Dynamic Observation Of Neutrophilic Airway Inflammatory Phenotype In Patients With Asthma And Clinical Significance

Background and Objectives:It is widely accepted that bronchial asthma is a heterogeneous disease of the chronic airway inflammation, in which many different cells(including eosinophils and mast cells, T lymphocytes, neutrophils, airway epithelial cells and smooth muscle cells) and cellular components play a role. Asthma airway inflammation is usually associated with airway hyperresponsiveness and variable expiratory airflow limitation closely. It is characterized by repeating symptoms of cough, chest tighting, wheeze and shortness of breath,and those symptoms often worse at night, Symptoms may resolve spontaneously or in response to medication(e.g. short-acting beta angnist albuterol).Bronchial asthma is one of clinical common diseases and frequently-occurring diseases, which have no difference in gender, age, area, racial. At present, the incidence and mortality of asthma remains high due to the lack of cognition and poor adherence to asthma in the worldwide, a substantial proportion of asthma patients failed to meet the clinical control fully, Poor control for asthma brings great influence to daily life, work, study, etc. meanwhile, it poses a great threat to life, especially acute exacerbation of asthma, brittle asthma, etc. According to incomplete statistics, asthma treatment leads to a great of family financial expenditure, social medical security expenditure directly or indirectly each year, especially in uncontrolled refractory asthma, although only about 5-10% of asthma prevalence, but the treatment of asthma total spending as much as 50% a year in total population. Above all, the current global situation to asthma is not optimistic, therefore, it is necessary to increase input in asthma prevention and treatment.A lot of research suggests that airway eosinophilic has played an important role in the chronic airway inflammation of asthma in the past, especially the TH2 driven eosinophilic inflammation. However, with the deepening of the research of asthma, it is increasingly concerned that there is considerably airway inflammatory heterogeneous in patients with asthma, it was found that asthma is not a single eosinophilic inflammation and different inflammatory phenotype has different individual treatment, management strategy and prognosis. However, assessment of lung function and symptom control as the main means of current asthma management not reflect asthma airway inflammation in different phenotypes, and cannot meet the needs of the clinical management of asthma completely. As a noninvasive research tool the induced sputum can identify different phenotypes of asthma airway inflammation by cellular immune inflammation type, inflammatory medium level, At present asthma can be divided into the following four categories according to the induced sputum cytology: eosinophilic asthma(EA), neutrophilic asthma(NA), mixed-granulocytic asthma(MA), pauci-granulocytic asthma(PA).Recently studies have reported that a large number of neutrophils were found in some severe asthmas, airway obstruction or resistance to corticosteroid in patients with asthma by bronchial biopsy, induced sputum and bronchoalveolar lavage fluid(BALF), There has significant negative correlation between neutrophilic airway inflammation and airway obstruction in patients with asthma, previous studies also reported increased neutrophilic percentage of asthma induced sputum may be a risk factor for incompletely reversible airway limitation, and the mechanism is unclear. In addition the treatment reactivity to inhaled corticosteroids, Green research have reported that neutrophilic asthma have poor reactivity compare with noneosinophilic asthma, especially poor improvement in the symptom and lung function after treatment. Berry also comes to similar conclusions.Neutrophilic asthma,as an important part in the airway inflammatory phenotypes of asthma. The current understanding of its clinical features and clinical significance is very poor. Neutrophilic airway inflammatory phenotype was studied by cross-section data mainly, and the dynamic observation and follow-up of neutrophilic airway inflammatory phenotype have not been reported. Which don’t explain the correlation between neutrophilic airway inflammation and pathogenesis or clinical control with asthma completely. So we will make a preliminary research correlation between the airways of the asthma airway inflammation phenotypic changes and clinical control by the dynamic observation.Methods:Part I. Dynamic observation of neutrophilic airway inflammatory phenotype in patients in patients with asthmaNeutrophilic asthma were recruited from the out-patient departments of Respiratory Diseases of Xinqiao Hospital between August 2011 and June 2014,all subjects will have 3 times clinical follow-up for 1-2 month interval each time, For the first time visit, we will collect all the subjects demographic information(including gender, age, height, weight, occupation, The age of onset, duration), smoking history, family history, history