Allergy And Airway Inflammation Analyses And Treatment Efficacy Of Budesonide/Formoterol In Mild Asthmatics

Background:Asthma is a common chronic respiratory disease, about 1-18% of the population in the world suffered from it, causing tremendous economic burden for patients and countries. Symptoms of asthmatics are episodes of breathless, chest tightness, cough, etc. Variable air flow limitation, airway hyper-responsiveness and airway inflammation are key characteristics of Asthma.Previously, asthma diagnosis and treatment follow-up are based on patients’ clinical features, bronchial dilation test or bronchial provocation test. As chronic inflammation is the essential characteristic of Asthma, it is feasible that detecting airway inflammation to guide diagnosing and treating asthmatic patients. At present, researchers focus on finding markers that can predict future asthmatic attacks, guide treatment, improve the prognosis of patients. Exhaled nitric oxide (FeNO) measurement is a direct, objective and precise method for quantitative inspection of airway inflammation, it has advantages of repeatable, easy to operate, easy to accept by patients, thus, its clinical application is causing much attention. Nitric oxide (NO) is a regulating factor that played an important role in many physiological and pathological processes. Airway NO comes mainly from bronchial and alveolar epithelial cells, catalyzed by nitric oxide synthase (NOS) on 1-arginine. FeNO measurement can be used for diagnosing asthma, identifying asthma phenotype, monitoring patients’compliance with medication, and predicting the possibility of acute attack of asthma, and some scholars believe that FeNO can guide medication dose changes in patients with asthma. Nevertheless, clinical applications of FeNO still exist many shortcomings, mainly, FeNO measurements are vulnerable to many factors, like Methacholine (Mch) bronchial provocation test and salbutamol bronchial dilation test, which are two important methods for diagnosing asthma, and it is controversial whether Mch bronchial provocation test and salbutamol bronchial dilation test have effects on the measurements of FeNO that well worth exploring.In recent years, asthma has been widely known as a heterogeneous disease, more and more researches focus on asthma classification to let patients get better treatments. Despite this, asthma phenotyping that based on patients’symptoms is still the most widely used and simplest method 。 Typical asthma (Typical Asthma TA), cough variant asthma (Cough Variant Asthma CVA) make up the majority population of asthma. according to the severity of disease each asthma subtype can be classified into mild, moderate and severe types. Pulmonary function is normal or almost normal in patients with mild asthma, and have good treatment effect, but these patients usually use drugs irregularly, causing recurrence of asthmatic symptoms. Patients with mild TA manifested with recurrent attacks of wheezing, chest tightness, or coughing symptoms which often associated with reversible airflow limitation, airway hyper-responsiveness and airway remodeling. CVA patients solely have cough, methacholine bronchial test confirmed the presence of airway hyper-responsiveness, symptoms improve after treatment of bronchodilators. CVA often thought to be early stage of TA, without treatment, about 30% of patients can develop into TA in a few years. Therefore, the goals of CVA treatment are not only to control symptoms, improve life quality, but more importantly, to prevent or slow down the development of CVA to TA. It is of great importance to understand the clinical features of patients with CVA, comparing that with mild TA patients, giving early intervention all do good to the prognosis of CVA.As similar to TA, the pathogenesis of CVA is chronic airway inflammation involved by many cells. Airway hyper-responsiveness and small airway dysfunction are common characteristics of patients with mild TA and CVA. There is big controversy about differences of allergies, airway inflammation and airway reactivity in CVA and TA patients. Similarly, in the treatment of CVA and TA, guides are not reaching a consensus。