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Role of Viruses in Exacerbations of Chronic Obstructive Pulmonary Disease

Academic Unit of Respiratory Medicine, St. Bartholomew's and Royal London School of Medicine and Dentistry, Dominion House, St. Bartholomew's Hospital, West Smithfield, London, United Kingdom

Correspondence and requests for reprints should be addressed to Jadwiga A. Wedzicha, M.D., Academic Unit of Respiratory Medicine, St. Bartholomew's and Royal London School of Medicine and Dentistry, Dominion House, St. Bartholomew's Hospital, West Smithfield, London EC1A 7BE, UK. E-mail: j.a.wedzicha{at}qmul.ac.uk

	ABSTRACT

TOP ABSTRACT RHINOVIRUS DETECTION OF RESPIRATORY VIRUS... INFLUENZA ARE COPD PATIENTS MORE... EFFECT OF RESPIRATORY VIRUSES... MECHANISMS OF VIRUS-INDUCED... RELATION OF VIRUSES TO... RESPIRATORY VIRUSES IN STABLE... OTHER INFECTIVE AGENTS CONCLUSIONS REFERENCES

 
Exacerbations of chronic obstructive pulmonary disease (COPD) are a major cause of morbidity and mortality and hospital admission. Respiratory viral infections, especially rhinoviruses, are a major cause of COPD exacerbations, with upper respiratory tract infections being associated with over 50% of COPD exacerbations. The presence of an upper respiratory tract infection leads to a more severe exacerbation and a longer symptom recovery time at exacerbation. Respiratory viral infections occurring during COPD exacerbations are more likely to lead to hospitalization. Sputum inflammatory markers were found to be higher in those patients with symptoms of a common cold or where rhinovirus was detected at exacerbation, thus suggesting that viral infections lead to greater airway inflammation and thus more severe exacerbations. COPD exacerbations are associated also with systemic inflammatory effects with increases in markers such as plasma fibrinogen and interleukin-6. Respiratory viruses have also been detected when the patients are stable, and this suggests that chronic viral infection may occur. Strategies to prevent viral infection will have a significant effect on the morbidity of COPD and will improve quality of life.

Key Words: respiratory viruses • chronic obstructive pulmonary diseases • exacerbations

There has been considerable recent interest in chronic obstructive pulmonary disease (COPD) exacerbations, as they are an important cause of the considerable morbidity, impaired health status, and mortality found in this condition (1). Exacerbations are episodes in the natural history of COPD when there is an increase in symptoms, especially the symptoms of increased dyspnea, increased sputum volume, and purulence (2). Exacerbations are associated with increased airway inflammation, although the inflammatory response at exacerbation has been shown to be variable and will depend on the trigger agent (3).

Some patients are prone to frequent exacerbations, and these frequent exacerbators have a worse health status and faster FEV₁ decline compared with infrequent exacerbators (2, 4, 5). Thus, strategies to reduce exacerbation frequency are urgently required. The development of appropriate therapies depends on an understanding of the important etiologic factors associated with exacerbations. A number of causative agents have been associated with COPD exacerbations, including bacteria and common pollutants, although respiratory viruses are one of the most important triggers of an exacerbation and are the subject of this review.

COPD exacerbations are more common in the winter months with colder temperatures (6) when there are more respiratory viral infections prevalent in the community. Patients may also be more prone to more severe exacerbations in the winter months, as lung function in patients with COPD shows small but significant falls with a reduction in outdoor temperature during winter (6).

Further evidence that respiratory viral infections are important triggers of exacerbations comes from the association of colds with exacerbations. In a prospective analysis of 504 exacerbations, where daily monitoring was performed, larger falls in peak flow were associated with symptoms of dyspnea and presence of colds and were related to longer recovery time from exacerbations (7). We have recently reported that up to 64% of exacerbations were associated with symptomatic colds, as assessed using daily diary card monitoring, and thus, it is likely that these exacerbations were precipitated by viruses (7). The various viruses that my lead to respiratory tract infections are listed in Table 1. The major viruses that cause upper and lower respiratory tract infections and that are thus associated with exacerbations are listed in Table 1.

