Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality worldwide [1]. The abnormalities of the airway and/or alveoli in COPD are caused by chronic inflammation which is usually mediated by neutrophils, cytotoxic CD8+ T-lymphocytes, and CD68+ monocytes/macrophages [2]. Eosinophils are important mediators of inflammation in asthma, and the eosinophil count has been used to differentiate between asthma and COPD [3]. On the other hand, in some patients with COPD, eosinophils seem to play a significant role in airway and parenchymal inflammation [4,5]. Studies have indicated that approximately a third of stable COPD patients have evidence of eosinophilic inflammation [6,7]. Patients with COPD who demonstrate peripheral blood eosinophilia respond favorably to systemic corticosteroids for the treatment of exacerbation. Additionally, inhaled corticosteroids (ICSs) are more effective in the prevention of acute exacerbation of COPD (AECOPD) in the aforementioned patients [8]. However, ICSs are also associated with side effects, such as dysphonia, candidiasis, and a small increase in the frequency of pneumonia [9]. In particular, the increase in the risk of pneumonia is a burden to patients with COPD, because their risk of pneumonia is higher than that of the general population [10]. On the other hand, a large retrospective study demonstrated that COPD patients with a blood eosinophil count of ≥2% had slightly fewer episodes of pneumonia than those with less than 2% of eosinophilia, regardless of ICS treatment [11]. The authors speculated that the antimicrobial defense role of eosinophils might have helped clear the lungs of infections, before progressing to pneumonia. In contrast, another study showed that in individuals with COPD and forced expiratory volume in 1 second (FEV₁) <50%, eosinophil count ≥0.34×10⁹ cells/L was associated with high risk of hospitalization due to pneumonia [12]. The role of eosinophils in the development and progression of pneumonia in patients with COPD requires further elucidation.

We performed a post hoc analysis of a prospective, multi-center, cohort study conducted at seven university-affiliated hospitals to define the serotype-specific prevalence of pneumococcal pneumonia. We evaluated the differences in clinical characteristics of COPD patients with and without eosinophilia, all of whom were hospitalized for the treatment of community-acquired pneumonia (CAP).

COPD is the comorbid condition that is associated with the highest incidence of hospitalization due to CAP (8.9 times higher than the control) [17]. In the present study, we evaluated the differences in the clinical characteristics of patients with COPD who were hospitalized because of CAP depending on the presence of eosinophilia. We performed a post hoc analysis of a prospective, multi-center, cohort study that we had previously conducted at seven university-affiliated hospitals to define the serotype-specific prevalence of pneumococcal pneumonia [14].

We observed a significant difference in some clinical features of pneumonia, depending on the presence of eosinophilia. The percentile of sputum culture was lower in eosinophilic patients, than in those without eosinophilia (Table 2). The sputum gram stain and culture is one of the most important diagnostic tools for the identification of pathogens in CAP. Among other factors, the burden of pathogens influences positive results for sputum culture [18]. The difference in the sputum culture rate between patients with and without eosinophilia, at least in part, could have derived from the clearing effect of infecting pathogens by eosinophils. The decreased burden of infectious pathogens in eosinophilic patients was reflected in the lowering of pneumonia severity and acute-phase reactants. Patients with eosinophilia showed lower PSI scores, lower neutrophil percentiles, and lower CRP levels, than those without eosinophilia (Table 2). The duration of antibiotic treatment and hospitalization were shorter in eosinophilic patients than for those without eosinophilia. Additionally, the cost of care was lower for patients with eosinophilia. The cost of medical care per day, cost of medication, and cost of examination were lower in eosinophilic patients (Table 2). As a major cause of morbidity and mortality worldwide, CAP is associated with excessive health-care consumption and cost. To the best of our knowledge, the present study is the first to provide information regarding the benefits of eosinophilia in terms of healthcare utilization and the cost of medical care in patients with COPD hospitalized for CAP.

No significant difference was identified in the clinical characteristics of COPD between patients with and without eosinophilia, including CAT, mMRC scores, and the number of acute exacerbations within 1 year. We expected patients with COPD and eosinophilia to use ICS more frequently than those without eosinophilia because COPD patients with eosinophilia (blood eosinophils ≥300/µL) experience frequent exacerbation, which requires ICS inhalation [19,20]. The percentile of patients with frequent exacerbation (≥2 within a year) did not differ between patients with and without eosinophilia, which might explain the lack of difference in ICS usage between the two groups (Table 1).

In large clinical trials for the treatment of COPD, GOLD groups B and D comprised the majority of patients [19,21]. In accordance, GOLD COPD group B was the most common, followed by group D in the present study (Table 1). Patients with CAP with PSI class III or higher are usually recommended for hospitalization [22]. In our study, most of the participants were classified as PSI class III or higher (Table 2). Thus, the COPD with CAP population in the present study can be considered representative of a real-world, standard population.

Eosinophils are white blood cells of the granulocytic lineage, and are involved in a wide array of host immune responses to infection, tissue remodeling, and the maintenance of other immune cells [23,24]. Although a high level of eosinophils (≥1,500/µL) can damage tissues, an adequate level of eosinophils is important for protection against infection [25]. For example, eosinophils behaved as a protective cell in patients with ventilator-associated pneumonia caused by Staphylococcus aureus [26]. Bacterial pneumonia is usually accompanied by an eosinopenic response, partly due to the activation of endogenous glucocorticoid production. For this reason, eosinopenia was suggested to be a good diagnostic marker for distinguishing between non-infection and infection [27]. In addition, eosinopenia was a reliable marker of severe disease and unfavorable outcome in pneumonia associated with SARS-CoV-2 and in hospitalized AECOPD patients with CAP [28,29]. The authors suggested the eosinophil count at admission as a prognostic marker of mortality in pneumonia. This is consistent with our finding that eosinophilia was associated with the decrease in the severity of pneumonia and acute-phase reactants. No deaths were reported in patients with eosinophilia, compared to the 13 deaths in patients without eosinophilia, although a small number of patients with eosinophilia did not show statistical significance (Table 2).

The present study has some limitations. The percentage of eosinophils was used to define eosinophilia (≥300/µL). However, peripheral blood eosinophilia is better defined by the absolute eosinophil count, than by the percentage of eosinophils. In addition, although the minimum requirement number for analysis was achieved, the target number of 384 was not reached, due to the SARS-CoV-2 pandemic. About 51% of all patients received systemic corticosteroid during hospitalization for pneumonia, for 5 to 7 days, maybe for the treatment of accompanying AECOPD. Although the statistics of percentage and duration did not differ in statistics, the favorable outcome of pneumonia in eosinophilic patients may be, in part, related to the effect of systemic corticosteroid on the accompanying AECOPD. Lastly, we were unable to prove the beneficial effects of eosinophilia on the mortality rate, because this study was not able to compare mortality between eosinophilia and non-eosinophilia groups.

Despite these limitations, we were able to find that eosinophilia serves as a favorable marker in assessing the severity of pneumonia, health-utility consumption, and cost of care in hospitalized CAP patients with COPD.