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Background: Subcutaneous immunotherapy has been the principal approach of immunotherapy in the treatment of allergic diseases. Several clinical studies with birch, alder or hazel pollen extract conducted as subcutaneous immunotherapy have been published suggesting a well-tolerated and clinically effective treatment. Only a few clinical studies of sublingual immunotherapy (SLIT) with these allergens have been published. This study investigated the clinical efficacy, safety and dose–response relationship of SLIT in children suffering from rhinoconjunctivitis with/without asthma.
Methods: Eighty-eight children (5–15 years) with a history of tree pollen-induced allergic rhinoconjunctivitis with/without seasonal asthma for ≥2 years were included. Allergy to tree pollen was confirmed by positive skin-prick test, positive specific IgE and positive conjunctival provocation test. The extract used was a glycerinated mixture of Betula verrucosa, Corylus avellana and Alnus glutinosa 100 000 SQ-U/ml. Children were randomized into three groups receiving SLIT 5 days a week for up to 18 months; dose group 1: accumulated weekly dose of 24 000 SQ-U; dose group 2: accumulated weekly dose of 200 000 SQ-U; and placebo.
Results: In the birch pollen season, dose group 2 showed a significant reduction of symptom (P = 0.01) and medication scores (P = 0.04) compared with placebo. Dose group 1 showed a significant reduction of symptom scores (P = 0.03). There were no statistical differences between dose groups 1 and 2. All children tolerated the treatment well.
Conclusion: SLIT with tree pollen extract provided dose-dependent benefits in tree pollen-allergic children in terms of significantly reduced symptoms and medication use. The treatment was well tolerated.
Subcutaneous allergen injection immunotherapy has been the principal immunotherapy approach in the treatment of allergic respiratory airway diseases (1). Routes (local and non-injection) differing from subcutaneous injections have been investigated: oral, nasal, bronchial and sublingual immunotherapy (SLIT) (2). As a result of the potential high tolerability, SLIT is an attractive form of specific immunotherapy. The most common way to administer SLIT is to keep the allergen extract under the tongue for 1–2 min and then swallow it. At present, SLIT-swallow is the most used route of administration, and its use is supported by an increasing number of controlled studies investigating safety and efficacy. Studies have been conducted with various allergen extracts, e.g. house dust mites (3–6), cat (7), moulds (8) and different types of pollen: weeds (9–11), olive tree (12) and grasses (13–19). The dose of allergen used for SLIT is generally higher than that for subcutaneous allergen injection immunotherapy (20), but there are several inconsistencies in the absolute dose used in the different studies. In order to establish a recommendation for the dose to be used for SLIT, information on the optimal dose must be achieved.
There are several published clinical studies with birch, alder or hazel pollen extract conducted as subcutaneous allergen injection immunotherapy. Results from these studies suggest that immunotherapy with tree pollen extracts is both well tolerated and clinically effective (21–27). It is expected that SLIT with birch, alder and hazel pollen extracts is also clinically effective and well tolerated. However, there are only few published clinical studies of SLIT with these allergens (28, 29).
In order to further elucidate the effect of SLIT, the present study was set up to investigate the efficacy, safety and dose–response relationship of tree pollen extract in children suffering from rhinoconjunctivitis with/without seasonal asthma caused by allergy to tree pollen. Our study is the first one using tree pollen extract in a double-blind placebo-controlled setting evaluating clinical efficacy, safety and dose–response relationship of SLIT.
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- Materials and methods
Subject disposition is provided in Fig. 1. A total of 134 children were screened, of whom 36 children did not fulfil the inclusion criteria and a total of 98 children were randomized. Eighty-eight (32 in dose group 1, 27 in dose group 2 and 29 in the placebo group) were included in the efficacy analyses.
The demographics of study subjects are presented in Table 2. Overall, 40.9% and 30.7% of the children had tree pollen allergic history with symptoms of asthma and atopic dermatitis, respectively. The severity of symptoms was in most cases moderate for rhinitis and conjunctivitis, and mild for asthma and atopic dermatitis. The mean number of years with rhinitis symptoms were 4.6 years (range 2–10), with conjunctivitis symptoms 4.6 years (range 2–10), with asthma 4.2 years (range 2–10) and with atopic dermatitis 7.6 years (range 3–12). There was no difference between treatment groups regarding the distribution of allergic history to allergens other than tree pollen, and there was no difference between the three groups regarding general characteristics and demographics.
