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CORRESPONDENCE: M. Miravitlles, Servei de Pneumologia, Institut Clínic de Pneumologia i, Cirurgia Toràcica (IDBAPS)Hospital Clínic i Provincial, Barcelona, Spain. Fax: 34 932275454. E-mail: marcm@separ.es
Keywords: bronchial colonisation, bronchial infection, chronic obstructive pulmonary disease, exacerbation
Received: January 28, 2002
Accepted February 6, 2002
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Abstract |
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 TOP Abstract Aetiology of chronic obstructive...Frequency and outcomes of...The "fall and rise"...Impact of colonisation and...Unanswered questionsReferences |
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Evidence indicates that the number of patients with pathogenic bacteria in respiratory secretions and the bronchial bacterial load increase during exacerbations. Furthermore, the local inflammatory response of the host parallels the increase in bacterial load. From these observations, it can be speculated that, for symptoms of acute exacerbation to appear, there must be a minimum bacterial load in the airways, i.e. a threshold above which the inflammatory reaction is severe enough to elicit clinical symptoms of exacerbation. This threshold may vary from patient to patient owing to different modifying factors. Some of these factors may be the recognised risk factors for relapse, such as increasing age, impairment of lung function, comorbid conditions or frequent exacerbations in the past.
Relapse rates after ambulatory treatment of acute exacerbation of COPD may be as high as 20–25% of cases. Relapses are associated with significant mordibity and increased costs.
A number of unanswered questions remain regarding exacerbations of chronic obstructive pulmonary disease. These include the role of viral infection, the importance of residual bacterial colonisation and the impact of new antibiotics on the treatment of exacerbations.
Chronic obstructive pulmonary disease (COPD) is one of the most prevalent diseases in developed countries. Furthermore, the number of individuals affected has grown since the 1980s 1. In Spain, the prevalence of COPD is 9% in adults aged 40–70 yrs, although only 22% of these are diagnosed 2. Tobacco smoking is the main aetiological factor for COPD. In a population-based study in Spain, 25% of the population aged 40–70 yrs were smokers and another 25% former smokers 3. Only 15–20% of smokers will develop COPD, and smokers with COPD exhibit higher tobacco consumption and greater dependence on nicotine than smokers who do not have COPD, and more than one-third have never tried to stop smoking 3. These figures indicate that the problem of COPD in most developed countries will continue to increase in the near future.
The chronic and progressive course of COPD is often aggravated by short periods of increasing symptoms, particularly increasing cough, dyspnoea and production of sputum which can become purulent. The majority of these exacerbations are caused by bronchial infection, and, if frequent, have been demonstrated to have a negative impact on quality of life in patients with COPD 4. Furthermore, acute exacerbations are the most frequent cause of medical visits, hospital admissions and death among patients with chronic lung disease 5. Persistence of bacteria in the lower airway has been associated with increased inflammation, which may potentially cause damage to the lungs.
Some of the existing evidence of the role of bacteria in acute exacerbations and the significance of bronchial colonisation in patients with COPD are reviewed in the present article.
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Aetiology of chronic obstructive pulmonary disease exacerbations |
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TOPAbstractAetiology of chronic obstructive...Frequency and outcomes of...The "fall and rise"...Impact of colonisation and...Unanswered questionsReferences |
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Published evidence indicates that respiratory infection may be responsible for 50–70% of exacerbations 17, with H. influenzae being the most frequent bacterium isolated in all series, followed by Moraxella catarrhalis, Streptococcus pneumoniae and Pseudomonas aeruginosa 7, 17–19. Viruses may account for 15–25% of all infective exacerbations, particularly influenza/parainfluenza viruses and adenoviruses. In a recent study, 26% of exacerbations of moderate-to-severe COPD patients (mean forced expiratory volume in one second (FEV1) 40% of the predicted value) were associated with rhinovirus infection 20.
