International Journal of Chronic Obstructive Pulmonary Disease Dovepress open access to scientific and medical research Open Access Full Text Article ORIGINAL RESEARCH Association Between Routine Blood Biomarkers and Clinical Phenotypes and Exacerbations in Chronic Obstructive Pulmonary Disease This article was published in the following Dove Press journal: International Journal of Chronic Obstructive Pulmonary Disease Alexa Nuñez 1,2, * Introduction: Chronic obstructive pulmonary disease (COPD) is associated with increased Viviana Marras 3, * lung and systemic inflammation. We aimed to identify associations between easy-to-obtain Matevz Harlander 4 blood biomarkers and the frequency and severity of exacerbations. Evgeni Mekov 5 Methods: Cross-sectional, multicentre study performed in four centres in Spain, Italy, Bulgaria, and Slovenia. Blood samples were obtained for blood cell count, C-reactive protein Cristina Esquinas 1 (CRP), alpha-1 antitrypsin (AAT) and fibrinogen analysis. The neutrophil/lymphocyte ratio Matjaz Turel 4 (NLR), platelet/lymphocyte ratio (PLR) and eosinophil/basophil ratio (EBR) were calculated. David Lestan 4 Firstly, patients were divided into clinical phenotypes according to the Spanish guidelines of Rosen Petkov 5 COPD, and secondly, patients were classified into 2 groups: non-exacerbators (≤1 ambula- Nikolay Yanev 5 tory exacerbation in the previous year) and exacerbators (≥2 ambulatory exacerbations or Pietro Pirina 3 1 hospitalisation in the previous year). A multivariate stepwise logistic regression model was Silvia Negri 3 performed to identify laboratory parameters associated with exacerbators. Marc Miravitlles 1,2,6 Results: A total of 355 patients with a mean age 66 years (SD=8.9) were included, and 64% Miriam Barrecheguren 1 were male. The mean FEV1% (forced expiratory volume in the first second) was 55% 1 Pneumology Department, Hospital (SD=20%), and the mean COPD Assessment Test (CAT) score was 15.6 (SD=7.9). One Universitari Vall d´Hebron/Vall d’Hebron hundred ninety-six (55.2%) patients were classified in the non-exacerbator group, and 159 Institut de Recerca (VHIR), Barcelona, (44.8%) were exacerbators. Patients in the exacerbators group presented lower haemoglobin Spain; 2Medicine Department, Autonomous University of Barcelona levels (p=0.019) and ERB (p= 0.023) but higher CRP levels (p=0.001). In the multivariate (UAB), Barcelona, Spain; 3Respiratory analysis, females, higher levels of CRP, lower FEV1% and low EBR were independently Unit, AOU Sassari, Sassari, Italy; related to exacerbators. 4 Department of Pulmonary Diseases, University Medical Centre Ljubljana, Conclusion: Female sex, having a more severe impairment of lung function, higher CRP Ljubljana, Slovenia; 5Department of levels and a lower EBR are associated with an exacerbator phenotype in COPD. Pulmonary Diseases, Medical Faculty, Keywords: COPD, blood cells, biomarkers, exacerbation, phenotypes Medical University of Sofia, Sofia, Bulgaria; 6CIBER de Enfermedades Respiratorias (CIBERES), Barcelona, Spain *These authors contributed equally to Introduction this work Chronic obstructive pulmonary disease (COPD) is characterised by chronic airflow limitation and persistent symptoms.1 COPD is mainly caused by tobacco smoking and is currently the third leading cause of death worldwide.1,2 Chronic airway and lung inflammation are the main characteristics of the pathogen- Correspondence: Marc Miravitlles Pneumology Department, Hospital esis of COPD and are associated with a collapse of small airways, parenchymal destruc- Universitari Vall d´Hebron, P. Vall tion and goblet cell proliferation in bronchial epithelium.3 Moreover, it is known that d’Hebron 119-129, Barcelona 08035, Spain COPD may be associated with systemic inflammation and comorbidities.4 Tel +34 934893000 The natural course of COPD is altered by episodes of exacerbations characterised Fax +34 93 274 82 08 Email marcm@separ.es by an increase of both pulmonary and systemic inflammation.5 In the last years, there submit your manuscript | www.dovepress.com International Journal of Chronic Obstructive Pulmonary Disease 2020:15 681–690 681 DovePress © 2020 Nuñez et al. This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms. http://doi.org/10.2147/COPD.S240720 php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. 