Abstract:
Background: There is limited evidence of the relationship
between peripheral blood eosinophils and clinical remission of acute
exacerbations of chronic obstructive pulmonary disease (AECOPD) at
different ages, especially in elderly patients, which was the objective
of the present study. Methods: This retrospective study
stratified patients by age (>65 or ≤65 years) and analyzed
the relationship between blood eosinophils (≥2% or <2%) and
AECOPD clinical remission at observing time points of 7, 10, 14, 21, and
28 days.
Results: Of 703 AECOPD cases analyzed, 616 were elderly
(>65 years), 272 of whom had eosinophilic exacerbations.
There were statistically significant differences in leukocyte count,
high-sensitivity C-reactive protein levels (hs-CRP), and hospital costs
between eosinophilic and non-eosinophilic AECOPD patients
(p <0.05, respectively). Among all AECOPD patients,
eosinophilic exacerbation was significantly associated with a higher
remission rate at 7 (hazard ratio [HR]=1.457 [1.072, 1.982]), 10
(HR=1.316 [1.108, 1.562]), 14 (HR=1.334 [1.102, 1.615]), 21
(HR=1.326 [1.125, 1.562]), and 28 days (HR=1.254[1.078, 1.459]).
The subgroup analysis showed that eosinophilic exacerbation yielded
better clinical remission than non-eosinophilic exacerbation in elderly
patients (>65 years old) at 7 (HR=1.521 [1.084,
2.136]), 10 (HR=1.319 [1.096, 1.588]), 14 (HR=1.374 [1.118,
1.689]), 21 (HR=1.326 [1.112, 1.582]), and 28 days (HR=1.234
[1.049, 1.451]), while no differences were observed in middle-aged
patients (between 45 and 65 years) at all time points (allp >0.05).
Conclusion : The eosinophilic phenotype was associated with
better clinical remission at 7, 10, 14, 21, and 28 days among elderly
but not in middle-aged patients with AECOPD.
Keywords: chronic obstructive pulmonary disease; acute
exacerbation; eosinophils; elderly; remission
1. Introduction
Chronic obstructive pulmonary disease (COPD) is a common chronic
respiratory disease with high morbidity and
mortality[1]. It is becoming a global
public health concern due to its high mortality, it was the fifth
leading cause of death in 2002 and is expected to rank third by 2030.
COPD accounts for over half of the patients with chronic respiratory
disease, making it the leading cause of global health care utilization
and expenditure[2]. In China,
nationwide epidemiology research showed that
the
overall prevalence of COPD was as high as 13.6% in people aged 40 years
or older, implying there would be about 100 million COPD patients in
China. [3]. Nationwide health policies
have been promoted to improve COPD prevention and management to reduce
economic burdens. However, the overall situation is still not as
optimistic as expected[4,
5].
COPD significantly impacts quality of life and family income, mainly due
to its acute exacerbation[6]. Acute
exacerbation of COPD (AECOPD) is characterized by increased systemic and
airway inflammation, leading to increased symptoms of dyspnea, sputum
purulence, and sputum volume. According to the Global Initiative for
Chronic Obstructive Lung Disease (GOLD) guidelines, AECOPD is one of the
leading causes of hospitalization and contributes significantly to
mortality[7]. In United States, AECOPD
causes 726,000 hospitalizations
annually[8]. In China, 44.4% of COPD
patients developed one or more exacerbations in the 2-year observation
period[9]. The impact of
hospitalization on acute exacerbations in elderly COPD patients is
significant, with readmission rates of 25–40% and mortality rates of
25–40% within 12 months after
discharge[10-12].
Appropriate early assessment is fundamental for implementing proper
initial treatment strategies and is associated with better outcomes and
lower risk of treatment failure as well as the efficient and fair
allocation of limited medical
resources[13]. In the last decade,
blood eosinophil count, an easy-to-use and easy-to-measure index which
is economically efficient and provides rapid results, has been
identified to be capable of measuring inflammatory response in AECOPD
patients[14,
15]. The prevalence of eosinophilic
COPD varies widely in different countries and regions, from 18.84% to
66.88%, with an average prevalence of
54.95%[16]. Compelling evidence has
confirmed that patients with higher sputum or peripheral blood
eosinophil counts are not only associated with better corticosteroid
response and lower rate of AECOPD treatment
failure[17,
18] but also with lower risk of
all-cause mortality[19]. A study from
Netherland reported that blood eosinophilia was associated with a higher
short-term (10-day) treatment success rate in AECOPD
patients[20], but the eosinophilic
phenotype was also reported to be associated with increased risk of
12-month COPD-related
readmission[21]. These studies
indicated the diverse roles of blood eosinophil in AECOPD. However,
limited evidence about the role of eosinophils in different age groups
of AECOPD patients was reported. As COPD patients with eosinophil levels
persistently >2% were more usual in older
population[22]. However,. Thus, a
better understanding of the relationship between eosinophilic phenotype
and AECOPD clinical remission in different age groups, especially in
elderly patients, is needed.
