Grass pollen specific sublingual/swallow immunotherapy in children: open-controlled comparison smong different treatment protocols
V. Di Rienzo*, P. Puccinelli**, F. Frati*** and S. Parmiani**
Clinica Villa Benedetta. Rome. Italy. *Clinica Villa Benedetta. Rome. Italy. **ALK-Abellò S.p.A. Milan. Italy. ***Unità Sanitaria n.º 8. Toscana. Arezzo. Italy.
Correspondence:
Silvano Parmiani
ALK-ABELLO'' S.p.A
Via Falzarego, 8
20021 Bollate (Milan)
Italy
e-mail: silvano_parmiani@allergia.it
SUMMARY
Background: sublingual-swallow immunotherapy has been recognized as safe and effective in adults. Different treatment schedules have been proposed and used, but the current experience in children is insufficient. We carried out a study to evaluate the clinical efficacy and the safety in children allergic to grass pollen, following different schedules.
Methods: an open study was performed with 3 parallel treated groups and a control group, each including 12 children suffering from rhinoconjunctivitis due to grass pollen. The patients underwent either a preseasonal treatment or a pre-coseasonal treatment during the grass pollen season. The analysis of the clinical outcome was based on the number of days with symptoms and/or drug consumption in the pollen peak month.
Results: significantly less days with symptoms and/or drug intake in all of the groups submitted to SLIT in comparison to the control group were found (p < 0.0001). Among the three schedules used, the best clinical results were obtained with the two pre-coseasonal treatments (p < 0.0001), with a preference for the schedule with the lowest maintenance dose according to the drug intake (p = 0.0267). Two patients belonging to the coseasonal schedule with the highest maintenance dose interrupted the treatment because of systemic mild side effects.
Conclusions: our data suggests that in children with rhinoconjunctivitis to grass pollen, SLIT is effective and well tolerated and that the pre-coseasonal schedule should be preferred to the preseasonal treatment. According to our data, the best maintenance dose during the pollen season for children, both for tolerance and clinical outcome, corresponds to 0.4 µg of the grass major allergen Group 5 administered three times a week.
Key words: Sublingual immunotherapy. Children. Allergy to grass. Preseasonal treatment. Coseasonal treatment.
RESUMEN
Introducción: la inmunoterapia vía sublingual ha sido reconocida como un tratamiento efectivo y seguro en adultos. Se han propuesto y usado diferentes pautas de tratamiento, pero la actual experiencia en niños no es suficiente. Se realizó un estudio para evaluar la eficacia clínica y la seguridad en los niños alérgicos al polen de gramíneas, siguiendo diferentes pautas de tratamiento.
Métodos: se llevó a cabo un estudio abierto con tres grupos paralelos tratados y un grupo control, incluyendo en cada grupo 12 niños con rinoconjuntivitis por polen de gramíneas. Los pacientes siguieron un tratamiento preestacional o un tratamiento precoestacional durante la polinización. El análisis de los resultados clínicos se basó en el número de días con sintomatología y/o consumo de medicación en el mes máxima polinización.
Resultados: el número de días con sintomatología y/o consumo de medicación fue significativamente menor en los grupos tratados con SLIT en comparación con el grupo control (p < 0,0001). De las tres pautas usadas, los mejores resultados clínicos se obtuvieron con los dos tratamientos precoestacionales (p < 0,0001), con predilección por la pauta con la dosis de mantenimiento más baja de acuerdo con la ingesta de fármacos (p = 0,0267). Se interrumpió el tratamiento en dos pacientes del grupo de pauta coestacional con la dosis más alta de mantenimiento debido a efectos adversos sistémicos leves.
Conclusiones: nuestros datos sugieren que en los niños con rinoconjuntivitis por polen de gramíneas, SLIT es eficaz y bien tolerada y que la pauta precoestacional debería ser de elección frente al tratamiento preestacional. De acuerdo con nuestros datos, la mejor dosis de mantenimiento durante la época de polinización para los niños, tanto por la tolerancia como por el resultado clínico, se corresponde con 0,4 µg de alergeno mayoritario de gramíneas Grupo 5 administrado tres veces por semana.
