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).