1https://doi.org/10.1183/20734735.0081-2021 Breathe | 2021 | Volume 17 | No 3
@ERSpublications
COPD exacerbations carry high risk for long-term disability and death. As the search for a
standardised measure continues, study investigators must ensure definitions are explicit and
justified to better understand how to prevent and manage these episodes. https://bit.ly/2UNqScy
COPD is the most prevalent chronic respiratory disease worldwide and a major cause of disability
and death. Acute exacerbations of COPD remain a key feature of the disease in many patients and
research assessing interventions to prevent and treat them requires a robust definition with high
sensitivity and specificity. To date, no such definition exists, and multiple dierent definitions are
used in clinical studies depending on the research question. The strengths and weaknesses of
current definitions are discussed in the context of evolving knowledge and dierent settings in which
studies are undertaken. Whether identification and recording of exacerbations remains essentially
clinical, or can be identified with a dependable biomarker, it should be sensitive and adaptable to
context while retaining clarity and facilitating data collection. This is essential to progress a better
understanding of the pathophysiology and phenotypic expression of exacerbations to reduce their
impact and personal burden for patients.
Cite as: Jenkins CR. Towards
precision in defining COPD
exacerbations. Breathe 2021;
17: 210081.
Review
Towards precision in defining
COPD exacerbations
Introduction
The global mortality and morbidity of COPD is high
and has not changed appreciably, unlike many other
noncommunicable diseases, over the past 20 years.
The Global Burden of Disease Study reported that
an estimated 545 million people worldwide had
a chronic respiratory disease in 2017, equivalent
to a 40% increase compared with the number
of individuals affected in 1990, an increase
disproportionate to global population growth [1].
COPD, with an overall global prevalence of 6%,
remained the most prevalent chronic respiratory
disease worldwide and made up 55% of chronic
respiratory disease prevalence among men and
women. This represents an increase in overall
prevalence of 6%, with a marked increase in women
over the same period [2, 3]. Chronic respiratory
disease is almost equally prevalent in high income
countries and low-middle income countries (LMICs),
although with vastly dierent aetiologies and
potentially still serious underdiagnosis in LMICs.
Chronic respiratory diseases account for 7% of total
all-cause deaths globally, and in 2017 were the third
leading cause of death, close behind cardiovascular
disease and cancer.
COPD, as the major portion of this high
prevalence, also confers very high morbidity [4].
Disability (disability-adjusted life years (DALYs))
due to chronic respiratory diseases increased 13%
between 1990 and 2017, and COPD accounted
for the lion’s share of this [1]. Some gains have
been made, the prevalence, mortality, and DALY
rates per 100 000 people dropping significantly
Christine R. Jenkins
1,2,3
christine.jenkins@sydney.edu.au
2 Breathe | 2021 | Volume 17 | No 3
Defining COPD exacerbations
between 1990 and 2017 when adjusted for
population growth and ageing. However, COPD
remains a major global health issue, with increasing
numbers of people aected and several of its major
causes still not addressed in many regions of the
world. This is despite the fact that much of the
burden of COPD can be prevented by primary and
secondary interventions ranging from public health
and government policy to health infrastructure,
skilled workforce development and community
health literacy [5]. Even in high income countries,
treatment-related costs consume a major portion
of healthcare budgets [6, 7], and a major portion
of these is the cost of exacerbations [7, 8]. Indirect
costs of work and productivity loss are also
substantial and just as great a burden for the patient
as for wider society [6].
Exacerbations of COPD
Although COPD is a progressive illness marked
by daily symptoms and in some patients, a slow
decline in lung function and quality of life [9, 10],
acute exacerbations of COPD remain a key feature
of the disease in many patients. Exacerbations are
more likely to occur in patients with a high symptom
burden, and in themselves add further burden of
disease and impairment of health status [9], as well
as risk of more frequent severe events [11–13].
