Exacerbations in chronic obstructive pulmonary disease: is prevention the key?
It’s World COPD day this month, and at a conference convened to mark it, one of the questions for debate was ‘Is it possible to eliminate exacerbations in COPD?” Probably not, but there is much that can help to reduce the risk
Chronic obstructive pulmonary disease (COPD) is a disease which manifests in different ways for different individuals. This has led to the development of guidelines which focus on identifying those who are symptomatic but not exacerbating versus those who are frequent exacerbators.1 The most appropriate pharmacological approach to managing each type of COPD can be identified by following the Global Strategy for the Prevention, Diagnosis and Management of COPD’s ‘ABCD’ algorithm which is based on much of the available evidence about how best to treat symptoms and reduce future exacerbation risk.1
In this article, we explore some of the factors that may influence the likelihood of patents suffering from exacerbations of their COPD and consider how these might inform practice. By the end of this article you should be able to:
- Recognise how acute exacerbations of COPD (AECOPD) are defined and categorised
- Understand how AECOPD can impact on holistic well-being
- Identify key risk factors which put people at risk of AECOPD
- Implement knowledge of those risk factors in order to reduce risk
- Give a rationale for where different inhaled therapies can be used to reduce AECOPD risk in specific patient types
ACUTE EXACERBATIONS OF COPD (AECOPD)
Definitions, categories and impact
AECOPD are often defined as being an acute worsening of the day-to-day symptoms experienced by people with COPD (productive cough, dyspnoea, inability to carry out activities of daily living) and which need a change in treatment.1 Reducing the risk of AECOPD can have a significant impact on an individual’s health status, both now and in the future. Although many studies have looked at the impact of a variety of pharmacological and non-pharmacological interventions on the risk of AECOPD, there are limitations to these studies. As is often the case with randomised control trials (RCTs), significant numbers and phenotypes of patients may be excluded because of co-morbidities or because they are frequent exacerbators. This means that these groups, who are often the ‘real-life’ patients seen in practice, have not been studied in these RCTs.2 Furthermore, trials which look at the impact of various interventions on COPD outcomes often focus on reducing the frequency of exacerbations as a key outcome but different patient groups may under- or over-report exacerbations, depending on their perception of symptom severity whereas hospital admissions and length of stay may be influenced the amount of social support patients have at home.3,4 This makes the scientific assessment of the frequency and severity of exacerbations and the impact of interventions on those exacerbations difficult to measure.
GOLD guidelines recommend that patients should be proactively asked about any exacerbations at their review.1 Details that should be recorded might include the frequency, severity, type and potential cause of the exacerbation. Any treatment taken (for example using a rescue pack) should also be recorded along with the response to treatment. This will ensure that all exacerbation data are captured effectively in order to optimise treatment and outcomes.
The effective prevention and management of acute exacerbations will not only reduce symptoms but will improve health status and the ability to carry out the activities of daily living.5 Reducing exacerbation frequency has also been shown to reduce mortality.6 Using the most effective treatment for each COPD phenotype may also affect the frequency of future exacerbations and the rate of loss of lung function.1 There is also some evidence to suggest that reducing AECOPD may impact on cardiovascular co-morbidities.7
CATEGORIES OF AECOPD
Many AECOPD are caused by infection, either viral or bacterial.8 However, not all exacerbations are infective. Bafadhel et al,9 categorised exacerbations as bacterial, viral, eosinophilic or pauci-inflammatory and suggested that markers such as interleukin 1β, eosinophil counts or others could be used to identify which category of exacerbation was happening in order to tailor treatment appropriately. There is already increasing interest in using eosinophil counts (in both blood and sputum) to predict exacerbation risk in people with COPD and to identify those who might need an inhaled corticosteroid to reduce their risk of future exacerbations.10 Further studies will be needed to assess exactly where these tests can be used most effectively and what the cut off points should be to inform treatment decisions for people with asthma, COPD and asthma/COPD overlap.