Table 2. Subject demographics
| ||Dose group 2||Dose group 1||Placebo|
|Age in years, mean (SD)||9.0 (2.7)||9.6 (3.1)||9.9 (3.0)|
|Severity of rhinitis|
| Mild, n (%)||3 (11.1)||7 (21.9)||3 (10.3)|
| Moderate, n (%)||17 (63.0)||16 (50.0)||18 (62.1)|
| Severe, n (%)||7 (25.9)||9 (28.1)||8 (27.6)|
|Duration of rhinitis in years, mean (SD)||4.1 (1.9)||5.0 (2.3)||4.6 (2.5)|
|Conjunctivitis, n (%)||26 (96.3)||31 (96.9)||29 (100)|
|Asthma, n (%)||9 (33.3)||17 (53.1)||10 (34.5)|
|Atopic dermatitis, n (%)||10 (37.0)||12 (37.5)||5 (17.2)|
| Grass pollen, n (%)||6 (22.2)||8 (25.0)||4 (13.8)|
| Animal dander, n (%)||5 (18.5)||5 (15.6)||7 (24.1)|
| Foods, n (%)||20 (74.0)||26 (81.3)||22 (75.8)|
|Duration of SLIT in months, mean (SD)||16.4 (3.5)||18.1 (2.5)||17.7 (3.1)|
In this study, statistical analyses were planned to be performed on a Bonferroni-corrected 1.5% significance level. Retrospectively, we altered the significance level to 5% as the power of the study was considered insufficient to demonstrate any statistically significant differences at the conservative 1.5% significance level. At a 5% significance level, we demonstrated that SLIT with a tree pollen extract, when compared with placebo, reduced allergic symptoms during the tree pollen season in tree pollen-allergic children suffering from rhinoconjunctivitis with or without seasonal asthma.
Symptom and medication scores are illustrated in Fig. 2A and B. The symptom scores were significantly higher in the placebo group compared with the active treatment groups during the birch pollen season, whereas the medication scores remained lower in dose group 2 compared with dose group 1 and placebo group. The nose and lung symptom scores appeared higher during the birch pollen season, whereas difference was less clear in eye symptom scores.
Figure 2. Average daily symptom score (A) and medication score (B) during the tree pollen season. Daily alder/hazel and birch pollen counts are included (grains per m3).
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Statistical comparison of the efficacy is presented in Table 3. Values were statistically significantly different in the reduction of symptom score (P = 0.01) during the whole tree pollen season for dose group 2 vs placebo. The same comparison revealed a marginal significance with the medication scores (P = 0.06). When the analysis was focused on the birch pollen season where the exposure and thereby the symptoms and need for medication was higher, a statistically significant difference in reduction of medication scores was found (P = 0.04). Significant differences during the whole pollen season were found for nose, eye and lung symptoms, when analysed separately (P = 0.04, 0.04 and 0.02, respectively).
Table 3. Comparison of Efficacy
| ||Dose group 2||Dose group 1||Placebo||Estimated reductiona (%) vs. placebo|
|Dose group 2|| P-valueb||Dose group 1|| P-valueb|
|Whole tree pollen season|
| Symptom score, mean (SD)||2.9 (3.4)||2.9 (2.2)||4.3 (2.6)||1.77 (40.8)||0.01||1.36 (31.2)||0.03|
| Medication score, mean (SD)||2.9 (3.4)||3.8 (4.4)||3.9 (4.6)||0.94 (39.7)||0.06||0.16 (6.6)||0.72|
|Birch pollen season|
| Symptom score, mean (SD)||4.0 (4.6)||4.2 (2.9)||6.0 (3.8)||2.36 (39.1)||0.01||1.69 (28.1)||0.04|
| Medication score, mean (SD)||3.6 (5.4)||5.3 (5.7)||5.1 (5.6)||1.47 (42.4)||0.04||0.14 (4.0)||0.83|
|Whole tree pollen season|
| Nose symptoms, mean (SD)||1.5 (1.4)||1.6 (1.1)||2.2 (1.4)||0.74 (34.9)||0.04||0.66 (31.1)||0.04|
| Eye symptoms, mean (SD)||0.8 (1.2)||0.9 (1.1)||1.1 (0.9)||0.46 (47.7)||0.04||0.31 (32.0)||0.10|
| Lung symptoms, mean (SD)||0.6 (1.1)||0.5 (0.5)||0.9 (0.8)||0.40 (48.3)||0.02||0.28 (34.2)||0.07|
No statistically significant differences in CPT, MBPT and LPSR between the treatment groups were seen. The analysis on MBPT was performed for asthma children only, but there was no statistical difference in this analysis.
One child in the placebo group never had any study medication. All 97 children who received study medication were included in the safety analysis. The adverse events (AEs) definitely or likely related to study medication are shown in Table 4. SLIT was generally well tolerated and nearly all adverse events related to treatment were local allergic reactions in the mouth.
