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Profile of systemic manifestations and muscle abnormalities in bronchiectasis:
differences between female and male patients
Xuejie Wang
PhD programme in Medicine Department of Medicine Universitat Autònoma de Barcelona
Profile of systemic manifestations and muscle abnormalities in bronchiectasis: differences
between female and male patients
Doctoral thesis presented by Xuejie Wang
Director:
Dr. Esther Barreiro Portela Tutor:
Dr. Juan Pedro-Botet Montoya
Barcelona, 2022
To my family
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AGRADECIMIENTOS
Los cinco años de tesis doctoral son un largo y difícil recorrido. No hubiera sido posible hacer este viaje sin el apoyo de todo el grupo. Agradezco de corazón la ayuda que me han prestado tanto a nivel profesional como a nivel personal.
Gracias a todos por haber sido una parte muy importante en mi vida.
Antes que todo, quisiera agradecer profundamente a mi directora, la Dra.
Esther Barreiro por haberme aceptado para llevar a cabo mi tesis doctoral en su grupo de investigación y por su guía y persistencia. Quiero expresar mi gratitud de manera especial por su confianza, su dirección y su enseñanza.
También le doy gracias por la dedicación de su tiempo durante todo el proceso de tesis doctoral. Le agradezco mucho también por cuidarme tanto en mi vida laboral como en mi vida personal.
Al Dr. Juan Pedro-Botet Montoya por haber sido mi tutor. Muchas gracias por su cariño, su simpatía y su confianza durante toda mi carrera.
A la Dra. Juana Martínez-Llorens por su enseñanza y sus valiosas sugerencias en las pruebas clínicas para los pacientes.
A la Dra. Ana Balaña-Corberó por su ayuda constante en la realización de las pruebas para los pacientes.
Al Dr. Jordi Garcia-Ojalvo por su ayuda en el análisis bioinformático durante los cuatro años.
Al Dr. Xavier Duran por su ayuda y sus consejos en todos los análisis estadísticos.
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Agradezco mucho a mis compañeros del laboratorio, María Guitart, María Pérez, Jun, Liyun, Laura, Daniel, Anna, Antonio, Adrián, Adriana, Carmen, Yinchen Xia, Jianhua Zha, José María Maiques y Mariela por sus ayudas tanto en el trabajo de laboratorio y el de hospital como en mi vida privada. Y gracias a mi compañera de piso Xiaotong Xi por su compañía.
Agradezco mucho a las enfermeras del Hospital del Mar (Mireia, Esmeralda, Laura y Conchi) por sus aportaciones y ayuda con los pacientes.
También agradezco de una manera especial a todos los pacientes que han participado en los estudios que contiene mi tesis doctoral, por su colaboración, comprensión y simpatía.
Por último, querría expresar mi agradecimiento y gratitud a mis padres y hermano por su dedicación, paciencia y apoyo. Muchas gracias por todo lo que han hecho durante el largo camino de mi tesis doctoral. Sin vuestro apoyo y palabras de ánimo, no hubiera sido posible acabar esta tesis.
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LIST OF ABBREVIATIONS
ATS: American Thoracic Society
APR: acute-phase reaction
APPs: acute-phase proteins
BSI: bronchiectasis severity index
BMI: body mass index
COPD: chronic obstructive pulmonary disease
CF: cystic fibrosis
CRP: C-reactive protein
DLCO: carbon monoxide transfer capacity
ERS: European Respiratory Society
ESR: erythrocyte sedimentation rate
EFACED: exacerbations with hospitalization in the previous year, FEV1 percent predicted, age, chronic colonization by Pseudomonas aeruginosa, radiological extension, dyspnea (modified Medical Research Council dyspnea scale) EMBARC: European Bronchiectasis Registry
FEV1:forced expiratory volume in the first second FVC: forced vital capacity
FFMI: fat-free mass index
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FACED: FEV1 percent predicted, age, chronic colonization by Pseudomonas aeruginosa, radiological extension, dyspnea (modified Medical Research Council dyspnea scale)
G-CSF: granulocyte colony stimulating factor
HS: handgrip strength
IL-8: interleukin 8
IL-6: interleukin 6 IL-1α: interleukin 1α
IL-1β: interleukin 1β
IgA: immunoglobulin A
IgG: immunoglobulin G
ICS: inhaled corticosteroids
IBW: ideal body weight
LC: lung cancer
LT-B4: leukotriene B4
MIP: maximal inspiratory pressure
MEP: maximal expiratory pressure
P: Pseudomonas aeruginosa
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QMVC: quadriceps maximal strength during isometric maximum voluntary contraction
RIBRON: Spanish Online Bronchiectasis Registry
SNIP: Sniff nasal inspiratory pressure
6MWT: 6-minute walk test
TNF-α: tumor necrosis factor-alfa
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TABLE OF CONTENTS
ABSTRACT ... 13
RESUMEN ... 19
1. INTRODUCTION ... 25
1.1. Bronchiectasis ... 26
1.1.1. Non-CF bronchiectasis ... 26
1.1.1.1. Definition ... 26
1.1.1.2. Etiology ... 27
1.1.1.3. Epidemiology ... 30
1.1.1.4. Pathophysiology ... 31
1.1.1.5. Clinical manifestations ... 33
1.1.1.6. Lung function ... 33
1.2. Systemic manifestations ... 35
1.2.1. Inflammation ... 37
1.2.1.1. Systemic inflammation in non-CF bronchiectasis ... 38
1.2.1.1.1. Circulating inflammatory cells ... 39
1.2.1.1.1.1. The role of eosinophils ... 39
1.2.1.1.2. Acute-phase reactants ... 40
1.2.1.2. Systemic inflammation differences between gender in non-CF bronchiectasis ... 41
1.2.2. Nutritional alterations ... 41
1.2.2.1. Factors involved in the pathophysiology of patients ... 42
1.2.2.2. Prevalence of nutritional abnormalities in non-CF bronchiectasis ... 43
1.2.2.3. Nutritional abnormalities differences between gender in non-CF patients ... 43
1.2.3. Skeletal muscle ... 44
1.2.3.1. Muscle contraction ... 44
1.2.3.2. Skeletal muscle function ... 45
1.2.3.2.1. Assessment of respiratory muscle function ... 45
1.2.3.2.2. Assessment of limb muscle function ... 46
1.2.3.3. Skeletal muscle dysfunction ... 50
1.2.3.4. Epidemiology of muscle dysfunction ... 50
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2. HYPOTHESIS ... 53
3. OBJECTIVES ... 57
3.1 Main objective ... 57
3.2 Secondary objectives ... 57
4. COMPENDIUM OF PUBLICATIONS ... 61
4.1. Article 1 ... 61
4.2. Article 2 ... 81
4.3. Article 3 ... 99
4.4. Article 4 ... 119
5. OVERALL SUMMARY OF RESULTS ... 145
5.1. Non-CF bronchiectasis patients in a large cohort study derived from RIBRON ... 145
5.2. Non-CF bronchiectasis derived from Bronchiectasis Multidisciplinary Unit at Hospital del Mar ... 146
6. OVERALL SUMMARY OF THE DISCUSSION ... 151
7. CONCLUSIONS ... 167
8. FUTURE PERSPECTIVES ... 171
9. BIBLIOGRAPHY ... 175
10. APPENDIX ... 195
10.1. Other publications ... 195
10.2. Communications ... 299
10.3. Scientific collaborations ... 335
10.4. Funding sources ... 337
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ABSTRACT
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Abstract
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ABSTRACT
Background: Chronic respiratory disease including COPD and lung cancer can contribute to several systemic effects with systemic inflammation, nutritional alterations and skeletal muscle dysfunction being the most common systemic manifestations.
