Sputum and Blood Eosinophilia Level of Patient With Chroni̇c Obstructive Pulmonary Disease (Copd) Exacerbation in Hospitalized

Sputum and Blood Eosinophilia Level of Patient With Chroni̇c Obstructive Pulmonary Disease (Copd) Exacerbation in Hospitalized | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Sputum and Blood Eosinophilia Level of Patient With Chroni̇c Obstructive Pulmonary Disease (Copd) Exacerbation in Hospitalized ozge gokturk, mecıt suerdem, baykal tulek, fikret kanat, burcu yormaz, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4693402/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Chronic obstructive pulmonary disease (COPD) is a common respiratory condition characterised by persistent airflow limitation and frequent exacerbations. In patients with COPD exacerbations, whether steroid therapy should be administered via inhalation or the systemic route remains unclear. To address this, we aimed to evaluate the response of sputum and blood eosinophil counts to systemic and inhaled steroids in hospitalised patients with COPD exacerbation. Our study included 58 patients hospitalised at a chest disease clinic for the treatment of COPD exacerbation. Upon admission, pre-induced sputum samples were collected. Patients were then randomly assigned to receive either intravenous methylprednisolone (40 mg/day) as a single daily dose in addition to standard exacerbation treatment (n=29) or budesonide (0.50 mg) via nebulisation at 12-h intervals for 7 days (n=29). Sputum haemograms and eosinophils were evaluated on the 14th and 45th days of treatment. In patients receiving intravenous steroid treatment, sputum eosinophil percentages were significantly reduced on days 14 (0.36±0.72) and 45 (0.28±0.53) compared to those at baseline (0.86±1.22) (p=0.041). Although decreases in the percentage of eosinophils in sputum, eosinophil count, and percentage in blood were observed on the 14th and 45th days compared to baseline values in patients receiving inhaled steroid treatment, these changes were not statistically significant (p>0.05). Adding systemic steroids to the treatment of severe COPD exacerbations is a rational approach. Further studies with longer follow-up periods are needed to determine the role of eosinophil levels in the blood and sputum as a marker for deciding on intravenous and inhaled steroid treatments. sputum eosinophilia blood eosinophilia COPD exacerbation steroid responsiveness Figures Figure 1 Figure 2 Figure 3 Introduction Chronic obstructive pulmonary disease (COPD) is heterogeneous and characterised by chronic respiratory symptoms (dyspnoea, cough, and sputum) as well as persistent and often progressive airway obstruction caused by airway (bronchitis/bronchiolitis) or alveolar (emphysema) abnormalities [1]. Some patients with COPD experience inflammatory involvement, characterised by increased eosinophil counts and ILC2 cell levels, similar to those seen in asthma [2]. Inhaled corticosteroids (ICSs) reportedly reduce exacerbation frequencies, improve quality of life, and reduce mortality in patients with COPD with a history of exacerbations [3,4]. Landis et al. reported that a blood eosinophil count of ≥300 cells/µL may help in identifying patients with COPD at higher risk of exacerbation and more likely to benefit from ICS treatment [5]. The relationship between the blood eosinophil count and effect of ICSs was examined in a review conducted by Singh et al. in 2022. The review found that ICSs had little or no effect in patients with lower blood eosinophil counts, whereas a stronger association was observed in those with higher eosinophil counts [6]. Specifically, ICS regimens showed minimal or no effect in patients with blood eosinophil counts <100 cells/µL. This threshold can be used to identify patients unlikely to benefit from ICS treatment [7]. Cohort studies have reported varying conclusions regarding the predictive value of blood eosinophil counts for future exacerbation risk. Some studies found no association, while others reported a positive association [5]. The relationship between the decrease in FEV1 and blood eosinophil count suggests that it may be used as a prognostic biomarker. A higher baseline blood eosinophil count (≥300 cells/µL) was associated with greater loss in FEV1 and increased exacerbation frequency after ICS discontinuation [8]. The reproducibility of blood eosinophil counts was considered reasonable [5]. Based on its ease of reproducibility, using a reproducible blood eosinophil count as a biomarker is recommended when deciding to add ICSs to bronchodilator therapy in conjunction with clinical evaluation. Recent literature underscores the prognostic value of eosinophil counts in the bloodstream of patients with COPD. Cui and Chen [9] provided compelling evidence that elevated blood eosinophil levels can serve as a robust biomarker for determining the severity of exacerbations and for guiding the customisation of treatment plans. The study suggested that individuals with higher eosinophil counts are more likely to benefit from targeted anti-inflammatory treatment, particularly when involving corticosteroid therapy [9]. The distinction between inhaled and intravenous corticosteroids is particularly crucial in this context. ICSs are primarily used to manage chronic inflammation and prevent frequent exacerbations. They deliver medication directly to the lungs, minimising systemic side effects compared to systemic corticosteroids. In contrast, systemic corticosteroids, which can be administered orally or intravenously, are generally reserved for acute management of exacerbations owing to their potent, rapid anti-inflammatory effects. Pearce et al. [10] explored the efficacy of combining systemic corticosteroids with ICSs in COPD exacerbation management. Their study confirmed that such a combination is particularly beneficial in patients with eosinophilic profiles, as it can enhance therapeutic outcomes by leveraging the anti-inflammatory properties of both the systemic and localised steroid pathways [10]. Discussions in The Lancet Respiratory Medicine highlighted the concept of blood eosinophil-guided therapy as a significant advancement in the personalised treatment of COPD exacerbations. This approach involves adjusting the dosage and type of corticosteroids based on real-time eosinophil counts, thereby optimising therapeutic efficacy and reducing the likelihood of adverse effects. This method promises to both enhance patient quality of life and decrease healthcare expenditures by reducing hospital readmissions and the duration of hospitalisation [11]. Exacerbations with increased sputum or blood eosinophil counts reportedly respond better to systemic steroids. However, further studies are warranted [12]. In this study, we aimed to investigate the effect of the treatment process on eosinophilic inflammation in the blood and sputum of patients hospitalised for COPD exacerbations who were treated with intravenous steroids (methylprednisolone 40 mg once daily) or inhaled steroids (budesonide 0.5 mg twice daily) for 7 days. Monitoring eosinophil counts as potential biomarkers for COPD exacerbations was a primary focus. Our investigation explored changes in eosinophil levels in both the blood and sputum among hospitalised patients with COPD undergoing steroid therapy, aiming to identify prospective biomarkers for assessing the treatment response and practical applications. We also aimed to address the issue of inhalation or intravenous administration of steroid therapy in patients with COPD exacerbation. Materials and methods Study design Between 6 February 2019 and 30 January 2020, a total of 58 patients were admitted to the Chest Diseases Clinic of Selçuk University Faculty of Medicine in Konya, Turkey, for treatment of COPD exacerbation. These patients were enrolled in a study to evaluate the efficacy of steroid treatments after meticulous selection based on the study's inclusion and exclusion criteria. The participants were divided into two groups: 29 received inhaled steroids and 29 received intravenous steroids. Blood and induced sputum samples were collected at baseline, and again on the 14th and 45th days of treatment for analysis. Using 3% hypertonic saline delivered through an ultrasonic nebuliser, induced sputum was collected and sent to the pathology laboratory where pathological smears were performed. The analyses included evaluating the percentage and counts of eosinophils in both the sputum and blood, along with haemogram values. The study protocol received approval from the Ethics Committee of Selçuk University Faculty of Medicine on 6 February 2019 (decision number, 2019/68), adhering to the Declaration of Helsinki principles. All participants were fully informed about the study details and provided written informed consent as per the ethical guidelines set by the Committee. This observational study initially evaluated 253 patients admitted to the Chest Diseases Clinic of Selçuk University Faculty of Medicine, with an aim to investigate the outcomes of COPD exacerbation interventions. Regarding screening and eligibility, upon admission, all 253 patients were preliminarily assessed for eligibility based on their diagnosis of COPD exacerbation. For detailed eligibility assessment , subsequent to the initial screening, a thorough review of medical histories and current health evaluations was conducted. Of the initial cohort, 238 patients met the preliminary inclusion criteria. F urther rigorous assessments, including necessary laboratory tests and physical examinations, resulted in 83 patients being confirmed as eligible. These patients consented to participate and were enrolled in the study. T hroughout the study, comprehensive follow-up was executed to monitor patient outcomes post-intervention. Of the enrolled participants, 58 successfully completed the entire follow-up protocol as designed. Attrition included 15 participants who withdrew from the study for various reasons, and 10 were excluded from the final analysis because of non-adherence to the intervention protocol or other exclusion criteria. T he final analysis was conducted on the dataset comprising the 58 patients who completed the follow-up. Inclusion criteria for the study We included patients aged over 40 years who were hospitalised because of COPD exacerbation, irrespective of whether they had comorbidities, such as hypertension or heart failure. Exclusion criteria for the study We excluded patients with a previous asthma diagnosis, radiologically