Skip to main content

Main menu

  • Home
  • Current issue
  • ERJ Early View
  • Past issues
  • ERS Guidelines
  • Authors/reviewers
    • Instructions for authors
    • Submit a manuscript
    • Open access
    • Peer reviewer login
    • WoS Reviewer Recognition Service
  • Alerts
  • Subscriptions
  • ERS Publications
    • European Respiratory Journal
    • ERJ Open Research
    • European Respiratory Review
    • Breathe
    • ERS Books
    • ERS publications home

User menu

  • Log in
  • Subscribe
  • Contact Us
  • My Cart

Search

  • Advanced search
  • ERS Publications
    • European Respiratory Journal
    • ERJ Open Research
    • European Respiratory Review
    • Breathe
    • ERS Books
    • ERS publications home

Login

European Respiratory Society

Advanced Search

  • Home
  • Current issue
  • ERJ Early View
  • Past issues
  • ERS Guidelines
  • Authors/reviewers
    • Instructions for authors
    • Submit a manuscript
    • Open access
    • Peer reviewer login
    • WoS Reviewer Recognition Service
  • Alerts
  • Subscriptions

COPD frequent exacerbators: time for the recycle bin?

Robert A. Stockley
European Respiratory Journal 2021 57: 2003758; DOI: 10.1183/13993003.03758-2020
Robert A. Stockley
Lung Investigation Unit, Queen Elizabeth Hospital Birmingham, Edgbaston, UK
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • For correspondence: r.a.stockley@bham.ac.uk
  • Article
  • Figures & Data
  • Info & Metrics
  • PDF
Loading

Abstract

The definition of frequent exacerbators has changed with time. The use of previous history to identify frequent exacerbators is far from robust and has implications for the instigation of therapy based on the current GOLD algorithm. https://bit.ly/33TfGxg

Introduction

COPD is a highly prevalent chronic disease with increased mortality and morbidity. The chronic symptoms result in impaired quality of life interspersed with episodes of acute worsening (exacerbations), which increase patient stress, and the likelihood of hospital admissions and death. These episodes are not only dangerous but also worsen background quality of life, increase the general healthcare burden and lead to disease progression [1, 2]. Therefore, they represent a key target in patient management and have become a primary clinical outcome measure in pharmaceutical drug registration.

The study of the causes and management of these episodes has led to an ever increasing literature in order to understand their nature, although therapeutic manipulations dominate with multiple large cohort trials and studies using variations of usual background inhaled therapies. The management, however, remains largely empirical, based on statistical generalisations.

In 1987 only 13 papers were published on exacerbations of COPD but included the classical “Anthonisen” paper describing the three major symptoms of such episodes, namely an increase in dyspnoea, new or increased sputum volume and new or increased sputum purulence [3]. This study confirmed that although many episodes resolved spontaneously, antibiotics were beneficial particularly if all three symptoms were present, which includes the purulence being consistent with a neutrophilic response to a heavy bacterial load [4, 5]. A change in 1–3 of these largely subjective symptoms remains central to diagnosing an exacerbation used in most of the literature to date.

In 2000 147 papers were published, introducing a clearer definition of exacerbation [6] that included the concept that it requires an increase in usual therapy or the addition of further therapeutic agents. Again this definition remains a cornerstone of the current diagnosis and retrospective identification of episodes, even though the treatments may not be specifically for exacerbations of COPD. Furthermore, clinical episodes of the acute change in the Anthonisen triad of symptoms may not receive extra treatment (the so called “unreported episodes”) and yet still have an impact on health status [7]. This issue remains largely unaddressed, although data suggests failure to change therapy reflects a subjective feeling of “wellness” or its rapid improvement [8].

In 2019 1163 papers were published on the topic, but despite the plethora of observational, scientific and interventional studies, have we really moved forward in this era of personalised medicine?

Frequent exacerbators

Many patients with COPD rarely have exacerbations, although the likelihood increases with disease severity and certain subtypes of COPD, including those with established cough and sputum production, those colonised with bacteria and those with concomitant bronchiectatic change.