Hypothesis: We hypothesized that patients with non-CF bronchiectasis may also present systemic inflammation, nutritional abnormalities, and a decrease in both respiratory and peripheral muscle function, and their alterations in muscle function may be much more severe in women than in men. We also hypothesized that low blood eosinophil levels may identify a more severe phenotype in bronchiectasis patients.
Objectives: Studies in patients derived from RIBRON: To identify different clusters of patients included in this registry that could discriminate differential phenotypes based on systemic parameters and to analyze gender differences in non-CF bronchiectasis patients. Study in patients derived from Hospital del Mar: To explore nutritional status and muscle function in patients with non-CF bronchiectasis, and their differences between female and male patients.
Methods: Studies in patients derived from RIBRON: In the current thesis, three different studies were performed in the context of RIBRON registry (February 2015 and October 2019): In each study, (n = 1092, 906, 2121 from studies #1 to
#3, respectively) bronchiectasis patients were used to analyze the objectives as mentioned above in terms of clinical feature, systemic inflammation and nutritional status. Specifically, cluster analyses were performed based on systemic inflammatory markers (eosinophils, neutrophils, lymphocytes,
Abstract
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hemoglobin and CRP) in studies #1 and #2. Study in patients recruited from Hospital del Mar: 150 bronchiectasis patients and 37 healthy controls were recruited from the Bronchiectasis Multidisciplinary Unit at Hospital del Mar (years 2019-2021, Barcelona). Body composition, lung function, blood parameters and respiratory and peripheral muscle function were analyzed.
Results: Studies in patients derived from RIBRON: 1092 patients were divided into 3 different clusters based on the following 5 markers: neutrophils, lymphocytes, eosinophils, CRP, and hemoglobin. The tendency of disease severity was increasing from clusters #1 to #3, named as mild, moderate and severe, respectively. Patients in cluster # 3 had higher number of exacerbations and hospitalization, higher prevalence of chronic colonization by PA and COPD, worse lung function, and higher levels of systemic inflammation. 906 patients were classified into two different clusters based on blood eosinophil counts (cutoff value: 100 cells/ µL) in which above threshold cluster of patients presented significantly better clinical outcomes, nutritional status and lower levels of systemic inflammation. Female bronchiectasis patients presented a less severe disease and lower levels of inflammatory biomarkers. Multivariate regression analysis evidenced strong relationships between the female gender and the following variables: total numbers of leukocytes and neutrophils, hemoglobin, hematocrit, creatinine, and BMI. Study in patients recruited from Hospital del Mar: Non-CF bronchiectasis presented a greater reduction in body mass index (BMI), fat free mass index (FFMI), FFM, fat tissue, upper and lower limb muscle strength, and respiratory muscle strength compared to healthy controls. Additionally, female patients had a greater decline in FFMI and quadriceps muscle function than males.
Abstract
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Conclusions: Three clusters were established based on the following 5 markers: neutrophils, lymphocytes, eosinophils, CRP, and hemoglobin, in which cluster # 3 of patients had more severe disease, worse lung function, and higher levels of systemic inflammation. High blood eosinophil levels (> 100 cells/ µL) identified a less severe phenotype and better clinical outcomes in patients with non-CF bronchiectasis. Gender differences in clinical outcomes, nutritional status (hemoglobin, hematocrit, creatinine, and BMI) and inflammatory biomarkers (total numbers of leukocytes and neutrophils) exist in bronchiectasis patients. Moreover, they present a decrease in both respiratory and peripheral muscle function and body composition. FFMI and quadriceps muscle function are much more altered in female patients than in males.
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RESUMEN
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Resumen
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RESUMEN
Introducción: Las enfermedades respiratorias crónicas, incluidas la EPOC y el cáncer de pulmón, pueden contribuir a varios efectos sistémicos, siendo la inflamación sistémica, las alteraciones nutricionales y la disfunción del músculo esquelético las manifestaciones sistémicas más comunes.
Hipótesis: Planteamos la hipótesis de que los pacientes con bronquiectasias no debidas a fibrosis quísticas (FQ) también pueden presentar inflamación sistémica, alteraciones nutricionales y disminución de la función muscular, tanto de los músculos respiratorios como periféricos, e hipotetizamos que las alteraciones en la función muscular pueden ser mucho más graves en mujeres que en hombres. Además, planteamos la hipótesis de que los niveles bajos de eosinófilos en sangre pueden identificar un fenotipo más grave de pacientes con bronquiectasias.
Objetivos: Estudios en pacientes derivados de RIBRON: Identificar diferentes agrupaciones de pacientes incluidos en este registro para discriminar fenotipos diferenciales en función de parámetros sistémicos y analizar las diferencias de género en pacientes con bronquiectasias no debida a FQ. Estudios en pacientes derivados del Hospital del Mar: Explorar el estado nutricional y la función muscular en pacientes con bronquiectasias no FQ, y sus diferencias entre pacientes femeninos y masculinos.
Métodos: Estudios en pacientes derivados de RIBRON: En la presente tesis se realizaron tres estudios diferentes en el contexto del registro RIBRON (febrero de 2015 - octubre de 2019): En cada estudio, (n = 1092, 906, 2121 de los estudios #1 a #3, respectivamente) en pacientes con bronquiectasias no debida
Resumen
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a FQ se analizaron los objetivos mencionados anteriormente en términos de características clínicas, inflamación sistémica y estado nutricional.
Específicamente, en los estudios #1 y #2 se realizaron análisis de conglomerados basados en marcadores inflamatorios sistémicos (eosinófilos, neutrófilos, linfocitos, hemoglobina y PCR). Estudio en pacientes reclutados del Hospital del Mar: 150 pacientes con bronquiectasias y 37 controles sanos fueron reclutados en la Unidad Multidisciplinar de Bronquiectasias del Hospital del Mar (años 2019-2021, Barcelona). En todos los participantes del estudio, se analizó la composición corporal, la función pulmonar, los parámetros sanguíneos y la función de los músculos respiratorios y periféricos.
