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The Proceedings of the American Thoracic Society 1:88-92 (2004)
© 2004 The American Thoracic Society

Exacerbations and Progression of Disease in Asthma and Chronic Obstructive Pulmonary Disease

Stephen I. Rennard and Stephen G. Farmer

University of Nebraska Medical Center, Omaha, Nebraska; and AstraZeneca Pharmaceuticals, Wilmington, Delaware

Correspondence and requests for reprints should be addressed to Stephen I. Rennard, M.D., Pulmonary and Critical Care Medicine, University of Nebraska Medical Center, 985885 Nebraska Medical Center, Omaha, NE 68198–5885. E-mail: srennard{at}unmc.edu


   ABSTRACT
TOP
 ABSTRACT
COPD EXACERBATION AND DISEASE...
 ASTHMA EXACERBATION AND DISEASE...
 CONCLUSIONS
 REFERENCES
 
Exacerbations, characterized by an increase in patients' symptoms above baseline, are characteristic of both chronic obstructive pulmonary disease (COPD) and asthma. Prevention of exacerbations and their expedient treatment are major goals for reducing the morbidity and cost of both conditions. Exacerbations, however, may also adversely affect the natural history of these disorders, perhaps by contributing to increased rates of lung function decline, systemic effects, and premature mortality. Although the available information is limited, the course of COPD is affected adversely by exacerbations in multiple ways. First, exacerbations likely lead to structural alterations in the lung and to permanently worsened airflow. Second, health status is adversely affected by exacerbations, and although the mechanisms are unclear, the effects are long lasting and may be irreversible. Less is known in asthma about the effect of exacerbations on natural history, but many of the same pathogenetic processes involved in COPD exacerbations likely play a role in some subjects with asthma as well. Future studies of how exacerbation affects the "natural history" of asthma and COPD will require a better understanding of the heterogeneity of exacerbations but promises to identify new therapeutic strategies to treat these disorders.

Key Words: chronic obstructive pulmonary disease • asthma • exacerbation • disease progression • emphysema

Exacerbation, a key clinical feature of both asthma and chronic obstructive pulmonary disease (COPD), is characterized by an acute (days to a few weeks) increase in patient symptoms above that experienced during the course of their normally stable disease. Because "stable" disease, in both asthma and COPD, is characterized by some variability in symptoms, however, the intensity and duration of increased symptoms required to qualify as an "exacerbation" are difficult to define. The definition of exacerbation is further complicated in that the symptoms that may be present in exacerbations of asthma or COPD are variable and may reflect heterogeneity of the trigger(s) of exacerbation and individual patient differences. Nevertheless, exacerbations are important clinical events, and they are appropriately the subject of considerable research.

Most therapeutic efforts directed at exacerbation in asthma and COPD have been designed either to prevent them or to stabilize the patient and accelerate recovery. Much less attention has been directed to the possibility that exacerbations may have long-term sequelae. Nevertheless, the available evidence supports the concept that acute exacerbations initiate pathophysiologic processes with relatively long-term consequences. In both asthma and COPD, exacerbations require increased therapeutic intervention and medication, frequently result in hospitalization, and in many cases cause death. They constitute the bulk of healthcare costs and represent a significant source of distress and danger to patients. Understanding the pathogenic mechanisms involved in these processes will create novel opportunities for intervention on behalf of COPD and asthma patients.


   COPD EXACERBATION AND DISEASE PROGRESSION
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 ABSTRACT
 COPD EXACERBATION AND DISEASE...
ASTHMA EXACERBATION AND DISEASE...
 CONCLUSIONS
 REFERENCES
 
The "British Hypothesis" suggested that mucus hypersecretion could contribute to accelerated loss of lung function in patients with COPD (1). An extension of this concept was that exacerbations of COPD could lead to transient worsening of airflow as well as to structural alterations in the lung, contributing to progressively irreversible (fixed) airflow limitation (1, 2). Although this hypothesis was rejected by Fletcher and colleagues, based on their study of British postal workers (3), more recent studies in larger data sets suggest that mucus hypersecretion has a significant, albeit small, effect in accelerating loss of lung function (4, 5). Furthermore, a recent prospective study following patients with severe COPD suggests that those with more frequent exacerbations deteriorate more rapidly (6). This effect, however, also appears to be small, as individuals experiencing exacerbations more often than the median lost lung function, on average, at 5 ml per year of FEV1 more rapidly than did those who had exacerbations less often than the median (Figure 1). Although not specifically designed to evaluate exacerbations, the Lung Health Study noted a similar impact of exacerbations on FEV1 rate of decline in smokers but no effect in ex-smokers (7).



