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BACKGROUND AND AIM:Bronchial asthma (referred to as asthma) is a chronic allergie inflammatory disease in airway. It correlates with eosinophils, mast cells, T lymphocytes (Th2) inflame matory cells, airway epithelial cells and cellular components.The airway inflammation leads to airway hyperresponsiveness and variable,reversible airflow limitation, the main symptoms of it include repeatedly wheezing, chest tightness, and cough. The main characteristics of asthma are persistent inflammation and recurrent symptoms.In recent years, the prevalence and mortality of asthma in many countries and regions had an upward trend, and had caused the attention of the World Health Organization and national governments. In worldwide, although medical and scientific research expenses increased significantly, clinical types of drugs also increased significantly compared with the previous, but patients with asthma get to completely controlled or partial controlled are still lower, mainly due to uncontrolled inflammation and the low level of asthma management. Currently, improvements in symptoms and lung function as the main evaluation indicators in the effects of asthma’s treatment, but those can not evaluate the inflammation of asthma directly and objectively, so have limitations in clinical application. FeNO as a marker of airway inflammation, can react airway inflammation objective and quantitative in patients with asthma. Compared with the traditional methods like bronchial mucosal biopsy, bronchoalveolar lavage, induced sputum cytology classification count, it is a non-invasive, simple and good repeated technology. FeNO used in asthma widespread, of course there are some problems to be solved. The research about FeNO in asthma and other diseases is very popular currently. A number of studies have confirmed that FeNO is associated with eosinophilic airway inflammation. Induced sputum cytology classification as the main criteria of asthma inflammation phenotypes also concern about the relationship of eosinophilic inflammation in patient with asthma. FeNO and inflammation phenotypes of asthma also worth exploring.NO was found as a relaxing factor play a role in vascular endothelial which is released by arteries and veins endothelium by Ignarro LJ and his colleague in1987. L-arginine is the substrate in the process of NO composite through a series of biochemical reactions by NOS. Alvin et al first found FeNO was significantly higher in patients with asthma than normal in1993. Guo FH et al found that high levels of inducible nitric oxide synthase (NOS2) enzyme expression in the epithelial cells of airways in patients with asthma, suggesting a role for NO in asthma pathogenesis.A number of studies confirmed that the major source of exhaled nitric oxide was airway epithelial cells, as a result of NOS2up-regulation which occurs with inflammation, so exhaled NO may be regarded as an indirect marker for up-regulation of airway inflammation, detect FeNO can react asthma airway inflammation.For a long time, a good method can response airway inflammation which can be accept by clinicians is lack., FeNO make up for this shortcoming to some extent. The clinical applications of it increasing widespread. It’s applications include population screening, diagnosis, monitoring airway inflammation, predict corticosteroids treatment response, management in asthma. Scince European Respiratory Society (ERS) develop a breath Guidelines for the determination of nitric oxide in1997to Global Initiative for Asthma (GINA) include it into asthma management program in2006, then Chinese Medical Association Respiratory list it in bronchial asthma prevention and treatment guidelines in2008, Opens up a new chapter in its application in our country.With the domestic clinical applications of FeNO increasing widespread, its defects gradually revealed. Large population studies were conducted in Europe, the United States and other countries, which provided the normal range or useful cut off points of FeNO, although those results are different. The main reason was the different including perpon. Previous studies have found that many factors may affect the normal FeNO level, including age, gender, smoking, allergy status, race, height, weight, eating habits, lung function level. But different studies get different conclusions, there were no unified understandings. In our country, the normal range or useful cut off points of FeNO have not been established, researches about the determinants of FeNO were also less. Thus establish domestic normal range of FeNO and its determinations are very important.Previous studies have found that FeNO as a marker of airway inflammation, mainly reactive airway eosinophilic inflammation. Including airway mucosal biopsy, bronchoalveolar lavage fluid, induced sputum cytology confirmed the relationship between eosinophilic inflammation and FeNO. However, asthma is not a simple eosinophilic airway inflammation, inflammatory cells and inflammatory molecules have an important role in the progress of it. There are several inflammation phenotypes in asthma most commonly described as eosinophilic, neutrophilic, mixed, and paucigranulocytic, which are classified by induced sputum. Some high level of FeNO asthma patients do not are eosinophilic inflammation phenotypes and some low level of FeNO are eosinophilic inflammation phenotypes in clinical practice. There are litter researches concern FeNO level and asthma inflammation phenotypes distribution in patients with asthma.Our study wants to address the problems which were explored above. Establish FeNO reference values in nonsmoking, healthy adults in south china and to determine the factors related to FeNO levels in part