Accepted Manuscript

Eosinophils in chronic obstructive pulmonary disease exacerbations are associated

with increased readmissions

Simon Couillard, MD, Pierre Larivée, MD, FRCPC, Josiane Courteau, PhD, Alain
Vanasse, MD, PhD, CMFC

PII: S0012-3692(16)60762-6
DOI: 10.1016/j.chest.2016.10.003
Reference: CHEST 734

To appear in: CHEST

Received Date: 22 June 2016

Revised Date: 27 September 2016
Accepted Date: 5 October 2016

Please cite this article as: Couillard S, Larivée P, Courteau J, Vanasse A, Eosinophils in chronic
obstructive pulmonary disease exacerbations are associated with increased readmissions, CHEST
(2016), doi: 10.1016/j.chest.2016.10.003.

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Manuscript word count: 2193

TITLE: Eosinophils in chronic obstructive pulmonary disease

exacerbations are associated with increased readmissions

Running title: Eosinophils, exacerbated COPD, and readmissions

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AUTHORS: Simon Couillard1, MD, simon.couillard.castonguay@USherbrooke.ca

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Pierre Larivée1,2, MD, FRCPC, pierre.larivee@USherbrooke.ca
Josiane Courteau1, PhD, josiane.courteau@USherbrooke.ca
Alain Vanasse1,3, MD, PhD, CMFC, alain.vanasse@USherbrooke.ca

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1
From: Centre de recherche du Centre Hospitalier Universitaire de
Sherbrooke (CHUS), 3001 12e Avenue Nord, Sherbrooke

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(Québec), QC J1H 5N4, Canada
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2
Service de pneumologie du Département de Médecine,
Faculté de médecine et des sciences de la santé, Université de
Sherbrooke, 3001 12e Avenue Nord, Sherbrooke (Québec),
QC J1H 5N4, Canada;
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Département de médecine familiale et de médecine
d’urgence, Faculté de médecine et des sciences de la santé,
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Université de Sherbrooke, 3001 12e Avenue Nord,

Sherbrooke (Québec), QC J1H 5N4, Canada;
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Descriptor 9.12 COPD: Outcomes

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Address for correspondence:

Dr Alain Vanasse
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12e Avenue Nord, Sherbrooke (Québec),

Canada, J1H 5N4
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E-mail: alain.vanasse@USherbrooke.ca
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Financial/nonfinancial disclosures: The authors have no conflicts of interest directly relevant to

the content of this study. SC has no conflicts of interest to disclose. PL has sponsored research

agreements with Boehringer Ingelheim, Novartis, and Sanofi; he has performed consultancy for

Boehringer Ingelheim and Merck; and he has received lecture fees from AstraZeneca, Boehringer

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Ingelheim, Merck, and Novartis. JC has no conflicts of interest to disclose. AV has sponsored

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research agreements and lecture fees for AstraZeneca and Janssen.

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Supported by local funds and the Fonds de Recherche en Santé du Québec

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Author contributions: SC: contributed to collection, analysis and interpretation of data, and
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preparation of the manuscript. PL: contributed to conceiving the study, validating collected data,

and reviewing the manuscript. JC: contributed to conceiving the study, collecting data,
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performing statistics, and reviewing the manuscript. AV: is the guarantor of this study, developed

the initial questions and contributed to the development of the protocol, validated collected data,
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and reviewed and approved the manuscript.

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At a Glance Commentary: A subset of patients with chronic obstructive pulmonary disease

(COPD) demonstrates eosinophilic inflammation either in their sputum or blood. Previous studies

regarding the association between increased blood eosinophils and poor readmission outcomes

are conflicting. The objective of this study was to investigate outcomes following severe COPD

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exacerbations in patients with higher blood eosinophil levels.

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We rigorously analyzed real-world observational data on the eosinophilic COPD phenotype,

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finding that eosinophil levels ≥ 200 cells/µL and/or ≥ 2% at admission for a severe exacerbation

of COPD, when assessed in a time frame free of systemic corticosteroids, is associated with an

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almost threefold increase in 12-month readmission for COPD, more than double 12-month all-
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cause readmission, and a shorter time to first COPD-related readmission.
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These findings reaffirm that adequately phenotyping specific COPD inflammatory profiles is
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worthwhile and of clinical importance.

