OR I G I NAL ART I C L E Long-term oxygen treatment need is less frequent in eosinophilic COPD patients Nilüfer Aylin Acet-Öztürk | Asli G. Dilektasli | Özge Aydın-Güçlü | Ezgi Demirdö�gen | Funda Coşkun | Ahmet Ursavaş | Mehmet Karada�g | Esra Uzaslan Faculty of Medicine, Department of Pulmonology, Uluda�g University, Bursa, Turkey Correspondence Asli G. Dilektasli, Faculty of Medicine, Department of Pulmonology, Uluda�g University, Bursa, 16120 Turkey. Email: asligorekd@gmail.com Abstract Introduction: Eosinophilic airway inflammation is a recognized inflammatory pattern in subgroups of patients with chronic obstructive pulmonary disease (COPD). However, there are still conflicting results between various studies concerning the effect of eosinophils in COPD patients. Our aim with this study was to evaluate eosinophilic inflammation and its relation to the clinical characteristics in a group of COPD patients. Methods: Stable COPD patients with FEV1% predicted < 50 or with ≥ 1 exacerbation leading to hospital admission or ≥2 moderate or severe exacerbation history were consecutively enrolled from outpatient clinics. Results: We included 90 male COPD patients, with a mean age of 63.3 � 9.2. Mean FEV1% predicted was 35.9 � 11.3. Eosinophilic inflammation (eosino- phil percentage ≥2%) was evident in 54 (60%) of the patients. Participants with eosinophilic inflammation were significantly older and had better FEV1 predicted % values. Eosinophilic COPD patients were characterized with better quality of life and fewer symptoms. COPD patients with noneosinophilic inflammation used supplemental long-term oxygen therapy (LTOT) more fre- quently compared to patients with eosinophilic inflammation (36.1% vs. 14.8%, p = 0.01). Eosinophilic inflammation is associated with less dyspnea severity measured by mMRC (OR: 0.542 95% CI: 0.342–0.859, p = 0.009) and less LTOT use (OR: 0.334 95% CI: 0.115–0.968, p = 0.04) regardless of age, severity of air- flow limitation, and having frequent exacerbation phenotype. Conclusion: Our study supports the growing evidence for a potential role of eosinophilic inflammation phenotype in COPD with distinctive clinical char- acteristics. Eosinophilic inflammation is inversely associated with dyspnea severity measured by mMRC and LTOT use independently from age, total number of exacerbations, St. George Respiratory Questionnaire (SGRQ) total score and FEV1% predicted. Received: 16 June 2021 Revised: 20 September 2021 Accepted: 22 September 2021 DOI: 10.1111/crj.13451 This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. © 2021 The Authors. The Clinical Respiratory Journal published by John Wiley & Sons Ltd. Clin Respir J. 2022;16:49–56. wileyonlinelibrary.com/journal/crj 49 https://orcid.org/0000-0002-6375-1472 https://orcid.org/0000-0003-1005-3205 https://orcid.org/0000-0002-7400-9089 mailto:asligorekd@gmail.com https://doi.org/10.1111/crj.13451 http://creativecommons.org/licenses/by/4.0/ http://wileyonlinelibrary.com/journal/crj KEYWORD S COPD, eosinophil, inflammation, supplemental oxygen 1 | INTRODUCTION Eosinophilic airway inflammation is a well-recognized inflammatory pattern in subgroups of patients with chronic obstructive pulmonary disease (COPD). Most fre- quently used methodology to identify eosinophilic inflammation in airway diseases is sputum eosinophil percentage.1,2 However, recent studies revealed a strong correlation between the peripheral blood eosinophil count and sputum eosinophils exacerbations in stable COPD3. In addition, a blood eosinophil count of 2% has 90% sensitivity and 60% specificity for detecting sputum eosinophilia of 3% in COPD.4 Definition of eosinophilic inflammation in stable COPD patients varies between studies, and there is no consensus on the definition of blood eosinophilic inflam- mation in the literature yet. Sputum eosinophilia has been observed in approximately 1/3 of stable COPD patients,3 while persistent and intermittent blood eosino- philia is seen in 37.4% and 49% of cases, respectively.5 Recent studies showed that blood eosinophil counts dur- ing stable COPD did not change within 1 month6 and demonstrated a reasonable repeatability and stability dur- ing a 12 month follow-up7. During acute exacerbation of COPD (AECOPD), reports show that eosinophilic airway inflammation is identified by blood eosinophils