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Time after onset of exacerbation (days)

fections in the community. COPD patients have been found to have increased hospital admissions, suggesting increased exacerbations when increasing environmental pollution occurs. During the December 1991 pollution episode in the UK, COPD mortality was increased together with an increase in hospital admissions of elderly COPD patients [28]. However, common pollutants especially oxides of nitrogen and particulates may interact with viral infections to precipitate an exacerbation rather than acting alone [29].

Viral infections

Studies in childhood asthma have shown that viruses, especially rhinovirus, can be detected by polymerase chain reaction from a large number of these exacerbations [30]. Rhinovirus has not hitherto been considered to be of much significance during exacerbations of COPD. In a study of 44 chronic bronchitics, Stott and colleagues found rhinovirus in 13 (14.9%) of 87 exacerbations of chronic bronchitis [31]. In 25 chronic bronchitics with 116 exacerbations over 4 years, Gump et al. found that only 3.4% of exacerbations could be attributed to rhinoviruses [32]. In a more recent study of 35 episodes of COPD exacerbation using serological methods and nasal samples for viral culture, little evidence was found for a rhinovirus aetiology of COPD exacerbation [33].

A number of studies have now shown that at least 50% of COPD exacerbations were associated with viral infections, and that the majority of these were due to rhinovirus [34-36]. Viral exacerbations were associated with symptomatic colds and prolonged recovery (Fig. 15.4) [10,36]. Seemungal and colleagues showed that that rhinovirus can be recovered from induced sputum more frequently than from nasal aspirates at exacerbation, suggesting that natural rhinovirus can infect the lower airway and be a cause of inflammatory changes at exacerbation [34]. Exacerbations associated with the presence of rhinovirus in induced sputum had larger increases in airway IL-6 levels [35], suggesting that viruses increase the severity of airway inflammation at exacerbation. This finding is in agreement with the data that respiratory viruses produce longer and more severe exacerbations and have a major impact on health care utilization [10,34]. Other viruses that may be important in triggering exacerbations are shown in Table 15.1.

Bacterial infection

Lower airway bacterial colonization has been shown to be common in COPD and has been found overall in approximately 30% of COPD patients. Colonization has been shown to be related to the degree of airflow obstruction and current cigarette smoking status [37]. Bacteria that have been usually associated with exacerbation are Haemophilus influenzae and Streptococcus pneumoniae. Some studies have shown increasing bacterial counts during exacerbation, while others have not confirmed these findings [38,39]. Soler and colleagues showed that the presence of potentially pathogenic organisms in bronchoalveolar lavage from COPD patients at bronchoscopy was associated with a greater degree of inflammation [40]. In a larger study, Hill and colleagues showed that the airway bacterial load was related to inflammatory markers [41]. They also found that the bacterial species was related to the degree of inflammation, with Pseudomonas aeruginosa colonization showing greater myeloperoxidase activity (an indirect measure of neutrophil activation).

Thus bacterial colonization in COPD is an important determinant of airway inflammation and further long-term studies are required to investigate whether bacterial colonization predisposes to the decline in lung function characteristic of COPD. Patel and colleagues have recently shown that patients with frequent exacerbations have increased sputum bacterial colonization, compared to patients with less frequent exacerbations [42] and this may explain the higher cytokine levels observed in the frequent exacerbator patient group [3].

How are bronchodilator therapies used at exacerbation?

Bronchodilators, especially inhaled b2-agonists and anticholinergic agents, are frequently used in the treatment of acute exacerbations of COPD. In patients with stable COPD, symptomatic benefit can be obtained with bron-chodilator therapy in COPD, even without significant changes in spirometry. This is probably due to a reduction in dynamic hyperinflation that is characteristic of COPD and hence leads to a decrease in the sensation of dyspnoea especially during exertion [43]. In stable COPD greater bronchodilatation has been demonstrated with anticholinergic agents than with beta-agonists. However, studies investigating bronchodilator responses in acute exacerbations of COPD have shown no differences between agents used and no significant additive effect of the combination therapy, even though combination of an anticholinergic and bronchodilator has benefits when patients are stable [44,45]. This difference in effect between the acute and stable states may be due to the fact that the larger doses of drug delivered in the acute setting produce maximal bronchodilatation, whereas the smaller doses administered in the stable condition may be having a submaximal effect.

Methylxanthines, e.g. theophylline, are sometimes used in the management of acute exacerbations of COPD. Although there is some evidence that theophyllines are useful in COPD, the main limiting factor is the frequency of toxic side-effects. The therapeutic action of theophylline is thought to be due to its inhibition of phosphodiesterase which breaks down cyclic AMP, an intracellular messenger, thus facilitating bronchodilatation. However, studies of intravenous aminophylline therapy in acute exacerbations of COPD have shown no significant beneficial effect over and above conventional therapy [46]. It is possible that some of the new phosphodiesterase inhibitors in development may have advantages, be more specific and possess a more favourable side-effect profile.