I; Investigate the main characteristics of different FeNO level in patients with asthma and the clinical phenotype law in part Ⅱ.SUBJECTS AND METHODS:Part I:Establish FeNO reference values in nonsmoking, healthy adults in south china and to determine the factors related to FeNO levels.A total of199nonsmoking, healthy adults were recruited from southern medical university, some communities and some nursing home in Guangzhou between Jun-2011to Dec-2011,18-80(38.3±18.39) years old,40people older than60years,100males and99females. First record the object general information through questionnaire, incluing gender, age, height, weight, smoking history, allergies, medication history, relevant medical history, physical examination and so on, then perfect exhaled nitric oxide detection and pulmonary function testing, the final step examine allergen-specific serum immunoglobulin E lever in those people.Part II:Investigate the main characteristics of different FeNO level in patients with asthma and the clinical inflammation phenotypes of those patients with different FeNO level.Selected clinic patients Southern Medical University Department of Respiratory Medicine between2011-6and2012-8, who are diagnosed asthma according to GINA guidelines. First, they were asked to complete the demographic information characteristics, including asthma control questionnaire, the daytime symptom scores, and the night symptom scores. Exhaled nitric oxide, lung function test, induced sputum cell count were also performed. A total of103patients with asthma were included in this research. According to the American Thoracic Society exhaled nitric oxide clinical practice guidelines,they were grouped three groups;2were grouped in low FeNO (<25ppb),38were grouped in intermediate FeNO (between25ppb and50ppb),43were grouped in high FeNO (>50ppb); The inflammation phenotypes in asthma classified by induced sputum were eosinophilic, neutrophilic, mixed, and paucigranulocytic, the number of the four groups were38,18,2,and8.STATSTICAL ANALYSIS:Statistical analyses were performed using SPSS13.0. Normality test of measurement data were carried out. If the data accord with normal distribution, they would be presented as means±SD, data of skewed distribution are presented as median (min, max). IF FeNO levels were not normally distributed, the analyses of FeNO values were performed with log-transformed values. The group characteristics were compared using the chi-square test for categorical variables and the Student’s t test for continuous variables. Correlations between continuous variables and FeNO levels were examined using Pearson’s correlation. The association between FeNO levels and related factors was determined by multivariate linear regression analysis. The three groups were compared using the Kruskl-Wallis H test, Multiple independent samples were analysed by Kndependent Samples Test. p values<0.05were statistically significant. RESULTS:Part Ⅰ:1. The average reference value of FeNO is16.93ppb in the people, the min is5ppb, the max value is47ppb. In the atopic subjects (FeNO levels were significantly higher than in nonatopic subjects (32.67±8.59ppb versus15.08±5.87ppb, p=.000), Male subjects showed significantly higher levels of FeNO than did females (18.80±7.91ppb versus26.0±14.2, ppb, p=001). In the older subjects (FeNO levels were significantly higher than in non-elderly subjects (20.73±10.84ppb versus15.98±7.15ppb,p=0.012).2. Bivariate analysis found that FeNO value and allergy status, age, gender, height, weight have significant positive correlation (P<0.05). In a multivariate linear regression analysis, FeNO levels were positively associated with atopy (P=0.000), gender (P=.001) and age (P=.000) after adjusting for atopy, gender, age, height, weight, a linear regression equation was FeNO=11.332+16.455atopy+3.279sex+0.057age, R2=0.488, F=61.891, P=0.000. FeNO levels showed a significant and independent association with atopy, gender and age.Part Ⅱ:1. In the three different level of FeNO groups, gender, body mass index, history of allergy, history of childhood asthma, allergic history, family history of asthma, ACQ7, daytime symptom scores, night time symptom scores, each group had no significant difference (P>0.05).2. Age have significant difference among the three groups, the group with high FeNO lower than the other groups (P=0.038), FEV1, FEV1%pred also have significant difference among the three groups, the group with high FeNO Higher than the other groups (P=0.017> P=0.022)3. FeNO levels in eosinophilic asthma were significantly higher than non- eosinophilic asthma(P<0.05), if based on four phenotypes of airway inflammation in asthma, three different levels of FeNO group phenotypes have not significant difference,(χ2=2.875, v=2, P=0.238), but in high FeNO group, eosinophilic asthma far more than the other three phenotypes.CONCLUSIONS:1. The average reference value of FeNO is16.93ppb in in healthy adults in south china, the min is5ppb, the max value is47ppb.2. FeNO levels showed a significant and independent association with atopy, gender and age.3. The asthma patients with different level of FeNO, gender, body mass index, history of allergy, history of childhood asthma, allergic history, family history of asthma, ACQ7, daytime symptom scores, night time symptom scores, had no significant difference (P>0.05), but age, FEV1, FEV1%pred had significant difference.4. FeNO levels in eosinophilic asthma were significantly higher than non-eosinophilic asthma, if based on four phenotypes of airway inflammation in asthma, three different levels of FeNO group phenotypes have not significant difference,, but in high FeNO group, eosinophilic asthma far more than the other three phenotypes.
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