Nghiên cứu biến đổi lâm sàng, thông khí phổi, mức độ kiểm soát và nồng độ một số cytokine huyết thanh ở bệnh nhân hen phế quản điều trị bằng ICS và LABA tt tiếng anh

1 ABBREVIATIONS ACT Assessment of asthma control evaluation BMI Body mass index ĐC Exacerbation GINA Global Initiative for Asthma HPQ Asthma ICS Inhaled corticocorticoids LABA Adrenergic agonists with long-acting β2 agonists RLTK Ventilation disorders TKP Pulmonary ventilation INTRODUCTION OF THE THESIS Introduction Bronchial asthma is a chronic disease that tends to increase Administration of inhaled corticosteroids (ICS) and long Acting 2 adrenergic agonists (LABA) is the primary treatment for asthma control, but the proportion of patients who are uncontrolled over time is still high (38, 5% to 64.4%) depending on the country Therefore, the evaluation of clinical changes, pulmonary ventilation and control levels as well as factors related to control levels have a very important role in the treatment of asthma control: treatment and adjustment to improve control effectiveness The essence of asthma control is to control airway inflammation and lung parenchyma Cytokines produced from lypmphocyte Th2 such as interleukin (IL) 4, 5, 13 and TNF-α are cytokines that play a key role in the inflammatory response in asthma Studies have shown that serum cytokine levels help assess inflammatory patterns, disease course, and response to treatment, especially treatment corticosteroids and the application of new therapies in asthma (cytokines resistance) Therefore, we conducted research on the subject: "Study on clinical changes, pulmonary ventilation, control levels and serum cytokines in patients with bronchial asthma treated with ICS and LABA" Research objectives: 1.1 Evaluate the clinical changes, pulmonary ventilation and control levels in patients with bronchial asthma treated with ICS and LABA after months 1.2 Assess changes in serum IL-4, IL-5, IL-13 and TNF-α levels according to control levels in patients with bronchial asthma who are treated with ICS and LABA after months The need of the subject Stemming from the fact that asthma is a global burden of disease and the trend is increasing The results of asthma control are challenging in clinical practice The evaluation of clinical changes, pulmonary ventilation, and control levels in patients treated with ICS and LABA will help physicians better understand the course of the disease as well as evaluate the results of control treatment in detail and more efficient Evaluation of changes in serum IL-4, IL-5, IL-13 and TNFα levels plays a role in the evaluation of disease control (inflammation control), contributing to improve asthma control present and in the future The new contributions of the thesis are as follow The results of the thesis evaluated the response after months of overall asthma control treatment from clinical changes, pulmonary ventilation and control level The results showed that clinical changes and pulmonary ventilation were parallel to the control level and the control level reached a high rate after the 2nd and 3rd month treatment The results of the thesis for the first time in Vietnam assessed the relationship between obesity and uncontrolled asthma level (OR = 0.05; p = 0.01;% CL = 0.006 - 0.46) The study also showed that serum IL-5, IL-13 and TNF-α levels were significantly reduced after months of treatment (0.075 pg/ml, 1.6 pg/ml, 0.1 pg/ml with 4.2 pg/ml, 11.97 pg/ml, 8.77 pg/ml) (p < 0.05) and correspond to the level of controlled asthma There is a correlation between decrease in IL-5, IL-13, and TNF-α levels compared with before treatment with good control and an increase in IL-5, IL-13, TNF-α levels compared to before treated with partial control and uncontrolled in patients after months of treatment (p < 0.05) The results of the thesis contribute to assessing posttreatment response and improving the effectiveness of current asthma control treatment in outpatient asthma management units The composition of the thesis The thesis has 126 pages: Introduction pages; Overview 34 pages; Subjects and research methods 17 pages; Research results 33 pages; 36 pages discussion; Conclusion 02 pages; Recommendations 01 page 149 references with 26 Vietnamese documents and 123 English documents CHAPTER 1: OVERVIEW 1.1 Control treatment of bronchial asthma 1.1.1 The reality of controlling asthma Research in both developed and developing countries has acknowledged the success of the asthma Global Strategy, but the status of asthma control in Asia-Pacific countries is still very low (average rate of asthma is controlled about 20%) The proportion of patients using ICS in controlled treatment is still low In Vietnam, the proportion of patients taking control accounted for 41.05%, uncontrolled accounts for a relatively high proportion (58.95%) This is also a challenge posed in asthma control practices in our country and around the world 1.1.2 Assess the level of disease: Assessing the level of asthma plays a very important role in controlled treatment: helping to classify the severity of the disease to access appropriate initial treatment; Evaluate post-treatment response to control and identify future risk