biomedicines Article Differences in Nutritional Status and Inflammatory Biomarkers between Female and Male Patients with Bronchiectasis: A Large-Cohort Study Xuejie Wang 1,2 , Carmen Villa 3 , Yadira Dobarganes 3 , Casilda Olveira 4,5 , Rosa Girón 6 , Marta García-Clemente 7 , Luis Maíz 8 , Oriol Sibila 9,10 , Rafael Golpe 11 , Rosario Menéndez 12 , Juan Rodríguez-López 13 , Concepción Prados 14 , Miguel Angel Martinez-García 10,12 , Juan Luis Rodriguez 15,16,17 , David de la Rosa 18 , Xavier Duran 19 and Esther Barreiro 1,10,20, * 1 Lung Cancer and Muscle Research Group, Pulmonology Department, Hospital del Mar-IMIM, Parc de Salut Mar, 08003 Barcelona, Spain; xue62392@gmail.com 2 Department of Medicine, Universitat Autònoma de Barcelona (UAB), 08035 Barcelona, Spain 3 Respiratory Department, Clínica Fuensanta, 28015 Madrid, Spain; mcvillac@gmail.com (C.V.); yadira.dobarganes@yahoo.es (Y.D.) 4 Respiratory Department, Hospital Regional Universitario de Málaga, 29003 Málaga, Spain; casi1547@separ.es 5 Instituto de Investigación Biomédica de Málaga (IBIMA), Universidad de Málaga, 29003 Málaga, Spain 6 Respiratory Department, Instituto de Investigación Sanitaria, Hospital Universitario de la Princesa, 28015 Madrid, Spain; rmgiron@gmail.com 7 Respiratory Department, Hospital Universitario Central de Asturias, 33071 Oviedo, Spain;  mgclemen@gmail.com  8 Respiratory Department, Hospital Ramon y Cajal, 28015 Madrid, Spain; luis.maiz@salud.madrid.org 9 Respiratory Department, Hospital Clínic, 08035 Barcelona, Spain; OSIBILA@clinic.cat Citation: Wang, X.; Villa, C.; 10 Centro de Investigación en Red de Enfermedades Respiratorias (CIBERES), Instituto de Salud Carlos Dobarganes, Y.; Olveira, C.; Girón, R.; III (ISCIII), 28015 Madrid, Spain; mianmartinezgarcia@gmail.com García-Clemente, M.; Maíz, L.; Sibila, 11 Respiratory Department, Hospital Lucus Augusti, 27080 Lugo, Spain; rafa898@separ.es O.; Golpe, R.; Menéndez, R.; et al. 12 Respiratory Department, Hospital Universitario y Politécnico La Fe, 46003 Valencia, Spain; Differences in Nutritional Status and rosmenend@gmail.com Inflammatory Biomarkers between 13 Respiratory Department, Hospital San Agustin, 33405 Avilés, Spain; juan_rodriguezl@hotmail.com 14 Respiratory Department, Hospital la Paz, 28015 Madrid, Spain; conchaprados@gmail.com Female and Male Patients with 15 Respiratory Department, Hospital Clínico San Carlos, 28015 Madrid, Spain; jlrhermosa@yahoo.es Bronchiectasis: A Large-Cohort Study. 16 Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), 28015 Madrid, Spain Biomedicines 2021, 9, 905. https:// 17 Departament of Medicine, Universidad Complutense de Madrid, 28015 Madrid, Spain doi.org/10.3390/biomedicines9080905 18 Respiratory Department, Hospital Santa Creu I Sant Pau, 08035 Barcelona, Spain; david.rosa23@gmail.com 19 Scientific and Technical Department, Hospital del Mar-IMIM, 08035 Barcelona, Spain; xduran@imim.es Academic Editor: Marika Cordaro 20 Department of Health and Experimental Sciences (CEXS), Universitat Pompeu Fabra (UPF), 08035 Barcelona, Spain Received: 2 July 2021 * Correspondence: ebarreiro@imim.es; Tel.: +34-93-316-0385; Fax: +34-93-316-0410 Accepted: 24 July 2021 Published: 28 July 2021 Abstract: We hypothesized that systemic inflammatory and nutritional parameters may differ be- tween male and female patients with non-CF bronchiectasis. In a large patient cohort from the Publisher’s Note: MDPI stays neutral Spanish Online Bronchiectasis Registry (RIBRON), clinical features, systemic inflammatory and with regard to jurisdictional claims in nutritional parameters were analyzed in male and female patients with bronchiectasis. Lung func- published maps and institutional affil- tion, disease severity using several scores, nutritional status, systemic inflammatory parameters, iations. and multivariate regression analyses were performed to identify differences between male and female patients in the target variables. The number of female patients included in the registry was greater than male patients and they had a less severe disease as measured by all three indices of disease severity, a lower degree of airway obstruction, worse diffusion capacity and airway trapping, Copyright: © 2021 by the authors. better nutritional parameters, and lower levels of inflammatory biomarkers. Multivariate regression Licensee MDPI, Basel, Switzerland. analysis evidenced that strong relationships were found between female gender and the following This article is an open access article variables: total numbers of leukocytes and neutrophils, hemoglobin, hematocrit, creatinine, and distributed under the terms and conditions of the Creative Commons body mass index (BMI). Multivariate regression analyses evidenced that nutritional parameters and Attribution (CC BY) license (https:// inflammatory biomarkers may be reliable indicators of gender-related differences in patients with creativecommons.org/licenses/by/ non-CF bronchiectasis. These findings deserve further attention in follow-up investigations in which 4.0/). the potential predictive value of those biomarkers should be thoroughly explored. Biomedicines 2021, 9, 905. https://doi.org/10.3390/biomedicines9080905 https://www.mdpi.com/journal/biomedicines Biomedicines 2021, 9, 905 2 of 17 Keywords: bronchiectasis; gender-related differences; systemic inflammation; nutritional status; biomarkers; disease severity 1. Introduction Non-cystic fibrosis (CF) bronchiectasis is a disease characterized by distortion of the airways which entails a range of clinical symptoms among the patients. The etiology of bronchiectasis varies widely from previous tuberculosis and other lung infections to genetic disorders [1–3]. Bronchiectasis is also commonly associated with other respiratory diseases, namely asthma and chronic obstructive pulmonary disease (COPD) [4]. Despite the prevalence of bronchiectasis being heterogeneous across geographical regions, recent evidence shows that it is increasing in many countries [4]. Sex-related differences may happen in several respiratory diseases including bronchiec- tasis [5,6]. Moreover, disease outcomes may also differ between male and female patients with chronic respiratory disorders [7]. Comorbidities, lung anatomy and physiology, chronic infection and inflammation, environmental factors, and altered host defense mech- anisms are the most relevant contributors to accounting for the reported gender differences in bronchiectasis patients [6,8]. Anatomical differences in lung and airway structure may also explain the greater susceptibility of female patients to experience lung infections at a younger age [6]. Nutritional abnormalities, delayed diagnosis, and socio-cultural inequality may also favor earlier infections to happen in female patients than in males [9,10]. Whether female patients with bronchiectasis exhibit a greater systemic proinflammatory profile than male patients remain to be fully elucidated. Phenotypic stratification is key in medical research as it allows for a better charac- terization of the patients that contribute to tailoring more specific treatments. In this regard, severity indices are useful tools that may help predict mortality [11]. As such, a cut-off value greater than 5 showed to reliably predict hospitalizations and all-cause mortality according to the FACED (FEV1 , age, chronic colonization, radiological exten- sion, and dyspnea) and bronchiectasis severity index (BSI) scores, as reported in a recent meta-analysis [12]. Furthermore, specific phenotypic characterization of female and male patients is also of relevance in clinical settings for the better management of patients with bronchiectasis. This information is clearly lacking in the literature. On this basis, we hypothesized that levels of systemic inflammatory parameters may differ between male and female patients with bronchiectasis. Thus, the main objectives were to analyze clinical features including systemic inflammatory cellular and soluble pa- rameters in male and female patients with bronchiectasis in a large-cohort of patients from the Spanish Online Bronchiectasis Registry (RIBRON) [13]. Thus, the specific objectives were to explore potential differences between male and female patients with bronchiectasis as to the following features: (1) lung function, (2) disease severity using several scores, (3) nutritional status, (4) systemic inflammatory parameters, and (5) to assess potential associations between either the inflammatory or the nutritional parameters with the clinical variables in each group of patients. Multiple regression analysis was used to confirm gender differences for the study variables. Moreover, the potential contribution of COPD to the study results was also analyzed in the investigation. 2. Materials and Methods 2.1. Study Design This was an observational, cross-sectional, prospective, and multicenter study, in which 43 centers from Spain participated within the frame of the RIBRON database be- tween February 2015 and October 2019 [13]. The quality of the data introduced in the registry was always monitored and ensured by an external contract research organization (CRO). Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines were followed in this study [14]. This was an observational, cross-sectional, prospective, and multicenter study, in which 43 centers from Spain participated within the frame of the RIBRON database be- tween February 2015 and October 2019 [13]. The quality of the data introduced in the reg- istry was always monitored and ensured by an external contract research organization Biomedicines 2021, 9, 905 3 of 17 (CRO). Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines were followed in this study [14]. 2.2. Study 2.2. Study Population Population The flow-chart The flow-chart of of the the patient patient recruitment recruitment for for the the purpose purpose of of the the study study isisshown shownin in Figure 1. Inclusion criteria were adult patients who had been diagnosed Figure 1. Inclusion criteria were adult patients who had been diagnosed with bronchiectasis with bronchiec- tasis using using a high-resolution a high-resolution computerized computerized tomographytomography (HRCT)(HRCT) [4,13,15–18]. [4,13,15–18]. A total A total number number of of 2121 were 2121 patients patients were analyzed analyzed in this in this study. study. clinical General Generaldataclinical suchdata such as anthro- as anthropometry, pometry,history, smoking smoking lunghistory, lung function, function, inflammatory hemogram, hemogram, inflammatory blood cells, blood cells, nutritional nutri- parame- tional ters, andparameters, and classification disease severity disease severity wereclassification analyzed. Thewere analyzed. patients included The in patients the registryin- cluded in the registry were all completely stable as defined by the were all completely stable as defined by the absence of any acute exacerbation in the last absence of any acute exacerbation four weeks or in theprior more last four weeks to study or Exclusion entry. more prior to study criteria entry.traction included Exclusion criteria in- bronchiectasis cluded cystic and/or traction bronchiectasis fibrosis and/ortest (sweat chloride cystic fibrosis and/or (sweat genetic chloride test confirmation), andand/or genetic age younger than 18 years old. confirmation), and The