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  		Figure 1. Lung function decline in patients with severe chronic obstructive pulmonary disease (COPD), stratified by exacerbation frequency. Subjects were followed for 5 years. Those with more exacerbations than the median (frequent) experienced a more rapid rate of lung function decline than those with fewer exacerbations than the median (infrequent). (Modified by permission from Donaldson and colleagues [6]).

 
It is important to stress, however, that exacerbations may also contribute to progression of COPD in ways independent of a possible acceleration of loss of lung function. In this context, health status measures that integrate many symptoms and patient-related activities show dramatic adverse effects after an exacerbation. After resolution of the exacerbation, health status measures improve. However, in contrast to lung function measures, which improve over a matter of a few weeks (8), health status improvement occurs quite slowly, consistent with the notion that health status measures features of the disease that are not related directly to FEV1. In a study following patients for 6 months after an exacerbation, Spencer and Jones reported that approximately 50% of the improvement occurs in the first month after the exacerbation (9). Approximately 25% of the improvement observed, however, did not occur until after 3 to 6 months after the exacerbation. Because their health generally declines with age, the prolonged recovery time of patients with COPD after an exacerbation suggests very long-lasting effects triggered by the exacerbation. Importantly, individuals who experienced a second exacerbation soon after the initial one demonstrated much less eventual recovery (10). Consistent with this, health status is worse among patients with COPD who experience more frequent exacerbations (between 3 and 8 in 1 year) compared with those who had exacerbations less frequently (between 0 and 2 in 1 year) (11).

The relationship between exacerbations and deteriorating health status is also observed with response to treatment. In this context, inhaled corticosteroids have been observed to reduce the frequency of exacerbations in COPD (12) and to reduce the rate at which health status declines (13). This contrasts with the lack of effect of inhaled corticosteroids on the observed rate of decline of FEV1 (14) and supports a role for exacerbations in directly causing the decline in health status.

It is possible that effects on rate of FEV1 decline too small to have been statistically significant were present. In this context, the Inhaled Steroids in Obstructive Lung Disease in Europe (ISOLDE) trial demonstrated a 9-ml effect of inhaled glucocorticoids in reducing the rate of decline in FEV1 that was not statistically significant. The extent to which this might result from reduction in exacerbations has not been reported.

The mechanisms by which exacerbations could contribute to decline in health status in COPD remain to be determined. It seems likely, however, that multiple mechanisms are involved. In this context, it seems equally likely that the heterogeneous stimuli that can lead to exacerbations will initiate multiple pathogenic processes with differing clinical consequences (Figure 2). This heterogeneity and variability may account for the relative difficulty of observing effects of exacerbations on the course of disease and the relatively small effects observed when all exacerbations are grouped together.



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  		Figure 2. Heterogeneity of exacerbations in asthma and COPD. Several distinct stimuli can lead to exacerbations in asthma and COPD. Some, such as viruses and air pollution, can cause exacerbations in both disorders, whereas other triggers are more characteristic for one condition, for example, allergen in asthma and bacteria in COPD. The multiple etiologies activate the cells present in the lung, likely to varying degrees depending on both the etiology and the individual patient. These cells, in turn, release a variety of mediators that lead to acute local and systemic effects and may result in altered tissue structure and function. Overlaps among the multiple limbs of the complex networks involved likely account for the similarities observed in exacerbations of asthma and COPD. The heterogeneity, however, makes precise definition of exacerbation difficult. It also creates the possibility of multiple potential targets for therapeutic intervention.

 
It seems plausible that some types of exacerbations may place patients at increased risk for specific complications. COPD exacerbations are associated with the acute production of increased levels of a variety of endogenous inflammatory mediators and cytokines (15–18). Exacerbations of COPD, however, are heterogeneous at a cellular level, and this may have clinical implications. Eosinophils may be present in a subset of patients with COPD (19), and increases in eosinophils may occur with exacerbations of COPD (20–22). The presence of eosinophils may indicate a greater likelihood of response to glucocorticoid therapy. There also appears to be considerable heterogeneity among patients with regard to the levels of individual cytokines, and this may have important clinical implications. For example, some exacerbations may be initiated by stimuli that lead to high levels of circulating tumor necrosis factor-{alpha}. This cytokine may then contribute to the cachexia and weakness that often characterizes patients with COPD. Similarly, stimuli that cause high levels of circulating interleukin-6 could lead to hypercoagulability (23) and contribute to the increased cofactors present in patients with COPD (24, 25) and to the thrombotic complications that are prominent comorbidities in many patients with COPD (26), particularly during exacerbations (27, 28). To what degree cigarette smoking independently contributes to these risks has yet to be determined. Systemic effects of mediators generated during an acute COPD exacerbation may also contribute to depression, osteopenia, and fluid retention, all prominent clinical features in many patients with COPD. Thus, it is reasonable that some exacerbations may lead to pathogenic pathways that contribute to specific types of morbidity. Health status instruments may be able to detect these effects, which may have a very different time course than the observed impairments of lung function.