The role of atypical microorganisms in exacerbations of COPD has recently received increased attention. In a series of 47 patients with exacerbated COPD and a mean FEV1 of 41% pred, Mogulkoc et al. 21 diagnosed Chlamydia pneumoniae infection serologically in 11 (22%), although in three of these cases other pathogenic bacteria were also found. Mycoplasma pneumoniae infection was diagnosed in three (6%). Interestingly, no clinical differences were found between patients with or without Chlamydia infection. It is important to point out the possibility that Chlamydia persists in the body indefinitely after acute infection 22, and this persistence could promote inflammation in the lungs of subjects with COPD and accelerate the progression of disease. However, a recent follow-up study failed to demonstrate any negative effect of chronic C. pneumoniae infection on the progression of airflow obstruction 23.
In view of the above, it would be useful to define certain easily obtainable patient characteristics that might indicate the possible aetiology of COPD exacerbations, thereby facilitating specific antibiotic treatment and reducing the high number of failures recorded with empirical treatment. Research in pneumonia has led to the identification of some risk factors associated with an increased probability of different microorganisms causing the episode, such as advanced age, comorbid conditions and alcohol consumption. However, no studies have attempted to identify patients with increased probability of having different causative pathogens in acute exacerbations of COPD. Only recently, two studies suggested that the degree of functional respiratory impairment in COPD patients indicates the presence of different PPMs in their sputum samples during the course of an exacerbation 18, 24. Individuals with severe pulmonary function impairment, manifested in an FEV1 of <50% pred, are at a six-fold higher risk of suffering acute exacerbations caused by H. influenzae or P. aeruginosa than patients presenting with an FEV1 of >50% pred. In patients with milder COPD, with an FEV1 of >50% pred, sputum culture was less effective, since non-PPMs of scant diagnostic value were isolated in most cases. Conversely, in more seriously affected patients, sputum culture often made it possible to identify PPMs in significant concentrations 18. This result concurs with the findings of Gompertz et al. 10, who observed that patients with purulent (infectious) exacerbations had more severely impaired FEV1 than those with mucoid exacerbations (table 1
). It also points to a greater influence of bacterial infection on exacerbations in this subgroup of patients with severe ventilatory impairment.
The importance of Pseudomonas in acute exacerbations in severe COPD has been confirmed by another study in a group of patients with severe exacerbations of COPD requiring mechanical ventilation. This study revealed an unexpectedly high rate of Gram-negative organism and Pseudomonas/Stenotrophomonas spp. isolation in respiratory samples from these patients; these pathogens accounted for 44% of all PPMs identified, whereas H. influenzae was found in 33% and S. pneumoniae constituted only 11% of PPMs isolated 19.
In conclusion, a variety of causes of acute COPD exacerbations exist. However, infection may account for approximately two-thirds of cases. The role of atypical microorganisms is receiving increasing attention, and, together with viruses, they may be the cause of one-third of infectious exacerbations. The rest are attributed to pathogenic bacteria. Unfortunately, clinical manifestations do not permit identification of the cause of the exacerbation, since viral and atypical exacerbations are associated with the same clinical symptoms and a similar inflammatory response. Only purulence of sputum has been associated with high bacterial load in respiratory secretions during exacerbations. Also, other studies have shown that microorganisms causing acute exacerbations of COPD are distributed unevenly among patients with differering degrees of severity, with those more severely affected showing a greater incidence of Pseudomonas and H. influenzae. The influence which the application of new empirical treatments according to the degree of functional impairment may have on improving disease progression is a subject which should be developed further in future clinical studies.