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Nuñez et al Dovepress has been increasing interest in describing biomarkers that symptoms (cough, expectoration, wheezing), and number could help predict the occurrence of exacerbations of of ECOPD in the previous 12 months collected from the COPD (ECOPD) and the clinical evolution of COPD, and clinical history, and the degree of dyspnoea assessed therefore, the use of these biomarkers could help in thera- according to the modified Medical Research Council peutic decision making.6 (mMRC) dyspnoea scale.13 The BODEx index14 (body Some of the biomarkers proposed in stable and exacer- mass index, airway obstruction, dyspnoea, severe exacer- bated COPD patients include neutrophil counts, C-reactive bations) was calculated,and the COPD Assessment Test protein (CRP), tumor necrosis factor α, interleukin (IL) 6, (CAT)15 score was obtained. IL-8 and fibrinogen.7,8 However, only fibrinogen has been Moderate ECOPD was defined as an acute increase in accepted as a reliable biomarker for use in clinical trials respiratory symptoms requiring ambulatory treatment with because of its repeatability and correlation with variables antibiotics and/or systemic corticosteroids. When the episode of COPD severity and prognosis, although it is not a good required treatment in a hospital setting or assistance in the predictor of the risk of ECOPD.9 emergency room for at least 24 hrs it was considered severe.6 Recent studies have proposed the use of other markers Firstly patients were divided into clinical phenotypes obtained in routine blood analysis, such as the neutrophil/ according to the GesEPOC criteria:16 1) non-exacerbator lymphocyte ratio (NLR), the platelet/lymphocyte ratio (NE): patients with 0 or 1 ECOPD in the previous year; 2) (PLR) and the eosinophil/basophil ratio (EBR), as markers exacerbator with emphysema (EE): patients presenting at of the risk and severity of ECOPD and as prognostic least two ECOPD in the previous year and clinical/radi- markers of hospital mortality due to ECOPD.10–12 ological or functional evidence of emphysema; 3) exacer- The importance of the identification of routine blood bator with chronic bronchitis (ECB): exacerbators with test biomarkers lays in better characterisation of COPD cough and expectoration for at least 3 months of the year patients and personalisation of the management of the over two consecutive years; and 4) asthma–COPD over- disease. The aim of our study was to identify the possible lap: patients with a concomitant diagnosis of asthma and/ associations between routine blood biomarkers and the or blood eosinophilia ≥ 300 cells/µL.17 frequency and severity of ECOPD in an international Secondly, they were classified into 2 groups: exacer- cohort of patients with COPD. bators, defined as patients with ≥ 2 ambulatory exacerba- tions or 1 hospitalisation, or non-exacerbators defined as Methods patients presenting ≤ 1 ambulatory exacerbation in the This was an observational, cross-sectional, multicentre previous year. Finally, patients were classified according study performed in pneumology departments of four to the new Global Obstructive Lung Disease (GOLD) teaching hospitals in Spain, Italy, Slovenia and Bulgaria. 