factors for timely and appropriate adjustment of treatment The evaluation methods are based on: clinical and pulmonary ventilation; The level of treatment required to control symptoms and exacerbations 1.1.3 Goals and strategies for controlling asthma The goals of controlled treatment include: Achieving good control of symptoms and maintaining normal physical activity for the patient; Minimize the risk of exacerbations, reduce the risk of fixed airway obstruction and side effects of the drug Strategies for controlling asthma include: control based treatment; treatment based on the amount of white blood cells in the sputum; Treatment is based on the concentration of FeNO in the exhaled breath 1.1.4 Steps for controlled treatment Treatment based on the degree of control is carried out in a continuous cycle including: Assessing the status of the disease, adjusting the treatment and reevaluating the response of the patient after treatment 5 In control-based asthma treatment, both areas of asthma control must be considered: symptom control and the future risk of the disease 1.1.5 Assessment of asthma control - Assessment of symptom-based control divided into levels: good control, partial control and uncontrolled - Assess the future potential risks including: the risk of developing exacerbations, the risk of developing a fixed airway obstruction and the risk of side effects of the drug - Evaluate factors related to bronchial asthma control results: patient-related factors, physician-related factors 1.2 Inflammatory response and the role of cytokines in controlling asthma 1.2.1 Inflammatory response in bronchial asthma Airway inflammation is the primary and most important mechanism in the pathogenesis of asthma When the airways come in contact with allergens or disease triggers, inflammation occurs The inflammatory response in the asthma involves inflammatory cells and inflammatory chemical mediators The process of airway inflammation in asthma occurs in stages: cable inflammation, chronic and airway reconstruction 1.2.2 The role of some cytokines in controlling asthma The cytokines have a key role in the inflammatory response of asthma The change of cytokines reflects the phenotype of inflammation, the course of the disease as well as the assessment of treatment response, especially anti-inflammatory therapy (corticosteroids) and molecular targeted treatment (IL resistance, antiTNF-α ) The main cytokines involved in the inflammatory process in asthma include cytokines produced from Th2 lymphocytes such as IL-4, IL-5, and IL-13 Along with these cytokines TNF-α is also an important proinflammatory cytokine in the asthma: amplifies the inflammatory process, increases bronchial response and is associated with disease progression (airway reconstruction in asthma) Currently, these cytokines are being focused on research, especially researching drugs against them in the treatment of difficult-to-treat asthma or severe uncontrolled asthma CHAPTER 2: OBJECTS AND METHODS 2.1 STUDY OBJECTS Including 66 patients who were diagnosed to be asthma, in addition to exacerbation and managed, controlled treatment at the asthma counseling room of the Center for Clinical Immune Allergy Bach Mai Hospital from February 2014 - August 2016 2.1.1 Criteria for selecting a patient - Diagnosed and identified asthma outside exacerbation according to GINA (2012): - Patient has not been controlled and treated at other medical facilities and has not been treated with ICS-LABA or treated weeks - Patients with acute infection in the upper respiratory tract and lower respiratory tract - Patients with coordinated diseases: heart failure, acute and chronic hepatitis, chronic glomerulonephritis, nephrotic syndrome, chronic renal failure, systemic disease, immune pathology, malignancy in organs - Patients are treated within the previous weeks with drugs such as antihistamines, corticosteroids - Patients not comply with treatment, periodically reexamination and testing within months 2.2 RESARCH CONTENT - General characteristics of the study subjects before controlled treatment - Evaluate clinical changes, pulmonary ventilation and control level in months - Assess the changes in serum IL-4, IL-5, IL-13 and TNF-α levels under control 2.3 STUDY METHODS 2.3.1 Research design Research design: Descriptive, prospective and longitudinal studies The sample size is calculated using the following formula: n = Z2(1-α/2) x p (1-p)/ d2 (1) In which: n is the sample size; p is the prevalence of bronchial asthma in Vietnam: we take it as 4% (0.04) according to research by Nguyen Van Doan et al (2011) d is the allowed coefficient in the study of 5%; The acceptance confidence is 95% then Z (1-α / 2) = 1.96 Applying formula (1), we get n = 60 In this study we selected 66 patients How to choose a Sample: Follow the convenient form Selecting from 120patients we selected 66patients who met the criteria required by the topic 2.3.2 Methods of data collection 2.3.2.1 Clinical Clinical examination and indications for taking samples for patients at 04 study points 2.3.2.2 Subclinical Measurement of pulmonary ventilation, blood sampling, serum extraction, storage and testing according to the