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Department of Clinical and Experimental Medicine, Centre of Research on Asthma and COPD, University of Ferrara, Ferrara; and Department of Oncology, Hematology, and Pneumonology, Section of Respiratory Diseases, University of Modena & Reggio Emilia, Modena, Italy
Correspondence and requests for reprints should be addressed to Leonardo M. Fabbri, M.D., Department of Respiratory Diseases, Via del Pozzo 71, 41100, Modena, Italy. E-mail: fabbri.leonardo{at}unimo.it
ABSTRACT
Smokers with stable chronic obstructive pulmonary disease have a chronic inflammation of the entire tracheobronchial tree characterized by an increased number of macrophages and CD8 T lymphocytes in the airway wall and of neutrophils in the airway lumen. Exacerbations of chronic obstructive pulmonary disease are considered to reflect worsening of the underlying chronic inflammation of the airways, caused mainly by viral and bacterial infections and air pollution. During exacerbations, the inflammatory cellular pattern changes, with a further increase of eosinophils and/or neutrophils and various inflammatory mediators—for example, cytokines (tumor necrosis factor-
, RANTES [regulated upon activation normal T cell-expressed and secreted], and eotaxin-1), chemokines (CXCL5 [ENA-78], CXCL8), chemokine receptors (CCR3, CXCR1, and CXCR2), adhesion molecules (E-selectin and ICAM-1), and markers of oxidative stress (H2O2 and 8-isoprostane, glutathione depletion). Worsening of inflammation is considered responsible for the deterioration of lung function and clinical status during exacerbations.
Key Words: airway • chemokines • cytokines • inflammation • leukocytes
Exacerbation of chronic obstructive pulmonary disease (COPD) is defined as an event in the natural course of the disease that is characterized by a change in the patient's baseline dyspnea, cough, or sputum beyond day-to-day variability and sufficient to warrant a change in management (1, 2). Recent studies have indicated that the state of health of patients with COPD is influenced by the presence and frequency of acute exacerbations (3) and that the frequency of COPD exacerbations is one of the most important determinants of health-related quality of life (3). Some patients are prone to frequent exacerbations, which is an important cause of hospital admissions and readmissions, and these episodes have a considerable impact on quality of life and activities of daily living (3). Exacerbations are caused or triggered by a variety of factors including viruses, bacteria, and air pollutants, and are associated with acutely increased worsening of existing (acute-on-chronic) airway inflammation (4). This in turn can lead ultimately to changes in the small airways and in lung parenchyma that may cause a decline in lung function.
NATURAL HISTORY OF COPD EXACERBATIONS
Studies in the 1960s suggested that exacerbations of respiratory symptoms are associated with a small transient decrease in respiratory function measured by spirometry and possibly do not alter the natural course of the disease (5). By contrast, recent studies have suggested that in patients with airway obstruction, exacerbations may indeed accelerate the decline in FEV1 (6, 7).
There have now been several large population studies (8–10) showing that the number and severity of exacerbations are lower in patients with mild to moderate COPD (FEV1 > 50% predicted), whereas in severe disease the rate of COPD exacerbations may increase to 1.5 to 2.5/patient/yr. These studies also show that there is a wide variation, with some individuals having frequent (> 3/yr) exacerbations. In a prospective study of a cohort of 101 patients with moderate to severe COPD followed over 2.5 yr, the median number of exacerbations was 2.4 (interquartile range, 1.3–3.84) exacerbations per patient/yr (11).
Patients with hypercapnic respiratory failure due to COPD exacerbations have a high hospital readmission rate and a mortality of 20% at 60 d, 47% at 1 yr, and 49% at 2 yr (12). Although the most common circumstance or cause of death in patients with COPD is respiratory failure (up to 35% of deaths [13]), comorbidities are also important. Several studies have investigated which variables predict death after admission for a COPD exacerbation and therefore identify at-risk subjects. The strongest predictors of mortality are age, signs of right ventricular hypertrophy, chronic renal failure, ischemic heart disease, and reduced FEV1 (12–14). In a prospective cohort study of 1,016 adult patients from five hospitals who were admitted for a COPD exacerbation with a PCO2 value greater than 50 mm Hg, survival was independently related to severity of the illness, body mass index, age, prior functional status, PaO2, inspiratory oxygen fraction (FiO2), congestive cardiac failure, serum albumin, and the presence of cor pulmonale (14, 15).