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Frequency and outcomes of exacerbations: risk factors for relapse |
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TOPAbstractAetiology of chronic obstructive...Frequency and outcomes of...The "fall and rise"...Impact of colonisation and...Unanswered questionsReferences |
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Outcomes following ambulatory treatment of acute COPD exacerbations have only recently merited attention. The known failure rates after ambulatory treatment were derived from clinical trials on antibiotics in chronic bronchitis and ranged 7–12% 30, 31. Nevertheless, these results cannot be extrapolated to everyday practice, since patients included in clinical trials consisted of chronic bronchitis patients (whatever that means) and included subjects with ages ranging 18–90 yrs, a significant proportion of which were never smokers and individuals without ventilatory impairment. Some studies have already shown the low relapse rate and low therapeutic value of antibiotics in such a population 32, 33. However, during the 1990s, some studies addressed this issue in observational "real-life" studies and showed a failure rate ranging 12–26% 34–39. Since relapse after initial treatment for acute exacerbation may lead to prolonged disability, a new course of antibiotics, an emergency visit or even hospital admission, it is crucial to identify patients most at risk of relapse. Identification of risk factors for failure of ambulatory treatment may permit the implementation of more aggressive broad-spectrum treatment and closer follow-up. In a further step, risk factors associated with relapse should be incorporated into management guidelines to aid general practitioners (GPs) in identifying at-risk patients. The first management guidelines for acute exacerbations of chronic bronchitis that included stratification of patients according to severity were the Canadian guidelines 40. The importance of risk factors for relapse was later explicitly recognised in the Latin American 41 and North American guidelines 42 for treatment of COPD exacerbations.
Among the risk factors for relapse, the severity of the underlying disease is one of the most important; patients with more severe dyspnoea at baseline are more at risk of returning to the GP with persistence or increase of symptoms 39. In a retrospective study of 1,001 COPD patients recruited in primary care, it was observed that increased severity of FEV1 impairment was independently associated with increased risk of suffering 
2 acute exacerbations·yr–1. Furthermore, FEV1 impairment was associated with increased risk of hospital admission during the same period 29. The consistent and important association of decreasing FEV1 with both the risk of frequent exacerbations and admissions is not surprising and needs no further discussion, since low FEV1 is a predominant risk factor for mortality from COPD in most epidemiological studies 43–45. This effect, among others, may be determined by the association of more severely impaired FEV1 and the isolation of more aggressive bacteria causing the exacerbations 18, 19, 24.
An association between the number of visits to the GP during the previous year for respiratory problems and increased risk of relapse was also observed; the risk of failure increased by 7.6% for each extra visit to the GP 39. The number of visits and number of previous exacerbations strongly correlated, suggesting that most visits to the GP were due to exacerbation symptoms. Similarly, Seemungal et al. 4, in a prospective study, found that frequent past exacerbations constituted one of the factors most strongly associated with recurrent exacerbations. In two other studies, the number of previous exacerbations was a risk factor for relapse after ambulatory treatment of an acute exacerbation of chronic bronchitis 34, 36. These results, together with those of the present author's group, suggest that there exists a subgroup of patients more prone to developing recurrent respiratory infections despite having the same degree of severity of underlying disease.
It has been observed that the presence of coexisting diabetes or significant cardiac disease is associated with increased risk of relapse on univariate analysis. However, after multivariate analysis, only ischaemic heart disease remained significant, with an increased risk of 63% 39. Similarly, other studies found coexistent cardiopulmonary disease to be a risk factor for referral to hospital after treatment for an acute exacerbation 34, 37, and cardiac comorbidity was found to be among the best predictors of mortality of COPD patients discharged after an acute exacerbation 46, 47. In a previous retrospective study, it was observed that the presence of ischaemic heart disease or cardiac insufficiency correlated strongly with an increased risk of hospital admission for decompensated COPD with an odds ratio of 1.97 (95% confidence interval 1.24–3.14) 29. Conversely, Adams et al. 37 observed no association between comorbidity and outcome in a hospital-based population of severe COPD patients (29% with an FEV1 of <35% and 27% with oxygen therapy). These results suggest that cardiac comorbidity is a risk factor for poor outcome, particularly in mild-to-moderate COPD patients; however, when the lung disease is severe, impairment of pulmonary function prevails over cardiac disease as a risk factor. Additionally, comorbidity appears to be a risk factor for severe life-threatening exacerbations, which may provoke admission and even be a cause of death, particularly in older patients 48.
