Future directions:
Accurate diagnosis is essential before AIT can be considered. The routine use of molecular diagnosis for allergic diseases and AIT, theorized in the late 1990s by Rudolf Valenta and colleagues119, is relatively recent and is still evolving. Constraints include the perceived complexity of this diagnostic approach and the slightly higher costs of test execution120-122. The recent development of a novel multiplex test containing both extracts and molecules relevant for pollen allergy (a sort of “molecular pollen test”) may help doctors in the prescription of the appropriate AIT products 123. The development of algorithms and clinical decision support systems integrated into apps for smartphones124 will facilitate the clinical interpretation of the outcome of IgE molecular assays, as shown in a recent pilot experience (Arasi, S et al. Clin Exp Allergy, in press). Different estimates confirm that CRD has a significant impact on AIT formula selection125-127.
To rely on correctly standardized and clinically documented AIT products, as well as to understand their limitations, is as important as correctly diagnosing patients.
With an increasing number of new intervention possibilities, it is essential to optimize the use of AIT58,128,129. Major allergen sensitization and the use of up to two different clinically-documented allergen preparation is a must. In fact, even in complex exposure regions, most of the patients are sensitized to a limited number of allergens130 and thus potentially eligible for AIT. An adequate dose of allergen as defined in dose-finding clinical trials will guarantee an adequate safety/efficacy balance. In the last years, an increasing number of allergen preparations developed with the highest pharmacological standards are available. This trend will continue and is expected to have a profound impact on AIT practice and to position it in the center of etiological management of allergic patients. In spite of correct diagnosis and the use of high-quality AIT products, a fraction of treated patients will not improve or will lose clinical benefit upon discontinuation after three years of intervention13. The need to advance on personalized medicine approaches to predict intervention outcome and safety − and to monitor AIT effect − is imperative131. System biology approaches are being explored to understand AIT response5. These new approaches help to understand biological effect kinetics and provide new tools to evaluate new AIT product approaches. The desensitization of allergen-specific effector cells plays a determinant role for AIT effect during the first two years of intervention, while regulatory response, which is initiated shortly after AIT initiation, will only have a meaningful clinical benefit after at least two/three years of administration. We need better formulas, including adjuvants and tolerogenic signaling molecules to reduce AIT duration6. At the same time, understanding severe phenotypes is needed. Recent data obtained by system biology approaches identify T cell proliferation, inadequate regulatory function, and collapse of repair homeostasis as main causes for non-response to intervention and evolution to severe phenotypes7-9,132. There are new possibilities of using these systemic signatures to explore the value of new biologics to stabilize severe phenotypes allowing ulterior AIT intervention.
While CRD has proved the value for correct patient inclusion and AIT standardization, we cannot expect that it will be of great value to predict intervention outcome or safety77. AIT is the only treatment in allergy able to modify the course of the disease, but for achieving this goal, the correct patients, with the correct product, with adequate treatment duration and compliance are needed. Even so, about 30% of patients will not benefit from this disease-modifying effect. This 70% effect, however, ranks at the top of successful pharmacological interventions. In 2003, Dr. Allen Roses, by that time vice president of the genetics division for GSK, commented that “The vast majority of medicines, more than 90 percent, only work in 30 or 50 percent of people”. Since then, massive efforts on personalized medicine are progressively changing the landscape. AIT has the potential of being the reference intervention in allergy, but for that, we need a commitment and upgrade of its clinical practice. The use of molecular allergology for diagnostic purposes will rapidly evolve in the next years and will be more linked to the identification of patients phenotypes and endotypes for an improved therapeutic approach, which implies the opening of the era of “precision allergology”121,122. CRD, today, provides a good starting point.