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ABSTRACT

Rationale: A subset of patients with chronic obstructive pulmonary disease (COPD)

demonstrates eosinophilic inflammation either in their sputum or blood. Previous studies

regarding the association between increased blood eosinophils and poor readmission outcomes

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are conflicting.

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Objective: Investigate outcomes following severe COPD exacerbations in patients with higher

blood eosinophils.

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Methods: With an observational study design, hospitalizations for severe COPD exacerbation

were retrospectively gathered. Patient health data previous to and up to one year following the

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index hospitalization were included. Patients were stratified into the eosinophilic group if the
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blood eosinophil level on admission was ≥200 cells/µL and/or ≥2% of the total white blood cell

count. Clinical outcomes were 12-month COPD-related readmission, 12-month all-cause

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readmission, length of stay, and time to COPD-related readmission. These outcomes were
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analysed using logistic, negative binomial, and Cox regression models.

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Results: A total of 167 patients were included: 55 with eosinophilia. Eosinophilia was associated

with an increased risk of 12-month COPD-related readmission (OR 3.59 [1.65-7.82], p=0.0013),
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an increased risk of 12-month all-cause readmission (2.32 [1.10-4.92], p=0.0277), and a shorter

time to first COPD-related readmission (HR 2.74 [1.56-4.83], p=0.0005). The length of stay was
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not statistically different between eosinophilic and non-eosinophilic patients. Sensitivity analyses
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using different eosinophilia definitions reveal a proportional increase in effect size with

increasing eosinophil cell count definitions for predicting 12-month readmissions.

Conclusion: Blood eosinophils can be used as a biomarker in severe COPD exacerbations for

predicting higher readmission rates. Word count: 235

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KEY-WORDS

Eosinophils, COPD, patient readmission, corticosteroids

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ABREVIATIONS

CBC: complete blood count

COPD: chronic obstructive pulmonary disease

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CVD: cardiovascular disease

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FEV1: forced expiratory volume in one second

FVC: forced vital capacity

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ICS: inhaled corticosteroid

LABA: long acting β2 agonist

LAMA: long acting muscarinic antagonist

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OR: odds ratio

PFT: pulmonary function tests

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RCT: randomized control trial

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SABA: short acting β2 agonist

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SAMA: short acting muscarinic antagonist

WBC: white blood cell

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INTRODUCTION

Chronic obstructive pulmonary disease (COPD) and its associated acute exacerbations account

for the highest per capita hospitalization rate among all ambulatory care sensitive conditions in

Canada1. In the United States, where COPD 30-day readmission rates are observed to be as high

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as 20%2, pay-for-performance programs such as the Hospital Readmissions Reductions Program

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are expected to target COPD outcomes as of October 20163. Despite smoking cessation

campaigns, public health efforts, and scientific progress, COPD morbidity and mortality continue

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to increase4.

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Though classically neutrophilic and Th1-mediated5, different COPD inflammatory profiles have
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recently gained interest. Eosinophilic inflammation has been observed in stable and exacerbated

COPD patients’ blood and sputum6,7. It has been hypothesized that “eosinophilic” COPD patients
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may represent a different phenotype8 which responds favorably to inhaled corticosteroids (ICS)
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and systemic corticosteroids11–13. Compared to other biological clusters, exacerbations with
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higher sputum eosinophil counts are more often non-infectious8,14,15. This phenotype can readily

be identified with blood eosinophils as a sputum eosinophils surrogate8. Of note, equal

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proportions of general and COPD populations – approximately 40%, depending on the cohort16,17

– demonstrate blood eosinophil levels ≥200 cells/µL and/or ≥2%. However, COPD patients’
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lungs have been shown to contain an excess number of eosinophils compared to controls18.
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Post-hoc analyses of prospective studies have shown inconsistent relationships between blood

eosinophils and increased exacerbation rates. In their analysis of the ECLIPSE cohort, Singh et

al. failed to demonstrate this association16. Siddiqui et al. and Pascoe et al., who studied

randomized controlled trials’ (RCT) cohorts, found increased exacerbation rates that mirrored
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increased eosinophils19,20. Vedel-Krogh et al. noted an association between eosinophil levels and

an increase in moderate to severe exacerbation rates amongst eosinophilic COPD patients in the

general population17. More recently, Bafadhel et al. did not find a significant difference between

eosinophilic and non-eosinophilic COPD patients regarding 12-month readmission rate and time

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to first exacerbation, though eosinophils in presence of corticosteroid therapy did predict a

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shorter hospital stay13. Conflicting results between these studies raise the possibility of a

confounding factor.