2019 A-D classification.18 We included ambulatory COPD patients of 40 years of age or older; current or former smokers with a smoking history Analysis of Biomarkers of at least 10 pack-years and a post-bronchodilator FEV1 Routine blood analyses were performed during stable (forced expiratory volume in the first second)/FVC (forced phase in all the patients. The following biomarkers were vital capacity) ratio < 0.7; and in stable state, at least 1 analysed: blood cell count, CRP, alpha1-antitrypsin (AAT) month following recovery from the last ECOPD. The and fibrinogen. In addition, the following indices were exclusion criteria were the presence of another chronic calculated: the NLR was defined as the absolute neutrophil respiratory disease (eg cystic fibrosis, severe bronchiecta- count divided by the absolute lymphocyte count, the EBR sis, cancer or restrictive lung disease) or systemic inflam- as the division between the absolute eosinophil count and matory disease and inability to complete the quality of life the absolute basophil count, and finally, the PLR was questionnaires. Patients were included consecutively if defined as the platelet count divided by the absolute lym- inclusion and exclusion criteria were fulfilled. phocyte count. Variables Statistical Analysis Sociodemographic characteristics and clinical COPD data Qualitative variables were described with absolute fre- were collected from all the patients. Other variables were quencies and percentages. The description of quantitative studied including spirometry, self-reported clinical variables was performed using the mean, standard submit your manuscript | www.dovepress.com International Journal of Chronic Obstructive Pulmonary Disease 2020:15 682 DovePress Dovepress Nuñez et al deviation (SD), median and quartiles. The Kolmogorov– COPD patients in Bulgaria had a higher rate of severe Smirnov test was used to assess the normality of ECOPD (p<0.001) and higher CRP levels (p<0.001) than distributions. patients from other countries (Table 1). The patient characteristics were compared according to the country, phenotype, the presence of previous ECOPD Characteristics of Patients According to and GOLD A to D groups. In the case of quantitative Clinical Phenotypes variables, the Student’s t-test (Mann–Whitney U-test if No significant differences were observed between clinical normality was not assumed) or ANOVA tests (in the case phenotypes in terms of age, sex or smoking history. of country and phenotype) were carried out. The Chi- However, COPD patients classified as ECB had a higher squared test (Fisher test for frequencies <5) was used for BMI (p<0.001) and more frequent moderate ECOPD in the comparison of categorical variables. the previous year than the remaining patients (p<0.001). A multivariate model was developed using backward Regarding blood biomarkers, ECB patients presented stepwise logistic regression analysis including the presence higher CRP levels (p<0.001) and NLR (p=0.024) but had of exacerbator phenotype as the dependent variable. a lower platelet count (p=0.018). Variables with a significance <0.2 in the univariate analysis COPD patients classified as EE had a higher degree of were included as independent variables. The results were dyspnoea (p<0.001), higher BODEx (p<0.001) and CAT described with odds ratios (OR), 95% confidence interval scores (p<0.001), a higher rate of ECOPD in the (CI) and p-values. For all the tests, p-values < 0.05 were previous year (p<0.001) and more severe lung function considered statistically significant. The statistical package impairment (p<0.001) than the remaining clinical phenotypes. SPSS (V 25) was used for the statistical analyses. ACO patients presented a lower degree of dyspnoea and better FEV1% (p<0.001) as well as a higher eosino- Results phil count (p<0.001), ELR (p=0.001) and EBR (p<0.001) A total of 355 patients were included. The mean age (SD) (Table 2). was 66 years (8.9) and 64.5% were male. Thirty-three per- cent were active smokers with a mean tobacco consumption Routine Blood Biomarkers According to of 40.8 (25.9) pack-years. The mean degree of dyspnoea the Presence of Exacerbations and (mMRC) was 1.8 (1), and the mean post-bronchodilator GOLD Groups FEV1% was 55% (19.9%). Patients had a