diagnosed pneumonia, diabetes mellitus, and organ malignancies. We also excluded patients who were immunocompromised, those receiving immunosuppressive therapy, and those who had received systemic or inhaled steroid therapy in the previous month. Study procedure Within the first 1 hour of admission, the patients were nebulized with a beta-2 agonist (salbutamol), followed by inhalation of 20 cc of 0.9% saline with an ultrasonic nebulizer (Otiflex, Kormed Co. Ltd., Seoul, South Korea), and their sputum was obtained. Nebulization was continued for at least 10 minutes. After 15 minutes or when at least 2 mL of quality sputum sample was obtained, nebulization was stopped. If a sufficient sputum sample could not be obtained, this procedure was repeated up to twice at a 0.5-hour interval. If at least 2 mL of good-quality sputum was not expectorated after three attempts, the procedure was terminated. These procedures were repeated on the 14th and 45th days of treatment. Sputum samples were sent to the pathology laboratory for eosinophil analysis. The baseline haemogram value, routinely checked in the first 1 hour of hospitalisation, was rechecked on days 14 and 45. Following induced sputum collection, 29 patients received intravenous methylprednisolone (40 mg/day) as a single daily dose in addition to standard exacerbation treatment for 7 days. The remaining 29 patients received budesonide (0.50 mg) via nebulization at 12-hour intervals for 7 days. After discharge, inhaled steroids were not used in the maintenance treatment of patients, and their treatment was limited to long-acting bronchodilators. For pathological smear evaluation, 5 cc of an alcohol-based red solution was added to the induced sputum samples to fix and remove erythrocytes. After centrifugation to separate the supernatant, the sample was placed in a BD Prepstain automatic staining machine (BD, Franklin Lakes, NJ, USA). The sputum samples were stained with Papanicolaou using the Prepstain Slide Processor Slide Stainer (TRIPATH, Hologic Inc., Marlborough, MA, USA). Microscope slides were prepared, and the ratio of eosinophils to the total number of cells was calculated by examining at least 10 fields at 400× magnification using a light microscope. Statistical analyses All statistical analyses were performed using R 3.6.0 (www.r-project.com). Data are presented as mean ± standard deviation, number (n), and percentage (%). Before the analyses, the normality of the data was assessed using the Anderson–Darling normality test. Student t-tests were used for numerical variables, while Yates and Fisher’s exact chi-square tests were used for categorical variables to analyse the demographic characteristics of the patients. The Friedman test was used to evaluate the steroid groups based on the measurement times. The Nemenyi multiple comparison test was used to identify significant groups. Results are illustrated with graphs. Statistical significance was set at p<00.5. Results This study included 58 patients hospitalised for COPD exacerbations. The patients were divided into two groups: 29 patients receiving inhaled steroid treatment and 29 patients receiving intravenous steroid treatment. Table 1 presents the demographic characteristics of the patients. The mean age of patients receiving inhaled steroid treatment was 64.34±8.57 years and 68.17±9.30 years in the group receiving intravenous steroid treatment. Male patients comprised 55.2% of inhaled steroid recipients and 48.3% of intravenous steroid recipients. No statistically significant differences were observed between the two groups in terms of mean age or sex. The body mass index (BMI) in the inhaled steroid treatment group was 29.41±7.82 and 31.86±8.98 in the intravenous steroid treatment group, with no statistically significant differences. Similarly, no significant differences were observed between the two groups in terms of cigarette smoking (packs/year) or biofuel exposure (years). Table 2 shows the percentage of eosinophils in the sputum and blood as well as the eosinophil count in the blood at baseline and on days 14 and 45 of treatment. Figures 1, 2, and 3 visualise the findings in columnar graphs. In patients receiving inhaled and intravenous steroid treatment, decreases in the percentage of eosinophils in the sputum and eosinophil count and percentage in the blood were observed on the 14th and 45th days compared to the baseline values. The decreases were particularly prominent on day 14. Although the percentage of eosinophils in the sputum and percentage and count of eosinophils in the blood decreased in absolute values on days 14 and 45 compared to baseline in patients receiving inhaled steroid treatment, no statistically significant change was found. In patients receiving intravenous steroid treatment, although all values decreased compared with those at baseline, only the percentage of eosinophils in the sputum showed a statistically significant decrease on the 14th and 45th days of treatment (p=0.041). Discussion COPD is a common respiratory condition characterised by persistent airflow limitation and frequent exacerbations. In patients with COPD exacerbations, the optimal route for administering steroid therapy—whether by inhalation or systemically—remains unclear. To address this, we aimed to evaluate the response of sputum and blood eosinophil counts to systemic and inhaled steroids in hospitalised patients with COPD exacerbation. In patients receiving intravenous steroid treatment, all values decreased compared to baseline; however, only the percentage of eosinophils in the sputum showed a statistically significant decrease on the 14th and 45th days of treatment. Systemic steroid treatment significantly decreased the percentage of sputum eosinophils. Although up to 40% of patients with COPD exhibit eosinophilic airway inflammation and systemic eosinophilia, the role of eosinophils in COPD pathophysiology remains inadequately understood. High sputum and blood eosinophil levels in patients with stable COPD are considered markers of high mortality and increased risk of frequent exacerbations. Epidemiological studies have demonstrated that circulating eosinophils significantly impact COPD outcomes [13]. In two extensive studies with over 30 years of follow-up, eosinophilia (blood eosinophils >275 cells/μL) increased the risk of all-cause mortality independent of age, sex, smoking, and lung function [14]. Another epidemiological study (Copenhagen General Population Study) reported an increased risk of all exacerbations, regardless of severity, with over two-fold increase in the risk of severe exacerbations at blood eosinophil levels >340 cells/μL [14]. Eosinophils may increase airway biopsies and sputum during COPD exacerbations [15]. In COPD exacerbations, blood eosinophil counts can help predict the clinical course, risk of rehospitalisation, length of hospitalisation, response to steroids, and mortality risk. A blood eosinophil count ≥2% increases the risk of all-cause rehospitalisation by 2.3 times and the risk of COPD-related rehospitalisation by 3.5 times [16]. Additionally, the blood eosinophil count is reportedly an independent predictor of mortality in COPD exacerbation [17]. A blood eosinophil count <50 cells/μL during the exacerbation period has been associated with prolonged hospitalisation and a threefold increase in mortality risk [17]. Sputum eosinophilia has long been recognised as a biomarker of the clinical benefit of systemic steroid therapy in patients with stable COPD [18], showing improvements in lung function, symptom reduction, and increased exercise capacity. A treatment approach targeting the reduction of sputum eosinophil counts with systemic steroid therapy has been shown to be beneficial in reducing symptoms and severe COPD exacerbations that require hospitalisation [19]. Patients with high sputum eosinophil counts showed decreased sputum eosinophil levels and significantly improved quality-of-life scores post-systemic steroid treatment [20]. Similar studies have shown that patients with high sputum eosinophil counts responded favourably to systemic steroid treatment [21]. These results highlight the efficacy of eosinophil-targeted systemic steroids in patients with COPD with an eosinophilic phenotype, suggesting that measuring the sputum eosinophil counts may help identify patients with COPD who have steroid-sensitive disease and guide treatment decisions. Similar to systemic steroid therapy, inhaled steroid therapy in patients with stable COPD and eosinophilic inflammation improves lung function, reduces exacerbations, and lowers sputum eosinophil counts [22]. In a study, patients with stable COPD and elevated blood eosinophil counts had reduced exacerbation rates when treated with inhaled steroids [23]. Brightling et al. demonstrated that in patients with stable COPD and sputum eosinophilia, high-dose inhaled mometasone treatment improved lung function without affecting sputum eosinophilia [18]. A meta-analysis suggested that inhaled steroid treatment may reduce sputum eosinophil counts in patients with stable COPD [24]. Barnes et al. reported that an inhaled salmeterol/fluticasone propionate combination reduced sputum eosinophil counts in patients with stable COPD [25]. Unfortunately, we did not have data on the sputum and blood eosinophil levels of our patients in the stable period, preventing us from comparing these levels with those during exacerbation. We were also unable to compare the eosinophil levels on days 14 and 45 post-exacerbation with the pre-exacerbation eosinophil levels, limiting our ability to assess the treatment’s effects on eosinophils during the stable period. Eosinophilic COPD exacerbations respond more rapidly to systemic steroid therapy than non-eosinophilic exacerbations, and treatment success is higher [4]. A similar finding was reported in a study comparing the prednisolone and placebo effects on eosinophilic exacerbations [26]. Treatment failure was significantly lower in the systemic steroid group compared to the placebo group (11% and 66%, respectively). However, there is no consensus on the optimal threshold for circulating eosinophil counts to guide systemic steroid therapy. A blood eosinophil value ≥2% during exacerbation is generally considered beneficial for oral steroid therapy [27]. Elevated sputum and blood eosinophil levels are considered good biomarkers for a favourable clinical response to steroid treatment during exacerbation, as well as in stable patients [28]. Current guidelines recommend