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Corticosteroids are the mainstay of treatment for severe COPD exacerbations. The eosinopenic

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effect of cortisone has long been recognized: originally by means of the Thorn test and later by
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formal pharmacodynamic testing. Eosinophil count is known to fall by more than 50% within the

first four hours following its administration, and then return to baseline within 24 hours21. As the
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relative timing of corticosteroid administration can potentially mask blood eosinophilia in COPD,
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it is plausible that a confounding bias arises when studying eosinophilic inflammation, response
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to corticosteroids, and clinical outcomes.

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Thus, the objective of this study was to investigate the association between higher blood

eosinophil counts and adverse clinical outcomes following severe COPD exacerbations. Special
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care was given to control the effect of corticosteroid administration on these variables.
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METHODS

Study design

With an observational study design, all severe exacerbations of COPD in Sherbrooke’s hospital

health centers between April 1st 2012 and March 31st 2013 were retrospectively screened through

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electronic medical records. The main diagnosis of hospitalization had to be registered as “acute

exacerbation of COPD”, with no mention of decompensated asthma in this field and no comorbid

bronchiectasis elsewhere. Patients had to have survived the index hospitalization. The

institutional Ethics Committee approved the protocol (FWA #00005894).

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Study patients

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All patients were ≥40 years of age and had COPD by symptoms, spirometry, and standard

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definition of the Global Initiative for Chronic Obstructive Lung Disease22. Upon candidate

reassessment, exclusion criteria were: admission for pneumonia, absence of obstructive pattern

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on pulmonary function tests (PFT), absence of a valid PFT any time between 1998 and one year
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after index hospitalization, COPD without exacerbation, mislabeled asthmatics (never-smokers

with or without obstructive spirometry and no mention of COPD in medical records), and
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referrals for tertiary care from outside the immediate region (“non-captive” patients). Based on
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available data, consensus was obtained between authors for questionable cases for selection in the

cohort. Patients with an initial complete blood count (CBC) taken in a corticosteroid-free time
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frame, defined as no systemic corticosteroid between one and 48 hours before venipuncture, were
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identified.

Data collection
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Data that was initially collected through electronic records consisted of: anthropometric

measures; comorbid conditions; inpatient laboratory blood tests’ dates, times and results; and

information pertaining to all previous hospitalizations on file and up to one year following the

index hospitalization. Deaths in the year following hospitalization were identified in the hospital

database. Additional data collected by manual extraction from medical files consisted of:

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smoking status; home oxygen use; baseline PFT results up to one year following index

hospitalization (PFT used, in order of priority: most recent PFT <5 years prior to admission, PFT

≥1 year after discharge, PFT between 1998 and <5 years prior); baseline and discharge inhaler

therapy; corticosteroid use within 48 hours before index admission, using patients outpatient

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medication list and medical notes; inpatient definitive treatment components, like corticosteroids

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and/or antimicrobial(s); and date and time of the first corticosteroid dose.

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Study variables and outcomes

The main independent variable was a blood eosinophil cell count ≥200 cells/µL and/or ≥2% of

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total white blood cell (WBC) count on the first inpatient CBC available during the index
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hospitalization (including emergency department care). This cut-off has previously shown high

sensitivity for predicting sputum eosinophilia8, and was thus considered to indicate an
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“eosinophilic COPD patient”. The primary outcomes were 12-month COPD-related readmission,
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12-month all-cause readmission, and hospital length of stay. The secondary outcome was time to

first COPD-related readmission.