Poor treatment outcome, as assessed by a return visit 4 wk after an exacerbation with a respiratory problem requiring further treatment, was also related to the severity of the airways obstruction. Other factors associated with poor treatment outcome after an exacerbation were the use of home oxygen therapy, frequency of exacerbations, history of previous pneumonia, and the use of maintenance oral corticosteroids (15).
Lung function changes, such as decreases in peak expiratory flow rate (PEFR) or FEV1 immediately before exacerbation, are generally small and not useful in predicting exacerbations, but larger decreases in PEFR are associated with dyspnea, longer recovery time after exacerbations, and the presence of symptomatic colds (11). Changes in pulmonary function, mainly FEV1 or PEFR, even when measured daily, are poorly sensitive in the individual diagnosis of exacerbations not requiring hospital admission, possibly because the individual variability is larger than the mean change occurring during an exacerbation (11). However, larger changes in lung function tests are associated with wheezing (16), viral colds (17), and improvement of lung function, particularly lung volumes, is related to improvement of dyspnea during remission (18).
In contrast to minor changes in lung function, symptoms of dyspnea, common colds, sore throat, and cough increase significantly during the prodrome phase of an exacerbation, suggesting that respiratory viruses are important triggers of exacerbations (11). However, the prodrome of COPD exacerbation is relatively short and not useful in predicting onset. As colds are associated with longer, and thus more severe exacerbations, a patient with COPD who develops a cold may be prone to more severe exacerbations and should be considered for early therapy at the onset of symptoms (19).
ASSESSMENT OF ACUTE EXACERBATIONS
Patients with acute exacerbations of COPD typically present with increased cough, changes in sputum volume and purulence, and greater breathlessness, wheezing, and chest tightness. Increased breathlessness is a prominent symptom in acute exacerbations. It can be explained by airway narrowing, or increased metabolic state, and increased ventilation–perfusion mismatch.
Several potential mechanisms of acute exacerbations could exert their influence by reducing the caliber of the airways (18, 20). As note above, diminished lung function is generally small and not useful in predicting exacerbations (11). However, in a longitudinal study of patients with moderate to severe COPD, significant decreases in PEFR, FEV1, and FVC were observed during exacerbations; the recovery time was related to the extent of the decreases, and the reduction in PEFR was greater in patients with increased dyspnea (11). Patients with larger decreases in PEFR were those with more severe exacerbations, requiring systemic steroid therapy (21). These findings are supported by intervention studies in COPD that have shown significant increases in PEFR and FEV1 on recovery of exacerbations (18, 22–25). An increased metabolic state associated with a systemic inflammatory response can also cause an increase in breathlessness (18, 20, 26, 27). A significant association between the change in breathlessness and the reduction in resting oxygen consumption after recovery from acute exacerbations of COPD has been reported (26, 27).
Hypoxemia is a common problem in acute exacerbations. Worsening of ventilation–perfusion matching is the most important determinant of hypoxemia in this setting, although low mixed venous oxygen tension is a contributing factor (28). The latter feature can be explained by higher oxygen use resulting from the increased work of breathing as well as by inadequate cardiac reserve to increase cardiac output. Finally, especially in severe COPD, both the increase in airway resistance and the decrease in inspiratory to expiratory time ratio lead to hyperinflation (20, 29), impeding the ventilatory pump by decreasing the efficiency of the respiratory muscles (30, 31), thereby contributing to the breathlessness experienced during these acute events. Measurements of arterial blood gases are therefore very important in the assessment of patients with acute exacerbations. Generally, an arterial PaO2 of less than 7.3 kPa or an acute or acute-on-chronic respiratory acidosis indicates acute respiratory failure requiring hospitalization. Particular attention should be paid to changes in mental status, which might also indicate the presence of respiratory failure.