Patients describe exacerbations as having a major
impact on their quality of life [9]. Unscheduled
visits to healthcare, whether primary, secondary
or tertiary, are costly [14, 15], disruptive and most
importantly to the patient, moments of extreme
physical [6] and emotional stress [16, 17], and for
some, life-threatening [18–20].
For the purposes of this introductory discussion,
I will define exacerbations of COPD clinically, as
episodes of acute worsening of symptoms, leading
to additional therapy and hospitalisations, that
punctuate a patient’s journey more frequently as
lung function and ventilatory impairment worsen
with time. However, as will become clear, within
and between patients with COPD, exacerbations
are heterogeneous events, with multiple causes,
dierent expression, and varying impact and clinical
responses. A satisfactory definition is not only a
semantic challenge, but also an epistemological
and environmental one. Most definitions of COPD
exacerbations contain both a symptom-based
component and an event-based component.
There are inadequacies with an emphasis on either
of these approaches [21], although alternative
definitions have not proven to be superior as a
general rule, even if fit for specific purposes, such as
clinical trials [22], database analysis [23] or studies
examining pathophysiology.
Exacerbations vary in frequency in individual
patients and most patients do not exacerbate
at exactly the same rate year aer year [24, 25].
In many studies [26], including the Evaluation of
COPD Longitudinally to Identify Predictive Surrogate
End-points (ECLIPSE) [27] and the Subpopulations
and Intermediate Outcome Measures in COPD
Study (SPIROMICS) [28], a significant proportion
of so-called frequent exacerbators or infrequent
exacerbators change status over a 3-year period,
indicating that propensity to exacerbation is not a
fixed property and either naturally or through both
pharmacological [29, 30] and nonpharmacological
[31] interventions, patients can change their
exacerbation status.
Exacerbation frequency is strongly related
to severity of airflow limitation as measured by
forced expiratory volume in 1 s (FEV
1
). This was
demonstrated in a recent study from Norway,
where the incidence rate ratios for utilisation-
defined acute exacerbations of COPD were 2.45
(95% CI 1.22–4.95), 3.43 (95% CI 1.59–7.38), and
5.67 (95% CI 2.58–12.48) with Global Initiative
for Obstructive Lung Disease (GOLD) spirometric
stages II, III, and IV, respectively [32]. Similarly in
an analysis of the Copenhagen General Population
Study [23], compared to individuals with GOLD 1,
the risk of exacerbations was 17-fold for GOLD 4,
five-fold for GOLD 3, and two-fold for GOLD 2.
At a population level, being more prone to
exacerbations is associated with being older, having
worse FEV
1
, lower levels of daily physical activity,
more hours of sedentary time in a day, a greater
number of comorbidities, higher dyspnoea scores
and higher probability of anxiety and depression
[25]. In the SPIROMICS population, having a
consistent acute exacerbation profile (≥1 event
per year for 3 years) was associated with higher
baseline symptom burden, previous exacerbations
and greater evidence of small airway abnormality on
computed tomography (CT), compared with having
no acute exacerbations [28].
Many investigators have developed tools
to enable practitioners to estimate the risk of
developing an exacerbation, most recently the
ASSESS tool [33]. In a study using the ECLIPSE 3-year
observational study to validate the ASSESS findings,
predicted exacerbation and observed exacerbation
rates were similar (1.31 versus 1.20 events per year
for all exacerbations and 0.25 versus 0.27 events per
year for severe exacerbations). Area under the curve
(AUC) was 0.73 (95% CI 0.70–0.76) for two or more
exacerbations and 0.74 (95% CI 0.70–0.78) for at
least one severe exacerbation. At an individual level,
many factors increase exacerbation risk, particularly
increasing age, worse FEV
1
, having a history of
exacerbations, a higher modified Medical Research
Council (mMRC) dyspnoea score [34], worse health
status measured by COPD Assessment Test (CAT)
or St George’s Respiratory Questionnaire (SGRQ),
having gastro-oesophageal reflux [35] and a chronic
bronchitis phenotype [9, 36].