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Statistical analyses
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The study variables were compared between eosinophilic and non-eosinophilic patients using the
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chi-2 test for categorical variables, and the t-test or the Wilcoxon rank test for continuous
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variables. For binary outcomes, associations between eosinophilia and outcomes were estimated

using logistic regression with stepwise selection (forcing age and sex in the models but all other

variables were considered only if they reached statistical significance). The association between

eosinophilia and the hospital length of stay was estimated using negative binomial regression

models23. For the secondary outcome “time to first COPD-related readmission”, patients were

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censured at the date of death if deceased or at the end of follow-up (365 days), and the

association with eosinophilia was estimated using Cox regression models and Kaplan-Meier

survival curves. Sensitivity analyses were performed using different definitions of eosinophilia:

1- by using a higher eosinophil cut-off (≥300 cells/µL or ≥3% of WBC); 2- by using only

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eosinophil cell count ≥200 cells/µL; 3- by using eosinophil cell count in three categories with

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thresholds corresponding to the median and the third quartile (<100, 100-200, ≥200 cells/µL); 4-

by using only eosinophil cell percent ≥2% of total WBC count; 5- by using eosinophil cell

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percent in 3 categories with thresholds corresponding to the median and the third quartile (<0.7%,

0.7%-2.0%, ≥2.0% cells/µL).

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RESULTS
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Four hundred forty-seven candidate hospitalizations were included and 236 were retained after

applying exclusion criteria. From them, only 167 patients had a corticosteroid free CBC available
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(Figure 1). Patients’ characteristics are presented in Table 1. Fifty-five patients had eosinophilia
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as defined by the ≥200 cells/µL and/or ≥2% cut-off. Except for eosinophil counts, all differences

between eosinophilic and non-eosinophilic patients were not statistically significant.

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Primary outcomes
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First, 12-month COPD-related readmission (censored for death) differed significantly between
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groups (adjusted OR [95% CI], eosinophilic vs non-eosinophilic: 3.59 [1.65-7.82], p=0.0013;

Table 2) as well as 12-month all-cause readmission (adjusted OR: 2.32 [1.10-4.92], p=0.0277;

Table 2). Relative number of deaths was similar between groups (n=14 in the non-eosinophilic,

n=6 in the eosinophilic). On the other hand, the hospital length of stay did not differ significantly

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between groups (median [interquartile range]: 5 [3-7] vs 5 [3-7] days, p=0.75; Table 2), and this

remained true even after controlling for the other covariables (exp(β)=1.19 [0.91-1.55],

p=0.2096; Table 2).

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Primary outcomes were also measured using different definitions of eosinophilia (Table 3). The

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association between higher eosinophils and 12-month COPD-related and all-cause readmission

remained essentially the same across definitions for cell counts ≥200 cells/µL or percent ≥2.0%.

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Compared to lower eosinophils levels (100 or 0.7%), intermediate cell counts (100-200) or

percent (0.7-2.0%) were not statistically associated with an increased risk of readmission (COPD

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or all-cause). On the other hand, the hospital length of stay did not differ significantly between
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groups, regardless of the definition used.
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Secondary outcome
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The Kaplan-Meier curve of the time to the first COPD-related readmission separated significantly

(Figure 2). Using the Cox model, the adjusted Hazard Ratio associated with eosinophilia was
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2.78 [1.58-4.89], p=0.0004.

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As said earlier, the relative timing of corticosteroid administration can potentially mask blood
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eosinophilia in COPD if we do not consider only patients with an initial CBC taken in a

corticosteroid-free time frame. To illustrate the possible bias arising if we do not take this into

account, we performed the analysis with the entire sample (n=236), including patients that were

not corticosteroid-free at time of CBC measurement. All primary outcomes were non-statistically

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significant in this case. Specifically, 12-month COPD-related readmission and 12-month all-

cause readmission in the entire sample did not differ significantly between eosinophilic and non-

eosinophilic patients (adjusted OR: 1.63 [0.86-3.10], p=0.1370; adjusted OR: 1.53 [0.81-2.90],

p=0.1935, respectively).