The mechanisms by which exacerbations may lead to progressive compromise of lung function are unknown. However, the acute inflammation that characterizes an exacerbation likely leads to lung tissue damage and as a result to initiation of repair mechanisms that restore pulmonary structure and function. In the airway, the initiation of repair processes occurs very rapidly after injury (29). This then leads to an orderly sequence of events with recruitment and proliferation of epithelial cells followed by their redifferentiation into mature epithelium (30–33). This is associated with a slightly delayed recruitment and proliferation of mesenchymal cells in the subepithelial tissues (34). Resorption of these cells and the connective tissue matrix they produce can lead to restoration of tissue structure and function (30). Persistence of the excess connective tissue, in contrast, could lead to peribronchial fibrosis, a characteristic feature of tissue remodeling associated with fixed airflow obstruction (35, 36). The mediators that regulate these processes remain to be defined, but transforming growth factor-ß and fibronectin, important mediators of tissue repair in many settings, have also been suggested to play a role in COPD as well as asthma (Figure 3) (37–39).



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  		Figure 3. A schematic representation of mediators in normal and abnormal repair after epithelial injury. Very rapidly after injury, epithelial cells are recruited to cover the wound. This is followed by an orderly process of epithelial proliferation and differentiation. Although the mediators responsible are incompletely defined, transforming growth factor-ß (TGF-ß) produced by the epithelial cells is believed to play an important role, in part through the stimulation of secondary mediators including fibronectin (Fn), a potent chemoattractant for airway epithelial cells. The same mediators can also stimulate subjacent mesenchymal cells leading to connective tissue production and alterations in tissue structure (see Rennard [81] and Spurzem and Rennard [82] for reviews).

 

   ASTHMA EXACERBATION AND DISEASE PROGRESSION
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 ABSTRACT
 COPD EXACERBATION AND DISEASE...
 ASTHMA EXACERBATION AND DISEASE...
CONCLUSIONS
 REFERENCES
 
Compared with COPD, less is known about the role of exacerbations in the natural history of asthma. Interestingly, the Childhood Asthma Management Program demonstrated no effect of inhaled corticosteroids on growth of lung function (as assessed by the change in FEV1 after the administration of a bronchodilator to children with asthma), despite improved asthma control and, therefore, fewer exacerbations (40). Although several studies have demonstrated that asthma per se may be associated with accelerated loss of lung function and the development of fixed airflow obstruction in adults (41, 42), the role of exacerbations in this process is not established. The effects of inhaled corticosteroids on exacerbations without an effect on noted lung growth in the Childhood Asthma Management Program study suggest that exacerbations may not affect lung growth. It is interesting, however, that not all patients with asthma seem to develop fixed airflow limitation. Rather, a subset of subjects with asthma appears to be at risk (43). Indeed, a recently published 26-year follow-up study in subjects with asthma reported that the 16% of those patients who eventually developed irreversible airflow obstruction had "COPD-like symptoms," including cough, phlegm, and dyspnea (44). Furthermore, the irreversible obstruction was associated with lower values of FEV1, lower reversibility (and, surprisingly, less bronchial hyperreactivity) at the initial screening, and relatively less use of inhaled corticosteroids at follow-up. Whether these are individuals who experience frequent exacerbation or whether they experience exacerbations of a particular type is unknown but presents several readily addressable questions.

Studies suggest a number of mechanisms by which exacerbations could contribute to fixed airflow limitation in asthma. Damage of the airway epithelium is a characteristic of this disorder, particularly during exacerbations (45, 46). As noted previously here, the repair responses initiated in response to damage can mediate not only reepithelialization but also stimulate the subjacent mesenchymal cells, potentially leading to peribronchiolar fibrosis and compromised lung function. Interestingly, studies in vitro suggest that Th2 cytokines, including interleukin-4, interleukin-5, and interleukin-13, stimulate epithelial cells and fibroblasts to promote a profibrotic response further (47–49). Whether such processes take place in vivo is unknown. However, increased expression of both Th2 and profibrotic cytokines has been described in the airways in asthma (38).