age research younger followed than 18 yearsthe guidelines of the World old. The research followedMedical Associa- the guidelines tion of theforWorld Research in Humans Medical (Seventh Association revisionin for Research ofHumans the Declaration (Seventhofrevision Helsinki, of Fortaleza, the Decla- Brazil, ration of Helsinki, Fortaleza, Brazil, 2013) [19]. Ethics approval was obtained Hospital 2013) [19]. Ethics approval was obtained from the Ethics Committee at the from the Josep EthicsTrueta Girona Committee at (# the001-2012, HospitalHospital Josep TruetaUniversitari Girona (# Dr.001-2012, Josep Trueta, Girona, Hospital Spain) Universitari in Dr.allJosep participating centers. Trueta, Girona, Signed Spain) informed in all written participating consent centers. was obtained Signed informed from written all con- the participants. sent was obtained from all the participants. Figure1.1.Flow-chart Figure Flow-chartof ofthe therecruitment recruitmentof ofthe thestudy studypatients. patients. 2.3. Study Variables and Scores The following clinical variables and parameters were obtained from all the study patients: anthropometry (age, sex, and body mass index (BMI)), lung function, chronic colo- nization by Pseudomonas aeruginosa (PA) and by other microorganisms, radiologic extension, dyspnea, the number of acute exacerbations and hospitalizations in the previous year, the Charlson index, smoking history and nutritional status. The FACED [20], EFACED [21], and BSI [22] scores were also calculated. On the basis of the study hypothesis, the target Biomedicines 2021, 9, 905 4 of 17 variables were defined as follows: total number of leukocytes and neutrophils, c-reactive protein (CRP), erythrocyte sedimentation rate (ESR), hemoglobin, hematocrit, creatinine, and BMI. 2.4. Statistical Analysis Quantitative variables are presented as mean (standard deviation), while qualitative variables are presented as the number of patients in each group along with the correspond- ing percentage. Gender differences (male versus female patients) were assessed using the T-student test for the continuous variables and the Chi-square test for the categorical variables. Disease severity scores (FACED, EFACED, and BSI) are also shown in histograms representing both male and female patients individually. Gender differences in prespecified systemic inflammatory parameters were assessed through multiple linear regression using a robust M-estimator for the target variables to control for the presence of outliers. The clinically meaningful confounders were the following: age, smoking history (never, current o ex-smokers), COPD, acute exacerbations, hospitalizations for exacerbations in the previous year, Charlson index, colonization by PA, the number of affected lobes, forced expiratory volume in one second (FEV1 %), and dyspnea. The multivariate regression beta coefficients are represented as black dots along with the corresponding confidence intervals in forest plots for each target variable. In the Y-axis all the confounder variables are plotted along with female gender, while in the X-axis the width of the confidence intervals is represented for all the forest plots. The zero value is represented as a dotted vertical line in each forest plot. The number of female and male patients is also provided in each forest plot. Furthermore, with the aim to explore the potential contribution of COPD per se to the study results, the same type of analyses were performed for all the variables, in which patients with COPD were excluded (58 female and 178 male patients). Additionally, never-smoker patients were also analyzed separately with the objective to explore whether cigarette smoke may have influenced the study results. Statistical analyses were performed using Stata 15.1 (StataCorp LLC, College Station, TX, USA). For all the analyses, the statistical significance was established as p < 0.05. 3. Results 3.1. Clinical Characteristics in Male and Female Patients In the registry, a total of 1368 female (64.5%) and 753 male patients (35.5%) were included prospectively. When all the patients were considered together, males were sig- nificantly older, had a more severe disease (FACED, EFACED, and BSI scores), more comorbidities (Charlson index), a greater number of hospitalizations due to acute exacerba- tions, a greater level of dyspnea, and the number of packs-year was greater than in female patients (Table 1). Furthermore, male patients exhibited mild airway obstruction, better diffusion capacity, and showed a lower degree of airway trapping than female patients (Table 1). Radiological extension was similar in both groups of patients. Similar results, ex- cept for dyspnea, were observed for most of the variables when patients with concomitant COPD were excluded from the analysis (Table 2). A subanalysis of lung function status was conducted in never-smoker patients as a whole (Table 3). In this subanalysis, male patients were significantly younger than females, airflow limitation was greater among the male patients, while diffusion capacity and air trapping values were significantly worse among the female patients (Table 3). The etiology of bronchiectasis was diverse as illustrated in Table 4. The proportions of female patients with post-infectious bronchiectasis and of unknown etiology were significantly greater than in male patients (Table 4). The proportion of COPD patients, however, was significantly greater among the latter patients than the former (Table 4). Biomedicines 2021, 9, 905 5 of 17 Table 1. Clinical parameters and nutritional and inflammatory status of all the study patients: females and males. Women Men N = 1368 N = 753 Anthropometric