short-term systemic steroid therapy for all severe COPD exacerbations, regardless of the eosinophilic phenotype [1]. However, for a more individualised treatment approach, systemic steroid treatment may be considered a more rational approach only for exacerbations with high blood eosinophil counts. The use of high-dose nebulised steroids has been suggested as an alternative to systemic steroid therapy for treating exacerbations [29]. In this case, high doses of nebulised steroids can be used for non-eosinophilic COPD exacerbations to achieve optimal clinical outcomes and avoid the side effects of systemic steroids. Günen et al. compared the efficacy of nebulised bronchodilator therapy with that of intravenous steroid therapy in 159 patients with COPD hospitalised for exacerbation [29]. Patients were divided into three groups: standard bronchodilator therapy, intravenous steroids (40 mg/day prednisolone), and nebulised budesonide (1,500 mcg twice daily) for 10 days. Arterial blood gas and pulmonary function test results improved rapidly in the second and third groups. No significant difference was observed in efficacy between patients receiving nebulised budesonide and those receiving intravenous steroid treatment. A similar study was conducted by Mirici et al. [30]. Forty patients with COPD hospitalised for moderate-to-severe exacerbations received nebulised budesonide (8 mg/day) or intravenous prednisolone (40 mg/day). The improvements in arterial blood gases and pulmonary function test results were comparable between the groups. These two studies indicated that high-dose nebulised steroid therapy could be a viable alternative to systemic steroid therapy in patients hospitalised for COPD exacerbation. Good clinical responses can be obtained with inhaled steroid therapy in patients with exacerbated COPD and high eosinophil counts in the blood and sputum. However, no significant decrease in the blood eosinophil count was observed in patients receiving inhaled steroid therapy for COPD exacerbation [31]. Bathoorn showed that inhaled steroid and beta-2 agonist combination therapy reduced sputum eosinophil counts during COPD exacerbation [32]. In their study, 45 patients with COPD exacerbation were treated with budesonide/formoterol (320/9 mcg four times daily), prednisolone (30 mg/day), or placebo for 14 days as outpatients. The primary endpoint of this study was to determine the efficacy on sputum eosinophil levels. Budesonide/formoterol (-57%) and prednisolone (-58%) significantly reduced sputum eosinophil counts compared to the placebo (+24%) (p = 0.01). Significant improvement in symptoms was also observed in steroid-treated patients. In the FLAME (Effect of Indacaterol Glycopyrronium and Fluticasone/Salmeterol in COPD Exacerbations) study, inhaled steroid use in patients with stable COPD did not reduce blood eosinophil levels and even increased it [33]. Similarly, in a retrospective analysis of 751 patients from the ISOLDE (Inhaled Steroids in Obstructive Lung Disease in Europe) study, inhaled steroid treatment did not change blood eosinophil levels [34]. In our study, while the blood eosinophil count and percentage decreased after inhaled steroid treatment compared to the baseline, there was a minimal increase at the 45th-day control compared to the 14th-day value. However, whether steroid treatment provides clinical benefits by reducing blood and sputum eosinophil counts remains unclear. In the study of COPD exacerbations, systemic inflammation markers such as C-reactive protein (CRP), neutrophils, and neutrophil-to-lymphocyte ratio (NLR) are crucial for understanding the underlying inflammatory processes. Elevated CRP levels have been associated with a significantly higher mortality risk in patients with COPD, underscoring its potential role in patient management and risk assessment [35]. Neutrophils, essential for bacterial clearance, are known to be dysfunctionally activated in COPD, contributing to tissue damage and exacerbation severity [36]. Similarly, an increased NLR has been correlated with adverse outcomes, suggesting its utility as a prognostic indicator [37]. Beyond these markers, the role of other mediators such as interleukins (IL-6, IL-8), tumour necrosis factor-alpha (TNF-α), and arginase activity also merit attention. IL-6 and IL-8 are potent mediators of inflammation, often elevated during COPD exacerbations and linked with disease progression and exacerbation severity [36]. TNF-α is another cytokine involved in systemic inflammation and has been associated with more severe health outcomes in patients with COPD [35]. Moreover, arginase activity, which modulates nitric oxide metabolism and airway remodelling, is elevated in exacerbated phases of COPD, contributing further to the inflammatory milieu [38]. Considering these multifaceted aspects, future research should incorporate these diverse inflammatory markers to provide a more comprehensive understanding of the inflammatory pathways in COPD exacerbations. Such studies could potentially lead to more targeted therapeutic strategies, improving management and outcomes for patients with COPD. The limitations of this study include the small sample size, lack of examination of inflammatory parameters other than eosinophils, and absence of pulmonary function tests. Re-exacerbation and mortality rates could have been evaluated within a 6-month or 1-year follow-up, but time constraints prevented this. However, as a continuation of the study, long-term follow-up is planned by contacting patients or their relatives via telephone. The absence of pulmonary function tests in this study represents a significant gap in the assessment of COPD exacerbation severity and its correlation with eosinophil levels. Pulmonary function tests, such as spirometry, provide essential information about lung capacity and airflow limitation, which are crucial for accurately diagnosing the severity of COPD exacerbations. The inclusion of these tests in future studies could enhance the clinical relevance of inflammatory markers by allowing researchers to directly correlate changes in eosinophil levels with functional respiratory outcomes. In conclusion, we assessed the effects of intravenous and inhaled steroids on sputum and blood eosinophil counts in patients hospitalised for severe COPD exacerbations. Our findings indicate that systemic steroid treatment significantly reduces sputum eosinophil counts, suggesting a potential therapeutic benefit in the management of severe COPD exacerbations by targeting eosinophilic inflammation. However, it is critical to acknowledge the limitations of our study, such as its confined hospital setting and the potential for variations in patient response to steroids, which could influence the generalisability of the results. Additionally, the short-term nature of the study restricts our ability to predict long-term outcomes. For clinical practice, we recommend measuring eosinophil levels in patients experiencing severe COPD exacerbations as a routine component of the diagnostic process. This approach can help determine the suitability of systemic steroid therapy, especially in patients with marked eosinophilia. Regular monitoring of eosinophil levels could provide insights into the efficacy of treatment and help in adjusting therapeutic strategies accordingly. Prospective longitudinal studies are necessary to further evaluate the role of eosinophil counts as a biomarker for systemic steroid efficacy in COPD management. Such research would provide deeper insights into the long-term benefits and optimise treatment protocols, enhancing overall patient care in severe COPD exacerbations. By integrating these recommendations, clinicians can make more informed decisions, potentially improving treatment outcomes for patients with severe COPD exacerbations. Declarations Acknowledgements The authors would like to thank all the participants who contributed to this study. We thank the laboratory staff for their technical support. Funding details The authors report no funding associated with the work featured in this article. Disclosure of interest The authors report there are no competing interests to declare. Data availability statement The authors confirm that the data supporting the findings of this study are available within the article. References Celli B, Fabbri L, Criner G, Martinez FJ, Mannino D, Vogelmeier C, et al. Definition and nomenclature of chronic obstructive pulmonary disease: time for its revision. Am J Respir Crit Care Med. 2022;206(11):1317–1325. doi: 10.1164/rccm.202204-0671PP. Kang J, Zheng J, Cai B, Wen F, Yao W, Zhang X, et al. Current situation of asthma–COPD overlap in Chinese patients older than 40 years with airflow limitation: a multicenter, cross-sectional, non-interventional study. 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Blood eosinophil guided prednisolone therapy for exacerbations of COPD: a further analysis. Eur Respir J. 2014;44(3):789–791. doi: 10.1183/09031936.00062614. Bafadhel M, Pavord ID, Russell REK. Eosinophils in COPD: just another biomarker? Lancet Respir Med. 2017;5(9):747–759. doi: 10.1016/S2213-2600(17)30217-5. Niewoehner DE, Erbland ML, Deupree RH, Collins D, Gross NJ, Light RW, et al. Effect of systemic glucocorticoids on exacerbations of chronic obstructive pulmonary disease. N Engl J Med. 1999;340(25):1941–1947. doi: 10.1056/NEJM199906243402502. Gunen H, Hacievliyagil SS, Yetkin O, Gulbas G, Mutlu LC, In E. The role of nebulised budesonide in the treatment of exacerbations of COPD. Eur Respir J. 2007;29(4):660–667. doi: 10.1183/09031936.00073506. Mirici A, Meral M, Akgun M. Comparison of the efficacy of nebulised budesonide with parenteral corticosteroids in the treatment of acute exacerbations of chronic obstructive pulmonary disease. Clin Drug Investig. 2003;23(1):55–62. doi: 10.2165/00044011-200323010-00007. Kerkhof M, Sonnappa S, Postma DS, Brusselle G, Agustí A, Anzueto A, et al. Blood eosinophil count and exacerbation risk in patients with COPD. Eur Respir J. 2017;50(1):1700761. doi: 10.1183/13993003.00761-2017. Bathoorn D. COPD exacerbations, inflammation and treatment. 2007. Roche N, Chapman KR, Vogelmeier CF, Herth FJF, Thach C, Fogel R, et al. Blood eosinophils and response to maintenance chronic obstructive pulmonary disease treatment. Data from the FLAME trial. Am J Respir Crit Care Med. 2017;195(9):1189–1197. doi: 10.1164/rccm.201701-0193OC. Burge PS, Calverley PM, Jones PW, Spencer S, Anderson JA, Maslen TK. Randomised, double blind, placebo controlled study of fluticasone propionate in patients with moderate to severe chronic obstructive pulmonary disease: the ISOLDE trial. BMJ. 2000;320(7245):1297–303. doi: 10.1136/bmj.320.7245.1297. Banerjee S, Khubchandani J, Onukogu C, Okpom C, Johnson, M. Elevated C-reactive protein and mortality risk among COPD patients . Egypt J Bronchol . 