[ Editorial ]
intravenous therapy3 and that a shorter duration (5 days)
Toward Personalized
Prescription of
Systemic Steroids for
Patients Hospitalized
With COPD
Exacerbations
Pierre-Régis Burgel, MD, PhD
Paris, France
Hospitalized exacerbations are important events in
patients with COPD because they are responsible for high
costs and have great impact on patient’s symptoms and
prognosis.1 Review of high-quality randomized clinical
trials in patients hospitalized for COPD exacerbations has
established that systemic steroids significantly reduced
treatment failure, were associated with earlier
improvement in lung function and dyspnea, and
shortened hospital stay.2 However, beneficial effects of
systemic steroids came with high rates of adverse effects
(including hyperglycemia), with one extra adverse effect
occurring for every six people treated.2 These conclusions
were based on studies that have used various protocols for
steroid administration, including studies that used very
high doses of steroids and administration of steroids for
up to 8 weeks.2 Subsequent studies have suggested that
low-dose steroids (30-40 mg/d) administered orally were
not associated with worse outcomes than high-dose
FOR RELATED ARTICLE SEE PAGE 320
AFFILIATIONS: From the Department of Respiratory Diseases, Cochin
Hospital.
FINANCIAL/NONFINANCIAL DISCLOSURES: The author has reported
to CHEST the following: P.-R. B. reports personal fees from Astra-
Zeneca, Boehringer Ingelheim, Chiesi, GSK, Novartis, Pfizer, and
Vertex for attending advisory boards and lecturing during the last 3
years. He was also the principal investigator of a clinical trial sponsored
by Novartis and received an unrestricted research grant from Boeh-
ringer Ingelheim France.
CORRESPONDENCE TO: Pierre-Régis Burgel, MD, PhD, Department of
Respiratory Diseases, Cochin Hospital, 27 rue du Faubourg St Jacques,
75014, Paris, France; e-mail: pierre-regis.burgel@aphp.fr
Copyright Ó 2016 American College of Chest Physicians. Published by
Elsevier Inc. All rights reserved.
DOI: http://dx.doi.org/10.1016/j.chest.2016.03.028
268 Editorial
of oral prednisone was noninferior to 14-day treatment.4
This led to current recommendations of using low-dose
short-term oral steroids in patients hospitalized for
COPD exacerbations with the aim of limiting adverse
events,1 which still occurred in approximately one to ten
patients.4 Because results of clinical trials provide only
limited information on the individual likelihood of
benefiting from or being harmed by a therapy,5 a more
personalized approach of steroid prescription in COPD
exacerbation is urgently required, with the aim of limiting
steroid prescription to patients who may show high
benefits and low rates of adverse effects.
In this issue of CHEST, Bafadhel et al6 examined the role
of blood eosinophil counts (a surrogate marker for
airway eosinophilia) as a possible marker for predicting
the effect of treatment, including systemic steroids, in
patients hospitalized for COPD exacerbations. The
authors performed a post hoc analysis of data obtained
in a previously performed two-center randomized
clinical trial, which examined the effect of early
rehabilitation intervention in patients with chronic
respiratory disorders hospitalized for acute care.6 Based
on data obtained in patients with a confirmed diagnosis
of COPD exacerbation and differential full blood count
taken within 12 h of admission, patients were stratified
into eosinophilic vs noneosinophilic exacerbations using
a cutoff value of $ 200 cells/mL and/or 2% blood
eosinophils. During hospitalization, 90% of the patients
received oral corticosteroids that were almost always
administered with antibiotic therapy. The authors
reported that 25% of subjects hospitalized for a COPD
exacerbation had an eosinophilic exacerbation and that
the length of hospital stay was shorter by 1.5 days in
these patients, whereas long-term (12 months) follow-up
showed no difference between the groups. The authors
concluded that acute events requiring hospitalization
associated with eosinophilic inflammation may show a
rapid response to corticosteroid treatment, hence
requiring a shorter length of hospital stay. As in any
(good) study, there are limitations to the present
analyses. Because almost all of the patients received oral
steroids, it remains unclear whether the reduced length
of stay was related to a better response to steroids or a
better outcome (independent of steroid treatment) in
[ 150#2 CHEST AUGUST 2016 ]
patients with eosinophilic exacerbations. Further, the
proposed 25% prevalence of eosinophilic exacerbations
will need confirmation because this number could have
been affected by exclusion of patients with missing data,
timing and dose of oral steroids received before entering
in the hospital, the inclusion of patients from only two
centers, and the choice of the cutoff values (eg, absolute
counts vs percentage). For example, in a recent study
examining 647 patients with COPD admitted to the ICU
for respiratory failure, the prevalence of patients with
blood eosinophils > 2% was < 10%.7 Another study that
was based on a retrospective hospital database analysis
found that among 3,084 patients hospitalized for
acute exacerbations of COPD, 17% had blood
eosinophilia $ 300 cells/mL and 40% had blood
eosinophilia $ 2%.8 Further studies are clearly required
to establish the prevalence of eosinophilic exacerbations
in various settings as well as the optimal cutoff values.