The economic costs of COPD associated with
exacerbations [8, 37] are substantial. However,
the arguments for using exacerbations as an end-
point extend beyond their economic impact, even
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Defining COPD exacerbations
though this has proven to be a vital aspect of the
regulatory process and approvals for drug availability
and aordability in global markets. The strongest
arguments for a robust definition primarily derive
from the very severe consequences of exacerbations
for patients [18, 20, 38].
A brief history
In early clinical trials of COPD, many dierent clinical
and physiological characteristics were studied, but in
particular, measures of airway obstruction. Despite
the reproducibility of the FEV
1
and its relationship to
other important clinical outcomes in patients with
COPD, it is not a sensitive measure of change during
acute exacerbations, can be dicult to perform when
patients are unwell, and does not relate strongly to
the symptom burden and impaired quality of life that
characterises acute exacerbations of COPD.
However, in 1987, significant progress was
made when A et al. [22] used a graded
definition of exacerbations in a trial of antibiotics
for COPD exacerbations. This definition contained
objective criteria that could be used in other studies
and enabled some quantification of individual
components. These exacerbations were described
by major and minor symptoms and somewhat
arbitrarily graded by type. Type 1 was characterised
by increased dyspnoea, sputum volume and sputum
purulence; type 2 when two of these symptoms
were present; and type 3 when one of the three
major symptoms was present in addition to at
least one of either an upper respiratory infection
within the past 5 days, fever without other cause,
increased wheezing or cough, or an increase in
respiratory rate or heart rate by 20% as compared
with baseline. Despite the appeal of these objective
features, and their subsequent use in many clinical
studies, they were not derived from a database or
case series describing individual characteristics or
patterns of exacerbation. They describe symptoms,
but do not relate to the underlying pathophysiology
or the likely evolution of the exacerbation.
Exacerbations were still variably described in
the literature and in small clinical trials prior to
a definition proposed in 2000 by R
R [39] in a paper summarising an expert
workshop that reached a consensus definition for
use in trials and studies. This definition describes
an exacerbation as “a sustained worsening of the
patient’s condition from the stable state and beyond
normal day to day variations, that is acute in onset
and necessitates change in regular medication in
a patient with underlying COPD” [39]. This was a
pivotal moment in defining exacerbations, as it
introduced a standardised definition for counting
exacerbations, was a realistic definition for clinical
trials and aligned with clinical care. Although the
requirement for symptom worsening limits its
use for identifying exacerbations in databases and
routinely collected healthcare data, the inclusion
of medication change could be used as a surrogate
marker if associated with a healthcare visit.
Subsequent to this, many studies incorporated
versions of these symptom descriptors, particularly
emphasising worsening of respiratory symptoms
that required treatment with oral corticosteroids
or antibiotics or both, as judged by the attending
clinician. Dyspnoea became the major, dominant
symptom, based on evidence from studies that
clearly highlighted its importance to patients and as
a trigger for initiating greater intensity of treatment
and seeking medical care.
The rationale behind each component of the
definition by RR [39] is explained
in the paper, which succinctly summarises the
subsequent challenges. 20 years of experience has
made investigators, epidemiologists and clinicians
well aware of its strengths and weaknesses, and it
is now worth revisiting this definition, and looking
at potential refinements that would add to its utility
while not reducing its capacity to be applied in many
dierent contexts. I will address each of these in
the light of the experience gained by investigators
as they implemented it in many dierent clinical
trials, observational studies and database analyses.
Dissecting the definition
Sustained worsening
from the stable state
RR [39] suggests “The terminology,
worsening of the patient’s condition, is relatively
imprecise because of the absence of established
clinical markers, signs, or symptoms”.
Sustained worsening of the stable state
Most patients find it dicult to identify the very early
stages of an exacerbation and to distinguish their
increased symptoms from day-to-day variability.