variables, x (SD) Age (years) 68.5 (14.4) 69.9 (15.3) * Disease severity, x (SD) FACED score 1.9 (1.6) 2.4 (1.8) *** EFACED score 2.4 (2) 3.1 (2.3) *** BSI score 7.2 (4.3) 8.1 (4.8) *** # exacerbations, previous year 1.6 (1.9) 1.5 (1.8) Hospitalizations for exacerbations in the previous year 0.5 (1.2) 0.7 (1.5) *** Charlson Index 1.6 (1.2) 2.2 (1.8) *** Radiological extension 2.8 (1.4) 2.8 (1.5) Dyspnea, mMRC 1.9 (0.9) 2.1 (1.0) *** Chronic colonization by PA, N (%) 311 (22.7) 189 (25.1) Smoking history Current smokers, N (%) 109 (8) 69 (9) Ex-smokers, N (%) 296 (22) 409 (54) *** Never smokers, N (%) 963 (70) 275 (37) *** Packs-year, x (SD) 24 (21) 39 (31) *** Lung function testing, x (SD) FEV1 , % predicted 77 (24) 68 (24) *** FVC, % predicted 86 (23) 79 (19) *** FEV1 /FVC, % 71 (12) 65 (15) *** DLCO , % predicted 82 (23) 86 (25) KCO , % predicted 78 (35) 87 (37) ** RV, % predicted 140 (42) 135 (56) TLC, % predicted 104 (19) 100 (21) * RV/TLC, % 53 (13) 47 (12) *** Nutritional status BMI, kg/m2 , x (SD) 25 (5) 27 (4) *** BMI grade kg/m2 <20, N (%) 173 (13) 45 (6) *** 20–25, N (%) 580 (42) 231 (31) *** ≥25, N (%) 614 (45) 476 (63) *** Hemoglobin, g/dL, x (SD) 13.21 (1.29) 14.31 (1.75) *** Hematocrit, %, x (SD) 40.38 (3.8) 43.4 (4.94) *** Creatinine, mg/dL, x (SD) 0.75 (0.29) 1.01 (0.55) *** Total proteins, g/dL, x (SD) 7.04 (0.61) 6.99 (0.65) Albumin, g/dL, x (SD) 4.19 (0.42) 4.18 (0.49) Systemic inflammatory markers Systemic inflammatory cells, x (SD) Total number of leukocytes, cells/uL 7.40 (3.67) × 103 8.43 (4.01) × 103 *** Total number of neutrophils, cells/uL 4.46 (2.41) × 103 5.26 (2.75) × 103 *** Neutrophils, % 58.96 (12.42) 62.47 (12.36) *** Total number of lymphocytes, cells/uL 2.12 (2.43) × 103 2.08 (2.88) × 103 Lymphocytes, % 29.29 (11.18) 25.59 (10.72) *** Total number of eosinophils, cells/uL 0.20 (0.20) × 103 0.21 (0.22) × 103 Eosinophils, % 2.85 (2.73) 2.82 (2.66) Platelets, cells/uL 260 (77) × 103 241 (75) × 103 *** Acute − phase reactants, x (SD) Alpha-1 antitrypsin, mg/dL 135.85 (42.41) 130.87 (39.79) CRP, mg/dL 5.30 (12.47) 6.01 (13.79) * Fibrinogen, mg/dL 434.12 (136.95) 433.64 (147.24) ESR, mm/h 21.00 (18.61) 15.29 (14.79) *** Continuous variables are presented as mean (standard deviation), while categorical variables are presented as the number of patients in each group along with the percentage for the study group. Definition of abbreviations: N, number; #, number; kg, kilograms; m, meters; BSI: bronchiectasis severity index, BMI, body mass index; FEV1 , forced expiratory volume in the first second; FVC, forced vital capacity; RV, residual volume; TLC, total lung capacity; DLco, carbon monoxide transfer; KCO , Krogh transfer factor; FACED: F, FEV1; A, Age; C, Chronic colonization by Pseudomonas aeruginosa; E, radiological extension; D, dyspnea; mMRC, modified Medical Research Council; PA: Pseudomonas aeruginosa; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; kg, kilogram; g, grams; dL, deciliter; uL, microliter; mg, milligrams; mm, millimeters; h, hour. Statistical analyses and significance: * p < 0.05; ** p < 0.01; *** p < 0.001 between men and women patients. Biomedicines 2021, 9, 905 6 of 17 Table 2. Clinical parameters and nutritional and inflammatory status of bronchiectasis patients excluding those with COPD: females and males. Women Men N = 1310 N = 575 Anthropometric variables, x (SD) Age (years) 68.3 (14.5) 67.4 (16) Disease severity, x (SD) FACED score 1.9 (1.6) 2.1 (1.7) ** EFACED score 2.4 (2) 2.7 (2.1) ** BSI score 7.1 (4.3) 7.2 (4.4) # exacerbations, previous year 1.6 (1.9) 1.5 (1.8) Hospitalizations for exacerbations in the previous year 0.5 (1.2) 0.5 (1.1) Charlson Index 1.6 (1.2) 2 (1.7) *** Radiological extension 2.8 (1.4) 2.8 (1.5) Dyspnea, mMRC 1.8 (0.9) 1.9 (0.9) Chronic colonization by PA, N (%) 302 (23.1) 139 (24.2) Smoking history Current smokers, N (%) 87 (7) 41 (7) Ex-smokers, N (%) 267 (20) 264 (46) *** Never smokers, N (%) 956 (73) 270 (47) *** Packs-year, x (SD) 21 (19) 29 (24) *** Lung function testing, x (SD) FEV1 , % predicted 78 (24) 72 (24) *** FVC, % predicted 87 (23) 81 (19) *** FEV1 /FVC, % 72 (12) 69 (14) *** DLCO , % predicted 84 (22) 89 (25) * KCO , % predicted 78 (35) 89 (38) ** RV, % predicted 138 (40) 128 (54) TLC, % predicted 103 (19) 97 (19) ** RV/TLC, % 53 (13) 45 (13) *** Nutritional status BMI, kg/m2 , x (SD) 25 (5) 27 (4) *** BMI grade kg/m2 <20, N (%) 165 (13) 35 (6) *** 20–25, N (%) 556 (42) 178 (31) *** ≥25, N (%) 588 (45) 362 (63) *** Hemoglobin, g/dL, x (SD) 13.2 (1.28) 14.34 (1.69) *** Hematocrit, %, x (SD) 40.34 (3.75) 43.45 (4.71) *** Creatinine, mg/dL, x (SD) 0.75 (0.3) 1.03 (0.62) *** Total proteins, g/dL, x (SD) 7.05 (0.6) 7.06 (0.63) Albumin, g/dL, x (SD) 4.21 (0.41) 4.25 (0.43) Systemic inflammatory markers Systemic inflammatory cells, x (SD) Total number of leukocytes, cells/uL 7.38 (3.72) × 103 8.05 (3) × 103 ** Total number of neutrophils, cells/uL 4.43 (2.39) × 103 5.03 (2.56) × 103 ** Neutrophils, % 58.8 (12.33) 61.77 (11.76) *** Total number of lymphocytes, cells/uL 2.13 (2.48) × 103 1.93 (0.79) × 103 Lymphocytes, % 29.42 (11.15) 26.4 (10.05) *** Total number of eosinophils, cells/uL 0.19 (0.2) × 103 0.21 (0.22) × 103 Eosinophils, % 2.84 (2.61) 2.86 (2.64) Platelets, cells/uL 260 (77) × 103 242 (76) × 103 ** Acute-phase reactants, x (SD) Alpha-1 antitrypsin, mg/dL 135.96 (43.24) 127.6 (40.1) * CRP, mg/dL 5.38 (12.63) 5.38 (12.3) Fibrinogen, mg/dL 432.01 (136.49) 420.73 (144.98) ESR, mm/h 21.15 (18.65) 14.69 (13.56) *** Continuous variables are presented as mean (standard deviation), while categorical variables are presented as the number of patients in each group along with the percentage for the