Measurement of Blood Eosinophils in Asthma and Chronic Obstructive Pulmonary Disease

Abstract

Eosinophils are important effector cells in airway inflammation, as pleiotropy and heterogeneity can be linked to various pathophysiologies in asthma and chronic obstructive pulmonary disease (COPD). Sputum eosinophils can reflect the heterogeneity of airway inflammation, and owing to their traits, blood eosinophils can be a surrogate and potential biomarker for managing both conditions. Blood eosinophils are activated via the stimulation of type 2 cytokines, such as interleukin (IL)-5, IL-4/13, granulocyte-macrophage colony-stimulating factor, IL-33, and thymic stromal lymphopoietin. There is sufficient evidence to support the relationship between the blood eosinophil count and clinical outcomes, including pulmonary function decline, exacerbations, all-cause mortality, and treatment response to inhaled corticosteroids and biologics. Thus, there is growing interest in the use of blood eosinophils for the management of these diseases. Compiling recent evidence, we herein review the significance of measuring blood eosinophils in asthma and COPD.

1．Importance of Evaluating Blood Eosinophilia in Asthma and COPD

Asthma and chronic obstructive pulmonary disease (COPD) are chronic inflammatory diseases of the airways with various patterns of inflammation. Both conditions are mediated by up- or downregulation of numerous inflammatory cells and signals. However, while the two conditions have similar clinical manifestations, there are distinct gaps in the inflammatory patterns of the airways with respect to the involvement of different inflammatory cells, signals, and responses to treatment.

The representative inflammatory cells of the airway in asthma are eosinophils, while those in COPD are neutrophils. However, there are also phenotypes of COPD in which eosinophilic inflammation of the airway is predominant under certain circumstances, such as exacerbation or asthma overlap. This means that eosinophilic inflammation of the airway in both diseases is a promising therapeutic target, as sputum eosinophilia can predict clinical outcomes, such as symptoms, pulmonary function decline, exacerbation, mortality, corticosteroid use (1) as well as the response of type 2 biologic agents (2). However, it is difficult for clinicians to measure the inflammatory status of the airways with a sputum examination due to the complicated processing. Instead, in the real-world clinical setting, blood eosinophil counts are measured as a surrogate marker of eosinophilic airway inflammation and have been shown to be significantly correlated with airway eosinophils (3-6).

Although interleukin (IL)-5 plays a crucial role in the eosinophil differentiation, maturation, activation, and survival of bone marrow CD34⁺ eosinophil progenitor cells, the eosinophil count is low because IL-5 is regulated under normal conditions, such as in healthy individuals (7). However, under chronic airway inflammation conditions, such as asthma and COPD, various cytokines, including IL-5, IL-3, granulocyte-macrophage colony-stimulating factor, IL-33, and thymic stromal lymphopoietin, are upregulated and promote this cascade (8). Consequently, the number of circulating eosinophils is speculated to increase. Therefore, these molecules are responsible for blood eosinophilia and serve as therapeutic targets for the treatment of asthma and COPD.

2．Relationship between Blood Eosinophilia and Clinical Outcomes of Asthma and COPD

Since eosinophils express diverse mediators and secrete specific proteins (9,10), pleiotropy and heterogeneity may be associated with various clinical outcomes, listed below.

A．Stability and diagnostic accuracy of blood eosinophil for distinguishing eosinophilic and non-eosinophilic airway inflammation

While eosinophils can serve as promising biomarkers for airway diseases, their biological stability remains a critical issue in clinical settings. Several studies have assessed the stability of blood eosinophils (4,11). It has been shown that when the mean blood eosinophil count in the general population was 128 cells/μL, the cut-off point of the 75th percentile was 210 cells/μL (12). However, as blood eosinophils are influenced by clinical parameters, such as age, smoking, atopy, metabolic syndrome, obesity, and allergic rhinitis (12-14), these effects should be considered when interpreting the pathophysiology or managing asthma and COPD (Fig. 1). In asthma and COPD, sex, race, and the body mass index affect the blood eosinophil count (15). Even if asthma control in patients is stable, the blood eosinophil counts still fluctuate substantially (16). In contrast, while blood eosinophils are stable over time in stable COPD, the counts are unstable in severe acute exacerbation of COPD (AECOPD) because of the variety of causes of AECOPD (17).