Therefore, this study investigated the role of peripheral blood
eosinophil count in the prediction of AECOPD clinical remission in
elderly and middle-aged patients.
2. Materials and Methods
AECOPD
patients were retrospectively enrolled from the Department of
Respiratory and Critical Care Medicine at the Affiliated Hospital of
Chengdu University from July 1, 2014, to December 31, 2016. Patient data
were extracted from the electronic medical record system; demographic,
clinical, laboratory, and pulmonary function data were collected at the
time of presentation. Data on clinical outcomes related to hospital
admission and length of hospital stay were also collected. In-hospital
remission was evaluated by defining five set time points (day 7, 10, 14,
21, and 28). The biological inflammatory state was assessed using
high-sensitivity C-reactive protein (hs-CRP) level and peripheral blood
count. Patients with missing information on peripheral blood count,
including eosinophil counts, were excluded. The study was approved by
the ethics community of the Affiliated Hospital of Chengdu University
(NO.: PJ2018-012-02).
2.1 Inclusion and exclusion criteria
2.1.1 Inclusion criteria
AECOPD patients were enrolled according to the following criteria: (1)
age ≥45 years; (2) a diagnosis of COPD based on the GOLD guidelines of
corresponding years; and (3) a
diagnosis of AECOPD based on expert consensus on the acute exacerbation
of chronic obstructive pulmonary disease in China; namely: worsening of
respiratory symptoms (typically dyspnea, cough, increased sputum volume,
and/or sputum purulence) beyond normal day-to-day variations and leading
to a change in medication, without alternative specific causes for
deterioration (such as pneumonia, congestive heart failure,
pneumothorax, pleural effusion, pulmonary embolism, and arrhythmia), as
identified by clinical examination and/or corroborative
testing[23,
24].
2.1.2 Exclusion criteria
Patients were excluded if: (1) the presence of other respiratory
diseases such as bronchial asthma, bronchiectasis, tuberculosis, lung
cancer, and other allergic diseases such as allergic rhinitis; (2)
missing information on peripheral blood counts and pulmonary function
tests; or (3) pregnancy and
lactation[25].
2.2 Definitions of eosinophilic exacerbation and clinical remission
2.2.1 Definition of elderly patients
This study defined elderly and middle-aged patients as those aged
>65 years and those aged ≥ 45 and ≤ 65 years,
respectively[26].
2.2.2 Eosinophilic exacerbation
This study defined eosinophilic exacerbation as a peripheral blood
eosinophil count on admission of
≥2%[17].
2.2.3 Clinical remission
Clinical remission was defined as: (1) the resolution of symptoms and
signs for 12–24 hours; (2) stable arterial blood gases for 12–24
hours; (3) patients with acceptable adherence to medication; (4)
patients who would be able to be successfully managed at home without
frequent dyspnea [20,
23].
2.2.4 Observation time points
The time of clinical remission for every patient was collected, and the
observation time points were set for statistical analysis at 7, 10 (time
point of early clinical remission evaluation), 14, 21, and 28 days.
2.3 Statistical analysis
Continuous variables are presented as means with standard deviation for
normally distributed variables and as medians (interquartile range
[IQR]) for non-normally distributed variables. For categorical
variables, data are presented as percentages. Student’s t-tests were
used to compare continuous parametric variables, while Mann–Whitney-U
tests were used to compare continuous non-parametrical variables.
Chi-squared and Fisher’s exact tests were used to compare categorical
data. The Cox proportional hazards model was used to analyze the
associations between blood eosinophilic levels and clinical remission at
different time points. Two-side P -value <0.05 were
considered statistically significant. R software (version 3.6.2, The R
Foundation for Statistical Computing, Vienna, Austria) was used to
perform the statistical analyses and draw the figures.
3. Results
3.1 Baseline characteristics
A total of 1427 cases were enrolled during the study period. After
applying the exclusion criteria, 703 AECOPD cases (84.6% male)
including 312 eosinophilic exacerbations and 391 non-eosinophilic
exacerbations, were considered eligible for the final analysis (Figure
1). Of these patients, 616 were older than 65 years (272 eosinophilic
exacerbations and 344 eosinophilic exacerbations) and 87 were
middle-aged (40 eosinophilic exacerbations and 47 eosinophilic
exacerbations).
The following indicators were significantly different between the
eosinophilic and non-eosinophilic exacerbation groups: neutrophils,
lymphocytes, monocytes, basophils, eosinophils, and hs-CRP levels (allp <0.05). No statistically significant differences in
the other factors were observed (p >0.05) (Table 1).
In elderly patients, there were statistically significant differences in
neutrophils, lymphocytes, monocytes, basophils, and hs-CRP levels
between eosinophilic and non-eosinophilic exacerbation groups (allp <0.05). In middle-aged patients, statistically
significant differences were observed in neutrophils, lymphocytes,
monocytes, and basophils between the eosinophilic and non-eosinophilic
exacerbation phenotypes, while no statistically significant differences
of hs-CRP were observed between these two groups (Tables 1).