study group. Definition of abbreviations: N, number; #, number; kg, kilograms; m, meters; BSI: bronchiectasis severity index, BMI, body mass index; FEV1 , forced expiratory volume in the first second; FVC, forced vital capacity; RV, residual volume; TLC, total lung capacity; DLco, carbon monoxide transfer; KCO , Krogh transfer factor; FACED: F, FEV1; A, Age; C, Chronic colonization by Pseudomonas aeruginosa; E, radiological extension; D, dyspnea; mMRC, modified Medical Research Council scale; PA, Pseudomonas aeruginosa; CRP, C-reactive protein; ERS, erythrocyte sedimentation rate; kg, kilogram; g, grams; dL, deciliter; uL, microliter; mg, milligrams; mm, millimeters; h, hour. Statistical analyses and significance: * p < 0.05; ** p < 0.01; *** p < 0.001 between men and women patients. Biomedicines 2021, 9, 905 7 of 17 Table 3. Lung function in never-smoker patients: females and males. Women Men N = 963 N = 275 Anthropometric variables, x (SD) Age (years) 69.7 (15.4) 64.7 (18) *** Lung function testing, x (SD) FEV1 , % predicted 77 (25) 73 (23) * FVC, % predicted 86 (24) 81 (18) *** FEV1 /FVC, % 71 (12) 69 (14) * DLCO , % predicted 85 (23) 90 (23) KCO , % predicted 80 (35) 94 (38) * RV, % predicted 135 (41) 125 (54) TLC, % predicted 101 (19) 97 (20) RV/TLC, % 53 (14) 44 (14) *** Continuous variables are presented as mean (standard deviation) for the study group. Definition of abbreviations: FEV1, forced expiratory volume in the first second; FVC, forced vital capacity; RV, residual volume; TLC, total lung capacity; DLco, carbon monoxide transfer; KCO, Krogh transfer factor. Statistical analyses and significance: * p < 0.05; *** p < 0.001 between male and female patients. Table 4. Etiology of non-CF bronchiectasis patients. Etiology, N, % Total Women Men Post-infectious 865, 40.8% 603, 44.1% 262, 34.8% *** Tuberculosis 262, 12.4% 167, 12.2% 95, 12.6% Childhood 160, 7.5% 127, 9.3% 33, 4.4 *** infections Necrotizing 53, 2.5% 38, 2.8% 15, 2.0% pneumonia Non-tuberculous 17, 0.8% 13, 1.0% 4, 0.5% mycobacteria Fungal infections 8, 0.4% 4, 0.3% 4, 0.5% Others 1621, 76.4% 1019, 74.5% 602, 79.9% ** Unknown etiology 382, 18% 285, 20.8% 97, 12.9% *** COPD 236, 11.1% 58, 4.2% 178, 23.6% *** Asthma 179, 8.4% 128, 9.4% 51, 6.8% * Systemic disorders 164, 7.7% 102, 7.5% 62, 8.2% Immunodeficiencies 85, 4.0% 53, 3.9% 32, 4.2% Inflammatory 37, 1.7% 29, 2.1% 8, 1.1% pneumonitis Inflammatory bowel 17, 0.8% 11, 0.8% 6, 0.8% diseases Congenital 15, 0.7% 6, 0.4% 9, 1.2% malformations Obliterative 11, 0.5% 8, 0.6% 3, 0.4% bronchiolitis Hyperimmune 6, 0.3% 4, 0.3% 2, 0.3% response Vasculitis 4, 0.2% 1, 0.1% 3, 0.4% Other etiologies 120, 5.7% 80, 5.8% 40, 5.3% Absolute number of patients and percentage for each etiologic condition. Definition of abbreviations: N, number; %, percentage; COPD: chronic obstructive pulmonary disease. Statistical analyses and significance: * p < 0.05; ** p < 0.01; *** p < 0.001 between the two groups of patients. 3.2. Nutritional Status in Male and Female Patients In male patients, BMI as a whole and the proportions of patients with BMI ≥ 25 kg/m2 were significantly higher than in female patients (Table 1). Moreover, the parameters hemoglobin, hematocrit, and creatinine levels were also significantly greater in male than in female patients (Table 1). Similar results were observed in this subanalysis after Biomedicines 2021, 9, 905 8 of 17 having excluded COPD patients (Table 2). No significant correlations were found between nutritional status and any of the clinical variables. 3.3. Inflammatory Parameters in Male and Female Patients Compared to female patients, in male patients, total numbers of leukocytes and neutrophils were significantly higher, while those of lymphocytes and platelets were lower (Table 1). Moreover, CRP levels were also increased in male compared to female patients, while ESR levels were greater in the latter group of patients (Table 1). Similar results were observed in this subanalysis after having excluded COPD patients (Table 2). No significant correlations were found between inflammatory parameters and any of the clinical variables. 3.4. Degree of Disease Severity Compared to male patients, female patients had a less severe disease as measured by BSI score, since greater proportions of females were classified as mild and moderate (Figure Biomedicines 2021, 9, x FOR PEER REVIEW 2A). When patients were classified according to EFACED and9FACED, of 18 a greater proportion of female patients also had a mild disease, while a higher proportion of male patients fell into the categories moderate and severe (Figure 2B,C, respectively). In the tients fell into subanalysis the categories in which COPD moderate and were patients severe (Figure excluded2B,C,for respectively). both femaleIn theand suba-male patients, nalysis in which COPD patients were excluded for both female and male patients, no sig- no significant differences were seen in BSI scores (Figure 3A), while the proportions of nificant differences were seen in BSI scores (Figure 3A), while the proportions of male malepatients patientswho who fell into fell into the EFACED the EFACED and FACED and FACED mildwere mild category category werefemale lower than lower than female patients (Figure patients (Figure3B,C, respectively). 3B,C, respectively). According According to FACED to FACED scores, scores, male male patients werepatients more were more severe than severe thanfemale female patients patients inin thethe subanalysis subanalysis (Figure(Figure 3C). 