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- Material and methods
Background: Immunotherapy through local routes is thought to be a valuable therapeutic option for respiratory allergy. We investigated the clinical efficacy and immunologic effects of sublingual immunotherapy (SLIT) in asthmatic children with mite-induced respiratory allergy.
Methods: Twenty-four patients (age range 8–15 years), suffering from mild to moderate asthma, with single sensitization to mite allergen, were enrolled. After a 1-year observation phase, patients were randomly allocated to one of two groups, and were given SLIT (sublingual-spit) as drops for 2 years according to a double-blind, placebo-controlled (DBPC) design. Symptoms/medication scores (diary card), visual analog scale, and immunologic parameters (house-dust-mite [HDM]-specific IgE, and total HDM-specific IgG and IgG4) were determined during the observation phase and during the DBPC treatment period.
Results: Twenty-one patients completed the study. At the beginning of the treatment, no difference in environmental allergenic pressure could be shown between the groups. After 2 years of therapy, there was a significant decrease in asthmatic symptoms (P=0.0001) and medication use (P=0.0001) in the active group compared to the placebo group. The visual analog score on overall asthma symptoms improved in the SLIT group (P=0.0001), but not in the placebo group. Nevertheless, the immunologic results did not show significant differences in HDM-specific IgE and total HDM-specific IgG or IgG4 between the active and placebo groups (P=NS). No relevant side-effects were recorded throughout the study.
Conclusions: Our results suggest that treatment for 2 years with SLIT is clinically safe and effective in significantly decreasing respiratory symptoms in children with mild to moderate asthma sensitized to HDM. On the other hand, the lack of changes of the immunologic parameters calls for further investigations with special reference to kinetics and mechanism(s) of action of this mode of treatment.
Asthma is currently defined as a chronic inflammatory disease in which allergens are often implicated as causative and triggering factors of respiratory attacks (1, 2). In children, the presence of allergy influences the persistence and severity of asthma (3), and perennial allergy such as that to house-dust mites (HDM) causes long-term inflammation with a variable degree of unspecific bronchial hyperreactivity (4).
Specific subcutaneous immunotherapy (SIT) with mite extracts has been shown to be effective (5, 6), with a greater improvement in children allergic to Dermatophagoides pteronyssinus than in adults (7). However, special attention should be paid to the safety of injective immunotherapy for mite allergy in patients with asthma triggered by this allergen, because of the risk of important side-effects such as irreversible bronchial obstruction (8, 9). In particular, children under 5 years of age present a significantly higher risk if systemic reactions occur (10, 11). According to the WHO position paper on immunotherapy, age under 5 years is a relative contraindication for allergen-specific immuno-therapy in children.
Some double-blind, placebo-controlled (DBPC) studies strongly support the clinical effectiveness of sublingual immunotherapy (SLIT) with grass, mite, and Parietaria extracts (12–20). The most frequent side-effect was the onset of oral/sublingual itching, but it was always described as mild and self-resolving. Headache, rhinorrhea, nasal obstruction, or urticaria was described only sporadically, and no severe adverse event was reported in these studies.
We recently performed a DBPC study in children suffering from mild to moderate asthma with a biologically standardized (BU) extract quantified in mass units (MU) (ALK-Abelló S.p.A.).
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- Material and methods
In this DBPC study, SLIT with a standardized extract of D. pteronyssinus was effective in reducing symptoms and use of medication in selected children with mild to moderate asthma. The dose of allergen administered on a yearly basis was around 3.25 times higher than the amount administered with the corresponding injective immunotherapy.
The concept of treating allergic diseases by noninjectable routes of immunotherapy dates back to the beginning of the 1900s (27), but documentation of the clinical efficacy of SLIT or sublingual/oral immunotherapy began to appear in scientific journals only in the 1980s. The evidence in support of SLIT, including some published DBPC studies (12–20) and many other controlled studies available as abstracts or full papers, led the WHO to recognize this approach as a possible therapeutic option (10). Most clinical trials have been conducted mainly in adults, while only three have been done in children (12, 19, 28). A total of 88 children allergic to HDM were studied in two DBPC studies (12, 28), while 64 children allergic to Olea pollen were studied in the third (19). One study with mites (12) and the study with Olea pollen (19) were able to show a statistically significant positive outcome with actively treated children.