	RHINOVIRUS

TOP ABSTRACT RHINOVIRUS DETECTION OF RESPIRATORY VIRUS... INFLUENZA ARE COPD PATIENTS MORE... EFFECT OF RESPIRATORY VIRUSES... MECHANISMS OF VIRUS-INDUCED... RELATION OF VIRUSES TO... RESPIRATORY VIRUSES IN STABLE... OTHER INFECTIVE AGENTS CONCLUSIONS REFERENCES

Early studies using serologic and cell culture diagnostic methods reported relatively small effects of rhinovirus at COPD exacerbations. In a study of 44 chronic bronchitics over 2 years, Stott and colleagues found rhinovirus in 13 of 87 exacerbations (14.9%) of chronic bronchitis (10). In a more detailed study of 25 patients with chronic bronchitis with 116 exacerbations over 4 years, Gump and colleagues found that only 3.4% of exacerbations could be attributed to rhinoviruses (11). In a study of 35 episodes of COPD exacerbation using serologic methods and nasal samples for viral culture, little evidence was found for a rhinovirus etiology of COPD exacerbation (12). Greenberg and colleagues recently also studied viral etiologies of COPD exacerbations and found using viral culture and serology that 27% of COPD exacerbations were associated with respiratory viruses, whereas in 44% of acute respiratory illnesses in control subjects were associated with viruses (13). In the patients with COPD, rhinoviruses accounted for 43% of the virus infections and were thus responsible for about a total of 12% of the exacerbations (13).

	DETECTION OF RESPIRATORY VIRUS BY POLYMERASE CHAIN REACTION

TOP ABSTRACT RHINOVIRUS DETECTION OF RESPIRATORY VIRUS... INFLUENZA ARE COPD PATIENTS MORE... EFFECT OF RESPIRATORY VIRUSES... MECHANISMS OF VIRUS-INDUCED... RELATION OF VIRUSES TO... RESPIRATORY VIRUSES IN STABLE... OTHER INFECTIVE AGENTS CONCLUSIONS REFERENCES

 
The availability of polymerase chain reaction (PCR) techniques for viral detection enabled a more detailed evaluation of the role of viruses, especially rhinoviruses at asthmatic and COPD exacerbations. Studies in childhood asthma have shown that rhinovirus can be detected by PCR from a large number of these exacerbations (9). We reported a study to evaluate the nature of respiratory viruses at COPD exacerbation using PCR techniques for the major respiratory viruses (14). Patients were sampled at exacerbation and also when stable. Up to 40% of COPD exacerbations were associated with viral infections, although this may be an underestimate due to difficulties in sampling at the very onset of an exacerbation when the virus can be detected. Rhinovirus was the most common respiratory virus detected and was found in 58% of viral exacerbations. The other viruses detected included coronavirus (11% of virus exacerbations), influenza A and B (16%), parainfluenza, adenovirus, and Chlamydia pneumoniae, which were each detected in one exacerbation. We also detected respiratory syncytial virus (RSV) in approximately 29% of exacerbations, although RSV was also found in a significant number of patients in the stable state (discussed later here). Rohde and colleagues also used PCR techniques to detect respiratory viruses and found viruses in a total of 56% of COPD exacerbations (15). As in the East London COPD cohort, rhinovirus was the most common virus detected in 36% of virus-associated exacerbations (15). In 10 of the 48 patients with COPD exacerbations (21%), multiple viruses were detected.

	INFLUENZA

TOP ABSTRACT RHINOVIRUS DETECTION OF RESPIRATORY VIRUS... INFLUENZA ARE COPD PATIENTS MORE... EFFECT OF RESPIRATORY VIRUSES... MECHANISMS OF VIRUS-INDUCED... RELATION OF VIRUSES TO... RESPIRATORY VIRUSES IN STABLE... OTHER INFECTIVE AGENTS CONCLUSIONS REFERENCES

 
The relatively low levels of influenza in the East London COPD study of virus detection may be related to the fact that 74% of the patients with COPD had received influenza immunization. In the study by Rohde and colleagues, influenza was associated with a slightly higher number at 25% of exacerbations (15). Because of the introduction of influenza immunization for patients with chronic lung disease, influenza has become a less prominent cause of exacerbation, although this is still likely to be an important factor at times of influenza epidemics.

In an older cohort of patients with chronic lung disease in the United States, studied by Nichol and colleagues, patients who were not vaccinated with influenza had twice the hospitalization rate in the influenza season compared with the noninfluenza season (16). In addition, influenza vaccination was associated with a lower risk of death (16). It is likely that in this study as patients were older the most common cause of the chronic lung disease was COPD, and as influenza vaccination has a number of health benefits, it is essential that all patients with COPD receive vaccination.