Palabras clave: Inmunoterapia sublingual. Niños. Alergia a gramíneas. Tratamiento preestacional. Tratamiento coestacional.
INTRODUCTION
For the last ten years, as a contribution to the search for a safer and simpler alternative to the well-known injective immunotherapy for respiratory allergic diseases, many studies on sublingual/swallow specific immunotherapy (SLIT) have been conducted. The scientific evidence coming from studies adequately conducted and published (1-6) has resulted in the recent WHO Position Paper (7) and the EAACI Position Paper (8), where it is stated that SLIT is an effective and safe treatment for respiratory allergic diseases in adults for allergens as grass, parietaria and mites. Moreover, SLIT was shown to be very well tolerated in adults by a large post-marketing surveillance study including more than five hundred patients (9).
As far as seasonal allergens are concerned, different schedules have been used in the published studies. In some of them a preseasonal treatment was used (10), in other studies a preseasonal treatment with daily administrations was followed by a coseasonal treatment with a reduced dosage (3, 11, 12). In some other studies the induction phase was performed with one or two administrations per day, followed by a maintenance without dosage reduction during the pollen season (4, 13-15). In all cases, a positive outcome was reported from the clinical point of view. For the injective immunotherapy, a reduction of the maintenance dose is normally recommended during the pollen season to avoid side effects or to avoid a worsening of the allergic symptoms due to the high allergenic load. With SLIT this precaution seems to be not needed, as the tolerance reported in the different trials is apparently not influenced by the schedule followed during the season.
As few studies are available with SLIT in children, we planned our study to assess the efficacy and tolerability of this therapy conducted according to different schedules with standardized grass allergenic extracts, according to an open-controlled parallel design.
MATERIAL AND METHODS
Patients
We selected for this trial 48 children (28M, 20F) aged between 5 and 12 years, according to the following criteria:
skin prick test positive to grass pollen extract (wheal at least corresponding to the wheal obtained with histamine 10 mg/ml);
no other clinically relevant sensitization to inhalant allergens;
specific IgE to grass pollen allergens, at least class 3;
a clinical history of rhinoconjunctivitis without asthmatic symptoms reported for at least the two previous years between the middle of April and the middle of June (peak period for grass pollination in Central Italy);
no clinical symptoms of asthma and/or oculorhinitis of allergic nature outside the grass pollen season;
no previous specific immunotherapy for any allergen.
Prick test
The prick tests were performed with a grass mix extract (Phleum pratense, Lolium perenne, Dactylis glomerata, Poa pratensis, Festuca pratensis), biologically standardized and with a concentration of the major allergen (Group 5 of grasses) on average corresponding to 10 µg/mL (16).
According to the supplier''s method (ALK-Abellò, Milan, Italy), a prick test with a potency of 100 Biological Units/mL is able to induce, on average in sensitive patients, a wheal of about 75 mm2 (17).
Study design
The study was designed as an open-controlled parallel group trial.
Thirty-six patients were selected before December 1996 and divided into three homogeneous groups (group A, B, C) as far as age, type and importance of symptoms were concerned. Each group was submitted to allergen specific immunotherapy according to a different schedule (Fig. 1).
Figure 1.--Study design.
All patients under observation, including the control group D, were allowed to use systemic antiallergic drugs on need during the season.
* Group A: the treatment was started at the beginning of January reaching the top dose (7 drops from vial 4, i.e. 0.7 µg of the major allergen Group 5) in 32 days. This dose was then taken three times a week until mid April, which was assumed to be before the beginning of pollination, and followed by a coseasonal treatment with 3 drops from vial 4 (i.e. 0.3 µg of the major allergen group 5). The treatment was administered three times a week until mid June, when the pollination period was assumed to end. According to this schedule, the amount of the grass major allergen Group 5 administered was around 33 µg.
* Group B: these 12 patients followed the same initial schedule, but were administered 4 drops daily from vial 4 (0.4 µg of the major allergen Group 5) from mid april to mid June. In this case, the amount of the grass major allergen Group 5 administered was around 96 µg.