RISK FACTORS FOR AECOPD
The Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-Points (ECLIPSE) study demonstrated that a previous history of AECOPD was a predictor of future risk.11 This is reflected in the GOLD ABCD algorithm which states that anyone who is a frequent exacerbator (defined as two or more exacerbations per year) should be targeted for treatment aimed at reducing that risk.1 According to Agusti and colleagues,12 other risk factors for AECOPD include being over 65, having more severe airflow limitation, having emphysema, experiencing a productive cough outside of exacerbations or the co-existence of poor health status (as defined by the St George’s Respiratory Questionnaire or the COPD assessment test). The presence of physical and psychological co-morbidities also influenced exacerbation risk, including gastro-oesophageal reflux and cardiovascular disease. Obviously smoking history, which is a strong predictor of COPD risk, is also a cardiovascular risk factor and it may be that cardiovascular disease (CVD) may influence the risk of exacerbations of COPD too. Troponin levels have been shown to increase in some patients suffering from acute exacerbations of COPD and this rise in troponin is a predictor of mortality in patients admitted with AECOPD.13 There is also the possibility that the similarities between the symptoms of AECOPD and heart failure may mean that some people are mistakenly diagnosed and treated as AECOPD when, in fact, they are presenting with acute decompensated heart failure. Some studies suggest that women are at greater risk than men although the reasons for this are unclear. Low body mass index and using long term oxygen therapy (LTOT) may also increase the risk.14 The BODE score (Body mass index, airflow Obstruction, Dyspnoea and Exercise capacity) was found to be a good predictor of outcomes including mortality,15 although it is sometimes said that this score is not easy to implement in the primary care setting because of the need to perform a six minute walking test to assess exercise capacity.
ACTING TO REDUCE RISK
Suissa et al16 suggested that following an initial hospital admission for exacerbation of COPD, there were up to two years of stable risk before the second exacerbation but that following a second exacerbation, further exacerbations became more frequent. Admission to hospital is a significant event as there may be a 50% 5-year mortality rate following admission for AECOPD.14 The onus is therefore on clinicians to take action to reduce the risk of further exacerbations after stage 1 and before stage 2 commences.
Some authors query whether frequent exacerbators really are having separate exacerbations or whether these ‘recurrences’ are, in fact, more suggestive of a failure of treatment for the original exacerbation.17 This has led to the suggestion that so-called frequent exacerbators may respond better to azithromycin rather than, for example, prescribing repeated courses of oral steroids and there is evidence to suggest this approach may be beneficial.18 However, in trials where a regimen of azithromycin 250mg daily has been used, objective reductions in hearing have been measured in study participants and as this is a known side effect of the drug, the risks and benefits should be weighed up before treatment commences. Azithromycin 250mg may therefore be given as a ‘pulsed’ treatment, giving 250mg three times a week to optimise outcomes whilst minimising risks.1
Evidence-based interventions which can reduce the risk of AECOPD include smoking cessation and the longer the period of abstinence from smoking, the greater the benefit.19 The period following any acute exacerbation of COPD is a valuable opportunity to discuss smoking cessation as the patient’s motivation to quit may be increased at this time. All primary care nurses should be prepared to offer smoking cessation advice and support in line with their code of conduct, and free online training is available to all staff via the National Centre for Smoking Cessation and Training at http://www.ncsct.co.uk/.
Pulmonary rehabilitation (PR) has also been shown to reduce readmission rates and mortality in people who have been admitted with AECOPD.20 Flu and pneumonia vaccinations can also reduce the risk of exacerbations.1 These three interventions (smoking cessation, PR and vaccinations) form the basis of the London Respiratory Network’s COPD pyramid (Figure 1) which is said to show the most cost-effective options for treating COPD.
Perhaps surprisingly, statins have also been shown to reduce exacerbations of COPD. Although they are not licensed to treat COPD, studies with statins have shown a reduction in exacerbations, possibly related to the anti-inflammatory, pleiotropic (multi-system) effects of statins.21
ROLE OF INHALED THERAPIES
When it comes to the role of the various inhaled therapy options in reducing exacerbation risk in COPD, there is evidence for long-acting bronchodilators, both beta2 agonists and anti-muscarinics, given separately or together as a dual bronchodilators. As well as reducing exacerbation risk in some patients, dual bronchodilators can optimise bronchodilation as well as reducing hyperinflation, a significant cause of breathlessness in patients with COPD.22 There are currently four dual bronchodilators available on the market. These are Anoro (umeclidinium and vilanterol in the Ellipta device), Duaklir (aclidinium and formoterol in the Genuair device), Ultibro (glycopyrronium and indacaterol in the Breezhaler device) and Spiolto (tiotropium and olodaterol in the Respimat device).
