The Proceedings of the American Thoracic Society 1:73-76 (2004)
© 2004 The American Thoracic Society
Similarities and Differences in Asthma and Chronic Obstructive Pulmonary Disease Exacerbations
Romain A. Pauwels
Department of Respiratory Diseases, Ghent University Hospital, Ghent, Belgium
Correspondence and requests for reprints should be addressed to Romain Pauwels, M.D., Ph.D., Department of Respiratory Diseases, Ghent University Hospital, De Pintelaan 185, B9000 Ghent, Belgium. E-mail: romain.pauwels{at}ugent.be
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ABSTRACT
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There is no generally accepted definition of an exacerbation either for asthma or for chronic obstructive pulmonary disease. There is little consistency among the symptomatic or functional criteria used in different studies. The most consistent criterion is the introduction of systemic corticosteroids for the acute worsening of the disease. The time course of an exacerbation does not seem to differ very much between asthma and chronic obstructive pulmonary disease (COPD). The decrease in peak flow rate is more pronounced in asthma than in COPD. The frequency of exacerbations is linked to disease severity both in asthma and COPD. Common causes are viral infections and increased environmental air pollution, whereas allergen exposure and bacterial infections are more specific for asthma and COPD exacerbations, respectively. Few data are available about the airway pathology of asthma or COPD exacerbations. Eosinophilia and/or neutrophilia have been associated with exacerbations in both diseases. Avoidance of the causal factors decreases exacerbation rate in both diseases. Pharmacologic prevention of exacerbations in asthma has been shown for inhaled corticosteroids, combination therapy with long-acting inhaled ß2-agonists and inhaled corticosteroids, and monoclonal anti-IgE. Inhaled corticosteroids, long-acting inhaled ß2-agonists, combination therapy with both, and the long-acting inhaled anticholinergic tiotropium decrease the exacerbation rate in COPD.
Key Words: asthma • chronic obstructive pulmonary disease • exacerbation • definition • prevention
Exacerbations of asthma and chronic obstructive pulmonary disease (COPD) are important events in the individual patient's medical history and in the natural course of these diseases. The occurrence of an exacerbation in asthma can be regarded as a failure of the maintenance therapy, and therapeutic guidelines recommend avoidance of exacerbations as one of their objectives (1). There is increasing evidence that exacerbations of COPD negatively influence the long-term loss of lung function in COPD (2, 3). Prevention of exacerbations has become an important outcome for the evaluation of therapeutic agents in both asthma and COPD (4, 5).
In reviewing the data available on the differences and similarities between exacerbations in asthma and COPD, one soon realizes the limited amount of scientific data that are available on this important topic. This fact should, however, be a stimulus for further efforts to study in depth the phenomenon of exacerbations in asthma and COPD, to agree on a proper definition, to understand the causes and the pathophysiology, and finally, to improve treatment and prevention of exacerbations.
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ABSENCE OF A UNIFORM AND GENERALLY ACCEPTED DEFINITION
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There is no generally accepted definition of an exacerbation for either asthma or COPD. For both diseases, an exacerbation can generally regarded to be "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 necessitates a change in regular medication" (6). This description differentiates exacerbations from a worsening of symptoms during a few hours that can be easily managed with rapid-acting bronchodilators. The descriptive definition does not really help when prospective quantification of exacerbation frequency or severity is needed.
In both diseases, exacerbations have been defined based either on changes in symptoms or airway function or on specific therapeutic interventions. There is little consistency among the symptomatic or functional criteria used in different studies.
The most consistent criterion in both diseases is the introduction of systemic corticosteroids for the acute worsening of the disease (4, 7–11). Many studies in asthma have used combined criteria. A severe exacerbation has been often defined as either a worsening of asthma necessitating the introduction of a course of systemic glucocorticosteroids or a decrease in peak expiratory flow rate (PEFR) in the morning on 2 consecutive days of at least 25% or 30% compared with baseline (4, 7, 11). The use of a course of systemic glucocorticosteroids for the treatment of an acute exacerbation of asthma might differ from physician to physician and from country to country. It is therefore to be recommended that in studies investigating the effect of a therapeutic intervention on severe exacerbations defined as courses of systemic glucocorticosteroids, randomization should be performed per physician and at least per country. A fall of the PEFR of at least 30% on 2 consecutive days is a less stringent criterion than the clinical criteria that are used to start a treatment with a course of systemic glucocorticosteroids. Indeed, an analysis of the exacerbations in the Formoterol And Corticosteroids Establishing Therapy (FACET) study showed that some patients who had an exacerbation defined on the PEFR criteria were not treated with systemic glucocorticosteroids (12). These exacerbations were associated with fewer symptoms and more short-lived falls in PEFR than the exacerbations treated with glucocorticosteroids.