Recommendations are made by GIN A guideline in 2014 that mild TA patients use daily low doses of corticosteroids (ICS) and long-acting beta 2-agonists (LABA) and on-need short-acting beta 2-agonists (SABA), but therapeutic drugs of CVA are not listed independently. Bronchodilators were recommended by ACCP guideline of United States and cough guide in our country to treat CVA. Nowadays, a growing number of studies suggest that ICS combined with bronchodilation agents have more benefits on CVA patients. Formoterol, as one of long-acting beta 2-agonists, can quickly relieve asthmatic symptoms. With the advent of budesonide/formoterol, more and more countries regard it as an alternative medicine of ICS+LABA+SABA. Budesonide/formoterol can be used not only as maintenance therapy, but also as relief medication, that is SMART treatment protocol (Symbicort(?) as both maintenance and reliever therapy).More and more evidence show that SMART treatment have better efficacy and safety compared with conventional ICS/LABA+SABA, even lower doses of ICS, budesonide/formoterol can effectively reduce the frequency of acute attacks in asthmatic patients. SMART protocol can also improve patients’airway hyper-responsiveness, PEF value. But whether budesonide/formoterol can be used for the treatment of CVA, treating efficacy differences between CVA and TA are poorly researched.Therefore, in order to clear the effects of Mch bronchial provocation tests and salbutamol bronchial dilation test on FeNO measurement, the differences of clinical features and treatment efficacy of budesonide/formoterol between CVA and TA patients, our study consists of three parts, namely:the effect and significances of Mch bronchial provocation test and salbutamol dilation test on measurements of fractional exhaled nitric oxide in patients with asthma, clinical characteristics analysis and treatment efficacy of Budesonide/formoterol in mild asthmatics. In order to provide clinical evidence for application of FeNO and drug uses of CVA and mild TA patients.Part Ⅰ:The effect and significances of Mch bronchial provocation test and Salbutamol bronchial dialation test on the measurement of FeNOObjective:To study the effects and significances of methacholine (Mch) bronchial provocation tests and salbutamol bronchial dilation test on measurements of fractional exhaled nitric oxide (FeNO) in patients with asthma.Methods:A total of 135 patients with asthma visited at respiratory clinic of Zhujiang hospital were enrolled based on the inclusion criteria and exclusion criteria. Patients were divided to receive either Mch bronchial provocation test or salbutamol bronchial dilation test based on their FEVl/FVC values and cooperative degree. Mch bronchial provocation test was performed by using Astograph Jupiter-21 (Astograh group)or APS-Pro airway reaction testing apparatus (APS group), salbutamol bronchial dilation test was performed by using Jaeger spirometry (Dilation group) We compared the differences between FeNO values measured before examinations (Pre-FeNO) and 5min after the completions of these examinations (Post-FeNO). SPSS20.0 software was used for data analysis.Results:1. Median of Pre-FeNO and Post-FeNO was 25 ppb,21 ppb respectively in Astograh group, with a significant decrease of FeNO value after the completion of the examination (t=2.767,P=0.009). Median of FeNO in APS group decreased significantly from 30.5 ppb to 23.5 ppb after the examination was completed (t=5.772, P=0.000), No difference of FeNO change (⊿FeNO) was obtained between the two Mch bronchial provocation test groups (U<918.000,P=0.117) Median of Pre-FeNO was 36 ppb and Post-FeNO 36 ppb in Dilation group. FeNO showed no significant change in salbutamol bronchial dilation test group (t=0.929, P=0.359).2. A significance difference between Pre-FeNO and Post-FeNO was found in patients who had positive provocation results in Astograh group (t=2.600,P=0.014), but not in the patients with negative results (t=1.643,P=0.176). Despite patients had positive saline or Mch provocation results or negative provocation results, there were significant differences between Pre-FeNO and Post-FeNO in APS group (P< 0.05).but, FeNO had no changes befor and after examination in dilation group.Conclusion:Our results confirm that salbutamol bronchial dilation test has minor effect on the measurement of FeNO, but Mch bronchial