* Group C: in this case, the patients followed a preseasonal treatment schedule, starting the treatment in October. The top dose (5 drops from vial 4, i.e. 0.5 µg of the major allergen Group 5) was administered three times a week only until mid April, when the administration was interrupted. This schedule corresponds to the administration of around 38 µg of the grass major allergen Group 5.
* Group D: 12 patients, who were examined for respiratory grass allergic symptoms just before the pollen season and therefore too late to be included in any of the groups before, were considered as control group.
Treatment
Patients under active therapy were treated with a commercially available SLIT preparation containing the grass pollen allergenic extract (Phleum pratense, Lolium perenne, Dactylis glomerata, Poa pratensis, Festuca pratensis), in glycerinated (50% V/V) and phenolated (0.3% W/V) physiological saline. The most concentrated vial of the therapy (vial 4) had a concentration of 25 Biological Units, corresponding to 2.5 µg/mL of the major allergen Group 5 of grasses. The other four vials were serial dilution of 1:5.
SLIT was administered in the morning on an empty stomach, keeping the allergen under the tongue for at least two minutes and then swallowing it. Breakfast was allowed 20 minutes after. SLIT was started from the vial with the lowest concentration (vial 0, 0.04 BU/mL) and the first doses were 1, 2, 3, 4 and 5 drops each administered for two consecutive days.
After this phase, drops had to be taken daily starting from one drop of the second vial and increasing by one drop every day up to 5 drops of the same vial and then repeating the procedure with the subsequent vials.
The top dose of 5 or 7 drops from vial 4 was reached after 30-32 days.
Rescue drugs
All patients were allowed to use systemic antihistamines (cetyrizine, 10 mg tablets or loratadine, 10 mg tablets) and/or corticosteroids (deflazacort, 6 mg tablets or betamethasone, 6 mg tablets) to control their symptoms. Topical drugs were avoided as it would have been difficult to check and quantify their consumption especially if used at need.
Parameters
To assess the efficacy of the treatment, patients (their parents) were asked to fill in every day cards registering the number of days they had oculorhinitis symptoms and had used the prescribed drugs.
Only the days of peak pollination, from May 1st to May 31st, when the symptoms were very evident, were taken into consideration.
Patients were also asked to report every side effect during both the initial and the maintenance phase.
Statistical analysis
The statistical analysis was performed through the variance analysis.
In the first step, we considered each of the four groups as independent, but a further analysis was also carried out considering the data from group A and B together. The two treatment protocols can be considered very similar (both are coseasonal treatments, in comparison to group C, preseasonal treatment), the difference being in the amount and frequency of administration of the top dose used for maintenance during the pollen season: 0.3 µg of the major allergen Group 5 three times a week for group A and 0.4 µg of the major allergen Group 5 every day for group B.
All the statistical analysis have been performed with the BMDP statistical software (BMDP Inc., Los Angeles, USA).
RESULTS
Clinical outcome
All groups treated with SLIT (A, B and C) showed a lower number of days with symptoms in comparison to the control group D, and this difference turned out to be statistically highly significant (p < 0.0001). Among treated groups, patients under preseasonal therapy (group C) had a higher number of days with symptoms (p < 0.0001) in comparison to patients under pre-coseasonal therapy (group A and B), while no statistically significant difference between group A and B could be shown (Fig. 2).
Figure 2.--Days with symptoms during the peak pollination month. For each patient (full circle) of each group A, B, C and D, the total days with symptoms are given with reference to the scale of the left. The average value for each group is given in brackets.
The variance analysis for days with drug consumption (antihistamines only or antihistamines plus corticosteroids) was highly significant as well (p < 0.0001) and patients belonging to the control group D used more drugs than patients in treated groups A, B and C (p < 0.0001).
Among treated patients, group A and group B used less drugs than group C (p < 0.0001), while the comparison between groups A and B showed a statistically significant difference (p = 0.0267) in favor of group A (Fig. 3).
Figure 3.--Days with drug consumption during the peak pollination month. The days with drug consumption for patients belonging to group A, B, C and D, are given, with reference to the scale of the left, separately for antihistamines (full circle *) and for corticosteroids (empty circle * ). The averagse value for each group is given in brackets.
