Pulmonary exacerbation: towards a definition for use in clinical trials. report from the eurocarecf working group on outcome parameters in clinical trials
Journal of Cystic Fibrosis Volume 10 Suppl 2 (2011) S79-S81
Pulmonary exacerbation: Towards a definition for use in clinical trials.
Report from the EuroCareCF Working Group on outcome parameters in
D. Bilton a,*, G. Canny b, S. Conway c, S. Dumcius d, L. Hjelte e, M. Proesmans f,
B. Tümmler g, V. Vavrova h, K. De Boeck f
a Royal Brompton Hospital, London, UK
b Our Lady's Hospital for Sick Children, Crumlin, Dublin 12, Ireland
c St. James' Hospital, LS9 7TF, Leeds, UK
d Vilnius University, 08661, Vilnius, Lithuania
e Karolinska, Stockholm CF Centre, Huddinge, 14186 Stockholm, Sweden
f University Hospital Leuven, 3000 Leuven, Belgium
g Medizinische Hochschule Hannover, 30625 Hannover, Germany
h University Hospital Motol, Prague, 150 06 Prague 5, Czech RepublicAbstract
Pulmonary exacerbations represent a key outcome variable in clinical trials of cystic fibrosis (CF). As there is variation in the trigger for
use of intravenous antibiotics compared to the use of oral antibiotics or new nebulised therapy for treatment of exacerbations, the consensusview is that use of intravenous antibiotics cannot be regarded as the key defining character for an exacerbation on its own. The consensusview is that the clinical need for additional treatment as indicated by a recent change in clinical parameters provides the best definition of anexacerbation. Which parameters to include as well as the problems associated with the use of scoring systems and symptom clusters are beingdiscussed. 2011 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved. Keywords: Pulmonary exacerbation; Cystic fibrosis; Outcome parameters; Definition; Consensus
fibrosis (CF), including RhDNase , Tobramycin (TOBI), Azithromycin  and hypertonic saline 
Pulmonary exacerbations are a key outcome measure in
iv There are significant costs associated with the requirement
for intravenous antibiotic therapy at home or in hospital
Pulmonary exacerbations exhibit a strong contribution in a
v As a result of i-iv above, reduction in pulmonary exacerba-
well validated survivorship model. Each acute pulmonary
tions can be considered an important endpoint independent
exacerbation had a negative impact on 5 year survival
There is consensus that pulmonary exacerbations represent
ii Pulmonary exacerbations have been shown to have a
a key outcome variable in clinical trials of CF.
profound negative impact on health related quality of life
2. Definition of pulmonary exacerbation
iii Pulmonary exacerbations have been a key secondary
endpoint in landmark studies of new therapies for cystic
2.1. Physician defined requirement to treat
The simplest definition of pulmonary exacerbation is a
* Corresponding author: D. Bilton, Royal Brompton Hospital, Respiratory
Medicine, Sydney Street, London SW3 6NP, UK. Tel: +44 (0)20 7352 8121.
physician defined requirement to intervene with new antibiotic
E-mail address: D.Bilton@rbht.nhs.uk (D. Bilton).
therapy, either oral or intravenous. This definition is open to
1569-1993/$ - see front matter 2011 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved. D. Bilton et al. / Journal of Cystic Fibrosis Volume 10 Suppl 2 (2011) S79-S81
variability depending on clinician preference and threshold
An exacerbation will be defined as the need for additional
for treatment. However, this simple definition was used
antibiotic treatment as indicated by a recent change in at least
effectively in the Azithromycin study  when exacerbations
were defined as the use of intravenous anti-Pseudomonal
• Change in sputum volume or colour
antibiotics or oral quinolones for seven or more days.
In the TOBI trial , use of intravenous antibiotics and
• Increased malaise, fatigue or lethargy
hospitalisation were used to characterise exacerbations and
revealed significant benefit in favour of the active treatment.
• Decrease in pulmonary function by 10% or more /
This definition is not recommended as a EuroCareCF
consensus as there may be variation in the prescription of
intravenous antibiotics and access to inpatient treatment indifferent countries. 2.3. Scoring system to define exacerbationAs there is variation in the trigger for use of intravenousantibiotics compared to the use of oral antibiotics or new neb-
Several studies have addressed the possibility of standard-
ulised therapy for treatment of exacerbations, the consensus
ising a symptom defined exacerbation score. However, these
view is that use of intravenous antibiotics cannot be regarded
are subject to the difficulty of deciding on the gold standard
as the key defining character for an exacerbation on its own.
for validation. If the gold standard is the physician's opinionthen variability is likely to be introduced. An Australian
2.2. Symptom defined requirement to treat
survey highlighted this problem . Rosenfeld et al. developed two scores which were validated in the intervention
Exacerbations can be usefully defined by a cluster of
arm of the TOBI trial. One score included lung function as
symptoms and signs as defined by Fuchs et al. .
a variable. The second had no requirement for lung function.
Clinical need for intravenous antibiotics as indicated by
The utility of this is obvious in terms of pan-European studies
presence of at least 4 of 12 possible signs or symptoms:
and the algorithm produces a score where the critical value of
2.6 or above represents a physician defined exacerbation. The
problem with this score is that it does not necessarily correlate
with a new treatment or intervention.
• Increased dyspnoea• Increased malaise, fatigue or lethargy
2.4. Symptom cluster that defines need for treatment
• Temperature over 38°C• Anorexia or weight loss
Rabin et al.  examined patient registry data in order to
predict the factors that were associated with new treatment.
The scoring system developed by Rabin et al.  defines
• Change in physical findings on examination of the chest
separate criteria for different age groups and in particular
• Decrease in pulmonary function by 10% or more
includes a definition of exacerbations for under 6 year olds.
The scoring system of Rabin et al.  appears easy to apply
This definition has proven useful in the landmark DNase
in clinical studies, but does not have a track record in clinical
study  and the large trial of hypertonic saline .
The criteria of Fuchs et al.  i.e.: symptom defined (4 out
The consensus view is that the scoring system of Rosenfeld
of 12) can be applied regardless of treatment. It is clear from
et al.  should not be used for European studies as the
the hypertonic saline study that there is a significant difference
defining score does not always correlate with a change in
in exacerbations defined as per the original criteria of Fuchs
treatment. The scoring system developed by Rabin et al. 
et al.  and an analysis involving symptoms identified by
could be used, but because it has no track record in clinical
Fuchs et al.  (hereafter termed Fuchs symptoms) regardless
trials we do not recommend it for current use. Future trialscould incorporate a validation of the scoring system of Rabin
The Fuchs symptoms defined exacerbation with or without
et al.  particularly in studies of children under 6 years of
requirement for treatment have shown utility in clinical trials
for both children and adults with CF. We recommend that thisdefinition is adopted for future clinical trials in Europe. Acknowledgements The consensus view is that the clinical need for additionaltreatment as indicated by a recent change in clinical pa-
This work was supported by the European Union
rameters provides the best definition of an exacerbation. The
Sixth Framework Programme (contract no. LSHM-CT-2005-
clinical parameters used should be those of the criteria ofConflict of interest The European Consensus Group wishes to validate modi-fied criteria of Fuchs et al.  as follows:D. Bilton et al. / Journal of Cystic Fibrosis Volume 10 Suppl 2 (2011) S79-S81References
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