mean CAT score Out of 355 COPD patients, 196 (55.2%) were classified in of 15.6 (7.9) and a mean BODEx index of 2.7 (2). Regarding the non-exacerbator group and 159 (44.8%) were classified clinical phenotypes,181 (51%) patients were classified as as exacerbators. On comparing blood parameters between NE, 73 (20.6%) as EE, 55 (15.5%) as ECB and 46 (13%) the two groups, we found that the exacerbators group as ACO. The mean rates of moderate and severe exacerba- presented lower haemoglobin levels (p=0.019) and EBR tions in the previous year were 0.8 (1.2) and 0.5 (0.9) respec- (p=0.023). In contrast, they presented higher CRP levels tively. The sociodemographic and clinical characteristics of (p=0.001). Figures 1 and 2 show the CRP levels and the the patients are shown in Table 1. EBR according to exacerbations, respectively. As for the rest of the biomarkers studied, we did not find significant Characteristics of Patients According to differences between groups. When comparing between the the Geographical Region GOLD groups, C and D patients presented higher levels of No significant differences were found in terms of age, CRP (p<0.05), and lower levels of AAT were observed in number of active smokers, BMI or CAT scores (Table 1). the group C (p<0.05). No other significant differences However, compared with patients from other countries, were found in the rest of the studied biomarkers. COPD patients in Spain had greater tobacco exposure Complete data are described in Table 3. (p<0.001), more severely impaired lung function in terms of FEV1% (p<0.001), a higher BODEx index and a higher Multivariate Analysis to Determine rate of moderate ECOPD. A higher BODEx index was Factors Associated with Exacerbations also observed in Bulgarian patients and more frequent Multivariate analysis showed that females (OR=5, moderate ECOPD in Italian patients. On the other hand, p=0.002), high levels of CRP (OR=1.35, p=0.049), submit your manuscript | www.dovepress.com International Journal of Chronic Obstructive Pulmonary Disease 2020:15 683 DovePress Nuñez et al Dovepress Table 1 Sociodemographic and Clinical Characteristics of COPD Patients Included Variable Global (N=355) Spain (N=80) Italy (N=82) Slovenia (N=97) Bulgaria (N=96) *p value Age, years 66.6 (8.9) 65.9 (8.9) 68.5 (10.3) 67.1 (8.1) 65.1 (8.1) 0.065 Sex, male (%) 229 (64.5) 57 (71.3) 59 (72) 53 (54.6) 60 (62.5) 0.049 Ex-smokers (%) 233 (66.8) 60 (75) 51 (67.1) 61 (62.9) 61 (63.5) 0.314 Pack-years (smokers/ex) 41 (26) 52 (32) 46 (28) 39 (22) 28 (15) <0.001 BMI (kg/m2) 25.8 (5) 25.1 (5.4) 26.1 (5.6) 25.6 (4.6) 26.3 (4.5) 0.421 mMRC 1.8 (1) 1.8 (0.9) 2 (1) 1.4 (1) 2.1 (1) <0.001 Cough (%) 240 (67.6) 45 (56.3) 50 (61) 55 (56.7) 90 (93.8) <0.001 Wheezing (%) 140 (39.4) 24 (30) 26 (31.7) 21 (21.6) 69 (71.9) <0.001 Sputum (%) 228 (64.4) 45 (56.3) 54 (65.9) 61 (62.9) 68 (71.6) 0.201 Dyspnoea (%) 295 (83.1) 64 (80) 70 (85.4) 82 (84.5) 79 (82.3) 0.793 FVC (mL) 2708 (956) 2395 (922) 2381 (715) 3060 (962) 2752 (1043) <0.001 FVC (%) 67.9 (18.3) 65.7 (18.4) 76.8 (16.6) 82.2 (19.3) 66.4 (18.9) <0.001 FEV1 (mL) 1475 (625) 1253 (581) 1518 (489) 1567 (697) 1525 (649) 0.005 FEV1 (%) 55 (19.9) 44.6 (16.4) 62.8 (16.1) 56.2 (21.6) 55.8 (20.2) <0.001 FEV1/FVC 54.2 (12.1) 51.7 (10.2) 60.5 (10.2) 50.1 (13.1) 55.7 (11.7) 0.412 Phenotypes(%) - NE 181 (51) 36 (45) 57 (69.5) 66 (68) 22 (22.9) <0.001 - ACO 46 (13) 8 (10) 7 (8.5) 18 (18.6) 13 (13.5) - EE 73 (20.6) 30 (37.5) 6 (7.3) 7 (7.2) 30 (31.3) - ECB 55 (15.5) 6 (7.5) 12 (14.6) 6 (6.2) 31 (32.3) BODEx index 2.7 (2) 3.3 (1.9) 2.1 (1.5) 1.9 (1.8) 3.3 (2.1) <0.001 CAT 15.6 (7.9) 15 (7.9) 17 (7.4) 14.9 (6.6) 15.6 (9.2) 0.294 Moderate exacerbations 0.8 (1.2) 1 (1.3) 1.2 (1.5) 0.5 (0.9) 0.7 (0.8) <0.001 Severe exacerbations 0.5 (0.9) 0.7 (1) 0.2 (0.5) 0.1 (0.4) 1.1 (0.9) <0.001 Leukocytes (x 103 μL) 8.4 (2.2) 8.5 (2.4) 8.1 (1.8) 8.2 (2.1) 8.6 (2.3) 0.342 Eosinophils (x 103 μL) 0.2 (0.4) 0.3 (0.6) 0.3 (0.3) 0.2 (0.1) 0.2 (0.2) 0.196 CRP (mg/dL) 2.4 (3.3) 0.9 (1.2) 0.8 (1.1) 1.5 (1.4) 4.4 (4.2) <0.001 AAT (mg/dL) 151 (34) 151 (37) 150 (48) 159 (28) 143 (25) 0.013 Fibrinogen (mg/dL) 4.6 (13.2) 7.2 (2.7) 3.3 (0.9) 3.9 (0.8) 4 (1) 0.269 Notes: Values are means (standard deviations), unless otherwise specified. *p value results when comparing data from the four countries by ANOVA or Chi-squared tests, considered statistically significant when <0.05. Abbreviations: BMI, body mass index; mMRC, modified Medical Research Council; FVC, forced vital capacity; FEV1, forced expiratory volume in the first second; NE, non- exacerbator; ACO, asthma-COPD overlap; EE, exacerbator with emphysema; ECB, exacerbator with chronic bronchitis; BODEx, body mass index; airway obstruction; dyspnoea; severe exacerbations; CAT, COPD assessment test; CRP, C-reactive protein; AAT, alpha1-antitrypsin. a lower FEV1% (OR=0.92, p=0.008) and a low EBR validated biomarkers to help recognize the frequent (OR=0.489, p=0.002) were significantly and indepen- exacerbator phenotype of COPD. The identification of dently related to being an exacerbator (Table 4). easy-to-obtain systemic biomarkers associated with fre- quent exacerbations may help physicians to identify at Discussion risk COPD patients and take adequate preventive mea- COPD is a chronic respiratory disease that is associated sures. In this context, we analysed data from this multi- with systemic inflammation,4 and increased systemic centre and international study in order to identify the inflammation may be associated with a higher risk of possible associations of different routine blood test bio- exacerbations and more or more severe comorbidities.4 markers with the history of ECOPD and clinical Exacerbations play an important role in the natural history phenotypes. of COPD, being one of the main causes of mortality.19 In our cohort, patients with exacerbations presented Nowadays, the best predictor of ECOPD is having lower levels of haemoglobin and EBR and higher levels a history of previous ECOPD,20,21 and there are still no of CRP. Moreover, in the multivariate analysis, females, submit your manuscript | www.dovepress.com International Journal of Chronic Obstructive Pulmonary Disease 2020:15 684 DovePress Dovepress Nuñez et al Table 2 Characteristics of the Patients According to the Clinical Phenotype Variables Non- ACO (N=46) Exacerbator with Exacerbator with *p value Exacerbator Emphysema (N=73) Chronic Bronchitis (N= 181) (N= 55) Age, years 67.1 (8.3) 65.5 (9.4) 66.6 (8.2) 65.9 (11) 0.650 Sex, male (%) 122 (67.4) 24 (52.2) 47 (64.4) 36 (65.5) 0.291 Ex smokers (%) 112 (63.3) 34 (73.9) 56 (79.7) 31 (58.5) 0.074 Pack-years (smokers and ex) 44(27) 31 (22) 41 (23) 37 (27) 0.010 BMI (kg/m2) 25.5 (4.9) 26.2 (4.8) 24.2 (4.2) 28.4 (5.8) <0.001 mMRC 1.6 (0.9) 1.5 (0.9) 2.3 (0.9) 2.1 (1) <0.001 FEV1 (%) 57.8 (18.4) 64.6 (16.1) 39.3 (16.6) 58.7 (20.5) <0.001 BODEx index 2 (1.6) 1.9 (1.5) 4.6 (1.8) 3.1 (1.7) <0.001 CAT 14.1 (7.1) 14.7 (7.5) 18.4 (8.8) 17.4 (7.9) <0.001 Moderate exacerbations 0.4 (0.5) 0.8 (1.2) 1.5 (1.3) 1.5 (1.6) <0.001 Severe exacerbations 0.1 (0.2) 0.6 (1) 1.3 (1) 1 (0.8) <0.001 Laboratory Findings Haemoglobin (g/dL) 14.5 (1.6) 14.5 (1.2) 14.2 (1.8) 14.2 (1.7) 0.511 Haematocrit (%) 44.2 (4.4) 43.8 (4.1) 44.3 (5.3) 44.3 (5.6) 0.937 Platelets (x 103 μL) 252 (78) 266 (62) 262 (70) 246 (64) 0.018 Fibrinogen (mg/dL) 5.3 (18.9) 3.7 (0.8) 4 (1) 4 (0.8) 0.269 CRP (mg/dL) 1.6 (2.3) 1.4 (1.4) 3.1 (3.8) 3.8 (4.5) <0.001 AAT (mg/dL) 154 (35) 141 (27) 148 (37) 154 (31) 0.013 Leukocyte (x 103 μL) 8.3 (2.3) 8.2 (1.8) 8.5 (2.3) 8.5 (2) 0.759 Neutrophil (x 103 μL) 5.5 (4.1) 6.2 (8.5) 5.5 (1.9) 5.4 (1.9) 0.803 Neutrophil (%) 62.2 (9.5) 59.6 (10.8) 64 (9.7) 62.5 (10.4) 0.136 Lymphocytes (x 103 μL) 2.4 (2.9) 2.8 (3.8) 2.1 (0.8) 2.1 (0.7) 0.506 Lymphocytes (%) 26.6 (8.4) 27.8 (9.4) 24.6 (8) 26.1 (9) 0.220 Eosinophils (x 103 μL) 0.2 (0.2) 0.5 (0.8) 0.2 (0.2) 0.2 (0.2) <0.001 Eosinophils (%) 2.4 (1.7) 3.8 (3) 2.3 (1.9) 