The clinical data of the current study show that HDM AIT in patents with allergic asthma concomitant with rhinitis results in a significant improvement in symptom and reduction in medication. We also found that non-invasive airway inflammation parameters FeNO and FnNO (which reflect total airway and upper airway allergic inflammation) and small airway function parameter (which represented by IOS R5) decreased after both half and one-year AIT in these mild and almost well controlled asthma patients. We saw a substantial increase of IgG4, while IgE remained unchanged, but ratio of IgE/IgG4 decreased along with the first year of immunotherapy process. The weakness of our study is lack of control group. As AIT has been a routine treatment for mild allergic asthma for more than a decade in our clinic, it is difficult to find enough patients willing to receive placebo or delayed AIT for controlled observation. We’ve only found 6 patients as the control group(data not shown), but the number of cases was too small for statistical analysis.
The standard AIT efficacy is the evaluation of clinical symptoms and rescue medications during natural allergen exposure, as defined by the EAACI task force following regulatory guidelines [5, 12]. For traditional clinical efficacy evaluation, the visual analog scale (VAS) is generally recommended for subjective symptom evaluation by allergic patients. The VAS can be a good means for assessing allergic patient’s feelings about the severity of their disease, especially during long-term follow-up of AR [2, 3]. The traditional clinical efficacy of AIT in allergic asthma is measured using medication scores as well as lung function test. Although the medication scores were used as primary endpoints in AIT trials done both worldwide and China [12–13], the score system has not covered mild to moderate asthma routine medication, for example ICS/LABA combination or LTRA. Thus, in this study, we use the medication score system including all the medication for allergic rhinits and asthma in order to evaluate overall treatment response for both AR and asthma. ACT (asthma control test) is widely used in evaluating asthma control status according to GINA guideline and numerous publications. But in patients with different disease severity, the improvement of ACT was more predominant in moderate asthma group when receiving AIT[14, 15]. In our study, most patients are well and partially controlled their asthma before treatment, so the subjects had a trend of symptom alleviation reflected by decreased ACT. With one year of HDM specific immunotherapy, both VAS and medication score were significantly improved, consistent with the results of most of the previous studies[13–15]. In addition, for subjects with continuous improvement (there was improvement during both the first and the second half year), most of this effect was gained during the first half year which means early effect of AIT in these mild asthma concomitant with rhinitis patients .
Measurement of FeNO is a simple and non-invasive assessment of airway inflammation severity in asthmatic patients . It has been used in epidemiological studies of allergic asthma as well as rhinitis , and recently it had been used as a supplemental tool for monitoring AIT treatment efficacy in asthmatic children . Within the nasal region, altered nasal NO levels (FnNO) have also been described in a number of conditions, including allergic rhinitis, sinusitis, and nasal polyps [7–9]. Few studies have yet investigated the effect of AIT on exhaled nitric oxide concentration , although AIT with D. pteronyssinus and D. farinae extracts has been found to induce exhaled NO in asthmatic children with mite allergy . However, the results from the previous studies are controversial and a clear demonstration of a reduction in exhaled NO in asthmatic patients taking subcutaneous immunotherapy(SCIT) is lacking [18, 20]. According to our data, exhaled NO levels decreased after SCIT with HDM, no matter from the airway reflected by FeNO or from the nose reflected by FnNO. It indicates that AIT is effective in reducing airway allergic inflammation. Again, most of this effect was gained during the first half year which means early effect of AIT.
Peripheral airway disease as indicated by increased frequency dependence of resistance and reactance measured by Impulse oscillometry system (IOS) which is a novel device for respiratory functional assessment especially in evaluation of lung mechanics . Peripheral airway impairment detected by IOS or spirometry (i.e., forced expiratory flow between 25% and 75%) commonly occurs, and each measurement may be complementary in predicting loss of control even with normal forced expiratory volume in 1 second . In recent years, IOS has been used in assessing airway resistance after bronchoprovocation [23, 24]. In small-airway obstruction situation like mild asthma, the value of both R5 (low frequencies which represents resistance from large and small airways) and R5-R20 (resistance from more peripheral airways) would elevate. In our study, R5 decreased significantly after half and one-year AIT. This may indicate R5 is a sensitive biomarker for pulmonary physiologic changes during AIT process. Besides, IOS reflects changes in the caliber of the small airways occur earlier in asthma, before the abnormalities in the larger airways characterized by spirometry [25, 26].
According to the indication of AIT, patients receiving HDM immunotherapy in our study were mild asthma patients with almost normal value of FEV1 and FEV1/FVC. It was difficult to improve these parameters after treatment because of lung function ceiling effect. As we know, for children, lung parameters like IOS were superior in identifying asthmatics then the conventional spirometry . But until now as we know, no related study has been done in adult patients with allergic asthma and rhinitis. Our results indicate IOS evaluation may be another lung mechanics biomarker during adult AIT process.
Elevated serum allergen specific IgE and related allergic symptom on allergen exposure to sensitized allergy like HDM are currently the sole standard for allergy diagnosis and inclusion criteria for starting AIT [28–30]. Serum biomarkers are important indicators reflecting AIT efficacy. Levels of specific IgE (sIgE) transiently increase during treatment and followed by gradually decreasing. Specific IgG subclasses especially antigen specific IgG4 has been fully studied during AIT . A correlation between allergen sIgG4 and clinical outcomes has been reported in some studies which had used immunoblotting and Pharmacia CAP system as we did in this work [32, 33]. Longitudinal data on serum specific sIgE and sIgG4 to Der p allergen during AIT are limited in Chinese populations. In the previous study, Chinese doctors found sIgE/sIgG4 ratios for Der p 1 and Der p 2 decreased continuously from 6 through 24 months of AIT in asthma and rhinits children . Allergen specific IgE/total IgE ratio is one of the biomarkers for monitoring clinical efficacy of AIT for allergic rhinoconjunctivitis and allergic asthma. But it is still controversial about the usefulness of serum t-IgE levels in the clinical diagnosis of allergy to common aeroallergens . As total IgE level in Chinese adult population may influenced by more factors such as parasite exposure during younger age . Thus, we combined allergen specific immunological parameter IgE and IgG4 level and use HDM IgE/IgG4 ratio to clinical outcome. It showed that HDM specific IgG4 increase as well as IgE/IgG4 decreased in the first year of AIT which may be a better biomarker to evaluate the early treatment efficacy compare to the traditional allergen specific IgE/total IgE ratio.
In conclusion, one-year HDM AIT improved allergic symptoms and reduced medication score in patients with allergic asthma and rhinitis. Non-invasive airway inflammation parameters such as FeNO and FnNO and small airway function parameter IOS were good parameters for evaluating early efficacy of AIT. HDM specific IgG4 and IgE/IgG4 may be good therapeutic indicator to reflect the efficacy of AIT during the first year of treatment.