| Objective:Asthma is a heterogeneous disease and variety of cells and cell components were involved.Most of the patients with asthma are characterized by eosinophilic airway inflammation regulated by Th2 cells.Since the early years in last century,researchers have found that the level of exhaled nitric oxide(FeNO)in asthmatic patients is significantly higher than that in healthy individuals.Accumulating evidences confirmed FeNO is a valuable biomarker for Th2 inflammation.Because the results of a number of FeNO related diagnostic studies were negative,the diagnostic value of FeNO is still controversial,which may be due to the low cut-off value.In recent years well-designed studies provided new evidences about the diagnostic value of FeNO in asthma which is reflected in NICE guidline.According to 2017 NICE guideline for asthma,FeNO level ≥ 40 ppb could be used fas a criteria for diagnosis of asthma.Afterward 40 ppb was used as the cut-off value in some follow-up studies,which greatly improved the diagnostic specificity.In order to vertify and definite the value of FeNO in the diagnosis of asthma,we conducted a meta-analysis and literature review.A total of 68 articles were included in this study.The population involved included Asia,America,Europe,etc.Subgroup analysis was performed according to different ages and cut-off values.Studies on patients with elevated FeNO mainly focus on short-term treatment response,while there are few studies undergoing long-term follow-up.To explore the changes of lung function,asthma symptoms and FeNO levels after regular medication in patients with different levels of FeNO is of great importance to asthma treatment and management.So we followed-up 220 asthma patients with good compliance,all over 14 years old.The asthma telated parameters as well as FeNO in short-term follow-up and long-term follow-up were compared,the characteristics of patients with asthmatic attack in one year follow-up were described and the value of FeNO in predicting acute attack were analyzed.In the clinical follow-up,we found that some patients,even after regular treatment for several months,their FeNO level still remains no less than 40 ppb.We try to identify whether these patients have unique clinical features、SNP mutation or inflammatory levels.Therefore,we analyzed the clinical characteristics,SNP mutation and Th2 related inflammatory factors.Asthma is often accompanied by other complications,such as rhinitis,sinusitis,gastroesophageal reflux disease.In our study,more than 70% of patients had rhinitis.Previous studies also found that rhinitis had a certain impact on FeNO.Some researchers believed that nasal exhaled nitric oxide(FnNO)had potential value in evaluating upper airway inflammation and studies had found the difference FnNO and FeNO levels between healthy individuals,asthma patients and asthma patients with rhinitis,but some researchers debated the value of FnNO.The value of FnNO still needs to be further clarified.We tried to explore the influencing factors of FnNO,the relationship between FnNO and FeNO,and the combination diagnostic value of upper and lower airway exhaled nitric oxide in patients with asthma and rhinitis.195 patients were included,in which 28 subjects just only with asthma and167 with asthma complicated with rhinitis.Materials and Methods:In the meta-analysis,we searched PubMed,EMBASE,Cochrane,Wan Fang,CNKI and VIP library databases,screened the literatures according to the inclusion and exclusion criteria.Data extracted were performed by Excel,quality evaluate and data analysis were performed by Revman and SPSS statistics 26.0.At the first visit patient’s baseline data were collected by questionnaire.The follow-up data included pulmonary function,ACT score,FeNO and FnNO,iNOS were measured by ELISA,Cytokines were measured by Luminex,SNP were detected by the first generation sequencing.Data analysis were performed by SPSS statistics 26.0.Results:1.68 literature were included in the meta-analysis,the diagnosis sensitivity,specificity,PPV,NPV of FeNO were 0.72(95%CI 0.68-0.76),0.81(95%CI 为0.77-0.84),3.74(95%CI 3.19-4.38),0.34(95%CI 0.30-0.39),respectively.The diagnostic odds ratio was 10.96(95%CI 8.59-13.99)and the AUC= 0.84(95%CI0.80-0.87).2.220 patients were included in short-time follow-up in which 143 were females and 77 were males.155 patients had rhinitis,24 patients had smoke history and 53 patients reported family history of asthma.125,51 and 44 patients were classified into the mild,moderate and severe group according FeNO levels at the first visit.The female patients accounted for 67.2%,68.6% and 54% in three groups respectively.The median age of subjects in three groups was 37,44 and 37.5 years.The severe group were higher and heavier,but there was no significant difference in BMI among the three groups.The incidences of rhinitis in mild,moderate and severe group were 64%,74.5% and 84.1% respectively.The average levels of FEV1%and FEV1/FVC at first visit were 79.56% and 69.95% respectively(P=0.033),which