The Correlation Between Exhaled Nitric Oxide And Airflow Obstruction In Patients With Asthma

BACKGROUND AND AIM:Bronchial asthma (referred to as asthma),as a chronic airway inflammation, its biggest feature is the variability of asthma symptoms. The inflammation will be changed in different periods of asthma treatment, and even in different seasons. Patients with subjective symptoms can not reflect the state of the airway inflammation objectively.There are obvious limitations on this respect of asthma medication regulation based on their subjective symptoms. Some material demonstrated that airway inflammation and airway hyperresponsiveness may still exist for a long time after the clinical symptoms had a remission, which also led to recurrent clinical symptoms, and make asthma can not get very well control. For this monitoring, evaluation airway inflammation to asthma has a very important clinical significance.The methods of airway inflammation detection include the invasive technique and noninvasive technique. The former are mainly refers to laage fluid from bronchoscopy and bronchial lining biopsy. Although as "gold standard" for the research of airway inflammation.but the invasive operation have limited their daily application in the monitoring of patients with asthma. On the other hand, non-invasive detection techniques are easier to accept for doctors and patients by virtue of its almost harmless to patients. Peripheral blood eosinophil count.induced sputum analysis, serum eosinophil cationic protein (ECP), signs of atopic IgE increased are used more commonly to evaluate the severity of airway inflammation. However, the sensitivity and specificity of these methods is not high and the operation is so time-consuming and laborious. So other non-invasive detecting techniques for biomarker, including exhaled nitric oxide, exhaled CO, exhaled air breathing condensate (EBC), is becoming the new hotting topic of research in the bronchial airway inflammation in asthma.Exhaled nitric oxide (FeNO) is becoming the new hot spot for one of airway inflammation in asthma for its advantages of simple, easy to operate, and repeatability to detect. Since1993, Alvin et al first found FeNO was significantly higher in patients with asthma than normal, more than2,000articles were reported in the international literature. European Respiratory Society (ERS) first to develop a breath Guidelines for the determination of nitric oxide in1997. After that many countries have carried out the detection of FeNO. Chinese Medical Association Respiratory Diseases also list FeNO in bronchial asthma prevention and treatment guidelines in2008.However, since the advent of FeNO, there are quite a lot of controversy on the clinical value for the asthmatics with the deepening of the study. And studies have found that FeNO were differences in different gender, age, ethnicity, and the accuracy of the measurement values will be affected by variety of factors. Study also showed that bronchoconstriction induced by histamine and methacholine inhalation can reduce FeNO levels. Silkoff PE et al showed that in the mild asthmatic subjects, inhalation of salbutamol increased FeNO by approximately10%, a change that persisted for at least1h. These suggest that FeNO levels are partly modulated by the level of airway obstruction in patients with asthma, and airway caliber should be taken into account when monitoring FeNO in asthma. In contrast, another study did not find any effect of methacholine bronchoconstriction or bronchodilator administration on FeNO in asthma. Kharitonov.SA, et al who reported that PGE2and PGF2a reduce exhaled NO, an effect not related to airway caliber changes. Also in1997, Yates DH et al reported that single high dose salbutamol does not increase FeNO in asthmatics who are not taking inhaled glucocorticosteroids (ICS).Therefore, the role of inhalation of β2agonist on FeNO value is not well understood especially during spontaneous airway obstruction in adult asthma patients. There are not yet a consistent conclusion in the correlation between FeNO and lung function, the severity of airway obstruction, the level of clinical symptoms of asthma control, and other indicators of reactive airway inflammation. This is more or less affect the vigorous application and promotion in our country. In the aim to provide a reference to asthma diagnosis, treatment and management, this study will discuss the practical problems, compare the influent factors, and explore the correlation between FeNO and index of pulmonary function, severity of airway obstruction, scores of clinical symptoms, EOS count of induced sputum, and the role of airfolow obstruction on FeNO value.SUBJECTS AND METHODS:Part Ⅰ:Investigation of the influence factors of Exhaled niric oxide in patients with asthmaA total of65asthmatic out-patients who see a doctor at the Dept of Respiratory Medicine, Nanfang Hospital, Southern Medical University (Guangzhou, China) between Mar-2010and Jun-2011were recruited,17～75(36.2±12.8)years old,35males and30females, asthma duration1months to50years, consisting intermittent and mild persistent patients9(13.8%), moderate18(27.7%), severe34(52.3%) according to the lung function FEV1%,4cases (6.1%) missing lung function material. In total,43newly diagnosed (steroid-naive) asthmatics,22asthmatics using ICS/LABA combination for at least one month were selected according to use of hormone therapy or not. They were asked to complete the demographic characteristics, Asthma Control Questionnaire, asthma control test (ACT) scales, the daytime symptom scores, and the night symptom scores. Exhaled nitric oxide test, Lung function test, blood cell count and induced sputum cell count were also performed.Part II:the influence of spontaneous airfolow obstruction on FeNO valuesIn total,20newly diagnosed (steroid-naive) asthmatics,16asthmatics using ICS/LABA (Salmeterol/fluticasone propionate, Budesonide/Formoterol) combination for at least one month,13COPD with Positive