The n e w e ng l a n d j o u r na l of m e dic i n e

Edi t or i a l

Eosinophil Biology in COPD

Christine F. McDonald, M.B., B.S., Ph.D.

Chronic obstructive pulmonary disease (COPD)
is a lethal disease that is predicted to become
the third leading cause of death globally within
3 years.1 Recent research has highlighted the
heterogeneity of the pathologic characteristics of
COPD, indicating that disease mechanisms are
complex. Inflammatory pathways implicating neu-
trophils have been emphasized,2 but attention has
recently focused on the persistent blood and air-
way eosinophilia that is found in up to 40% of
patients with COPD, even in the absence of a
history of asthma; such patients have a higher
risk of exacerbations than patients without eo-
sinophilia.3,4
Guidelines have generally recommended a “one
size fits all” approach to the treatment of patients
with differing clinical features of COPD. Howev-
er, current interest centers on searching for vari-
ous phenotypes that may have different responses
to treatment among patients with chronic ob-
structive diseases — either asthma or COPD —
including the presence or absence of sputum or
blood eosinophilia. The linking of these obstruc-
tive pulmonary diseases brings to mind the propo-
sition offered by Orie and Sluiter in the 1960s,
dubbed the “Dutch hypothesis,”5 in which they
attempted to explain why airway obstruction de-
velops in only a proportion of smokers. They sug-
gested that an interplay of host and environmental
factors led to the clinical phenotype underlying
obstructive airway diseases, such as asthma and
COPD, and called for careful subgrouping and
phenotyping of patients who had what they de-
scribed as “chronic nonspecific lung disease.”6
Current research has seen a renaissance of this
approach, notably in the present context, with re-
spect to the role of eosinophils, aided in part by
the availability of biologic interventions that can
specifically target these cells.
Paul Ehrlich described eosinophils in 1879
after the discovery of granule-containing cells
with eosin-staining affinity. Eosinophils develop
in bone marrow and circulate briefly before be-
ing distributed to organs including the thymus
and gastrointestinal tract7 and, to a much lesser
extent, the lung.8 Transcription factors and cyto-
kines such as interleukin-3, interleukin-5, and
granulocyte–macrophage colony-stimulating fac-
tor (GM-CSF) are essential for the differentiation
of eosinophils, and interleukin-5 plays a key role
in their maturation, recruitment, and activation
at sites of inflammation. Although small num-
bers of resident lung parenchymal eosinophils
have been described,8 airway eosinophils are not
normally present in healthy persons but rather
are trafficked from bone marrow in association
with infection or inflammation. Eosinophils are
important cells in asthma, contributing to airway
inflammation and bronchial hyperresponsive-
ness. The clinical benefits of monoclonal anti-
bodies targeting interleukin-5 in severe eosino-
philic asthma have confirmed a pathogenic role
of eosinophils in this condition. However, the
contribution of eosinophils, if any, to the patho-
genesis of COPD remains unclear. Recent post
hoc analyses of data from a number of studies
involving patients with COPD have highlighted
the blood eosinophil count as a potentially im-
portant biomarker of response to glucocorticoid
treatment,9 but whether targeting interleukin-5
to reduce eosinophil activity can also affect clini-
cal outcomes in COPD is not known.
Now Pavord and colleagues have compared
the interleukin-5 inhibitor mepolizumab with