2024;18(1):38. doi: 10.2165/00044011-200323010-00007. Lonergan M, Dicker AJ, Crichton ML, Keir HR, Van Dyke MK, Mullerova H, et al. Blood neutrophil counts are associated with exacerbation frequency and mortality in COPD . Respir Res . 2020;21:1-10. doi: 10.1186/s12931-020-01514-7. Günay E, Sarınç Ulaşlı S, Akar O, Ahsen A, Günay S, Koyuncu T, et al. Neutrophil-to-lymphocyte ratio in chronic obstructive pulmonary disease: a retrospective study . Inflammation . 2014;37:374–380. doi: 10.1007/s10753-013-9746-1. Rodríguez-Guzmán MJ, Peces-Barba Romero G, Pérez Rial S, Serrano del Castillo C, Palomero Rodríguez MÁ, Mahillo-Fernandez I, et al. Elevated levels of arginase activity are related to inflammation in patients with COPD exacerbation . BMC Pulm Med . 2021;21(1):271. doi: 10.1186/s12890-021-01625-0. Tables Table 1: Demographic and clinical characteristics of the patients Inhaled steroid (n=29) Intravenous steroid (n=29) p Age (year) ( mean ± standard deviation’ ) 64.34 ± 8.57 68.17 ± 9.30 0.109 ŧ Sex 0.793 # Man (n, %) 16 (55.2) 14 (48.3) Woman (n, %) 13 (44.8) 15 (51.7) BMI 29.41 ± 7.82 31.86 ± 8.98 0.273 ŧ Smoker 0.430 # No (n, %) 13 (44.8) 17 (58.6) Yes (n, %) 16 (55.2) 12 (41.4) Biomass 0.595 # No (n, %) 18 (62.1) 15 (51.7) Yes (n, %) 11 (37.9) 14 (48.3) ŧ Mann–Whitney-U test # Yates ki-kare ǂ Fisher exact test BMI, body mass index Table 2: Baseline, 14th-day, and 45th-day eosinophil and p-values of patients receiving inhaled and intravenous steroid treatment Parameters Treatment Baseline 14th day 45th day P Values of eosinophil percentages in the sputum (%) Inhaled steroid 0.90 ± 2.02 0.41± 0.91 0.38± 0.78 0.230 Intravenous steroid 0.86±1.22 a 0.36±0.72 b 0.28±0.53 b 0.041 Values of blood eosinophil count (k/UL) Inhaled steroid 193.79±195.9 160.34±130.01 176.21±188.6 0.990 Intravenous steroid 124.48±153,0 123.79 ± 129.87 117.59±141.4 0.380 Values of eosinophil percentages in the blood (%) Inhaled steroid 2.20 ± 2.02 1.80 ± 1.42 2.17 ± 1.96 0.172 Intravenous steroid 2.50 ± 8.12 1.49 ± 1.60 1.58 ± 1.69 0.325 Additional Declarations No competing interests reported. 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16:09:19","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4693402/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4693402/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":65787275,"identity":"f04f7bf4-1204-4022-8d27-cef341ed8a54","added_by":"auto","created_at":"2024-10-02 16:38:56","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":105158,"visible":true,"origin":"","legend":"\u003cp\u003eValues of eosinophil percentages in the sputum in patients receiving intravenous and inhaled steroid therapy\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-4693402/v1/70ec8d629f5b00daa35d56ef.png"},{"id":65787273,"identity":"f64e9c27-9434-44d3-ba4f-561605408782","added_by":"auto","created_at":"2024-10-02 16:38:56","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":122859,"visible":true,"origin":"","legend":"\u003cp\u003eValues of blood eosinophil count in patients receiving intravenous and inhaled steroid therapy\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-4693402/v1/71e9ee2680cb50e396c64360.png"},{"id":65787276,"identity":"0028b297-abe2-49f0-9471-5d2b9ae50ec2","added_by":"auto","created_at":"2024-10-02 16:38:56","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":122132,"visible":true,"origin":"","legend":"\u003cp\u003eValues of eosinophil percentages in the blood in patients receiving intravenous and inhaled steroid therapy\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-4693402/v1/404df82493b966d57da3bf85.png"},{"id":93565933,"identity":"f2dfe18e-306e-497b-bd48-44374d5e4890","added_by":"auto","created_at":"2025-10-15 08:24:59","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1105486,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4693402/v1/8ab4351c-a715-41d9-932e-b79fb574f1b8.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"\u003cp\u003eSputum and Blood Eosinophilia Level of Patient With Chroni̇c Obstructive Pulmonary Disease (Copd) Exacerbation in Hospitalized\u003c/p\u003e","fulltext":[{"header":"Introduction","content":"\u003cp\u003eChronic obstructive pulmonary disease (COPD) is\u0026nbsp;heterogeneous and characterised by chronic respiratory symptoms (dyspnoea, cough,\u0026nbsp;and\u0026nbsp;sputum) as well as persistent and often progressive airway obstruction caused by airway (bronchitis/bronchiolitis) or alveolar (emphysema) abnormalities [1]. Some patients with COPD experience inflammatory involvement,\u0026nbsp;characterised by increased eosinophil counts and ILC2 cell levels, similar to those seen in asthma [2].\u003c/p\u003e\n\u003cp\u003eInhaled corticosteroids (ICSs) reportedly reduce exacerbation frequencies, improve quality of life,\u0026nbsp;and reduce mortality in patients with COPD with a history of exacerbations [3,4]. Landis et al. reported that a blood eosinophil count of \u0026ge;300 cells/\u0026micro;L may help in identifying patients with COPD at higher risk of exacerbation and more likely to benefit from ICS treatment [5].\u003c/p\u003e\n\u003cp\u003eThe relationship between the blood eosinophil count and effect of ICSs was examined in a review conducted by Singh et al. in 2022. The review found that ICSs had little or no effect in patients with lower blood eosinophil counts, whereas a stronger association was observed in those with higher eosinophil counts [6]. Specifically, ICS regimens showed minimal or no effect in patients with blood eosinophil counts \u0026lt;100 cells/\u0026micro;L. This threshold can be used to identify patients unlikely to benefit from ICS treatment [7].\u003c/p\u003e\n\u003cp\u003eCohort studies have reported varying conclusions regarding the predictive value of blood eosinophil counts for future exacerbation risk. Some studies found no association,\u0026nbsp;while others reported a positive association [5]. The relationship between the decrease in FEV1 and blood eosinophil count suggests that it may be used as a prognostic biomarker. A higher baseline blood eosinophil count (\u0026ge;300 cells/\u0026micro;L) was associated with greater loss in FEV1 and increased exacerbation frequency after ICS discontinuation [8]. The reproducibility of blood eosinophil counts\u0026nbsp;was considered reasonable [5]. Based on its ease of reproducibility, using\u0026nbsp;a\u0026nbsp;reproducible blood eosinophil count as a biomarker is recommended when deciding to add ICSs to bronchodilator therapy in conjunction with clinical evaluation.\u003c/p\u003e\n\u003cp\u003eRecent literature underscores the prognostic value of eosinophil counts in the bloodstream of patients with COPD. Cui and Chen [9] provided compelling evidence that elevated blood eosinophil levels can serve as a robust biomarker for determining the severity of exacerbations and for guiding the customisation of treatment plans. The study suggested that individuals with higher eosinophil counts are more likely to benefit from targeted anti-inflammatory treatment, particularly when involving corticosteroid therapy\u0026nbsp;[9].\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe distinction between inhaled and intravenous corticosteroids is particularly crucial in this context. ICSs are primarily used to manage chronic inflammation and prevent frequent exacerbations. They deliver medication directly to the lungs, minimising systemic side effects compared to systemic corticosteroids. In contrast, systemic corticosteroids, which can be administered orally or intravenously, are generally reserved for acute management of exacerbations owing to their potent, rapid anti-inflammatory effects. Pearce et al. [10] explored the efficacy of combining systemic corticosteroids with ICSs in COPD exacerbation management. Their study confirmed that such a combination is particularly beneficial in patients with eosinophilic profiles, as it can enhance therapeutic outcomes by leveraging the anti-inflammatory properties of both the systemic and localised steroid pathways [10].\u003c/p\u003e\n\u003cp\u003eDiscussions in \u003cem\u003eThe Lancet Respiratory Medicine\u003c/em\u003e highlighted the concept of blood eosinophil-guided therapy as a significant advancement in the personalised treatment of COPD exacerbations. This approach involves adjusting the dosage and type of corticosteroids based on real-time eosinophil counts, thereby optimising therapeutic efficacy and reducing the likelihood of adverse effects. This method promises to both enhance patient quality of life and decrease healthcare expenditures by reducing hospital readmissions and the duration of hospitalisation [11].\u003c/p\u003e\n\u003cp\u003eExacerbations with increased sputum or blood eosinophil counts reportedly respond better to systemic steroids. However, further studies are warranted [12]. In this study, we aimed to investigate the effect of the treatment process on eosinophilic inflammation in the blood and sputum of patients hospitalised for COPD exacerbations who were treated with intravenous steroids (methylprednisolone 40 mg once daily) or inhaled steroids (budesonide 0.5 mg twice daily) for 7 days. Monitoring eosinophil counts as potential biomarkers for COPD exacerbations was a primary focus. Our investigation explored changes in eosinophil levels in both the blood and sputum among hospitalised patients with COPD undergoing steroid therapy, aiming to identify prospective biomarkers for assessing the treatment response and practical applications. We also aimed to address the issue of inhalation or intravenous administration of steroid therapy in patients with COPD exacerbation.