P2. Influenza vaccination

Annual influenza vaccination reduces by about 50% the development of severe respiratory complications and hospitalisation or death from both respiratory disease and all causes^168,169 [evidence level I]. The vaccine used in Australia does not contain a live virus and cannot cause an infection. Side effects include a sore arm the following day and possibly a mild fever and arthralgia at five to eight days caused by the immune response. The vaccine usually contains three strains (2A and 1B), which are adjusted annually based on epidemiological data. It should be given in early autumn to all patients with moderate to severe COPD.^168,169 A second vaccination in winter increases antibody levels.⁷

P3. Pneumococcal vaccination

Pneumococcal vaccination is known to be highly effective in preventing invasive bacteraemic pneumococcal pneumonia, but may be less effective in elderly or immunosuppressed patients.¹⁷⁰ There is no direct evidence of its efficacy in preventing pneumococcal exacerbations of COPD¹⁷¹, but prevention of pneumonia in these patients with already reduced respiratory reserve is a worthy goal in its own right,^{170, 172, 173} so pneumococcal vaccination (polyvalent covering 23 virulent serotypes) is recommended in this group [evidence level II].⁷  There is no evidence or rationale for vaccinating more frequently in COPD.

P4. Haemophilus influenzae vaccination

Six randomised trials of oral mono-bacterial whole cell killed non-typable haemophilus influenzae vaccine¹⁷⁴ found a significant reduction in the incidence of bronchitic episodes three months after vaccination, but the effect had disappeared by nine months. The severity of exacerbations in the treatment group as measured by the requirement to prescribe antibiotics was reduced by 65% at six months. However, a larger clinical trial is needed to assess longer term prognosis. [evidence level I] Furthermore, this is not currently available in Australia or New Zealand.

P5. Immuno-modulatory agents

The available evidence suggests that the putative immuno-modulatory agent OM-85 BV is well tolerated¹⁷⁵ [evidence level I]. However, consistent results across important clinical outcomes, such as exacerbation and hospitalization rates, are lacking to determine whether it is effective. Further randomized, controlled trials enrolling large numbers of persons with well-defined COPD are necessary to confirm the effectiveness of this agent.

P6. Antibiotics

Current evidence does not support long-term antibiotic use to prevent exacerbations in patients with COPD^176,177 [evidence level I]. However, they should be used in exacerbations with an increase in cough, dyspnoea, sputum volume or purulence (see Section X).

Prophylactic antibiotics in chronic bronchitis/ COPD have a small but statistically significant effect in reducing the days of illness due to exacerbations of chronic bronchitis. However, they do not have a place in routine treatment because of concerns about the development of antibiotic resistance and the possibility of adverse effects. The available data are over 30 years old, so the pattern of antibiotic sensitivity may have changed and there is a wider range of antibiotics in use.¹⁷⁸

P7. Anticholinergics

A Cochrane review of nine RCTs (6,584 patients) found that tiotropium reduced the odds of a COPD exacerbation (OR 0.74, 95% CI 0.66 to 0.83) and related hospitalisations (OR 0.64, 95% CI 0.51 to 0.82) compared to placebo or ipratropium. The number of patients who would need to be treated with tiotropium for one year was 14 (95% CI 11 to 22) to prevent one exacerbation and 30 (95% CI 22 to 61) to prevent one hospitalisation⁵⁰ [Evidence Level I]. Another systematic review of 22 trials with 15,276 participants found that anticholinergic use also significantly reduced respiratory deaths (RR 0.27, 95% CI 0.09 to 0.81) compared with placebo. It would be necessary to treat 278 patients with anticholinergic agents to prevent one death¹⁷⁹ [evidence level I].

P8. Glucocorticoids

The effect of inhaled glucocorticoids on decline in lung function has become clearer with the publication of a pooled analysis of individual patient data from 7 prospective randomised studies¹⁸⁰. This study included 3,911 participants, and in contrast to previous systematic reviews^181,182 was able to allow for potential baseline confounders and effect modifiers. Over the first 6 months following randomisation, treatment with inhaled glucocorticoids increased the mean FEV1 by 2.42 (Standard Deviation 0.19%) compared to placebo. This equated to an absolute difference of 42mls for males and 29mls for females, but this improvement with inhaled glucocorticoids was attenuated by continued cigarette smoking. Between 6-36 months after randomisation, there was no statistically significant difference between inhaled glucocorticoid and placebo treatment in the decline in FEV1. There was no association between the initial increase in FEV1 and mortality. Neither this study, nor previously published systematic reviews addressed the issue of long-term adverse effects of inhaled glucocorticoids.

These data do not support the use of inhaled glucocorticoids in all people with COPD, however they are indicated for patients with a documented response to inhaled glucocorticoids or severe disease with frequent exacerbations^{72,76,183,134} [evidence level II]. In patients with severe COPD, high dose inhaled glucocorticoids reduce the rate of acute exacerbations¹⁸⁴ [evidence level I], although it has been suggested this data has not been correctly analysed¹⁸⁵ and a Cochrane Systematic Review is awaited¹⁸⁶. High dose inhaled glucocorticoids slow the rate of decline in quality of life in patients with moderate to severe disease¹⁸³. The effect of inhaled glucocorticoids on mortality remains unclear, while a pooled analysis of individual patient data including 5,085 participants with all severities of COPD found a 27% lower all-cause mortality for inhaled glucocorticoids compared to placebo¹⁸⁷ ; this has not been replicated in a recent large randomised controlled trial involving 3,058 participants (Hazard ratio 1.06, 95% CI 0.88-1.27)⁷⁵. The long-term adverse effects of inhaled glucocorticoids are unknown, but caution is needed when ceasing inhaled glucocorticoid treatment given the observation that abrupt withdrawal may be associated with increased symptoms of exacerbation⁷⁷.

P9. Mucolytic agents

These drugs (eg, bromhexine, N-acetylcysteine, ambroxol, potassium iodide and glycerol guaiacolate) have multiple potential actions in COPD. These include decreasing the viscosity of sputum, or as antioxidant, anti-inflammatory, or antibacterial agents. A Cochrane Review concluded that, in patients with COPD or chronic bronchitis who have a higher than average rate of exacerbations, chronic treatment with oral mucolytic agents was associated with a small, but significant, reduction in acute exacerbations and total number of days of disability.¹⁸⁸

However, the trials in the review are not consistent in this finding. A recent large RCT of N-acetylcysteine at 600 mg/day did not confirm an overall reduction in exacerbations, although a significant reduction was still seen in the subgroup who were not on concomitant treatment with inhaled steroids¹⁸⁹ [evidence level II].

P10. Regular review

Regular review, with objective measures of function and medication review, is recommended in the hope that this may reduce complications and the frequency or the severity (or both) of exacerbations and admissions to hospital.⁷  There is at present no evidence to support this hope.