Allergen immunotherapy for asthma: Looking “Back to the Future”
Authors: Matteo Bonini, Marek Jutel
Journal: Allergy (2019)

Asthma is a heterogeneous chronic syndrome which represents a relevant socioeconomic burden in both adults and children. Global asthma prevalence has been reported to be of approximately 300 million people, with an estimate of increasing figures up to 400 million by 2025.1 Among the identified distinct phenotypes and endotypes,2 allergic asthma represents one of the most well-characterized and relevant nosologic entities, with atopy playing a key role in the disease risk, onset, and progression. Current pharmacological treatment strategies effectively control clinical symptoms and the underlying inflammatory process, but do not affect the dysregulated immune response, having therefore limited impact on the disease progression. In addition, despite optimal treatment, a significant number of patients experience uncontrolled forms of the disease, thus representing a relevant unmet medical need. Indeed, uncontrolled asthma is responsible for impaired quality of life, increased number of visits to the emergency room and hospitalizations, and disproportionate use of healthcare resources. Allergen immunotherapy (AIT) is the only treatment of allergy capable of disease modification.3 Since its introduction, almost a century ago, AIT has been mainly performed subcutaneously (SCIT) and confined to the management of allergic rhinitis with several clinical trials consistently supporting its efficacy in reducing symptoms and medication use, reliable safety, and prevention against the progression to allergic asthma.4 In more recent years, following new promising literature findings5 and the report that adding house-dust-mite (HDM) sublingual immunotherapy (SLIT) to maintenance medications improved time to first moderate or severe asthma exacerbation,6 the use of AIT has been also proposed for the treatment of allergic asthma. Accordingly, the current version of the Global INitiative on Asthma (GINA) guidelines suggests adding HDM SLIT for sensitized asthmatic patients in steps 3 and 4 not under control, with concomitant allergic rhinitis and preserved lung function (forced expiratory volume in the 1st second—FEV1 > 70% of predicted).1 In order to bring definite clarity on the issue, the European Academy of Allergy and Clinical Immunology (EAACI) recently performed a systematic review and meta-analysis to assess the effectiveness, cost-effectiveness, and safety of AIT in asthma. Ninety-eight studies enrolling a total of 7413 patients were included. IT was administered subcutaneous and sublingual in 54 and 34 trials, respectively, using different allergen extracts (ie, HDM, grass, cat, and dog) and adopting various protocols. The very accurate and methodologically robust analysis of the selected studies showed that AIT can achieve substantial reductions in short-term symptom and medication scores in allergic asthma.7 As secondary outcomes, SCIT also improved quality of life and small airways function (assessed through FEF 25%-75% values), as well as decreased specific airway hyperreactivity. Moreover, the recently published EAACI Guidelines on Allergen Immunotherapy for HDM-driven allergic asthma provided evidence-based practical recommendations on how optimally applying AIT in asthma.8 Despite all the above, real-life data reveal that the use of AIT in asthma is at present very limited and evidence is still lacking on the role of AIT on several relevant asthma endpoints, such as the disease control and progression. Furthermore, the reported beneficial effect of AIT in childhood asthma has been recently questioned, based on studies performed in children not treated according to GINA guidelines. Therefore, after more than 20 years from the dispute opened by the paper of Adkinson et al,9 reporting no significant benefit for AIT in allergic children with perennial asthma who were receiving appropriate medical treatment over a two-year period, the debate appears to be still open. In this current issue of Allergy, article by Schmitt and co-workers investigated through a large population-based cohort study run in Germany on comprehensive routine healthcare data, whether AIT had an influence on the progression of asthma severity. The study population consisted of all patients aged 12 years or older developing incident asthma during the 10-year observation period. Database from the AOK PLUS health insurance showed, among forty thousand asthmatics, 10% of them received AIT. Analyses performed robustly showed that AIT was associated with a significantly decreased risk of asthma progression, in particular from GINA steps 1-3 and steps 3-4, mainly in the younger group. Although data available do not allow to draw conclusions about patients with sensitizations to different allergens or application of specific allergen products, the study strongly suggests that AIT not only may prevent the occurrence of asthma in subjects with allergic rhinitis and reduce symptom and medication scores in short term but may also meaningfully influence the progression of asthma severity. The study has some limitations, correctly disclosed by the authors. For instance, only step-up interventions were recorded and not step-down ones which could have been of interest for documenting a possible steroid-sparing effect of AIT. Moreover, the natural course of asthma is a dynamic process affected by multiple variables. Studies of long-term effects on asthma control should therefore include clinical and functional endpoints aside the assessment of prescribed medications and better rely on prospective randomized controlled trials (RCTs) rather than on retrospective surveys. However, there is an increasing interest in postauthorization efficacy studies (PAES) and real-life data because of their possibility to evaluate effectiveness and cost-effectiveness. The study of Schmitt et al is an excellent example of how “big data” derived from registries, healthcare or insurance records, patient and physician surveys, and biobanks, when included in large data platforms, may offer additional relevant information to those provided by RCTs. Of course, real-life data are quite heterogeneous and require rigid control of accuracy. However, the analysis of “big data” may conveniently allow stratifications of the study population according to the demographic characteristics and sub-group identification depending on the AIT allergen, administration route, and protocol. This will hopefully provide additional robust elements to properly answer, as recommended by the main regulatory bodies and scientific societies and in accordance with the current precision medicine approach, the old but still open question about who really benefits from AIT.10 The authors declare that they have no conflicts of interest.