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MINISTRY OF EDUCATION AND TRAINING MINISTRY OFHEALTH The study was completed in: HANOI MEDICAL UNIVERSITY HANOI MEDICAL UNIVERSITY Sicence advisors: NGUYEN TRAN NGOC HIEU A/Prof PhD Nguyen Thi Dieu Thuy PhD Luong Cao Dong Reviewer 1: STUDY OF ASTHMA CONTROL STATUS IN CHILDREN WITH BRONCHIAL ASTHMA AND ALLERGIC RHINITIS Reviewer 2: Reviewer 3: Major: Pediatrics Code: 9720106 Thesis will be defended at The Commission for PhD thesis assessment SUMARRY OF MEDICAL DOCTORAL THESIS of Ha Noi Medical University At …., date…., 2022 Thesis can be consulted at: - National Library of Vietnam - Library of Hanoi Medical University HANOI, 2022 RELATED PUBLICATIONS Nguyen Tran Ngoc Hieu, Nguyen Thi Dieu Thuy, Lương Cao Don Applying of CARATkids questionaire for assessment of asthma control in children with asthma combined allergic rhinitis Journal of 108 - Clinical Medicine and Pharmacy 2020; 15(3): 63-67 Nguyen Tran Ngoc Hieu, Luong Cao Dong and Nguyen Thi Dieu Thuy Role of airway nitric oxide for asthma controls in children with asthma combined allergic rhinitis Journal of Medical Research Ha Noi Medical University 2020; 131(7): 141 - 147 H Nguyen - Tran - Ngoc, Th Nguyen - Thi - Dieu, D Luong Cao et al Study of asthma control status in children with bronchial asthma and allergic rhinitis Journal of Functional Ventilation and Pulmonology 2021; 37(12): 7-12 INTRODUCTION Bronchial asthma (BA) and allergic rhinitis (AR) are the most common chronic airway diseases in children For the purpose to help evaluate BA control in patients with co-morbidity of AR, the Control allergic rhinitis and asthma test for children (CARATkids) was developed to in 2010 for simultaneous control of both asthma and allergic rhinitis (BA-AR) in children This asthma control toolkit is relatively easy to use, but the results are quite subjective, depending on the awareness and care about the disease by the parents and the children with the disease Both BA and AR are chronic inflammatory diseases of airways, and airway nitric oxide levels objectively reflect the airway inflammation Measuring Nasal Nitric Oxide (nNO) and Fractional Exhaed Nitric Oxide (FeNO) is a non-invasive exploratory method to assess airway inflammation in both upper and lower respiratory airways In Vietnam, there have only few studies been on the value of the CARATkids questionnaire as well as its correlation with the nitric oxide in the upper airways in patients with BA, especially in children with asthma and allergic rhinitis In order to evaluate the correlation between nNO concentration and asthma control status, we conducted the project "Study of asthma control status in children with bronchial asthma and allergic rhinitis" with the following objectives: Determining nasal nitric oxide threshold value in children with asthma and allergic rhinitis at Vietnam National Children's Hospital in the period 2016 - 2019 Evaluating asthma control status in children with asthma and allergic rhinitis Determining asthma phenotype in children with asthma and allergic rhinitis NEW FINDINGS OF THE THESIS Focus of the Thesis is studying the bronchial asthma in children with allergic rhinitis, which is a new problem in Vietnam Determining the nasal nitric oxide threshold value in children with asthma and allergic rhinitis and assess the status of asthma control in this subject Confirming the value of the questionnaire in assessing the simultaneous control of both asthma and allergic rhinitis in children (CARATkids) in Vietnamese children Identifying airway inflammation and asthma phenotype in children with asthma and allergic rhinitis provides the clinicians with a basis for the decisive diagnosis and prevention of bronchial asthma with allergic rhinitis THESIS STRUCTURE The thesis consists of 126 pages, including: introduction (2 pages), literature review (36 pages), subjects and method (22 pages), results (32 pages), discussion (30 pages), conclusion (2 trang), some limitations of the study (1 page), recommendations (1 page) There are 27 tables, 15 figures, 19 graphs, diagrams, appendices, 151 references in the thesis Chapter LITERATURE REVIEW 1.1 Overview of Asthma and Allergic Rhinitis 1.1.1 Defination of asthma and allergic rhinitis Defination of asthma: The Global Initiative for Asthma (GINA) 2020 difined “Asthma is a heterogeneous desease, usually characterized by chronic airway inflammation It is defined by the history of respiratory symptoms such as wheeze, shortness of breath, chest tightness and cough that vary over time