Surprisingly, the severity of the exacerbation did not influence the outcome of the study of Miravitlles et al. 39. However, the severity of the episode was a determinant of outcome in placebo-controlled studies 49. Since almost all of the present author's patients were receiving broad-spectrum antibiotics, these results suggest that, under broad-spectrum antimicrobial treatment, the severity of exacerbation symptoms is no longer a risk factor for relapse. These results, in a large cohort of patients, confirmed the observations of previous studies 34, 36, 37, which also failed to find any significant effect of exacerbation severity on outcome in smaller populations.
Other risk factors for poor outcome include increasing age 29, 47 and the presence of chronic mucus hypersecretion (CMH), both of which are facilitating factors for exacerbations. In a previous population-based study, CMH was found to be a significant predictor of COPD-related death with implicated pulmonary infection 50. However, to the present author's knowledge, no previous studies had investigated the relationship between CMH and the probability of admission due to COPD exacerbation. The results of Miravitlles et al. 29 suggest that CMH renders the patient more prone to suffering recurrent exacerbations. Other observations suggest that, in severely exacerbated COPD patients, CMH may also be a risk factor for death 43. A summary of risk factors for relapse or admission is presented in table 2.
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The "fall and rise" or quantitative hypothesis of acute bacterial chronic obstructive pulmonary disease exacerbations |
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TOPAbstractAetiology of chronic obstructive...Frequency and outcomes of...The "fall and rise"...Impact of colonisation and...Unanswered questionsReferences |
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From these observations, it can be speculated that, for symptoms of acute exacerbation to appear, there must be a minimum bacterial load in the airways, a threshold above which the inflammatory reaction is severe enough to elicit clinical symptoms of exacerbation. This threshold may be difficult to establish and may vary from patient to patient owing to different modifying factors. Factor candidates for modulating the threshold for clinical symptoms may be intrinsic to the patient or extrinsic, and are summarised in table 3.
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(TNF-) in sputum 11. Some workers have shown that increased concentrations of TNF- induce hyperreactivity in respiratory smooth muscle 60, others have demonstrated that exposure to cigarette smoking induces eosinophilic airway inflammation 61, and, finally, patients with COPD may show increased eosinophilic inflammation during not only exacerbations 62 but also the stable phase, with intensity of eosinophilic inflammation correlated directly with concentration of neutrophils and inversely with FEV1 63. Thus, bronchial hyperresponsiveness may also have additive effects with bacterial colonisation, and hyperresponsive patients may react with exaggerated bronchial obstruction and respiratory symptoms to lower levels of bronchial inflammation; 4) Chronic mucus hypersecretion. By favouring colonisation, chronic mucus hypersecretion may facilitate the growth of bacteria and rapid achievement of a cfu concentration above the threshold 64; 5) Impairment of host defences. Any impairment in host defences, either locally within the bronchial mucosa or systemically, such as impairment of antibody responses 65, may facilitate bacterial adhesion and faster growth; 6) Nonspecific factors. Elderly patients or patients with significant comorbid conditions may feel worse with lower levels of bronchial inflammation and thus the threshold for these patients may be lower. Extrinsic factors that may decrease the threshold include the following: 1) Type of bacteria colonising the airway. Some studies have shown that bacteria differ in their ability to elicit an inflammatory response 8, 11. Therefore, the magnitude of the response varies among different species. This factor may complement the effect of impairment of pulmonary function, since patients with more severe airflow limitation suffer more frequently from exacerbations caused by more aggressive bacteria such as H. influenzae or P. aeruginosa 18, 24, both of these bacteria being among those that provoke a greater inflammatory reaction in the host 8, 11. Consequently, impairment of pulmonary function may decrease the threshold owing to both a lower respiratory reserve and the association with more pro-inflammatory bacteria; 2) Lower temperature. Some studies have shown lower temperature to be associated with decreased lung function in patients with COPD 14. Thus, a lower inflammatory burden may be required to trigger exacerbations during winter months; 3) Air pollution. Air pollution has been associated with increased number of acute exacerbations 15. Pollutants may induce bronchial inflammation similar to that induced by cigarette smoking, which adds to the inflammation originating from bacteria; 4) Treatment of COPD. From the description of these factors, it is easy to assume that any drug that improves pulmonary function (increases FEV1) may exhibit a protective effect against exacerbations by raising the threshold. Such exacerbation-preventing effects have been observed with various bronchodilators (ipratropium bromide 66, salmeterol xinafoate 67, and tiotropium 68). It is reasonable to suppose that the greater and more persistent the bronchodilator effect the better the prevention of exacerbations will be. If the hypothesis that eosinophils play a major role in exacerbations of COPD is true, it may explain the observed effect of inhaled steroids on prevention 25 and/or decreasing the severity of exacerbations 26 by modulating inflammation produced by colonisation and again raising the threshold. Patients treated with long-term inhaled steroids may need very high bacterial loads to overcome the anti-inflammatory effect of such drugs.