3C). Figure 2. In all the patients as a whole, histograms of the proportions of patients who were classified as mild, moderate, or Figure 2. In all the patients as a whole, histograms of the proportions of patients who were classified as mild, moderate, severe according or severeto BSI (A), according to EFACED (B)EFACED BSI (panel A), and FACED (B) and(C) for both FACED (C) forfemale (red(red both female color) and color) andmale male (grey color) (grey color) pa-patients. Score tients. subdivisions wereScore assubdivisions follows: (1)were as follows: BSI: (1) BSI: mild: 0–4, mild: 0–4, moderate: moderate: 5–8, severe: 5–8, severe: ≥9, (2)≥ 9,EFACED: (2) EFACED: mild:0–3, mild: 0–3, moderate: moderate: 4–6, severe: 4–6, severe: 7–9; and (3) FACED: mild: 0–2, moderate: 3–4, severe: 5–7. Statistical significance: * p ≤ 0.05; ** p ≤ 0.01; *** p ≤ 7–9; and (3) FACED: 0.001 between mild: 0–2,male female and moderate: 3–4, patients for score. 5–7. Statistical significance: * p ≤ 0.05; ** p ≤ 0.01; *** p ≤ 0.001 eachsevere: between female and male patients for each score. 2021, 9, 905 Biomedicines 2021, x FOR PEER REVIEW 109of 18 of 17 Figure 3. In bronchiectasis patients with no COPD, histograms of the proportions of patients who were classified as mild, Figure 3. Inorbronchiectasis moderate, patients severe according with to BSI (A),noEFACED COPD, histograms of the(C) (B) and FACED proportions of patients for both female (red who color)were andclassified male (greyas color) mild, moderate, or severe according to BSI (A), EFACED (B) and FACED (panel C) for both female (red color) and male (grey patients. Score subdivisions were as follows: (1) BSI: mild: 0–4, moderate: 5–8, severe: ≥ 9, (2) EFACED: mild: 0–3, moderate: color) patients. Score subdivisions were as follows: (1) BSI: mild: 0–4, moderate: 5–8, severe: ≥ 9, (2) EFACED: mild: 0–3, 4–6, severe: 7–9; and (3) FACED: mild: 0–2, moderate: 3–4, severe: 5–7. Statistical significance: * p ≤ 0.05 between female moderate: 4–6, severe: 7–9; and (3) FACED: mild: 0–2, moderate: 3–4, severe: 5–7. Statistical significance: * p ≤ 0.05 between and male female andpatients for eachfor male patients score. each score. 3.5.Multivariate 3.5. MultivariateAnalysis AnalysisofofSystemic SystemicInflammatory Inflammatory and and Nutritional Nutritional Parameters Parameters in in Male Male and and Female Patients Female Patients Multivariate regression Multivariate regression analysis analysis showed showed thatthat total total numbers numbers of of leukocytes leukocytes andand neu- neu- trophils were significantly and inversely associated with female gender trophils were significantly and inversely associated with female gender (β = −0.55, 95%CI: (β = − 0.55, 95% CI: −0.85, −0.85, −0.25, p =−0.000 0.25, pand = 0.000 β = and −0.35, −0.60, β =95%CI: −0.35, 95% CI: −0.60, −0.10; p =−0.007, 0.10; pFigure = 0.007,4A,B, Figure 4A,B, respec- respectively). Nonetheless, no significant associations were found between tively). Nonetheless, no significant associations were found between female gender and female gender and CRP CRP levels levels (β = −95%CI: (β = −0.02; 0.02; 95% −0.17, −0.17, CI: 0.12; p =0.12; p =Figure 0.755, 0.755, 4C). Figure 4C). Significant Significant positivepositive associ- associations were seen between female gender and ESR levels ations were seen between female gender and ESR levels (β = 4.07, 95%CI: 2.09, (β = 4.07, 95% 6.04; CI: 2.09, p= 6.04; p = 0.000, Figure 4D). Furthermore, negative associations were 0.000, Figure 4D). Furthermore, negative associations were detected between hemoglobin, detected between hemoglobin, hematocrit, hematocrit, and creatinineand creatinine levels, BMI, andlevels, femaleBMI, andinfemale gender gender the patients (β in the patients = −1.31, 95%CI: (β = − 1.31, 95% CI: − 1.48, − 1.14; p = 0.000, β = − 3.44, 95% CI: − 3.97, −1.48, −1.14; p = 0.000, β = −3.44, 95%CI: −3.97, −2.91; p = 0.000, β = −0.22; 95%CI: −0.24,− 2.91; p = 0.000, −0.2; −0.22; pβ==0.000, 95% and β =CI: −0.24, −2.03; −0.2;−2.47, 95%CI: p = 0.000, −1.59;and β = −2.03; p = 0.000), 95% Figure CI: −respectively). 5A–D, 2.47, −1.59; pNotably, = 0.000), Figure 5A–D, respectively). Notably, all these differences were independent of the presence all these differences were independent of the presence of COPD (Figures 4A–D and 5A– of COPD (Figure 4A–D and Figure 5A–D). 5D). Biomedicines 2021, 9, x FOR PEER REVIEW 11 of 18 Biomedicines 2021, 9, 905 10 of 17 Figure 4. Cont. Biomedicines 2021, 9, x FOR PEER REVIEW 12 of 18 Biomedicines 2021, 9, 905 11 of 17 Figure 4. Independent associations between female gender and the following variables: total number of leukocytes (A), total number of neutrophils Figure (B), CRP 4. Independent levels (C), ESR associations levelsfemale between (D). Multivariate gender androbust regression the following analysis was variables: totalused to perform number the analysis. of leukocytes (A), Confidence total number intervals andofstatistical neutrophils (B), CRPare significance levels (C), ESR in represented levels each(D). Multivariate figure panel. Betarobust regression coefficients analysis was are represented used dots. as black to per- The zero value form the analysis. Confidence intervals and statistical significance are represented in each figure panel. Beta coefficients is represented as a red dotted vertical line in each forest plot. The model was adjusted by age, smoking history (never, current, or areex-smokers), representedexacerbations as black dots.mild-moderate, The zero value hospitalizations is represented asduea red to dotted verticalinline exacerbations theinprevious each forest plot. year, The model Charlson Index,was colonization by adjusted by age, smoking history (never, current, or ex-smokers), PA, numbers of affected lobes, FEV1 %, and dyspnea score for each variable.exacerbations