in 9.6%–45% of cases8–12 and by sputum eosinophilia in 28% of cases.4 Eosinophilic inflammation in AECOPD is associated with a shorter hospital stay,12,13 higher COPD-related readmission rate, and a shorter time to the first COPD-related hospital readmission.10,14–17 Noneosinophilic inflammation in AECOPD that require intensive care hospitalization is associated with a prolonged ICU stay and NIMV failure.7 Emphysema % shown in computed tomography (CT) at baseline5 and self-reported emphysema18 is not differ- ent between eosinophilic and noneosinophilic patients; however, emphysema progression during follow-up is greater in noneosinophilic COPD patients.5 In contrast with these studies Hastie et al. showed that while blood eosinophil count is not related with emphysema, patients with sputum eosinophilia greater than 1.25% had higher emphysema indices, air trapping, and functional small airway disease.19 Long-term oxygen therapy (LTOT) use7,10 and oxygen saturation5,12 also indicate no differ- ence between the two inflammation groups. Emerging evidence shows a potential role for eosino- philic inflammation indicating distinctive clinical features in COPD and a potential marker for tailored treatment approach.20–27 Our aim in this study was to evaluate eosinophilic inflammation and its’ relation to the clinical characteristics of COPD patients such as exacerbation history, LTOT, and domiciliary noninvasive mechanical ventilation (NIMV). 2 | MATERIALS AND METHODS 2.1 | Study setting and study population Designed as a cross-sectional study based on two pulmo- nary medicine departments, (Uluda�g University Faculty Hospital Department of Pulmonary Diseases and Turkan Akyol Chest Diseases Hospital) outpatient clinic in between February 2016 to February 2017. We consecu- tively enrolled stable COPD patients with (1) FEV1% pred <50 or (2) ≥ 1 exacerbation leading to hospital admis- sion, or (3) ≥2 moderate or severe exacerbation history. The institutional ethical committee approved the study protocol, and written informed consent was obtained from all participants. Exclusion criteria comprised con- comitant asthma, lung malignancy, or exacerbation within 1 month. 2.2 | Definitions COPD patients were defined as those with chronic airway inflammation symptoms, history of exposure to risk fac- tors, and fixed airflow limitation in spirometry.28 Airflow limitation was confirmed by postbronchodilator FEV1 /FVC < 0.70. Airflow limitation was classified according to FEV1% predicted: >80% were defined as GOLD 1, while FEV1% predicted between 80 and 50, between 50 and 30, and below 30 were defined as GOLD 2, GOLD 3, and GOLD 4, respectively. Stable COPD was characterized as requiring no increase in bronchodilator use, no use of oral corticosteroids or antibiotics, no unscheduled doctor visits, or hospitalization over the previous 4 weeks. 2.3 | Definition of AECOPD AECOPD was defined as an acute event characterized by a worsening of the patient’s respiratory symptoms beyond normal variation and leading to a change in medication, 50 ACET-ÖZTÜRK ET AL. while frequent exacerbators were defined as patients experiencing two or more exacerbations per year.28 2.4 | Definition of eosinophilic COPD Patients with blood eosinophil percentage ≥2% were defined as eosinophilic COPD patients. The cut-off value for eosinophilic inflammation was defined as 2% because of reported high correlation rates with sputum eosino- philia3 and the previous reports showing potential clini- cal relevance.5 2.5 | Measurements A detailed, structured questionnaire incorporating risk factors, smoking status, disease history, and comorbid conditions was completed for each patient. Exacerbation history was obtained from both medical records and the patients’ declarations. LTOT use and domiciliary NIMV were recorded according to patient’s declaration. Dys- pnea severity was assessed using the modified Medical Research Council (mMRC) Dyspnea Scale and health- related quality of life was assessed with St. George Respi- ratory Questionnaire (SGRQ).29,30 SGRQ and mMRC scales were validated in Turkish.31,32 Spirometry was per- formed before and after administration of short-acting β2-agonist (albuterol) by using Vmax Encore System (Sensormedics, Viasys, Yorba Linda, CA, USA) in accor- dance with ATS/ERS recommendations.33 Venous blood samples were taken from every patient for obtaining a total blood count. 