The structural features that contribute to fixed airflow limitation in asthma remain controversial. The most widely studied structural abnormality is probably thickening of the lamina reticularis (50, 51), and this assessed relatively easily with endobronchial biopsy. Several studies have demonstrated an association of this parameter with worsening lung function (52) and with duration of disease in asthma (53). Other studies, however, have failed to demonstrate these features (54–56). Moreover, the functional significance of thickening of the laminar reticularis has been debated. Other structural abnormalities in the airway, including accumulation of interstitial collagen and smooth muscle hypertrophy, have been suggested as causes for the development of fixed airflow limitation in asthma (45, 52, 57). In particular, disease of the small airways may play a prominent role in asthma as it does in COPD. One study, using the method of collateral ventilation, assessed via bronchoscopy, described both increased resistance and decreased compliance of the small airways in asthma patients (58).

Emphysema, in contrast to conditions in which airflow is impaired because of increased airways resistance, is characterized by reduced airflow secondary to loss of lung elastic recoil. In COPD, a loss of lung elasticity may result from tissue destruction consequent to inflammation (59, 60). Although this is believed to be a relatively slow process, it is possible that exacerbations could result in accelerated damage, perhaps via proteolytic tissue destruction caused by neutrophil proteases, which have been reported to increase in the lungs at exacerbation of COPD (61). Neutrophils are also prominent in asthma exacerbations (62). Proteolytic degradation of elastin has also been noted both in stable asthma (63, 64) and after fatal asthma (65). A loss of elasticity has been noted with chronic asthma (66) and reversibly during asthma exacerbations (67), although the anatomic basis for these physiologic changes remains to be defined.

A body of evidence, however, suggests that emphysema can also result from failure of tissue repair. In this context, the increased alveolar size and numbers of alveolar fenestrae that develop with age (68, 69), sometimes termed "senile emphysema" (70, 71), are believed to be a progressive failure of tissue repair analogous to the development of osteoporosis (72, 73). A number of insults can compromise tissue repair mechanisms, thereby accelerating the development of emphysema. Included among these are starvation (74, 75) and acute exposure to cigarette smoke (76, 77). Acute administration of tumor necrosis factor-{alpha} in animals can lead to the development of emphysema (78). Similarly, blockade of vascular endothelial growth factor has a similar effect (79). All of these are consistent with the concept that acute illnesses characterized by a catabolic state may be associated with episodic development of emphysema. Whether such occurs during COPD exacerbations remains to be determined.

Interestingly, lung elastic recoil may also be abnormal in asthma. Although the alveolar walls remain intact, as evidenced by normal diffusion capacity, lung elastic recoil decreases, particularly with age in subjects with asthma (66, 80). There is, as a result, a decrease in FEV1 and an increase in total lung capacity with air trapping. This effect has been termed "pseudoemphysema." Interestingly, exacerbations of asthma are associated with acute loss in lung elasticity (67). Although this generally reverses with resolution of the exacerbation, the lung elasticity does not always return to normal. Neither the structural basis for the loss of elasticity in acute or chronic asthma nor whether acute exacerbations result in permanent losses in elasticity is known (67).


   CONCLUSIONS
TOP
 ABSTRACT
 COPD EXACERBATION AND DISEASE...
 ASTHMA EXACERBATION AND DISEASE...
 CONCLUSIONS
REFERENCES
 
Acute exacerbations of asthma and COPD can result in a number of consequences that potentially can contribute to disease progression. Structural alterations could contribute to airway and peripheral lung remodeling with increased airway resistance or to alveolar wall alterations and loss of lung elastic recoil. Systemic effects could contribute to a wide range of clinical features, including cachexia and muscle weakness or to an increased risk of thrombosis and tissue ischemia. It seems likely that the diverse etiologies that lead to exacerbations will initiate a variety of inflammatory processes each with differing clinical consequences. Defining the biological mechanisms that underlie the apparent heterogeneity of exacerbations will help identify potential therapeutic targets. Therapies that successfully mitigate the long-term effects of exacerbations would offer a novel approach in the management of both COPD and asthma.


   FOOTNOTES
 
Supported by Larson Endowment, University of Nebraska Medical Center.

(Received in original form June 25, 2003; accepted in final form December 5, 2003)


   REFERENCES
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 ABSTRACT
 COPD EXACERBATION AND DISEASE...
 ASTHMA EXACERBATION AND DISEASE...
 CONCLUSIONS
 REFERENCES
 

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