This has several immediate consequences for
patients, regarding commencing treatment [40] and
achieving the best possible outcomes [41]. Under-
recognition of exacerbations is a concern [41, 42],
in that these events may lead to worse outcomes,
specifically longer duration, poorer quality of life
and increased risk of hospitalisation [43, 44], but
over-reporting can also occur (events that are
identified by patients as an exacerbation but are
not accompanied by symptom change in diary
cards [44], or do not result in healthcare contact
or change of treatment [42]). In most studies,
unreported exacerbations have less intense and
oen fewer symptoms [43] and appear to be milder
events [40] even though they have a cumulative
impact on health status [41, 44]. Whether in a
clinical trial or through routinely collected data,
worsening of the stable state is limited by its
dependence on patient recognition, which it is
well established can result in both over- [45] and
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Defining COPD exacerbations
undercounting [46]. Compared with reported
exacerbations, unreported exacerbations usually
show a lower median number of key symptoms, less
worsening for each key symptom, and a significantly
lower proportion of exacerbations with two and
three key symptoms. Conversely, more unreported
exacerbations (83.3%) than reported exacerbations
(28.8%) exhibited a single worsening symptom.
With regard to the absence of established clinical
markers, signs, or symptoms, it is an unfortunate
fact that we are still struggling to develop, test and
embed these in clinical and research practice. We
know the specific symptoms most oen associated
with an exacerbation, but we do not have an adequate
scoring system to rank these, even though we have
several validated tools focused on symptoms that
enable us to better understand the impact of COPD
in patients’ lives, particularly the CAT and the SGRQ.
Both are highly useful for assessments of change
over time from an exacerbation, but they were not
designed to detect and measure exacerbations
in themselves [47]. Tools to detect and measure
the onset, severity and resolution of an acute
deterioration have proven challenging to develop.
What are the key symptoms of a COPD
exacerbation? A et al. [22]. carefully
divided exacerbation symptoms into major and
minor, particularly focused on achieving a definition
suitable for a clinical trial of antibiotics. A similar
categorisation has been useful in other analyses,
but it is crucial to acknowledge that patients’
symptoms [48], their perceptions [49] and ability
to grade these vary markedly. Cultural [49], age-
related and gender-based [36, 50, 51] dierences
also influence this, as does severity of COPD [34, 52].
Patient-reported outcome (PRO) measures vary
greatly in sensitivity and specificity for identification
of exacerbations in patients with COPD [53, 54], and
specific definitions [55] and tools for this purpose
must be carefully chosen [56, 57].
Dyspnoea is a major symptom of COPD and
intensifies during exacerbations [46, 58]. Most
patients recognise it as a clear indication that they
are more unwell [40]. Cough and sputum, and
chest symptoms are also key symptoms and with
dyspnoea account for most of the quantitative
change from the stable state during an exacerbation
[49, 59]. Many other symptoms are highly
variable, dependent on underlying aetiology of the
exacerbation, clinical disease features, whether the
patient has a chronic bronchitic or emphysematous
phenotype, the presence of comorbidities and the
cultural setting of the patient and their carers.
Systemic features such as marked fatigue may be
prominent but lack specificity and so the respiratory
symptoms are essential to identify worsening of the
patient’s condition as due to a COPD exacerbation.
Severity
Severity is another aspect of worsening: how much
worse? Exacerbation grading is variably defined
in clinical studies and trials. The grading most
commonly accepted or used in studies involves
an event-based assessment for moderate–severe
exacerbations. In randomised controlled trials
(RCTs) exacerbations are oen classified as mild if
they are treated with short-acting bronchodilators
only; moderate if treated with short-acting
bronchodilators plus antibiotics and/or oral
corticosteroids; and severe if the patient visits the
emergency room (ER) or requires hospitalisation
because of an exacerbation [60]. In some RCTs,
exacerbations resulting in admission to intensive
care or death are categorised as very severe [61].
These definitions have varied considerably in
clinical trials, oen depending on the intervention
and its anticipated primary eect [62]. In many
RCTs mild exacerbations are defined on symptoms
alone, particularly an increase in, or new onset
of, cough, sputum, dyspnoea, wheezing or chest
tightness [63].