ETIOLOGY OF COPD EXACERBATION
The main etiologic factors in acute exacerbations are thought to be viral infections, bacterial infections, and air pollutants.
Viral Infections
Recent studies have shown that about one-half of COPD exacerbations are associated with viral infections, the majority of which are due to rhinovirus (32–36). Clinically, viral exacerbations are often associated with symptomatic colds and prolonged recovery (11). However, both Seemungal and colleagues (33, 34) and Rohde and colleagues (32) showed that rhinovirus can be recovered from sputum more frequently than from nasal aspirates at exacerbation, suggesting that wild-type rhinovirus can infect the lower airway and contribute to inflammatory changes at exacerbation (34). It has also been found that exacerbations associated with the presence of rhinovirus in induced sputum have larger increases in airway interleukin (IL)-6 levels (34), suggesting that viruses increase the severity of airway inflammation at exacerbation. This finding is in agreement with the data showing that respiratory viruses produce longer and more severe exacerbations and have a major impact on health care utilization (33–35). Interestingly, frequent exacerbators (i.e., those whose exacerbation frequency is greater than the median) experience more colds than infrequent exacerbators (36), whereas the likelihood of an exacerbation during a cold is unaffected by exacerbation frequency (36). Systemic inflammatory markers are also increased where there is evidence of airway viral infection (37).
Intercellular adhesion molecule (ICAM)-1 is the major receptor for rhinoviruses, the most frequently identified virus at exacerbations. There is some evidence that individuals with COPD have increased epithelial expression of ICAM-1 (38, 39), and this would suggest enhanced susceptibility to rhinovirus infection. However, there is no evidence to date that patients with COPD have more viral infections, though the inflammatory effect of the rhinovirus infection may be greater in patients with COPD, and this may lead to the characteristic lower airway symptoms of an exacerbation (40). In addition to the effects on cytokine generation, rhinovirus can stimulate mucus production from the airway epithelium (41), thereby potentiating sputum production during exacerbations (19).
Bacterial Infections
The lower airways of 25 to 50% of patients with COPD are colonized by bacteria, especially noncapsulated Haemophilus influenzae, Streptococcus pneumoniae, and Moraxella catarrhalis. This colonization has been correlated to the severity of COPD and cigarette smoking (42, 43). The presence of bacteria in the lower airways of patients with stable COPD implies a breach of host defense mechanisms, and it is associated with increased airway inflammation that parallels airway bacterial load (44). Airway bacterial colonization is variable in stable patients, and those patients who exhibit more changes in the nature of bacterial colonization exhibit faster declines in lung function (45). Interestingly, an association was found between higher sputum IL-8 levels, higher bacterial load, and faster decline in FEV1 (45). By influencing airway inflammation, lower airway bacterial colonization could also modulate the occurrence of exacerbations, a concept supported by the recent finding of increased inflammation and exacerbation frequency in patients with COPD with a higher airway bacterial load (46). In addition, H. influenzae strains isolated from patients during COPD exacerbations often induce more airway inflammation than do colonizing strains, suggesting that they may be more virulent than colonizing strains (47). These findings, taken together, support the concept that bacteria infecting the airway during COPD exacerbations mediate increased airway inflammation and contribute to decreased airway function (47).
At exacerbation, there is an increased chance of detecting bacteria, especially if the exacerbation is associated with the presence of purulent sputum (48). Sethi and colleagues have suggested that isolation of a new bacterial strain in patients with COPD who were regularly sampled was associated with an increased risk of an exacerbation, although this does not conclusively prove that bacteria are the direct cause of exacerbations (49). With antibiotic therapy, bacterial load and airway inflammation decrease, and the rate of resolution of the airway inflammatory changes is related to the clearance of bacteria from the sputum (50). Atypical bacteria have also been proposed as a cause of COPD exacerbations, especially Chlamydia pneumoniae (51). However, it is not clear whether C. pneumoniae is a true pathogen at exacerbation or an innocent bystander. In recent studies no relationship was found between C. pneumoniae detection and airway inflammatory markers (52). Further investigation is required to evaluate its role in the pathogenesis of exacerbation.