Some of the “episodes” may have nothing to do with COPD itself, but reflect other comorbidities especially cardiovascular disease and ambient pollution. In addition, viral and bacterial colonisation are common even in the stable state and although identified in exacerbations, may not be the driving aetiology. Increased inflammation in the lung is only a feature of some episodes and usually those associated with a likely bacterial or viral aetiology, especially when it changes.

However, increased and partially reversible airflow obstruction is also a feature even in primary care [9], which drives the acute therapeutic management and most of the current “preventative” strategies.

To dissect these issues and determine whether they can be prevented requires large cohorts of patients studied over prolonged periods. This can be partially offset by studying patient cohorts enriched for those who are likely to have recurrent episodes during the period of study.

This “frequent exacerbator” phenotype (defined initially as three or more episodes in a year) was first described by Seemungal et al. [1], who also noted the impact of such episodes on health status, and Donaldson et al. [2], who noted the contribution to physiological progression (albeit on average <10 mL decline in forced expiratory volume in 1 s (FEV1) per year). However, with improvements in patient management such recorded episodes have become less likely [10] and a “frequent exacerbator” has more recently been defined as having two or more episodes each year. In the classical paper by Hurst et al. [11] using the ECLIPSE cohort, the best predictor of the “frequent exacerbator” was the preceding history. However from personal experience and that of clinical trials enriched for such patients, the reality is that those recruited have an average exacerbation frequency between 1 and 1.5 per year. Nevertheless, interventions with two or three inhaled therapies produce statistical reductions in the average rate of up to 30%. This in turn leads to generalisations that influence starting or follow-up therapy for long term management as stated in the current Global Initiative for Chronic Obstructive Lung Disease (GOLD) algorithms [12] and many guidelines whereby “frequent exacerbators” are prescribed dual or triple inhaled therapy. This strategy depends on identifying such patients by word of mouth or, at best, previous medical records.

Time to rethink

Exacerbations are sporadic events with multiple causations and even the number of episodes from medical records fails to note the “unreported episodes” by definition.

The study reported by Sadatsafavi et al. [13] in the current issue of the European Respiratory Journal recognises this frequent exacerbator conundrum and analysed “reported” episodes in two major cohorts noting divergent data concerning the prevalence of “frequent exacerbators”, one of which (SPIROMICS) found such individuals to be rare [14], whereas the other (ECLIPSE), that lead to the Hurst et al. [11] paper of identification from previous history, found them to be more prevalent. This was probably related to the former cohort having a significant proportion of patients with less severe COPD and who were hence less likely to exacerbate. However, although the stability of exacerbation phenotype was statistically likely in both cohorts, past history as a predictor of future episodes was at best marginally better than tossing a coin. The implications of this theoretical and observational analysis may not influence the statistical outcome of large clinical trials but means a rethink of how our personalised algorithms of patient management should be designed. Unless of course, we remain happy to manage COPD as if each is the average patient with the average likelihood of exacerbations using the average therapeutic strategy: surely a retrograde step in individual patient management and a move towards triple therapy for all, which clearly has a financial impact, and a one course fits all management plan. In a synchronous publication the same group published the outcome of a new tool (ACCEPT) which takes into account multiple other factors from the placebo arms of several large interventional studies [15]. This tool, using relatively easily obtainable features, including the previous number of episodes, in addition to age, sex, smoking status, FEV1, St George's Respiratory Questionnaire score, body mass index and medications. This tool proved better (at least statistically) than history alone in predicting future episodes, although the receiver operating characteristic (ROC) curves look less convincing. However, the ROC curves for severe (hospital admission) episodes do show a clearer advantage using the composite dataset advocated in ACCEPT.

The alternative is to bin the term “frequent exacerbator” and move towards the “recurrent exacerbator” based on accurate monitoring of episodes and defining their nature. This requires a change of approach with a proactive format and based (as with GOLD [12]) on a newly diagnosed patient, be that at hospital admission or first medical visit achieving a diagnosis.