Resultados: Estudios en pacientes derivados de RIBRON: 1092 pacientes fueron divididos en 3 agrupaciones diferentes basadas en los siguientes 5 marcadores: neutrófilos, linfocitos, eosinófilos, PCR y hemoglobina. El nivel de gravedad de la enfermedad fue en aumento desde los grupos #1 a #3, denominados como leve, moderado y grave, respectivamente. Los pacientes del grupo #3 tuvieron un mayor número de exacerbaciones y hospitalizaciones, mayor prevalencia de colonización crónica por Pseudomonas aeruginosa y EPOC, peor función pulmonar y niveles más altos de inflamación sistémica que los grupos #1 y #2. 906 pacientes se clasificaron en dos grupos diferentes en función de los recuentos de eosinófilos en sangre (valor de corte: 100 células/
µl) en los que los pacientes por encima del umbral presentaron resultados clínicos y estado nutricional significativamente mejores, y niveles más bajos de inflamación sistémica. Las pacientes femeninas con bronquiectasias presentaron una enfermedad menos grave según su evaluación mediante la puntuación obtenida en FACED, EFACED y BSI, un menor grado de
Resumen
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obstrucción de las vías respiratorias y niveles más bajos de biomarcadores inflamatorios. El análisis de regresión multivariante evidenció fuertes relaciones entre el género femenino y las siguientes variables: número total de leucocitos y neutrófilos, hemoglobina, hematocrito, creatinina e IMC. Estudio en pacientes reclutados del Hospital del Mar: Las bronquiectasias no FQ presentaron una disminución de índice masa corporal (IMC), índice masa magra (FFMI), contenido graso, y fuerza de los músculos periféricos (extremidades superiores e inferiores) y respiratorios en comparación con los controles sanos. Además, las mujeres con bronquiectasias presentaron una mayor disminución del FFMI y de la fuerza muscular en las extremidades inferiores que los hombres.
Conclusiones: Se establecieron tres grupos teniendo en cuenta los siguientes 5 marcadores: neutrófilos, linfocitos, eosinófilos, CRP y hemoglobina, en los cuales los pacientes del grupo #3 presentaban una enfermedad más grave, con peor función pulmonar y niveles más altos de inflamación sistémica. También se identificaron dos fenotipos diferentes de pacientes según el recuento de eosinófilos en sangre. Los pacientes con bronquiectasias no FQ con niveles altos de eosinófilos en sangre (> 100 células/ µl) presentaban un fenotipo menos grave y con mejores resultados clínicos. Además, varios parámetros nutricionales (hemoglobina, hematocrito, creatinina e IMC) y biomarcadores inflamatorios (número total de leucocitos y neutrófilos) pueden ser indicadores confiables de las diferencias relacionadas con el género de los pacientes con bronquiectasias. Por otro lado, los pacientes con bronquiectasias no FQ presentan una disminución de la composición corporal y de la función muscular tanto respiratoria como periférica, presentando una mayor afectación muscular de las extremidades y del FFMI en las pacientes femeninas.
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INTRODUCTION
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1. INTRODUCTION
In the current thesis, the most relevant objectives were to assess nutritional status and muscle function in patients with non-cystic fibrosis (CF) bronchiectasis, and differences between female and male patients. Given that systemic inflammation is a common manifestation of chronic respiratory disease, the role of systemic inflammatory cells (especially eosinophils) and their differences between female and male non-CF bronchiectasis patients also were explored. The current investigation was conducted in the context of the Spanish Online Bronchiectasis Registry (RIBRON) and in a subgroup of patients who were prospectively and consecutively recruited in the Bronchiectasis Multidisciplinary Unit at Hospital del Mar (years 2019-2021, Barcelona) (Figure 1)
Figure 1. Scheme of the current thesis.
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1.1. Bronchiectasis
Bronchiectasis is a heterogeneous disease that results from various etiologies.
The origin of the word bronchiectasis is derived from the Greek word, bronchi known as “windpipe” and ektasis known as “dilatation”. The condition was first proposed by Laennec (1) in the year 1819. As the centuries passed, despite being at the beginning an entity considered to be an “orphan”, it has been possible to diagnose more and more accurately, thanks to advances, especially in thoracic imaging techniques. Recently, also for this reason and innovations in their treatments, bronchiectasis is gaining progressive interest. According to the Chest Foundation (2–4), bronchiectasis was classified into two types: CF and non-CF bronchiectasis. The current thesis focusses on non-CF bronchiectasis.
1.1.1. Non-CF bronchiectasis
1.1.1.1. Definition
Non-CF bronchiectasis is a chronic inflammatory bronchial disease with permanent dilatation of bronchial lumen that can occur as a result of different causes. Clinically, patients usually present with chronic cough, expectoration, and breathlessness, and less frequently rhinosinusitis, fatigue, hemoptysis, thoracic pain, and weight loss, as well as with recurrent acute infections characterized by symptoms of fever, productive cough, mucopurulent expectoration, and dyspnea. The presence of chronic bronchial infection and progressive decline in lung function leads to a deterioration in the quality of life and an increase the morbidity and mortality (5–7).
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1.1.1.2. Etiology
Bronchiectasis is a heterogeneous and complex disease that is caused by numerous conditions, both pulmonary and systemic. The relative frequency of these etiologies depends on the geographical regions and characteristics of the patients. Recently, several studies have demonstrated that the prevalence of etiology of bronchiectasis was different according to the various factors abovementioned (8,9). WEI-JIE GUAN at all. (8) and QIAN QI et al. (9) described that in Guangzhou and Shandong, China, the three most common etiology were idiopathic (46%-66%), postinfectious (16-27%) and immunodeficiency (3.8%-8.8%), followed by asthma (0-5.4%), aspergillosis (2.7%-4%), gastroesophageal reflux (0-4.1%), congenital lung malformation (0- 2.0%), Kartagener syndrome (0-1.4%), rheumatoid arthritis (1.4%-2.1%), COPD (0-0.7%), and foreign bodies (0.2%-0.7%). However, Olveira C and Chalmers had shown the most frequent etiology were post-infectious (20-30%) and idiopathic (24.2-40%), followed by COPD (0-15%) or primary immunodeficiencies (5.8-9.4%) (10,11).
Table1 Etiology of the non-CF bronchiectasis according to the following guideline (12).