of asthma treatment, history of asthma hospitalization, merge history of disease and chest X-ray, blood routine, pulmonary function, induced sputum, asthma control test(ACT), inhalation allergen prick test etc. All subjects will be given treatment according to GANA(2011 edition). We will collect pulmonary function, induced sputum, ACT at second and third time visit. After all the visits,changes of subjects asthmatic phenotype will be generalized by the induced sputum neutrophilic percentage, and they will be divided into 2 groups: The stable group of phenotype with neutrophilic asthma, the unstable group of phenotype with neutrophilic asthma. At last,it will be Analyzed that if there is statistically significant difference between neutrophils phenotypic stability and clinical control(ACT, FEV1 % Pred.) after treatment.Part II. The correlation between neutrophilic airway inflammation and clinical control in patients with asthmaNeutrophilic asthma were recruited from the out-patient departments of Respiratory Diseases of Xinqiao Hospital between August 2011 and June 2014,we will collect all the subjects demographic information(including gender, age, height, weight, occupation, The age of onset, duration), smoking history, family history, history of asthma treatment, history of asthma hospitalization, merge history of disease and chest X-ray, blood routine, pulmonary function, induced sputum, ACT score, inhalation allergen prick test etc. At last, clinical features of neutrophilic asthma will be generalized, and it will be analyzed that correlation between neutrophilic airway inflammation and clinical control in patients with asthma by correlation analysis in cross-sectional study.Results:Part I.1. A total of the 48 neutrophilic asthma subjects were recruited, but only 42 neutrophilic asthma subjects have finished 3 times follow-up at last. At second time visit, neutrophilic asthma:29 cases(69.05%), eosinophilic asthma:7 cases(16.67%),mixed-granulocytic asthma:0 cases(0%), pauci-granulocytic asthma: 6 cases(14.29%), At third time visit, neutrophilic asthma:24 cases( 57.14%), eosinophilic asthma:7 cases(16.67%),mixed- granulocytic asthma:3 cases(7.14%), pauci-granulocytic asthma: 8 cases(19.05%).2. All subjects were divided into 2 groups according the different counts of sputum cells: the stable group of phenotype(20 cases), unstable group of phenotype(22 cases).3. At fist time visit, Two groups of asthma subjects have no statistically significant difference in gender, age, duration, BMI, smoking, family history, inhalation allergen skin prick test, in the past 1 year history of hospitalization, ACT, eosinophilic percentage, the total eosinophilic count, neutrophilic percentage, the total neutrophilic count, the total inflammatory cell count. The FEV1 pred is( 64.53±22.57) % 、( 79.78±24.49) % respectively in the stable group and the unstable group of phenotype with neutrophilic asthma, and there have statistically significant difference in FEV1pred(P=0.043). But here have no statistically significant difference in ACT,FEV1 pred at the second and third time visit(P>0.05).4. ACT have substantial improvement in two groups of asthma subjects by 2-4 months anti-inflammation treatment, there was statistically significant difference between the two groups in ACT(P<0.01). FEV1 pred have a tendency to improvement after treatment, but there was no statistically significant difference between the two groups in lung function(P>0.05).Part II.1.Of the 40 neutrophilic asthma subjects were recruited, 26 cases(65.00%)were female, Mean age(42.70±13.75)years, The age of onset 31 cases(77.50%)were after 12 years, Asthma duration(11.32±12.25)years, ACT(17.15±4.80)scores, The percentage of neutrophil and eosinophil was(73.79±5.83)% and(0.49±0.80)% respectively in induced sputum. The count of neutrophil and eosinophil was(5.25±2.09)106 /g and(0.03±0.06)106 /g respectively in induced sputum,FEV1pred(75.50±21.83)%2. There was significantly correlation between the induced sputum neutrophil percentage or the total neutrophil count or the total inflammatory cell count and ACT and FEV1%pred in patients with neutrophilic asthma(p<0.05, r is-0.373、-0.530、-0.519、0.552 respectively). But correlation between the induced sputum eosinophil percentage or total eosinophil count and ACT or FEV1%pred did not be found.Conclusions:1. 52% of neutrophilic asthma is not stable in airway inflammation phenotype.2. The stable group of phenotype with neutrophilic asthma has a poor lung function compare with the unstable group at the base lines.3. The stable group and the unstable group of airway inflammation phenotype with neutrophilic asthma have substantial improvement in symptoms and have a tendency to improve lung function after treatment, but there was no statistically significant difference between the two groups in lung function.4. Neutrophilic asthma clinical features are variety.5. There is correlation between neutrophilic airway inflammation and lung function in patients with neutrophilic asthma, which indicates neutrophilic airway inflammation maybe association with airflow limitation.