Other definitions of exacerbation severity used
in RCTs have included any inhaled medication
increases in mild exacerbations, systemic
corticosteroids only in moderate exacerbations
[62, 64], and in the severe category, only hospital
admissions or deaths [65]. The inclusion of ER
presentations in the severe category depends on
geography [66], access and aordability of care
and in many settings does not indicate a severe
exacerbation on clinical grounds. It may thus over-
estimate the prevalence of severe exacerbations.
In some high income countries, patients requiring
admission based on clinical severity form only a
small proportion of all those with exacerbations
[18, 32], whereas in other settings admissions
are those most commonly recorded in a trial, and
many community based events go unrecorded [67].
It is also important to note that in many countries,
self-management of exacerbations is based on a
written action plan [68] and a patient’s own supply
of antibiotics or corticosteroids, which may also
result in under-reporting if the patient fails to recall
the event or does not seek medical assistance at
the time [54, 69]. Some RCTs of COPD therapies
have required sustained symptom changes that
may be purposeful in terms of the intervention [58,
70, 71], but can also result in under-recognition if
prespecified criteria are not met [62, 71].
The absence of established clinical markers
Biomarkers have the potential to identify COPD
exacerbations in the real world for patients and
clinicians, and in clinical trials. An ideal exacerbation
biomarker would be an accessible, reproducible,
externally validated objective measure that either
signals an exacerbation or confirms one, when
associated with symptoms. Such a biomarker
would help to eliminate the subjectivity of symptom
worsening beyond day-to-day variability, but no
such marker has yet been identified, despite major
investment in cohort studies and clinical trials.
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Defining COPD exacerbations
Many investigators have tried to identify a blood
test that may be an eective biomarker for COPD
exacerbations. The prime contenders, based on
current evidence would be C-reactive protein (CRP)
or fibrinogen, as raised levels are associated with
a greater probability of exacerbating. One problem
with both biomarkers in COPD is that an elevation
may be a continuous, almost steady state for some
patients [72]. In the ECLIPSE study, inflammatory
biomarkers in peripheral blood were quantified
in 1755 COPD patients followed over 3 years.
At baseline, 30% of COPD patients did not show
evidence of systemic inflammation whereas 16%
had persistent systemic inflammation evidenced
by elevations in the assessed markers [72]. A high
white cell count has been associated repeatedly
with some exacerbations and exacerbation
propensity, but is a nonspecific finding, indicative of
many types of infection and likely to rise if patients
have already commenced systemic steroids. High
blood neutrophil counts were also associated with
a frequent exacerbation phenotype and mortality
in ECLIPSE [35, 73]. Similarly, elevation of blood
eosinophils ≥3% or ≥300 cells·mm
−3
appears to
identify a subpopulation of patients at higher risk of
exacerbations and a greater probability of a positive
benefit from short-course corticosteroids, but this
feature varies and may be evident when clinically
stable and during an exacerbation. Eosinophilia
may also indicate more benefit in exacerbation
reduction from inhaled corticosteroids [74], but
background counts or those taken at exacerbation
do not have any rule-in or rule-out utility. Given this
is a long term (albeit fluctuating) phenotypic marker,
it lacks sensitivity and specificity for identifying
exacerbations.
Biomarker repeatability was assessed in a
subset of patients with COPD, ex-smoker controls
with normal lung function and healthy nonsmokers
selected from the ECLIPSE cohort, at baseline and
3 months, with CRP showing wide variability [75].
Fibrinogen was the most repeatable biomarker and
weakly correlated with 6-min walking distance,
exacerbation rate, BODE (body mass index, airflow
obstruction, dyspnoea, exercise capacity) index
and MRC dyspnoea score. Several inflammatory
markers appear to reflect longer term disease
activity: CRP, fibrinogen, interleukin-6 and
surfactant protein-D were significantly elevated
in subjects with exacerbations within 30 days of
the 3-month visit compared with those individuals
that did not exacerbate [72]. Persistence of a
high CRP in ECLIPSE was a flag for predisposition
to recurrence and overall higher exacerbation
frequency, but did not have specificity for accurate
timing [76]. In other studies, lower interleukin-15
concentrations, and higher interleukin-8
concentrations were associated with higher
probability of having >1 exacerbation per year.