Etiology Associated subtype disorders
idiopathic Unknown etiology
Post-infectious Tuberculosis, Childhood infections, Fungal infections, Mycobacteria non-tuberculous, Necrotizing pneumonia
(bacterial or viral pneumonia, pertussis)
Obliterative bronchiolitis Postinfectious/unknown cause, Swyer-James-
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MacLeod Syndrome
Genetic diseases Alpha1-Antitrypsin Deficiency, Primary Ciliary dyskinesia, Kartagener syndrome
Inflammatory bowel diseases Ulcerative colitis, Crohn’s disease, Celiac disease Congenital malformations Mounier-Kuhn Syndrome, Williams-Campbell
syndrome, Bronchopulmonary dysplasia
Inflammatory pneumonitis Aspiration, Gastroesophageal reflux, Inhalation of gases or drugs
Bronchial obstruction Tumor, Foreign bodies, Extrinsic compression
Hyperimmune response Post-lung transplant, Allergic bronchopulmonary aspergillosis
Vasculitis Granulomatosis with polyangiitis, Churg-Strauss Syndrome, Behçet disease
COPD Asthma
Immunodeficiencies Acquired immunodeficiency syndrome (AIDS), Immunoglobulin deficiency, Job syndrome
Systemic disorders Rheumatoid arthritis, Systemic Lupus Erythematosus, Sjogren's syndrome, Marfan syndrome, Relapsing polychondritis, Ankylosing spondylitis, Ehlers-Danlos syndromes, Sarcoidosis, Systemic sclerosis
Moreover, non-CF bronchiectasis also can be classified in several ways based on the different etiology which are described as follows:
1) According to their location, bronchiectasis is classified into two types:
localized (in which just was involved one lobe) and diffuse (multilobar) (13).
2) In addition, bronchiectasis also can be divided into three groups based on morphology proposed by Reid (14): cylindrical, varicose, and cystic (13). Among
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them, the most common type of bronchiectasis is cylindrical, followed by the varicose and cystic form in the HRCT (15), in which the cylindrical is more mild and cystic is more severe according to the clinical severity (16). Interestingly, although the previous classification can correlate proportionally to the clinical severity, it is not related to the etiology of bronchiectasis or the relationship between them is indeed very poor (17).
a) Cylindrical: The cylindrical bronchiectasis is also known as tubular and presents a regular form with the distal diameter a little dilated, in which an airway obstruction by the mucous cap will be observed; b) Varicose: It is irregular bronchi with a more dilated airway and constriction; c) Cystic: It is known as saccular, accompanied by progressively dilated bronchi towards the peripheral airways which end in large cysts, sacks, or grapes (5). This is the gravest form of bronchiectasis and is commonly found in patients with CF (18).
3) Possibly the best study of the pathology of bronchiectasis was realized by Whitwell who showed that the bronchial wall was infiltrated with inflammatory cells (19). It has been shown that loss of elastin, smooth muscle and even cartilage, was related to the dilatation of bronchi. Therefore, bronchiectasis has been classified into the following three subtypes by Whitwell:
a) Follicular: The follicular subtype is the major form that keeps up a correspondence to cylindrical bronchiectasis. A large amount of infiltration of inflammation in the bronchial wall of the small airways is the primary feature of the subtype, which is composed of lymphoid follicles and, thus, contributes to the small airway obstruction. On the other hand, the damage
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of elastin, smooth muscle and even cartilage leads to the dilatation of the large airways. Interestingly, the adjacent parenchyma will be damaged due to the extension of infiltrated inflammation; b) Saccular: it corresponds to the form cystic as described above; c) Atelectatic. The summarize of bronchiectasis classification is shown in table 2.
Table 2 Classification of bronchiectasis
Classification Types
Radiology Localized Diffuse Radiology by
Reid (14)
Cylindrical Varicose Cystic
Radiology by Whitwell (19)
Follicular Saccular Atelectatic
1.1.1.3. Epidemiology
Bronchiectasis is in frequency the third chronic inflammatory disease of the airways, after asthma and COPD, and it is quite frequent to see an overlap of bronchiectasis-asthma and bronchiectasis-COPD (5,6). However, the prevalence of non-CF bronchiectasis is still unknown nowadays. One of the studies described that the prevalence of bronchiectasis has been estimated at 42 to 566 cases per 100,000 inhabitants (5), whereas other authors have reported the prevalence as 53 to 566 cases per 100,000 inhabitants (7), and the higher percentage in women and the elderly also were observed (5,20,21).
Moreover, female non-CF bronchiectasis patients seem to present decreased exercise capacity, body weight and self-care which have also been shown in some patients with asthma (20). Actually, since a huge number of
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bronchiectasis patients are initially diagnosed with COPD or asthma, the prevalence of bronchiectasis may still be underestimated. These data confirm that it is not a rare disease, as it exceeds the 5 cases per 10,000 residents identified as an orphan disease in Europe. Currently, we are witnessing a significant increase in the number of diagnosed cases of non-CF bronchiectasis, possibly due to the increasing longevity of the population, the chronicity of the generative diseases, its recently studied association with other highly prevalent entities (such as asthma or COPD) and, above all, to the widespread use of imaging techniques (high-resolution computed tomography of the chest [HRCT]) that confirm its diagnosis.
1.1.1.4. Pathophysiology
Non-CF bronchiectasis is characterized by inflammation and microbial infection in the airways and lungs. The pathophysiology of bronchiectasis is still poorly understood, but Cole’s “vicious cycle hypothesis” is the most well-known model of non-CF bronchiectasis development (22–24). It is considered that in non-CF bronchiectasis, there must have been an initial event that compromised mucociliary clearance, made it difficult to evacuate mucus, and remained in contact with the epithelium for an extended period (23). In case of the initial insult, airway structural damage permits bacterial infection of the lower airway.
Generally, a potentially pathogenic microorganism is the one that initiates a chain of harmful events that produce an increase in neutrophils and pro- inflammatory cytokines such as interleukin 8 (IL-8), IL-6, IL-1α, and IL-1β, tumor necrosis factor-alfa (TNF-α) as well as leukotriene B4 (LT-B4) and also the granulocyte colony stimulating factor (G-CSF) (18,25,26). These factors
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progressively destroy the integrity of the bronchial wall as well as the ciliary system, which is the important player in the airway cleaning mechanism. At the same time, proteolytic enzymes such as elastase and metalloprotease are released by neutrophils. These released enzymes will increase epithelial damage to the lung, and therefore cause a greater alteration in mucociliary clearance, which will restart this vicious circle (22), leading to the development of the condition and worsening consequences for patients (Figure 2). Therefore, inflammation of the bronchi after an infection is the onset of the appearance of non-CF bronchiectasis, although it is also the factor that would perpetuate the presence of germs in the airway, inflammatory cells, and mediators, and deteriorate progressively of respiratory function (27–31). Furthermore, systemic inflammatory parameters in non-CF bronchiectasis patients with stable phase were also increased (28,29,32,33). In addition, some of these parameters of systemic inflammation correlate with certain variables indicative of severity, such as the extent of bronchiectasis, impaired respiratory function, or even the quality of life of the patients (33,34).
Figure 2. Pathogenesis of bronchiectasis (Adapted from Cole 1986 (22) )
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1.1.1.5. Clinical manifestations
The clinical manifestations of non-CF bronchiectasis are variable and broad- spectrum. The most common symptoms of bronchiectasis were cough and chronic expectoration, as well as recurrent respiratory infections and chronic inflammation, or even remained asymptomatic (3,35). The chronic expectoration may be mucous, mucopurulent, or even purulent, and occasionally hemoptoic, and sometimes accompanied by a foul odor characteristic of the pathology form which can be graded on 8-point scores by Murray sputum purulence scale (5).
