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- Material and methods
Background: We assessed the efficacy of preseasonal local allergoid immunotherapy in a group of children with asthma and/or rhinitis and/or rhinoconjunctivitis due to grass pollen.
Methods: We randomly assigned 24 children allergic to grass pollen to receivelocal allergoid immunotherapy for 3 months before the pollen season and 24 such patients to receive identically appearing placebo. The immunotherapy consisted of tablets of monomeric allergoid grass pollen allergens held in the mouth until they dissolved and then swallowed. The study was double-blind. Symptoms and medications were scored on diary cards during the pollen season. Nasal eosinophil cationic protein levels were measured by the monoclonal antibodies EG1 and EG2 outside the pollen season and at low and at high pollen concentration during the pollen season.
Results: The active-treatment group had a statistically significant reduction of total symptoms (P<0.05), especially bronchial symptoms (P<0.05), in comparison with the placebo group. Immunotherapy was well tolerated and compliance was good. Nasal levels of EG2 and EG1 increased significantly during the pollen season, but there was no difference between groups. EG2/EG1 increased significantly only in the placebo group during natural allergen exposure (P<0.01).
Conclusions: Our results suggest that this immunotherapy is effective for the treatment of asthma due to grass pollen in children.
Subcutaneous specific immunotherapy is considered to be effective for allergic diseases ( 1). However, injection immunotherapy may be inconvenient and, in rare cases, causes severe systemic reactions ( 1). With a view to improving the safety and acceptability of treatment, renewed interest is being shown in noninjected allergenic extracts, such as the oral and sublingual routes. Both the WHO ( 2) and the EAACI-ESPACI Working Group on Local Immunotherapy ( 3) have stated that there is evidence of the clinical efficacy of sublingual-swallow immunotherapy (SLIT) ( 4–13), but not of oral or sublingual-split immunotherapy. SLIT and injective immunotherapy were equally effective in adults with grass pollen allergy ( 14). The EAACI-ESPACI position paper ( 3) did not recommend SLIT for normal clinical use in children, since only a few controlled clinical trials had evaluated the efficacy and the safety of SLIT in children. However, a post-marketing surveillance study has recently found that SLIT is safe in children ( 15).
Children can hardly keep the extracts under the tongue. There is a lack of data showing that the sublingual mucosa can absorb allergenic molecules better than other mucosal sites (dorsal surface of the tongue, labia, cheeks, and soft palate). In the present study, the immunotherapy dosage consisted of tablets of monomeric allergoid grass pollen allergens to be held in the mouth until they dissolved, after which the residue was swallowed (oromucosal-swallow immuno-therapy [OSI]) ( 16).
A reduction in both the cellular infiltration and the expression of intercellular adhesion molecule (ICAM-1) in the conjunctiva after allergen challenge was found after 1 year of SLIT ( 9). Furthermore, a reduction of neutrophils, eosinophils, and ICAM-1 expression after specific nasal challenge was detected after preseasonal SLIT with Parietaria ( 17).
Activation of eosinophils occurs during the pollen season. Nasal levels of eosinophil cationic protein (ECP) have been found to increase significantly during natural allergen exposure in patients allergic to pollen ( 18, 19). Moqbel et al. found that the anti-ECP monoclonal antibody EG2 recognized activated eosinophils and a minority of resting eosinophils while the anti-ECP monoclonal antibody EG1 recognized both activated and resting eosinophils ( 20). Therefore, the EG2/EG1 ratio is considered to be more reliable in identifying activated eosinophils.
We are not aware of studies on immunotherapy with grass pollen administered orally in children. Therefore, we performed a randomized, placebo-controlled study in children allergic to grass pollen to evaluate the clinical efficacy and the safety of local allergoid immunotherapy. We also determined nasal levels of ECP by monoclonal antibodies (EG1 and EG2) outside the pollen season and during the season in order to assess allergic inflammation.
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- Material and methods
Forty-four out of 48 patients (91.6%), all 24 in the active treatment group and 20 of 24 given placebo, completed the study and reached the cumulative dosage of 37 250AU. Four patients in the placebo group dropped out, three because they moved away, and one because of a mild side-effect (abdominal pain). Characteristics of the immunotherapy and placebo groups are listed in Table 1. There were no statistically significant differences between the two groups at entry into the study. Two 4-year-old children were included in the study. One child took placebo, and the other received active treatment.