Table 4. Adverse events – definitely or likely related to study medication
| ||Dose group 2 na (%) Eb||Dose group 1 n (%) E||Placebo n (%) E|
|Population||32 (100.0)||33 (100.0)||32 (100.0)|
|All events||17 (53.1) 143||13 (39.4) 41||8 (25.0) 25|
|Allergic reaction||2 (6.3) 2||–||–|
|Abdominal pain||1 (3.1) 1||2 (6.1) 2||–|
|Oral local reactions||16 (50.0) 137||12 (36.4) 38||8 (25.0) 24|
|Rhinitis||–||1 (3.0) 1||1 (3.1) 1|
|Flushing||1 (3.1) 3||–||–|
There was a dose–response relationship with highest frequency of AEs in dose group 2. However, no subjects from this dose group withdrew from the study because of AEs. It is therefore assumed that the occurrence and severity of local allergic reactions in the mouth is acceptable to the children. One child in dose group 1 withdrew from the study because of abdominal pain, related to treatment.
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- Materials and methods
We performed a double-blind, placebo-controlled study of clinical efficacy and safety of SLIT with tree pollen extract in children suffering from tree pollen-induced rhinoconjunctivitis in Finland where tree pollen is the most common cause of allergic rhinoconjunctivitis. Our study is one of the largest SLIT studies ever performed among children and in addition to the double-blind placebo-controlled setting, the possible dose–response relationship of SLIT was also evaluated. In this study, we demonstrated that SLIT with a tree pollen extract, when compared with placebo, reduced allergic symptoms during the tree pollen season in tree pollen allergic children suffering from rhinoconjunctivitis with or without seasonal asthma. For dose group 2, this reduction was statistically significant (P = 0.01). Moreover, the comparison between dose group 2 and placebo during the birch pollen season showed a reduction in the asthma and hay fever medication (P = 0.04). No serious AEs with relationship to the study drug occurred during the study and no AEs represented a previously unsuspected important adverse effect of the study drug.
Therefore, this study demonstrated that SLIT is safe to use in children with tree pollen allergy. SLIT may cause local allergic reactions in the mouth. However, the severity and occurrence is acceptable to the children as no children stopped treatment because of the most frequently reported AE related to treatment.
The use of allergen-specific immunotherapy by the sublingual route, SLIT, has been increasing in clinical practice. This is due to the user-friendliness, its ease of administration and documented safety (30, 31). Clinical safety of SLIT has been analysed in two systematic reviews. The systematic review of the efficacy of SLIT in allergic rhinitis (32) shows that SLIT is a safe treatment which significantly reduces symptoms and medication requirements in allergic rhinitis in the adult population; but these results could not be confirmed in the paediatric group. A systematic review on the efficacy of SLIT in allergic asthma and rhinoconjunctivitis in children (33) showed that SLIT can be currently considered to have low to moderate clinical efficacy in children of at least 4 years of age, monosensitized to house dust mite, and suffering from mild to moderate persistent asthma.
No statistically significant differences in MBPT, CPT and LPSR were found. The systemic effect of SLIT is inducing the clinical efficacy, i.e. to decrease symptom and medication scores, even though we could not show any significant changes in the objective target organ, provocation test in the eye or in the non-specific bronchial hyperreactivity in these children. In LPSR, there was no change during the course of therapy in any of the groups. However, in a subpopulation of this study population, randomly chosen for an immunological study (34), it was observed that reduction in LPSR was associated with downregulation of IL-5 mRNA expression and absence of asthma symptoms 5 years later.
The WHO guidelines (1) recommend high-dose SLIT and that the dose level should be at least 50 times the dosage used for subcutaneous allergen injection immunotherapy. This is based on the assumption that allergen extracts from different sources and different manufacturers are comparable; however, this is not the case. Because of the heterogeneity of allergens used, in the selection of patients, in the maintenance doses and in the time course of treatment, it is rather impossible to draw general conclusions on immunotherapy from studies performed with a single specific product and on therapies with different routes or methods of administration. In the future different immunotherapy products have to be proved to be effective and safe in individual clinical studies.
Overall, it is concluded from our study that SLIT with a SQ-standardised allergen extract of a mixture of the three most important tree pollen species, birch, alder and hazel, reduces allergic symptoms during the tree pollen season in tree pollen-allergic children. The treatment is well tolerated and useful for self-administration. The treatment outcome is dose-dependent with a more pronounced effect on reduction in symptoms and need for symptomatic medication in the highest dose tested.