In addition to the above-mentioned symptoms, patients with bronchiectasis also can present dyspnea, hemoptysis of variable intensity, intermittent chest pain, or fatigue (5,36). Finger clubbing and cyanosis are also the symptoms of bronchiectasis although they are rare and appear in late stages. Rhinosinusitis is customary, specifically in immunodeficiencies and primary ciliary dyskinesia, which is the contributor to infertility (36). It should be noticed that the exacerbation of non-CF bronchiectasis is usually caused by the increase in airway bacterial density by bacteria flora colonization or by the acquisition of opportunistic microorganisms (37).
However, the recurrence of chronic infections caused by multidrug-resistant germs can lead to the deterioration of symptoms and quality of life. In addition, the disease can be a contributor to the impact of systemic manifestations, which will aggravate the quality of the life (38).
1.1.1.6. Lung function
Patients with bronchiectasis which is characterized by recurrent infection and inflammation, frequently present a decline of lung function due to the
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heterogeneous etiology (27,39). In several studies were observed that the obstruction of the airway was present in patients with bronchiectasis (27), whereas the total volume of the lung function was also reduced. Generally, the airway obstruction was evaluated by the forced expiratory volume in the first second (FEV1) and the forced vital capacity (FVC) post-bronchodilator. The obstructive function pattern was defined as the ratio FEV1/FVC <70% (40–43).
Currently, the consensus of the American Thoracic Society (ATS) and the European Respiratory Society (ERS) (44,45), based on the postbronchodilator FEV1 value, is the most widely used to classify the severity of airway limitation (Table 3).
Table 3 Classification of the severity of the airflow limitation severity according to ATS/ERS (44,45).
The degree of the severity of the obstructive functional pattern is associated with a large number of factors which the influence on the natural history of bronchiectasis is still not well characterized, although the various etiologies,
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chronic colonization by Pseudomonas aeruginosa, exacerbations, and systemic inflammation contributes to the most common factors of non-CF bronchiectasis (10,31,46–48)
The relationship between the carbon monoxide transfer capacity (DLCO) and bronchiectasis also has been investigated in recent years. Previous studies have demonstrated that DLCO was decreased in non-CF bronchiectasis patients (49–51).
1.2. Systemic manifestations
Chronic respiratory disease including COPD, bronchiectasis and lung cancer (LC) is not only related to respiratory symptoms but also can contribute to several effects of the extra-pulmonary system, as known as systemic manifestations: osteoporosis, cardiovascular disease, nutritional alterations, skeletal muscle dysfunction, systemic inflammation, depression and fatigue (52–55). Specifically, in these patients, the systemic manifestations of the disease are mainly considered as nutritional alterations, skeletal muscle dysfunction, and systemic inflammation (52,56–58), which also are the topics in the thesis. These systemic effects have negative consequences on the tolerance to exercise and daily activities which can worsen their quality of life and mortality (59–66).
In the latest decades, the relationship between systemic manifestations and chronic airway diseases such as COPD is well characterized (37,53,67).
Regarding peripheral muscle function, especially in lower limbs, reduced muscle strength was observed in 33% of COPD patients (60,68–71). Moreover, previous studies have also evidenced dysfunction of respiratory muscle in
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COPD patients (72–74). It has also been demonstrated that nutritional abnormalities take place commonly in COPD (75–77).
Several factors have been shown to involve in the pathophysiology of nutritional abnormalities, skeletal muscle dysfunction and sarcopenia in COPD (59–64).
The most important contributors of nutritional depletion, weakness of muscle function and atrophy are deconditioning and physical inactivity (59–64).
Previous studies have reported the potential gender differences in chronic respiratory disease in recent years (78). Disease outcomes may also differ between male and female patients in chronic respiratory patients (79). Airway anatomy, chronic infection and inflammation, transformed host defense mechanisms, and environmental factors account for the major factors that lead to the sex differences in patients with bronchiectasis (80,81). In addition, peripheral muscle dysfunction in gender differences was observed in patients with COPD. Compared to male COPD patients with advanced-stage, female patients presented a greater reduction of peripheral muscle dysfunction (82).
Moreover, nutritional alterations are more pronounced in women than in men COPD patients (76).
The association of systemic manifestation with non-CF bronchiectasis is also studied, even though the mechanism of the response is unclear related to bronchiectasis etiology and severity (37,53,55,83,84). Although nutritional alterations (4,85–87), peripheral (55,65) and respiratory muscle dysfunction (88,89), and systemic inflammation (85,86) has been described in several patients with non-CF bronchiectasis, it is still indistinct whether there are nutritional deficiencies and impaired muscle function in non-CF bronchiectasis
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according to the few literature reviews. Moreover, whether their differences between female and male non-CF bronchiectasis patients may exist is also unelucidated.
Therefore, the following section has proceeded. As described in the former section, systemic inflammation, along with nutritional alterations and skeletal muscle dysfunction, was considered as systemic manifestation. First of all, a brief introduction of systemic inflammation will be carried out, secondly, nutritional abnormalities and skeletal muscle dysfunction will be described.
1.2.1. Inflammation
Inflammation is a response of the immune system to damage in the organism which can be caused by diverse deleterious stimuli such as mechanical (fracture), infectious (bacterium or virus), chemical (by contact with irritants), or physical agents, and infected or damaged cells. The inflammatory response can be classified into two types: local (in the pulmonary) and systemic (beyond the pulmonary) (29,48).
Local inflammation is related to the airway structure and adjacent parenchyma destruction (13). Systemic inflammation is the cardinal contributor to the pathogenesis of bronchiectasis, which has an impact on the quality of life, loss of weight and skeletal muscle dysfunction (90,91). However, so far, the mechanism of systemic inflammation in chronic respiratory diseases such as COPD and non-CF bronchiectasis has not been established, which is very important for us to understand the pathogenesis of these underlying diseases and develop new therapy (90). Several studies had reported the hypothesis
“spill-over” that pulmonary inflammation spills into the systemic circulation (92),
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while other authors are against this hypothesis because they have not been able to find an association between the cytokines in the airway and those detected in the systemic circulation (91,93).Therefore, it seems more likely that extrapulmonary manifestations arise in parallel with lung disease, both caused by the same noxious stimulus (94).
1.2.1.1. Systemic inflammation in non-CF bronchiectasis
As mentioned above, non-CF bronchiectasis patients can present inflammatory responses both locally and systemically. It has been evidenced that the local inflammatory markers such as neutrophils, pro-inflammatory cytokines (IL-8, IL- 6, IL-1α, and IL-1β), TNF-α and the G-CSF have increased in non-CF bronchiectasis (18,25,26). Moreover, it also has been found that a high proportion of non-CF bronchiectasis patients presented systemic inflammatory markers (18). It has been assumed that in terms of a high degree of local inflammation, the degree of systemic inflammation also will be higher due to the
"spill-over" of local inflammatory markers into the bloodstream in those patients (18). It has also demonstrated a positive correlation between the systemic inflammatory markers and the severity of the disease (28), but a negative correlation with lung function, exercise capacity, and physical activities (18,28).