It is reassuring to note that the protective effect of budesonide on severe exacerbations in the inhaled Steroid Treatment As Regular Therapy (START) study was comparable using either the very stringent definition of a severe asthma-related event (emergency treatment at a healthcare institution, including systemic glucocorticosteroids and nebulized bronchodilators) or the number of courses of systemic glucocorticosteroids (Table 1) (13).
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TABLE 1. The effect of the definition of a severe exacerbation on the number (percentage) of patients with at least one severe exacerbation
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Other clinical studies have used broader definitions of exacerbations of asthma than the ones mentioned previously here. This variety of definitions makes it very difficult to compare the therapeutic activities of different antiasthma drugs on an outcome such as exacerbations.
Major studies in COPD on the effect of inhaled glucocorticosteroids or the combination of a long-acting inhaled ß2-agonist and an inhaled glucocorticosteroid have used the same definition of an exacerbation, namely a worsening of symptoms leading to the prescription of a course of antibiotics and/or oral glucocorticosteroids (5, 14–16). Further analysis of the data shows that a course of oral glucocorticosteroids helps to define more severe exacerbations and discriminates better between different therapeutic interventions. As for asthma, also in COPD, less stringent definitions of an exacerbation have been used, preventing the comparison between different treatment modalities (17, 18).
A definition based on symptoms (increase in dyspnea, sputum volume, and sputum purulence) has been very valid for the identification of COPD exacerbations where a treatment with antibiotics is warranted (19). Similarly, symptom-based definitions of COPD exacerbations have been used to define possible causes and mechanisms involved in their pathogenesis (20–23).
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TIME COURSE OF AN EXACERBATION
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The time course of an exacerbation does not seem to differ very much between asthma and COPD. Symptoms start to increase and PEFR to decrease approximately 1 week before the decision is taken to treat the exacerbation, and it takes about the same length of time for full recovery in the majority of patients (12). One study suggests a more abrupt beginning and a prolonged recovery period for COPD exacerbations (20). This apparent difference might be explained by the way an exacerbation is defined (course of oral glucocorticosteroids compared with a threshold in symptoms), by the way the results for the measured parameters are expressed (mean data compared with a percentage of patients fully recovered), and by the treatment of the exacerbation. Oral glucocorticosteroids have been shown to shorten the recovery period after an exacerbation (24). The increase in symptom scores and the decrease in PEFR are more pronounced in asthma than in COPD (12, 20). The daily monitoring of individual symptoms or PEFR does not allow predicting in individual patients the development of an exacerbation in neither asthma nor COPD.
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EXACERBATIONS AND DISEASE SEVERITY
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The frequency of exacerbations is linked to disease severity in both asthma and COPD. Table 2 illustrates the frequency of severe exacerbations, defined in a similar way in different studies in asthma. It is clear that patients with mild asthma can develop severe exacerbations, and the frequency of exacerbations does not seem to differ very much between mild and moderate asthma.
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TABLE 2. Frequency of severe exacerbations (exacerbations/patient/year) in different intervention studies in asthma
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The frequency of exacerbations in COPD is significantly related to the baseline FEV1. When the patients in the Inhaled Steroids in Obstructive Lung DiseasE (ISOLDE) study were stratified into mild (FEV1 of 50% or more predicted) and moderate-to-severe COPD (less than 50% predicted), the exacerbation rate in the placebo-treated group was 0.92 year (–1) in the mild group compared with 1.75 year (–1) in the moderate-to-severe group (25). The inverse relationship between baseline FEV1 and the exacerbation rate was confirmed in the TRial of INhaled STeroids ANd long-acting ß2-agonists (TRISTAN) study (15).
