The editorial content below has been developed solely between Guidelines in Practice and the expert author.
Guest Editor—Dr Elizabeth Sapey
Honorary Respiratory Consultant, Queen Elizabeth Hospital, Birmingham
Senior Lecturer in Respiratory Medicine, University of Birmingham
‘Exacerbations of COPD are complex and important events that negatively impact patients’ quality of life and health status and are associated wth a faster decline in lung function. This email considers strategies for the pharmacological management of patients with exacerbations and is designed to support your everyday clinical practice.’
What is an exacerbation
An exacerbation of chronic obstructive pulmonary disease (COPD) is defined as an acute worsening of symptoms that results in additional therapy.1
Exacerbations are complex; they are associated with increased airway inflammation, increased mucus production, and gas trapping, all of which contribute to breathlessness and cough.2
Exacerbations are classified as mild, moderate, or severe based on the amount of treatment needed to control symptoms:2
- mild exacerbations require only an increase in bronchodilators
- moderate exacerbations require steroids and perhaps antibiotics
- severe exacerbations require hospitalisation.
Exacerbations are important events that:1,3
- lead to increased rates of hospitalisation, readmission, and death
- negatively affect quality of life and health status
- are associated with a faster decline in lung function.
Worryingly, people with mild COPD experience the fastest decline in lung function after an exacerbation,4 but most patients with COPD are not diagnosed until they have moderate or severe disease.5 Recognising COPD earlier may, therefore, provide an opportunity to prevent this decline in lung health.
Aims of treatment
We have two goals when caring for a patient with an exacerbation of COPD:2
- to minimise the impact of the current exacerbation
- to reduce the chances of that patient having future exacerbations.
Studies have linked earlier treatment with reductions both in the duration of exacerbation symptoms and in the rate of hospitalisation.6 For this reason, much emphasis is placed on early management and on self-management with rescue packs for patients at risk of exacerbations.7
Causes of exacerbations
It is important to remember that the majority of exacerbations are caused by viral infections, with the human rhinovirus, which causes the common cold, thought to be the most common cause.8 Bacterial infections are less common causes, and exacerbations can also be triggered by environmental factors, such as temperature change.2,9
Is this chest infection really an exacerbation of COPD?
Although some patients will present with an exacerbation of symptoms when they already have a diagnosis of COPD, far too many patients receive treatments for recurrent chest infections or annual episodes of winter bronchitis without it being recognised that they have COPD.
There can be a delay of years before a formal diagnosis of COPD is made,10 and this diagnostic delay is associated with poorer patient outcomes, including:5,6
- a faster decline in lung health
- more symptoms
- increased hospital admissions.
We should actively consider a diagnosis of COPD in patients over 35 years of age who have a risk factor (generally smoking) and who present with chest infections or episodes of bronchitis. These patients should be invited for a review (with spirometry) once the symptoms of the chest infection have cleared.7
Acute exacerbations: diagnosis
The symptoms of COPD are complex and can be variable on a daily basis; diagnosing an exacerbation of COPD can sometimes be difficult for both patients and healthcare professionals. Breathlessness can be frightening, and feelings of panic and anxiety are common11—patients with other medical conditions, who are frail, or who lack robust social support can struggle to manage even a small change in breathlessness and cough.
Identifying exacerbations is further complicated by the lack of a blood test or biomarker that can diagnose the exacerbation and identify the likely cause. There are, however, some factors that might point us in the right direction.
Increased breathlessness is the most common symptom of an exacerbation and responds to bronchodilators and steroids
Some definitions of exacerbations take the daily variability of COPD into account, suggesting that an exacerbation is a: ’change in the patient’s baseline dyspnoea, cough, and/or sputum that is beyond normal day-to-day variations’.12
This can be a helpful question to ask a patient; ‘is your breathing/cough or sputum production worse than on a “normal day” for you?’