Systemic inflammatory mediators can be used as markers of the intensity of the host inflammatory response to lung infection (95). In addition, the level of systemic inflammatory markers such as the number of leukocytes, neutrophils, eosinophils counts, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), immunoglobulin A (IgA), immunoglobulin G (IgG), and TNF-α increased in patients with stable non-CF bronchiectasis (18,28). In addition, fibrinogen is
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also an important type of systemic inflammatory marker, which is positively correlated with the severity of the disease (32).
1.2.1.1.1. Circulating inflammatory cells
Previous studies have shown an increase in blood inflammatory cells, especially neutrophils, eosinophils and lymphocytes in patients with chronic respiratory disease (96,97). Since immunodeficiencies and susceptible host defense are the main factors leading to the pathogenesis of bronchiectasis, neutrophils are considered to be one of the most relevant contributors to against infection in non-CF bronchiectasis (95). It has been found that the activation of blood neutrophils could enhance cytotoxicity and migration response through various mechanisms such as phagocytosis, release the inflammatory mediators which lead to the destruction of the endothelium (25,98). Eosinophils release proteins that are cytotoxic and can result in airflow obstruction and bronchial epithelial damage (99,100). Recent studies also indicate that circulating lymphocytes may have an abnormal function with an increase in cytochrome oxidase activity (101). Interestingly, neutrophils, eosinophils and lymphocytes were negatively related to the degree of the disease severity and decline of lung function (95,97).
1.2.1.1.1.1. The role of eosinophils
The role of eosinophils in the pathogenesis of bronchiectasis is not fully understood (25). However, previous studies had demonstrated that eosinophil counts are the major indicator of the prognosis and the response to therapy of the underlying disease (102,103). Martinez-Garcia et al. (104) and Alberti et al.
(102) have elucidated a positive correlation between the high blood eosinophil counts (cut-off point: >3% or >150 cells/uL) and the better response to the
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treatments with inhaled corticosteroids (ICS) in patients with bronchiectasis. In addition, other chronic respiratory disorders such as COPD have also shown that the high blood eosinophil counts correspond to a better therapeutic effect of ICS (105). Actually, many studies have investigated the relationship between clinical outcomes and the level of blood eosinophil counts. However, the results are controversial. Ciro Casanova et al. have shown that in patients with COPD, the high level of circulating eosinophil counts (⩾300 cells/μL) was correlated positively with better outcomes and survival (106). On the contrary, Robert et al.
and Guy et al. have reported that patients with COPD showing high levels of eosinophils are a contributor to future exacerbations (107,108).
1.2.1.1.2. Acute-phase reactants
Infection, burn, operation and trauma can quickly induce the body to produce non-specific reactions dominated by defense, such as elevated body temperature, elevated blood glucose, enhanced catabolism, negative nitrogen balance, and rapid increase of some protein concentrations in plasma produced by the liver (109,110). This multifaceted reaction is called acute-phase reaction (APR), and the expressed proteins are defined as acute-phase proteins (APPs) (109,110). APP is classified into two types: positive and negative. Positive APPs are CRP, fibrinogen, alpha1 antitrypsin and ceruloplasmin, which is related to the increased production whereas the negative is albumin, transferring, transcortin and retinol-binding protein which is known as the decreased APPs, induced by cytokines such as IL6 o TNF-α (109,110).
All of them are virtuous inflammatory markers, regulated by inflammatory signals and change quickly with the change of the disease (110). Among them,
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CRP and fibrinogen are the two most important contributors to the diagnostic tool. Previous studies have shown that CRP and fibrinogen levels are higher in patients with non-CF bronchiectasis patients, whether in acute exacerbation or stable stage. It also has been found that the CRP and fibrinogen levels are negatively associated with lung function, exercise capacity and disease severity (31,33). Furthermore, Thomsen et al. demonstrated that a highly positive correlation (2-4 times) appears to be possible between systemic inflammation markers (CRP, fibrinogen, and systemic inflammatory cells) and the risk of development of comorbidities (cardiovascular diseases, diabetes mellitus, LC, and pneumonia) (111).
1.2.1.2. Systemic inflammation differences between gender in non-CF bronchiectasis
Regarding the potential gender-related differences of these inflammatory serum biomarkers, there is not enough published literature to draw reliable conclusions.
And there is no literature describing whether there are gender differences in non-CF bronchiectasis.
1.2.2. Nutritional alterations
Nutritional alterations are one of the most common systemic manifestations in different chronic respiratory disorders such as COPD, CF, LC, and non-CF bronchiectasis which are very diverse depending on the characteristics and the underlying disease of each patient. In the advanced stage of nutritional abnormalities, a clinical consequence with marked weight and muscle mass loss was involved, considered as cachexia. However, it should be noted the marked loss of body weight is not evident in the earliest stages of nutritional
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deficiencies. Thus, the early diagnostic and stratification of nutritional disorders are very important for personalized therapy. The diagnosis of the nutritional depletion is mainly based on the following variables which are simplest but less specific: body weight, percentage of ideal body weight (%IBW) or body mass index (BMI), or the body composition such as fat-free mass index (FFMI). The most common diagnostic cut-off points for impaired nutritional status are defined as follows: %IBW < 80%-90% or BMI < 18.5 kg/m2 (112,113). In addition, the nutritional abnormalities can be stratified into four categories using BMI: 1) mild (17-18.4 kg/m2), 2) moderate (16-16.9 kg/m2), 3) severe (15-15.9 kg/m2), and 4) very severe (< 15 kg/m2) (114). Nevertheless, anthropometric assessments can be useful but insensitive to mild-moderate nutritional disorders.
In fact, the most important variable involved in body composition to evaluate the nutritional status is FFMI. It is defined that the value of FFMI in females was lower than 14.5-15 kg/m2, and in males, 16-18 kg/m2 (115). Furthermore, nutritional status also can be evaluated by blood parameters such as total proteins, albumin, prealbumin, hemogram, and hematocrit (15).
1.2.2.1. Factors involved in the pathophysiology of patients
Patients with non-CF bronchiectasis, not only have respiratory symptoms but also demonstrate nutritional abnormalities frequently. The factors involved in the development of nutritional abnormalities are heterogeneous. As mentioned by several studies, the deleterious factors involved in COPD also can cause deficiencies in non-CF bronchiectasis (53). Nutritional status can be affected by several factors such as physical inactivity, systemic inflammation, alterations in
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gas exchange, hormonal alterations, medical treatment, and the consequence of comorbidities and aging (53,59–64).