	ARE COPD PATIENTS MORE SUSCEPTIBLE TO RESPIRATORY VIRUS INFECTION?

TOP ABSTRACT RHINOVIRUS DETECTION OF RESPIRATORY VIRUS... INFLUENZA ARE COPD PATIENTS MORE... EFFECT OF RESPIRATORY VIRUSES... MECHANISMS OF VIRUS-INDUCED... RELATION OF VIRUSES TO... RESPIRATORY VIRUSES IN STABLE... OTHER INFECTIVE AGENTS CONCLUSIONS REFERENCES

 
As some patients with COPD have a history of frequent exacerbations, it would be an attractive hypothesis that these patients showed an increased susceptibility to infection with viruses. However, in the study by Greenberg and colleagues, there was no evidence that patients with COPD showed a greater susceptibility to respiratory virus infection in the form of more infections compared with control subjects (13). However, PCR techniques were not used in this study to detect all of the respiratory viral infections, and thus, it is possible that in this study some of the infections were missed.

Using the median number of exacerbations as a cutoff point, we have previously classified patients with COPD as frequent and infrequent exacerbators (2). Quality of life was significantly worse in the frequent compared with the infrequent exacerbators. Factors predictive of frequent exacerbations included the exacerbation frequency in the previous year. In our study of Seemungal and colleagues of respiratory virus detection by PCR (14), at least one virus was detected in 64% of patients, and these patients had a higher exacerbation frequency than patients in whom viruses were not detected. Thus, patients with a history of frequent exacerbations may be more susceptible to respiratory viral infections, although further work is required to study the nature of this susceptibility. However, patients with frequent exacerbations may be more likely to report exacerbations, and thus, increased recovery of viruses could be due to reporting bias.

One possibility is that patients with a history of frequent exacerbation develop upregulation of intercellular adhesion molecule (ICAM-1), which is the major receptor for the major group of human rhinovirus, and this requires evaluation. Retmales and colleagues have shown that latent expression of adenoviral E1A protein in alveolar epithelial cells of patients with emphysema may increase ICAM-1 expression and this could be a potential mechanism for greater susceptibility to rhinovirus infection in COPD (17). In further work, Higashimoto and colleagues have shown that E1A-transfected human bronchial epithelial cells show increased expression of ICAM-1, interleukin (IL)-8, and the transcription factor nuclear factor-B (18).

However, patients with COPD are chronically colonized with airway bacteria, and the bacterial load is related to airway inflammation and disease progression (18, 19). We have also shown that soluble ICAM production in primary bronchial epithelial cells from patients with COPD after stimulation with tumor necrosis factor- is higher with increasing airway bacterial load (20). This relationship between soluble ICAM-1 release and bacterial count suggests that patients with bacterial colonization may be more susceptible to developing virus-associated exacerbations and may explain our previous finding that patients with a history of frequent exacerbations have a higher incidence of bacterial colonization (21). Further study is required of the interactions between viruses and airway bacteria at COPD exacerbations.

	EFFECT OF RESPIRATORY VIRUSES ON EXACERBATION SEVERITY

TOP ABSTRACT RHINOVIRUS DETECTION OF RESPIRATORY VIRUS... INFLUENZA ARE COPD PATIENTS MORE... EFFECT OF RESPIRATORY VIRUSES... MECHANISMS OF VIRUS-INDUCED... RELATION OF VIRUSES TO... RESPIRATORY VIRUSES IN STABLE... OTHER INFECTIVE AGENTS CONCLUSIONS REFERENCES

 
There is evidence from work in patients presenting as emergency admissions with acute asthma that patients with asthma with infective exacerbations caused by respiratory viruses were more likely to be admitted to hospital and had an increased length of stay (22). Patients with asthmatic exacerbations caused by viruses also had increased airway inflammatory markers (22). As discussed earlier, the presence of a common cold at exacerbation leads to more severe exacerbations (7). In our study of patients with COPD, respiratory viruses were associated with a longer median symptom recovery time at exacerbation of 13 days compared with 6 days for nonviral exacerbations (14). Viruses were also found to be associated with a slower rate of symptom score resolution (Figure 1). We also showed that exacerbations associated with common colds showed higher levels of airway inflammatory markers compared with those without a history of colds (3) (Figure 2).