mild-moderate, hospitalizations due to exacerbations in the previous year, Charlson Index, colonization by PA, numbers of affected lobes, FEV1%, and dyspnea score for each variable. Biomedicines 2021, 9, x FOR PEER REVIEW 13 of 18 Biomedicines 2021, 9, 905 12 of 17 Figure 5. Cont. Biomedicines 2021, 9, x FOR PEER REVIEW 14 of 18 Biomedicines 2021, 9, 905 13 of 17 Figure 5. Independent associations between female gender and the following variables: hemoglobin levels (A), hematocrit levels (B), creatinine Figure levels (C), associations 5. Independent BMI values (D). Multivariate between robust and female gender regression analysisvariables: the following was usedhemoglobin to perform levels the analysis. Confidence intervals (A), hematocrit and statistical significance are represented in each figure panel. Beta coefficients are represented as black levels (B), creatinine levels (C), BMI values (D). Multivariate robust regression analysis was used to perform the analysis. dots. The zero value is represented Confidence as a red intervals dotted and vertical statistical line in each significance areforest plot. The represented model in each waspanel. figure adjusted Betaby age, smoking coefficients history (never, are represented as current, or ex-smokers), black dots. Theexacerbations zero value is mild-moderate, represented as ahospitalizations due line red dotted vertical to exacerbations in each forestinplot. the previous The modelyear, wasCharlson adjustedIndex, colonization by by age, smoking history PA, numbers of(never, affectedcurrent, lobes, FEVor ex-smokers), 1 %, and dyspneaexacerbations mild-moderate, score for each variable. hospitalizations due to exacerbations in the previous year, Charlson Index, colonization by PA, numbers of affected lobes, FEV1%, and dyspnea score for each variable. 4. Discussion In the present study, the proportions of female patients included in the registry 4. Discussion were twice as great as those of male patients. Interestingly, female patients had a less In the present study, the proportions of female patients included in the registry were severe disease as measured by all three indices of disease severity, a lower degree of twice as great as those of male patients. Interestingly, female patients had a less severe airway obstruction, worse diffusion capacity and airway trapping, even when non-COPD or never-smoker patients were analyzed separately, a greater prevalence of idiopathic Biomedicines 2021, 9, 905 14 of 17 etiology, better nutritional markers, and lower levels of inflammatory parameters except for ESR. Multivariate regression analysis evidenced that strong relationships were found between female gender and the variables total numbers of leukocytes and neutrophils, ESR, hemoglobin, hematocrit, creatinine, and BMI. In view of these findings, the study hypothesis has been confirmed to a great extent. In the current investigation, male patients exhibited greater scores of disease severity along with a higher degree of airway obstruction, while showing better lung diffusion capacity and lower air trapping than female patients. These findings were confirmed in the subanalysis after having excluded the COPD patients in both groups. These results are somehow in line with those previously reported [13], in which airflow limitation was less prominent in female patients with bronchiectasis than in men. In keeping with, disease severity scores were increased in male patients compared to females, despite that the degree of radiological extension was similar between both genders [13]. However, airway trapping and diffusion capacity were significantly better in male patients than in females in all the analyses: total population, when COPD patients were excluded, and when only never-smoker patients were analyzed separately. In fact, it has been demonstrated that respiratory function differs between males and females probably due to anatomical and size differences [23]. These results warrant further attention in future investigations. In the present study, substantial differences were observed between female and male patients as to the nutritional parameters assessed in the registry. As such, BMI was significantly greater in the male patients than in the females. Furthermore, when patients were subdivided according to three different degrees of BMI, a greater percentage of male patients fell into the category of a BMI > 25 kg/m2 than female patients. These are relevant findings that suggest that BMI may influence disease morbidity and prognosis as reported in another large cohort of patients with bronchiectasis [24]. In the multivariate regression analysis, BMI was also significantly associated with female gender. Hence, these results confirm the relevance of BMI as a discriminatory end-point between male and female patients with bronchiectasis. Lastly, it should also be mentioned that greater numbers and proportions of female patients (173, 13%) fell into the category of BMI < 20 kg/m2 than in male patients (45, 6%). These results were also confirmed in the subanalysis, in which the COPD patients were excluded. Importantly, levels of the nutritional parameters—hemoglobin, hematocrit, and creatinine—were significantly greater in the male than in the female patients. Multi- variate regression analyses also confirmed the associations seen between each of those blood parameters with female gender. Differences in hemoglobin levels were also reported in male and female patients with COPD, in whom this blood parameter was demonstrated to have predictive value during hospitalizations and at hospital discharge [25,26]. As far as we are concerned, these are novel findings in patients with