X2.2 Optimise treatment

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An exacerbation of COPD may involve an increase in airflow limitation, excess sputum production, airway inflam­mation, infection, hypoxia, hypercarbia and acidosis. Treat­ment is directed at each of these problems.

  • Bronchodilators: Inhaled beta-agonist (eg, salbutamol, 400–800mcg; terbutaline, 500–100mcg) and antimuscarinic agent (ipratropium, 80mcg) can be given by pressurised metered dose inhaler and spacer, or by jet nebulisation (salbutamol, 2.5–5 mg; terbutaline, 5 mg; ipratropium, 500mcg). The dose interval is titrated to the response and can range from hourly to six-hourly. There is a lack of evidence in favour of one mode of delivery over another for bronchodilators during exacerbations of COPD. In a Cochrane Review by van Geffen (van Geffen 2016) there were no differences between nebulisers and pressured metered dose inhalers plus spacer regarding the primary outcomes of FEV1 at one hour (MD 36 ml, 95% CI −38 to 110, n=40) and serious adverse events (OR 1.00 95% 0.18 to 5.53; n=70) [evidence level I].
  • Corticosteroids: Oral corticosteroids hasten resolution and reduce the likelihood of relapse. Up to two weeks’ therapy with prednisolone (40–50 mg daily) is adequate. Longer courses add no further benefit and have a higher risk of side effects.
  • Antibiotics: Antibiotics are given for purulent sputum to cover for typical and atypical organisms.
  • Controlled oxygen therapy: This is indicated in patients with hypoxia, with the aim of improving oxygen saturation to 88 to 92%. Use nasal prongs at 0.5–2.0 L/minute or a Venturi mask at 24% or 28%. Minimise excessive oxygen administration, which can worsen hypercapnia.
  • Ventilatory assistance: This is indicated for increasing hypercapnia and acidosis. Non-invasive ventilation by means of a mask is the preferred method.

Although the adherence to pharmacological, rehabilitation and vaccination management as recommended in GOLD have each been shown to reduce health care costs, uptake of GOLD recommendations has had little evaluation. A study in a Victorian hospital setting demonstrated significant overuse of antibiotics and oxygen therapy, as well as a greater evidence practice gap in general medical units than respiratory medical units (Tang 2014) [evidence level III-2].

X2.2.1 Inhaled bronchodilators for treatment of exacerbations

In exacerbations of COPD, the immediate bronchodilator effect is small, but may result in significant improvement in clinical symptoms in patients with severe obstruction.

Studies of acute airflow limitation in asthma indicate that beta-agonists are as effectively delivered by metered dose inhaler and spacer as by nebuliser (Cates 2006) [evidence level I]. The applicability of this evidence to patients with COPD is unknown. There is evidence in patients with a COPD exacerbation that a dry powder inhaler delivering formoterol is as effective in improving lung function as a metered dose inhaler delivering salbutamol, with or without a spacer device (Selroos 2009) [evidence level II]. An adequate dose should be used. The dose equivalent to 5 mg of salbutamol delivered by nebuliser is 8–10 puffs of 100mcg salbutamol by metered dose inhaler and spacer. Limited evidence indicates dry powder inhalers are as effective as other delivery devices for the administration of short-acting bronchodilators in the setting of exacerbations of COPD (Selroos 2009)[evidence level II]. Airflow in the nebuliser should be 6 L per minute or higher to achieve an appropriate aerosol, but using high- flow oxygen should be avoided as this may worsen carbon dioxide retention (Bardlsey 2018).

People with COPD often have cardiac co-morbidities, although these may be undiagnosed at the time of presentation with a COPD exacerbation. Such patients may be susceptible to adverse events from high dose, frequent short acting beta agonists. A review by Kopsaftis (Kopsaftis 2018b) identified 10 relevant randomised or controlled trials and demonstrated that higher (5mg versus 2.5mg) doses of salbutamol were associated with increased risk of tremors, elevated heart rate, palpitations and lower blood pressure, but without evidence of any additional benefit.  Given that elevated cardiac stress markers during COPD exacerbations are predictive of 30 day mortality (Chang 2011), the review authors recommend caution in prescribing frequent high doses of short-acting beta agonists, such as doses of salbutamol exceeding 2.5mg, when treating exacerbations of COPD [evidence level I].

A small (n=30) single centre pilot randomised controlled trial performed in New Zealand (Mukerji 2015) [evidence level II] showed that 2g IV magnesium when added to standard bronchodilator therapy in an exacerbation of COPD significantly improved FEV₁ at 120 mins (mean percentage change in FEV₁ was 27.07% with magnesium versus 11.39% in the placebo group, 95% CI 3.7-27.7, oxygen titration p=0.01). Asthma was excluded on clinical grounds on review of past spirometry. Larger trials with meaningful clinical endpoints are required before this can be recommended as standard therapy.

