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- Publisher
- Hindawi Publishing Corporation
- Copyright
- Copyright © 2012 Alice Köhli-Wiesner et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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- 1687-9783
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- 10.1155/2012/790910
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Abstract
Hindawi Publishing Corporation Journal of Allergy Volume 2012, Article ID 790910, 5 pages doi:10.1155/2012/790910 Clinical Study Induction of Specific Immunotherapy with Hymenoptera Venoms Using Ultrarush Regimen in Children: Safety and Tolerance 1 1 1 Alice Kohli-W ¨ iesner, Lisbeth Stahlberger, Christian Bieli, 1 1, 2 Tamar Stricker, and Roger Lauener Christine Kuhne-C ¨ enter for Allergy Research and Education, University Children’s Hospital Zurich, Steinwiesstraße 75, 8032 Zurich, Switzerland Children’s Allergy and Asthma Hospital, Hochgebirgsklinik Davos, 7265 Davos, Switzerland Correspondence should be addressed to Alice Kohli-W ¨ iesner, alice.koehli@kispi.uzh.ch Received 14 April 2011; Accepted 16 June 2011 Academic Editor: Mary Beth Hogan Copyright © 2012 Alice Kohli-W ¨ iesner et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Background & Objective. Ultrarush induction for specific venom immunotherapy has been shown to be reliable and efficacious in adults. In this study its safety and tolerance in children was evaluated. Methods. Retrospective analysis of 102 ultrarush desensitizations carried out between 1997 and 2005 in 94 children, aged 4 to 15 years. Diagnosis and selection for immunotherapy were according to recommendations of the European Academy of Allergy and Clinical Immunology. Systemic adverse reactions (SARs) were described using the classification of H. L. Mueller. Results. All patients reached the cumulative dose of 111.1 µg hymenoptera venom within 210 minutes. Six patients (6%) had allergic reactions grade I; 2 patients (2%) grade II and 5 patients (5%) grade III. Three patients (3%) showed unclassified reactions. SARs did not occur in the 15 patients aged 4 to 8 years and they were significantly more frequent in girls (29%) compared with boys (12%) (P = 0.034, multivariant analysis) and in bee venom extract treated patients (20%) compared to those treated with wasp venom extract (8%) (OR 0.33, 95% Cl 0.07–1.25). Conclusion. Initiation of specific immunotherapy by ultrarush regimen is safe and well tolerated in children and should be considered for treating children with allergy to hymenoptera venom. 1. Introduction patients and 80% in bee venom allergic patients [4]. Different protocols have been published for the stepwise increase of the Hypersensitivity to hymenoptera venom affects approxi- dose of the insect venom during initiation of subcutaneous mately 1%–5% of the general population. In Switzerland the specific immunotherapy [5–9]: the conventional regime, prevalence is estimated to be 3.5% in the general population with injections using increasing doses every one to two weeks and 0.4%–0.8% in children aged 4 to 16 years. It is one of the over a period of 2 to 4 months, rush immunotherapy extend- three most common causes of immediate type anaphylactic ing over approximately 1 week and ultrarush protocols, in reactions, the other two major causes being drugs and foods which the maintenance dose is achieved in 1-2 days. The [1]. A field sting in a hymenoptera venom allergic patient latter has been shown to be effective and time-saving in can cause a spectrum of reactions ranging from severe local adults [5]. The aim of this retrospective study was to swelling to anaphylactic shock with circulatory collapse. Sev- investigate the safety and tolerance of ultrarush induction in eral cases of death are attributed to hymenoptera allergy desensitization in children. yearly, mostly in adults. A systemic grading of reactions to immunotherapy is Specific immunotherapy (SIT) is the only known causal necessary in order to evaluate the safety of the treatment treatment for venom-allergic patients [2, 3]. In subjects with and in order to compare various regimens [10]. In this study a history of generalized reactions to insect sting SIT results we chose to use a modified version of the classification of in up to 95% rate of protection in wasp venom allergic generalized allergic reactions introduced by H. L. Mueller in 2 Journal of Allergy 0.1 1 10 20 30 50 Dose (µg) 0 30 60 90 150 210 Minutes 30 30 30 60 60 Minutes interval Figure 1: Ultrarush induction regimen in desensitization with subcutaneous venom injections. 