However, none of these biomarkers have proven
to be useful for contemporaneous confirmation
of an exacerbation.
The definition acknowledges that a
patient’s stable state may fluctuate,
and therefore includes the wording,
beyond normal day-to-day variations
The usefulness of daily diaries in identifying
exacerbations has been well demonstrated by the
evidence that has emerged from the East London
cohort and others like it. This is a prospective
longitudinal cohort of COPD patients recruited
from outpatient clinics of the London Chest and
Royal Free Hospitals, London, UK and followed for a
minimum of 2 years. Daily measures of symptoms,
medication use, hospitalisations and clinic visits were
recorded by each participant, including symptom
increases above baseline, enabling identification
of COPD exacerbations. These cohorts have yielded
exceptionally valuable information about symptoms,
frequency of flare-ups, healthcare contact,
management and outcomes. It is however crucial
to appreciate that daily record keeping over months
to years is arduous and those who do it well may be
a subset and not necessarily representative of the
broader COPD population. The development of PRO
tools have enabled standardisation of these measures
and have been a vital addition to understanding the
pattern and impact of exacerbations at an individual
level [56], as well as facilitating comparisons across
dierent demographic groups.
Electronic diaries and smartphone-based
applications that enable text entry, responses to
questions and uploading of physiological data such
as heart rate, respiratory rate, airflow measurements
and oximetry are an inevitable development from
such diaries. Automatically collected data from
nanodevices and microchips have opened up a
ra of possibilities for self-monitoring, home care,
outreach services and early discharge [46].
Electronic diaries have the benefit of real time
data entry and upload, eliminating entries based on
recall and helping to prevent fictional entries, oen
by automatically entering a time and date stamped
measurement (such as peak flow). Several PROs
have been automated and embedded in electronic
diaries [77], recording symptom frequency and
severity of daily COPD symptoms. These diaries
may also have soware that computes day-to-day
variability and signals to patients when symptom
scores or peak flow rates deviate by more than a pre-
determined margin from normal. Tools, such as the
Exacerbations of COPD Tool (EXACT) questionnaire
[48, 78], can be integrated into smartphones,
providing a validated, sensitive questionnaire that
enables acute symptom changes to be recorded
for the detection of exacerbations in clinical trials.
A sustained worsening
that is acute in onset
A key feature of the definition provided by
RR [39] is that the exacerbation
6 Breathe | 2021 | Volume 17 | No 3
Defining COPD exacerbations
is defined by being acute in onset. This is also
stated in the current definition as it appears in the
Global Strategy for the Diagnosis, Management,
and Prevention of Chronic Obstructive Pulmonary
Disease: “An exacerbation of COPD is defined as
an acute worsening of respiratory symptoms that
results in additional therapy” [79]. However,
there is now good evidence from a variety of
sources [38, 80] that exacerbations may be of
a gradual onset and this should be reflected in
the definition.
In a careful and highly informative analysis of the
East London COPD cohort data, A et al. [80]
defined an exacerbation commencement date
as the first of two or more consecutive days on
which the patient recorded two or more new
or worsening symptoms, at least one of which
was a major symptom, 55% of these resolved
spontaneously. Amongst those who developed
an exacerbation, the onset was sudden in 56%
and the exacerbation threshold was crossed on
the same day symptoms began. By contrast, 44%
of exacerbations were characterised by gradual
onset of symptoms with a median duration from
symptom onset to exacerbation of 4 days. Patients
who experienced sudden onset exacerbations
had greater mean daily symptom scores, greater
peak symptom scores, earlier peak symptoms and
shorter median recovery times back to baseline
health status. Gradual onset exacerbations were
statistically associated with a longer duration of
exacerbation recovery (OR 1.28, 95% CI 1.06–
1.54, p<0.010). Others have also shown that
COPD exacerbations may exhibit a gradual onset,
and these may also be more likely to be slower
to resolve.