Acute exacerbations: treatment
Current guidance recommends increasing short-acting bronchodilators and starting oral corticosteroids (30–40 mg of oral prednisolone a day) when a change in breathlessness interferes with the activities of daily living.1,7
Studies suggest that corticosteroids limit the duration of an acute exacerbation of COPD,13 but how long should you treat for? Recently this has been clarified, with the REDUCE study suggesting that there is no clinical benefit in treating for longer than 5 days (see below).14
Duration of treatment with corticosteroids—the REDUCE study14
- 314 patients with an exacerbation of COPD were randomised to receive 40 mg of prednisolone daily for either 5 or 14 days
- Treatment for 5 days was shown to be non-inferior to treatment for 14 days in terms of symptom control and the rate of re-exacerbation
- Results suggest there that there is no clinical benefit in treating for longer than 5 days.
Studies have also suggested that it might be possible to use blood eosinophil levels to guide oral steroid use in exacerbations of COPD even further, with patients with a raised blood eosinophil count showing the greatest benefit following treatment.15 These results are promising but must be replicated in larger studies before being adopted into clinical practice.
An exacerbation associated with purulent sputum is likely to be bacterial
Studies suggest that the majority of COPD exacerbations are caused by viruses,16 meaning that most patients experiencing an exacerbation should not be prescribed an antibiotic. Given the well-publicised issues that we face with antibiotic resistance, it is vital that antibiotics are limited to those who really need them. Bacterial exacerbations of COPD are associated with purulent sputum, and viral and environmentally triggered exacerbations are not.9
For bacterial exacerbations, studies suggest that a short course of therapy with antibiotics (5 days) may be as effective as a longer course.17 Longer courses are only recommended in patients with bronchiectasis or other chronic infections such as abscesses.
The colour of a patient’s sputum can be used as a guide to help you decide if antibiotics are needed. Consider prescribing antibiotics where there is new or worsening sputum purulence and consider withholding antibiotics when sputum remains clear, grey, or yellow.18
Case study: Tracey
Age: 52 years old
Smoking status: former smoker, 30 pack-year history
No formal diagnosis of COPD
Symptoms: attends with symptoms of a chest infection; breathlessness, a tight chest, and white sputum for 3 days—has presented with similar symptoms twice in the last year.
There is no obvious indication for antibiotics (white sputum) but you:
- prescribe a short-acting bronchodilator (and check her inhaler technique) and a 5-day course of steroids (prednisolone 30 mg daily)
- invite her back for a health check in 6 weeks.
After 6 weeks Tracey is feeling much better and ‘back to her normal self’, however, on closer questioning, she admits that she has been breathless when hurrying for a couple of years.
You do spirometry:
- FEV1: 62% predicted
- FEV1/FVC ratio: 60%.
You confirm that the last flare up of chest symptoms was in fact an exacerbation of COPD and place her on the COPD register.
FEV1=forced expiratory volume in 1 second; FVC=forced vital capacity
Strategies to reduce further exacerbations
Not all patients with COPD experience severe (requiring hospitalisation) or frequent (two or more per year) exacerbations. The best predictor of whether someone is at risk of an exacerbation is whether they have experienced exacerbations in the past.2,9
A history of past exacerbations can be used to predict future risk of exacerbations, allowing medications that are aimed at preventing exacerbations to be focused on patients who have this risk.
Exacerbation frequency can be reduced by:2,19–22
- smoking cessation
- pneumococcal and influenza vaccinations
- exercise and pulmonary rehabilitation.
A number of clinical trials have confirmed that bronchodilators (long-acting muscarinic antagonists [LAMAs] and long-acting beta2 -agonists [LABAs]) reduce exacerbations in patients with COPD.2,23–25
Newer combination inhalers consisting of a LAMA and a LABA in a single device have proven even more effective at reducing exacerbations and symptoms of breathlessness compared with monotherapy.2,26
Inhaled corticosteroids (ICS) also have an important role in reducing exacerbations, when prescribed with a LABA.2,27
Choosing an inhaled therapy
A recent Cochrane review concluded that LAMA/LABA combination inhalers were more effective than ICS/LABA inhalers at reducing exacerbations and improving FEV1, while also being associated with a lower risk of pneumonia.28 There are situations where a steroid may be preferred, but current evidence supports the use of bronchodilators first to avoid exacerbations (usually a combination LAMA/LABA inhaler) and then stepping up to triple therapy (LAMA and an ICS/LABA inhaler) where exacerbations persist.2
For those that continue to exacerbate, mucolytics are effective in patients with COPD and chronic bronchitis, especially those with severe COPD.29 Long-term antibiotics have been used in those who continue to experience exacerbations,30 although clinical trials have been limited in number—these patients might benefit from a review in secondary care.