Considering all patients submitted to the pre-coseasonal treatment together (group A and B), there was a significant favourable difference in comparison to group C (preseasonal treatment) and to the control group D, as regards both symptoms and consumption of drugs. The result is statistically significant for all comparisons (A + B vs C; A + B vs D; C vs D: p < 0.0001).
From a quantitative point of view, the two pre-coseasonal groups A and B showed on average a 52% reduction of the number of days with symptoms and a reduction around 64% in days with consumption of drugs, in both cases in comparison with the control group D.
Side effects
During the maintenance in group B, the treatment was interrupted in two cases due to the appearance of a cutaneous erythematous reaction in the submandibular area, slight edema of the eyelids and worsening of the oculorhinitis symptoms.
No side effects were reported during the induction phase or during the maintenance in all other patients.
DISCUSSION
Only one clinical study with a pre-coseasonal schedule in children allergic to olive pollen has been published up to now (15), while a few studies have been conducted with mite extracts according to a perennial schedule (1, 5, 18, 19).
In all of these studies but one (5) a good clinical outcome was reached both for rhinoconjunctivitis and asthma.
The analysis of our data shows that SLIT for grass allergens is well tolerated in children and is able to induce a clinical improvement significantly reducing days with symptoms and drug consumption in comparison to the control group. The improvements were obtained with all of the schedules followed, but the two precoseasonal treatments schedules proved more effective than the preseasonal treatment. This result is quite surprising, because the preseasonal schedule involves a longer treatment period and a slightly higher cumulative dosage, at least in comparison to group A: around 195 days of treatment for group C, compared with around 165 days for groups A and B; 38 µg of the grass major allergen for the preseasonal therapy C, 33 µg and 96 µg respectively for the two pre-coseasonal schedules A and B.
The dosages used in our trial were respectively 5 times higher (for group A and C) and 15 times higher (group B) than the dosage administered with the classical injective therapy of the same producer in a pre-cosseasonal treatment.
According to our data, it is not important to begin the therapy very early before the pollen season, but the key point for the best results with SLIT seems to be the administration of the treatment during the pollen season.
Furthermore, the schedule with the lowest coseasonal dosage seems to be better tolerated in children (no side effects with the schedule A) and as effective as the highest coseasonal dosage schedule when the parameter days with symptoms is considered, or better when the drug consumption parameter is considered.
In our experience, SLIT has a very high compliance in children with pollen rhinoconjunctivitis: this is not surprising, considering that this therapy can be started very near to the pollen season, the top dose is reached in one month, the administration is self-managed, the therapy can be interrupted after the pollen season and the clinical benefit is already reached in the first season.
Traditional symptomatic drugs commonly used in adults, should be associated to specific immunotherapy in allergic children because it has been shown that allergy vaccines in children can prevent further evolution of the disease (20) and avoid new sensitizations (21).
It has also been shown that with SLIT there is no risk of anaphylactic shock due to a too rapid absorption of the allergen extract, because there is no absorption but a prolonged contact of the allergen with the oral mucosa after the administration (22). The experimental evidence seems to indicate the involvement of an oral tolerance mechanism (23). This view is in keeping with our data, since the best results obtained prolonging the administration of the allergen until the end of the pollen season could be explained by the induction and maintenance of the oral tolerance to the allergen.
All together this data agrees with what occurs in food allergy where the patient in time is able to clinically tolerate various foods although positive IgE values persist (24).
There is no doubt that further studies are needed to elucidate and understand the real mechanism but the evidence available up to the present shows that the SLIT treatment is clinically effective (7) and can affect the allergic inflammation relieving symptoms and decreasing drug consumption (25), even if significant variations of IgE and IgG seem to occur only when the therapy lasts for more than 18 months (3, 12, 13, 26).
CONCLUSIONS
According to our data and to the available clinical evidence, SLIT in allergic children with respiratory symptoms is a valid alternative to the traditional subcutaneous immunotherapy because of its high compliance, the good tolerance, the early clinical results, as well as the low direct and indirect costs of the treatment.
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