Discussion
Our EMR-based observational study of inpatients with AECODP receiving corticosteroids treatment demonstrated that higher levels of blood eosinophils were significantly associated with a lower risk of corticosteroid treatment failure, and these associations persisted even after adjustment for other conventional risk factors. Moreover, eosinophils were associated with treatment failure among patients with different smoking status, indicating that smoking status did not modify the association between eosinophils and corticosteroid treatment failure.
Recently, level of blood eosinophils has emerged as a potential biomarker in patients with COPD, based on the observation that levels of blood eosinophils appear to be associated with subsequent risk for exacerbation and to predict the response to corticosteroids treatment in clinical trials.10 11 25 In some previous studies of patients with COPD, a cut-off value of 2% for blood eosinophils has been widely used to predict COPD exacerbations.13 26 We used the threshold of 2% and found that >44% of patients with higher eosinophils in AECOPD were hospitalised. Several studies have reported that elevated absolute blood eosinophil counts at stable COPD may be associated with a higher risk of exacerbation.11 27 In contrast, others also found higher levels of blood eosinophils have been associated with fewer infections and perhaps a better survival.28–31 Recently, there has been an increasing interest in investigating the association between blood eosinophils and response to corticosteroids treatment in patients with AECOPD,13 32 33 and some studies also have used blood eosinophils to guide corticosteroids treatment.13 32 34 A randomised clinical trial on antibiotic prescription based on C reactive protein levels versus the Global Initiative for Chronic Obstructive Lung Disease (GOLD)-guided strategy with 207 exacerbations in patients with AECOPD showed that higher blood eosinophils were associated with higher short-term treatment success rates.9 Another post hoc analysis found that patients with blood eosinophil counts >200 cells/μL had a lower reduction in exacerbation rate.35 In this study using a relatively large sample of Chinese population, it was confirmed that elevated levels of blood eosinophils were significantly associated with 26% reductions in the risk of treatment failure.
In healthy smokers, antioxidant defences would be activated to protect against oxidative stress caused by smoke. Patients with COPD are unable to resist oxidative stress and, as a result, develop a resistance to corticosteroids.36 This theory might imply that quitting smoking would restore steroid responsiveness, however, studies have shown that even patients with COPD who stop smoking fail to respond to corticosteroids.16 This may be due to persistent oxidative stress from irreversible airway inflammation.37 A clinical meta-analysis of seven studies found that former smokers with COPD who were treated with inhaled corticosteroids showed greater improvements in lung function and fewer exacerbations than current smokers with COPD.17 There is a possibility that this is the result of corticosteroid resistance caused by smoking. However, a post hoc analysis of the Groningen Leiden Universities Corticosteroids in Obstructive Lung Disease (GLUCOLD) study, which included persistent smokers and former smokers, reported former smokers had less decline in lung function at 30 months.38 The results of this study indicated that cigarette smokers were more responsive to corticosteroids compared with former smokers. According to our study, there was no significant difference between smokers and non-smokers when it came to the association with treatment failure. Besides, a lower rate of treatment failure in current smokers was compared with former smokers and never smokers (23.3% vs 31.0%, 28.8%). This phenomenon might be explained by the ‘smoker’s paradox’.39 In one sense, the paradox is related to the sick-quitter effect, which is mainly caused by former smokers being in a sick and unhealthy physical state and having to give up smoking. Smoking patients, on the other hand, may be in better physical condition and may not passively choose to quit smoking due to their illness (online supplemental table 4). Furthermore, this study included hospitalised patients with AECOPD who were older (51.8% were >70 years of age), thus there may be a survivor bias in this study. It is possible for the bias created by these factors, to some extent, lead to a non-significant association between smoking and corticosteroid treatment failure, as well as the interaction between smoking and elevated blood eosinophils on the response to systematic corticosteroid therapy. Future prospective cohort studies or clinical trials are needed to confirm our findings.