\u003c/p\u003e"},{"header":"Materials and methods","content":"\u003cp\u003e\u003cstrong\u003e\u003cem\u003eStudy design\u003c/em\u003e\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eBetween 6 February 2019 and 30 January 2020, a total of 58 patients were admitted to the Chest Diseases Clinic of Sel\u0026ccedil;uk University Faculty of Medicine in Konya, Turkey, for treatment of COPD exacerbation. These patients were enrolled in a study to evaluate the efficacy of steroid treatments after meticulous selection based on the study\u0026apos;s inclusion and exclusion criteria. The participants were divided into two groups: 29 received inhaled steroids and 29 received intravenous steroids. Blood and induced sputum samples were collected at baseline, and again on the 14th and 45th days of treatment for analysis. Using 3% hypertonic saline delivered through an ultrasonic nebuliser, induced sputum was collected and sent to the pathology laboratory where pathological smears were performed. The analyses included evaluating the percentage and counts of eosinophils in both the sputum and blood, along with haemogram values. The study protocol received approval from the Ethics Committee of Sel\u0026ccedil;uk University Faculty of Medicine on 6 February 2019 (decision number, 2019/68), adhering to the Declaration of Helsinki principles. All participants were fully informed about the study details and provided written informed consent as per the ethical guidelines set by the Committee.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThis observational study initially evaluated 253 patients admitted to the Chest Diseases Clinic of Sel\u0026ccedil;uk University Faculty of Medicine, with an aim to investigate the outcomes of COPD exacerbation interventions. Regarding\u0026nbsp;\u003cstrong\u003escreening and eligibility,\u003c/strong\u003e upon admission, all 253 patients were preliminarily assessed for eligibility based on their diagnosis of COPD exacerbation. For\u0026nbsp;\u003cstrong\u003edetailed eligibility assessment\u003c/strong\u003e, subsequent to the initial screening, a thorough review of medical histories and current health evaluations was conducted. Of the initial cohort, 238 patients met the preliminary inclusion criteria.\u0026nbsp;\u003cstrong\u003eF\u003c/strong\u003eurther rigorous assessments, including necessary laboratory tests and physical examinations, resulted in 83 patients being confirmed as eligible. These patients consented to participate and were enrolled in the study.\u0026nbsp;\u003cstrong\u003eT\u003c/strong\u003ehroughout the study, comprehensive follow-up was executed to monitor patient outcomes post-intervention. Of the enrolled participants, 58 successfully completed the entire follow-up protocol as designed. Attrition included 15 participants who withdrew from the study for various reasons, and 10 were excluded from the final analysis because of non-adherence to the intervention protocol or other exclusion criteria.\u0026nbsp;\u003cstrong\u003eT\u003c/strong\u003ehe final analysis was conducted on the dataset comprising the 58 patients who completed the follow-up.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eInclusion criteria for the study\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe included patients\u0026nbsp;aged\u0026nbsp;over 40 years who were hospitalised because of COPD exacerbation, irrespective of whether they had comorbidities, such as hypertension or heart failure.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eExclusion criteria for the study\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe excluded patients with a previous\u0026nbsp;asthma\u0026nbsp;diagnosis, radiologically diagnosed pneumonia, diabetes mellitus, and organ malignancies. We also excluded patients who were immunocompromised, those receiving immunosuppressive therapy, and those who had received systemic or inhaled steroid therapy in the previous month.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eStudy procedure\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWithin the first 1 hour of admission, the patients were nebulized with a beta-2 agonist (salbutamol), followed by inhalation of 20 cc of 0.9% saline with an ultrasonic nebulizer (Otiflex, Kormed Co. Ltd., Seoul, South Korea), and their sputum was obtained. Nebulization was continued for at least 10 minutes. After 15 minutes or when at least 2 mL of quality sputum sample was obtained, nebulization was stopped. If a sufficient sputum sample could not be obtained, this procedure was repeated up to twice at a 0.5-hour interval. If at least 2 mL of good-quality sputum was not expectorated after three attempts, the procedure was terminated. These procedures were repeated on the 14th and 45th days of treatment. Sputum samples were sent to the pathology laboratory for eosinophil analysis. The baseline haemogram value, routinely checked in the first 1 hour of hospitalisation, was rechecked on days 14 and 45. Following induced sputum collection, 29 patients received intravenous methylprednisolone (40 mg/day) as a single daily dose in addition to standard exacerbation treatment for 7 days. The remaining 29 patients received budesonide (0.50 mg) via nebulization at 12-hour intervals for 7 days. After discharge, inhaled steroids were not used in the maintenance treatment of patients, and their treatment was limited to long-acting bronchodilators. For pathological smear evaluation, 5 cc of an alcohol-based red solution was added to the induced sputum samples to fix and remove erythrocytes. After centrifugation to separate the supernatant, the sample was placed in a BD Prepstain automatic staining machine (BD, Franklin Lakes, NJ, USA). The sputum samples were stained with Papanicolaou using the Prepstain Slide Processor Slide Stainer (TRIPATH, Hologic Inc., Marlborough, MA, USA). Microscope slides were prepared, and the ratio of eosinophils to the total number of cells was calculated by examining at least 10 fields at 400\u0026times; magnification using a light microscope.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eStatistical analyses\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll statistical analyses were performed using R 3.6.0 (www.r-project.com). Data are presented as mean \u0026plusmn; standard deviation, number (n), and percentage (%). Before the analyses, the normality of the data was assessed using the Anderson\u0026ndash;Darling normality test. Student t-tests were used for numerical variables, while Yates and Fisher\u0026rsquo;s exact chi-square tests were used for categorical variables to analyse the demographic characteristics of the patients. The Friedman test was used to evaluate the steroid groups based on the measurement times. The Nemenyi multiple comparison test was used to identify significant groups. Results are illustrated with graphs. Statistical significance was set at p\u0026lt;00.5.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eThis study included 58 patients hospitalised for COPD exacerbations. The patients were divided into two groups: 29 patients receiving inhaled steroid treatment and 29 patients receiving intravenous steroid treatment. Table 1 presents the demographic characteristics of the patients. The mean age of patients receiving inhaled steroid treatment was 64.34\u0026plusmn;8.57 years and 68.17\u0026plusmn;9.30 years in the group receiving intravenous steroid treatment. Male patients comprised 55.2% of inhaled steroid recipients and 48.3% of intravenous steroid recipients. No statistically significant differences\u0026nbsp;were observed between the two groups in terms of mean age or sex. The body mass index (BMI) in the inhaled steroid treatment group was 29.41\u0026plusmn;7.82 and 31.86\u0026plusmn;8.98 in the intravenous steroid treatment group, with no statistically significant differences. Similarly, no significant differences\u0026nbsp;were observed between the two groups in terms of cigarette smoking (packs/year) or biofuel exposure (years).\u003c/p\u003e\n\u003cp\u003eTable 2 shows the percentage of eosinophils in the sputum and blood as well as the eosinophil count in the blood at baseline and on days 14 and 45 of treatment. Figures 1, 2, and 3 visualise the findings in columnar graphs. In patients receiving inhaled and intravenous steroid treatment, decreases in the percentage of eosinophils in the sputum and eosinophil count and percentage in the blood were observed on the 14th and 45th days compared to the baseline values. The decreases were particularly prominent on day 14. Although the percentage of eosinophils in the sputum and percentage and count of eosinophils in the blood decreased in absolute values on days 14 and 45 compared to baseline in patients receiving inhaled steroid treatment, no statistically significant change was found. In patients receiving intravenous steroid treatment, although all values decreased compared with those at baseline, only the percentage of eosinophils in the sputum showed a statistically significant decrease on the 14th and 45th days of treatment (p=0.041).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eCOPD is a common respiratory condition characterised by persistent airflow limitation and frequent exacerbations. In patients with COPD exacerbations, the optimal route for administering steroid therapy\u0026mdash;whether by inhalation or systemically\u0026mdash;remains unclear. To address this, we aimed to evaluate the response of sputum and blood eosinophil counts to systemic and inhaled steroids in hospitalised patients with COPD exacerbation. In patients receiving intravenous steroid treatment, all values decreased compared to baseline; however, only the percentage of eosinophils in\u0026nbsp;the\u0026nbsp;sputum showed a statistically significant decrease on the 14th and 45th days of treatment. Systemic steroid treatment significantly\u0026nbsp;decreased\u0026nbsp;the percentage of sputum eosinophils.\u003c/p\u003e\n\u003cp\u003eAlthough up to 40% of patients\u0026nbsp;with COPD\u0026nbsp;exhibit eosinophilic airway inflammation and systemic eosinophilia, the role of eosinophils in COPD pathophysiology remains inadequately understood. High sputum and blood eosinophil levels in\u0026nbsp;patients with\u0026nbsp;stable COPD are considered markers of high mortality and increased\u0026nbsp;risk of\u0026nbsp;frequent exacerbations. Epidemiological\u0026nbsp;studies have demonstrated that circulating eosinophils significantly impact COPD outcomes [13]. In two extensive studies with over 30 years of follow-up, eosinophilia (blood eosinophils \u0026gt;275 cells/\u0026mu;L) increased the risk of all-cause mortality independent of age, sex, smoking,\u0026nbsp;and lung function [14]. Another epidemiological\u0026nbsp;study (Copenhagen General Population Study) reported an increased risk of all exacerbations,\u0026nbsp;regardless of severity, with over two-fold\u0026nbsp;increase in the risk of severe exacerbations at blood eosinophil levels \u0026gt;340 cells/\u0026mu;L [14].