Bronchodilator Test who were diagnosed according to Global Initiative for COPD (GOLD) criteria were selected for the study from patients seen at the Dept of Respiratory Medicine, Nanfang Hospital, Southern Medical University between Mar-2010and Jun-2011including the patients from part I.STATISTICAL ANALYSIS:The results were analyzed by 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); Bivariate analysis between the FeNO and demographic variables and other clinical data was performed. Multiple linear regression was constructed to evaluate the relationship between FeNO and the related factors. Within-group changes used paired-samples T test. We used chi-squared analyses to compare the counting data and One-Way ANOVA to compare the between-group clinical data changes and LSD or Tambanes’s T3methods were used to compare differences between three groups. We controlled the covariates found in baseline values when we analyzed the diastolic variable data. Significance was accepted when P<0.05. RESULTS:Part Ⅰ:1.65eligible asthmatic out-patients were recruited into survey and completed the scales and examination, the Male35cases (53.85%). female30cases (46.15%), age17to75years (36.67±12.81). FeNO values were between5.0～147.0ppb(47.16±34.26ppb), the43initial asthma patients with FeNO value51.05±34.91ppb, the22treated asthma39.19±32.25ppb,11cases with previous history of smoking but had quit smoking more than one year,29patients suffering from allergic rhinitis,13cases with other allergic diseases (including drugs, food allergies),11cases with a family history of asthma,18cases of childhood asthma history, the during of asthma1month to50years (median3.0years).2. A variety of clinical symptom score in the assessment of asthma control level keep in consistent, and the have a significant correlation with lung function in patients. The symptoms more lighter (that is a lower ACQ7score, a higher ACT score), reflected in pulmonary function indexes, the more lower degree of obstruction (FEV1%higher), while no significant correlation with airway inflammation indicators--FeNO.3. The value of exhaled NO of initial asthma patients (51.05±34.91) is higher than that of treated asthma patients (39.19±32.25), but no significant difference between the two groups (t=-0.131, P=0.196)..4. To classify the patients, we used FEV1%pred as degree, asthma was divided into intermittent and mild persistent9cases, moderate persistent18cases and severe persistent34cases, of which the state of airway obstruction of severe persistent asthma patients was severest, ACQ7score was highest, ACT lowest, but the FeNO was heaviest; the airway obstruction of intermittent and mild persistent patients was ligher, the value of exhaled nitric oxide was higher, and ACQ7lower, ACT higher. 5. Exhaled nitric oxide (FeNO) had a positive correlation with sputum EOS%(r=0.327. p=0.022), but had no correlation with sputum NEU%(r=-0.180, p=0.215), MAC%(r=-0.165p=0.257), LYM%(r=0.045, p=.761). No correlation between FeNO and peripheral circulating inflammatory cells.6. We made the influential variables into multiple linear regression, and ste pwise regression was used. In stepwise regression equation:Y=24.150-0.849X1+4.542X2+17.726X3, R2=0.513, the equation test:F=13.703, P<0.001.51.3%of FeNO values can be explained by the change of age (XI), daytime sympto ms (X2), FEV1(X3). From the equation we knowed that FeNO showed a po sitive correlation with daytime symptoms, and FEV1, but had a negative correl ation with age (years).Part Ⅱ:1. There were no significant differences between patients in BMI、age、smoking and gender. The disease severity(FEV1%)of COPD patients we recruited was greater than those of patients with asthma. COPD patients had a higher percentage of sputum neutrophils compared with asthma patients. In contrast, compared with COPD patients, patients with asthma had a significantly greater percentage of sputum eosinophils.2. There are significant differences in pre-FeNO values in three groups, and when we made pre-FeNO,FEV1%and MMEF75%as a covariate to compare the three groups post-FeNO values, we found there still exist significantly differences (F=8.023, P=0.001). Pairwise comparison, untreated asthma had higher level of FeNO compared with the treated group,and the COPD group (P=0.001), while the COPD group had no significant difference compared with the treated asthma group(P=0.395). The level of FeNO before and after bronchodilators, only in the initial diagnosed asthma, the pre-FeNO was significantly higher than the post-FeNO, no difference in treated asthma,while the post-FeNO was lower than pre-FeNO in COPD patients.3. Comparison of spirometry parameters measured before and after inhalation of salbutamol400ug showed a significant increase in FEV1and maximum expiratory flow rate at75%of vital capacity (MEF75%) in the steroid-naive asthma patients and in treated asthmatics groups and COPD patients. However, evaluating separately the three patient groups, no correlations between FEV1%, improvement rate in FEV1%or changes in FEV1(expressed as the absolute increase in FEV1), and prebronchodilator FeNO values, or post-bronchodilator FeNO or the absolute increase in FeNO.CONCLUSIONS:1. The level of Exhaled nitric oxide (FeNO) is determined mainly by age, FEV1, and daytime symptoms;2. Exhaled nitric oxide (FeNO) that mainly reflect the degree of center airway inflammation, especially eosinophils in airway inflammation.3. The values of FeNO have no correlation with the level of asthma control.4. Compared with the intermittent and mild persistent patients, patients with moderate to severe obstruction have more lower level of FeNO.5. After inhaled bronchodilators, the significantly increase of FeNO only is founded in the initial diagnosed asthma, altuough the three groups both have a significant airflow obstruction.6. In the initial asthma group, FeNO values after inhaled bronchodilator failed to show a better correlation with the index of pulmonary function and inflammatory cells.