2.6 | Statistical analyses Data were analyzed using Statistical Package for Social Sciences (SPPS) version 22. Means and standard devia- tions were reported for normally distributed continuous data and medians and interquartile ranges (ICR) for non- normally distributed continuous data. Exacerbation rates and hospitalization within previous year were reported according to one sample poisson distribution test. Corre- lations between nonnormally distributed data were calcu- lated by the Spearman test. Comparison of the two groups with nonnormally and normally distributed data was analyzed with the Mann–Whitney U test and the Student t-test, respectively. Candidate risk factors related with eosinophilic inflammation were evaluated firstly by univariate analysis and then possible risk factors with p values below 0.10 were evaluated by multiple logistic regression model to identify independent predictors of eosinophilic inflammation. Values of p < 0.05 were con- sidered statistically significant. 3 | RESULTS We enrolled 90 male stable COPD patients, with a mean age of 63.3 � 9.2 years old. Mean FEV1 predicted % was 35.9 � 11.3. By GOLD spirometric classification 86.6% of the patients were GOLD III or IV (Table 1). About 33.3% of the group were frequent exacerbators. About 12.2% were using domiciliary NIV, and 23.3% were on LTOT. Clinical characteristics of study group are presented in Table 1. Absolute number of blood eosinophil count and blood eosinophil percentage were 195 [100–265] and 2.21% [1.3%–3.1%]. Eosinophilic inflammation (defined as blood eosinophil percentage ≥2%) was evident in 54 (60%) of the patients. Participants with eosinophilic inflammation were significantly older (p = 0.04) and had higher FEV1 predicted % values (p = 0.03), Table 2. Eosinophilic COPD patients were characterized by better quality of life with lower SGRQ total scores (p = 0.03) and less dyspnea with lower mMRC (p = 0.009) scores. We found that LTOT use was more frequent in patients with non- eosinophilic inflammation (blood eosinophil <2%) com- pared with patients with eosinophilic inflammation (p = 0.01), Table 2. On the other hand, smoking status and frequency of acute exacerbations in the last 12 months were similar between eosinophilic and non- eosinophilic patients, Table 2. We included age, total number of exacerbations, mMRC score, SGRQ total score, FEV1% predicted, and LTOT use in a multiple logistic regression model to iden- tify independent predictors of eosinophilic inflammation (Table 3). Eosinophilic inflammation is inversely associ- ated with dyspnea severity measured by mMRC (OR: 0.50 [0.30–0.83], p = 0.008) and LTOT use (OR: 0.29 [0.09–0.90], p = 0.03). 4 | DISCUSSION The prevalence of eosinophilic inflammation defined as >2% eosinophils is 60% in our study population con- sisting of COPD patents with FEV1% predicted <50 or with ≥1 exacerbation leading to hospital admission or ≥2 moderate or severe exacerbation history. Eosinophilic COPD patients are older and have higher FEV1% predicted. These patients are characterized by fewer symptoms according to mMRC scores and better quality of life defined by SGRQ scores. Noneosinophilic COPD patients needed LTOT more frequently. Other clinical ACET-ÖZTÜRK ET AL. 51 measurements like smoking status, comorbidities, and number of exacerbations in the last year were not signifi- cantly different between groups. Determination of COPD disease severity is complex and includes lung functions, measure of breathlessness, quality of life, and exacerbation frequency. Our findings concerning age, lung functions, and severity of symptoms are in accordance with the study of Singh et al., which reported on 1483 patients from the ECLIPSE cohort. Singh et al. stated that patients with persistent eosinophil ≥2% were older, mostly male, with higher FEV1%, and lower SGRQ and mMRC scores.5 Likewise, Negewo et al. showed that patients with eosinophilic inflammation had higher FEV1%predicted, better BODE scores, and less symptoms measured by mMRC and SGRQ.3 In addition to these results, eosinophilic patients had higher chemo- kine ligand 18, with lower club cell protein 16 and CXCL8 levels, which indicate different activated path- ways.5 In contrast with our results Hastie et