Introduction
Immnoglobulin E (IgE), the fifth and last immunoglobulin to be identified, was first reported in 1966 [
1]. Measurements of total and antigen-specific IgE are helpful for diagnosing allergic diseases. IgE is a critical factor for the development of bronchial hyperresponsiveness in asthmatics [
2]. Epidemiological studies have shown that total IgE level is higher in patients with asthma, particularly in children, than in non-asthmatics [
3]-[
5]. Recently, a longitudinal analysis of European Community Respiratory Health Survey data showed that total IgE was associated with new-onset asthma among atopics [
6]. Meanwhile, the association between total IgE level and non-atopic asthma remains controversial [
7],[
8].
Total IgE level is higher in children with severe asthma than in those with mild to moderate asthma [
9]. In The Epidemiology and Natural History of Asthma: Outcomes and Treatment Regimens study, an association between a high level of total IgE and asthma severity was observed among younger subjects with difficult-to-treat or severe asthma [
10],[
11]. In a study conducted by de Marco et al., a high level of IgE was a strong predictor of moderate-to-severe asthma among 856 European adult patients with asthma [
12]. However, recent global multicenter clinical trials, such as the Severe Asthma Research Program [
13] and the European Network For Understanding Mechanisms of Severe Asthma [
14], showed no correlation between asthma severity and levels of total and antigen-specific IgE, raising suspicion that IgE may not play a role in the deterioration of asthma control in patients with adult asthma. In recent years, a recombinant humanized monoclonal anti-IgE antibody, omalizumab, has been used in patients with allergic severe asthma [
15],[
16]. Its effectiveness reminds us of the functional importance of IgE in severe asthma.
In general, serum total IgE concentration seems to peak in early adolescence and decrease with age [
17]-[
19]. However, longitudinal change in IgE is heterogeneous among patients with adult asthma. Although there have been several large-scale cross-sectional studies of total IgE and antigen-specific IgE [
20],[
21], only one multicenter study has assessed longitudinal change in total IgE and prevalence of IgE sensitization in the same population [
22]. This study showed an overall decrease in total IgE over 10 years, in line with previous cross-sectional studies [
17]-[
19]. Meanwhile, few studies have interpreted longitudinal change in total IgE in individuals.
The aim of the present study was to investigate the association between longitudinal change in total IgE and asthma control to elucidate the role of longitudinal change in IgE in patients with asthma.
Methods
Study design
This was a retrospective study conducted in the allergy and pulmonary units of the Showa University Hospital, Tokyo, Japan, between January 2011 and December 2012. The study protocol was approved by the Showa University ethics committee and written informed consent was obtained.
Study subjects
Out of 854 asthmatic patients, we recruited 154 patients, whose longitudinal changes in total IgE in the preceding 10 (±2) years could be obtained. All patients had been regularly followed at Showa University Hospital. Individuals with chronic obstructive pulmonary disease (COPD) or other lung disease, smoking history greater than 20 pack-years, being treated with omalizumab, vocal cord dysfunction, or neurological disease were excluded. No participants, even those who had high IgE level, had parasitic infections. Asthma was diagnosed based on cough, breathlessness or dyspnea, and demonstration of airflow variability. The latter was determined according to a reversible airflow limitation that represented an increase in forced expiratory volume in 1 s (FEV1) of 12% or 200 mL after the inhalation of salbutamol.
Data collection
Baseline data including medical history, Asthma Control Test (ACT) score, spirometry, fractional exhaled nitric oxide (FeNO), percent peripheral eosinophils, total and specific IgE [Dermatophagoides pteronissinus (house dust mite: HDM), Cryptomeria japonica (cedar), Ambrosia artemisiifolia (ragweed), Candida albicans (candida), Aspergillus fumigatus (aspergillus), Alternaria alternata (alternaria), dog dander, cat dander, Bombyx mori (moth), and Blatta orientalis (cockroach)] were collected at enrollment. The definition of atopic type was being positive to crude house dust-specific IgE.
Asthma control was assessed using the validated Japanese version of the ACT. Patients were subjectively evaluated for the degree of impairment caused by their asthma during the preceding 4 weeks by responding to five questions using a five-point scale.
Spirometry was performed using an AS-302 spirometer (Minato Medical Science Co., Ltd., Osaka, Japan) in accordance with American Thoracic Society/European Respiratory Society guidelines [
23],[
24] to determine FEV
1, forced vital capacity (FVC), and FEV
1/FVC (FEV
1%). The highest value from three technically satisfactory attempts was recorded. FEV
1 and FVC values were expressed as a percentage of the predicted value.
FeNO was measured by a portable device (NIOX MINO, Aerocrine AB, Solna, Sweden) at an expiratory flow rate of 50 mL/s for 10 s.
Serum total IgE levels, measured with a fluorescent enzyme immunoassay (ImmunoCAP-FEIA, Phadia, Freiburg, Germany) were transformed logarithmically to normalize their distribution. A zero was replaced with a value half of the lowest value observed before log transformation. Antigen-specific IgE was also measured with ImmunoCAP-FEIA, and levels higher than class 2 were considered as positive. The longitudinal change in total IgE (?IgE) was calculated as log total IgE at present – log total IgE 10 years ago. An increase or decrease in total IgE was arbitrarily designated as a variation of >0.15 log10 kU/L.