Long-acting muscarinic antagonists (LAMAs) such as tiotropium have been shown to be more effective than LABAs such as salmeterol.23 There is also evidence for inhaled corticosteroids (ICS),24 but these should always be given as a licensed product containing both an ICS and a LABA. However, GOLD states that LAMA/LABAs may be preferable to an inhaled ICS/LABA combination in some people due to the risk:benefit ratio of dual bronchodilators versus inhaled steroids in COPD, particularly where high dose ICS products have been used.25,26 ICS/LABAs licensed for COPD include twice daily doses of Seretide 500mcg via the Accuhaler (and similar products such as Sirdupla, Airflusal and Aerivio), Symbicort 400/12mcg via the Turbohaler or the pMDI device (and similar products such as Duoresp 320/9mcg via the Spiromax device and Fobumix 320/9mcg via the Easyhaler device), Fostair 200/12mcg via the NextHaler or the pMDI, or Relvar 92/22mcg once daily via the Ellipta device. Patient choice is important as is ensuring that they can use their device. However, decisions may also be made on factors such as the total daily dose equivalence of the ICS or the preferred LABA as those which contain formoterol (Symbicort, Fostair, Duoresp, Fobumix) will have a faster onset of action than those containing other LABA molecules such as salmeterol or vilanterol and this may impact on the individual’s ability to carry out their activities of daily living, which may also affect exacerbation risk. It is essential to remember that if there is any evidence or history compatible with reversible airways disease, an ICS is always indicated.27
There is now an inhaler which contains all three ingredients – an ICS, a LABA and a LAMA – which is licensed for people with moderate to severe COPD who are not controlled with an ICS/LABA alone. Trimbow® is the first single device with triple therapy on the market and contains extra fine beclometasone with formoterol (as in Fostair®) with glycopyrronium as the LAMA. Each dose leaving the device contains 100 micrograms of extra fine beclometasone, 6 micrograms of formoterol fumarate dihydrate and 10 micrograms of glycopyrronium, and patients take a fixed dose of two puffs daily. Studies using Trimbow in this population showed that using the triple therapy resulted in better outcomes, including exacerbations, than using the ICS/LABA combination or tiotropium alone.28,29
Overall, however, it is important to recognise that even the most effective of these interventions mentioned above will only reduce exacerbations but that none of them prevent exacerbations altogether. More research is needed if this goal is to be achieved.
CONCLUSION
In conclusion, people with COPD are at risk of acute exacerbation. Several risk factors have been identified for these exacerbations and individuals should be assessed based on these risk factors. Previous exacerbation history is an important predictor of future risk but people may under report or fail to recognise when they have had an exacerbation, and this may affect the healthcare professional’s perception of their ongoing risk. Information about AECOPD should be sought proactively to avoid this. There are many evidence based interventions to reduce exacerbation risk, including smoking cessation, vaccinations and pulmonary rehabilitation. Inhaled therapies can also help to manage and prevent exacerbations. The most appropriate, holistic management strategy will be achieved by taking a personalised approach to each individual patient:
- Recognise the impact of acute exacerbations of COPD (AECOPD) on holistic well-being
- Identify key factors that put people at risk of AECOPD
- Implement knowledge about risk factors in order to reduce risk
- Give a rationale for the different treatment approaches to reducing the risk of AECOPD
REFERENCES
1. Global Initiative for Obstructive Lung Disease. Global strategy for the diagnosis, management and prevention of COPD, 2017 http://www.goldcopd.org
2. Kennedy-Martin T, Curtis S, Faries D, et al. (2015). A literature review on the representativeness of randomized controlled trial samples and implications for the external validity of trial results. Trials 2015; 6: 495. http://doi.org/10.1186/s13063-015-1023-4
3. Seemungal TA, Donaldson GC, Bhowmik A, et al. Time course and recovery of exacerbations in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2000;161(5):1608-1613. doi: http://DX.DOI.ORG/10.1164/AJRCCM.161.5.9908022
4. Gaude GS, Rajesh B, Chaudhury A, et al. Outcomes associated with acute exacerbations of chronic obstructive pulmonary disorder requiring hospitalization. Lung India"¯: Official Organ of Indian Chest Society 2015;32(5):465–472. http://doi.org/10.4103/0970-2113.164150
5. Qureshi H, Sharafkhaneh A, Hanania NA. Chronic obstructive pulmonary disease exacerbations: latest evidence and clinical implications. Therapeutic Advances in Chronic Disease 2014;5(5):212–227. http://doi.org/10.1177/2040622314532862
6. Schmidt SAJ, et al. The impact of exacerbation frequency on mortality following acute exacerbations of COPD: a registry-based cohort study. BMJ Open 2014; http://bmjopen.bmj.com/content/4/12/e006720.full
7. Pavord ID, Jones PW, Burgel PR, et al. Exacerbations of COPD. International Journal of Chronic Obstructive Pulmonary Disease, 2016;11(Spec Iss): 21–30. http://doi.org/10.2147/COPD.S85978
8. Seemungal T, Harper-Owen R, Bhowmik A, et al. Respiratory viruses, symptoms, and inflammatory markers in acute exacerbations and stable chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2001;164(9):1618-1623. doi: http://dx.doi.org/10.1164/ajrccm.164.9.2105011
9. Bafadhel M, McKenna S, Terry S, et al. Acute exacerbations of chronic obstructive pulmonary disease: identification of biologic clusters and their biomarkers. Am J Respir Crit Care Med. 2011;184(6):662-671. doi: http://dx.doi.org/10.1164/rccm.201104-0597OC
10. Brightling CE, Monteiro W, Ward R, et al. Sputum eosinophilia and short-term response to prednisolone in chronic obstructive pulmonary disease: a randomised controlled trial. Lancet. 2000;356(9240):1480–1485
11. Agusti A et al. Characterisation of COPD heterogeneity in the ECLIPSE cohort. Respir Res 2010;11:122
12. Agusti A, Calverley PM, Decramer M, et al. Prevention of exacerbations in chronic obstructive pulmonary disease: knowns and unknowns. J COPD F. 2014; 1(2): 166-184. doi: http://doi.org/10.15326/jcopdf.1.2.2014.0134
13. Chang CL, Robinson SC, Mills GD, et al. Biochemical markers of cardiac dysfunction predict mortality in acute exacerbations of COPD. Thorax. 2011;66(9):764-768. doi: http://dx.doi.org/10.1136/thx.2010.155333
14. Garcia-Aymerich J, et al. Lung function impairment, COPD hospitalisations and subsequent mortality Thorax 2011;66:585-590.