al. showed reduced FEV1%predicted and higher rate of exacerbations in eosinophilic COPD patients.19 Wu et al. included 40 112 COPD patients in stable or exacerbation phase in recent meta-analysis to identify clinical characteristics of eosinophilic inflammation in COPD. Using cut-off value for blood eosinophil of 2%, 54.9% of the study population were identified as eosinophilic COPD. Eosinophilic patients were male predominant, had higher BMI, and had higher ischemic heart disease. While FEV1% predicted did not differ between groups, lower rate of GOLD stage 1 was identified in eosinophilic group.34 In patient-level meta-analysis by Pavord et al. blood eosino- philia >2% was present in 37 of the 10 861 patients and FEV1%predicted did not differ between eosinophilic and noneosinophilic patients.35 In our study patients with noneosinophilic inflamma- tion tended to have more frequent exacerbations leading to hospitalization and higher total number of total exac- erbations. Lonergan et al. included 7220 COPD patient and had a mean 9-year follow-up period. The study showed that the rate of severe exacerbations was lower in high eosinophilic COPD patients, and patients with high blood neutrophil count were related with higher mortal- ity.36 Similarly, number of COPD-related in-patient days within severe COPD patients and overall mortality for all COPD patients were greater in noneosinophilic COPD patients in the study from Finland.37 However, there are some studies indicating an association between elevated blood eosinophil count and exacerbations.38,39 Vedel- Krogh et al. calculated a 1.76-fold increased risk of severe exacerbation related with high blood eosinophil counts.18 Kerkhof et al. found an elevated risk exacerbation related with eosinophils but only in ex-smoker COPD popula- tion.40 This difference between studies might be result of selection of study population. Study from Viinanen et al.37 had similar results with our study and had a simi- lar population (FEV1%predicted ≤50%). However, Vedel- Krogh et al.18 and Kerkhof et al.40 included all COPD TAB L E 1 Population characteristics (n = 90) Age 63.3 � 9.2 Smoking status Current smokers, n (%) 17 (18.9) Ex-smokers, n (%) 73 (81.1) Number of comorbidities 1.0 [0.0–2.0] AECOPD history Number of AECOPD requiring hospitalization in the last 12 months 0.0 [0.0–1.0] Number of AECOPD requiring emergency admissions in the last 12 months 0.0 [0.0–1.0] Total number of AECOPD in the last 12 months 1.0 [0.0–2.0] Frequent exacerbators, n (%) 30 (33.3) Pulmonary Function Tests FEV1/FVC, % 67.2 [63–70] FEV1 predicted % 35.9 � 11.3 FVC predicted % 43.0 � 13.9 GOLD due FEV1 GOLD 2, n (%) 12 (13.3) GOLD 3, n (%) 47 (52.2) GOLD 4, n (%) 31 (34.4) Using domiciliary NIMV, n (%) 11 (12.2) Using LTOT, n (%) 21 (23.3) Quality of life and dyspnea SGRQ total score 42.6 � 18.6 SGRQ symptom score 53.2 � 20.9 SGRQ activity score 58.8 � 22.1 SGRQ impact score 30.0 � 18.8 mMRC score 2.0 [1.0–3.0] Hemogram values Leukocyte count, (x109/L) 8819.1 � 2461.9 Neutrophil, (%) 63.3 � 9.6 Lymphocyte, (%) 25.7 � 8.7 Eosinophil, (%) 2.2 [1.3–3.1] Hb, (g/dl) 13.9 � 1.5 Platelet, (x109/L) 251022.0 � 65581.4 Note: Data were expressed as numbers (percentages), mean � SD, or median (IQR). Abbreviations: AECOPD, acute exacerbation of COPD; COPD, chronic obstructive pulmonary disease; LTOT, long-term oxygen treatment; mMRC, modified Medical Research Council Dyspnea Scale; NIMV, noninvasive mechanical ventilation; SGRQ, St. George Respiratory Questionnaire. 52 ACET-ÖZTÜRK ET AL. patients with spirometric values and excluded asthma patients but Müllerova et al.38 used ICD codes to select patients and did not exclude asthma patients. In our study, eosinophilic inflammation is inversely and independently associated with long-term supplemen- tal oxygen need. In studies evaluating eosinophilic exac- erbations, there is no statistical difference between the two groups, regarding the need for long-term supplemen- tal oxygen7,10; however, in these studies, eosinophil mea- surements were taken during a state of exacerbation rather than in stable state, which could explain this difference. Wells et al. followed 678 moderate–severe COPD patients for 5 years to evaluate risk factors associated TAB L E 2 Clinical characteristics of eosinophilic and noneosinophilic COPD subgroups