View larger version (13K): [in this window] [in a new window]   Figure 1. Graph showing the cumulative percentage of viral (circles) and nonviral (squares) exacerbations recovering symptomatically with respect to time after onset during 150 chronic obstructive pulmonary disease (COPD) exacerbations (p = 0.006) (reproduced from Seemungal and colleagues [14] with permission).

View larger version (24K): [in this window] [in a new window]   Figure 2. Induced sputum interleukin (IL)-6 levels in the absence and presence of a natural cold. Data are expressed as medians (interquartile range) (reproduced from Reference [3] with permission).

	MECHANISMS OF VIRUS-INDUCED EXACERBATIONS

TOP ABSTRACT RHINOVIRUS DETECTION OF RESPIRATORY VIRUS... INFLUENZA ARE COPD PATIENTS MORE... EFFECT OF RESPIRATORY VIRUSES... MECHANISMS OF VIRUS-INDUCED... RELATION OF VIRUSES TO... RESPIRATORY VIRUSES IN STABLE... OTHER INFECTIVE AGENTS CONCLUSIONS REFERENCES

 
There are a number of mechanisms that may be involved in the association between viruses and exacerbations. The major group of rhinovirus (accounting for 90% of total rhinovirus types) attaches to airway epithelium through ICAM-1, inducing ICAM-1 expression, which promotes inflammatory cell recruitment and activation, as seen in exacerbations (23). The minor rhinovirus group uses members of the low-density lipoprotein–receptor family as cell surface receptors, although ICAM-1 surface expression may be also upregulated (23). There is some evidence for upregulation of ICAM-1 in the bronchial mucosa of patients with chronic bronchitis (24), and thus, ICAM-1 is an important therapeutic target in COPD exacerbations associated with rhinoviruses, as blockage of ICAM-1 may prevent rhinovirus infection.

The most likely explanation for the increase in inflammatory cytokines at exacerbations is that rhinovirus causes direct lower airway inflammation, perhaps through an upregulated ICAM-1 receptor. There is now increasing evidence from experimental rhinovirus infections that respiratory viruses can infect the lower airway (25, 26). Experimental rhinovirus infection has been shown to increase sputum IL-6 in normal subjects and subjects with asthma (27–29). In patients with COPD, we showed that that rhinovirus can be recovered from induced sputum more frequently using PCR techniques than from nasal aspirates at exacerbation, suggesting that wild-type rhinovirus can infect the lower airway and contribute to inflammatory changes at exacerbation (30). Rohde and colleagues also recently confirmed that the yield of viruses in sputum is higher than in the upper airway (15). As is the case for common colds discussed previously here, we also found that exacerbations associated with the presence of rhinovirus in induced sputum had larger increases in airway IL-6 levels compared with exacerbations in which rhinovirus was not detected (30). This suggests that viruses increase the severity of the airways inflammation at exacerbation. This finding is in agreement with the data that respiratory viruses produce longer and more severe exacerbations (7, 14) and thus have a major impact on healthcare use.

In our work, rises in cell counts and IL-8 were more variable with COPD exacerbation marked heterogeneity in the degree of the inflammatory response at exacerbation (3). The exacerbation IL-8 levels were related to sputum neutrophil and total cell counts, indicating that neutrophil recruitment may be a source of airway IL-8 at exacerbation. Lower airway IL-8 has been shown to increase with experimental rhinovirus infection in normal patients and patients with asthma in some studies (28), but not in others (29). However, patients with COPD already have upregulated airway IL-8 levels when stable that is related to their high sputum neutrophil load (31), and this could also explain the variable exacerbation rises. COPD exacerbations are associated with a less pronounced airway inflammatory response than asthmatic exacerbations (32), and this may explain the relatively reduced response to steroids seen at exacerbation in patients with COPD, relative to patients with asthma (23–39).

Viral infections have been associated with increased oxidant stress that is increased at COPD exacerbation (40). Rhinovirus infection of human respiratory epithelial cells increases production of reactive oxygen species and stimulates the activation of nuclear factor-B important in the regulation of the IL-8 gene (41). Viral infections can also induce the expression of stress–response genes (e.g., heme–oxygenase-1) and genes encoding antioxidant enzymes (e.g., glutathione peroxidase, manganese superoxide dismutase) (42). These antioxidant enzymes may be important in protecting against the effects of the virally mediated inflammation at COPD exacerbation. We have also shown that exacerbations are associated with increased airway and systemic endothelin-1 levels (43). Endothelin-1 is an important bronchoconstrictor peptide that has been found to be proinflammatory and mucogenic and has been also implicated in the pathogenesis of virally mediated inflammation (44). Sputum ET-1 levels increase at COPD exacerbation, and these increases are related to sputum IL-6 levels. Further work with specific ET receptor antagonists is required to determine the role of ET-1 and may provide a new therapeutic option for virus-induced inflammation associated with COPD exacerbations.