\u003c/p\u003e\n\u003cp\u003eEosinophils may increase airway biopsies and sputum\u0026nbsp;during COPD\u0026nbsp;exacerbations [15]. In COPD exacerbations, blood eosinophil counts can help predict\u0026nbsp;the\u0026nbsp;clinical course, risk of rehospitalisation, length of hospitalisation, response to steroids,\u0026nbsp;and mortality risk. A blood eosinophil count \u0026ge;2% increases the risk of all-cause rehospitalisation by 2.3 times and the risk of COPD-related rehospitalisation by 3.5 times [16].\u0026nbsp;Additionally, the blood\u0026nbsp;eosinophil count is reportedly an independent predictor of mortality in COPD exacerbation [17]. A blood eosinophil count \u0026lt;50 cells/\u0026mu;L during the exacerbation period has been associated with prolonged hospitalisation and a threefold increase in mortality risk [17].\u003c/p\u003e\n\u003cp\u003eSputum eosinophilia has long been recognised as a biomarker of\u0026nbsp;the\u0026nbsp;clinical benefit of systemic steroid therapy in patients with stable COPD [18], showing improvements\u0026nbsp;in lung function, symptom reduction,\u0026nbsp;and increased exercise capacity. A treatment approach targeting the reduction of sputum eosinophil counts with systemic steroid therapy has been shown to be beneficial in reducing\u0026nbsp;symptoms and severe COPD exacerbations\u0026nbsp;that\u0026nbsp;require hospitalisation [19]. Patients with high sputum eosinophil counts showed decreased sputum eosinophil levels and significantly\u0026nbsp;improved quality-of-life scores post-systemic steroid treatment [20]. Similar studies have shown that patients with high sputum eosinophil counts responded favourably\u0026nbsp;to systemic steroid treatment [21]. These results highlight the efficacy of eosinophil-targeted systemic steroids in patients with COPD with\u0026nbsp;an\u0026nbsp;eosinophilic phenotype, suggesting that measuring the sputum eosinophil counts may help identify patients with COPD who have steroid-sensitive disease and guide treatment decisions.\u003c/p\u003e\n\u003cp\u003eSimilar to systemic steroid therapy, inhaled steroid therapy in patients with stable COPD and eosinophilic inflammation improves\u0026nbsp;lung function, reduces\u0026nbsp;exacerbations, and lowers sputum eosinophil counts [22]. In a study, patients with stable COPD and elevated blood eosinophil counts had reduced exacerbation rates when treated with inhaled steroids [23]. Brightling et al. demonstrated that in patients with stable COPD and sputum eosinophilia, high-dose inhaled mometasone treatment improved lung function without affecting sputum eosinophilia [18]. A meta-analysis suggested that inhaled steroid treatment may reduce sputum eosinophil counts in patients with stable COPD [24]. Barnes et al. reported that\u0026nbsp;an\u0026nbsp;inhaled salmeterol/fluticasone propionate combination reduced sputum eosinophil counts in patients with stable COPD [25].\u003c/p\u003e\n\u003cp\u003eUnfortunately, we did not have data on the sputum and blood eosinophil levels of our patients in the stable period, preventing us from comparing these levels with those during exacerbation. We were also unable to compare the eosinophil levels on days 14 and 45 post-exacerbation with the pre-exacerbation eosinophil levels, limiting our ability to assess the treatment\u0026rsquo;s effects on eosinophils during the stable period.\u003c/p\u003e\n\u003cp\u003eEosinophilic COPD exacerbations respond more rapidly to systemic steroid therapy than\u0026nbsp;non-eosinophilic\u0026nbsp;exacerbations, and treatment success is higher [4]. A similar finding was reported in a study comparing the prednisolone and placebo effects on eosinophilic exacerbations [26]. Treatment failure was significantly lower in the systemic steroid\u0026nbsp;group\u0026nbsp;compared to the placebo group (11% and 66%, respectively). However, there is no consensus on the optimal threshold for circulating eosinophil counts to guide systemic steroid therapy. A blood eosinophil value \u0026ge;2% during exacerbation is generally considered beneficial for oral steroid therapy [27].\u003c/p\u003e\n\u003cp\u003eElevated sputum and blood eosinophil levels are considered good biomarkers\u0026nbsp;for a favourable\u0026nbsp;clinical response to steroid treatment during exacerbation,\u0026nbsp;as well as in stable patients [28]. Current guidelines recommend short-term systemic steroid therapy for all severe COPD exacerbations, regardless of\u0026nbsp;the\u0026nbsp;eosinophilic phenotype [1]. However, for a more individualised treatment approach, systemic steroid treatment may be considered a more rational approach only for exacerbations with high\u0026nbsp;blood\u0026nbsp;eosinophil counts. The use of high-dose nebulised steroids has been suggested as an alternative to systemic steroid therapy for treating exacerbations [29]. In this case, high doses of nebulised steroids can be used for non-eosinophilic COPD exacerbations to achieve optimal clinical outcomes\u0026nbsp;and avoid the side effects of systemic steroids. G\u0026uuml;nen et al. compared the efficacy of nebulised bronchodilator therapy with\u0026nbsp;that of\u0026nbsp;intravenous steroid therapy in 159 patients\u0026nbsp;with COPD\u0026nbsp;hospitalised for exacerbation [29]. Patients were divided into three groups: standard bronchodilator therapy, intravenous steroids (40 mg/day prednisolone), and nebulised budesonide (1,500 mcg twice daily) for 10 days. Arterial blood gas and pulmonary function test results improved rapidly in the second and third groups. No significant difference was observed in efficacy between patients receiving nebulised budesonide and\u0026nbsp;those receiving\u0026nbsp;intravenous steroid treatment. A similar study was conducted by Mirici et al. [30].\u003c/p\u003e\n\u003cp\u003eForty patients\u0026nbsp;with COPD\u0026nbsp;hospitalised for moderate-to-severe exacerbations received nebulised budesonide (8 mg/day) or intravenous prednisolone\u0026nbsp;(40 mg/day). The improvements in arterial blood gases and pulmonary function test results\u0026nbsp;were comparable between the groups. These two studies indicated that high-dose nebulised steroid therapy could be a viable alternative to systemic steroid therapy in patients hospitalised for COPD exacerbation. Good clinical responses can be obtained with inhaled steroid therapy in patients with exacerbated COPD and high eosinophil counts in the blood and sputum. However, no significant decrease in the blood eosinophil count was observed in patients receiving inhaled steroid therapy for COPD exacerbation [31].\u003c/p\u003e\n\u003cp\u003eBathoorn showed that inhaled steroid and beta-2 agonist combination therapy reduced sputum eosinophil counts\u0026nbsp;during COPD exacerbation [32]. In their study, 45 patients with COPD exacerbation were treated with budesonide/formoterol (320/9 mcg four times daily), prednisolone (30 mg/day), or placebo for 14 days as outpatients. The primary endpoint of this study was to determine the efficacy on sputum eosinophil levels. Budesonide/formoterol (-57%) and prednisolone (-58%) significantly reduced sputum eosinophil\u0026nbsp;counts\u0026nbsp;compared to\u0026nbsp;the\u0026nbsp;placebo (+24%) (p = 0.01). Significant improvement in symptoms was also observed in steroid-treated patients.\u003c/p\u003e\n\u003cp\u003eIn the FLAME (Effect of Indacaterol Glycopyrronium and Fluticasone/Salmeterol in COPD Exacerbations) study, inhaled steroid use in patients with stable COPD did not reduce blood eosinophil levels and even increased it [33]. Similarly, in a retrospective analysis of 751 patients from the ISOLDE (Inhaled Steroids in Obstructive Lung Disease in Europe) study, inhaled steroid treatment did not change blood eosinophil levels [34]. In our study, while the blood eosinophil count and percentage decreased after inhaled steroid treatment compared to\u0026nbsp;the\u0026nbsp;baseline, there was a minimal increase at the 45th-day control compared to the 14th-day value. However, whether steroid treatment provides clinical benefits by reducing blood and sputum eosinophil counts remains unclear.\u003c/p\u003e\n\u003cp\u003eIn the study of COPD exacerbations, systemic inflammation markers such as C-reactive protein (CRP), neutrophils, and neutrophil-to-lymphocyte ratio (NLR) are crucial for understanding the underlying inflammatory processes. Elevated CRP levels have been associated with a significantly higher mortality risk in patients with COPD, underscoring its potential role in patient management and risk assessment\u0026nbsp;[35].\u0026nbsp;Neutrophils, essential for bacterial clearance, are known to be dysfunctionally activated in COPD, contributing to tissue damage and exacerbation severity\u0026nbsp;[36]. Similarly, an increased NLR has been correlated with adverse outcomes, suggesting its utility as a prognostic indicator\u0026nbsp;[37].\u003c/p\u003e\n\u003cp\u003eBeyond these markers, the role of other mediators such as interleukins (IL-6, IL-8), tumour necrosis factor-alpha (TNF-\u0026alpha;), and arginase activity also merit attention. IL-6 and IL-8 are potent mediators of inflammation, often elevated during COPD exacerbations and linked with disease progression and exacerbation severity\u0026nbsp;[36]. TNF-\u0026alpha; is another cytokine involved in systemic inflammation and has been associated with more severe health outcomes in patients with COPD\u0026nbsp;[35].\u0026nbsp;Moreover, arginase activity, which modulates nitric oxide metabolism and airway remodelling, is elevated in exacerbated phases of COPD, contributing further to the inflammatory milieu\u0026nbsp;[38].\u003c/p\u003e\n\u003cp\u003eConsidering these multifaceted aspects, future research should incorporate these diverse inflammatory markers to provide a more comprehensive understanding of the inflammatory pathways in COPD exacerbations. Such studies could potentially lead to more targeted therapeutic strategies, improving management and outcomes for patients with COPD.\u003c/p\u003e\n\u003cp\u003eThe limitations of this study include the small sample size, lack of examination of inflammatory parameters other than eosinophils,\u0026nbsp;and absence of pulmonary function tests. Re-exacerbation and mortality rates could have been evaluated within\u0026nbsp;a 6-month or 1-year follow-up, but time constraints prevented this. However, as a continuation of the study, long-term follow-up is planned by contacting patients or their relatives via telephone.