X2.2.2 Systemic corticosteroids for treatment of exacerbations

Walters et al report that there is high-quality evidence that systemic corticosteroids reduce treatment failure (defined as additional treatment, hospital admission/re-admission for index episode, return to emergency department, unscheduled physician visit for the index episode), improve lung function, shorten recovery and reduce the severity of exacerbations of COPD (Walters 2014) [evidence level I]. Systemic corticosteroids reduced the risk of treatment failure by over half compared with placebo in nine studies (n=917) with median treatment duration 14 days, odds ratio (OR) 0.48 (95% CI 0.35-0.67). The number needed to treat to avoid one treatment failure is 9. Similar results were found in a more recent meta-analysis (Koarai 2024) [evidence level I]. There is no evidence that treatment with corticosteroids alters mortality.

Unlike earlier reviews this review included four papers that compared intravenous corticosteroids with oral corticosteroids and two papers with ventilated patients in ICU. In patients requiring ventilation in ICU, pooled data did not show a reduction in length of stay, duration of ventilation or mortality in those receiving corticosteroids compared with placebo (Walters 2014). Walters et al concluded that there is no evidence of benefit for intravenous treatment compared with oral treatment with corticosteroids on treatment failure, relapse or mortality. Hyperglycaemia rates were higher with intravenous corticosteroids.

With regards to duration of treatment, a meta-analysis by Walters et al (Walters 2018) concluded that five days of oral corticosteroids is likely to be sufficient [evidence level I].

In summary, a 5-day course of oral prednisolone of 30mg to 50mg is adequate. In patients who have been on oral corticosteroids for longer than 14 days, tapering may be necessary. Patients on long-term oral corticosteroid therapy (> 7.5 mg prednisolone daily for more than 6 months) are at risk of developing osteoporosis. Prevention and treatment of corticosteroid-induced osteoporosis should be considered. Longer courses of prednisolone may increase mortality and pneumonia (Sivapalan 2019).

A meta-analysis by You et al (2020) compared outcomes of acute exacerbations of COPD (AECOPD) with and without eosinophilia (defined as an eosinophil count ≥2% or an absolute eosinophil count ≥0.34×109). Outcomes were better overall for eosinophilic AECOPD, with decreased hospital mortality (OR 0.59, 95% CI 0.31-0.95, p=0.03), decreased length of stay (OR 0.72,95% CI-1.44 to -0.00, p=0.05), higher FEV₁ (mean difference =0.14, 95% CI 0.08-0.2, p<0.00001) and a lower risk of arrhythmias 9 (OR 1.5, 95% CI 1.01-2.21, p=0.04). It was noted that there were more males among the non- eosinophilic group (OR 1.34, 95% CI 1.15-1.56, p=0.0002), but that steroid use did not differ between the groups (You 2020). Many studies in this meta-analysis were single centre and retrospective in design.

Another systematic review and meta-analysis examined the relationship between blood eosinophil count and clinical outcomes of patients with acute exacerbations of COPD (AECOPD), where the cut-off for those in the eosinophilic group was ≥2% (Liu 2024) [evidence level I]. Fourteen cohort studies and one case control study were included in the meta-analysis. Compared with the non-eosinophilic group, those with eosinophilic AECOPD had a lower risk of mortality (RR=0.65, 95% CI 0.54-0.77, p<0.001), shorter length of hospital stay (WMD=-1.56, 95% CI –2.15 to -0.96, p<0.001), and a higher re-admission rate (RR=1.07, 95% CI 1.01-1.13, p=0.029). No difference was found in rate of hospitalisation or invasive ventilation between the groups.

There is emerging evidence that blood eosinophil levels could be used as a biomarker to determine which patients require oral corticosteroids for exacerbations of COPD. In a double-blind RCT in primary practice in the UK, patients with COPD with frequent exacerbations were randomised to blood eosinophil-directed treatment (point-of-care eosinophils ≥2%: prednisolone 30 mg daily for 14 days, or eosinophils <2%: placebo) versus standard care (prednisolone 30 mg daily for 14 days) (Ramakrishnan 2024) [evidence level II]. All patients also received doxycycline 200 mg daily for 7 days. In a modified intention-to-treat analysis, 144 exacerbations were studied in 93 participants. Blood eosinophil-directed treatment was non-inferior to standard care (RR 0.60 for treatment failure, defined at 30 days as re-treatment with antibiotics or steroids, hospitalisation, or death; 95% CI 0.33 to 1.04), and reduced oral steroid use by 33%. There were no differences in lung function or quality of life at 14 days. Whilst these results are promising for minimising overuse of prednisolone, additional studies with large numbers of patients, shorter courses of prednisolone and inclusion of hospital-based settings are required, before recommendations can be made for biomarker-stratified oral steroid therapy of COPD exacerbations in clinical practice. Point of care eosinophil testing is not routinely available in Australia, and the 14-day course of prednisolone is longer than what is currently recommended.