Air Pollution
COPD exacerbations could also be induced by increases in air pollution. Evidence to support a role for air pollution has been based on epidemiologic studies that have implicated increases of sulfur dioxide (SO2), nitrogen dioxide (NO2), particulate matter less than or equal to 10 µm in aerodynamic diameter, and black smoke particulate matter in changes in chronic respiratory symptoms and increased respiratory mortality in patients with COPD (53–56). These urban studies have investigated high numbers of hospital admissions at times of increased atmospheric pollution and they have concluded that air pollution may account for approximately 6 to 9% of admissions, depending on the time of year (55). Patients with COPD have also been shown to be at increased risk of death associated with urban particle air pollution, although many of the events may be cardiovascular rather than respiratory (56). The role of systemic and pulmonary inflammatory responses to ambient particulates was reviewed recently by van Eeden and colleagues (57).
The effects of diesel particulates, SO2, ozone, and NO2 have been studied and potential mechanisms by which airway inflammation is enhanced have been proposed. Recent bronchoscopic studies have shown that exposure of healthy volunteers to diesel exhaust results in increased number of neutrophils (58, 59). Studies in vitro have shown that diesel exhaust particles stimulated production of proinflammatory cytokines such as granulocyte-macrophage colony–stimulating factor (GM-CSF) and IL-8, both of which may be involved in increasing neutrophilic inflammation (60). Ozone exposure has been shown to be associated with markers of nasal inflammation in nonatopic children (61), and SO2 and NO2 have been shown to enhance the airway response to inhaled allergens (62). Thus, potential mechanisms exist whereby changes in air pollution can cause exacerbations of respiratory symptoms in COPD.
AIRWAY INFLAMMATION DURING COPD EXACERBATIONS
Although it often has been assumed that exacerbations are associated with increased airway inflammation, there is little information on the nature of the acute-on-chronic inflammation that characterizes these episodes. Most of the data currently available refer to soluble indirect markers of airway inflammation rather than inflammatory cell infiltration per se. Indeed, it is difficult to perform bronchial biopsies during an exacerbation in patients with moderate to severe COPD.
Smokers with stable COPD have an ongoing inflammatory response involving the entire tracheobronchial tree, characterized by an increase of macrophages and CD8 T lymphocytes in the airway wall and neutrophils in the airway lumen (63). This cellular pattern changes during exacerbations, when eosinophils and neutrophils become the major component of the inflammatory response (63, 64). The emerging concept is that an increase in airway inflammation is central to the pathogenesis of exacerbations. Any stimulus that acutely increases airway inflammation could lead to increased bronchial tone, increased bronchial wall edema, and increased mucus production. These processes could also worsen ventilation–perfusion mismatch and expiratory flow limitation. Corresponding clinical manifestations would include worsening gas exchange, dyspnea, cough, and sputum production and purulence, which are the cardinal manifestations of an exacerbation.
Among soluble mediators, endothelin-1 has been proposed as one possible mediator for increased airflow obstruction via bronchospasm induction. In addition, endothelin-1 may stimulate mucus secretion, promote airway edema, increase vascular and airway smooth muscle proliferation, and up-regulate production of cytokines (65). The concentration of this peptide, which is produced by the bronchial epithelium, alveolar macrophages, and pulmonary endothelium, is higher in the sputum of patients with stable COPD (66) as compared with healthy subjects. Recent studies have shown that concentrations of endothelin-1 are increased in induced sputum at exacerbation, suggesting it may play a role in the pathophysiology of acute episodes (65).