\u003c/p\u003e\n\u003cp\u003eThe absence of pulmonary function tests in this study represents a significant gap in the assessment of COPD exacerbation severity and its correlation with eosinophil levels. Pulmonary function tests, such as spirometry, provide essential information about lung capacity and airflow limitation, which are crucial for accurately diagnosing the severity of COPD exacerbations. The inclusion of these tests in future studies could enhance the clinical relevance of inflammatory markers by allowing researchers to directly correlate changes in eosinophil levels with functional respiratory outcomes.\u003c/p\u003e\n\u003cp\u003eIn conclusion, we assessed the effects of intravenous and inhaled steroids on sputum and blood eosinophil counts in patients hospitalised for severe COPD exacerbations. Our findings indicate that systemic steroid treatment significantly reduces sputum eosinophil counts, suggesting a potential therapeutic benefit in the management of severe COPD exacerbations by targeting eosinophilic inflammation. However, it is critical to acknowledge the limitations of our study, such as its confined hospital setting and the potential for variations in patient response to steroids, which could influence the generalisability of the results. Additionally, the short-term nature of the study restricts our ability to predict long-term outcomes. For clinical practice, we recommend measuring eosinophil levels in patients experiencing severe COPD exacerbations as a routine component of the diagnostic process. This approach can help determine the suitability of systemic steroid therapy, especially in patients with marked eosinophilia. Regular monitoring of eosinophil levels could provide insights into the efficacy of treatment and help in adjusting therapeutic strategies accordingly. Prospective longitudinal studies are necessary to further evaluate the role of eosinophil counts as a biomarker for systemic steroid efficacy in COPD management. Such research would provide deeper insights into the long-term benefits and optimise treatment protocols, enhancing overall patient care in severe COPD exacerbations. By integrating these recommendations, clinicians can make more informed decisions, potentially improving treatment outcomes for patients with severe COPD exacerbations.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors would like to thank all the participants who contributed to this study. We thank the laboratory staff for their technical support.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding details\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors report no funding associated with the work featured in this article.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDisclosure of interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors report there are no competing interests to declare.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors confirm that the data supporting the findings of this study are available within the article.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eCelli B, Fabbri L, Criner G, Martinez FJ, Mannino D, Vogelmeier C, et al. \u003cem\u003eDefinition and nomenclature of chronic obstructive pulmonary disease: time for its revision.\u003c/em\u003e Am J Respir Crit Care Med. 2022;206(11):1317\u0026ndash;1325. doi: 10.1164/rccm.202204-0671PP.\u003c/li\u003e\n\u003cli\u003eKang J, Zheng J, Cai B, Wen F, Yao W, Zhang X, et al. \u003cem\u003eCurrent situation of asthma\u0026ndash;COPD overlap in Chinese patients older than 40 years with airflow limitation: a multicenter, cross-sectional, non-interventional study.\u003c/em\u003e Ther Adv Respir Dis. 2020;14:1753466620961699. doi: 10.1177/1753466620961699.\u003c/li\u003e\n\u003cli\u003eSingh D, Roche N, Halpin D, Agusti A, Wedzicha JA, Martinez FJ. \u003cem\u003eCurrent controversies in the pharmacological treatment of chronic obstructive pulmonary disease.\u003c/em\u003e Am J Respir Crit Care Med. 2016;194(5):541\u0026ndash;549. doi: 10.1164/rccm.201606-1179PP.\u003c/li\u003e\n\u003cli\u003eAgusti A, Fabbri LM, Singh D, Vestbo J, Celli B, Franssen FME, et al. \u003cem\u003eInhaled corticosteroids in COPD: friend or foe?\u003c/em\u003e Eur Respir J. 2018 Dec 13;52(6):1801219. doi: 10.1183/13993003.01219-2018. \u003c/li\u003e\n\u003cli\u003eLandis SH, Suruki R, Hilton E, Compton C, Galwey NW. \u003cem\u003eStability of blood eosinophil count in patients with COPD in the UK clinical practice research datalink.\u003c/em\u003e COPD. 2017;14(4):382\u0026ndash;388. doi: 10.1080/15412555.2017.1313827.\u003c/li\u003e\n\u003cli\u003eSingh D, Agusti A, Martinez FJ, Papi A, Pavord ID, Wedzicha JA, et al. \u003cem\u003eBlood eosinophils and chronic obstructive pulmonary disease: a global initiative for chronic obstructive lung disease science committee 2022 review.\u003c/em\u003e Am J Respir Crit Care Med. 2022;206(1):17\u0026ndash;24. doi: 10.1164/rccm.202201-0209PP.\u003c/li\u003e\n\u003cli\u003eBafadhel M, Peterson S, De Blas MA, Calverley PM, Rennard SI, Richter K, et al. \u003cem\u003ePredictors of exacerbation risk and response to budesonide in patients with chronic obstructive pulmonary disease: a post-hoc analysis of three randomised trials.\u003c/em\u003e Lancet Respir Med. 2018;6(2):117\u0026ndash;126. doi: 10.1016/S2213-2600(18)30006-7.\u003c/li\u003e\n\u003cli\u003eWatz H, Tetzlaff K, Wouters EF, Kirsten A, Magnussen H, Rodriguez-Roisin R, et al. \u003cem\u003eBlood eosinophil count and exacerbations in severe chronic obstructive pulmonary disease after withdrawal of inhaled corticosteroids: a post-hoc analysis of the WISDOM trial.\u003c/em\u003e Lancet Respir Med. 2016;4(5):390\u0026ndash;398. doi: 10.1016/S2213-2600(16)00100-4.\u003c/li\u003e\n\u003cli\u003eCui Y, Chen Y. \u003cem\u003eBlood eosinophils in chronic obstructive pulmonary disease: A potential biomarker\u003c/em\u003e. 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10.2165/00044011-200323010-00007.\u003c/li\u003e\n\u003cli\u003eKerkhof M, Sonnappa S, Postma DS, Brusselle G, Agust\u0026iacute; A, Anzueto A, et al. \u003cem\u003eBlood eosinophil count and exacerbation risk in patients with COPD.\u003c/em\u003e Eur Respir J. 2017;50(1):1700761. doi: 10.1183/13993003.00761-2017.\u003c/li\u003e\n\u003cli\u003eBathoorn D. \u003cem\u003eCOPD exacerbations, inflammation and treatment.\u003c/em\u003e 2007.\u003c/li\u003e\n\u003cli\u003eRoche N, Chapman KR, Vogelmeier CF, Herth FJF, Thach C, Fogel R, et al. \u003cem\u003eBlood eosinophils and response to maintenance chronic obstructive pulmonary disease treatment. Data from the FLAME trial.\u003c/em\u003e Am J Respir Crit Care Med. 2017;195(9):1189\u0026ndash;1197. doi: 10.1164/rccm.201701-0193OC.\u003c/li\u003e\n\u003cli\u003eBurge PS, Calverley PM, Jones PW, Spencer S, Anderson JA, Maslen TK. \u003cem\u003eRandomised, double blind, placebo controlled study of fluticasone propionate in patients with moderate to severe chronic obstructive pulmonary disease: the ISOLDE trial.\u003c/em\u003e BMJ. 2000;320(7245):1297\u0026ndash;303. doi: 10.1136/bmj.320.7245.1297.\u003c/li\u003e\n\u003cli\u003eBanerjee S, Khubchandani J, Onukogu C, Okpom C, Johnson, M. \u003cem\u003eElevated C-reactive protein and mortality risk among COPD patients\u003c/em\u003e. \u003cem\u003eEgypt J Bronchol\u003c/em\u003e. 2024;18(1):38. doi: 10.2165/00044011-200323010-00007.\u003c/li\u003e\n\u003cli\u003eLonergan M, Dicker AJ, Crichton ML, Keir HR, Van Dyke MK, Mullerova H, et al. \u003cem\u003eBlood neutrophil counts are associated with exacerbation frequency and mortality in COPD\u003c/em\u003e. \u003cem\u003eRespir Res\u003c/em\u003e\u003cem\u003e.\u003c/em\u003e 2020;21:1-10. doi: 10.1186/s12931-020-01514-7.\u003c/li\u003e\n\u003cli\u003eG\u0026uuml;nay E, Sarın\u0026ccedil; Ulaşlı S, Akar O, Ahsen A, G\u0026uuml;nay S, Koyuncu T, et al. \u003cem\u003eNeutrophil-to-lymphocyte ratio in chronic obstructive pulmonary disease: a retrospective study\u003c/em\u003e. \u003cem\u003eInflammation\u003c/em\u003e\u003cem\u003e. \u003c/em\u003e2014;37:374\u0026ndash;380. doi: 10.1007/s10753-013-9746-1.\u003c/li\u003e\n\u003cli\u003eRodr\u0026iacute;guez-Guzm\u0026aacute;n MJ, Peces-Barba Romero G, P\u0026eacute;rez Rial S, Serrano del Castillo C, Palomero Rodr\u0026iacute;guez M\u0026Aacute;, Mahillo-Fernandez I, et al. \u003cem\u003eElevated levels of arginase activity are related to inflammation in patients with COPD exacerbation\u003c/em\u003e. \u003cem\u003eBMC Pulm Med\u003c/em\u003e. 2021;21(1):271. doi: 10.1186/s12890-021-01625-0.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003e\u003cstrong\u003eTable 1: Demographic and clinical characteristics of the patients\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"25%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25%\" valign=\"top\"\u003e\n \u003cp\u003eInhaled\u0026nbsp;steroid\u0026nbsp;(n=29)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25%\" valign=\"top\"\u003e\n \u003cp\u003eIntravenous\u0026nbsp;steroid\u0026nbsp;(n=29)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25%\" valign=\"top\"\u003e\n \u003cp\u003ep\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eAge (year)\u0026nbsp;(\u003c/strong\u003emean\u0026nbsp;\u0026plusmn; standard deviation\u0026rsquo;\u003cstrong\u003e)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25%\" valign=\"top\"\u003e\n \u003cp\u003e64.34 \u0026plusmn; 8.57\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25%\" valign=\"top\"\u003e\n \u003cp\u003e68.17\u0026nbsp;\u0026plusmn; 9.30\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25%\" valign=\"top\"\u003e\n \u003cp\u003e0.109\u003csup\u003eŧ\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eSex\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25%\" valign=\"top\"\u003e\n \u003cp\u003e0.793\u003csup\u003e#\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eMan\u0026nbsp;(n, %)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25%\" valign=\"top\"\u003e\n \u003cp\u003e16\u0026nbsp;(55.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25%\" valign=\"top\"\u003e\n \u003cp\u003e14\u0026nbsp;(48.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eWoman\u0026nbsp;(n,\u0026nbsp;%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25%\" valign=\"top\"\u003e\n \u003cp\u003e13\u0026nbsp;(44.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25%\" valign=\"top\"\u003e\n \u003cp\u003e15\u0026nbsp;(51.