15. Faganello MM, Tanni SE, Sanchez FF, et al. BODE index and GOLD staging as predictors of 1-year exacerbation risk in chronic obstructive pulmonary disease. Am J Med Sci. 2010;339(1):10-14. doi: http://dx.doi.org/10.1097/MAJ.0b013e3181bb8111
16. Suissa S, Dell’aniello S, Ernst P. Long-term natural history of chronic obstructive pulmonary disease: severe exacerbations and mortality. Thorax. 2012;67(11):957-963. doi: http://dx.doi.org/10.1136/thoraxjnl-2011-201518
17. Soler-Cataluna JJ, Rodriguez-Roisin R. Frequent chronic obstructive pulmonary disease exacerbators: how much real, how much fictitious? COPD. 2010;7(4):276-284. doi: http://dx.doi.org/10.3109/15412555.2010.496817
18. Albert RK, Connett J, Bailey WC, et al; for the COPD Clinical Research Network. Azithromycin for prevention of exacerbations of COPD. N Engl J Med. 2011;365:689-698. doi: http://dx.doi.org/10.1056/NEJMoa1104623
19. Au D, et al. The effects of smoking cessation on the risk of chronic obstructive pulmonary disease exacerbations. J Gen Intern Med 2009;24:457–463
20. Puhan MA et al. Pulmonary rehabilitation following exacerbations of chronic obstructive pulmonary disease. Cochrane Database Syst Rev 2011;10: CD005305.
21. Lawes CM, Thornley S, Young R, et al. Statin use in COPD patients is associated with a reduction in mortality: a national cohort study. Prim Care Respir J. 2012;21(1):35-40. doi: http://dx.doi.org/10.4104/pcrj.2011.00095
22. O’Donnell D, et al. Lung hyperinflation in COPD: applying physiology to clinical practice COPD Research and Practice 2015;1:4
23. Halpin DG, et al. Effect of tiotropium on COPD exacerbations: A systematic review Respiratory Medicine 2016;114:1–8
24. Ernst P, Saad N, Suissa S. Inhaled corticosteroids in COPD European Respiratory Journal 2015;45:525-537
25. Suissa S, Kezouh A, Ernst P. Inhaled corticosteroids and the risks of diabetes onset and progression. Am J Med 2010;123:1001-1006 http://www.amjmed.com/article/S0002-9343(10)00648-0/pdf
26. Crim C et al. Pneumonia risk in COPD patients receiving inhaled corticosteroids alone or in combination: TORCH study results. Eur Respir J 2009;34(3):641–647
27. GINA Report. What’s new in GINA 2017? http://ginasthma.org/2017-gina-report-global-strategy-for-asthma-management-and-prevention/
28. Singh D, Papi A, Corradi M, et al. Single inhaler triple therapy versus inhaled corticosteroid plus long-acting β2 agonist for chronic obstructive pulmonary disease (TRILOGY): a double-blind, parallel group, randomised controlled trial. Lancet 2016;388:963-973
29. Vestbo J, Papi A, Corradi M, et al. Single inhaler extrafine triple therapy versus long-acting muscarinic antagonist therapy for chronic obstructive pulmonary disease (TRINITY): a double-blind, parallel group, randomised controlled trial. Lancet 2017;389:1919-1929 http://dx.doi.org/10.1016/S0140-6736(17)30188-5