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DISCUSSION

The main finding of this study is that increased eosinophils at admission, when defined by a cut-

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off of ≥200 cells/µL and/or ≥2% of WBC count, can predict a more than threefold increase in 12-

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month readmission for COPD, a more than double increase in 12-month all-cause readmission,
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and a shorter time to first COPD-related readmission. The influence of eosinophil cell counts on

readmissions is consistent throughout the sensitivity analyses conducted on our data.

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Previous studies have tentatively associated clinical outcomes with eosinophilia in COPD;
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careful attention to methodological differences reveals that positive studies were exempt of the
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confounding effect of systemic corticosteroid use. Singh et al., when studying the ECLIPSE

cohort, classified eosinophilia according to yearly stable-state CBCs and did not give thorough
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consideration to systemic corticosteroid use as possible bias. Their study failed to find a

significant association with exacerbation rates16. Siddiqui et al. and Pascoe et al., in their post-
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hoc analyses of RCT cohorts, excluded patients having used systemic corticosteroids ≤4 weeks

before enrollment19,20,24. Accordingly, these studies achieved clinical significance regarding the

association between higher eosinophil cell levels and exacerbation rates. Vedel-Krogh et al.

analyzed the Copenhagen General Population Study cohort, presumably using the participants’

baseline CBC, i.e. at the moment of enrollment between 2003 and present25. They reported

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inhaled corticosteroid use, and made no mention of systemic corticosteroids. Though they did

find an association between eosinophil counts and exacerbation rates, the impact of systemic

corticosteroids was not assessed17. Also, the clinical usefulness of older baseline CBC compared

with at-admission CBC to identify the eosinophilic COPD phenotype is debatable26. Bafadhel et

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al. identified corticosteroid use before admission, but determined a ≤4 week cut-off for their

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subgroup analysis, losing much power and diluting the eosinopenia association with very recent

corticosteroids use. Readmission outcomes were not significantly different13. Throughout these

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studies, one can postulate that lack of consideration of the impact of systemic corticosteroids use

might have led to mitigated results.

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The antagonism of eosinophils by corticosteroids has long been recognized and studied21,27,28.

Here, we considered only patients with no corticosteroid treatment ≤48 hours before the
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measurement of eosinophil cells counts. This timeframe was justified by previous data which
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demonstrated eosinopenia between 4-24 hours following cortisone administration21. Of particular

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interest, the association between increased readmission rates and blood eosinophil levels became

non-statistically significant in the whole sample (n=236) if we disregard recent corticosteroid use
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before identifying the eosinophilic inflammatory profile a COPD patient.

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A methodological difference with previous studies is the exclusion of so-called “COPD

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exacerbations secondary to pneumonia” (n=103 exclusions). Clinically speaking, we differentiate

COPD exacerbation – i.e. Anthonisen symptoms29 without consolidation on imagery – from

pneumonia, as these diagnoses differ in their pathophysiology and treatment

components/duration. Moreover, concomitant eosinophilia and pulmonary consolidation evoke a

broad range of diagnoses30, most of which would respond favorably to corticosteroids.

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The major strengths of this study are its pathophysiological-driven design, consideration of the

effect of relative timing of systemic corticosteroid administration on eosinophils, and evaluation

of several different eosinophilia definitions. Even if its observational design carries the usual

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indication bias, no other sample has ever been assembled exclusively to study the association

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between blood eosinophils and readmission rates, a characteristic which permitted more latitude

in choice of selection criteria, and study measurements. Though all potential variables related to

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the selected outcomes were not included, we are confident the most important ones were taken

into account. Nevertheless, the data is retrospective in nature, and as such the signals provided by

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our study must be interpreted with care. Further studies with larger samples are needed to clarify
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the issue of which eosinophil count or percent thresholds are associated with an increased risk of

readmissions. Lastly, the absolute eosinophil cell count was relatively imprecise in our
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laboratory, as they were rounded by hundred cells/µL.

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In conclusion, we report that higher blood eosinophils at admission for severe exacerbation of

COPD, when assessed in a corticosteroid-free time frame, is associated with a more than
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threefold increase in 12-month readmission for COPD, a more than double 12-month all-cause

readmission, and a shorter time to first COPD-related readmission. These findings reaffirm that
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adequately phenotyping specific COPD inflammatory profiles is worthwhile and of clinical

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importance.