Eosinophil < %2 n = 36 Eosinophil ≥ %2 n = 54 p Age 61.0 � 7.7 64.8 � 9.8 0.04 Current smoking status, n (%) 7 (19.4) 10 (18.5) 0.91 Number of comorbidities 1.0 [0.0–1.0] 1.0 [0.0–2.0] 0.33 AECOPD history Number of AECOPD requiring hospitalization in the last 12 months 0.0 [0.0–1.7] 0.0 [0.0–1.0] 0.07 Number of AECOPD requiring emergency admissions in the last 12 months 0.0 [0.0–1.7] 0.0 [0.0–1.0] 0.14 Total number of AECOPD in the last 12 months 1.0 [0.0–2.7] 0.0 [0.0–2.0] 0.07 Frequent exacerbators, n (%) 15 (41.6) 15 (27.7) 0.17 Pulmonary function tests FEV1/FVC 67.4 [62.2–69.7] 67.2 [63–70] 0.53 FEV1 predicted % 32.8 � 11.1 38 � 11.1 0.03 FVC predicted % 40.5 � 14 44.7 � 13.7 0.16 GOLD due FEV1 0.07 GOLD 2, n (%) 2 (5.5) 10 (18.5) GOLD 3, n (%) 19 (52.7) 28 (51.8) GOLD 4, n (%) 15 (41.6) 16 (29.6) Using domiciliary NIMV, n (%) 6 (16.6) 5 (9.2) 0.33 Using LTOT, n (%) 13 (36.1) 8 (14.8) 0.01 Quality of life and dyspnea SGRQ total score 48.2 � 21.1 39.2 � 16.3 0.03 SGRQ symptom score 55.1 � 23.7 51.9 � 19.4 0.51 SGRQ activity score 66.1 � 24.4 54.4 � 19.5 0.02 SGRQ impact score 36.1 � 20.6 26.3 � 16.7 0.02 mMRC score 2.0 [2.0–4.0] 2.0 [1.0–3.0] 0.009 Hemogram values Leukocyte count, (x109/L) 9305.0 � 3192.2 8495.0 � 1783.6 0.12 Neutrophil, (%) 66.3 � 10.7 61.3 � 8.3 0.01 Lymphocyte, (%) 24.3 � 9.7 26.6 � 8 0.21 Neutrophil-lymphocyte ratio 2.80 [1.83–4.35] 2.36 [1.92–2.98] 0.17 Eosinophil, (%) 1.1 [0.6–1.6] 2.8 [2.3–4.2] <0.001 Hb, (g/dl) 14.1 � 1.8 13.8 � 1.1 0.31 Platelet, (x109/L) 259166.6 � 64032.8 245592.5 � 66629.7 0.33 Note: Data were expressed as numbers (percentages), mean � SD or median [IQR]. Abbreviations: AECOPD, acute exacerbation of COPD; COPD, chronic obstructive pulmonary disease; LTOT, long-term oxygen treatment; mMRC, modified Medical Research Council Dyspnea Scale; NIMV, noninvasive mechanical ventilation; SGRQ, St. George Respiratory Questionnaire. ACET-ÖZTÜRK ET AL. 53 with the development of resting hypoxemia and supple- mental oxygen need. This study showed a negative corre- lation between baseline emphysema and follow-up oxygen saturation.41 Singh et al. showed that emphysema progression was statistically greater in noneosinophilic COPD patients.5 Oh et al. proved that severity of emphy- sema was independently and negatively correlated with blood eosinophil count.42 Independent risk factors for air trapping measured by thoracic CT in asthmatic patients are high levels of airway neutrophils and worse airflow obstruction.43 Considering these evidence, we can hypothesize that one of the reasons behind LTOT need in noneosinophilic patients may be the higher emphysema progression. But further studies are needed to evaluate this relation. 4.1 | Limitations Our study population included only male patients with FEV1% predicted <50 or with ≥1 exacerbation leading to hospital admission or ≥2 moderate or severe exacerbation history which is a constraint on generalizations. There is also missing data regarding possible risk factors for long- term supplemental oxygen need; known risk factors such as heart failure, emphysema, and pulmonary artery enlargement34 were not assessed. 5 | CONCLUSION Our study supports the growing evidence of eosinophilic inflammation phenotype in COPD with differentiable clinical characteristics. Eosinophilic inflammation is inversely associated with dyspnea severity measured by mMRC and LTOT use independently from age, total number of exacerbations, SGRQ total score, and FEV1% predicted. ACKNOWLEDGMENT None to declare. ETHICS STATEMENT The institutional ethical committee approved the study protocol (number: 2015-17/21), and written informed consent was obtained from all participants. AUTHOR CONTRIBUTIONS Nilüfer Aylin Acet Öztürk designed research/study, “per- formed research/study collected data, analyzed data, and wrote the paper. Aslı Görek Dilektaşli designed research/ study, “performed research/study, collected data, ana- lyzed data, and wrote the paper. Özge Aydin Güçlü designed research/study, “performed research/study col- lected data, and wrote the paper. Ezgi Demirdö�gen designed research/study, contributed important reagents, analyzed data, and wrote the paper. Funda Coşkun designed research/study, contributed important reagents, analyzed data, and wrote the paper. Ahmet Ursavaş designed research/study, contributed