Further, several studies suggest that the
particular symptom thresholds and definitions
within a symptomatic event clearly influence
the identification of those events [44, 81].
Establishing a low threshold, however, has risks
and may distort treatment eects. These risks
include over-sensitivity and the inclusion of small
changes in symptoms that are part of day-to-day
variability, or milder exacerbations that may be
shorter-lived or have only a small impact [46]. In
some study designs, low treatment thresholds
may have been deliberately included to enable a
primary end-point to be reached more rapidly, or
an intervention to appear to have greater ecacy
in reducing exacerbations. However, the nature of
the treatment that is changed is also important in
counting exacerbations. Some clinical trials have
defined an exacerbation as an event in which
bronchodilators and/or inhaled medications
are increased, and there are dierent impacts
depending on which these are. Medications such
as short-acting β
2
-agonists treat the symptoms,
primarily dyspnoea, whereas others, such as
inhaled corticosteroids, can address the underlying
mechanisms in some patients and may reverse
the exacerbation.
The definition requires that the
change in condition necessitates
a change in regular medication
As already noted, a problem with symptom or
treatment defined COPD exacerbations, is what
constitutes a change in regular medication. Not only
does the word “change” matter, but also regular
medication [82]. This is more of an issue than it used
to be because patients across the world are taking very
dierent medications as their regular medications
[32]. In medium-high income countries, patients
may be prescribed best practice medications based
on current guidelines and a well-resourced healthcare
system and aordable medications [79]. For some
patients in high income settings and most in low
income countries, their regular medications are short-
acting β
2
-agonists and antimuscarinics alone [83, 84].
Most commonly, prescription of systemic
corticosteroids or antibiotics signifies the recognition
of an exacerbation by the health professional or the
patient. These two players, the patient and the health
professional involved in exacerbation identification
can have very dierent perspectives [85, 86], and
may alter treatments for dierent reasons [40, 49]. In
RCTs, the randomisation may be trusted to distribute
this variability evenly between the intervention arms,
but the problem of identifying reasons for treatment
change, and sometimes the true severity of the event
remains. It is now well known that in winter, the
prescription of antibiotics during exacerbations is
more common [34, 87], but this may be empiric
and does not necessarily indicate careful clinical
assessment for a bacterial aetiology.
Local access to healthcare services and
aordability of care are immensely important
in determining whether a moderate–severe
exacerbation is recorded. People living in regional
and remote communities, even in high income
countries [66], oen have much more significant
diculty accessing timely medical care, more
hospital admissions and longer length of stay.
People in low income countries may not have
access to short-acting inhaled medications
unless they present to hospital [84, 88]. Given
the burden of COPD falls disproportionately on
these communities, there is a need to address this
deficiency in the definition of COPD exacerbations
in order to accurately estimate the burden of COPD
and the urgent need for preventative measures to
reduce this. Health literacy, poverty, geographical
access to care and aordability of medications
all influence the measurement of exacerbations
in socioeconomically deprived areas, whether
an event-based or symptom/treatment-based
definition is used. The mechanisms for the
development of COPD in low income settings result
from exposure to a range of noxious agents and
inhalations that extend far beyond tobacco [89, 90],
and along with early life respiratory insults [84]
may also contribute to failure to achieve normal
lung growth in early adult life [90, 91]. Symptom
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Defining COPD exacerbations
worsening and treatment response may be dierent
in these diverse aetiologies of COPD and much more
research is needed to fully explore this.
What do we need
for the future?
In summary, the definition of a COPD exacerbation
proposed in 2000 has served well as a template
for many carefully conducted RCTs, clinical cohort
studies and database analyses. Each of these
purposes has necessitated slightly modified
versions of the definition, based on the rationale
for the study and the data collected. This has led to a
plethora of exacerbation definitions which although
only superficially dierent, can have very marked
repercussions for estimations of burden of COPD
and the eects of treatment.