provocation tests can significantly decrease measured FeNO value in patients with asthma, thus, FeNO should measure before Mch bronchial provocation test.Part Ⅱ:Clinical characteristics analysis of CVA and mild TA patientsObjective:To understand and compare clinical characteristics of CVA and TA patients.Methods:A total of 42 patients with mild asthma were enrolled based on the inclusion criteria and exclusion criteria. All the selected patients were required to complete the general data acquisition, completed symptom assessing questionnaires (asthma control test (ACT), asthma control questionnaire-7 (ACQ-7)), and completed the measurement of FeNO, Pulmonary function test, Mch bronchial provocation as well as the common inhalation allergen specific serum IgE screening. SPSS20.0 software was used for data analysis.Results:1.31 of 42 patients allergic to dust mites (73.8%),11 to house dust (26.2%),18 to pollens (42.9%),4 to grass (9.5%),9 to molds (21.4%) and 13 to dander (31%).2.20 patients’airway inflammation type was eosinophilic (47.6%),22 was non-eosinophil inflammation (53.4%), FeNO value 25ppb was used to define inflammation type.3. There were no significant differences of allergic rhinitis, allergen history and family history between CVA and TA patients(P>0.05). Disease history lasted longer in TA patients (F=11.730, P<0.05), But height, weight, age, symptom scores (ACT, ACQ-7), allergen sIgE, airway inflammation (FeNO), pulmonary function were of no significant differences between two groups. Airway reactivity level were amazingly different (z=-2.642, P=0.008), hyper-responsiveness in TA patients was stronger than CVA。4. lnFeNO had strong positive correlation with lndust-sIgE and lnnhouse dust-sIgE in TA patients (r= 0.533,0.546, P< 0.05). AHR showed moderate positive correlation with house dust-sIgE (p=-0.536, P<0.05), AHR had moderate positive correlation with FeNO (p=-0.468, P<0.05), but there were no obvious correlation between lnFeNO and lnsIgE, FeNO and AHR, slgE and AHR in CVA patients (P> 0.05).Conclusions:1.Patients with mild asthma are allergic to a variety of allergens, dust mite is the most common allergen.eosinophil and non-eosinophil inflammation are about the same in mild asthmatics.2. There are no significant differences of clinical characteristics between CVA and TA patients, but CVA is the early stage of TA.3.Allergen exposure may respond for the cause of airway inflammation and hyper-responsiveness of TA patients, but not for CVA.PartⅢ:Treatment efficacy of budesonide/formoterol in CVA and mild TA patientsObjective:To understand whether SMART protocol of budesonide/formoterol can treat CVA and TA patients and compare treatment efficacy.Methods:Patients were the same with Part II.All patients received budesonide/ formoterol (160 μg/4.5μg),1 inhalation, twice daily, plus as needed usage (SMART protocol), budesonide nasal spray agent (64 μg) (1 spray, twice daily) was allowed if patients have allergic rhinitis. Loratadine (10mg once daily) was allowed if patients have allergic diseases, such as urticarial. Guiding patients to avoid allergen contact based on their sIgE screening results, teaching them the knowledge of asthma and the correct use of drug device. We collected the baseline date and follow-up data of each visit. Content of follow-up were the same with Part Ⅱ. SPSS20.0 software was used for data analysis.Results:1. SMART protocol of budesonide/formoterol can improve symptom scores of ACT and ACQ-7 from under control level to control and keep stable in CVA and TA (F-6.99,28.45,4.11,4.43,P<0.05)2. There were no significant differences of FeNO before and after treatment in CVA and TA patients(F=2.51,1.24,P>0.05)3. There were no significant differences of FEV1, MMEF, MEF75 and MEF50, MEF25 before and after treatment in CVA and TA patients (P>0.05),PEF changed significantly in CVA (F=5.78,P=0.000),but not in TA patients (P>0.05)4. As for AHR, it got better in CVA patients, and some CVA patients had normal AHR (F=6.08,P<0.05),but not in TA patients (F=1.05,P>0.05)Conclusions:1. SMART protocol of budesonide/formoterol can be used to treat CVA and TA patients. CVA patients had better treatment efficacy than TA patients.2. More data is needed to determine whether FeNO can guide asthma treatment.