The former clearly represents a severe event and such patients would still be classified as GOLD group D, as indicated in figure 1, and should be managed along the current algorithm with dual bronchodilator therapy, with or without inhaled corticosteroids (ICS) depending on baseline eosinophil count [16]. However, a different strategy might be more applicable, based on the current weakness of previous history to tip the patient from box B to box D as intimated by the current paper by Sadatsafavi et al. [13]. Here the approach may be based on the stable state driving symptoms alone, and hence starting in box B, with introduction of a long-acting bronchodilator and a lack of improvement or continuing disabling dyspnoea at follow-up leading to a change or addition of a second agent, respectively.

FIGURE 1
  • Download figure
  • Open in new tab
  • Download powerpoint
FIGURE 1

Implications for the Global Initiative for Chronic Obstructive Lung Disease (GOLD). For new patients with a high symptom load, GOLD places them in box B or D, depending on the exacerbation history. One hospital admission still places the patient in box D and the current algorithm still applies. However, if the patient has a history of two or more exacerbations the current publication [13] suggests this cannot be assumed to be a long term pattern. Therefore, it seems logical to put such new patients into box B and start therapy with a long-acting β-agonist (LABA) or long-acting muscarinic antagonist (LAMA) and review progress, changing or adding the alternative depending on symptom response. The use of a monitoring tool to document and characterise exacerbations and provide relevant rescue packs seems reasonable for sporadic events. For those with multiple recurrent events, the addition of inhaled corticosteroids (ICS) may be indicated if the eosinophil count is high [16], but alternative strategies would be indicated for those with low eosinophil counts depending on the documented features of the COPD patient and the characterisation of the episodes.

Continued management should therefore include symptom monitoring and, in particular, documentation of features of exacerbations utilising the Anthonisen criteria together with documented requests for intervention. Its appropriateness will provide a clear understanding of whether the episodes likely represent a bacterial origin (documented purulent sputum episodes) or are on the background of a documented baseline eosinophilia. Either can be managed on an as-required basis to start with, or if recurrent (three or more per year?) on the basis of an appropriate long term antibiotic or anti-inflammatory strategy (as applied in bronchiectatic guidance) or with the introduction of ICS based on the background eosinophil count [16].

Is it too late to start again?

The answer is likely to be yes for established patients already on a multidrug treatment strategy. However, adapting a more cautious and staged approach for newly diagnosed patients may well be the opportunity to adjust our therapeutic approach. Current therapy (even triple) does not prevent all exacerbations, so it is not just an anti-inflammatory or bronchodilatory strategy we need. Although part of the impact of such a strategy may be to reduce the symptomatology of some episodes, moving them into the “non-reported” category rather than modifying their pathophysiological nature. For instance, although purulent exacerbations are inflammatory and proteinase rich, increasing tissue damage, if they represent the only Anthonisen symptom they are rarely treated [17], which might just be the time to do so and protect lung structure. So our strategy should be to treat both the symptoms of the episode and its nature.

The time has come to review all the lessons of the past 30 years and treat patients as individuals rather than applying statistical generalisations with average outcomes of saving 30% of an exacerbation per patient per year. It is up to us!

Shareable PDF

Supplementary Material

This one-page PDF can be shared freely online.

Shareable PDF ERJ-03758-2020.Shareable

Footnotes

  • Conflict of interest: R.A. Stockley has nothing to disclose.