Based on this hypothesis, acute exacerbation of COPD is an inflammatory process driven by bacteria in the airways. The presence of one or more modifying factor implies that different cfu concentrations are required in different patients to initiate an exacerbation. When many modifying factors are present, the number of bacteria needed for an exacerbation to occur will be very low or even zero (mucoid or noninfectious exacerbations), whereas, when few or no modifying factors are present, high bacterial loads are required for clinical symptoms to appear. In this latter case, the signs of bacterial infection will be evident with purulence and high bacterial loads in sputum (purulent or infectious exacerbations; see table 1).
The inflammatory nature of the exacerbation explains the beneficial effect of oral steroids in this indication, whereas the effect of antibiotics is controversial. Antibiotics may not have a significant effect on exacerbations with many modifying factors (low threshold/low bacterial load), but are beneficial in exacerbations with few modifying factors (high threshold/high bacterial load), which can be identified by the characteristics of the sputum 9.
Basic research is still required to support or reject this hypothesis; however, some observations support it. In clinical trials with antibiotics in acute exacerbations of chronic bronchitis, a prolonged time to the next exacerbation has been observed in patients in whom the bronchial pathogen is eradicated after an acute exacerbation 69. This favours the "fall and rise" hypothesis, since patients from whom bacteria are effectively eradicated would require longer for the threshold of bacterial numbers to be reached compared with patients who were cured of the exacerbation but in whom bacteria still persisted after antibiotic treatment. This hypothesis would also explain why patients with acute exacerbations may be clinically cured even without eradication of the bacterial pathogen 70. It is not proof that this particular bacterium is not the cause of the exacerbation, but a demonstration that the antibiotic needs only to reduce bacterial counts to below the threshold to eliminate symptoms. Nevertheless, if eradication also occurs, the time required for the number of cfu to rise above the threshold will be longer (fig. 1).
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Impact of colonisation and infection on chronic obstructive pulmonary disease patients |
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TOPAbstractAetiology of chronic obstructive...Frequency and outcomes of...The "fall and rise"...Impact of colonisation and...Unanswered questionsReferences |
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Inflammation related to bacterial colonisation is not limited to that caused by IL-8. Recent work has shown increased TNF- concentrations in the sputum of patients colonised by H. influenzae 55, 73. The same authors have demonstrated that inflammation intensity is not related to the degree of airway obstruction but to colonisation by H. influenzae of respiratory secretions 56; consequently, H. influenzae is a stronger inflammatory stimulus than COPD severity. However, a relationship exists between the degree of airway limitation and prevalence of colonisation; Zalacain et al. 53 observed that 40% of their 88 patients with stable COPD (mean FEV1 of 55% pred) were colonised, mainly by H. influenzae. They found that severe airflow obstruction was associated with a relative risk of colonisation of 5.1 compared to mild obstruction. Similarly, Monsó et al. 54 found bacterial colonisation in 22% of their patients, with this low frequency probably being due to the milder disease of this group of patients (mean FEV1 of 74% pred). In any event, these results, obtained with very sensitive and specific techniques, such as the protected specimen bush, highlight the high frequency of bacterial colonisation in COPD, even in mild COPD patients. However, this high frequency does not mean that colonisation is a "normal" or innocent finding.