Figure 1.

Relationship between influential factors and clinical outcomes via blood eosinophilia.

A study assessing the diagnostic accuracy of blood eosinophils in airway eosinophilic inflammation of patients with moderate to severe asthma reported that the area under the receiver operating characteristic (ROC) curve (AUC) was 0.89 (95% confidence interval 0.72-0.98) (18). In that report, on setting 270 eosinophils/μL blood as the cut-off, the sensitivity and specificity for diagnosing airway eosinophilic inflammation were estimated to be 60% and 90%, respectively.

B．Pulmonary function decline

There is a correlation between elevated blood eosinophil counts and the forced expiratory volume in 1 second (FEV₁) decline in adults with asthma (19). Similarly, elevated blood eosinophil counts can predict an accelerated pulmonary function decline in COPD (20). This evidence supports the hypothesis that structural lung abnormalities can accompany eosinophilia (20). Furthermore, the blood eosinophil count at an early stage of airway disease may be a predictor of the pulmonary function decline (21).

C．Exacerbation

Blood eosinophilia is correlated with an increased risk of asthma exacerbation (22,23), so with increasing blood eosinophil counts, exacerbation becomes more severe. However, whether or not the blood eosinophil count can predict exacerbation in COPD remains unclear. The phenotypes of airway inflammation in COPD exacerbation are heterogeneous (24), and eosinophilic predominance in airway inflammation during exacerbation is a clinical phenotype of COPD. However, in moderate COPD exacerbation, blood eosinophil counts ≥2% can be used to detect subpopulations that may benefit from systemic corticosteroid treatment (25). In addition, blood eosinophils of severe COPD exacerbation have been reported to stratify treatment approaches using antibiotics and corticosteroids more effectively than C-reactive protein levels (7).

D．Mortality

High blood eosinophil counts in patients with asthma have been shown to correlate with an increased mortality risk (26). Furthermore, blood eosinophilia in COPD with asthma-like features is associated with an improved survival (27-29). This suggests that the prognosis is better in patients with asthma and COPD with blood eosinophilia receiving appropriate treatment than in those receiving inappropriate treatment and that its estimation is important for managing these diseases.

E．Treatment response

A blood eosinophil count of >3% or >300 cells/μL can predict clinical outcomes, such as the risk of exacerbation or a good response to corticosteroid treatment, in cases of asthma or COPD (30-35). In asthma, the baseline eosinophil count is a predictor of the response to usual treatments, such as inhaled corticosteroid (ICS) (36-39), and assists in clinical decision-making. Blood eosinophil levels are correlated with airflow limitation, airway hyper-responsiveness, exacerbation, asthma control, and the quality of life (QOL) (40,41). As the pathophysiology of COPD is heterogeneous, precision medicine is needed to manage this disease. A treatable trait based on phenotypic recognition or on understanding of endotypes is a new identical concept to realize the precision medicine strategy (42). The blood eosinophil count is considered a treatable trait and a relevant biomarker for ICS usage in order to reduce the risk of future exacerbations in COPD (33-35). The Global Initiative for Chronic Obstructive Lung Disease also recommends blood eosinophils be used as a guide for ICS treatment in patients with COPD, based on the exacerbation pattern (43). Cases with blood eosinophils >300 cells/μL with severe exacerbation, ≥2 moderate exacerbations, or a history of concomitant asthma are recommended for strong ICS use. However, when the eosinophil count is <100 cells/μL in groups at high risk for bronchial infection, ICS is not recommended (44). If the blood eosinophil count is 100-300 cells/μL and the patient experiences a moderate exacerbation, ICS use should be considered (Table).