What is the role of steroids at acute exacerbation?

In patients with stable COPD, only about 10-15% of patients show a positive response to oral corticosteroids using spirometry [47] and, unlike the situation in asthma, steroids have little effect on airway inflammatory markers in patients with COPD [48,49]. Corticosteroids have traditionally been used in the management of acute exacerbations of COPD, although there has only recently been evidence of their beneficial role in the acute situation [21-27].

A number of early studies have investigated the effects of corticosteroid therapy, though these studies were generally small. Thompson and colleagues gave a 9-day course of prednisolone or placebo in a randomized manner to out-patients presenting with acute exacerbations of COPD [25]. Unlike the previous studies, these patients were either recruited from out-patients or from a group that were pre-enrolled and self reported the exacerbation to the study team. In this study patients with exacerbations associated with acidosis or pneumonia were excluded, so exacerbations of moderate severity were generally included. Patients in the steroid-treated group showed a more rapid improvement in PaO2, alveolar-arterial oxygen gradient, FEV1, peak expiratory flow rate and a trend towards a more rapid improvement in dyspnoea in the steroid-treated group.

Seemungal and colleagues followed a cohort of COPD patients in the East London study and described the effect of therapy with prednisolone on COPD exacerbations diagnosed and treated in the community [10]. Exacerbations treated with steroids were more severe and associated with larger falls in peak flow rate. The treated exacerbations also had a longer recovery time to baseline for symptoms and peak flow rate. However, the rate of peak flow rate recovery was faster in the prednisolone-treated group, though not the rate of symptom score recovery. An interesting finding in this study was that steroids significantly prolonged the median time from the day of onset of the initial exacerbation to the next exacerbation from 60 days in the group not treated with prednisolone to 84 days in the patients treated with prednisolone. If short course oral steroid therapy at exacerbation does prolong the time to the next exacerbation, then this could be an important way to reduce exacerbation frequency in COPD patients.

In another recent study, Davies and colleagues randomized patients admitted to hospital with COPD exacerbations to treatment with prednisolone or placebo [26]. In the prednisolone-treated group, the FEVj rose faster until day 5, when a plateau was observed in the steroid-treated group. Changes in the prebronchodilator and postbronchodilator FEV1 were similar suggesting that this is not just an effect on bronchomotor tone, but involves faster resolution of airway inflammatory changes or airway wall oedema with exacerbation. Length of hospital stay analysis showed that patients treated with prednisolone had a significantly shorter length of stay. Six weeks later, there were no differences in spirometry between the patient groups and health status was similar to that measured at 5 days after admission. Thus the benefits of steroid therapy at exacerbation are most obvious in the early course of the exacerbation.

Niewoehner and colleagues performed a randomized controlled trial of either a 2-week or 8-week prednisolone course at exacerbation compared to placebo, in addition to other exacerbation therapy [27]. The primary end point was a first treatment failure, including death, need for intubation, readmission or intensification of therapy. There was no difference in the results using the 2- or 8-week treatment protocol. The rates of treatment failure were higher in the placebo group at 30 days, compared to the combined 2- and 8-week prednisolone groups. As in the study by Davies and colleagues, the FEVj improved faster in the prednisolone-treated group, though there were no differences by 2 weeks. In contrast, Niewoehner and colleagues performed a detailed evaluation of steroid complications and found considerable evidence of hyperglycaemia in the steroid-treated patients. Thus steroids should be used at COPD exacerbation in short courses of no more than 2 weeks duration to avoid risk of complications.

Do antibiotics have benefit for COPD exacerbations?

As COPD exacerbations frequently present with increased sputum purulence and volume, antibiotics have traditionally been used as first-line therapy. However, viral infections may be the triggers in a significant proportion of acute infective exacerbations in COPD and antibiotics used for the consequences of secondary infection. A study investigating the benefit of antibiotics in over 300 acute exacerbations demonstrated a greater treatment success rate in patients treated with antibiotics, especially if their initial presentation was with the symptoms of increased dyspnoea, sputum volume and purulence [5]. A randomized placebo-controlled study investigating the value of antibiotics in patients with mild obstructive lung disease in the community concluded that antibiotic therapy did not accelerate recovery or reduce the number of relapses [50]. A meta-analysis of trials of antibiotic therapy in COPD identified only nine studies of significant duration and concluded that antibiotic therapy offered a small but significant benefit in outcome in acute exacerbations [51].

What are the various models of supported discharge at exacerbation of COPD patients?