The inflammation associated with bronchial colonisation is not an "all or nothing" phenomenon. Different species elicit different degrees of inflammatory reaction. The most intense inflammation is generated by P. aeruginosa, followed by H. influenzae, whereas M. catarrhalis and H. parainfluenzae provoke a significantly milder reaction 8, 11. Another important aspect of bronchial inflammation is the association between increased bacterial load in respiratory secretions and the increased amount of cytokine release 8, 57. This observation supports the quantitative hypothesis (fall and rise) of bacterial exacerbations, since the intensity of inflammation parallels the increase in bacterial load. In agreement with this hypothesis, exacerbated patients show increased concentrations of bacteria in their respiratory secretions 7 and increased concentrations of granulocyte inflammatory markers (myeloperoxidase, IL-8 and TNF-) together with IL-6 74 and leukotriene B4 10, 12, all of which return to normal levels after antibiotic treatment 10, 12. However, some inflammatory activity persists even after 1 month, as evidenced by some cytokine concentrations 75 or by increased exhaled nitric oxide levels 76. This inflammation parallels the appearance of clinical symptoms and impairment of pulmonary function, which, in as much as 25% of cases, do not return to pre-exacerbation values, even after 35 days 75.
The impact of repeated exacerbations on pulmonary function is a matter of intense debate 78, 79. It would seem logical that repeated episodes may potentially damage lung tissues and lead to an accelerated rate of decline in pulmonary function. This is supported by a number of experimental observations. 1) Exacerbations are associated with transient decreases in pulmonary function, which, in some cases, take weeks to return to baseline levels 77. 2) Patients suffering from recurrent exacerbations have been shown to exhibit increased concentrations of inflammatory markers in their sputum even in the stable phase, suggesting persistent inflammation and potential lung damage 12. 3) Neutrophils are attracted into the airway lumen during exacerbations 80. Neutrophils release proteinases, which are incompletely neutralised, during phagocytosis 10, 12. Increased levels of neutrophils in sputum correlated with a rapid decline in FEV1 in a 15-yr follow-up study 81. 4) In cross-sectional studies, a greater bacterial load in respiratory secretions has been associated with increased inflammation and decreased lung function 56. 5) The urinary excretion of desmosine and isodesmosine, products of the degradation of lung elastin, are significantly increased during exacerbations of COPD compared with the stable phase 82, coinciding with an increase in free elastase levels during exacerbations 10, 12. Furthermore, higher urinary concentrations of desmosine have been associated with a faster decline in FEV1 in COPD 83. 6) A correlation has been found between the number of previous exacerbations and the extent of emphysema by computed tomography (CT) 84.
The negative impact of exacerbations on lung function has been demonstrated in a longitudinal study in patients with emphysema due to 1-antitrypsin deficiency. In this 2-yr follow-up study, Dowson et al. 85 observed a significant correlation between exacerbation frequency and rate of decline in FEV1. Interestingly, lung density, as assessed by quantitative high-resolution CT (HRCT) and transfer factor of the lung for carbon monoxide (TL,CO), was more sensitive to changes than FEV1.
Very recently, results from the Lung Health Study, involving 5,887 smokers followed up for 5 yrs, demonstrated that the number of respiratory infections influenced the rate of decline in FEV1 in those who continued smoking 59. Smokers suffered an extra 7-mL decline in FEV1 for every additional exacerbation.