important reagents, analyzed data, and wrote the paper. Mehmet Karada�g designed research/study, contributed important reagents, analyzed data, and wrote the paper. Esra Uzaslan designed research/study, contributed important reagents, collected data, and wrote the paper. All authors contrib- uted in data collection and analysis. All authors have read and approved the final draft. FUNDING INFORMATION Financial support was not provided. CONFLICT OF INTEREST Authors have no conflict of interest regarding this paper. DATA AVAILABILITY STATEMENT The data that support the findings of this study are avail- able from the corresponding author upon reasonable request. ORCID Nilüfer Aylin Acet-Öztürk https://orcid.org/0000-0002- 6375-1472 TAB L E 3 Multivariable analysis of predictors for eosinophilic inflammation Univariable analysis Multivariable analysis OR (95% CI) p OR (95% CI) p Age 1.04 (0.99–1.09) 0.05 - - Total number of exacerbations 0.75 (0.57–0.98) 0.03 - - FEV1% pred 1.04 (1.00–1.08) 0.03 - - SGRQ total score 0.97 (0.94–0.99) 0.03 - - mMRC 0.52 (0.33–0.82) 0.005 0.50 (0.30–0.83) 0.008 LTOT 0.30 (0.11–0.84) 0.02 0.29 (0.09–0.90) 0.03 54 ACET-ÖZTÜRK ET AL. https://orcid.org/0000-0002-6375-1472 https://orcid.org/0000-0002-6375-1472 https://orcid.org/0000-0002-6375-1472 Özge Aydın-Güçlü https://orcid.org/0000-0003-1005- 3205 Ezgi Demirdö�gen https://orcid.org/0000-0002-7400- 9089 REFERENCES 1. Eltboli O, Brightling CE. Eosinophils as diagnostic tools in chronic lung disease. Expert Rev Respir Med. 2013;7(1):33-42. 2. Spanevello A, Migliori GB, Sharara A, et al. Induced sputum to assess airway inflammation: A study of reproducibility. ClinExp Allergy. 1997;27(10):1138-1144. 3. Negewo NA, McDonald VM, Baines KJ, et al. Peripheral blood eosinophils: A surrogate marker for airway eosinophilia in sta- ble COPD. Int J Chron Obstruct Pulmon Dis. 2016;11: 1495-1504. 4. Bafadhel M, McKenna S, Terry S, et al. Acute exacerbations of chronic obstructive pulmonary disease: Identification of bio- logic clusters and their biomarkers. Am J Respir Crit Care Med. 2011;184(6):662-671. 5. Singh D, Kolsum U, Brightling CE, et al. Eosinophilic inflammation in COPD: Prevalence and clinical characteris- tics. Eur Respir J. 2014;44(6):1697-1700. https://doi.org/10. 1183/09031936.00162414 6. Landis SH, Suruki R, Hilton E, Compton C, Galwey NW. Stability of blood eosinophil count in patients with COPD in the UK clinical practice research datalink. COPD. 2017;14(4): 382-388. https://doi.org/10.1080/15412555.2017.1313827 7. Oshagbemi OA, Burden AM, Braeken DCW, et al. Stability of blood eosinophils in patients with chronic obstructive pulmonary disease and in control subjects, and the impact of sex, age, smoking, and baseline counts. Am J Respir Crit Care Med. 2017;195(10):1402-1404. https://doi.org/10.1164/rccm. 201701-0009LE 8. Saltürk C, Karakurt Z, Adiguzel N, et al. Does eosinophilic COPD exacerbation have a better patient outcome than non- eosinophilic in the intensive care unit? Int J Chron Obstruct Pulmon Dis. 2015;10:1837-1846. https://doi.org/10.2147/ COPD.S88058 9. Hasegawa K, Camargo CA Jr. Prevalence of blood eosinophilia in hospitalized patients with acute exacerbation of COPD. Respirology. 2016;21(4):761-764. https://doi.org/10.1111/resp. 12724 10. Bafadhel M, Greening NJ, Harvey-Dunstan TC, et al. Blood eosinophils and outcomes in severe hospitalized exacerbations of COPD. Chest. 2016;150(2):320-328. https://doi.org/10.1016/j 11. Couillard S, Larivée P, Courteau J, Vanasse A. Eosinophils in COPD exacerbations are associated with increased readmissions. Chest. 2017;151(2):366-373. https://doi.org/10. 1016/j.chest.2016.10.003 12. Bafadhel M, Davies L, Calverley PM, Aaron SD, Brightling CE, Pavord ID. Blood eosinophil guided prednisolone therapy for exacerbations of COPD: A further analysis. Eur Respir J. 2014; 44(3):789-791. https://doi.org/10.1183/09031936.00062614 13. Serafino-Agrusa L, Scichilone N, Spatafora M, Battaglia S. Blood eosinophils and treatment response in hospitalized exacerbations of chronic obstructive pulmonary disease: A case-control study. Pulm Pharmacol Ther. 2016;37:89-94. https://doi.org/10.1016/j.pupt.2016.03.004 14. Ko FWS, Chan KP, Ngai J, et al. Blood eosinophil count as a predictor of hospital length of stay in COPD exacerbations. Respirology. 