1966 [11]. This classification is presented in Table 2 for quick Figure 1. All patients were treated with a standardized pu- reference. rified venom preparation (ALK Pharmalgen, Trimedal) given in subcutaneous injections. The cumulative dose of 111.1 µg 2. Methods hymenoptera venom was reached after 210 minutes using at least 6 injections. In the case of side effects, the interval 2.1. Patients. Medical records of 94 children treated with the between the doses was extended. The patients were observed ultrarush induction regime in the intensive care unit of the in the intensive care unit with intravenous access, continu- University Children’s Hospital of Zurich between January ous measurements of the oxygen saturation, and repeated 1997 and December 2005 were analysed retrospectively; the measurements of the blood pressure. Three hours after the clinical data is summarized in Table 1. Indication for SIT was last injection the patients were discharged to home. Booster a combination of an immediate systemic allergic reaction injections were given later as follows: on day 7 two doses grade III or IV after a hymenoptera field sting and detection of 50 µg (ALK Pharmalgen, Trimedal) were given with an of specific IgE antibodies to the venom, as recommended interval of 30 minutes, and 3 and 7 weeks after the ultrar- by the European Academy of Allergy and Immunology Sub- ush procedure the patients received 100 µgofAlutard committee on insect venom allergy [4, 6]. Patients with less (Aluminiumhydroxid-depot-preparation, ALK) subcutane- severe reactions were included when the risk of exposure was ously. During the entire therapy the children did not receive very high, for example, when a wasp nest was in close prox- premedication with antihistamines. imity to the home, or when the fear from getting a sting If both wasp and bee venoms sensitizations were re- caused anxiety and a significant limitation in the quality of quired; they were administered in separate protocols a few life. days apart. The study population included 24 girls and 70 boys; 61 of the patients were allergic to bee venom, 33 to wasp-venom; 3. Results and 8 boys to both. These 8 boys were considered twice in the evaluation. The patients were divided into three groups Between January 1997 and December 2005 94 children, aged according to age: group A included 15 patients aged 4 to 8 4 to 15.1 years, including 70 males and 24 females, underwent years, in group B there were 60 subjects aged 8 to 12 years and induction of specific immunotherapy using ultrarush regime in group C 27 patients aged 12 to 15 years. The classification in the intensive or intermediate care unit of the University of generalized allergic reactions according to H. L. Mueller Children’s Hospital of Zurich. A total of 102 ultrarush which was used to define the adverse reactions is shown in immunotherapy induction procedures were performed, in Table 2. all of which the cumulative dose of 111.1 µgwas reached. 61 patients were treated with bee venom, 33 with wasp ven- 2.2. Tests. Sensitization was detected by skin prick tests with om, and 8 boys with both. Average duration of the procedure 10, 100, and 300 µg/mL purified insect venom extract (Phar- was3.5 hourswitharangeof2.5 to 5.5hours. malgen, ALK) and/or intradermal tests with 0.00001, 0.001, 0.01, 0.1, and 1.0 µg/mL purified venom extract (ALK-SQ, 3.1. Adverse Reactions. All patients had local swelling and ALK-Scherax, Germany). The tests were considered positive redness of the upper arm with a diameter of less than if a weal of at least 3 mm in diameter occurred after 15 10 cm. As summarized in Table 3,Systemicsideeffects were minutes, and, in the case of intradermal tests, a reaction was observed in 16 subjects (16%), 11 of them required treat- considered positive at a concentration of 1 µg/mL or less. ment. 6 patients (6%) showed an allergic reaction grade I, Positive (1% histamine hydrochloride) and negative (sodi- 2 girls (2%) grade II, and 5 patients (5%) developed a grade um-chloride 0.9%) control tests were performed. In addition III reaction, 1 of these 5 subjects recovered spontaneously. levels of specific IgE were determined in serum (Pharmacia No grade IV reactions occurred. 3 (3%) patients showed a ImmunoCAP System, Sweden); they were considered nega- reaction which could not be classified according to Mueller, tive when less than 0.35 kU/L. namely, prickle of the tongue and throat and dizziness. 2.3. Induction of Specific Immunotherapy Using the Ultrarush Severe adverse reactions occurred mainly after injection of Regime. The ultrarush induction regime is described in 50 µg venom (9 subjects) and more often in bee venom (13 Journal of Allergy 3 Table 1: Clinical data of children undergoing ultrarush venom immunotherapy. No. patients Total 94 Bee venom ultrarush Wasp venom ultrarush Age in years Range 4.0–15.1 Mean, median 10.4, 10.5 Gender Boys 78 (76.5 %) 47 (46.1%) 31 (30.4%) Girls 24 (23.5 %) 18 (17.6%) 6 (5.9%) Allergen Bee venom 57 (55.9 %) 65 (63.7%) Wasp venom 29 (28.4 %) 37 (36.3 %) Both 8 (7.8 %) Grade of reaction to field sting I1(1.0%) 1 0 II 20 (19.6%) 13 7 III 60 (58.8%) 37 23 IV 15 (14.7%) 9 6 Other (Sensitisation) 6 (5.9%) 5 1 Table 2: Classification of allergic reactions after HL Mueller, modified. Reaction Large local reaction Swelling at site of sting with diameter >10 cm, lasting >24 h Grade I Generalized urticaria, itching, malaise, anxiety Any of the above, plus two or more of the following: angiooedema (grade II also if alone), constriction in Grade II chest, nausea, vomiting, diarrhoea, abdominal pain, dizziness Any of the above, plus two or more of the following: dyspnoea, wheezing, stridor (any of these alone are Grade III grade III), dysphagia, dysarthria, hoarseness, weakness, confusion, fear of death Any of the above, plus two or more of the following: drop of blood pressure, collapse, loss of Grade IV consciousness, incontinence (urine, stool), cyanosis patients, 20%) than in wasp venom (3 patients, 8%) al- (210 min) protocol with a cumulative dose of 101.1 µgvenom lergic subjects; this latter tendency however, was not statis- compared to 6-hour and to 4-day protocols, which attained tically significant (OR 0.33, 95% Cl 0.07–1.25, P = 0.0955). cumulative doses of 226.6 µg and 527.6 µg, respectively [5, Overall, 29% of the girls, compared to only 12% of the 7]. The nine years of experience with initiation of specific boys, developed a systemic adverse event; this difference was immunotherapy to insect venom by ultrarush protocol in statistically significant (P = 0.034, multivariant analysis). paediatric subjects, which is summarized in this paper, None of the patients in group A (4 to 8 years of age) showed demonstrates that ultrarush insect venom immunotherapy is systemic side effects compared to 18% in group B (8 to a well-tolerated and safe induction regimen also in children. 