2.5 (2) <0.001 NLR 2.8 (1.6) 2.7 (2) 3.1 (1.7) 3.4 (3.9) 0.024 ELR 0.1 (0.1) 0.2 (0.4) 0.1 (0.1) 0.1 (0.1) 0.001 EBR 4.2 (3.3) 8 (10) 3.4 (3.1) 3 (3) <0.001 PLR 133 (71) 138 (87) 144 (59) 132 (76) 0.708 Platelets (x 103 μL) 252 (72) 266 (62) 262 (70) 246 (64) 0.459 Notes: Values are means (standard deviations), unless otherwise specified. *p value results when comparing data between all the clinical phenotypes by ANOVA or Chi- squared tests, considered statistically significant when <0.05. Abbreviations: BMI, body mass index; mMRC, modified Medical Research Council; FVC, forced vital capacity; FEV1, forced expiratory volume in the first second; NE, non- exacerbator; ACO, asthma-COPD overlap; EE, exacerbator with emphysema; ECB, exacerbator with chronic bronchitis; BODEx, body mass index; airway obstruction; dyspnoea; exacerbations; CAT, COPD assessment test; CRP, C-reactive protein; AAT, alpha1-antitrypsin; NLR, neutrophil/lymphocyte ratio; ELR, eosinophil/lymphocyte ratio; EBR, eosinophil/basophil ratio; PLR, platelet/lymphocyte ratio. a more impaired FEV1%, higher levels of CRP and was not identified as an associated independent factor in a lower EBR were variables independently and signifi- the multivariate analysis. cantly associated with exacerbations. Regarding inflammatory blood biomarkers, we found Low haemoglobin concentrations are commonly higher CRP concentrations in patients with more exacer- observed in COPD patients and have been studied as bations, especially in those with chronic bronchitis. CRP is a prognostic factor in this disease.22,23 As an example, the prototypical acute-phase reactant and is a useful bio- several studies have observed that presenting low haemo- marker to detect infection and tissue injury. CRP has been globin concentrations during admission due to ECOPD is used to control the progression of chronic diseases such as related to increased mortality after discharge.24–26 In the inflammatory rheumatoid diseases and as a biomarker of present study, patients reporting at least two ECOPD or future cardiovascular events.27 In COPD, previous studies one hospitalisation in the previous year had significantly have described elevated CRP levels as a good predictor for lower haemoglobin concentrations, although haemoglobin readmission and a marker of poor outcome after an submit your manuscript | www.dovepress.com International Journal of Chronic Obstructive Pulmonary Disease 2020:15 685 DovePress Nuñez et al Dovepress 4 infections and a higher hospital stay.37 On the other hand, p= 0.01 basophils are related to inflammatory responses in immune diseases.38 The use of EBR as a biomarker in COPD was 3 C- reactive protein (mg/dL) previously described by Xiong et al,12 who demonstrated that a higher EBR was associated with a lower rate of 2 exacerbations and better survival. In accordance these results, a lower EBR was observed in our patients with frequent exacerbations. As expected, the highest EBR was 1 observed in patients with ACO, who also had higher eosi- nophil levels, suggesting that increased eosinophilic inflam- mation in COPD is a marker of better prognosis compared 0 Non-exacerbators Exacerbators with other phenotypes of the disease.11,34 In contrast to previous data, we could not replicate the Figure 1 C- reactive protein (CRP) in exacerbators and non-exacerbators. Notes: Non-exacerbators: patients with ≤ 1 ambulatory exacerbation in the relationship found between some other biomarkers and previous year; Exacerbators: patients with ≥ 2 ambulatory exacerbations or 1 exacerbations. In our study, neither the NLR nor the PLR hospitalisation in the previous year. Abbreviation: CRP, C-reactive protein. or platelet count, were significantly elevated in patients with a history of exacerbations. However, the NLR was significantly elevated if the exacerbators had the chronic 7 bronchitis phenotype. In contrast, exacerbators with p= 0.023 6 emphysema showed a higher but