Interestingly, Bafadhel et al6 found that eosinophil
counts and proportion of eosinophilic exacerbations
were markedly lower in patients with consolidation on
chest radiographs. Recent data from the European
COPD audit9 suggest that COPD exacerbations with
alveolar consolidation are treated in approximately
93% of cases with antibiotics and 79% of cases with
systemic steroids. If blood eosinophils are indeed a
marker of steroid responsiveness, it is tempting to
speculate that overprescription of systemic steroids
could be particularly high in this group of patients.
Finally, it remains unclear whether high blood
eosinophil count is triggered by a stimulus at the time of
the exacerbation or whether it represents a stable
endotype in patients with COPD. A subgroup of patients
with stable COPD appear to have mildly elevated blood
eosinophils, a feature that has been suggested to predict
the efficacy of fixed combination of inhaled
corticosteroids/long-acting b-agonists on reducing the
risk of exacerbation.10 However, there also appears to be
some variability in longitudinal eosinophil counts
because data from a recent clinical trial indicate that
one-half of the patients with a history of sputum
eosinophils $ 3% within the previous year had blood
eosinophils < 200 mL at study entry.11 Longitudinal
follow-up of blood eosinophil counts in patients with
journal.publications.chestnet.org
eosinophilic exacerbations will provide answers to this
important question.
In conclusion, severe COPD exacerbations are clearly
heterogeneous, and blood eosinophils represent a
promising biomarker for personalizing prescription of
oral steroids in patients hospitalized with COPD
exacerbations. The Bafadhel et al6 study provides
rationale for designing a multicenter randomized clinical
trial assessing the possibility of limiting prescription of
systemic steroids to patients with eosinophilic COPD
exacerbations. Until such data are available, it will not be
possible to translate this proposal into daily practice.
References
1. Global Initiative for Chronic Obstructive Lung Disease. Global
strategy for the diagnosis, management and prevention of COPD.
http://www.goldcopd.org/. Accessed May 24, 2016.
2. Walters JA, Tan DJ, White CJ, Gibson PG, Wood-Baker R,
Walters EH. Systemic corticosteroids for acute exacerbations of
chronic obstructive pulmonary disease. Cochrane Database Syst Rev.
2014;9:CD001288.
3. Lindenauer PK, Pekow PS, Lahti MC, Lee Y, Benjamin EM,
Rothberg MB. Association of corticosteroid dose and route of
administration with risk of treatment failure in acute exacerbation of
chronic obstructive pulmonary disease. JAMA. 2010;303(23):
2359-2367.
4. Leuppi JD, 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.
5. Kent DM, Hayward RA. Limitations of applying summary results of
clinical trials to individual patients: the need for risk stratification.
JAMA. 2007;298(10):1209-1212.
6. Bafadhel M, Greening NJ, Harvey-Dunstan TC, et al. Blood
eosinophils and outcomes in severe hospitalized exacerbations of
COPD. Chest. 2016;150(2):320-328.
7. Salturk C, Karakurt Z, Adiguzel N, et al. Does eosinophilic COPD
exacerbation have a better patient outcome than non-eosinophilic in
the intensive care unit? Int J Chron Obstruct Pulmon Dis. 2015;10:
1837-1846.
8. Hasegawa K, Camargo CA Jr. Prevalence of blood eosinophilia in
hospitalized patients with acute exacerbation of COPD. Respirology.
2016;21(4):761-764.
9. Saleh A, Lopez-Campos JL, Hartl S, Pozo-Rodriguez F, Roberts CM.
The effect of incidental consolidation on management and outcomes
in COPD exacerbations: data from the European COPD audit. PLoS
One. 2015;10(7):e0134004.
10. Pavord ID, Lettis S, Locantore N, et al. Blood eosinophils and
inhaled corticosteroid/long-acting beta-2 agonist efficacy in COPD.
Thorax. 2016;71(2):118-125.
11. Brightling CE, Bleecker ER, Panettieri RA Jr, et al. Benralizumab for
chronic obstructive pulmonary disease and sputum eosinophilia: a
randomised, double-blind, placebo-controlled, phase 2a study.
Lancet Respir Med. 2014;2(11):891-901.
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