1.2.2.2. Prevalence of nutritional abnormalities in non-CF bronchiectasis
A study of 93 bronchiectasis patients has shown that fourteen percent of patients had nutritional abnormalities, which are based on a BMI of less than 18.5 kg/m2 (86). Moreover, another study demonstrated that the prevalence of nutritional depletion (BMI of < 20 kg/m2) was approximately 31% in 33 bronchiectasis patients (116). Impaired nutritional status was positively associated with decreased respiratory function and was a predictive contributor to survival and mortality in chronic respiratory patients (4,117). In addition, a recent study found that 12.3% (61 of 496 ) bronchiectasis patients presented malnutrition with a BMI less than 18.5 kg/m2 which was associated with a reduced lung function, but it was not related to the disease severity and other clinical outcomes (21).
1.2.2.3. Nutritional abnormalities differences between gender in non-CF patients
The prevalence of gender differences in nutritional abnormalities in non-CF bronchiectasis remains unclear established in the literature. Recently, a study has reported that nutritional alterations are more pronounced in females than in male bronchiectasis patients (21). The study including 496 non-CF bronchiectasis patients has shown that the prevalence of underweight patients was 7% in men and 13% in women (21).
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1.2.3. Skeletal muscle
The human body has about 600 muscles. Among them, the three main types of muscle are as follows: smooth muscle, skeletal muscle, and myocardium. The skeletal muscle accounts for one of the most important types, which constitutes about 40% of total body weight and contains 50-75% of all body protein (118).
This tissue is a specialized tissue with the ability to contract and relax voluntarily in response to messages (nerve impulses) that come from the nervous system.
The most important function of the skeletal muscle includes movement, producing power and strength, and maintaining posture (118). Muscle mass is attributed to the balance of the synthesis and destruction of protein (118).
Furthermore, the muscle can function by using the energy obtained in the process of protein degradation as mechanical energy. Thus, the normal status of skeletal muscle is very important for maintaining daily activities and preventing a variety of diseases (118).
1.2.3.1. Muscle contraction
The mechanism of skeletal muscle contraction is based on the filament slip theory. According to the corresponding theory, muscles receive nerve impulses from motor nerve endings which will cause excitation of the muscle membrane.
Then, muscle cells generate action potentials, which produce an increase of the concentration of Ca2+ in the sarcoplasm, weakening the binding of troponin I and actin and changing the conformation of tropomyosin. The actin site that was originally covered is exposed and immediately comes into contact with the myosin head, which will activate the decomposition process of ATP to provide energy for muscle contraction. Under certain conditions, the cross-bridge
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reversibly binds to the actin on the thin muscle filaments, resulting in the relative sliding of the thick and thin muscle filaments, therefore, leading to muscle contraction (119).
1.2.3.2. Skeletal muscle function
Skeletal muscle function is mainly characterized by performing contractions to generate or stop the movement and by the capacity of maintaining the posture (118,120). Moreover, the movement necessary to perform daily activities such as walking, writing, or breathing is dominated by the system. Muscles also can prevent bones or joint damages and can protect the interior organs from exterior hurt (118,120).
The primary feature of skeletal muscle is that it has the ability to produce force (as known as strength) and to maintain the submaximal effort in a period (as known as endurance) (121–123). Strength depends fundamentally on muscle mass, while endurance is determined by the aerobic capacity of the specific muscle. The 2 properties can be measured in various muscle groups in the daily clinic. Numerous tests are recommended to evaluate the respiratory and peripheral muscle function, as well as to identify the tolerance to exercise (6- minute walk test). The section will only focus on the following tests which are the main objectives of the thesis.
1.2.3.2.1. Assessment of respiratory muscle function
Pressure in the mouth. The maximum pressures generated in the mouth, both inspiratory (MIP) and expiratory (MEP), are more specific in assessing the strength of the respiratory muscles (55,89,124–127). They are usually
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performed by means of static maneuvers (without airflow), using occludable oral pieces with a small hole, which prevents the closure of the glottis and the use of the buccinator muscles. The MIP (generally determined from residual volume [RV]) reflects the force exerted by all inspiratory muscles, while the MEP (normally determined from total lung capacity [TLC]) essentially expresses the force of the expiratory muscles of the abdominal press (124). As in any voluntary maneuver, it is recommended to achieve 3 acceptable maneuvers and with a variation of less than 5%. There are reference values for a healthy Mediterranean population (92,128). On the other hand, maximum inspiratory pressure values greater than -80 cmH2O in males or -70 cmH2O in females make it possible to exclude the presence of muscle dysfunction (124).
Sniff nasal inspiratory pressure (SNIP). It is determined by nasal pressure during maximum inhalation (SNIP) (124,128,129). This is a natural and dynamic maneuver performed with the subject in a sitting position and after the occlusion of a nostril by a pressure catheter connected to a digital polygraph. It is usually done from the functional residual capacity (124,128–131), performing a minimum of 10 maneuvers and selecting the highest value. Although the results in terms of SNIP are usually interpreted in the form of absolute values (cm H2O), reference values are also used (128,132). Moreover, values greater than −70 cm H2O (males) or −60 cm H2O (females) exclude inspiratory muscle dysfunction (124).
1.2.3.2.2. Assessment of limb muscle function
Upper limb muscle function: Hand-grip dynamometry
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Skeletal muscle function can be assessed of either muscle strength or endurance, and the former is most broadly assessed in the clinics (59–64).
Handgrip strength was evaluated using a specific dynamometer which is a simple technique. Although the results in terms of handgrip strength (HS) are usually interpreted in the form of absolute values (kg), reference values for the Mediterranean population are also used, such as those of Luna-Heredia et al (133). The maximum voluntary contraction of the flexor muscles of the hand was assessed. The highest value out of three reproducible maneuvers (<5%
variability among them) was accepted as the valid measurement for each subject (133,134).
Relationship between upper muscle function and non-CF bronchiectasis
To date, few studies have demonstrated the relationship between the muscle function of upper limbers and non-CF bronchiectasis. Recently, Camargo et al.
have found that bronchiectasis patients of younger age and severe airway obstruction have weakness of the upper muscles (65). However, in a study of 20 bronchiectasis patients and 20 control subjects, no difference in upper muscle strength was found between the two groups (55). Moreover, in patients with non-CF bronchiectasis, there are no studies to demonstrate whether exist gender differences in upper limb muscle dysfunction.
Lower limb muscle function: Isometric maximum voluntary contraction of quadriceps femoris
Quadriceps muscle strength is evaluated by means of isometric maximum voluntary contraction through the extension of the quadriceps with the leg fixed at the ankle and connected to a dynamometer (62,63). The force can be
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expressed as absolute values and with respect to the reference values (68,135).
The highest value from three brief reproducible maneuvers (< 5% variability among them) was accepted as the QMVC for each subject (133,134).
Relationship between lower limber muscle function and non-CF bronchiectasis
The relationship between the lower limbers muscle function and non-CF bronchiectasis is still not very clear due to the few studies. Recently, Camargo et al. have found that bronchiectasis patients of younger age and severe airway obstruction also had weakness of the lower muscles (65). Ozalp et al. have observed that lower limb strength had a tendency to be lower in non-CF bronchiectasis compared to control subjects (55). In addition, it has been found that in non-CF bronchiectasis, peripheral muscle dysfunction can be related to the decline of exercise capacity (55). However, in patients with non-CF bronchiectasis, there is no literature describing whether there are gender differences in lower limb muscle dysfunction.