non-significant PLR. Eosinophil-basophil ratio Elevated NLRs have been associated with the risk of 5 exacerbations in previous studies, although no differences 4 between different types of exacerbators (i.e chronic bronchitic, emphysematous or ACO) were reported.39,40 3 An elevated platelet count has been described to be asso- 2 ciated with worse COPD morbidity, more severe lung function impairment, a higher likelihood of presenting 1 ECOPD41 and with increased mortality during an 0 Non-exacerbators Exacerbators exacerbation.42 Similarly, an elevated PLR has been pro- posed as a useful marker for increased risk of exacerba- Figure 2 Eosinophil/basophil ratio (EBR) in exacerbators and non-exacerbators. Notes: Non-exacerbators: patients with ≤ 1 ambulatory exacerbation in the tions and mortality after discharge for an ECOPD.43–45 previous year; Exacerbators: patients with ≥ 2 ambulatory exacerbations or 1 Some of the differences observed in the associations hospitalisation in the previous year. between biomarkers and exacerbations between our study and previous studies may be related to the inclusion cri- ECOPD.28,29 Elevated baseline CRP levels have also been teria. Most of the previous studies included patients during associated with higher mortality,30 and together with an ambulatory or hospital ECOPD, and therefore, signifi- a high fibrinogen and leukocyte count were also associated cantly increased inflammatory biomarkers would be with increased risk of having exacerbations.31 expected. In our study, the patients were included during In addition, AAT levels were lower in ACO and EE. a stable state and associations between the serum concen- Higher AAT and CRP levels have shown to be associated trations of biomarkers with a previous history of ECOPD with an increased risk of COPD in the general population were analysed. Although this interference was eliminated without AAT deficiency;32,33 however, the reduced levels of from our study by including only stable patients, it cannot AAT observed in ACO patients have not been described be ruled out that patients with frequent exacerbations and previously.34,35 chronic bronchitis may have chronic colonization and this Eosinophils are end-stage cells produced under the influ- might explain some elevated biomarkers, such as CRP. ence of macrophage colony-stimulating factor, interleukin The main limitation of our study was the cross- (IL)-3 and the late differentiation factor IL-5.36 Non eosino- sectional design that did not allow analysis of the prog- philic exacerbations in COPD are related to more severe nostic value of the biomarkers, but rather, only the submit your manuscript | www.dovepress.com International Journal of Chronic Obstructive Pulmonary Disease 2020:15 686 DovePress Dovepress Nuñez et al Table 3 Blood Biomarkers According to Non-Exacerbator/Exacerbator Phenotype and GOLD Groups Laboratory parameters Non- Exacerbators Exacerbators GOLD Groups (N=196) (N=159) Group A Group B Group C Group D (N= 45) (N= 148) (N= 20) (N= 142) Haemoglobin (g/dL) 14.5 (1.5) 14.2 (1.6)a 14.6 (1.5) 14.5 (1.6) 14.8 (1.3) 14.1 (1.7) Haematocrit (%) 44 (4.6) 44.2 (4.9) 44.5 (4.4) 44.1 (4.5) 46.2 (3.8) 43.8 (5.2) Platelets (x 103 μL) 251 (77) 260 (66) 261.6 (75) 249.3 (79) 245.3 (61) 261.5 (67) Fibrinogen (mg/dL) 3.8 (0.8) 3.9 (0.9) 4 (0.9) 5.5 (2.8) 3.8 (0.9) 3.9 (0.9) CRP (mg/dL) 1.6 (2.2) 3.0 (3.9)b 1.4 (1.6) 1.7 (2.5) 2.8 (3.2) 3 (3.9)c AAT (mg/dL) 153 (34) 149 (33) 144.9 (34) 155.6 (35) 134 (34) 152 (33)c Leukocyte (x 10 μL)3 8.3 (2.2) 8.4 (2.1) 8.2 (2) 8.3 (2.3) 8.2 (2.1) 8.4 (2.1) Neutrophil (x 103 μL) 5.7 (2.7) 5.3 (1.8) 5.1 (1.7) 6 (6.5) 5.1 (1.6) 5.4 (1.9) Lymphocyte (x 103 μL) 2.5 (3.3) 2.1 (0.7) 2.1 (0.6) 2.6 (3.9) 2.2 (0.8) 2.1 (0.7) Eosinophils (x 103 μL) 0.2 (0.4) 0.2 (0.2) 0.2 (0.2) 0.3 (0.5) 0.2 (0.2) 0.2 (0.2) Eosinophils (%) 2.4 (1.8) 2.7 (2.3) 2.7 (1.4) 2.4 (1.9) 2.6 (2.2) 2.7 (2.3) Basophil (x 103 μL) 0.5 (0.8) 0.5 (0.5) 0 (0) 0.1 (0.1) 0.1 (0.1) 