Recently, a post hoc analysis of three RCTs has found that only eosinophil count and smoking status were independent predictors of response to budesonide in patients with COPD without asthma history, with the greatest benefit of corticosteroids treatment seen in current smokers with higher blood eosinophil.40 Compared with RCT studies, our real-world study included a broader population with a diverse spectrum of patients with AECOPD. Different eligibility criteria might contribute to differences in results. A cohort study found an interaction between eosinophil and smoking status on COPD exacerbation risk.20 But eosinophil count was measured at stable COPD, which might explain the inconsistency with our results. In addition, smoking status was categorised differently, and the study outcomes are also different. We focused on in-hospital outcomes and short-term exacerbation readmission (30-day), not on 1-year exacerbation risk. Some of the differences inevitably result from variability in eosinophil count, which is an inherent limitation of single measurement. Another real-world observational study conducted in 1290 Chinese patients admitted for AECOPD found that the hospitalisation time following treatment with systemic corticosteroids was shorter in patients with eosinophilia than patients without eosinophilia with smoking history (median 8 vs 9 days, p=0.046), and the results were similar between the two groups in patients without smoking history (p=0.376).41 Another substudy analysis of the Corticosteroid Reduction in COPD (CORTICO-COP) RCT showed that smoking status did not influence the role of eosinophils as a biomarker in guiding corticosteroid treatment.19 However, the small sample size (n=318) may have been insufficient to power the statistical analysis. Similarly, our study based on a real-world setting observed that regardless of smoking, higher levels of eosinophils reduced the risk of corticosteroid treatment failure. And there was no interaction between smoking and eosinophils on corticosteroids treatment. We also found a lower risk of corticosteroid treatment failure in patients receiving inhaled combined systemic corticosteroids, compared with only inhaled corticosteroids. It can thus be suggested that patients with eosinophilic AECOPD might benefit more from systemic corticosteroid treatment, regardless of whether they smoke. The mechanisms behind the complex interaction between active smoking and corticosteroid benefit remain unclear, and further research is needed to elucidate them.
The study has several key strengths. First, the present study assessed the interaction effect of smoking status with blood eosinophils on the effectiveness of systematic corticosteroid among inpatients with AECOPD. It provides the first evidence that higher eosinophil levels are associated with a lower risk of treatment failure, regardless of smoking, and thus smoking does not modify the association between higher eosinophil levels and better response to corticosteroids. Second, this study was of a ‘real-life’ nature, which made it more relevant to clinical management of patients with AECOPD. Third, we have adjusted for available confounding factors, such as age, gender, CCI, number of AECOPD hospitalisations in the previous year, white blood cell count and antibiotic usage, to ensure the reliability of the results.
This study also has some limitations. First, although potential risk factors were adjusted for, we still cannot exclude the unavailable confounding factors which were not analysed in our study, such as socioeconomic status, exacerbation severity and pharmaceutical treatments, thus might bias our results to some extent. Second, lung function data before AECOPD hospitalisation was not available due to the retrospective nature of this study. In addition, the study population consisted mainly of elderly patients (mean age: 71.0 years), with only a limited number of patients (<10%) undergoing spirometry either during hospitalisation or at discharge. Third, the smoking status was collected from medical records and patient recall bias42 may have biased the observed associations. Fourth, blood levels of eosinophils have variability,43 but we only used the eosinophil count at admission. However, it is clinically unfeasible to measure peripheral blood eosinophils a few times before deciding whether corticosteroid therapy should be administered. In such cases, patients may miss the ideal timing to start corticosteroids treatment. Finally, this study used data from one of the top medical institutions in China that specialises in respiratory diseases, representing the highest standard of medical treatment for patients with AECOPD, enabling us to conduct this real-world study to assess the effectiveness of corticosteroid therapy. Nevertheless, it should be noted that our results and conclusions may not necessarily be representative of other hospital populations or generalisable to other levels of hospitals or regions. Further studies involving RCTs and prospective cohorts are necessary to confirm our findings.