X2.2.3 Antibiotics for treatment of exacerbations

Bacterial infection may have either a primary or secondary role in about 50% of exacerbations of COPD (Macfarlane 1993, Wilson 1998, Miravitlles 1999, Patel 2002). Haemophilus influenzae, Streptococcous pneumoniae and Moraxella catarrhalis are most commonly involved (Macfarlane 1993, Soler 1998, Murphy 1999). Mycoplasma pneumoniae and Chlamydia pneumoniae have also been reported (Macfarlane 1993, Mogulkoc 1999). As lung function deteriorates (FEV₁ < 35%), Pseudomonas aeruginosa and Staphylococcus aureus are often encountered (Macfarlane 1993, Soler 1998, Miravitlles 1999). Multi drug resistant Pseudomonas aeruginosa is associated with 6-fold increased risk of death (Montero 2009) [evidence level III-2].

Nonetheless, sputum colour was shown to have limited value as a stand-alone test in diagnosing bacterial infection in a systematic review and meta-analysis of 13 studies by Spies et al (Spies 2023) [evidence level I).

A re-examination of data from the placebo arm of a Spanish antibiotic trial that recruited patients with mild to moderate COPD from primary care confirmed that sputum purulence increased the likelihood of treatment failure 6-fold. A CRP elevated greater than 40 mg/L was also independently associated with a 13-fold increase in the risk of treatment failure (Miravitlles 2013) [evidence level III-2].

A study of 220 patients hospitalised with exacerbations of COPD with clinical features of infection, randomised to CRP-guided antibiotic therapy (antibiotics if CRP ≥ 50mg/L) or GOLD criteria based antibiotic treatment found a significant reduction in antibiotic use in the CRP guided group, with an absolute reduction in antibiotic use of 14.5% (Prins 2019) [evidence level II]. An open label RCT (n=653) of patients in the UK showed that in patients with COPD exacerbations treated in primary care, use of point-of-care CRP testing to guide prescribing of antibiotics lowered patient-reported antibiotic use (OR 0.31, 95% CI 0.20-0.47) (Butler 2019) [evidence level II]. The judicious use of CRP testing in primary or tertiary care may assist in determining the need for antibiotics for exacerbation management.

El Moussaoui et al (El Moussaoui 2008) conducted a systematic review of 21 randomised controlled trials of antibiotics in exacerbations of chronic bronchitis and COPD. There were similar rates of clinical or bacteriological cure with short courses (≤ 5 days) and longer courses of antibiotics [evidence level I]. A related systematic review (Falagas 2008) found that patients receiving short courses experienced fewer adverse effects than those receiving longer courses. It would be necessary to treat 26 (95% CI 15 to 134) patients with short course antibiotics to prevent one adverse effect. However, the antibiotics evaluated were late generation cephalosporins, macrolides and fluoroquinolones, which are not those recommended in Australia.

Procalcitonin is an acute phase reactant. Procalcitonin levels increase in bacterial infections but do not increase in viral infections or auto-immune inflammation (Gilbert 2011). Procalcitonin has been proposed as a measure to determine if patients with an exacerbation of COPD require oral antibiotics.  In most clinical trials, use of antibiotics was discouraged if procalcitonin was 0.1ng/ml or lower and encouraged if procalcitonin was above 0.25ng/ml.

A meta-analysis of eight randomised or quasi-randomised trials, evaluating 1,062 patients, compared procalcitonin-based protocols to initiate or discontinue antibiotics, versus standard care in COPD exacerbation (Mathioudakis 2017). Procalcitonin-based protocols decreased antibiotic prescription (relative risk (RR) 0.56, 95% CI 0.43–0.73) without affecting clinical outcomes such as rate of treatment failure, length of hospitalisation, exacerbation recurrence rate or mortality (low to moderate quality evidence). Since the publication of this meta-analysis, a further trial has also reported that procalcitonin-based protocols reduce antibiotic use without increasing complications (Wang 2016).