bronchiectasis. Creatinine is a marker of renal function, since it is excreted by the kidneys and is a product of muscle protein metabolism, thus it can be also used as an indicator of nutritional status in patients. In the current investigation, levels of creatinine were significantly greater in male patients than in females, despite that in both groups, levels of this marker were within the normal ranges for men and women, respectively. The subanalysis without the COPD patients also revealed similar results, suggesting that the increase in plasma creatinine levels was independent of this disease in this series of bronchiectasis patients. In the multivariate regression analyses, the significant differences in creatinine levels between male and female patients were confirmed. These findings suggest that muscle protein metabolism was higher among the male patients. Similar findings were also reported in a cohort of patients with COPD [27]. Total levels of leukocytes and neutrophils were significantly increased in male patients compared to females in both types of analyses, when patients were considered as a whole and after excluding those with concomitant COPD. Importantly, white blood cell counts were shown to significantly correlate with current smoking status and COPD severity as well as to predict poor lung function and quality of life in the patients [28]. Indeed, Biomedicines 2021, 9, 905 15 of 17 it was proposed that white blood cell counts may be used as a reliable biomarker of disease progression and severity among patients with COPD [28]. In the present study, the multivariate regression analyses evidenced that both total numbers of leukocytes and neutrophils were statistically different between male and female patients. The presence of COPD did not affect the encountered differences between male and female patients regarding the numbers of white blood cells. The number of blood lymphocytes may be another potential biomarker of nutritional status in chronic respiratory patients [29,30]. In a previous investigation [29], no significant differences in lymphocyte counts were detected between malnourished and well-nourished COPD patients. In the current study, the percentage of lymphocytes was lower in male than in female bronchiectasis patients. Nonetheless, as the values were within the normal ranges (20–40%) in both groups, we believe that the contribution of sex-related differences in lymphocyte counts to alterations in the nutritional status of the study patients was probably negligible. Furthermore, significant differences were also detected in other blood parameters such as CRP and ESR between female and male patients. Nonetheless, those differences were not confirmed in the multivariate analyses for CRP, thus implying that factors other than gender-related issues may account for the differences seen in CRP levels between the two groups of patients. Interestingly, ESR levels were within normal ranges in both male and female patients and as previously demonstrated in a population-based study [31], values were also greater in females than in males in the present investigation. 5. Study Critique The current investigation is based on a large number of well-characterized patients that were recruited from different participating centers in the registry. Having said that, a few limitations need to be reported. This is a clinical descriptive study in which differences between male and female patients with bronchiectasis have been demonstrated in several nutritional and systemic inflammation biomarkers. Gender-related differences as to the potential predictive value of the target biomarkers, however, have not been explored in the current investigation. Follow-up studies will be required in order to show the relative weight of each biomarker in disease progression and severity in female and male patients with bronchiectasis. Despite these concerns, the present study will serve as the basis for the design of follow-up investigations intended to address such a relevant question in the near future. Finally, an external validation of our results would be also desirable in future investigations. 6. Conclusions Our study shows that several nutritional parameters and inflammatory biomarkers may be reliable indicators of gender-related differences in patients with bronchiectasis. The reported findings herein deserve further attention in follow-up investigations in which the potential predictive value of those biomarkers should be thoroughly explored. Author Contributions: Study conception and design: E.B., X.W. and M.A.M.-G.; Patient assessment and recruitment: X.W., C.V., Y.D., C.O., R.G. (Rosa Girón), M.G.-C., L.M., O.S., R.G. (Rafael Golpe), R.M., J.R.-L., C.P., M.A.M.-G., J.L.R., D.d.l.R. and E.B.; Statistical analyses and data interpretation: X.W., E.B. and X.D.; Manuscript drafting and intellectual input: E.B., X.W., M.A.M.-G., C.O., R.G. (Rosa Girón), M.G.-C., R.G. (Rafael Golpe), J.L.R. and D.d.l.R.; Manuscript writing final version: E.B. All authors have read and agreed to the published version of the manuscript. Funding: This study has been supported by FIS 18/00075, FIS 21/00215 (FEDER, ISC-III) & CIBERES (ISC-III), SEPAR 2020, and ZAMBON-PHARMA (Spain). Institutional Review Board Statement: The research followed the guidelines of the World Medical Association for Research in Humans (Seventh revision of the Declaration of Helsinki, Fortaleza, Brazil, 2013). Ethics approval was obtained from the Ethics Committee at the Hospital Josep Trueta Girona (# 001-2012, Hospital Universitari Dr. Josep Trueta, Girona, Spain) in all participating centers. 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