0 (0) NLR 2.8 (1.6) 3.0 (2.7) 2.6 (1.1) 2.9 (1.8) 2.8 (1.5) 3.1 (2.8) ELR 0.1 (0.2) 0.1 (0.1) 0.1 (0.1) 0.1 (0.2) 0.1 (0.1) 0.1 (0.1) EBR 5.0 (6.1) 3.6 (3.1)a 5.6 (5.9) 4.9 (6.2) 3 (2.4) 3.7 (3.2) PLR 134 (72) 141 (72) 134.1 (62) 131.9 (76) 128.9 (53) 142.3 (74) Notes: Values are means (standard deviation), unless otherwise specified; ap value <0.05 when comparing the non-exacerbator and exacerbator groups; bp value < 0.01 when comparing the non-exacerbator and exacerbator groups; cp value <0.05 when comparing the GOLD groups (A, B, C and D). Abbreviations: CRP, C-reactive protein; AAT, alpha1-antirypsin; NLR, neutrophil/lymphocyte ratio; ELR, eosinophil/lymphocyte ratio; EBR, eosinophil/basophil ratio; PLR, platelet/lymphocyte ratio. Table 4 Univariate and Multivariate Logistic Regression Analyses to Determine Factors Associated with Exacerbations Variable Univariate Multivariate Odds Ratio (95% Confidence Interval) p value Odds Ratio (95% Confidence Interval) p value Age 0.98 (0.96–1.01) 0.248 – – Sex (female) 1.33 (0.85–2.04) 0.215 5 (1.17–8.33) 0.002 Pack-years 0.99 (0.98–1.00) 0.041 – – mMRC 1.70 (1.35–2.13) <0.001 – – CAT score 1.06 (1.03–1.09) <0.001 – – FEV1% 0.97 (0.96–0.99) <0.001 0.92 (0.89–0.98) 0.008 Laboratory parameters: ● White blood cells 1.03 (0.94–1.14) 0.486 – – ● Haemoglobin 0.98 (0.97–1.00) 0.077 – – ● Platelets 1.00 (0.99–1.005) 0.274 – – ● Fibrinogen 1.19 (0.93–1.54) 0.157 – – ● CRP 1.18 (1.06–1.30) 0.002 1.35 (1.01–1.83) 0.049 ● AAT 0.99 (0.99–1.00) 0.266 – – ● NLR 1.06 (0.96–1.18) 0.254 – – ● ELR 0.86 (0.20–3.68) 0.845 – – ● EBR 0.92 (0.85–0.99) 0.048 0.48 (0.31–0.76) 0.002 ● PLR 1.00 (0.99–1.01) 0.298 Abbreviations: mMRC, modified Medical Research Council; CAT, COPD Assessment Test; FEV1, forced expiratory volume in the first second; CRP, C-reactive protein; AAT, alpha1-antitrypsin; NLR, neutrophil/lymphocyte ratio; ELR, eosinophil/lymphocyte ratio; EBR, eosinophil/basophil ratio; PLR, platelet/lymphocyte ratio. associations. Therefore, it would be necessary to evaluate characterization in terms of bronchial colonization and these biomarkers as prognostic factors in a study with CT scan evidence of emphysema or bronchiectasis. a prospective design, including populations with patients In conclusion, together with female sex and having with different degrees of disease severity and better a lower FEV1, higher CRP levels and a lower EBR were submit your manuscript | www.dovepress.com International Journal of Chronic Obstructive Pulmonary Disease 2020:15 687 DovePress Nuñez et al Dovepress associated with a higher rate of exacerbations in COPD. If Novartis, Mundifarma, Glaxo Smith Kline, all unrelated to confirmed in prospective studies, these routine blood biomar- this manuscript. Marc Miravitlles has received speaker or kers can be useful for physicians to detect patients at high risk consulting fees from AstraZeneca, Bial, Boehringer of presenting exacerbations. Ingelheim, Chiesi, Cipla, CSL Behring, Laboratorios Esteve, Ferrer, Gebro Pharma, GlaxoSmithKline, Grifols, Kamada, Ethics and Consent Statement Menarini, Mereo Biopharma, Novartis, pH Pharma, Rovi, All the procedures in this study were performed in accor- Sanofi, Sandoz, TEVA, Verona Pharma and Zambon, and dance with the ethical standards of the Institutional research grants from GlaxoSmithKline and Grifols, unrelated Review Boards and with the Declaration of Helsinki. The to this manuscript. Miriam Barrecheguren has received study was approved by the Ethics Committee of the speaker fees from Grifols, Menarini, CSL Behring, GSK and Hospital Vall d´Hebron, Barcelona, Spain (number: consulting fees from GSK, Novartis and Gebro Pharma. The PR(AG) 417/2017). Written informed consent was authors report no other conflicts of interest in this work. obtained from all the study participants. Funding References This research did not receive any specific grant from 1. 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