and in intensity, together with variable expiratory airflow limitation Definition of allergic rhinitis: According to Allergic Rhinitis and its Impact on Asthma (ARIA) 2008, rhinitis is defined as an inflammation of the lining of the nose and is characterized by nasal symptoms including anterior or posterior rhinorrhoea, sneezing, nasal blockage and/or itching of the nose These symptoms occur during two or more consecutive days for more than hour on most days Allergic rhinitis is clinically defined as a symptomatic disorder of the nose induced after allergenexposure by an IgE-mediated inflammation 1.1.2 Epidemiology of Bronchial Asthma (BA) and Allergic Rhinitis (AR) Epidemiological studies have shown that AR and BA often coexist in the same patient Patients with moderate - severe persistent allergic rhinitis have a higher risk of asthma than those with intermittent mild asthma Most patients with asthma have symptoms of allergic rhinitis Rhinitis is an independent allergic factor in asthma risks 1.1.3 Risks factors for bronchial asthma and allergic rhinitis Asthma and allergic rhinitis often share common disease risk factors, such as indoor and outdoor allergens, or medications like aspirin 1.1.4 The pathogenetic relationship between bronchial asthma and allergic rhinitis There are now many controversial opinions about the pathogenesis of BA, but it is agreed by most that BA is a complex disease characterized by airway chronic inflammation, hyperresponsiveness and structural changes, resulting in obstruction of airflow Allergic rhinitis and bronchial asthma share the type of allergy mechanism with the participation of IgE antibody Asthma and allergic rhinitis share the same allergen as a trigger factor The nasal and bronchial mucosa are similar, so they have similar reactivity Both diseases are inflammatory airway diseases, with the same inflammatory cells and inflammatory mediators that are released by allergen exposure Asthma and rhinitis both cause airway obstruction In addition, the upper airway has a protective role of the lower airway 1.1.5 Controlling allergic rhinitis helps to control bronchial asthma Children with asthma and allergic rhinitis are more likely to be hospitalized and incur higher treatment costs than the patients with asthma alone Allergic rhinitis greatly affects the life quality of children with bronchial asthma Therefore, good treatment of allergic rhinitis can contribute to well controlled of asthma 1.2 Asthma phenotype in children over years old and adults The term “phenotype” (PNT) is intended to describe recognizable clinical features that are not directly related to the underlying pathophysiology In bronchial asthma, asthma phenotype describes the clinical features and inflammatory morphology as well as the responses to treatment In 2020, GINA classified asthma phenotypes as follows: allergic asthma; non-allergic asthma; late-onset asthma; asthma with persistent airflow limitation; asthma with obe sity 1.3 Diagnosis of bronchial asthma and allergic rhinitis 1.3.1 Diagnosis of asthma in children older than years Diagnostic criteria of asthma in children older than years old according to GINA 2016: - Typical symptoms are wheeze, shortness of breath, chest tightness and cough - Confirmed variable expiratory airflow limitation: + At least once during diagnostic process when FEV1 is low, confirm that FEV1/FVC is reduced 4 + An evidence of lung function changes compared with healthy subjects: • Increase in FEV1 of >12% predicted after administration of bronchodilator • Average daily diurnal PEF variability >13% • Increase in FEV1 by >12% and >200 mL (or PEF† by >20%) from baseline after weeks of treatment, outside respiratory infections + Bronchial reconstitution test may be repeated when symptoms are present in the morning or after bronchodilator administration - Personal and family history: The child's history of previous recurrent respiratory symptoms; the child may have allergic rhinitis or eczema - Clinical examination: Clinical examination of asthmatic patients usually shows no symptoms unless the patient is in an acute asthma attack If a child has persistent asthma, the chest cavity may become deformed 1.3.2 Diagnosis of allergic rhinitis Diagnosis of allergic rhinitis according to ARIA 2008 - Personal and family history of allergies - Functional symptoms: Having at least of the following symptoms (occurring frequently, lasting at least hour/day): Clear rhinorrhea; uninterrupted sneezing; stuffy nose; itchy nose; allergies in the conjunctiva such as red, itchy eyes - Physical symptoms: mucus excess on the floor of the inferiror and middle sulcus rhinalis; enlarged and wet turbinates, especially inferior turbinates; pale nasal mucosa; nasal polyps may exist - Subclinical: Prick test may be positive for respiratory allergens; specific IgE quantification; stimulation test with specific allergen 1.4 Treatment of bronchial asthma having allergic rhinitis 1.4.1 Targeted treatment of asthma having allergic rhinitis - Control the current asthma symptoms - Control the current allergic rhinitis symptoms - Reduce the future risk of asthma and allergic rhinitis 1.4.2 Treatment regimen for asthma having allergic rhinitis - Preventive treatment of plasma to GINA 2016 Asthma Treatment Recommendations in children older than years - Treatment of allergic rhinitis to ARIA 2008 Allergic Rhinitis Treatment Recommendations - Simultaneous treatment regimen of asthma with allergic rhinitis: combination of both asthma and allergic rhinitis treatment regimens in which priority is given to drugs capable of simultaneously controlling asthma with allergic rhinitis such as LTRA, omalizumab, etc on request 1.4.3 Assessment of asthma and allergic rhinitis control - Assessment of asthma control to GINA 2016 - Assessment of asthma control to the Asthma Control Test (ACT) - Assessment of asthma and allergic rhinitis control to the Control allergic rhinitis and asthma test for children (CARATkids) - Assessment of asthma control by exhaled nitric oxide level of the American Thoracic Society (ATS) 1.5 Role of nitric oxide in bronchial asthma and allergic rhinitis 1.5.1 Nitric oxide biosynthesis The endogenous nitric oxide (NO) molecule is derived from the reaction between oxygen and nitrogen of the amino acid L-Arginin under the action of the enzyme NO synthase (NOS) There are three types of NOS enzymes in the bronchi participating in NO synthesis: NOS-1, NOS-2, and NOS-3 In which NOS-1 and NOS-3 always exist and produce NO continuously in small quantities, called basic NOS enzyme NOS-2 known as inducible NOS or iNOS is found in airway epithelial cells and some inflammatory cells, producing NO at a slower rate but in large quantities 1.5.2 Origin of nasal nitric oxide Nasal nitric oxide (nNO) is produced in the nose and paranasal sinuses Each of these regions can contribute to the generation of nNO In addition, nNO is produced by the nasal mucosal epithelium and inflammatory cells (eosinophils) involved in up-regulation of inducible nitric oxide (iNOS) enzymes The nasal cavity has a special vascular system that causes changes in nasal cavity volume and changes in the flow and/or volume of blood from nose, which could theoretically affect nNO production and absorption 1.5.3 Origin of bronchial nitric oxide Exhaled nitric oxide (FeNO) originates mainly from the bronchial epithelium In the presence of airway inflammation, NOS-2 is activated by airway epithelial cells and inflammatory cells increasing endogenous NO levels Under normal physiological conditions, the bronchial epithelium produces approximately 0.05 pico liters per second (pl/s) of NO over an area of cm2 In the presence of an inflammatory response, the airway epithelium produces approximately 7.4 pico liters per second per cm2 area The phenomenon of NO proliferation can last from 7-10 days 1.5.4 Role of nitric oxide in asthma and allergic rhinitis FeNO levels provide a direct assessment of airway inflammation associated with eosinophilia The change in FeNO levels manifests as early as 1-2 weeks compared with the change in FEV1 after many months With the eosinophilic asthma phenotype, FeNO significantly reduces in asthmatic patients after corticosteroids administration This means, FeNO can assess the severity of the inflammatory process as well as the degree of treatment response to corticosteroids in asthmatic patients nNO levels increase in people with allergic rhinitis Patients suffering from allergic rhinitis with or withour bronchial asthma have statistically higher levels of FeNO and nNO than those with vasomotor rhinitis and the controls Several studies have shown a decrease in nNO level with topical corticosteroids The nNO value is closely related to the outcome of asthma control, especially in patients with asthma and allergic rhinitis nNO levels have been suggested as a predictor of poor asthma control 1.5.5 Methods for measuring airway nitric oxide Nowadays, there are three different techniques used to measure exhaled nitric oxide: electrochemical sensors, chemiluminescence sensors, and laser spectroscopy FeNO and nNO levels