Statistical analyses
Results were expressed as mean ± SD for continuous variables. FeNO values were transformed logarithmically to normalize their distribution. All analyses were performed using JMP version 10 (SAS Institute Inc., Cary, NC, USA). Differences in the continuous variables between groups were tested by analysis of variance (ANOVA); if the differences between groups were significant, comparisons were made by unpaired t-test. Categorical variables were analyzed with ? 2 tests. A value of P <0.05 was considered significant for all statistical assessments.
Discussion
In the present study, we found that patients with a longitudinal increase in total IgE used on-demand OCS more frequently, were more likely to have been treated at levels above Step 4, had more episode of acute exacerbation within a year, had lower ACT scores, and were more likely to have uncontrolled asthma than patients with a longitudinal decrease in IgE or no change in IgE. In addition, more airway obstructions were observed among patients with a longitudinal increase in IgE. These results suggest that a longitudinal increase in IgE is associated with poor asthma control. To our knowledge, this is the first study to investigate the clinical role of longitudinal change in total IgE in patients with adult asthma and to demonstrate the possible association between a longitudinal increase in IgE and poor control of adult asthma. Recent global trials showed no association between absolute IgE levels and asthma severity in patients with adult asthma [
13],[
14]. Considering these previous global trials, our interpretation of the present study is that a measurement of longitudinal change but not absolute value in total IgE predicts, to some extent, asthma control in clinical practice.
Longitudinal changes in IgE vary considerably among individual in patients with adult asthma, as shown in Figure
1. We stratified adult asthma patients according to the longitudinal change in IgE to identify characteristics of patients with increased IgE. We found that the mean age of patients with a longitudinal increase in IgE was higher than that of patients with a decrease or no change in IgE, suggesting that an increase in total IgE is associated with aging among patients with uncontrolled asthma. Previous epidemiological studies showed that mean total IgE levels in patients with asthma decreased with age [
20],[
26]. The participants in these studies were younger, (mostly less than 60) than those who enrolled in our study. In addition, these studies were cross-sectional rather than longitudinal. Thus, the results of these studies cannot be easily compared with our data. Further investigation of longitudinal changes in total and antigen-specific IgE in adult asthma, particularly over the age of 60, is needed.
Previous studies have shown that males and current smokers have higher IgE levels than females and non-current smokers, respectively [
27]-[
29]. In the current study, there were no significant differences in gender or current smoking status between three groups (Table
1). The reasons for this are still unclear, but one possible reason for the lack of a difference in smoking status is that participants whose smoking history was greater than 20 pack-years were excluded for exclusion of COPD.
The total IgE level reflects both specific and unspecific IgE. Matricardi et al. followed total and allergen-specific IgE levels in children from birth to 13 years of age [
30]. This study revealed that the evolution of total IgE was extremely heterogeneous but was parallel with that of allergen-specific IgE from the age of 5 onwards. Furthermore, Carsin et al. demonstrated that total IgE level is related to new-onset asthma, but this association is almost entirely explained by specific IgE [
31]. In the present study, specific IgE to HDM was the most prevalent, followed by cedar-specific IgE. The prevalence of specific IgE to HDM and cedar did not differ between groups, indicating that these antigen-specific IgE did not contribute to the longitudinal increase in total IgE. The prevalence of specific IgE to fungi, such as aspergillus and alternaria, was higher in the increased IgE group than in the other two other groups. In particular, significant difference was observed for aspergillus-specific IgE. This suggests that specific IgE to fungi, especially aspergillus, might have contributed to the longitudinal increase in total IgE and also to poor control in the increased IgE group. This is clinically plausible, since sensitization to aspergillus is one of the factors that results in difficult-to-treat asthma, such as allergic bronchopulmonary aspergillosis (ABPA) and severe asthma with fungal sensitization (SAFS) [
32]. In addition, a previous study showed that specific IgE to
Aspergillus fumigatus contributed to an increased risk of adult onset of asthma [
33]. To the best of our knowledge, this is the first report indicating the association between aspergillus-specific IgE and a longitudinal increase in total IgE in patients with adult asthma.
There are several limitations to our study. First, although we showed that patients with increased IgE had a higher prevalence of aspergillus-specific IgE than patients with decreased or unchanged IgE, a longitudinal change in aspergillus-specific IgE could not be shown. Thus, to demonstrate directly the contribution of aspergillus-specific IgE to the increase in total IgE and poor control of asthma, we should assesse the association between longitudinal change in aspergillus-specific IgE and longitudinal change in total IgE and control levels.
Second, the treatments of patients were not taken into consideration in this study. The treatments of all patients enrolled in this study have changed, usually a number of times, during the past 10 years. Therefore, we could not account for the treatments in our analysis. It remains unclear how treatments affect longitudinal changes in total IgE and antigen-specific IgE.
In conclusion, this is the first study to investigate the clinical roles of longitudinal change in serum total IgE in patients with asthma. We demonstrated that longitudinal increase in total IgE is associated with poor asthma control and a higher prevalence of aspergillus-specific IgE in patients with adult asthma, suggesting a significant contribution of IgE in the pathophysiology of severe asthma. Further prospective analysis is needed to validate our data.
Authors’ contributions
AT performed the major part of the analysis, contributed to the interpretation of the results and drafted the manuscript. MJ, KH, YM, HM, MY, SO, YW, MY, and SS contributed to the analysis of the study, and supported the development of the manuscript. TY and HS participated in the interpretation of the results, and contributed to the development of the manuscript. MA conceived the outline of the current analysis, and supervised its completion. All authors agreed with the final draft of the manuscript.
Competing interests
The authors declare that they have no competing interests.