Infiltration of the airway wall with inflammatory cells could also contribute to airflow limitation. This has been described extensively in stable COPD, in which increased numbers of CD8+ lymphocytes and neutrophils (63, 65) are found. At exacerbation, inflammation becomes more marked with recruitment of neutrophils and eosinophils and increased CD4+ lymphocytes in the bronchial mucosa (67, 68). At exacerbation, elevated markers of neutrophilic inflammation have also been found in sputum along with increased vascular protein leakage that may lead to edema of the airway wall (69). T cell-mediated immunity has been recently evaluated in sputum samples at exacerbations: decreased CD4/CD8 and CD8-IFN-
/CD8-IL-4+ve cell ratios were observed at the onset of severe episodes requiring hospitalization (70). This evidence suggests that an imbalance in T lymphocyte subpopulations might be associated with the development of severe COPD exacerbations.
Increased mucus production is considered an important feature of many acute episodes of COPD. An increase in mucus production would lead to an increase in sputum production that characterizes many acute episodes of COPD as well. The presence of sputum in the airways would be expected to reduce the airway caliber and this effect would be enhanced if the viscosity of the sputum also increased. Such secretions, because they are harder to clear, would result in plugging of smaller airways and hence increased breathlessness (71).
Eosinophils
Patients with mild to moderate COPD exacerbations show an increased number of eosinophils in their bronchial mucosa (72). Although this suggests an "asthmatic profile," the observed eosinophils are not degranulated (as they would be in asthma) and are not associated with increased IL-5 expression (72). A recent study suggests that the expression of regulated upon activation, normal T cell-expressed and secreted chemokine (RANTES), which is able to induce eosinophil recruitment, is increased in the airway mucosa at exacerbation (68). RANTES induction may be mediated by tumor necrosis factor (TNF)- (73), whose increase at exacerbation could potentially drive eosinophil recruitment (74). The relative importance of the eosinophilia remains to be determined, but several eosinophil products may cause inflammatory damage to the airway (eosinophil peroxidase, major basic protein, eosinophil cationic protein, metalloproteinases, platelet activating factor, and cysteinyl leukotrienes) (75) and, together with histamine, can cause bronchospasm. Increases of eotaxin-1, a CC chemokine involved in eosinophil recruitment and activation, and its receptor CCR3 have also been reported at exacerbation (76). Furthermore, serum and sputum levels of eosinophil cationic protein are higher in patients with exacerbations than in those with stable COPD (77, 78).
Neutrophils
Another major finding in airway secretions and bronchial biopsy specimens during COPD exacerbations is an increase in neutrophils (79) that is also associated with the presence or change in sputum purulence (79, 80). The importance of neutrophils in COPD exacerbations has also been underlined by the finding that the percentage of neutrophils in the distal airspace has a negative linear relationship with the severity of airways obstruction as assessed by the FEV1/FVC ratio (81). Neutrophil recruitment during COPD exacerbations appears to be mediated by various molecules. Indeed, the up-regulation of the two important neutrophil chemoattractants CXCL5 (ENA-78) and CXCL8 (IL-8) and their receptors CXCR1 and CXCR2 has been observed in bronchial biopsy specimens in severe COPD exacerbations (82). Similarly, increased levels of CXCL8 have been detected in large airway secretions during both severe and very severe exacerbations (81). Furthermore, exacerbation has been also associated with increase in LTB4 expression (69), which is another important mediator of neutrophil recruitment.
Soluble Mediators
Several inflammatory markers are increased in the respiratory system during COPD exacerbations. Increased sputum TNF- at exacerbation (83, 84) could contribute to up-regulating the expression of endothelial adhesion molecules, thus facilitating cell migration as well as activating neutrophils directly (85). TNF- may also increase the expression of RANTES and, through this pathway, modulate eosinophil recruitment at exacerbation (68).