increased by 16.03% and 7.17% in the first month after standard treatment(P<0.001).FEV1% in mild,moderate and severe groups increased 8.44%,15.75%and 11.52% after 1 month of standard treatment.FEV1% maintained around 90% in next several months.FEV1/FVC increased 7.45%,7.75% and 5.67% respectively in mild,moderate and severe groups after 1 month of standard treatment(P<0.001;P=0.006;P<0.001).The median level of FeNO was 88.5 ppb at the first visit,which decreased to 52 ppb(P<0.001)after 1 month of standard treatment the dropped to 45 ppb after 3 months of standard treatment.The median FeNO levels of mild,moderate and severe group were 67,115 and 182.5ppb at the first visit,and decreased to 43,50 and 92.5ppb(P<0.001)after 1 month of treatment.After 3months of follow-up,the level of FeNO decreased to 43,41.5,56 ppb and 56 ppb in mild,moderate and severe groups.The median levels of ACT in total,mild,moderate and severe groups were19,20,19 and 11 at the first vist,then increased to23,23,24 and 23(P<0.001;P=0.001;P=0.001;P=0.005)after one month of standard treatment.3.A total of 173 asthma patients were followed-up for more than 6 months(long-term follow-up group),in which 131 patients were followed-up for more than one year,and 71 patients for more than two years.The total average levels of FEV1%and FEV1/FVC were 77.63% and 68.52% respectively at the first visit,which increased to 87.11% and 72.01%(P<0.001;P=0.006)at the 6th month.FEV1 decreased from 86.35% to 81.46% at 24 th month compared with 12 th month(P=0.012).FEV1 in mild,moderate and severe group increased at 6th month and remained stable at 12 th and 24 th month.FEV1/FVC in the severe group increased at6 th month and FEV1/FVC had slightly change in the mild and moderate increase groups at 6th,12 th and 24 th month compared to the first visit.The total median level of FeNO was 88 ppb at the first visit and decreased to 46.5 ppb(P<0.001)at 6th month.No significant change were observed at 12 th and 24 th month.The level of FeNO in mild,moderate and severe group decreased at 6th month compared to the first visit.The level of FeNO in mild group slightly increased at 24 th month compared with the 12 th month.And the level of FeNO in severe group increased at12 th and 24 th month compared with 6th month.The ACT scores in the whole group and the three groups increased at 6th month,and remained stable at 12 th and 24 th month.4.A total of 131 patients were followed-up for more than one year,17 patients had asthmatic attack for at least one time.The average age of patients with and without acute attack was 47.3 and 38.1 years.The median FeNO levels at first visit were 102 and 83 ppb(P=0.017)and were102.5 and 53 ppb(P=0.001),after one month of treatment.FeNO in patients with or without exacerbation were 73 vs.45 ppb,96 vs.43.5 ppb and 76 vs.43 ppb(P=0.020;P=0.006;P=0.016)at 3rd,6th and12 th months after treatment,respectively.The best cut-off value of FeNO level at the first visit for predicting asthmatic attack within one year was 96 ppb(AUC =0.746,P = 0.012,sensitivity:100%,specificity: 47.9%).The best cut-off value of FeNO level after therapy was 70.5ppb(AUC = 0.824,P = 0.001,sensitivity: 90%,specificity: 69.9%);FeNO level at the first month was an independent risk factor for asthma attack(OR= 1.02,95CI:1.00-1.04).5.The patients with more than 6 months` follow-up were divided into sustaind,fluctuated and decreased group according to FeNO fluctuation level.There were 61,70 and 42 patients,with 12,4 and 4 smokers in each group.The median blood eosinophil count were 0.49,0.29 and 0.22(× 109 / L)(P=0.046)in the three groups.There were significant differences in smoking history and blood eosinophil count in three groups.The average levels of IL-5 were 4.83 pg / ml,3.18 pg / ml and 2.97 pg/ ml in sustaind,fluctuated and decreased group,respectively(P=0.007).The level of IL-5 in sustaind group was significantly higher than those in fluctuated and decresed group.The AUC of IL-5 in predicting persistent high FeNO was 0.738,and the optimal cut-off value was 2.98pg/ml(sensitivity: 90.5%,specificity: 54.2%).IL-5 and smoking history were independent risk factors for persistent high FeNO(OR= 2.18,14.26).There was no significant difference in genotype and allele frequencies of rs7216389,rs8069176,rs743507 and rs3742879 in the sustaind,fluctuated and decresed group.In rs743507 genotype CT and TT,IL-5 and TNF-αlevels were different of statistically significant(P=0.007;P=0.032).6.After treatment,the level of FeNO was correlated with the IL-5(correlation coefficient 0.261,P = 0.030).After adjusting the level of FeNO,it was found that there was no significant correlation between iNOS and IL-4,IL-5,IL-9,IL-13,IL-17 A,IL-33,TNF-α,IFN-γ.There were 63 patients with FeNO level < 100 ppb,3 patients with 100 ppb ≤ FeNO level < 150 ppb,and 4 patients with FeNO level ≥150ppb.The levels of iNOS and IL-13 were 1617.97 ± 1201.90 pg/ml,3067.67 ±348.53 pg/ml,1302.73 ± 1241.58 pg/ml and 7.35 ± 8.39 pg/ml,4.22 ± 2.35 pg/ml,2.10 ± 1.08 pg / ml,respectively(P<0.05).Ig E,IL-4,IL-5 and IL-17 A could explain 33.4% of FeNO changes after treatment.Regression equation: FeNO level =35.780 + 0.020 × Ig E-0.324 × IL-4 + 13.535 × IL-5-2.030 × IL-17A(R2 = 0.334,P= 0.001).7.In the study on the values of FeNO and fn NO in asthma with or without rhinitis,195 patients were included with 124 females and 71 males.There were 28 patients only with asthma and 167 asthma patients complicated with rhinitis.A total of 461 records were collected in follow-up.Gender was an independent risk factor for rhinitis in asthmatic patients(OR=0.288,P = 0.010).FnNO and FeNO alone or in combination were not valuable in diagnosis of asthma with rhinitis.There was no correlation between FnNO and FeNO in patients with simple asthma,asthma complicated with rhinitis or with symptomatic rhinitis(P>0.05).Smoking was negatively correlated with the level of FnNO(P=0.003).There was no significant difference in FeNO,FnNO,ACT,FEV1%,FEV1 / FVC among three groups(P>0.05).Lower FeNO was related with well controlled asthma,but there were no significant differences in FnNO level among well controlled,poor controlled and uncontrolled groups(P>0.05).No significant difference was observed in FnNO level,FEV1%,FEV1 / FVC and rhinitis symptoms before and after the use of ICS or ICS/LABA(all P > 0.05),while FeNO level decreased and ACT increased by 5.69points(both P < 0.05).There was no significant difference in FnNO,FEV1 / FVC and rhinitis symptoms before and after the use of rhinitis drugs(all P > 0.05).However,after using rhinitis drugs,FeNO level decreased,ACT increased by 2.4points and FEV1% increased by 4.98%(P < 0.05).Conclusion:1.FeNO has certain diagnostic value in diagnosis of asthma.Age,region,types of asthma and cut-off value all have a certain impact on the diagnostic efficiency of FeNO.But it is lack of enough evidence supporting FeNO as a sole diagnostic criteria.2.We divided patients with increased FeNO level(≥ 40ppb)into mild,moderate and severe groups.We found that more than 70% of those patients were accompanied with rhinitis.The severe group showed higher height,heavier weight,higher incidence of rhinitis and worse ACT score.3.The results of short-term follow-up showed that the overall lung function improved most significantly after the first month of regular treatment,and then FEV1 and FEV1 / FVC in mild,moderate and significant groups remained stable at3 rd and 5th months of follow-up.The overall level of FeNO decreased gradually in 3months after treatment.The decline was obvious in the first month in mild group,and were significant in 3 months in moderate and severe group.The total and three groups’ ACT scores increased significantly after the first month.And at 3rd and 5th months,the median ACT score maintained at 23-24.4.The long-term follow-up results showed that the improvement of pulmonary function was mainly in 6 months,and FEV1% decreased slightly at 24 th month.FEV1/FVC was improved mainly in the severe group,while the FEV1/FVC was not significantly improved in the mild and moderate groups.The level of FeNO decreased mainly within 6 months,and slightly increased in mild group at 24 th month.While relapsed at 12 th and 24 th months in severe group.The ACT score of overall and each group were maintained at about 23 points after 6 months of treatment,and no significant fluctuation was observed in the followingl months.5.The patients with acute attack in one year were older than those without acute attack,with higher FeNO at the first visit and slower decline of FeNO.The level of FeNO at the first visit and after 1 month of treatment have a good predictive value for the risk of acute attack within one year.6.The results of analysis of FeNO level,iNOS,inflammatory factors and SNP showed that there was a correlation between FeNO level and IL-5 in peripheral blood after treatment.Patients with persistent high FeNO had higher IL-5 level which suggesting that persistent high FeNO level in patients after standard treatment represented that IL-5-mediated eosinophilic inflammation was not well controlled.IL-5 and smoking history were independent risk factors for persistent high FeNO,and IL-5 level had a predictive value for the persistent high FeNO.The levels of iNOS and IL-13 were different in patients with different levels of FeNO.IL-5 and TNF-α were different between the genotypes CT and TT of rs743507.Ig E,IL-4,IL-5and IL-17 A could explain 33.4% of FeNO changes after treatment.7.FnNO and FeNO alone or combination had no value in the diagnosis of asthma with rhinitis,and FnNO and FeNO had no significant correlation in asthma patients.The control state of asthma was correlated with FeNO level,but not correlation with FnNO.The treatment of rhinitis can improve the asthma symptoms,lung function and FeNO level,but has no significant effect on FnNO,suggesting that the limited diagnostic value of the current FnNO detection technology in asthmatic patients accompanied with rhinitis. |
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