	RELATION OF VIRUSES TO SYSTEMIC INFLAMMATION IN COPD

TOP ABSTRACT RHINOVIRUS DETECTION OF RESPIRATORY VIRUS... INFLUENZA ARE COPD PATIENTS MORE... EFFECT OF RESPIRATORY VIRUSES... MECHANISMS OF VIRUS-INDUCED... RELATION OF VIRUSES TO... RESPIRATORY VIRUSES IN STABLE... OTHER INFECTIVE AGENTS CONCLUSIONS REFERENCES

 
Recently, associations have been described between chronic bronchitis and death from cardiovascular disease (45). Plasma fibrinogen is an independent risk factor for cardiovascular disease (46), and we have shown that plasma fibrinogen is increased in COPD, thus perhaps explaining why patients with COPD with moderate to severe disease are more susceptible to ischemic events (47). At exacerbation, we found further increased levels of IL-6 and plasma fibrinogen (47). IL-6 is produced by blood monocytes and stimulates the production of fibrinogen in the liver. We also found that plasma fibrinogen levels were higher in the presence of colds and with detection of respiratory viral infections at COPD exacerbation (14, 47). This suggests that respiratory viral infections are associated with increased systemic inflammatory markers and also may predispose to an increased risk from vascular disease.

Epidemiologic studies have suggested that infections, especially those of the respiratory tract, may be involved in the onset of myocardial infarction and stroke (48), and thus, patients who are frequent exacerbators with their recurrent viral infections as triggers may be particularly susceptible to cardiovascular disease. A recent study of influenza immunization in older patients has shown that immunization is associated with a reduction in the risk of hospitalization for heart disease and stroke, thus providing more evidence for the link between respiratory viral infection and vascular disease (49).

	RESPIRATORY VIRUSES IN STABLE COPD

TOP ABSTRACT RHINOVIRUS DETECTION OF RESPIRATORY VIRUS... INFLUENZA ARE COPD PATIENTS MORE... EFFECT OF RESPIRATORY VIRUSES... MECHANISMS OF VIRUS-INDUCED... RELATION OF VIRUSES TO... RESPIRATORY VIRUSES IN STABLE... OTHER INFECTIVE AGENTS CONCLUSIONS REFERENCES

 
We also found in the study from the East London COPD cohort that some exacerbations were associated with RSV, although more patients had RSV detected in the stable state than at exacerbation (14). In none of these samples was the RSV detected by culture or serology, and the detection disappeared when the sensitivity of the PCR was reduced, suggesting that the colonization with virus was low grade. However, we found that patients in whom RSV was detected were more likely to have elevated systemic inflammatory markers (14). This implies that RSV may be a cause of chronic infection in COPD, and further evaluation of the role of RSV at COPD exacerbation is required. Viruses apart from RSV were detected in 16.2% of patients with stable COPD by PCR. Rhinoviruses were the most common virus detected in the stable state as well as exacerbation, being found in 7.3% of stable patients with COPD and coronaviruses in 5.9% of stable patients. There was also a tendency for patients in whom these viruses were detected in stable COPD to give a history of more frequent exacerbations in the year before recruitment.

	OTHER INFECTIVE AGENTS

TOP ABSTRACT RHINOVIRUS DETECTION OF RESPIRATORY VIRUS... INFLUENZA ARE COPD PATIENTS MORE... EFFECT OF RESPIRATORY VIRUSES... MECHANISMS OF VIRUS-INDUCED... RELATION OF VIRUSES TO... RESPIRATORY VIRUSES IN STABLE... OTHER INFECTIVE AGENTS CONCLUSIONS REFERENCES

 
C. pneumoniae has been proposed as a trigger for exacerbations in patients with COPD. Using IgM and IgG antibody titers, C. pneumoniae has been identified as the etiologic factor in 5% of COPD exacerbations in outpatients (50), whereas Blasi and coworkers identified C. pneumoniae in 4% of COPD exacerbations (51). Mogulkoc and colleagues in a relatively small sample of patients with exacerbations detected high IgG titers to C. pneumoniae in 7 of 49 exacerbations, suggesting that C. pneumoniae was associated with approximately 16% of COPD exacerbations (52). Karnak and colleagues detected serologic evidence of recent C. pneumoniae infection in 34% of patients with COPD having acute exacerbations, although microbiological examination of the sputum found potentially pathogenic microorganisms in 60% of the patients with COPD, suggesting that C. pneumoniae was not the sole agent responsible for the exacerbation (53).