2020;25(3):259-266. https://doi.org/10.1111/resp. 13660 15. Siddiqui SH, Guasconi A, Vestbo J, et al. Blood eosinophils: A biomarker of response to extrafine beclomethasone/formoterol in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2015;192(4):523-525. https://doi.org/10.1164/rccm. 201502-0235LE 16. Pascoe S, Locantore N, Dransfield MT, Barnes NC, Pavord ID. Blood eosinophil counts, exacerbations, and response to the addition of inhaled fluticasone furoate to vilanterol in patients with chronic obstructive pulmonary disease: A secondary analysis of data from two parallel randomised controlled trials. Lancet Respir Med. 2015;3(6):435-442. https://doi.org/10.1016/ S2213-2600(15)00106-X 17. Singh D, Kampschulte J, Wedzicha JA, et al. A trial of beclomethasone/formoterol in COPD using EXACT-PRO to measure exacerbations. Eur Respir J. 2013;41(1):12-17. https:// doi.org/10.1183/09031936.00207611 18. Vedel-Krogh S, Nielsen SF, Lange P, Vestbo J, Nordestgaard BG. Blood eosinophils and exacerbations in chronic obstructive pulmonary disease. The Copenhagen gen- eral population study. Am J Respir Crit Care Med. 2016;193(9): 965-974. 19. Hastie AT, Martinez FJ, Curtis JL, et al. Association of sputum and blood eosinophil concentrations with clinical measures of COPD severity: An analysis of the SPIROMICS cohort. Lancet Respir Med. 2017;5(12):956-967. https://doi.org/10.1016/S2213- 2600(17)30432-0 20. Siva R, Green RH, Brightling CE, et al. Eosinophilic airway inflammation and exacerbations of COPD: A randomised con- trolled trial. Eur Respir J. 2007;29(5):906-913. 21. Calverley PM, Tetzlaff K, Vogelmeier C, et al. Eosinophilia, frequent exacerbations, and steroid response in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2017;196(9):1219-1221. https://doi.org/10.1164/rccm.201612- 2525LE 22. Barnes NC, Sharma R, Lettis S, Calverley PM. Blood eosino- phils as a marker of response to inhaled corticosteroids in COPD. Eur Respir J. 2016;47(5):1374-1382. 23. Bafadhel M, McKenna S, Terry S, et al. Blood eosinophils to direct corticosteroid treatment of exacerbations of chronic obstructive pulmonary disease: A randomized placebo- controlled trial. Am J Respir Crit Care Med. 2012;186(1):48-55. https://doi.org/10.1164/rccm.201108-1553OC 24. Roche N, Chapman KR, Vogelmeier CF, 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. 25. DiSantostefano RL, Hinds D, Le HV, Barnes NC. Relationship between blood eosinophils and clinical characteristics in a cross-sectional study of a US population-based COPD cohort. Respir Med. 2016;112:88-96. 26. Baloira Villar A, Pallarés SA. Chronic obstructive pulmonary disease with eosinophilia, an emerging phenotype? Arch Bronconeumol. 2016;52(4):177-178. 27. Bhatt SP. Eosinophils in COPD: The Janus of phenotyping response to therapy? Lancet Respir Med. 2016;4(9):681-683. ACET-ÖZTÜRK ET AL. 55 https://orcid.org/0000-0003-1005-3205 https://orcid.org/0000-0003-1005-3205 https://orcid.org/0000-0003-1005-3205 https://orcid.org/0000-0002-7400-9089 https://orcid.org/0000-0002-7400-9089 https://orcid.org/0000-0002-7400-9089 https://doi.org/10.1183/09031936.00162414 https://doi.org/10.1183/09031936.00162414 https://doi.org/10.1080/15412555.2017.1313827 https://doi.org/10.1164/rccm.201701-0009LE https://doi.org/10.1164/rccm.201701-0009LE https://doi.org/10.2147/COPD.S88058 https://doi.org/10.2147/COPD.S88058 https://doi.org/10.1111/resp.12724 https://doi.org/10.1111/resp.12724 https://doi.org/10.1016/j https://doi.org/10.1016/j.chest.2016.10.003 https://doi.org/10.1016/j.chest.2016.10.003 https://doi.org/10.1183/09031936.00062614 https://doi.org/10.1016/j.pupt.2016.03.004 https://doi.org/10.1111/resp.13660 https://doi.org/10.1111/resp.13660 https://doi.org/10.1164/rccm.201502-0235LE https://doi.org/10.1164/rccm.201502-0235LE https://doi.org/10.1016/S2213-2600(15)00106-X https://doi.org/10.1016/S2213-2600(15)00106-X https://doi.org/10.1183/09031936.00207611 https://doi.org/10.1183/09031936.00207611 https://doi.org/10.1016/S2213-2600(17)30432-0 https://doi.org/10.1016/S2213-2600(17)30432-0 https://doi.org/10.1164/rccm.201612-2525LE https://doi.org/10.1164/rccm.201612-2525LE https://doi.org/10.1164/rccm.201108-1553OC 28. http://goldcopd.org/global-strategy-diagnosis-management- prevention-copd-2016/ 29. Jones PW, Quirk FH, Baveystock CM. The St George’s Respira- tory Questionnaire. Respir Med. 1991;85(Suppl.B):25-31. 