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 The n e w e ng l a n d j o u r na l
placebo in patients with COPD in two 12-month
randomized, controlled, parallel-group trials
(METREX and METREO), which are described in
the Journal.10 The aim of the trials was to evaluate
the efficacy and safety of mepolizumab as an
add-on to triple therapy with an inhaled gluco-
corticoid, a long-acting β2-agonist, and a long-
acting muscarinic antagonist. Recruited patients
had a forced expiratory volume in 1 second (FEV1)
that was 20 to 80% of the predicted value, had
had at least two moderate exacerbations or one
severe exacerbation in the previous 12 months,
and had been taking triple therapy for at least 12
months before the trial. Patients with a current
diagnosis of asthma and nonsmokers with a his-
tory of asthma were excluded, although smokers
with a history of asthma were not excluded. The
effect of these inclusion and exclusion criteria on
the observed results is unclear. In METREX, treat-
ment with 100 mg of mepolizumab was com-
pared with placebo, and patients were stratified
according to whether they had an eosinophilic
phenotype — that is, a blood eosinophil count
of 150 per cubic millimeter or higher at screening
or of 300 per cubic millimeter or higher during
the previous year. In METREO, two different
doses of mepolizumab (100 mg and 300 mg) were
compared with placebo in patients who had an
eosinophilic phenotype.
In METREX, the annual rate of moderate or
severe exacerbations was significantly lower in
the mepolizumab group than in the placebo
group (1.40 vs. 1.71 per year; rate ratio, 0.82; 95%
confidence interval, 0.68 to 0.98; P = 0.04). The
time to a first exacerbation was also significantly
longer in the mepolizumab group than in the
placebo group, but there were no significant dif-
ferences in outcomes when patients were not
stratified according to eosinophilic phenotype.
In contrast, no significant differences in exacer-
bation rates were detected in METREO. There
was no significant between-group difference in
the rate of exacerbations that led to an emer-
gency department visit or hospitalization or in
measures of patients’ symptoms in either trial.
What do these findings tell us about the
heterogeneity of COPD — and how does this re-
late to the Dutch hypothesis? In the past, “lump-
ing together” patients with different clinical COPD
phenotypes may have prevented the detection of
clinical responses in subgroups. The results of
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Copyright © 2017 Massachusetts Medical Society. All rights reserved.
of m e dic i n e
the current trials indicate that a subgroup of
patients with COPD may benefit from biologic
therapies, but I think that blood eosinophil count
is an imperfect biomarker and that other disease
factors confound the eosinophil signal, even in
carefully selected subgroups. Perhaps genetic
and environmental factors such as those empha-
sized in the Dutch hypothesis — for example,
intensity and duration of smoking or allergy and
atopy — play a considerably more important role
in COPD than had previously been appreciated.
What is clear is that these trials should promote
further prospective studies aimed at clarifying
the role of eosinophils in COPD. They should also
encourage the development of new strategies for
further stratifying patients, as an alternative to
focusing solely on eosinophils. Applying the les-
sons of the past to our current understanding of
disease processes has the potential to ultimately
improve care for patients with COPD.
Disclosure forms provided by the author are available with the
full text of this editorial at NEJM.org.
From the Department of Respiratory and Sleep Medicine, Aus-
tin Health, and the Institute for Breathing and Sleep, Heidel-
berg, VIC, and the University of Melbourne, Parkville, VIC —
both in Australia.
This editorial was published on September 12, 2017, at NEJM.org.
1. Adeloye D, Chua S, Lee C, et al. Global and regional esti-
mates of COPD prevalence: systematic review and meta-analysis.
J Glob Health 2015;​5(2):​020415.
2. Hoenderdos K, Condliffe A. The neutrophil in chronic ob-
structive pulmonary disease. Am J Respir Cell Mol Biol 2013;​48:​
531-9.
3. Singh D, Kolsum U, Brightling CE, et al. Eosinophilic in-
flammation in COPD: prevalence and clinical characteristics.
Eur Respir J 2014;​44:​1697-700.
4. Vedel-Krogh S, Nielsen SF, Lange P, Vestbo J, Nordestgaard
BG. Blood eosinophils and exacerbations in chronic obstructive
pulmonary disease — the Copenhagen General Population
Study. Am J Respir Crit Care Med 2016;​193:​965-74.
5. Orie NGM, Sluiter HJ, eds. Bronchitis: an international sym-
posium. Springfield, IL:​C.C. Thomas, 1961.
6. Postma DS, Weiss ST, van den Berge M, Kerstjens HA, Kop-
pelman GH. Revisiting the Dutch hypothesis. J Allergy Clin Im-
munol 2015;​136:​521-9.
7. Blanchard C, Rothenberg ME. Biology of the eosinophil. Adv
Immunol 2009;​101:​81-121.
8. Mesnil C, Raulier S, Paulissen G, et al. Lung-resident eosino-
phils represent a distinct regulatory eosinophil subset. J Clin
Invest 2016;​126:​3279-95.
9. Loureiro CC. Blurred lines: eosinophilic COPD: ACOS or
COPD phenotype? Rev Port Pneumol (2006) 2016;​22:​279-82.
10. Pavord ID, Chanez P, Criner GJ, et al. Mepolizumab for eo-
sinophilic chronic obstructive pulmonary disease. N Engl J Med.
DOI:​ 10.1056/NEJMoa1708208.
DOI: 10.1056/NEJMe1710326
Copyright © 2017 Massachusetts Medical Society.