However, one of the problems with relating C. pneumoniae infection to exacerbation is that many patients with COPD have had exposure to previous C. pneumoniae infection, and thus, chlamydial serology is not the best technique to evaluate the cause of COPD exacerbation. In addition, chronic infection with C. pneumoniae may be a feature of COPD. One study using tissue samples from lung resections found increased immunohistochemical staining for C. pneumoniae in patients with COPD as compared with staining in patients with normal lung function (54). However, a recent study has suggested that the presence of antibodies to C. pneumoniae has no effect on the natural history of COPD (55). Seemungal and colleagues in our group showed no relationship between chlamydial serology and exacerbation frequency or disease progression; thus, the significance of persistent antibodies against C. pneumoniae is not known (56).

Recently, Blasi and colleagues have reported that the presence of C. pneumoniae DNA in sputum of patients with COPD was related to disease severity and increased airway bacterial colonization (57). In a further analysis in the same study, the authors reported that patients who had evidence of C. pneumoniae DNA detection in peripheral blood mononuclear cells had a higher exacerbation frequency over a 2-year follow-up period than those who were PCR negative. Seemungal and colleagues found no evidence of C. pneumoniae DNA in induced sputum in stable patients, although they did detect C. pneumoniae at exacerbation (56). There was no relationship between C. pneumoniae detection at excerbation and exacerbation frequency or disease severity. More importantly, unlike the case of rhinovirus triggered exacerbations, we found no relationship between C. pneumoniae detection and inflammatory markers, suggesting that C. pneumoniae exacerbations are no different from exacerbations without C. pneumoniae detection (56).

One group has reported that serologic evidence of infection with Legionella species is high in patients with hospitalizations due to COPD, although the exact relevance of this finding is not clear, as in the majority of the exacerbations, other pathogens were also reported. (58). Mycoplasma pneumoniae is an uncommon cause of COPD exacerbation, with less than 1% of exacerbations diagnosed by complement fixation or culture methods (11, 59). Another more recent study using also serologic techniques found that M. pneumoniae was associated with only 6% of COPD exacerbation (52). However, the results of analysis of samples for M. pneumoniae using PCR have not been reported.

	CONCLUSIONS

TOP ABSTRACT RHINOVIRUS DETECTION OF RESPIRATORY VIRUS... INFLUENZA ARE COPD PATIENTS MORE... EFFECT OF RESPIRATORY VIRUSES... MECHANISMS OF VIRUS-INDUCED... RELATION OF VIRUSES TO... RESPIRATORY VIRUSES IN STABLE... OTHER INFECTIVE AGENTS CONCLUSIONS REFERENCES

 
The etiology of COPD exacerbation is complex, and a number of factors have been shown to be associated with exacerbations. However, the available evidence suggests that respiratory viruses, especially infections with rhinovirus, the cause of the common cold, are the most important triggers of exacerbations. Respiratory viruses are also associated with more severe exacerbations and may have important interactions with cold temperature and common pollutants. Although bacteria have been implicated in COPD exacerbations for many years and antibiotics are used for therapy, there is little information available about the nature of interactions between viruses and bacteria. Respiratory viral infections are an important target for therapy in COPD, and prevention of viral infection may reduce exacerbation frequency and hence improve health status. A reduction of COPD exacerbation will probably have an important impact on the considerable morbidity and mortality associated with COPD.

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

	REFERENCES

TOP ABSTRACT RHINOVIRUS DETECTION OF RESPIRATORY VIRUS... INFLUENZA ARE COPD PATIENTS MORE... EFFECT OF RESPIRATORY VIRUSES... MECHANISMS OF VIRUS-INDUCED... RELATION OF VIRUSES TO... RESPIRATORY VIRUSES IN STABLE... OTHER INFECTIVE AGENTS CONCLUSIONS REFERENCES

 

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