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Acknowledgements: We thank Roxanne Dault for her assistance in data collection, Marie-Pierre

Garant for her assistance in statistical analyses, Annie Benoit for English editing, and Felix-

Antoine Vézina for manuscript revision.

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26. Bafadhel M, McKenna S, Terry S, et al. Blood eosinophils to direct corticosteroid

treatment of exacerbations of chronic obstructive pulmonary disease: A randomized
placebo-controlled trial. Am J Respir Crit Care Med 2012;186(1):48–55.
27. Essellier A, Jeanneret R, Morandi L. The mechanism of glucocorticoid eosinopenia;
contribution to the physiology of eosinophile granulocytes. Blood 1954;9.5:531–549.
28. Wallen N, Kita H, Weiler D, Gleich GJ. Glucocorticoids inhibit cytokine-mediated
eosinophil survival. J Immunol 1991;147(10):3490–3495.
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Pulmonary Disease. Ann Intern Med [Internet] 1987 [cited 2016 Mar 30];106(2):196.
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30. Jeong YJ, Kim K-I, Seo IJ, et al. Eosinophilic lung diseases: a clinical, radiologic, and
pathologic overview. Radiographics [Internet] 2007;27(3):617–37; discussion 637–9.
Available from: http://www.ncbi.nlm.nih.gov/pubmed/17495282

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FIGURE LEGENDS

Figure 1.

Flowchart of patient enrollement process.

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Figure 2.

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Kaplan-Meier curves for time before first COPD-related readmission (Time_COPD; days after

discharge) in patients with a corticosteroid-free CBC, eosinophilic (n=55, blue line) vs non-

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eosinophilic patients (n=112, red line); follow-up 365 days post-discharge, data censored for

death; p=0.007.

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TABLE 1 - Patient characteristics

Parameter Total Eosinophilic COPD Non-eosinophilic
p-value
(n=167) (n=55) COPD (n=112)
Male 86 (51.5) 28 (50.9) 58 (51.8) 0.915
Age, y 71.4 ± 10.3 69.3 ± 11.0 72.3 ± 9.8 0.076
Comorbidities CVD 61 (36.5) 16 (29.1) 45 (40.2) 0.162

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Diabetes 40 (24.0) 11 (20.0) 29 (25.9) 0.402
Asthma 9 (5.4) 5 (9.1) 4 (3.6) 0.138

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Charlson comorbidity index 1 [0-2] 1 [0-2] 0 [0-2] 0.481
Smoking status Ex-smoker 78 (46.7) 29 (52.7) 49 (43.8) 0.274

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Current smoker 89 (53.3) 26 (47.3) 63 (56.2)
FEV1 (post-bronchodilator), % predicted 52.2 ± 17.9 53.3 ± 19.2 51.6 ± 17.2 0.585

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FEV1/FVC, % 47.6 ± 12.3 47.7 ± 13.1 47.5 ± 12.0 0.910

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GOLD stage (according to FEV1) I 13 (7.8) 5 (9.1) 8 (7.1) 0.373
II 80 (47.9) 28 (50.9) 52 (46.4)
III 59 (35.3) 15 (27.3) 44 (39.3)

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IV 15 (9.0) 7 (12.7) 8 (7.1)
Hospitalized for COPD in the previous year 27 (16.2) 9 (16.4) 18 (16.1) 0.962

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Home oxygen use 17 (10.2) 9 (16.4) 8 (7.1) 0.169

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Baseline inhalator use ICS 119 (71.3) 38 (69.1) 81 (72.3) 0.665
LABA 114 (68.3) 36 (65.4) 78 (69.6) 0.585
LAMA 112 (67.1) 34 (61.8) 78 (69.6) 0.312
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SAMA 7 (4.1) 1 (1.8) 6 (5.4) 0.428
None or SABA prn only 33 (19.8) 14 (25.4) 19 (17.0) 0.195
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Post-discharge ICS use 137 (82.0) 43 (78.2) 94 (83.9) 0.363

