Untitled

ß-Glucuronidase Immunotherapy in Dust Mite Allergic Children A Double-Blind Randomized Placebo-
Controlled Trial With Short-Term
ß-Glucuronidase Therapy in Children
With Chronic Rhinoconjunctivitis
and/or Asthma Due to Dust Mite
E Galli,1 MS Bassi,2 E Mora,3 M Martelli,4 S Gianni,1 G Auricchio,1 1 Research Center San Pietro, Fatebenefratelli Hospital, AfaR, Rome, Italy 4Santa Maria Bianca Hospital, Mirandola, Italy 5Department of Pediatrics, Tor Vergata University, Rome, Italy Abstract. Background: Enzyme potentiated desensitization, in which ß-glucuronidase (BG) is administered
with low doses of mixed allergens, was proposed in the 1970s for specifi c immunotherapy. The BG currently
commercially available in a purifi ed and standardized preparation devoid of any allergen has been suggested as a
regulator in the allergic immune response, acting on the cytokine-network of type 2 helper T cells. A double-blind
trial with a single-dose of BG proved effective in preventing symptoms in adult patients with rhinoconjunctivitis
due to grass pollens.
Objective: The aim of this randomized double-blind placebo-controlled trial was to confi rm the safety and
effectiveness of double-dose intradermal BG immunotherapy in preventing symptoms in children suffering from
chronic rhinoconjunctivitis and/or asthma due to dust mite.
Method: We randomized 125 children with dust-mite related chronic rhinoconjunctivitis and/or asthma to the BG
treated group (67) or the placebo group (58). All patients were screened before treatment (T0), at BG or placebo
administration (T1 and T3), and at 3 and 9 months after T1 (T2 and T4). Drug intake and bronchial, nasal and
ocular symptoms were recorded in a diary.
Results: Patients in both groups completed the study and BG treatment was well tolerated without side effects.
Signifi cant differences in symptoms were observed, in particular for conjunctivitis (P = .008). The total drug intake
for allergic symptoms was signifi cantly lower in the treated group than in the placebo group (P < .01).
Conclusions: BG immunotherapy is effi cacious, safe, and well tolerated in allergic children. Moreover, good
compliance with the administration of 2 doses per year and the lack of signifi cant side effects makes the benefi t/risk
ratio of this treatment particularly favorable.
Key words: ß-glucuronidase. Immunotherapy. Children. Allergic diseases.
J Investig Allergol Clin Immunol 2006; Vol. 16(6): 345-350 Resumen. Antecedentes: La desensibilización potenciada con enzimas, en que se administra ß-glucuronidasa (BG)
con dosis bajas de alérgenos mixtos, se propuso en 1970 como inmunoterapia específi ca. Se ha sugerido que la
BG disponible comercialmente en una preparación estandarizada y purifi cada, sin ningún alérgeno, funciona como
reguladora de la respuesta inmunitaria alérgica, actuando sobre la red de citocinas de los linfocitos T cooperadores
del tipo 2. En un estudio de doble ciego con una sola dosis de BG, se demostró la efectividad de esta enzima para
prevenir los síntomas de rinoconjuntivitis debida a pólenes de gramíneas en pacientes adultos.
Objetivo: El objetivo de este estudio aleatorizado controlado con placebo y doble ciego fue confi rmar la seguridad
y efi cacia de una doble dosis de inmunoterapia con la administración de BG intradérmica para la prevención de
los síntomas en niños que padecían rinoconjuntivitis crónica o asma debido al ácaro del polvo.
Métodos: Aleatorizamos a 125 niños con rinoconjuntivitis o asma relacionadas con el ácaro del polvo en un
grupo tratado con BG (67) o en un grupo con placebo (58). Se realizó el cribado de todos los pacientes antes del
tratamiento (T0), al administrar la BG o el placebo (T1 y T3), y tres y nueve meses después de la fase T1 (T2 y
T4). Se registró en un diario la toma de fármacos, y los síntomas bronquiales, nasales y oculares.
Resultados: Los pacientes de ambos grupos completaron el estudio y el tratamiento con BG se toleró bien y sin
efectos secundarios. Se observaron diferencias signifi cativas en los síntomas, en particular de la conjuntivitis
(P = 0,008). La toma total de fármacos para controlar los síntomas alérgicos fue signifi cativamente menor entre
los sujetos del grupo al que se administró tratamiento activo comparado con el grupo al que se administró un
placebo (P < 0,01).
Conclusiones: La inmunoterapia con BG es efi caz, segura y bien tolerada por los niños alérgicos. Lo que es más,
el cumplimiento de la administración de dos dosis al año y la ausencia de efectos secundarios importantes hace
que la relación benefi cio-riesgo de este tratamiento sea especialmente favorable.