Exercise capacity
The 6-minute walk test (6MWT) is a simple exercise that consists of measuring the distance walked quickly by the patient on a hard, flat surface over a period of 6 minutes (136–138). All the subjects will be encouraged for every minute and will interrupt the test when symptoms of dyspnea are presented. Moreover, the levels of symptoms such as dyspnea and the discomfort of lower limbs were quantified by a modified Borg scale. When the patient takes the walk test for the first time, it is recommended to repeat it a second time, with an interval of about one hour, and choose the one with the longest distance (139).
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The 6MWT is the most popular among the different field tests (136,140). It has a good level of standardization (136,141,142) with reasonable reproducibility (143). Moreover, it is very useful for evaluating the functional status of patients, as well as for measuring the effects of different interventions in a wide variety of chronic respiratory diseases (139).
The 6-minute walk test corresponds to a high-intensity sustainable submaximal exercise (139,144) that can be used to evaluate the different functions (cardiac, respiratory, and muscular, and oxygen transport). The evaluation of submaximal exercise tolerance is a relevant factor for the prognosis in chronic respiratory disorders (139).
Although the results in terms of distance are usually interpreted in the form of absolute values (meters), reference values are also used, such as those of Enright et al. (138). In summary, the 6-minute walk test is highly recommended in the clinic as a simple exercise test for assessing the functional status and the effect of certain interventions in patients with chronic respiratory and cardiovascular diseases. The simplicity, safety, reproducibility, and high predictive value of the test make it simple for the study of aerobic capacity in the clinic.
Previous studies have shown that the 6-minute walk test is very useful and offers very reliable and comparable measurements over time and between individuals (145). It is of great benefit in the routine clinic. The 6MWT can reflect the subjects' ability to carry out daily activities (139,145) and can predict mortality in non-CF bronchiectasis patients (146).
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1.2.3.3. Skeletal muscle dysfunction
The process of the decline of the ability of muscles to produce force (strength) or to the maintenance of the effort (endurance) is defined as muscle dysfunction, generally, resulting from the imbalance of the synthesis and degradation of protein which is due to the reduction of the size and number of myofibers (60,147).
Several factors can disturb skeletal muscle function such as altered diet and nutrients, the consequence of underlying disorders or age, and the loss of physical activities or movement. As the impact of physical inactivity or prolonged immobilization, a decrease in muscle mass is generated, attributed to the absence of muscle contraction (148,149). In the case of reduced activity or immobility, the weakening of muscle function, whether accompanied by muscle atrophy or not, will have many effects on the daily life of the patients (147).
1.2.3.4. Epidemiology of muscle dysfunction
The prevalence of muscle dysfunction in non-CF bronchiectasis patients is still unclear due to the few studies about this research. Nevertheless, it has been reported in several studies that the presence of muscle dysfunction (55,65), the reduction of physical activities, and even the increase of mortality also appeared in patients with non-CF bronchiectasis (86,150).
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HYPOTHESIS
52
Hypothesis
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2. HYPOTHESIS
Systemic manifestations such as muscle dysfunction, nutritional abnormalities and inflammation are frequent in chronic respiratory diseases such as COPD. In the current thesis, we hypothesized that patients with non-CF bronchiectasis may also have a decrease in muscle function, both respiratory and peripheral muscles, nutritional abnormalities and systemic inflammation, and their alterations in muscle function may be much more severe in women than in men.
Furthermore, high levels of blood eosinophil counts have a better response to treatment in these patients. Therefore, we also hypothesized that low blood eosinophil levels may identify a more severe phenotype in bronchiectasis patients.
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OBJECTIVES
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Objectives
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3. OBJECTIVES
3.1 Main objective
To explore systemic inflammation, nutritional status and muscle function in patients with non-CF bronchiectasis, and differences between female and male patients. Moreover, the role of systemic inflammatory cells (especially eosinophils) and their differences between female and male non-CF bronchiectasis patients also were explored.
3.2 Secondary objectives
1. To identify different clusters of patients included in this registry that could discriminate differential phenotypes on the basis of blood neutrophil, eosinophil, and lymphocyte counts along with C reactive protein and hemoglobin levels, and to analyze potential differences between the clusters in several parameters (lung function, disease severity, nutritional status, and systemic inflammation).
To achieve this objective, the following study was carried out:
Study #1. Clustering analysis identified differential phenotypic groups of bronchiectasis patients in a large-cohort study
2. To identify a cut-off value of the blood eosinophil counts among the patients included in RIBRON registry that could discriminate differential phenotypic clusters; to analyze the potential differences in the several clinical and analytical parameters between the clusters and to explore the potential associations between eosinophil and other blood cells with the disease severity scores and the number of hospitalizations and exacerbations.
Objectives
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To achieve this objective, the following study was carried out:
Study #2. Phenotypic Clustering in Non-Cystic Fibrosis Bronchiectasis Patients: The Role of Eosinophils in Disease Severity
3. To analyze gender differences in lung function, disease severity, nutritional status, and systemic inflammatory parameters, and potential associations between either the inflammatory or the nutritional parameters with the clinical variables in a large-cohort of patients from RIBRON.
To achieve this objective, the following study was carried out:
Study #3. Differences in Nutritional Status and Inflammatory Biomarkers between Female and Male Patients with Bronchiectasis: A Large-Cohort Study
4. To explore the differences in alterations in MIP, MEP, SNIP, hand grip, quadriceps muscle strengths, body composition and blood analytical biomarkers between female and male patients with mild bronchiectasis and correlations between lung function and the extrapulmonary parameters.
To achieve this objective, the following study was carried out:
Study #4. Respiratory and peripheral muscle weakness and body composition abnormalities in non-cystic fibrosis bronchiectasis patients:
gender differences
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COMPENDIUM OF PUBLICATIONS
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4. COMPENDIUM OF PUBLICATIONS
4.1. Article 1
Title:
Systemic Inflammatory Biomarkers Define Specific Clusters in Patients with Bronchiectasis: A Large-Cohort Study
Authors
Xuejie Wang, Carmen Villa, Yadira Dobarganes, Casilda Olveira, Rosa Girón, Marta García-Clemente, Luis Máiz, Oriol Sibila, Rafael Golpe, Rosario Menéndez, Juan Rodríguez-López, Concepción Prados, Miguel Angel Martinez- García, Juan Luis Rodriguez, David de la Rosa, Xavier Duran, Jordi Garcia- Ojalvo and Esther Barreiro
Journal:
Biomedicines 2022, 10(2), 225
DOI: 10.3390/biomedicines10020225 Impact Factor:
6.081(2020), Quartile: Q1
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