WBC count at admission, cells x109/L
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10.3 ± 3.9 10.3 ± 3.9 10.3 ± 4.0 0.993

Eosinophil count, cells x109/L 0.1 [0.0-0.2] 0.3 [0.2-0.4] 0 [0.0-0.1] < .001
Eosinophil count, % of WBC 0.7 [0.2-2.0] 3.1 [2.0-4.2] 0.4 [0.1-0.7] < .001
Definitive inpatient therapy Corticosteroid 151 (90.4) 51 (92.7) 100 (89.3) 0.478
Antimicrobial(s) 145 (86.8) 45 (81.8) 100 (89.3) 0.180
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n (%) or mean ± SD or median [Interquartile range]; CBC: complete blood count; CVD: cardiovascular Disease; GOLD: Global
initiative for chronic Obstructive Lung Disease; ICS: inhaled corticosteroid; LABA: long acting β-agonist; LAMA: long acting
muscarinic antagonist; SABA: short acting β-agonist; SAMA: short acting muscarinic antagonist; WBC: white blood cells

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TABLE 2 - Association between eosinophilia and outcomes
Eosinophilic COPD Non-eosinophilic
Outcome (n=55) COPD (n=112)
n (%) n (%) Crude OR Adjusted OR
12-month COPD-related readmission 26 (47.3) 28 (25.0) 2.54 [1.27 - 5.08]** 3.59 [1.65 – 7.82]**

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12-month all-cause readmission 37 (67.3) 60 (53.6) 1.68 [0.85 - 3.31] 2.32 [1.10 – 4.92]*
Median [IQR] Median [IQR] Crude exp(β) Adjusted exp(β)

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Length of stay, days 5 [2-6] 5 [3-7] 1.15 [0.88 – 1.50] 1.19 [0.91 – 1.55]
IQR: Interquartile range; OR (logistic regression) or exp(β) (negative binomial regression) [95% CI]; *p<0.05; **p<0.01; ***p<0.001

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TABLE 3 - Association between eosinophilia and outcomes according to eosinophilia definition
12-month COPD-related
12-month all-cause readmission Length of stay
readmission
Definition of eosinophilic patients Adjusted OR Adjusted OR Adjusted exp(β)
1. < 200 cells/µL and < 2% (n=112) Ref Ref Ref
≥ 200 cells/µL or ≥ 2% (n=55) 3.59 [1.65 – 7.82]** 2.32 [1.10 – 4.92]* 1.19 [0.91 – 1.55]

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2. < 300 cells/µL and < 3% (n=131) Ref Ref Ref

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≥ 300 cells/µL or ≥ 3% (n=36) 3.21 [1.34 – 7.71]** 1.42 [0.62 – 3.26] 1.00 [0.73 – 1.38]
3. < 200 cells/µL (n=116) Ref Ref Ref

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≥ 200 cells/µL (n=51) 3.12 [1.42 – 6.88]** 2.17 [1.01 – 4.66]* 1.23 [0.94 – 1.62]
4. < 100 cells/µL (n=68) Ref Ref Ref

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100-200 cells/µL (n=48) 1.45 [0.59 – 3.58] 1.41 [0.63 – 3.18] 0.83 [0.60 – 1.13]

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≥ 200 cells/µL (n=51) 3.66 [1.51 – 8.91]** 2.51 [1.09 – 5.78]* 1.15 [0.86 – 1.55]
5. < 2% (n=123) Ref Ref Ref

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≥ 2% (n=44) 3.57 [1.60 – 8.00]** 1.89 [0.86 – 4.13] 1.01 [0.76 – 1.35]

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6. < 0.7% cells/µL (n=78) Ref Ref Ref
0.7-2.0% cells/µL (n=45) 1.45 [0.58 – 3.61] 1.79 [0.78 – 4.10] 1.05 [0.77 – 1.43]
≥ 2.0% cells/µL (n=44)
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4.12 [1.69 – 10.0]** 2.16 [0.93 – 5.00] 1.02 [0.75 – 1.39]
OR (logistic regression) or exp(β) (negative binomial regression) [95% CI]; Ref: reference group; *p<0.05; **p<0.01; ***p<0.001
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