Palabras clave: ß-glucuronidasa. Inmunoterapia. Niños. Enfermedades alérgicas.
Introduction
The aim of this double-blind randomized trial was to confi rm the safety and the effectiveness of immunotherapy In the last two decades, allergen specifi c immunotherapy with a double dose of BG in preventing symptoms in by subcutaneous administration of the allergen has children suffering from chronic rhinoconjunctivitis and/or gradually fallen out of favor, particularly because of limited compliance and risk of rare but life-threatening anaphylactic reactions [1-4]. For this reason, local (noninjected) means for administering immunotherapy Patients and Methods
have been proposed and developed. The main one is sublingual immunotherapy [5-8]. Several double-blind Study Design
controlled trials have indicated that such therapy is safe and clinically effective for some allergens in both pediatric and The protocol for this randomized controlled trial was adult patients [9, 10]. In particular, childrenʼs compliance approved by the ethics committee of San Pietro Hospital with sublingual immunotherapy is an important positive Fatebenefratelli. It was carried out in accordance with aspect of this therapy. However, it is expensive and needs to good clinical practice, and informed consent was obtained be continued for several years with daily administration.
from all patientsʼ parents. The children were enrolled in Immunotherapy with enzyme-potentiated desensitization, September and October 2004 and randomly assigned to in which ß-glucuronidase (BG) is injected with low doses either the BG group or the placebo group. All patients were of a mixture of allergens, was proposed in the 1970s seen before treatment (T0), when BG immunotherapy or and has been demonstrated to be safe and effective placebo were injected (T1, October, and T3, February, in rhinoconjunctivitis, asthma, and food hyperkinetic before the peak of the dust mite season), and at 3 and 9 syndrome [11-14], although some authors have obtained months following T1 (T2, January and T4, June). During opposite results [15]. Nowadays BG is commercially clinical follow-up patients were allowed to use oral available for intradermal administration in purifi ed and antihistamines (cetirizine), topical steroids (fl uticasone) standardized preparations devoid of any allergen. It has and ß -agonists for symptoms control. Each day, patients been suggested that BG might play a role in the immune fi lled in a diary recording symptoms and drug intake response to allergy by redirecting the cytokine network of throughout the study (September 2004 – June 2005). At T1 type 2 helper T cells; specifi cally, its immunological effects and T4 peripheral blood was collected from patients for the involve the differentiation and maturation of dendritic immunological study and prick tests were performed.
cells, thus modifying the response of the immune system to subsequent allergen exposure [16]. A double-blind trial in which a single-dose of BG was used demonstrated the Patients
effectiveness of the treatment to prevent symptoms in adults with rhinoconjunctivitis due to grass pollen [17].
One hundred twenty-five children with dust-mite J Investig Allergol Clin Immunol 2006; Vol. 16(6): 345-350 ß-Glucuronidase Immunotherapy in Dust Mite Allergic Children allergy (to Dermatophagoides pteronyssinus and/or Diary Card
Dermatophagoides farinae), chronic rhinoconjunctivitis, and/or asthma were randomly assigned to the BG treated At enrollment (September – October) and during group (67 children: 37 male and 30 female; mean ± SD the follow-up (until June 2005), patients recorded their age, 10.5 ± 3.9 years), or to the placebo group (58 children: bronchial, nasal and ocular symptoms every day. Nasal 31 male and 27 female; age, 11.2 ± 2.7 years) (table). The symptoms included rhinorrhea, nasal itching, nasal inclusion criteria were based on a) personal history of obstruction, and sneezing. Ocular symptoms were tearing, allergic rhinoconjunctivitis and/or asthma lasting at least 2 itching, and redness. Bronchial symptoms were cough, years; b) positive prick tests to one of the dust mite extracts wheezing, and shortness of breath. Patientsʼ diary data prepared as hydroglyceral solutions, titrated at 20 000 were used to calculate a mean score (0, none; 1, mild; 2, Bodansky units per milliliter (SARM Allergeni, Guidonia, moderate; 3, severe) for each symptom for each month Rome, Italy), assessed according to usual practice [18] of follow-up. Drug intake was recorded daily and a (allergens eliciting a wheal diameter at least 3 mm greater mean score for each month was calculated on the basis than the negative control were considered positive); and of the assumption or not of allowed drugs, whether c) positive ADVIA Centaur immunoassay system (Bayer oral antihistamines (cetirizine), topical preparations Diagnostic, Tarrytown, New York, USA) to one of the dust (fl uticasone) or ß -agonists. Patientsʼ subjective evaluation of the disease was assessed on a visual analogue scale.
