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.