30. Bestall JC, Paul EA, Garrod R, Garnham R, Jones PW, Wedzicha JA. Usefulness of the Medical Research Council (MRC) dyspnoea scale as a measure of disability in patients with chronic obstructive pulmonary disease. Thorax. 1999; 54(7):581-586. 31. Polatlı M, Yorgancıo�glu A, Aydemir Ö, et al. Validity and reli- ability of Turkish version of St. George’s Respiratory Question- naire Tuberk Toraks. 2013;61(2):81-87. 32. Yorgancıo�glu A, Polatlı M, Aydemir Ö, et al. Reliability and validity of Turkish version of COPD assessment test. Tuberk Toraks. 2012;60(4):314-320. 33. Miller MR, Hankinson J, Brusasco V, et al. ATS/ERS task force. Standardisation of Spirometry Eur Respir J. 2005;26(2): 319-338. 34. Wu HX, Zhuo KQ, Cheng DY. Prevalence and baseline clinical characteristics of eosinophilic chronic obstructive pulmonary disease: A meta-analysis and systematic review. Front Med (Lausanne). 2019;10(6):282. https://doi.org/10.3389/fmed.2019. 00282 35. Pavord ID, Lettis S, Anzueto A, Barnes N. Blood eosinophil count and pneumonia risk in patients with chronic obstructive pulmonary disease: A patient-level meta-analysis. Lancet Res- pir Med. 2016;4(9):731-741. https://doi.org/10.1016/S2213-2600 (16)30148-5 36. Lonergan M, Dicker AJ, Crichton ML, et al. Blood neutrophil counts are associated with exacerbation frequency and mortal- ity in COPD. Respir Res. 2020;21(1):166-176. https://doi.org/10. 1186/s12931-020-01436-7 37. Viinanen A, Lassenius MI, Toppila I, et al. The burden of chronic obstructive pulmonary disease (COPD) in Finland: Impact of disease severity and eosinophil count on healthcare resource utilization. Int J Chron Obstruct Pulmon Dis. 2019;14: 2409-2421. https://doi.org/10.2147/COPD.S222581 38. Müllerov�a H, Hahn B, Simard EP, Mu G, Hatipo�glu U. Exacer- bations and health care resource use among patients with COPD in relation to blood eosinophil counts. Int J Chron Obstruct Pulmon Dis. 2019;14:683-692. https://doi.org/10.2147/ COPD.S194367 39. Trudo F, Kallenbach L, Vasey J, et al. Clinical and economic burden of eosinophilic COPD in a large retrospective US cohort. Int J Chron Obstruct Pulmon Dis. 2019;14:2625-2637. https://doi.org/10.2147/COPD.S220009 40. Kerkhof M, Sonnappa S, Postma DS, et al. Blood eosinophil count and exacerbation risk in patients with COPD. Eur Respir J. 2017;50(1):1700761. https://doi.org/10.1183/13993003.00761- 2017 41. Wells JM, Estepar RS, McDonald MN, et al. Clinical, physio- logic, and radiographic factors contributing to development of hypoxemia in moderate to severe COPD: A cohort study. BMC Pulm Med. 2016;16(1):169-178. 42. Oh YM, Lee KS, Hong Y, et al. Blood eosinophil count as a prognostic biomarker in COPD. Int J Chron Obstruct Pulmon Dis. 2018;13:3589-3596. https://doi.org/10.2147/COPD.S179734 43. Busacker A, Newell JD Jr, Keefe T, et al. A multivariate analy- sis of risk factors for the air-trapping asthmatic phenotype as measured by quantitative CT analysis. Chest. 2009;135(1): 48-56. https://doi.org/10.1378/chest.08-0049 How to cite this article: Acet-Öztürk NA, Dilektasli AG, Aydın-Güçlü Ö, et al. Long-term oxygen treatment need is less frequent in eosinophilic COPD patients. Clin Respir J. 2022; 16(1):49-56. doi:10.1111/crj.13451 56 ACET-ÖZTÜRK ET AL. https://doi.org/10.3389/fmed.2019.00282 https://doi.org/10.3389/fmed.2019.00282 https://doi.org/10.1016/S2213-2600(16)30148-5 https://doi.org/10.1016/S2213-2600(16)30148-5 https://doi.org/10.1186/s12931-020-01436-7 https://doi.org/10.1186/s12931-020-01436-7 https://doi.org/10.2147/COPD.S222581 https://doi.org/10.2147/COPD.S194367 https://doi.org/10.2147/COPD.S194367 https://doi.org/10.2147/COPD.S220009 https://doi.org/10.1183/13993003.00761-2017 https://doi.org/10.1183/13993003.00761-2017 https://doi.org/10.2147/COPD.S179734 https://doi.org/10.1378/chest.08-0049 info:doi/10.1111/crj.13451 Long-term oxygen treatment need is less frequent in eosinophilic COPD patients 1 INTRODUCTION 2 MATERIALS AND METHODS 2.1 Study setting and study population 2.2 Definitions 2.3 Definition of AECOPD 2.4 Definition of eosinophilic COPD 2.5 Measurements 2.6 Statistical analyses 3 RESULTS 4 DISCUSSION 4.1 Limitations 5 CONCLUSION ACKNOWLEDGMENT ETHICS STATEMENT AUTHOR CONTRIBUTIONS FUNDING INFORMATION CONFLICT OF INTEREST DATA AVAILABILITY STATEMENT REFERENCES