  • Received October 7, 2020.
  • Accepted October 12, 2020.
  • Copyright ©ERS 2021
https://www.ersjournals.com/user-licence

References

  1. ↵
    1. Seemungal TA,
    2. Donaldson GC,
    3. 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: 1608–1613. doi:10.1164/ajrccm.161.5.9908022
    OpenUrlCrossRefPubMedWeb of Science
  2. ↵
    1. Donaldson GC,
    2. Seemungal TAR,
    3. Bhowmik A, et al.
    Relationship between exacerbation frequency and lung function decline in chronic obstructive pulmonary disease. Thorax 2002; 57: 847–852. doi:10.1136/thorax.57.10.847
    OpenUrlAbstract/FREE Full Text
  3. ↵
    1. Anthonisen NR,
    2. Manfreda J,
    3. Warren CP, et al.
    Antibiotic therapy in exacerbations of chronic obstructive pulmonary disease. Ann Intern Med 1987; 106: 196–204. doi:10.7326/0003-4819-106-2-196
    OpenUrlCrossRefPubMedWeb of Science
  4. ↵
    1. Stockley RA,
    2. O'Brien C,
    3. Pye A, et al.
    Relationship of sputum color to nature and outpatient management of acute exacerbations of COPD. Chest 2000; 117: 1638–1645. doi:10.1378/chest.117.6.1638
    OpenUrlCrossRefPubMedWeb of Science
  5. ↵
    1. Hill AT,
    2. Campbell EJ,
    3. Hill SL, et al.
    Association between airway bacterial load and markers of airway inflammation in patients with chronic bronchitis. Am J Med 2000; 109: 288–295. doi:10.1016/S0002-9343(00)00507-6
    OpenUrlCrossRefPubMedWeb of Science
  6. ↵
    1. Rodriguez-Roisin R
    . Towards a consensus definition for COPD exacerbations. Chest 2000; 117: 398S–401S. doi:10.1378/chest.117.5_suppl_2.398S
    OpenUrlCrossRefPubMedWeb of Science
  7. ↵
    1. Jones PW,
    2. Lamarca R,
    3. Chuecos F, et al.
    Characterisation and impact of reported and unreported exacerbations: results from ATTAIN. Eur Respir J 2014; 44: 1156–1165. doi:10.1183/09031936.00038814
    OpenUrlAbstract/FREE Full Text
  8. ↵
    1. Vijayasaratha K,
    2. Stockley RA
    . Reported and unreported exacerbations of COPD: analysis by diary cards. Chest 2008; 133: 34–41. doi:10.1378/chest.07-1692
    OpenUrlCrossRefPubMedWeb of Science
  9. ↵
    1. White AJ,
    2. O'Brien C,
    3. Hill SL, et al.
    Exacerbations of COPD diagnosed in primary care: changes in spirometry and relationship to symptoms. COPD 2005; 2: 419–425. doi:10.1080/15412550500346477
    OpenUrlCrossRef
  10. ↵
    1. Andreas S,
    2. Röver C,
    3. Heinz J, et al.
    Decline of COPD exacerbations in clinical trials over two decades – a systematic review and meta-regression. Respir Res 2019; 20: 186. doi:10.1186/s12931-019-1163-2
    OpenUrl
  11. ↵
    1. Hurst JR,
    2. Vestbo J,
    3. Anzueto A, et al.
    Susceptibility to exacerbation in chronic obstructive pulmonary disease. N Engl J Med 2010; 363: 1128–1138. doi:10.1056/NEJMoa0909883
    OpenUrlCrossRefPubMedWeb of Science
  12. ↵
    1. Singh D,
    2. Agusti A,
    3. Anzueto A, et al.
    Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Lung Disease: the GOLD science committee report 2019. Eur Respir J 2019; 53: 1900164. doi:10.1183/13993003.00164-2019
    OpenUrlAbstract/FREE Full Text
  13. ↵
    1. Sadatsafavi M,
    2. McCormack J,
    3. Petkau J, et al.
    Should the number of acute exacerbations in the previous year be used to guide treatments in COPD? Eur Respir J 2021; 57: 2002122. doi:10.1183/13993003.02122-2020
    OpenUrlAbstract/FREE Full Text
  14. ↵
    1. Han MK,
    2. Quibrera PM,
    3. Carretta EE, et al.
    Frequency of exacerbations in patients with chronic obstructive pulmonary disease: an analysis of the SPIROMICS cohort. Lancet Respir Med 2017; 5: 619–626. doi:10.1016/S2213-2600(17)30207-2
    OpenUrl
  15. ↵
    1. Adibi A,
    2. Sin DD,
    3. Safari A, et al.
    The Acute COPD Exacerbation Prediction Tool (ACCEPT): a modelling study. Lancet Respir Med 2020; 8: 1013–1021. doi:10.1016/S2213-2600(19)30397-2
    OpenUrl
  16. ↵
    1. Stockley RA,
    2. Halpin DMG,
    3. Celli BR, et al.
    Chronic obstructive pulmonary disease biomarkers and their interpretation. Am J Respir Crit Care Med 2019; 199: 1195–1204. doi:10.1164/rccm.201810-1860SO
    OpenUrl
  17. ↵
    1. Ejiofor SI,
    2. Stolk J,
    3. Fernandez P, et al.
    Patterns and characterisation of COPD exacerbations using real-time data collection. Int J COPD 2017; 12: 427–434. doi:10.2147/COPD.S126158
    OpenUrl
PreviousNext
Back to top
View this article with LENS
Vol 57 Issue 2 Table of Contents
European Respiratory Journal: 57 (2)
  • Table of Contents
  • Index by author
Email