procedure of Clinical Immune Allergy Center - Bach Mai Hospital 2.3.3 Process engineering 2.3.3.1 Pulmonary ventilation The studied patients were all performed with pulmonary ventilation at 04 times: before treatment, after 1, and months using a MicroSpiro HI-601 automatic respirator 2.3.3.2 Quantification of serum cytokines Quantify the concentration of serum cytokines according to the principle of fluorescent micro-particle immune adsorption technique 2.3.3.3 Treatment of asthma control with ICS and LABA The treatment was conducted according to a 5-step regimen according to GINA guidelines (2012) 2.4 DATA PROCESSING Study data is coded and processed by SPSS 20.0 software CHAPTER 3: RESULTS 3.1 CLINICAL CHANGE, VENTILATION AND CONTROL LEVEL 3.1.1 Patient characteristics before controlled treatment Table 3.1: Age and gender Gender Male Female Age(old years) n % n % < 20 1,5 1,5 20 - 29 4,5 12,1 30 - 39 13,6 13,6 40 - 49 1,5 7,6 50 - 59 3,0 13 19,7 ≥ 60 9,1 12,1 Total 22 33,3 44 66,7 (45,3 ± 16,82) ( X  SD) n 11 18 15 14 66 Total % 3,0 16,7 27,3 9,1 22,7 21,2 100 The median age of the studied patient is (45.3 ± 16.82) years, of which the age group of 30-39 accounts for the highest proportion (27.3%) The proportion of women is 66.7% higher than that of men (66.7% compared to 33.3%) Table 3.3: Some clinical features of the patient Ratio n % Clinical characteristics (n = 66) 16 24,2 Obesity 46 69,7 Normal BMI 6,1 Thin (21,89 ± 2,95) ( X ± SD) 14 21,2 Early Onset 52 78,8 Late 1,5 No bouts Number of 45 68,2 ≤ times/ week times with 20 30,3 symptoms day > time/ week 0 / week Daily 16 24,2 Is not 1,5 Number of time/week 25 37,9 times night ≤ times/month symptoms 22 33,3 > 2times/month Regularly < 20 points ACT score 20 - 24 points 25 points ( X ± SD) 46 20 3,0 69,7 30,3 0,0 (17,71 ± 2,83) Before treatment, the average control of BMI of patients was (21.69 ± 2.95), in which obese patients accounted for the proportion (24.2%) Most patients had late onset with an incidence of 78.8% The number of patients with symptoms ≤ time/week accounted for the highest proportion (68.2%) The proportion of patients who have nocturnal symptoms ≤ times/month accounts for the largest 10 proportion (37.9%) The average of ACT scores of patients was (17.71 ± 2.83), in which the highest proportion of patients with ACT scores < 20 (69.7%) 3.1.2 Clinical changes after controlled treatment Table 3.8: Changes in asthma grades with duration of treatment (n=66) Time Asthma Level Before treatment(1) After After After month(2) months(3) months(3) n % n % I 10,6 22 33,3 II 26 39,4 III 14 21,2 IV n p* % n 53 80,3 56 30 45,5 11 16,7 84,8 p2&3= 0,004 4,5 p3&4= 0,005 13 19,7 4,5 1,5 % p1&2= 0,034 19 28,8 1,5 1,5 6,1 The number of patients of grades IV, III and II decreased The number of first-line patients increased markedly after 1, and months of controlled treatment, with (p 0.05) Table 3.30: Multivariate regression analysis of factors related to the level of asthma control after months 13 Control level Uncontrolled (n = 7) (1) OR (p, 95%CI) Partly control (n=6) (2) Good Control 1 1,3 0,5 (1,0; 0,22 – 7,2) (0,39; 0,08-2,51) 1,3 (0,66; 0,37 4,65) - Normal 1 - Obesity 0,05 2,3 3,6 (0,009; 1,0212,62) Factors (n = 53) Gender: - Male - Female BMI: (0,01; 0,006 - 0,46) (0,65;0,25-25,22) Onset of illness: - Late 1 - Soon 0,36 0,7 3,9 (0,01; 0,06 - 4,664) (1,0; 0,07 – 6,74) (0,18; 0,4632,94) There was a relationship between obese people and unchecked asthma level, p = 0.01 The number of normal E leukocytes is closely related to well-controlled asthma level after months p = 0.04 3.2 CHANGE OF LEVELS OF BLOOD CYTOKINE AFTER CONTROLLED TREATMENT 3.2.1 Change in the concentration of cytokines according to the time of controlled treatment Bảng 3.33: Changes in serum IL-5 concentration compared with pre-treatment over time of control (n = 66) 14 Changes in IL-5 levels compared to before treatment Constant After After month(1) months(2) n % n % 51, 34 55 83,3 40, 27 11 16,7 After months(3) n % p 0,0 p*1&2< 0,001 Decreased compared 63 95,5 p*1&3 = 0,010 with before treatment p*2&3 = 0,042 Increase compared with 7,6 0,0 4,5 before treatment Median ** 0,75 0,25 0,075 pa&2 = 0,011 (min - max) (0,02 - 6,46) (0,075-4,62) (0,032-117,45) pa&3 = 0,001 After months of controlled treatment, the highest proportion of patients with IL-5 levels decreased compared to before treatment (95.5%) and the average concentration of IL-5 decreased significantly compared to before treatment ( p < 0.001) Bảng 3.34: Changes in serum IL-13 concentrations compared with pre-treatment over time over control (n = 66) Changes in IL-13 After After After levels compared to month(1) months(2) months(3) p before treatment n % n % n % Constant 13 19,7 0 0 Decreased compared with before 27 40,9 24 36,4 64 97 p*1&2 = 0,003 p*1&3 = 0,776 treatment Increase compared p*2&3 = 0,027 with before 26 39,4 42 63,6 3,0 treatment Median ** 6,73 9,97 1,6 pa&3 < 0,001 (min - max) (1,6-3808,52) (7,3-64,91) (0,43-53,22) After months of controlled treatment, the proportion of patients with decreased IL-13 concentration accounted for 97% and the average concentration of IL-13 serum decreased significantly compared to before treatment (p