Some of these trials evaluated efficacy after less than 1 year of treatment, in spite of the possibility that a longer duration of treatment might improve the clinical efficacy (14–17, 29, 30). The amount of allergenic extract administered also varied widely from the homeopathic dosages used in the study by Scadding & Brostoff (31) to the high dosages used in other studies, which in some cases were up to 200 times the dosage used for conventional injective immunotherapy (14–16, 19, 28, 29).
The present DBPC study shows that a significant placebo effect (or a spontaneous improvement of patients) takes place during the first year of specific immunotherapy, but not during the following year. This could partly explain the contrasting results obtained in short-duration studies with mite allergens. In spite of this confusing situation, we have shown a significantly greater improvement in children given active treatment than those given placebo SLIT treatment, with a decrease in the use of medication, the average number of asthma episodes, and nighttime symptoms. These changes were confirmed by the improvement in the VAS.
It must be emphasized that these results were obtained with a cumulative dose only around 3.25 times higher than the dose normally administered as injection therapy, and in spite of a significantly worse basal condition (in terms of average number of asthma episodes) in the actively treated group. In our opinion, the long (1 year) observation period before treatment was started and the prolonged treatment period (2 years) in our trial allowed us to achieve these results, which confirm the positive findings of other long-term studies (12, 18, 20) and contradict some negative short-term studies (28, 29).
From a quantitative point of view, the placebo effect was limited to a reduction of around 30% in the use of medication during the first year of treatment, with no further improvement during the second year. In contrast, active therapy achieved significant improvement during the first year and further improvement during the second year, so that at the end of the trial the cumulative decrease in use of medication in children who were given active SLIT was around 68%, clearly a larger reduction than in the placebo group.
This difference between the placebo and the active groups was not only significant from the statistical point of view, but was also clearly perceived by the actively treated subjects, as shown by the VAS.
The improvement of the VAS in the active group compared to the placebo group and to the baseline value took place only after the first 16 months of treatment. This observation may be explained by the fact that all patients started the treatment from a relatively good situation due to at least 1 year of pharmacologic treatment and environmental measures taken during the observation phase. In this situation, the major changes of asthmatic symptoms needed for significant self-assessed improvement of the VAS took place only 16 months after the beginning of the treatment. Of course, a long-lasting treatment needs good patient compliance, especially when the treatment is performed at home, and the clinical benefit becomes evident only after more than 1 year. In any event, our 3-year-long study, with only three dropouts from the placebo group, shows that if patients undergoing SLIT are properly selected, instructed, and followed-up, good compliance can be reached.
Contrasting results have been obtained for specific IgE and IgG. Some studies have reported evidence of a change in allergen-specific antibodies (12, 13, 15, 20), whereas others, as in our trial, found no change (16, 19, 28), although this lack of objective change was not related to the patients' clinical outcome. These contradictory results may reflect the fact that IgG is not directly involved in reducing the release of allergic mediators, and can therefore be regarded as a “bystander” or epiphenomenon of the systemic administration of a significant amount of allergen (32, 33).
In our study, no patients showed systemic reactions, and local reactions (slight swelling and itching of mouth and lips) occurred in only two patients. These findings are in good agreement with the other published studies and with a large postmarketing surveillance study of SLIT (34).
Most published studies have used the sublingual-swallow technique. In our study, we used the sublingual-spit technique, but we cannot rule out the possibility that some of the allergen administered could have been swallowed. On the other hand, preliminary data on the kinetics of SLIT in healthy persons, as studied with radiolabeled allergen, show that no direct sublingual absorption occurs, and there is no risk that absorption through the oral mucosa may occur too rapidly, while a significant amount of the administered allergen persists in the mouth for several hours (35). These studies support the hypo-thesis that the locally retained allergen is slowly absorbed and processed through the local oral immune system.
Our data, combined with the available evidence, show that SLIT is efficacious, safe, and well tolerated, and permits significant socioeconomic savings (15, 18) because it is a self-administered treatment. In our opinion, however, SLIT must be prescribed by a specialist, and patients must be instructed to follow the schedule of administration carefully and to attend clinical follow-up visits at least every 3 months.
Some aspects of SLIT which need further investigation and development are as follows:
the kinetics of the extracts
the duration of treatment
the role of the sublingual lymph nodes, which may be crucial in the absorption of allergens in the oral cavity.
We conclude that, despite some problems which need further study, SLIT with a biologically standardized extract of D. pteronyssinus in children with mild to moderate asthma can be considered effective in carefully selected patients with proper follow-up carried out at a specialized center.