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
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 . 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 . A double-blind trial in which a single-dose of BG was used demonstrated the
effectiveness of the treatment to prevent symptoms in adults with rhinoconjunctivitis due to grass pollen .
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/orDiary 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 
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
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
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.
We thank Dr Luigi Pappagallo for data processing and
Allergen avoidance and specifi c immunotherapy are
currently the only means of changing the course of allergic
diseases by affecting their natural history or progression. A variety of approaches are being used in the attempt
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Why does my doctor call this treatment Photopheresis is called other names like photoimmunetherapy or extracorporeal photoimmune therapy orECP. These refer to the same treatment. Will my health insurance pay for this? Medicare has approved photopheresis forreimbursement whether you are an inpatient oroutpatient where the treatment is medically necessaryand reasonable. A number of insurance
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