Case study: Robert
Age: 64 years old
Smoking status: current smoker, 35 pack-year history
- breathlessness that has worsened steadily over 2 years
- frequent chest infections
- recurrent exacerbations—at least two per year
- FEV1: 42% predictedFEV1/FVC ratio: 47%.
FEV1=forced expiratory volume in 1 second; FVC=forced vital capacity
Suggested treatment pathway for Robert, the exacerbating patient
LAMA=long-acting muscarinic antagonist; LABA=long-acting beta2-agonist; ICS=inhaled corticosteroid; CT=computerised tomography
Current evidence suggests that 60-70% of patients with COPD are prescribed an inhaled steroid, but many of these patients have never experienced frequent or severe exacerbations of COPD31 and therefore may not need them. Recent studies demonstrate that it is possible to stop inhaled steroids in patients with COPD who have never experienced frequent exacerbations. Stopping the steroid did not cause a deterioration in symptoms or exacerbations in most patients although studies have included a step down approach to withdrawing the steroid.32 This gives us all the opportunity to review our prescribing habits, and try alternative medications for patients, based on the clinical evidence that is now available.
Bronchodilators are an effective means to reduce exacerbation frequency and dual bronchodilators (LAMA/LABA in one inhaler) appear more effective than monotherapies. Inhaled steroids should be reserved for patients who exacerbate despite optimal bronchodilation.
Despite optimising inhaled therapies, there will still be a group of patients who continue to exacerbate and seek healthcare advice for flare ups of their symptoms. These patients can be particularly challenging to manage and I will discuss these in the next installment.
- Vogelmeier C, Criner G, Martinez F, et al. Global strategy for the diagnosis, management, and prevention of chronic obstructive lung disease 2017 report: GOLD executive summary. Eur Respir J 2017; 49: 1700214.
- Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. GOLD, 2018. Available at: goldcopd.org
- Anzueto A. Impact of exacerbations on COPD. Eur Respir Rev 2010; 19 (116): 113–118.
- Dransfield M, Kunisaki K, Strand M, et al. Acute exacerbations and lung function loss in smokers with and without chronic obstructive pulmonary disease. Am J Respir Crit Care 2017; 195 (3): 324–330.
- Bachouch I, Fessi R, Chermiti F, et al. Delay in diagnosis of COPD leading to poor prognosis of disease. Eur Respir J 2015; 46: PA3671.
- Wilkinson T, Donaldson G, Hurst J, et al. Early therapy improves outcomes of exacerbations of chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2004; 169: 1298–1303.
- NICE. Chronic obstructive pulmonary disease in over 16s: diagnosis and management. NICE Clinical Guideline 101. NICE, 2010. Available at: www.nice.org.uk/cg101
- George S, Garcha D, Mackay A, et al. Human rhinovirus infection during naturally occurring COPD exacerbations. Eur Respir J 2014; 44: 87–96.
- Sapey E, Stockley R. COPD exacerbations 2: aetiology. Thorax 2006; 61: 250–258.
- Walters J, Hansenb E, Walters E, Wood-Baker R. Under-diagnosis of chronic obstructive pulmonary disease: a qualitative study in primary care. Respir Med 2008; 102: 738–743.
- Halpin D, Hyland M, Blake S, et al. Understanding fear and anxiety in patients at the time of an exacerbation of chronic obstructive pulmonary disease: a qualitative study. JRSM Open 2015; 6 (12): 2054270415614543.
- Hurst J, Wedzicha J. What is (and what is not) a COPD exacerbation: thoughts from the new GOLD guidelines. Thorax 2007; 62: 198–199.
- Woods J, Wheeler J, Finch C, Pinner N. Corticosteroids in the treatment of acute exacerbations of chronic obstructive pulmonary disease. Int J Chron Obstruct Pulmon Dis 2014; 9: 421–430.