It is essential that we acknowledge the imprecise
aspects of our dierent exacerbation definitions,
particularly as healthcare is changing so rapidly
and events previously associated with most severe
exacerbations, such as hospitalisations, are much
less common. Other contemporary influences may
lead to changes in our capacity to record the true
burden of exacerbations. As an example, the trend
to phenotype patients and their exacerbations for
targeted treatment approaches, would result in fewer
recorded events if guidelines advise against systemic
corticosteroids for an exacerbating patient with low
eosinophils. Administrative pressures to reduce
admissions, the increase in patient self-management
capacity and the wider availability of home-based
care through clinical outreach services must be
considered as changes that could also influence the
recording of severe exacerbations if the commonly
used definitions in large RCTs are retained.
We focus on exacerbations because of their
impact on patients and healthcare systems. In
the past 20 years, billions of dollars have been
spent conducting RCTs to assess the ecacy of
medications and interventions to reduce their
frequency and severity, with mean reductions of
∼20% through optimal treatment regimens in
highly selected patients, but there is a persistent
residual exacerbation rate which remains a major
burden. I have not addressed the aetiology of COPD
exacerbations in this review, but the experience of
the coronavirus disease 2019 (COVID-19) pandemic
has demonstrated that social distancing, masking
and hand hygiene have had a major impact
in reducing exacerbations [92] and hospital
admissions [93], an observation that has been made
around the world in vastly dierent settings [94].
We must make immediate use of this information
for the good of our patients and clinical trials with
careful counting of exacerbations are probably not
needed to demonstrate the benefits of avoiding
exposure to respiratory viruses.
It is likely that the dierent definitions of a
COPD exacerbation will evolve as the search for
a standardised measure continues, and probable
that there will never be a single definition that
can meet all purposes. Whether identification and
recording of exacerbations remains essentially
clinical, or can be identified with a dependable
biomarker, it should be sensitive and adaptable
to context while retaining clarity and facilitating
data collection. In every study, investigators should
ensure that variations on the commonly accepted
definition are made explicit and entirely justified.
Research is urgently needed to explore the use of
definitions in low income countries to enable a
better understanding of the impact of the causes,
impact and management of COPD exacerbations in
circumstances dramatically dierent to middle to
high income countries where the majority of large
COPD trials are undertaken. Finally, we have much
more to do to progress a better understanding of
the pathophysiology, aetiology and phenotypic
expression of exacerbations to reduce their impact
and personal burden for patients.
Affiliations
Christine R. Jenkins
1,2,3
1
Respiratory Group, The George Institute for Global Health, Sydney, Australia.
2
UNSW Sydney, Sydney, Australia.
3
Concord Clinical School, University of Sydney, Sydney, Australia.
Conflict of interest
C.R. Jenkins reports receiving a research grant, paid to their institution, from GlaxoSmithKline, outside the
submitted work. Payment or honoraria for lectures, presentations, speaker bureaus, manuscript writing or
educational events from Boehringer Ingelheim, GlaxoSmithKline, AstraZeneca, Novartis and Sanofi-Genzyme
(member of local and global advisory boards for asthma and COPD, speaker at online/video conferences/
educational events 2019–2021), outside the submitted work. Payment for expert testimony from Novartis (advice
to Therapeutics Goods Authority Australia), outside the submitted work. Support for attending meetings and/or
travel from Boehringer Ingelheim, AstraZeneca, Novartis and Sanofi-Genzyme (for global advisory boards 2019),
outside the submitted work. Participation on a Data Safety Monitoring Board or Advisory Board for an AstraZeneca
funded study, independent DSMB, outside the submitted work. Leadership or fiduciary role in other board, society,
committee or advocacy group, paid or unpaid for the Lung Foundation Australia, outside the submitted work.
8 Breathe | 2021 | Volume 17 | No 3
Defining COPD exacerbations
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