Table.

ICS Use Recommendation according to Association between Exacerbation Pattern and Blood Eosinophil.

Eosinophil count	>300 cells/μL	100-300 cells/μL	<100 cells/μL
Exacerbation pattern
Severe exacerbations or ≥2 moderate exacerbations concomitant asthma	◎	○	△
1 Moderate exacerbation	○	○	△
Repeated infectious pneumonia History of mycobacterial infection	△	△	×

◎, strong ICS use, ○, consider ICS use, △, alternative treatment for ICS, ×, ICS avoid use, moderate exacerbations were defined by the increase of symptoms requiring oral antibiotic and/or a short course of oral steroid therapy, severe exacerbations were defined by the increase of symptoms requiring hospitalization or emergency room visits.

Blood eosinophils play an important role in the pathogenesis of severe asthma. Eosinophilia is associated with the production of several inflammatory cytokines. Since eosinophils specifically express the IL-5 receptor, IL-5 is a key player in eosinophilia, and biologics that can target IL-5 signaling are useful for managing difficult asthma. In fact, a higher baseline blood eosinophil count leads to a greater response of anti-IL-5 monoclonal antibody mepolizumab, resulting in a greater reduction in exacerbations (45). Benralizumab, an IL-5-receptor monoclonal antibody, has also been reported to improve clinical outcomes, such as systemic glucocorticoid overuse, symptoms, the QOL, and exacerbations in the real world (46). A blood eosinophil count ≥150 cells/μL can predict treatment efficacy when biologics are used (45,47,48). These findings suggest that eosinophilia can serve as a biomarker for response to biologics.

3．Topics in Blood Eosinophils

A．Phenotype of eosinophils

Inflammatory eosinophils (iEOS) are distinct from the regulatory eosinophil subset, resident eosinophils (rEOS). Although iEOS enhance inflammation, rEOS may have key homeostatic functions. Therefore, the above discrepancies may also be due to differences in the ratio of eosinophil phenotypes between the stable and acute phases (49). However, data on eosinophil phenotypes have mainly originated from mouse studies, and the concept has not been confirmed in humans.

B．ETosis in airway eosinophils

Active cytolytic eosinophil degranulation and cytolytic cell death in the airway have attracted increasing attention. This phenomenon releases eosinophil extracellular chromatin to form DNA via a cytolytic extracellular trap cell death (ETosis) (50). Airway eosinophil ETosis (EETosis) is closely associated with Charcot-Leyden crystal (CLC) formation (51) which contains galectin-10 as a protein component. Extracellular crystallization of galectin-10 is speculated to occur, leading to exacerbation of airway mucus secretion (52).

Conclusion

Eosinophils exhibit pleiotropy and heterogeneity and can be associated with various clinical outcomes, such as a pulmonary function decline, exacerbation, all-cause mortality, and treatment response, in asthma and COPD. In summary, blood eosinophils can serve as surrogate markers for eosinophilic airway inflammation and easily accessible inflammatory biomarkers in asthma and COPD (Fig. 2A). Therefore, the measurement of blood eosinophils may help improve medical efficiency in the management of asthma and COPD (Fig. 2B).

Figure 2.

(A) The phenotypic diagnosis based on blood eosinophils. (B) Predicting the effect of targeted treatment by the blood eosinophil phenotype. The clinical outcomes of diseases can be improved by targeted therapy based on the eosinophilic phenotype of asthma and COPD. Dotted and solid lines depict the time course of clinical outcomes, such as the pulmonary function decline, exacerbations, mortality, and treatment response, by each strategy. Dotted lines: Eosinophils target therapy in eosinophilic phenotype of asthma and COPD, Solid lines: No eosinophils target therapy in eosinophilic phenotype of asthma and COPD.

The authors state that they have no Conflict of Interest (COI).