COPD exacerbations are one of the most important causes of hospital admissions, especially during the winter months when they are most frequent. Thus there is a particular need to devise strategies to reduce the hospital admissions associated with exacerbations. There has arisen a need to develop different models of supported discharge, where patients are discharged back early to the community with increased support and care packages and a number of these have been evaluated [54-57].

In a randomized study, Cotton and colleagues allocated patients to discharge on the next day or usual management and observed no differences in mortality or readmission rates between the two groups [55]. There was a reduction in hospital stay from a mean of 6.1 days to 3.2 days. In another larger study by Skwarska and colleagues, patients were randomized to discharge on the day of assessment or conventional management [56]. Again there were no differences in readmission rates, although these were high at around 30% of the study populations at 3 months. There were no differences in visits to primary care physicians and health status measured 8 weeks after discharge was similar in the two groups. The authors also demonstrated that there were significant cost savings of around 50% for the home support group, compared to the admitted group. Davies and colleagues found no differences in mortality or readmission rate between the home and hospital treated group [57]. How ever, only about 25% of patients presenting for hospital admission with a COPD exacerbation are suitable for home therapy and thus selection is required [56,57]. Other considerations need to be taken into account in organizing an assisted discharge service, in that resources have to be released for the nurses to follow the patients and the benefits may be seasonal, as COPD admissions are a particular problem in the winter months.

Can COPD exacerbations be prevented?

As upper respiratory tract infections are common factors in causing exacerbation, influenza and pneumococcal vaccinations are recommended for all patients with significant COPD. A study that reviewed the outcome of influenza vaccination in a cohort of elderly patients with chronic lung disease found that influenza vaccination is associated with significant health benefits with fewer outpatient visits, fewer hospitalizations and a reduced mortality [58]. Early studies on long-term antibiotics in exacerbation prevention have not shown a benefit on exacerbation frequency. However, recent data suggests that lower airway bacterial colonization in COPD increases the exacerbation frequency [42]. The same study shows that patients with bacterial colonization were also more likely to have more severe exacerbations, as shown by a longer recovery time [42]. Thus with the introduction of new and more effective antibiotics, new and well designed studies are required to assess the effects of long-term antibiotics on exacerbation frequency in COPD.

Mucolytic agents have also been prescribed in COPD though their use worldwide is very variable with little use in the UK and more prescriptions in mainland Europe. A recent meta-analysis was published that assessed the effects of oral mucolytics in COPD [59]. A total of 23 randomized controlled trials were identified and the main outcome was that there was a 29% reduction in exacerbations with mucolytic therapy. The number of patients who had no exacerbations was greater in the mucolytic group and days of illness was also reduced, though mucolytics had no effect on lung function. The drug that contributed most to the beneficial results in the review was N-acetylcysteine, though the mechanism of action of N-acetylcysteine is not entirely clear and may be a combination of mucolytic and antioxidative effects. These early studies are mostly small and further large studies on the effects of mucolytics are in progress and the results will be available in the next few years.

In the ISOLDE study of long-term inhaled fluticasone in patients with moderate to severe COPD, a reduction in exacerbation frequency was shown. However, the overall exacerbation frequency was relatively low in that study and this was probably due to a retrospective assessment of exacerbations [60]. The effect of inhaled steroids was greater in patients with more impaired lung function, suggesting that this is the group to target with long-term inhaled steroid therapy. Another earlier study suggested that the severity of exacerbations may be reduced with inhaled steroid therapy [61]. An observational study showed that exacerbations were increased following withdrawal of inhaled steroids though this study was not placebo controlled [62]. Two recent studies have also shown that small reductions in exacerbations can be achieved with bronchodilator therapy, though both studies involved relatively short periods of therapy at 12 weeks [63,64]. Recently the new long-acting anticholinergic drug tiotropium has been shown to reduce exacerbations by 24% when studied over a 1-year period [65].

Do exacerbations contribute to disease progression in COPD?

Early epidemiological studies suggested that exacerbations do not contribute to decline in lung function and thus disease progression in COPD [1]. However, as discussed earlier not all exacerbations recover to baseline levels and this incomplete recovery from an exacerbation may lead to decline in lung function. Recent data from the Lung Health Study shows that in patients who continue to smoke cigarettes, decline in lung function is greater if they have had exacerbations [66]. In another recent study patients who had a history of frequent exacerbations had a faster decline in lung function than patients who had infrequent exacerbations, though the difference between FEV1 decline in frequent and infrequent exacerbators was relatively small [67]. Overall probably only about 25% of the fall in lung function can be attributed to the effects of exacerbation. However, these data suggest that COPD exacerbation is an important target for therapy. Reduction of COPD exacerbation frequency may not only improve quality of life and reduce hospital admission, but it may have a more important role in reducing the progression of COPD.

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