A meta-analysis of RCTs and observational studies investigating the impact of a procalcitonin-based protocol on antibiotic prescription and clinical outcomes in patients with COPD exacerbations, found that the use of procalcitonin-based protocols significantly reduced the length of antibiotic treatment in COPD exacerbation (MD = -2.01 days, 95% CI -3.89 to -0.14 days, p=0.04, moderate quality, and MD = -1.64 days, 95% CI -2.91 to -0.36 days, p=0.01, very low quality for RCTs and observational study, respectively), while no apparent effects were found on length of hospital stay, treatment failure and all-cause mortality. The effect of procalcitonin on antibiotic duration was no longer significant (MD = -1.88 days, 95% CI -3.95 to 0.19 days, p=0.08, and MD = -1.72 days, 95% CI -4.28 to 0.83 days, p=0.19, respectively), when studies with high risk of bias were excluded. Procalcitonin has limited value in guiding antibiotic use in COPD exacerbation (Chen 2020) [evidence level I].

It is important to note that patients with pneumonia were excluded from these trials. Based on the evidence from these trials, it may be possible to withhold antibiotic therapy in patients presenting to the emergency department with an exacerbation of COPD, who are afebrile, have no pneumonia on chest imaging, and have a serum procalcitonin level of <0.1ng/ml. This test is not currently funded by Medicare in Australia and is only available in some centres.  Despite promising data from multiple clinical trials, cross-sectional and longitudinal analysis of over 200,000 COPD admissions from 505 US hospitals did not show a change in antibiotic prescribing rates or duration of use in hospitals that had begun using procalcitonin testing (Lindenauer 2017). The authors conclude that further implementation research is required.

Therapeutic guidelines: antibiotic (Therapeutic Guidelines Limited 2019) recommend the use of oral agents such as amoxycillin or doxycycline.

A retrospective cohort study from the Danish registry of COPD by Bagge et al (2021) examined outcomes following patients redeeming prescriptions for amoxycillin (AMX) or amoxycillin clavulanic acid (AMC) for presumed community exacerbations of COPD. They found pneumonia hospitalisation or death by all cause after 30 days was decreased with AMX compared to AMC (adjusted HR 0.6, 95% CI 0.5-0.7, p<.0001). This was also observed for all cause hospitalisation or death (aHR 0.8, 95% CI 0.8-0.9, p<0.0001). Although confounding by severity is not excluded, the findings of this study support the recommendation broad -spectrum antibiotics such as AMC should not be the drug of first choice for outpatient exacerbations of COPD (Bagge 2021) [evidence level III-2].

If pneumonia, Pseudomonas, Staphylococcus, or resistant organisms are suspected, appropriate antibiotics should be used.

Typically, a course of antibiotics should be five days. A systematic review and meta-analysis by Llor et al (2022) including only patients with spirometrically-proven COPD (n=eight trials) concluded that there were no significant differences in clinical cure rates or bacterial eradication rates of short courses of antibiotics (≤5 days) compared with longer courses (≥6 days). Nonetheless, the majority of studies included fluroquinolones as first line therapy, which is not common practice in Australia, raising questions about the face validity of this study [evidence level I] (Llor 2022). A historical population-based cohort study found that co-treatment of an exacerbation with oral corticosteroids and oral antibiotics significantly increased the time to subsequent exacerbations (median 312 versus 418 days, p<0.001 to next compared to oral corticosteroids alone) (Roede 2008)[evidence level III-2].

Two Australian retrospective case series of hospitalised COPD patients have found that antibiotic treatment was guideline concordant in less than 15% of cases (Brownridge 2017, Fanning 2014). This was due to over-use of intravenous antibiotics and prescription of dual antibiotics. Further efforts are needed to increase adherence to the use of oral antibiotics in patients hospitalised with exacerbations of COPD, where appropriate.

Radiologically proven pneumonia in patients with COPD, especially in those who have been frequently hospitalised, may not be restricted to the above organisms. Gram-negative organisms, Legionella spp. and even anaerobic organisms may be responsible. Initial empiric antibiotic therapy should be tailored according to clinical and radiographic criteria.

X.2.2.4 Combined systemic corticosteroids and antibiotics for treatment of exacerbation

A randomised placebo controlled trial (Daniels 2010) has provided evidence to support the traditional practice of treating exacerbations with a combination of systemic corticosteroids and antibiotics.  In this study, hospitalised patients were commenced on a tapering dose of prednisolone and randomised to receive doxycycline 200mg daily or placebo for 7 days.  Clinical cure, defined as complete resolution of signs and symptoms, at day 10 was significantly higher in the antibiotic treated group compared to placebo (OR 1.9, 95% CI 1.2 to 3.2, NNT = 7, 95% CI 4 to 523).  By day 30, the primary end point, there was no significant difference in clinical cure. Serious adverse effects occurred in 9% of the doxycycline group (7 deaths) and 5% of the placebo group (3 deaths).  Medication adverse events were similar between groups, 3% in the doxycycline group and 4% in the placebo.