- Leuppi J, Schuetz P, Bingisser R, et al. Short-term vs conventional glucocorticoid therapy in acute exacerbations of chronic obstructive pulmonary disease: the REDUCE randomized clinical trial. JAMA 2013; 309 (21): 2223–2231.
- Bafadhel M, McKenna S, Terry S, et al. Blood eosinophils to direct corticosteroid treatment of exacerbations of chronic obstructive pulmonary disease: a randomized placebo-controlled trial. Am J Respir Crit Care Med 2012; 186 (1): 48–55.
- Wedzicha J. Role of viruses in exacerbations of chronic obstructive pulmonary disease. Proc Am Thorac Soc 2004; 1: 115–120.
- Moussaoui R, Roede B, Speelman P, et al. Short-course antibiotic treatment in acute exacerbations of chronic bronchitis and COPD: a meta-analysis of double-blind studies. Thorax 2008; 63: 415–422.
- Woolhouse I, Hill S, Stockley R. Symptom resolution assessed using a patient directed diary card during treatment of acute exacerbations of chronic bronchitis. Thorax 2001; 56: 947–953.
- Tønnesen P. Smoking cessation and COPD. Eur Respir Rev 2013; 22 (127): 37–43.
- Poole P, Chacko E, Wood-Baker R, Cates C. Influenza vaccine for patients with chronic obstructive pulmonary disease. Cochrane Database of Systematic Reviews 2006; 1: CD002733.
- Varkey J, Varkey A, Varkey B. Prophylactic vaccinations in chronic obstructive pulmonary disease: current status. Curr Opin Pulm Med 2009; 15 (2): 90–99.
- Puhan M, Gimeno-Santos E, Scharplatz M, et al. Pulmonary rehabilitation following exacerbations of chronic obstructive pulmonary disease. Cochrane Database Syst Rev 2011; 10: CD005305.
- Kew K, Mavergames C, Walters J. Long-acting beta2-agonists for chronic obstructive pulmonary disease. Cochrane Database Syst Rev 2013; 10: CD010177.
- Halpin D, Vogelmeier C, Pieper M, et al. Effect of tiotropium on COPD exacerbations: a systematic review. Respir Med 2016; 114: 1–8.
- Vogelmeier C, Hederer B, Glaab T, et al. Tiotropium versus salmeterol for the prevention of exacerbations of COPD. N Engl J Med 2011; 364 (12): 1093–1103.
- Wedzicha J, Decramer M, Ficker J, et al. Analysis of chronic obstructive pulmonary disease exacerbations with the dual bronchodilator QVA149 compared with glycopyrronium and tiotropium (SPARK): a randomised, double-blind, parallel-group study. Lancet Respir Med 2013; 1 (3): 199–209.
- Yang I, Fong K, Sim E, et al. Inhaled corticosteroids for stable chronic obstructive pulmonary disease. Cochrane Database Syst Rev 2007; 2: CD002991.
- Horita N, Goto A, Shibata Y, et al. Long-acting muscarinic antagonist (LAMA) plus long-acting beta-agonist (LABA) versus LABA plus inhaled corticosteroid (ICS) for stable chronic obstructive pulmonary disease (COPD). Cochrane Database Syst Rev 2017; 2: CD012066.
- Poole P. Role of mucolytics in the management of COPD. Int J Chron Obstruct Pulmon Dis 2006; 1 (2): 123–128.
- Brill S, Law M, El-Emir E, et al. Effects of different antibiotic classes on airway bacteria in stable COPD using culture and molecular techniques: a randomised controlled trial. Thorax 70 (10): 930–938.
- White P, Thornton H, Pinnock H, et al. Overtreatment of COPD with inhaled corticosteroids—implications for safety and costs: cross-sectional observational study. PLoS One 2013; 8 (10): e75221.
- Magnussen H, Disse B, Rodriguez-Roisin R, et al. Withdrawal of inhaled glucocorticoids and exacerbations of COPD. N Engl J Med 2014; 371: 1285–1294.