Association of Serum Specific IgE Antibody Level with Cough Variant Asthma：A Meta-analysis

LIU Wanjun，LIN Lina，AN Tong，CHEN Lie，CHEN Liping*

（1.Postgraduate of Grade 2016， Shenyang Medical College， Shenyang 110034，China；2.Department of Respiratory Medicine，The Second Affiliated Hospital of Shenyang Medical College）

Cough variant asthma（CVA） is a special phenotype of asthma solely presenting with dry and persistent coughing，and it has no other classic asthma symptoms，such as wheezing or shortness of breath［1］.According to a prospective and muiticenter survey on the etiology of chronic cough，CVA is one of the most common causes of chronic cough in China［2］.Patients with CVA have airway hyperresponsiveness（AHR）demonstrated by methacholine challenge［3-4］.Coughing soon disappeared after starting either or albronchodilators，theophylline or terbutaline，but recurred when these were stopped［5］.CVA can respond to bronchodilator treatment，while it is difficult to diagnose because the cough may be the only symptom.Several studies suggested that the levels of serum IgE in patients with CVA were significantly higher than those in healthy controls，which may be valuable for the diagnosis of CVA，however the sample sizes are small.Therefore，we performed a comprehensive meta-analysis of the availableliterature for the potential association between IgE and CVA in Chinese population.

1 Materials and methods

1.1 Search strategy The following databases were searched from the time that the databases were built to February 2017：China National Knowledge Infrastructure （CNKI） ， Weipu，Wanfang and PubMed.The following keywords were searched for，including“IgE”and“cough variant asthma”.“English and Chinese language publications”and“human species”were limited for searching strategy.

1.2 Inclusion criteria Eligible published studies were included with the following selection criteria：（1）case-control studies；（2）English and Chinese language publications；（3）studies on the association between IgE level and CVA；（4）patients with CVA were clearly diagnosed（international or domestic standards），and the sources of controls were described clearly.

1.3 Exclusion criteria The exclusion criteria mainly included：（1） duplication；（2） incomplete data；（3）case reports，comments and reviews.

1.4 Data extraction and quality assessment Two investigators independently searched the articles and extracted data from the eligible studies according to the selection criteria listed above.If there were disagreements between the two investigators，a third reviewer gave an opinion.

Quality assessment was conducted by using the Newcastle-Ottawa scale（NOS）.The quality of casecontrol studies was evaluated by examining three items：selection of cases and controls，comparability of cases and controls，and ascertainment of exposure.In addition to the“comparability”of 2 stars，a maximum of 1 star was awarded for each item within the“selection”and“exposure”categories.

1.5 Statistical analysis All statistical analysis were conducted using the Review Manager 5.3 software.The strength of association between the IgE level and CVA risk was assessed by odds ratios（OR s） and 95% confidence intervals （CI s）.Heterogeneity among the included studies was checked，and aP＞0.1 for Q statistic or I2＜50%indicated a lack of heterogeneity across studies，and fixed-effects model was used，otherwise random effects model was used.Visual inspection of funnel plot asymmetry was used to evaluate potential publication bias.

2 Results

2.1 Study characteristics Nine eligible articles describing the association between IgE level and CVA in the above databases were included，as shown in Figure 1［7-15］.A total of 490 cases and 451 controls eligible for the criteria were included in the meta analysis.The quality score of each study，evaluated by the NOS， ranged from 7 to 8.Detailed characteristics of the eligible studies were shown in Table 1.

Figure 1 Flow chartof literature selection

Table 1 Characteristics of studies included in the meta-analysis

Figure 2 Forest plot of meta-analysis on IgE level and CVA

2.2 Quantitative data synthesis The main results of this meta-analysis were shown in Figure 2.Random effects model was used in the analysis because of the heterogeneity.The results showed that IgE level was 2.18-fold higher in cases than that in controls（95%CI：1.59 to 2.77，P＜0.05）2.3 Heterogeneity and sensitivity analysis As shown in Figure 2，there was heterogeneity between the eligible studies（I2=92%）.And possible reasons for the heterogeneity included：（1）the inconsistent diagnostic criteria for CVA；（2）different experimental instruments and reagents；（3）the relatively small number of cases and controls；（4）only Chinese language publications included in this analysis.

A sensitivity analysis was carried out by omitting each study in turn to examine the influence of each study on the pooled OR.And the results showed that the pooled OR s， from 1.84 to 2.38， were not considerably affected by omitting any individual study，which indicated that our results were stable and credible.

2.4 Publication bias A inverted funnel plot was constructed to identify any publication bias of the eligible studies，as displayed as Figure 3.The result showed that there was publication bias among the studies included in this meta-analysis.

Figure 3 Inverted funnel plot of meta-analysis on IgE level and CVA.Each point represented an individual study for the indicated association

3 Discussion and conclusion

CVA is a special type of asthma with chronic cough as the soly or main manifestation，without obvious wheezing［1］.Exposure to sensitized allergens may exacerbate asthma by promoting airway inflammation，airflow obstruction，and AHR［1］.And IgE-mediated allergic reaction may play a role in the pathogenesis of CVA［15］.Several studies suggested that the levels of serum IgE in patients with CVA were significantly higher than those in healthy controls［6-14］.The results of this meta-analysis also showed that the serum IgE level in CVA patients was higher than that in controls group（OR=2.18，95%CI：1.59 to 2.77，P＜0.05），which indicated that IgE might be involved in the pathogenesis of CVA.

However，this meta-analysis still had several limitations，which may have influenced the findings.First，only nine eligible Chinese studies were included in this study，so publication bias could not be excluded.Second，the meta-analysis focused only on IgE levels and did not take the possibility of other factors，such as environmental and genetic risk factors.In addition，heterogeneity was confirmed in this analysis.

In conclusion，the high level of serum IgE is a risk factor for CVA and can be used as an important index for clinical diagnosis of children with CVA.

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