12 years of age) and 19% in group C (12 to 15 years of Few side effects were observed, no cardiac or circulatory side age).All butone reaction occurred within30minutes after effects and no systemic allergic reactions in the youngest age injection of venom. In one boy generalised urticaria devel- group (4–8 years). Three subjects had unclassified reactions oped 3 hours after injection. with prickle of the tongue and throat and dizziness. These reactions did not fit the usual categories of allergic reactions, and it was not clear whether they were related directly 4. Discussion to the immunotherapy or whether they were caused by the circumstances of the treatment (hospitalization in the When starting specific immunotherapy, various protocols intensive/intermediate care unit, subcutaneous injections, for increasing the dose of allergen up to the maintenance monitoring, etc.). In order to assess this question a control dose have been introduced in the past years, attempting to group undergoing the same procedures but getting placebo maximize protection, minimize side effects, and optimize injections would be needed. However, this was beyond the patient convenience. It is difficult to compare the results scope of this retrospective study. because the regimens differ. Increasing data in adults demon- Antihistamines are efficiently and widely used to suppress strate good tolerance and safety for the ultrarush induction allergic symptoms. There are studies which support the in insect venom immunotherapy. For example, Birnbaum et al. found fewer systemic reactions with a 3.5-hour strategy of premedication with antihistamines in order to 4 Journal of Allergy Table 3: Subjects with side effects. Sex Age (y) Insect Grade at sting Side effects Grade At dose in µgTherapy Generalized urticaria, cough (no wheezing, Antihistamines, F8.1 Bee II II 50 no dyspnoea, no Corticosteroids i.v. stridor) M9.5 Bee Sensit.(IV) Dizziness other 30 None M 9.5 Bee II-III Generalyzed urticaria I 30 Antihistamines i.v. Antihistamines, Urticaria, dyspnoea, M 10.9 Bee III III 30 Corticosteroids i.v., wheezing Salbutamol-inhalation Antihistamines, Generalized urticaria; Corticosteroids i.v.dito + M 14.7 Bee III dyspnoea, constriction IIII 2050 inhal. of in chest Adrenalin/Salbutamol Urticaria about 3 h Antihistamines, F 10.3 Bee II-III after last injection I50 Corticosteroids i.v. (50 µg) Slight dyspnoea;fast, F 10.4 Bee II spontaneous III 1 None normalization Generalized urticaria, Antihistamines, M 12.1 Bee III-IV I30 itching in the throat Corticosteroids i.v M 10.5 Bee II-III Itching in the throat other 50 Cetirizin per os Antihistamines, Chest pain, inspiratory Corticosteroids i.v., stridor, chest pain, Adrenalin-inhalation dito + F 8.7 Bee III IIIIII 1050 in-and expiratory Salbutamol-inhalation, stridor Corticosteroids i.v. (before going home) Slight periorbital Antihistamines i.v. after F 14.1 Bee III II 1, 30 and 50 swelling 1ug Itching in meatus acusticus, rash chest, M 15.1 Bee II I50 None several urticarial lesions on the left arm Antihistamines and Dysphagia, passing F 15.0 Wasp III III 0.1 Corticosteroids i.v, and dyspnea again before going home Slight prickle of the F 11.3 Wasp III other 10 None tongue Redness and one none, 1 Levocetirizine per M 10.3 Bee IV urticarial lesion on the I50 os before going home left cheek M 10.7 Wasp III Generalyzed urticaria I 50 Levocetirizin per os Local redness and swelling, sometimes overheating and itching at the injection site. All children Therapy if needed: Coldpack and/or Antihistamin gel reduce allergic side effects and enhance the safety and efficacy protocol performed in a paediatric intensive or intermediate of allergen-specific immunotherapy [12, 13]. However, there care unit allows for much better monitoring of the patients is also data which suggests that medication with antihis- compared to the conventional desensitization protocol per- tamines may impair allergen-specific immunotherapy [14]. formed in an outpatient setting. Its short duration is much The patients in this retrospective study did not receive treat- more convenient for the patients and their parents, and it ment with antihistamines prior to immunotherapy. has the additional advantages of achieving rapid protection The results presented in this paper compare favourably as well as reduction in costs. Based on the results presented with the frequency of side effects reported in adults and in this paper and due to these considerations, we suggest with the incidence of severe adverse reactions in conventional that the ultrarush induction regimen for desensitization, and rush protocols [5, 7, 15–20]. 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Published: Jul 19, 2011