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eBMI\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25%\" valign=\"top\"\u003e\n \u003cp\u003e29.41 \u0026plusmn;\u0026nbsp;7.82\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25%\" valign=\"top\"\u003e\n \u003cp\u003e31.86\u0026nbsp;\u0026plusmn; 8.98\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25%\" valign=\"top\"\u003e\n \u003cp\u003e0.273\u003csup\u003eŧ\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eSmoker\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25%\" valign=\"top\"\u003e\n \u003cp\u003e0.430\u003csup\u003e#\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eNo\u0026nbsp;(n,\u0026nbsp;%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25%\" valign=\"top\"\u003e\n \u003cp\u003e13\u0026nbsp;(44.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25%\" valign=\"top\"\u003e\n \u003cp\u003e17\u0026nbsp;(58.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Yes (n, %)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25%\" valign=\"top\"\u003e\n \u003cp\u003e16\u0026nbsp;(55.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25%\" valign=\"top\"\u003e\n \u003cp\u003e12\u0026nbsp;(41.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eBiomass\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25%\" valign=\"top\"\u003e\n \u003cp\u003e0.595\u003csup\u003e#\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eNo\u0026nbsp;(n,\u0026nbsp;%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25%\" valign=\"top\"\u003e\n \u003cp\u003e18\u0026nbsp;(62.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25%\" valign=\"top\"\u003e\n \u003cp\u003e15\u0026nbsp;(51.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eYes\u0026nbsp;(n,\u0026nbsp;%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25%\" valign=\"top\"\u003e\n \u003cp\u003e11\u0026nbsp;(37.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25%\" valign=\"top\"\u003e\n \u003cp\u003e14\u0026nbsp;(48.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026nbsp;\u003csup\u003eŧ\u003c/sup\u003e Mann\u0026ndash;Whitney-U test\u003c/p\u003e\n\u003cp\u003e\u003csup\u003e#\u003c/sup\u003e Yates ki-kare\u003c/p\u003e\n\u003cp\u003e\u003csup\u003eǂ\u003c/sup\u003e Fisher exact\u0026nbsp;test\u003c/p\u003e\n\u003cp\u003eBMI, body mass index\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2: Baseline, 14th-day, and 45th-day eosinophil and p-values of patients receiving inhaled and intravenous steroid treatment\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.497257769652652%\" valign=\"top\"\u003e\n \u003cp\u003eParameters\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.173674588665447%\" valign=\"top\"\u003e\n \u003cp\u003eTreatment\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.270566727605118%\" valign=\"top\"\u003e\n \u003cp\u003eBaseline\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.82998171846435%\" valign=\"top\"\u003e\n \u003cp\u003e14th day\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.270566727605118%\" valign=\"top\"\u003e\n \u003cp\u003e45th day\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.957952468007313%\" valign=\"top\"\u003e\n \u003cp\u003eP\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.497257769652652%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eValues of eosinophil percentages in the sputum (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.173674588665447%\" valign=\"top\"\u003e\n \u003cp\u003eInhaled\u0026nbsp;steroid\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.270566727605118%\" valign=\"top\"\u003e\n \u003cp\u003e0.90 \u0026plusmn; 2.02\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.82998171846435%\" valign=\"top\"\u003e\n \u003cp\u003e0.41\u0026plusmn;\u0026nbsp;0.91\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.270566727605118%\" valign=\"top\"\u003e\n \u003cp\u003e0.38\u0026plusmn;\u0026nbsp;0.78\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.957952468007313%\" valign=\"top\"\u003e\n \u003cp\u003e0.230\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.497257769652652%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.173674588665447%\" valign=\"top\"\u003e\n \u003cp\u003eIntravenous \u0026nbsp; \u0026nbsp; steroid\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.270566727605118%\" valign=\"top\"\u003e\n \u003cp\u003e0.86\u0026plusmn;1.22\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.82998171846435%\" valign=\"top\"\u003e\n \u003cp\u003e0.36\u0026plusmn;0.72\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.270566727605118%\" valign=\"top\"\u003e\n \u003cp\u003e0.28\u0026plusmn;0.53\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.957952468007313%\" valign=\"top\"\u003e\n \u003cp\u003e0.041\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.497257769652652%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eValues of blood eosinophil count (k/UL)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.173674588665447%\" valign=\"top\"\u003e\n \u003cp\u003eInhaled\u0026nbsp;steroid\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.270566727605118%\" valign=\"top\"\u003e\n \u003cp\u003e193.79\u0026plusmn;195.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.82998171846435%\" valign=\"top\"\u003e\n \u003cp\u003e160.34\u0026plusmn;130.01\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.270566727605118%\" valign=\"top\"\u003e\n \u003cp\u003e176.21\u0026plusmn;188.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.957952468007313%\" valign=\"top\"\u003e\n \u003cp\u003e0.990\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.497257769652652%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.173674588665447%\" valign=\"top\"\u003e\n \u003cp\u003eIntravenous\u0026nbsp;steroid\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.270566727605118%\" valign=\"top\"\u003e\n \u003cp\u003e124.48\u0026plusmn;153,0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.82998171846435%\" valign=\"top\"\u003e\n \u003cp\u003e123.79\u0026nbsp;\u0026plusmn; 129.87\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.270566727605118%\" valign=\"top\"\u003e\n \u003cp\u003e117.59\u0026plusmn;141.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.957952468007313%\" valign=\"top\"\u003e\n \u003cp\u003e0.380\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.497257769652652%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eValues of eosinophil percentages in the blood (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.173674588665447%\" valign=\"top\"\u003e\n \u003cp\u003eInhaled\u0026nbsp;steroid\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.270566727605118%\" valign=\"top\"\u003e\n \u003cp\u003e2.20 \u0026plusmn; 2.02\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.82998171846435%\" valign=\"top\"\u003e\n \u003cp\u003e1.80 \u0026plusmn; 1.42\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.270566727605118%\" valign=\"top\"\u003e\n \u003cp\u003e2.17 \u0026plusmn; 1.96\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.957952468007313%\" valign=\"top\"\u003e\n \u003cp\u003e0.172\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.497257769652652%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.173674588665447%\" valign=\"top\"\u003e\n \u003cp\u003eIntravenous\u0026nbsp;steroid\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.270566727605118%\" valign=\"top\"\u003e\n \u003cp\u003e2.50 \u0026plusmn; 8.12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.82998171846435%\" valign=\"top\"\u003e\n \u003cp\u003e1.49 \u0026plusmn; 1.60\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.270566727605118%\" valign=\"top\"\u003e\n \u003cp\u003e1.58 \u0026plusmn; 1.69\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.957952468007313%\" valign=\"top\"\u003e\n \u003cp\u003e0.325\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"sputum eosinophilia, blood eosinophilia, COPD exacerbation, steroid responsiveness","lastPublishedDoi":"10.21203/rs.3.rs-4693402/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4693402/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eChronic obstructive pulmonary disease (COPD) is a common respiratory condition characterised by persistent airflow limitation and frequent exacerbations. In patients with COPD exacerbations, whether steroid therapy should be administered via inhalation or the systemic route remains unclear. To address this, we aimed to evaluate the response of sputum and blood eosinophil counts to systemic and inhaled steroids in hospitalised patients with COPD exacerbation.\u003cstrong\u003e \u003c/strong\u003eOur study included 58 patients hospitalised at a chest disease clinic for the treatment of COPD exacerbation. Upon admission, pre-induced sputum samples were collected. Patients were then randomly assigned to receive either intravenous methylprednisolone (40 mg/day) as a single daily dose in addition to standard exacerbation treatment (n=29) or budesonide (0.50 mg) via nebulisation at 12-h intervals for 7 days (n=29). Sputum haemograms and eosinophils were evaluated on the 14th and 45th days of treatment.\u003cstrong\u003e \u003c/strong\u003eIn patients receiving intravenous steroid treatment, sputum eosinophil percentages were significantly reduced on days 14 (0.36±0.72) and 45 (0.28±0.53) compared to those at baseline (0.86±1.22) (p=0.041). Although decreases in the percentage of eosinophils in sputum, eosinophil count, and percentage in blood were observed on the 14th and 45th days compared to baseline values in patients receiving inhaled steroid treatment, these changes were not statistically significant (p\u0026gt;0.05).\u003cstrong\u003e \u003c/strong\u003eAdding systemic steroids to the treatment of severe COPD exacerbations is a rational approach. Further studies with longer follow-up periods are needed to determine the role of eosinophil levels in the blood and sputum as a marker for deciding on intravenous and inhaled steroid treatments.\u003c/p\u003e","manuscriptTitle":"Sputum and Blood Eosinophilia Level of Patient With Chroni̇c Obstructive Pulmonary Disease (Copd) Exacerbation in Hospitalized","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-10-02 16:38:51","doi":"10.21203/rs.3.rs-4693402/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"0bd78a8c-b37e-4107-bd2a-41959544e9fd","owner":[],"postedDate":"October 2nd, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-10-15T08:24:30+00:00","versionOfRecord":[],"versionCreatedAt":"2024-10-02 16:38:51","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4693402","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4693402","identity":"rs-4693402","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}