Thank you for your interest in spreading the word on European Respiratory Society .

NOTE: We only request your email address so that the person you are recommending the page to knows that you wanted them to see it, and that it is not junk mail. We do not capture any email address.

Enter multiple addresses on separate lines or separate them with commas.
COPD frequent exacerbators: time for the recycle bin?
(Your Name) has sent you a message from European Respiratory Society
(Your Name) thought you would like to see the European Respiratory Society web site.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Print
Citation Tools
COPD frequent exacerbators: time for the recycle bin?
Robert A. Stockley
European Respiratory Journal Feb 2021, 57 (2) 2003758; DOI: 10.1183/13993003.03758-2020

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero

Share
COPD frequent exacerbators: time for the recycle bin?
Robert A. Stockley
European Respiratory Journal Feb 2021, 57 (2) 2003758; DOI: 10.1183/13993003.03758-2020
del.icio.us logo Digg logo Reddit logo Technorati logo Twitter logo CiteULike logo Connotea logo Facebook logo Google logo Mendeley logo
Full Text (PDF)

Jump To

  • Article
    • Abstract
    • Introduction
    • Frequent exacerbators
    • Time to rethink
    • Is it too late to start again?
    • Shareable PDF
    • Footnotes
    • References
  • Figures & Data
  • Info & Metrics
  • PDF
  • Tweet Widget
  • Facebook Like
  • Google Plus One

More in this TOC Section

  • Long-term outcome of co-infection of COVID-19 and TB
  • Leukocyte telomere length: personalised medicine for fibrotic ILD?
  • An attack of asthma is not an attack of the heart
Show more Editorials

Related Articles

Navigate

  • Home
  • Current issue
  • Archive

About the ERJ

  • Journal information
  • Editorial board
  • Press
  • Permissions and reprints
  • Advertising

The European Respiratory Society

  • Society home
  • myERS
  • Privacy policy
  • Accessibility

ERS publications

  • European Respiratory Journal
  • ERJ Open Research
  • European Respiratory Review
  • Breathe
  • ERS books online
  • ERS Bookshop

Help

  • Feedback

For authors

  • Instructions for authors
  • Publication ethics and malpractice
  • Submit a manuscript

For readers

  • Alerts
  • Subjects
  • Podcasts
  • RSS

Subscriptions

  • Accessing the ERS publications

Contact us

European Respiratory Society
442 Glossop Road
Sheffield S10 2PX
United Kingdom
Tel: +44 114 2672860
Email: journals@ersnet.org

ISSN

Print ISSN:  0903-1936
Online ISSN: 1399-3003

Copyright © 2023 by the European Respiratory Society