Status of immunotherapy: is the time ripe for the secondary prevention of asthma and allergy?

Allergen-specific immunotherapy or allergen vaccination is the practice of administering increasing amounts of allergen(s) (the allergic extract or vaccine) to subjects with allergy to achieve a hyposensitization and to reduce the symptoms occurring during the natural exposure to the allergen(s) itself. Articles, reviews and meta-analyses provide data concerning recent progress in understanding the mechanisms of action of immunotherapy and potential future directions [1].

However, there is a disparity in the translation of scientific knowledge of this treatment modality into the practice of giving immunotherapy to patients [2].

Allergic disease is now considered a major burden in westernized societies, approximately a third of children suffer from allergy of some nature, with varying prevalence depending on the diagnosis [3,4]; although asthma prevalence appears to be stabilizing in developed communities, that of atopic dermatitis continues to increase, as does asthma prevalence in regions of rapid economic development [5–8].

Immunotherapy is the only antigen-specific immunomodulatory treatment routinely available; however, so far it is substantially used as a therapeutic approach of allergic respiratory diseases [9].

New data demonstrate the efficacy of specific immunotherapy (SIT), not only as a therapeutic agent, but also as a preventive strategy to reduce the onset of new sensitizations to nonrelated allergens [10–12], progression from allergic rhinitis to asthma [13,14] and to improve the long-term outcome of already established asthma [12,15].

Moreover, knowledge exists regarding the duration of therapeutic effects after discontinuation of SIT in adults [16] and children [17].

The first report on specific immunotherapy is more than 95 years old [18]; however, it is presently considered a ‘new strategy to counter allergy’ [19]. Recent published data have highlighted the safety and effectiveness of sublingual immunotherapy (SLIT) in patients with sensitization to foods [20]; in addition, subcutaneous immunotherapy (SCIT) using a preparation of house dust mite (HDM) was effective in reducing eczema in patients with chronic atopic dermatitis and allergic sensitization to HDM allergens in a dose-dependant manner [21].

Moreover, in the review that gave rise to this editorial the authors underline the mechanisms of action and efficacy of SIT [22].

On the other hand, SLIT, used so far in Europe, Asia and Australia for the treatment of allergic respiratory diseases, represents the major issue under debate towards the new immunomodulatory treatments of immunoglobulin (Ig)E-mediated disorders; in fact, the use of nasal route (local nasal immunotherapy [LNIT]) is progressively declining, but SLIT is considered an efficacious and safe alternative to SCIT [23].

New directions in the management of childhood asthma and allergy include early recognition and early intervention with environmental control and administration of long-term control therapy [24,25].

Hopefully, this movement will result in improved methods to diagnose and alter the natural history of asthma and other allergic disorders.

Inhaled glucocorticoid (ICS) therapy improves asthma control, but it is not clear whether this treatment can prevent the progression of asthma [26,27].

The early intervention on asthma and allergy with HDM avoidance measures remains a contentious issue [28,29].

A number of randomized, controlled trials have shown that HDM avoidance is effective in the secondary prevention of atopic dermatitis [30]. Allergen avoidance should remain an essential part of the management of allergic diseases, even if the benefit of mattress covers is in doubt [29].

SIT is actually a cumbersome treatment, often nonstandardized in application, with different perspectives in the USA and Europe. Notwithstanding this, it is the one etiological therapy of IgE-mediated allergic respiratory diseases.

The ‘historical’ studies with SCIT were performed in children aged 3–14 years [15,31], and neither serious side effects nor life-threatening events were reported. Nonetheless, a subsequent well-conducted trial reported severe asthma, generalized urticaria, angio-edema and anaphylaxis in treated children below the age of 5 years [32]. Since then, the preschool age is generally considered a prudent limit for immunotherapy in view of the possibility of severe side effects. Indeed, this age is considered a relative contraindication for SCIT [33] since severe side effects are more difficult to treat in very young children, and injection IT carries the risk of important untoward reactions [34]. However, recent data have demonstrated that SLIT is safe in young children and offers new possibilities for the treatment of pediatric patients [35,36].

Of note, an essential tenet of secondary preventive strategies is the awareness that there is a ‘critical window’ in early life during which the developing immune system is set on its eventual course [37].

Both exposure and response to allergens are pivotal for children who transit through this critical window with (or without) the development of persistent allergic diseases.

Careful selection of allergic children is the most important question to be faced, with the awareness that the early use of SIT alters the natural history of allergic diseases by suppressing airway inflammation at a time when a child is only intermittently symptomatic [38].

Therefore, the crucial issue is the development of new strategies for asthma when the disease first manifests itself in early childhood [39].

Relief of allergic symptoms and long-lasting efficacy are two goals that can be attained in allergic children treated with SIT; these effects are of particular relevance in pediatric patients where a preventive effect on the onset of asthma and prolonged duration of this effect are expected.

Early treatment of allergic diseases represents an important challenge, which, on theoretic grounds might be even more effective in younger children in whom allergic specific T-helper 2 memory is less well established and hence, more susceptible to downregulation; therefore, the time is ripe to expand on the concept of SIT, in order to define its clinical potential particularly in children with IgE-mediated allergic disorders.