are given in ppb (parts per billion) There are two methods of measuring FeNO: online measurement and offline measurement The most common method of measuring nNO is to insert a cannula into the nasal cavity through the nostrils, aspirating the internal airflow (5 mL/s) while the patient holding breath (10s) in order to have direct analysis of nitric oxide level in the nose Another method is to measure nNO during air flow circulating when the patient is still breathing normally through one nostril, air is withdrawn through the other nostril at a rate of 5mL/s nNO can also be measured through nasal mask with a single nasal exhalation at a fixed flow rate using hand-held devices 1.6 Some studies on nitric oxide concentration and control of bronchial asthma and allergic rhinitis in the World and Vietnam 1.6.1 Studies in the World In 2005, Struben et al: study of the normal value of nNO in children aged to 17 years 2014, Kumar et al: Study of the correlation between FeNO, nNO and allergic status in asthma and allergic rhinitis In 2017, Amaral et al.: Study of the validation and the cutoff values of the Control of Allergic Rhinitis and Asthma Test for children (CARATkids) in Brazil 1.6.2 Studies in Vietnam In 2017, Duong Quy Sy et al.: Study of nNO concentrations in the diagnosis of allergic rhinitis in subjects with and without bronchial asthma In 2018, Pham Khac Tiep: Study of applying the CARATkids scale in asthma and allergic rhinitis control in children aged 6-12 at the Department of Immunology - Allergy - Rheumatology, Vietnam National Children's Hospital In 2019, Duong Quy Sy et al.: Study of the therapeutic effect on nasal nitric oxide in patients with persistent allergic rhinitis CHAPTER SUBJECTS AND STUDY METHODS 2.1 Study Subjects 2.1.1 Patients with asthma and allergic rhinitis - 124 patients diagnosed with bronchial asthma and allergic rhinitis who visited hospital for medical examination and treatment at Vietnam National Children's Hospital were invited to participate in the study - Selection criteria BA patients with AR: the patients diagnosed with bronchial asthma according to GINA 201654 and allergic rhinitis according to ARIA 2008 + Patients between and 15 years old + Patients with BA diagnosed for the first time + Patients diagnosed with BA but has not received preventive treatment + Patients with BA that have quit prophylactic therapy for more than months + Patients with allergic rhinitis symptoms, previously or currently examined and diagnosed with allergic rhinitis + Patients not in an acute asthma attack + Patients undergo the study with consent and supervision of the parents or regular caregivers - Exclusion criteria + Patients classified as having stage asthma with no indication for asthma prophylaxis Patients with asthma having other diseases such as congenital heart disease, hepato-biliary disease, kidney and urinary tract disease, neurological disorders, cognitive disorders, etc + Patients unable to understand and follow instructions when participating in respiratory function and airway NO concentration measurements 2.1.2 Controls - Asthmatic patients without allergic rhinitis from to 15 years of age have the selection and exclusion criteria similar to those with bronchial asthma having allergic rhinitis, but they don’t have allergic rhinitis - Healthy children aged -15 years old These children absolutely have no history of wheezing, allergic rhinitis or other allergic conditions; no systemic diseases No parents or siblings as family’s history with asthma or allergic rhinitis 2.1.3 Study Location - The study was conducted at the Department of Immunology Allergy - Rheumatology, Vietnam National Children's Hospital 2.1.4 Research time - The study was conducted from October 1, 2016 to December 31, 2019 2.2 Study Methods Study design: - Objective 1: Cross-sectional descriptive study - Objective 2: Longitudinal follow-up study, comparing before and after treatment - Objective 3: Descriptive study Every asthmatic child with or without allergic rhinitis had been invited to participate in the study four times: 1st time: at the first visit (T0) 2nd time: re-examination after month (T1) 3rd time: re-examination after months (T3) 4th time: re-examination after months (T6) Healthy children were invited to participate in the study once (T0): children were examined and measured for airway nitric oxide levels and respiratory function 2.2.1 Study sample size - Applying the convenient sampling method: all children qualified for selection and visited the Department of Immunology - Allergy - Rheumatology during the study period were invited to participate in the study Bronchial asthma group with allergic rhinitis - Sample size for objective 1: Apply the formula to estimate the average index: S2 n = 21-a/2 (X )2 n: number of patients studied With confidence interval 0,95 (α = 0,05) 21-a/2 = 1,96 ε : the relative deviation between the sample parameter and the population parameter, ranging from 0,05-0,5 (0,2-0,3) S: variance According to Struben's study, the value of nNO in healthy 6-17 years oldsis 449 ± 115 (ppb)91 1152 n = 1,96 * = 101 (449x0,05)2 - Sample size for objectives and 3: choose a convenient sample size - At least 101 children with BA with AR were estimated to participate in the study Asthmatic children without allergic rhinitis: As the percentage of asthmatic children without allergic rhinitis is low, we purposefully selected 30 qualified asthmatic children without allergic rhinitis from to 15 years old (22 boys; girls) for the study Healthy children: we selected 30 healthy children aged from to 15 years old (19 boys; 11 girls) whose parents and they themselves agreed to participate in the study These are children who have regular health check-ups at the Vietnam National Children's Hospital 2.2.2 Study Steps Step 1: Selecting patients for the study (T0) Patients visiting the National Children's Hospital for medical examination were asked about their illness, clinically examined, and tested to confirm the diagnosis of bronchial asthma (with and without accompanying allergic rhinitis) Asthmatic children and their parents were interviewed for assessment of pre-treatment asthma control according to GINA criteria + 10 11 and ACT questionnaire, and asthmatic children with allergic rhinitis were interviewed with a CARATkids questionnaire Patients were appointed for blood count tests, IgE, respiratory function measurement (CNHH), FeNO, nNO, prick test with respiratory allergens The healthy children were measured CNHH, FeNO, nNO Step 2: Bronchial asthma was treated according to GINA 2016, allergic rhinitis to ARIA 2008 Step 3: Re-examination, assessment of asthma control - allergic rhinitis and adjustment of preventive medicine - Time of re-examination: After month of treatment (T1), After months of treatment (T3) After months of treatment (T6) - Clinical examination, checking for treatment adherence and spraying method - Interviewing the asthma control tables according to GINA, ACT and CARATkids (for athmatic children with allergic rhinitis) - Measuring FeNO, nNO and CNH - Adjusting asthmatic prophylaxis according to GINA 2016 guidelines and allergic rhinitis controller according to ARIA 2008 Step 4: Input and process data 2.3 Data collection methods 2.3.1 General information and related factors Ask and a physical exam to gather the following information: - Age - Gender: male, female - Weight and height - BMI by age and sex - Age of onset of wheezing - Age at diagnosis of asthma - Exposure to tobacco smoke - Personal and family allergy history - Level of asthma control according to GINA 2016 - Level of asthma control according to the ACT scale - Control asthma and allergic rhinitis according to the CARATkids scale 2.3.2 Paraclinical indicators - Checking the blood count using automatic counter Sysmex XN3000 Quantifying IgE in blood by Cobus 6000 Prick testing with respiratory allergens using allergen preparations made by Stallergenes France - Measuring the respiratory function and testing for bronchial rehabilitation by KOKO device made in the US Measuring FeNO and nNO by HYPAIR FeNO of Medisoft, Belgium 2.4 Data processing The collected data was coded in a unified form; entered and analyzed using SPSS 16.0 software; suitable statistical algorithms were used 2.5 Study ethics Comply with the study ethics The study has been approved by the Ethics Committee of Hanoi Medical University, the Decision No 101/HĐĐĐHYHN CHAPTER STUDY RESULTS - During the study period, there were 124 children with asthma and allergic rhinitis, 30 asthmatic children without allergic rhinitis and 30 healthy children aged from 6-15 years old who were eligible to participate in the study 3.1 Characteristics of nasal nitric oxide in children with bronchial asthma having allergic rhinitis *Nasal nitric oxide concentrations in children with asthma and allergic rhinitis, asthma without allergic rhinitis and healthy children 12 13 The nNO concentration in children with BA-AR was 1594.5 (104 3674) ppb, higher than that in children with BA was 444.5 (105 - 2971) ppb ((p
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