute infective exacerbations of chronic bronchitis found that one of the factors predicting exacerbation was also the exacerbation rate in the previous year (24). Evidence that exacerbation frequency is a characteristic of an individual's disease is also suggested by the finding that frequent exacerbators have increased airway inflammatory changes, with increased sputum levels of airway inflammatory cytokines, such as IL-6 and IL-8 when stable, compared with infrequent exacerbators (1), and also increased lower airway bacterial colonization (25).
Furthermore, we found in our cohort that patients with a history of frequent exacerbations have faster lung function decline than patients with infrequent exacerbations (26). In a 4-yr study, we showed that patients who were frequent exacerbators had a faster decline in FEV1, with a 40-ml decline/yr in this group, as opposed to 32 ml/yr in the infrequent group (p < 0.05; Figure 2). Similar results were obtained when we studied changes in peak flow rate that were collected on a daily basis; we showed that changes in peak flow were greater in the frequent exacerbators. We then calculated that the contribution of COPD exacerbation to FEV1 decline is approximately 25%, with cigarette smoking still being the strongest factor affecting FEV1 decline in patients with COPD.
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We have reported that, in 25% of exacerbations, lung function and symptoms do not return to baseline values by 5 wk, and by 3 mo there was still a significant level of nonrecovery of exacerbation (3). Thus, the incomplete recovery at exacerbation may be one of the main reasons for the faster FEV1 decline in the frequent exacerbators. As discussed above, we have also shown that, with time, COPD exacerbations become longer and more severe (13), and thus an associated increase in inflammation could contribute to the increased rate of disease progression.
Recently, we have completed a study observing changes in inflammatory markers and exacerbation frequency over a 7-yr period (27). Patients were divided into infrequent and frequent exacerbator groups by the median annual exacerbation frequency. Patients with frequent exacerbations had a faster rise in plasma fibrinogen over time, suggesting that this patient group may be at greater risk of cardiovascular morbidity. Patients with frequent exacerbations also showed a faster rise in sputum IL-6 compared with the rise seen in infrequent exacerbators. This study also showed a close association between the progression of airway inflammation and FEV1 decline, with higher levels of assayed inflammatory markers related to faster disease progression over the period of the study.
It is now recognized that respiratory viruses are important triggers of exacerbations (6–9), but it is not known whether frequent exacerbators have a greater susceptibility to viral exacerbations. We have recently completed an epidemiologic study and showed that patients with a history of frequent exacerbations have an increased chance of acquiring an upper airway cold, compared with infrequent exacerbators (28). However, the likelihood of exacerbation during a cold was unaffected by exacerbation frequency. These data suggest that susceptibility to frequent exacerbation is associated with increased susceptibility to the common cold via a mechanism that is most likely to be related to increased acquisition of the cold virus. One of the potential mechanisms for this observation may be that airway epithelial cell intercellular adhesion molecule-1 expression (the major receptor for human rhinovirus, the principal cause of the common cold) is up-regulated in frequent exacerbators; this hypothesis needs further study as do the mechanisms underlying susceptibility to nonviral triggers to exacerbation.
FUNCTIONAL EFFECTS OF EXACERBATIONS
Patients with COPD suffer from decline in activity with disease progression and some eventually become housebound. Spruit and colleagues have shown that peripheral muscle weakness worsens during exacerbation, potentially contributing to reduced functionality and therefore to deconditioning (29). We have studied the relationship between COPD exacerbations and daily activity by asking patients to record changes in symptoms for exacerbations and daily outdoor activity on diary cards (30). Exacerbations were associated with a significant fall in outdoor activity for up to 5 wk after the onset of an exacerbation. We also found that patients who were frequent exacerbators had a faster decline in functional status, as measured by time spent outdoors, than patients who were infrequent exacerbators. In this study, the time spent outdoors was related to health status using the validated tool of the St. George's Respiratory Questionnaire. Thus, patients with frequent exacerbations are more likely to become housebound and therefore are a subpopulation that needs targeting in pulmonary rehabilitation programs.
Recently, Man and colleagues reported a randomized controlled study of early community pulmonary rehabilitation (within 10 d after hospital discharge), after hospitalization for COPD exacerbations compared with usual therapy (31). The early rehabilitation group showed significant improvements in exercise tolerance and health status at 3 mo compared with the usual-care group. However, we have previously shown that patients with severe dyspnea in the Medical Research Council grade 5 group do not respond well to pulmonary rehabilitation (32). It is thus intriguing to speculate why pulmonary rehabilitation works well early after hospital admission for a COPD exacerbation. One of the reasons may be more motivation at this stage or that deconditioning is greater, as discussed above, at exacerbation, but then responds better to exercise training. Thus, further longer studies are required on the effects of pulmonary rehabilitation instituted early after an exacerbation, and which include careful health economic assessment.
CONCLUSIONS
COPD exacerbations have important effects on patients, including reducing health status, increasing airway inflammation and disease progression, worsening peripheral muscle weakness, and reducing daily activities. Patients who are frequent exacerbators and those with severe exacerbations are most at risk from the effects of the exacerbation. Costs incurred in managing exacerbations are very high, particularly for the severe exacerbations requiring hospital admissions, and these exacerbations in particular need to be prevented. Pharmacologic therapy can reduce exacerbation frequency, but also patient awareness of the consequences of the exacerbation may encourage earlier presentation for therapy and thus an improved outcome.
FOOTNOTES
Conflict of Interest Statement: J.A.W. has received honoraria for lectures at meetings and/or attendance at advisory boards from the following companies: Glaxo, and then GlaxoSmithKline (GSK); Boehringer Ingelheim; AstraZeneca; Bayer; Novartis; and Aventis Pasteur. She has received research grants totaling approximately $300,000 from GSK for studies of various aspects of COPD exacerbations. She has received a grant of approximately $450,000 for a study of tiotropium in COPD and $25,000 from AstraZeneca for a health economic study, and $300,000 from Aventis Pasteur for a study of viral epidemiology of COPD. T.W. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript.
(Received in original form October 22, 2005; accepted in final form January 31, 2006)
REFERENCES
This article has been cited by other articles:
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  M. G. Foreman, D. L. DeMeo, C. P. Hersh, J. J. Reilly, and E. K. Silverman Clinical determinants of exacerbations in severe, early-onset COPD Eur. Respir. J., December 1, 2007; 30(6): 1124 - 1130. [Abstract] [Full Text] [PDF]
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