GM-CSF is increased in bronchoalveolar lavage fluid during exacerbations (79). This cytokine stimulates differentiation of granulocytes and macrophages and can activate them directly, providing another mechanism whereby neutrophils—as well as eosinophils and macrophages—can contribute to inflammatory changes within the airways. Neutrophilic inflammation during exacerbations shows resolution usually within 5 d after treatment, in parallel with clinical recovery (69). Sputum IL-6 is increased at exacerbation, and its levels are higher when exacerbations are associated with symptoms of the common cold. Interestingly, experimental rhinovirus infection has been shown to increase sputum IL-6 levels in healthy subjects and in patients with asthma (86).
Neutrophil and macrophage degranulation results in release of elastases and other proteinases that may cause epithelial damage, reduce ciliary beat frequency (87), stimulate mucus secretion by goblet cells (88), and increase the permeability of the bronchial mucosa, resulting in airway edema and protein exudation into the airway (69). These changes, especially in the small airways, may adversely affect airflow and lead to increased breathlessness, as well as to the mucus secretion and purulence that are characteristic of some exacerbations.
During COPD exacerbations oxidative stress is increased in the lung, possibly because of a large burden of activated inflammatory cells in the lower airways as a result of the release of cytokines and up-regulation of cell adhesion molecules (89). Also the newly recruited neutrophils participate in oxidative stress, which is thought to be an important component of inflammation through the activation of oxidant-sensitive transcription factors that leads to increased transcription of proinflammatory genes. Critical to the effects of oxidative stress is the protective counterbalance of antioxidant systems. A shift in this oxidant–antioxidant balance could result in an increase in oxidative stress that may cause cellular damage. In this regard, glutathione appears to be an important antioxidant in the lungs and is present in high concentrations in the epithelial lining fluid (90). During severe COPD exacerbations glutathione is depleted, indicating increased oxidative stress (81). Several other indirect markers of oxidative stress have been investigated in exhaled breath condensate: notably, both hydrogen peroxide and 8-isoprostane concentrations are increased at exacerbation (91, 92), suggesting the involvement of oxidative stress in acute episodes.
Systemic Inflammation
COPD is now recognized as a systemic disorder, the extrapulmonary manifestations of which involve diverse organs, resulting in skeletal muscle dysfunction, muscle wasting (93), osteoporosis (94), and atherosclerosis and its associated complications (94). Skeletal muscle dysfunction is also common in patients with COPD. It is characterized by specific anatomic and functional changes and contributes significantly to limited exercise capacity and reduced quality of life (95). Lower peripheral muscle force occurs during acute COPD exacerbations (95), and the reduced peripheral muscle force present at hospital admission partially recovers at discharge (96). Current evidence suggests that extrapulmonary manifestations of COPD are also caused by an inflammatory process (94). Importantly, there is a general association between the severity of the airflow obstruction and the severity of extrapulmonary end-organ damage in patients with COPD. Recently it has been observed that COPD exacerbations are associated with increased levels of soluble markers of systemic inflammation in serum (97). Furthermore, the degree of systemic inflammation correlated with the degree of lower airway inflammation and was greater in the presence of a sputum bacterial pathogen, suggesting that the systemic inflammatory response at exacerbation is proportional to that occurring in the lower airway and is greater in the presence of a bacterial pathogen (97).
CONCLUSIONS
Exacerbations of COPD cause morbidity, hospital admission, and mortality and strongly influence quality of life. Some patients are prone to frequent exacerbations, which may be associated with considerable physiologic deterioration and increased airway inflammation. The evidence suggests that bacteria, viruses, and changes in air quality interact with host factors and with each other to produce increased inflammation, characterized mainly by the presence of neutrophils and eosinophils, in the lower airway. Various mediators are responsible for neutrophil and eosinophil recruitment. All these features lead to the development of lung function disturbances and respiratory symptoms that characterize exacerbations of COPD.
ACKNOWLEDGMENTS
The authors would like to thank Dr. Elisa Veratelli for scientific secretarial assistance.
FOOTNOTES
Conflict of Interest Statement: None of the authors has a financial relationship with a commercial entity that has an interest in the subject of this manuscript.
(Received in original form December 5, 2005; accepted in final form January 16, 2006)
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