**6. Clinical efficacy of SLIT still matter of a debate**

to the clinical data, more targeted therapies include monoclonal antibodies against IgE and against various proallergic cytokines (e.g., anti-IL-5, anti-IL-13, and anti-IgE). Although expensive, these therapies are useful in the management of selected patients who are usually

Although all story of immunotherapy seems to be a new one, the first routes of immunotherapy dates back to 1911 when two English researchers used water solution of hay fever pollen extracts for treating hypersensitized patients. They noticed that hypodermal inoculation of specific allergen could have some benefit. Without a sound knowledge of basic and clinical immunology immunotherapy was pure empiric, not so widely used treatment for decades [41, 42]. The second very important step in the history of sublingual immunotherapy was the findings of a group of German researchers who showed that sublingual route of allergen-specific immunotherapy could be equally clinical effective as subcutaneous route [4, 43]. They performed a small double-blind placebo control crossover trail. The maximum subcutaneous tolerated dose of a house dust mite (HDM) extract was given sublingual as drops three times daily [44]. They showed an improvement in symptoms and improvement in nasal inspiratory peak flow. A few years later Scadding's and Brostoff proved a clinical efficacy of low dose sublingual immunotherapy in patients with allergic rhinitis sensitized to house dust mites in a double-blind placebo-controlled trial (DB-PCT) [45] whereas Italian allergist were the first one who showed clinical efficacy of SLIT for patients with allergic rhinitis and/or asthma sensitized also to house dust mites. Those study included both adults and children population [46]. In early 1990s, the first commercial available sublingual immune drops were developed. Since the introduction of sublingual immune drops, the scientific community has been seeking for improvement. When evaluating the findings from clinical trials with sublingual immunotherapy drops, it became clear that this therapy was more likely to be effective when administered once daily and higher doses. Moreover, pharmacokinetic studies of SLIT showed that only a very small proportion of liquid extracts was taken up into superficial layer of sublingual mucosa. Searching for a way to augment local allergen uptake sublingual rapidly dissolving tablets were developed. These tablets facilitated the delivery of high concentration of allergen in a small volume. This concept led to the clinical and commercial development of high-dose sublingual AIT using fast-dissolving tablets [47]. Early papers with sublingual allergen immunotherapy demonstrated positive results, and in 1993, the European Academy of Allergy and Clinical Immunology was the first official organization to recognize that sublingual administration could be a "promising route" for allergic desensitization. Two studies from 1999 to 2001 showed a satisfied safety profile of sublingual route for both children and adults [48–51]. From 1998, the World Health Organization recommended SLIT as an "a viable alternative to the injection route in adults" [52]. Wilson Cochrane review from 2003 analyzed 49 randomized control trials (RCTs) with 4589 children and adults affected by allergic rhinitis (with or without asthma or conjunctivitis)

unresponsiveness to standard pharmacological treatment [40].

106 Allergen

**5. History of sublingual allergen-specific immunotherapy**

Although a great number of various meta-analyses and DB-PC-RCTs have showed clinical efficacy of SLIT in children population diagnosed allergic rhinitis and/or asthma [55], due to significant clinical and methodological heterogeneity, some issues are still a matter of debate. One ofthe main issues to be solved is long-term efficacy, particularly after cessation ofthe treatment. Results from several European clinical trials in pediatric and adult patients with grass pollen-induced rhinoconjunctivitis have shown that grass AIT reduces daily rhinoconjunctivitis symptom scores compared with patients receiving only symptomatic medications. The proportion of days with minimal or no symptoms increase in patients on SLIT. The same study also showed the improvement of quality of life in children on SLIT. The beneficial effects were observed for three consecutive years of treatment as well as during the first year following cessation period, indicating a disease modifying effect and persistence of efficacy despite discontinuation of therapy [56–60]. Due to the fact that majority of atopic patients are poly sensitized, one of the most important issues to be answered is SLIT efficacy in those patients. Recent study confirmed clinical efficacy of SLIT in reducing nasal and ocular symptoms and the use of rescue medications, also observed no differences in clinical efficacy in mono- and poly-sensitized patients [61]. However, the cross-protection against unrelated allergens seems to be limited [62]. Although it passed more than a decade of proven clinical efficacy of SLIT, data of long-lasting effects are still missing. Results from a 15-year-long prospective study by Marogna et al. [63] show that long-lasting effects of SLIT are in direct correlation with the treatment's duration. Some study suggested that 4 years of SLIT may be associated with more favorable effects than 3 years of treatment [64]. As the only immune modulatory treatment for allergic diseases, preventive role of AIT is of a great interest. Some authors are very doubtful concerning the adherence and tolerability of the treatment particularly in the pediatric population [65], whereas the other one claimed that even 1 or 2 years of treatment is sufficient to mediate immunological response [66, 67]. The second important issue on SLIT is long-lasting effects. After a 12 years of follow-up period Eng et al. showed preventive effects of SLIT 6 years after the treatment termination comparing with the standard pharmacotherapy [68]. Although the best candidates for allergen-specific immunotherapy are mono sensitized patients Malling et al. in their study showed that desensibilization with the predominant allergen in polysensitized participants can be similar effective [69]. In the light of preventive effects of immunotherapy and possibility to have impact on further evolution of allergic diseases (atopic march), the opportunity to use this kind of

treatment invery young children is of agreat importance, but several issues have tobe answered [70–72]. Immunotherapy can overcome problems related to the long-term pharmacotherapy [73], adherence and compliance to the standard treatment. Low-adherence and bad compliance to a long-term pharmacotherapy, both drug (problems with the usage of inhaled drugs) and non/drug-related factors can be overcome with the introduction of immunotherapy. All chronic diseases have an impact on quality of life due to high score of school absenteeism, impaired school performance, frequent emergency unit visits. Children with allergic diseases especially those with asthma showed low physical activity performance [74, 75]. High level of anxiety as well as higher incidence of depression and other physiological disorders can be seen in children and adolescents with asthma, allergic rhinitis and atopic dermatitis. A certain number of studies confirmed the impact of SLIT on all previous mentioned aspects of quality of life [76, 77].