Why is it so difficult to demonstrate the influence of respiratory infections on the rate of decline in FEV1 despite all the existing evidence? Several reasons account for this difficulty. Firstly, longitudinal studies are difficult and expensive to perform. Furthermore, owing to the slow progression of COPD, large populations must be followed up for prolonged periods of time, with appropriate control groups, for small effects to become evident. Secondly, exacerbations are limited in number; an average patient may suffer 1 or 2 exacerbations·yr–1, which represents 7–20 days with symptoms or 10–50 days·yr–1 with increased inflammation. Even if an effect exists, many years would be required to accumulate enough days with increased inflammation for this effect to become clinically evident. Thirdly, no clear definition of exacerbation exists and many exacerbations are not reported to the attending physician 4, 77, making it difficult to investigate the influence of such episodes on the progression of the disease. Finally, FEV1 may not be sufficiently sensitive to detect small effects on the progression of COPD. Other outcome measures such as HRCT or TL,CO may be more sensitive in detecting the deleterious effects of infections on disease progression 85.
The influence of infections on the progression of COPD has become evident in patients with added risk factors for rapid progression of the disease, such as active smokers 59 or patients with 1-antitrypsin deficiency 85. These observations suggest that respiratory infections have a real effect on the progression of the disease, but that the magnitude is so small that in individuals with no other risk factors, large groups of patients with extended follow-up periods are required to detect such a small effect.
A further consequence of acute exacerbations of COPD is the great economic burden associated with attention to exacerbated COPD patients. The mean total cost of an acute COPD exacerbation was estimated to be 140 Euros in a recent study on primary care in Spain, the major part being due to hospitalisations, which represented 58% of the total cost, followed by the drug acquisition cost at 32.2% 86. These costs may not be applicable to other countries because of the differences in reference prices, management practices and healthcare systems; however, if the high prevalence of COPD and the frequency of exacerbations are considered, it is very easy to understand the magnitude of the healthcare burden derived from this disease.
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Unanswered questions |
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TOPAbstractAetiology of chronic obstructive...Frequency and outcomes of...The "fall and rise"...Impact of colonisation and...Unanswered questionsReferences |
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The significance and prevalence of viral infection in COPD exacerbations have been increasingly recognised 20, 87. Viral infections have been associated with increased inflammation 20, 87 and viruses may persist in the airways 87. Furthermore, latent adenoviral infection has been implicated in increased inflammation in patients with COPD 88. However, the prevalence of viral infection as a cause of exacerbations, the role of viruses in the progression of ventilatory impairment and the possible interaction between viruses and bacteria in the lower airways have yet to be defined.
Another aspect that requires further investigation is the impact of bronchial bacterial colonisation and infection on the progression of the disease, as commented on previously. Haemophilus influenzae has been detected intracellularly in patients with chronic obstructive pulmonary disease exacerbations 16 and the same pathogen has been detected diffusely in the bronchial epithelium, submucosa of bronchi, bronchioles, interstitium and alveolar epithelium of patients with end-stage chronic obstructive pulmonary disease, suggesting a relationship with the pathogenesis of the disease 51. New evidence is required regarding the complex relationship between microorganisms and host, particularly considering that important therapeutic implications may derive from these findings. Controversy still exists as to the need for antibiotic therapy in exacerbations, but, in the near future, other issues such as bacterial eradication, speed of recovery, prevention of exacerbations or even treatment of colonisation may figure in the debate.
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References |
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TOPAbstractAetiology of chronic obstructive...Frequency and outcomes of...The "fall and rise"...Impact of colonisation and...Unanswered questionsReferences |
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induces hyperreactivity in tracheal smooth muscle of the guinea-pig in vitro. Eur Respir J 1998;12:45–49.[Abstract]
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  M. I. Restrepo and A. Anzueto Guidelines for the diagnoses and treatment of adult lower respiratory tract infections: a true "European cooperative effort" Eur. Respir. J., December 1, 2005; 26(6): 979 - 981. [Full Text] [PDF]
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