Neither systemic nor local adverse reactions were observed during treatment. Compliance with treatment was very good for all patients.
Total symptom scores during the pollen season (as weekly mean) were lower in the treated group than with placebo, the difference being statistically significant (mean [SD] 9.5 [7.2] vs 14.5 [8.3]; P<0.05) ( Fig. 1). The scores related to each nasal, ocular, and bronchial symptom were lower in the treated group, but the difference was statistically significant only for bronchial symptoms (2.4 [2.7] vs 4.6 [3.5]; P<0.05) ( Fig. 1). Drug consumption scores (weekly mean) did not differ appreciably between the two groups ( Fig. 1).
Figure 1. Weekly mean (95% CI) of symptom and medication scores in immunotherapy and placebo groups during pollen season. Columns represent mean values. Differences between two groups for weekly mean total symptom score and weekly mean bronchial symptom score were significant (P<0.05).
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The symptom-medication scorein the immunotherapy group was lower than in the placebo group during the pollen season in all weeks. This difference was statistically significant at week 3 (P<0.05), week 7 (P<0.05), and week 8 (P<0.03) ( Fig. 2). Mean weekly grass-pollen counts for the period of exposure to grass pollen from the centers participating in the study are shown in Fig. 2. Because of the weekly pollen concentration, five of the weeks were considered to have a very high pollen concentration (average weekly pollen count more than 80 pollen grains per cubic meter), and four to have a high pollen concentration. The symptom-medication score for weeks with elevated pollen con-centration was significantly lower in the immunotherapy group than in the placebo group (10.1 [3.3] vs 16.84 [4.3]; P<0.03). There was no significant difference between actively treated and placebo patients for the symptom-medication score under moderate pollen exposure (8.75 [4.6] vs 11.5 [6.2]; P>0.05).
Figure 2. Mean (95% CI) symptom-medication scores and pollen counts in grass-pollen season. Significance of differences between immunotherapy and placebo groups: *P<0.05; **P<0.03.
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In the immunotherapy group, we found a significant increase during the pollen season for nasal levels of EG1 and EG2 ( Table 2). We observed a similar increase in the placebo group. Comparison of EG1 and EG2 levels showed no difference between the placebo and immuno-therapy groups ( Table 2).
Table 2. Median (range) and mean (standard deviation [SD]) values of nasal levels of EG1, EG2, and EG2/EG1 ratio in immunotherapy and placebo groups, at baseline, before starting immunotherapy treatment (January) (T0), at low pollen concentrations (T1) and at moderate pollen concentrations (T2)
| ||Median (range) Mean (SD) |
|EG1 (μg/l)||6.6 (0.5–7.5)||19.2 (2.1–105)**||17.5 (0.1-200)*|
| ||10.3 (9.7)||28.9 (29.6)||53.6 (74.7)|
|EG2 (μg/l)||0.1 (0.1–12.8)||3.6 (0.1–41)*||2.1 (0.1–97.2)*|
| ||1.9 (3.4)||8.7 (11.5)||12 (24.5)|
|EG2/EG1 (%)||14.7 (0.4–100)||20.8 (1.4–85.4)||22.7 (0.2–100)|
| ||19.0 (25)||28.0 (27)||31.6 (35)|
|EG1 (μg/l) ||6.9 (0.1–31)||11.6 (0.1–135)*||8.3 (0.1–200)|
| ||10.3 (9.8)||30 (39)||36.6 (59.5)|
|EG2 (μg/l)||0.1 (0.1–3.8)||2.3 (0.1-38.3)*||0.1 (0.1–200)*|
| ||0.8 (1.3)||5.7 (10.3)||16.0 (48)|
|EG2/EG1 (%)||4.0 (0.5–100)||10.0 (1.2–100)**||13.5 (0.3–100)|
| ||14.9 (29)||18.0 (23)||38.0 (41)|
The EG2/EG1 ratio showed a significant increase at low pollen concentrations in comparison with baseline (T0) in the placebo group ( Table 2). In the immunotherapy group, the EG2/EG1 ratio did not change in the pollen season ( Table 2); the between-groups comparison showed no difference.