There are indications that the frequency of exacerbations influences the long-term decline in lung function in COPD. Kanner and colleagues (2) analyzed Lung Health Study data to assess the effect of self-reported lower respiratory illnesses resulting in physician visits on lung function. Over 5 years, the frequency of these illnesses had a significant effect on rate of decline of FEV1 only in smokers. In smokers averaging one lower respiratory illness per year over 5 years, there were additional declines in FEV1 of 7 ml/year (p = 0.001). Smokers with more than one such illness per year had greater declines. Donaldson and colleagues (3) followed 109 patients with moderate-to-severe COPD for 4 years. Exacerbations were identified from symptoms, and the effect of frequent or infrequent exacerbations (more or less than 2.92 per year) on lung function decline was examined. Patients with frequent exacerbations had a significantly faster decline in FEV1 of –40.1 ml/year than infrequent exacerbators in whom FEV1 changed by –32.1 ml/year. Frequent exacerbators also had a greater decline in FEV1 if allowance was made for smoking status.
No data on the relationship between exacerbation rate and lung function decline are available in asthma.
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CAUSES OF EXACERBATIONS
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Viral infections have been associated with and are thought to be causally related to exacerbations of both asthma and COPD. In a community-based longitudinal study in children aged 9 to 11 years and having symptoms suggestive of asthma, viruses were detected in approximately 80% of the episodes of decreased PEFR or increased symptoms (26). In patients aged 17 to 50 years and admitted to the hospital for acute asthma, viruses were detected in 26% of them compared with 18% in patients with stable asthma (27). Viral respiratory pathogens are found more often in induced sputum of COPD patients hospitalized with an acute exacerbation than in COPD patients hospitalized for another reason (28). Respiratory virus infections are associated with more severe and frequent exacerbations in COPD (29).
Bacterial respiratory infections seem to play a minor role in triggering asthma exacerbations, although the role of Mycoplasma pneumoniae and Chlamydia pneumoniae infections in asthma is still debated (22, 30, 31). The possible causal role of bacteria in COPD exacerbations has recently been strengthened (32).
Increased environmental air pollution is associated with increased exacerbations of asthma and COPD (33–36). Smoking is a well known cause of exacerbations in both asthma and COPD (37, 38). Allergen exposure is a well known trigger of asthma exacerbations (27). In a substantial part of the exacerbations of asthma or COPD, no cause can be identified.
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PATHOLOGY OF EXACERBATIONS
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Few data are available about the airway pathology during asthma or COPD exacerbations. The majority of the data in fatal asthma show an increase in inflammatory cell infiltrates, mainly eosinophils, but some patients had an exclusive neutrophilic inflammation (39). Data from sputum obtained during moderate to severe exacerbations of asthma also show either a dominant eosinophilic or neutrophilic inflammation (40, 41). The cellular pattern might be related to the cause of the asthma exacerbation. Data on induced sputum during exacerbations of COPD show an increase in the total number and the different types of inflammatory cells (42). One biopsy study in patients with a mild exacerbation of chronic bronchitis showed an increase in mucosal eosinophils (43). Although to a lesser extent, the number of neutrophils and T-lymphocytes was also increased.
Sputum inflammatory markers other than cells have also been followed during exacerbations of asthma and COPD. Asthma exacerbations are associated with increases in sputum interleukin-5, eotaxin, and interleukin-8 concentrations (40, 44, 45). An increase in sputum tumor necrosis factor-
, interleukin-8, interleukin-6, leukotriene B4, and endothelin-1 has been described during exacerbations of COPD (42, 46–50).
The data on pathology, including sputum cellular and inflammatory markers, do not allow us to differentiate clearly the findings between exacerbations of asthma and COPD. Indeed, a direct comparison has not been made.
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PREVENTION OF EXACERBATIONS
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Avoidance of the causal factors decreases exacerbation rate in both asthma and COPD. Pharmacologic prevention of exacerbations in asthma has been shown for inhaled corticosteroids (4, 11, 13), combination therapy with long-acting inhaled ß2-agonists and inhaled corticosteroids (4, 11), and monoclonal antibody against IgE (51). Inhaled corticosteroids (5, 15), long-acting inhaled ß2-agonists (15), combination therapy with long-acting inhaled ß2-agonists and inhaled corticosteroids (15, 16), and the long-acting inhaled anticholinergic tiotropium (17, 18) have been shown to decrease the exacerbation rate in COPD (Table 3). The relative protective effect of the different drugs cannot be deduced from the current data because of differences in populations and in the definitions of exacerbations.
(Received in original form June 25, 2003; accepted in final form January 30, 2004)
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ABSTRACT
ABSENCE OF A UNIFORM...