Exclusion criteria were a) a previous report of clinical allergy to shellfi sh, b) specifi c immunotherapy treatment within the previous 3 years, and c) presence of other Adverse Event Recording
Any local or systemic symptom occurring within 4 hours after BG treatment was recorded under supervision Immunotherapy
and documented at the study site. Small areas of temporary local erythema and a brief stinging sensation after injection The BG preparation (kindly supplied by SARM) were considered normal. Patients were asked to report any consisted of 100 µg of BG derived from the shellfi sh delayed (within 48 hours) local or generalized symptoms.
Haliotis species and purifi ed by column chromatography (Seravac Ltd, Johannesburg, South Africa), in a total volume of 0.05 mL of buffered saline solution. Placebo Statistical Analysis
consisted of 0.05 mL of buffered saline solution packed Intragroup evolution was analyzed by using the identically to the BG preparations. BG and placebo were Wilcoxon or Friedman tests. The intergroup comparison twice administered intradermally, the fi rst time in October was performed with the Mann – Whitney test. Two- (T1) and the second time in February (T3), before the peak sided tests were used and P values of less than .05 were * Data are presented as mean ± SD for specifi c IgE and total IgE. M indicates male; F, female, SPT, skin prick test.
J Investig Allergol Clin Immunol 2006; Vol. 16(6): 345-350 Results of the comparison of duration of therapy and Patients in both treated and placebo groups completed symptom scores in the BG- and placebo-treated groups the study. Demographic features were comparable between are depicted in the figure. We found that in patients the groups and no signifi cant differences were found in with conjunctivitis, the BG treatment was signifi cantly age, sex, or sensitization to other allergens (table). BG associated with both a shorter period of pharmacological treatment was well tolerated overall and there were no treatment (part A of the fi gure) and a better symptom score (part B of the fi gure) (P = .032 and P = .008, respectively). Duration, Additional Therapy
Symptoms Improvement
f Treatment
Conjunctivitis
f Treatment
f Treatment
Rhinitis
Analysis of additional therapy duration and symptoms improvement in children with conjunctivitis, asthma and/or rhinitis and intradermally treated twice with a 100 µg of ß-Glucuronidase (BG) preparation or placebo (Pb). Administrations were performed in October and March, and analysis was carried out by comparing the improvements during the periods between the fi rst and second dose injections (1D-2D) and between the second dose injection and the follow-up analysis (2D-FU).
J Investig Allergol Clin Immunol 2006; Vol. 16(6): 345-350 ß-Glucuronidase Immunotherapy in Dust Mite Allergic Children Moreover, such effects were evident from the time of only apparently a contradiction. In fact, during the fi rst the fi rst injection and stable after the second one. In period (after the fi rst injection) children were taking particular, we observed clinically signifi cant results of additional drugs, and that is probably why the first pharmacological treatment, since no additional therapy symptoms report was positive. Therefore, children stopped was needed by conjunctivitis-affected BG-treated children taking more drugs, but this caused symptoms to exacerbate (P = .802). On the other hand, none of the analyzed as observed at the second time-point. Thus, it appears that parameters improved for children with asthma (P = .174) at the transient symptoms improvement observed in rhinitis- the end of the therapy (parts C and D of the fi gure), except affected children was due to additional drug intake. for a transient symptom improvement observed after the The good compliance with treatment with a single fi rst BG injection. We observed an intermediate situation double-dose administration, the lack of signifi cant side in patients with rhinitis. The transient improvement with effects and the lower cost in comparison with subcutaneous BG treatment (part F of the fi gure) vanished after the end and sublingual immunotherapy makes the benefi t/risk ratio of treatment (P = .156). On the other hand, pharmacological of this therapy particularly favorable.
treatment duration was greatly decreased by the therapy In conclusion, this study shows that double-dose BG (P = .036), although a second administration was required immunotherapy is safe, well tolerated, and effi cacious in to achieve that effect (part E of the fi gure).
the treatment of allergic children, especially those affected On the whole, total drug consumption during the by conjunctivitis. Future studies should address the long- entire follow-up period was signifi cantly lower in the term effects of this new modality of immunotherapy and treated group than in the placebo group (P < .01), and the compare it with conventional immunotherapy.
holistic evaluation of the treatment by parents of BG group children revealed clear improvement in 74.6% of cases. Only 4.55% reported worsening. Acknowledgments
We thank Dr Luigi Pappagallo for data processing and Discussion
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J Investig Allergol Clin Immunol 2006; Vol. 16(6): 345-350

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