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Our results show that OSI for grass pollen is effective in reducing respiratory symptoms, particularly asthma, after 3½ months' preseasonal treatment in children. However, the improvement in nasal and ocular symptoms did not reach statistical significance. The symptom-medication score was reduced in the immunotherapy group compared with the placebo group during the pollen season in all weeks. However, a significant reduction was reached only when patients were exposed to high levels of pollen. The latter observations may limit the clinical relevance of a short preseasonal course of OSI.
The efficacy of oral immunotherapy in double-blind, placebo-controlled studies has been recently reviewed ( 2). In 2/6 studies, there was evidence of clinical efficacy. Controlled trials with SLIT have shown its effectiveness in adults allergic to grass pollen with rhinitis ( 5, 7, 8) and asthma ( 8, 13). SLIT was associated with a clinically significant improvement in children with asthma due to mites ( 9) or olive pollen ( 12). Our trial differs from previous investi-gations because: 1) we studied children with grass-pollen hypersensitivity; 2) the allergenic product was an original formulation; 3) the allergenic product was applied to the oral cavity and then swallowed.
The oral-soluble tablets have advantages over conventional drops of aqueous extracts in that it is easier to define the dosage and harder to make mistakes, as in counting the drops.
The mechanisms through which sublingual or oral immunotherapy acts are unclear ( 25). Kinetic studies of radiolabeled allergens showed that allergens that are kept under the tongue and then swallowed stay in the oral mucosa for a long time, up to 18–20 h after swallowing ( 26). The ingested portion of the allergen is quickly absorbed in the gastrointestinal tract. This suggests that both mucosa-associated lymphoid tissue and gut absorption capacity are involved ( 27).
Animal studies showed that high sublingual allergen doses suppressed IgE production ( 28). Fanta et al. ( 29) showed a significant decrease of the proliferative response of peripheral blood lymphocytes to grass pollen after sublingual-split immunotherapy. More-over, a significant increase in the levels of serum specific IgG, IgG4, and IgE was observed ( 29). However, some studies found that SLIT did not affect serum specific IgE, IgG, and IgG4 or skin test reactions to grass pollen ( 13, 14). Oral immuno-therapy has been found to reduce specific IgE levels and enhance levels of IgG4 and IgG1 in children ( 30).
We determined nasal levels of ECP outside the pollen season and during natural pollen exposure in order to evaluate whether immunotherapy could modify eosinophil activity, which is a relevant part of allergic inflammation. Our results showed that nasal ECP significantly increased both in the placebo group and in actively treated patients during the pollen season. These findings agree with the results of an open study that showed a significant enhancement of ECP in nasal secretions during the pollen season in both drug-treated patients and in patients treated with injective immunotherapy ( 18).
The percentage of activated ECP is more reliably evaluated by the EG2/EG1 ratio, since the monoclonal antibodies EG1 and EG2 have been shown to detect, respectively, total and activated ECP ( 19). We found that the EG2/EG1 ratio significantly increased only in the placebo group during the pollen season. The augmentation of the EG2/EG1 ratio was greater in the placebo group than in the immunotherapy group under natural pollen exposure, even if this was not statistically significant. Taken together, these results may indicate a possible role of immunotherapy in decreasing eosinophil activation. This may be consistent with studies reporting a decrease of the cellular infiltrate of neutrophils and eosinophils and of ICAM-1 expression on epithelia after SLIT ( 10, 17). We found, however, that nasal levels of EG1 and EG2 were not associated with immunotherapy, suggesting that former observations may represent chance findings. Further studies comparing ECP with symptoms and pollen data throughout the grass-pollen season are warranted to clarify the interpretation of these parameters. These studies must also take into account the fact that different methods of sample preparation may influence the reactivity of EG1 and EG2 ( 31).
Systemic reactions to oral ( 2) and sublingual immunotherapy (5–9, 15), principally gastrointestinal symptoms, urticaria, rhinitis, and asthma, appear to be rare. Anaphylaxis never occurred. In this study, only one mild reaction was observed as a consequence of OSI.
The present study concludes that a preseasonal course of OSI with grass pollen allergens is more effective than placebo in the treatment of asthmatic symptoms in allergic children. However, our findings require further confirmation by investigating a greater number of children.