Cluster-Immuntherapie bei saisonaler allergischer Rhinitis: Erfahrungen zur Sicherheit einer Initialtherapie mit Depot-Allergoiden (Purethal®)

Zusammenfassung

Hintergrund: Neben der Allergenkarenz ist die Hyposensibilisierungstherapie oder spezifische Immuntherapie (SIT) die einzige kausale Behandlungsmöglichkeit von Patienten mit allergischer Rhinokonjunktivitis. Die Effektivität der SIT ist abhängig vom spezifischen Allergen, der Qualität und Gesamtdosis der verabreichten Allergenextrakte und dem Applikationsschema. Bei der klassischen SIT wird ein Allergenextrakt repetitiv in ansteigenden Dosen subkutan injiziert. Es existieren unterschiedliche Therapie-Schemata für die subkutane SIT. Bei der Cluster-Therapie werden hierzu 2 - 3 Injektionen je Behandlungstag in wöchentlichen Abständen verabreicht.

Patienten: Wir untersuchten in dieser Studie 64 Patienten (33 Frauen, 31 Männer) im Alter von 18 bis 54 Jahren (Altersdurchschnitt: 26,9 ± 5,1 Jahre) hinsichtlich auftretender Nebenwirkungen des Cluster-Therapieschemas in der Dosissteigerungsphase.

Ergebnisse: Die Gesamtzahl der übersteigerten Lokalreaktionen (> Grad 1) betrug n = 77 entsprechend 15,2 % aller Injektionen. Hiervon waren 68 (88 %) Sofortphasenreaktionen, 8 (11 %) Spätphasenreaktionen und 1 (1 %) sowohl Sofort- als auch Spätphasenreaktionen. Von allen übersteigerten Lokalreaktionen waren 48 (62 %) Grad-1-Reaktionen, 15 (20 %) Grad-2-Reaktionen, 13 (17 %) Grad-3-Reaktionen und eine (1 %) Grad-4-Reaktion. Die Gesamtzahl der systemischen Reaktionen betrug n = 22 entsprechend 4,3 % aller Injektionen. Hiervon waren 19 (86 %) Sofortphasenreaktionen, 3 (14 %) Spätphasenreaktionen. Von allen systemischen Reaktionen wurden 18 (82 %) dem Stadium 1 zugeordnet und 4 (18 %) dem Stadium 2. Reaktionen entsprechend Stadium 3 und 4 wurden nicht beobachtet.

Es bestanden keine Alters- oder Geschlechtsabhängigkeiten hinsichtlich des Auftretens übersteigerter Lokalreaktionen und/oder systemischer Reaktionen (alle p > 0,05).

Schlussfolgerungen: Art und Anzahl der unerwünschten Reaktionen bei dem verwendeten Cluster-SIT-Schema entsprechen somit dem bei anderen Schemata üblichen Rahmen. Die Verwendung von Allergoiden erlaubt zudem eine Durchführung der Dosissteigerungsphase in lediglich 2 Behandlungstagen. Unter Sicherheitsaspekten könnte daher die Cluster-SIT zu einer interessanten Alternative herkömmlicher Therapieschemata für die Dosissteigerungsphase werden.

Abstract

Background: Specific immunotherapy (SIT) represents the only specific treatment that can be offered to allergic patients apart from allergen avoidance. SIT has been widely used in pollen allergic rhinitis. Clinical efficacy has been demonstrated in several controlled clinical trials and depends on the specific allergen the individual patient is sensitive to, the quality and total amount of allergen applied, and the SIT schedule. In classic SIT, gradually increasing dosages of the allergen extract are injected subcutaneously. Several dosage schedules for subcutaneous SIT can be applied. In Cluster-SIT, 2 - 3 injections per day of treatment are given once a week during induction treatment.

Patients: In this study, we investigated 64 patients (33 female, 31 male) from 18 to 54 years (26.9 ± 5.1 years) in terms of side-effects of Cluster-SIT during induction treatment.

Results: The total amount of enlarged local reactions (> grade 1) was n = 77 or 15.2 % of all injections. Of these, 68 (88 %) were classified as immediate reactions, 8 (11 %) were late phase reactions and 1 (1 %) was immediate as well as late phase reaction. Of all enlarged local reactions, 48 (62 %) were grade 1 reactions, 13 (17 %) were grade 2 reactions, 13 (17 %) were grade 3 reactions and 1 (1 %) was a grade 4 reaction. The total amount of systemic reactions was n = 22 or 4.3 % of all injections. Of these, 19 (86 %) were classified as immediate reactions, 3 (14 %) were delayed reactions. Of all systemic reactions, 18 (82 %) were grade 1 reactions and 4 (18 %) grade 2 reactions. Grade 3 or grade 4 reactions did not occur. There were no differences in gender or age regarding the occurrence of side effects (all p > 0.05).

Conclusions: Frequency and severity of adverse side effects in Cluster-SIT correspond to those in other dosage schedules. On behalf of security aspects, Cluster-SIT could become an interesting alternative dosage schedule for dose increase during SIT. Furthermore, in Cluster-SIT with allergoids, induction treatment can be carried out in two treatment days of approximately 2.5 hours each.

Spezifische Hyposensibilisierungsbehandlung - spezifische Immuntherapie - Cluster-Immuntherapie - allergische Rhinokonjunktivitis - Allergoid

Specific immunotherapy - Cluster-Immunotherapy - allergic rhinoconjunctivitis - allergoids

Literatur

• 1 Noon L. Prophylactic inoculation of hay fever.  Lancet. 1911;  1 572-573
• 2 Bousquet J, Lockey R F, Malling H J. WHO Position Paper: Allergen immunotherapy: therapeutic vaccines for allergic deseases.  Allergy. 1998;  53
• 3 Sennekamp J, Kersten W, Fuchs E, Hornung B. Empfehlungen zur Hyposensibilisierung mit Allergenextrakten. Ärzteverband Deutscher Allergologen (ÄDA).  Allergologie. 1990;  13 185-188
• 4 Malling H J, Weeke B. Position Paper Immunotherapy of the EAACI.  Allergy. 1993;  48 9-35 (and Appendicies)
• 5 Klimek L, Reske-Kunz A B, Saloga J. Spezifische Immuntherapie - Hyposensibilisierung. Stuttgart; Georg Thieme Verlag 1999
• 6 Mellerup M T, Hahn G W, Poulsen L K, Malling H J. Safety of allergen-specific immunotherapy. Relation between dosage regimen, allergen extract, disease and systemic side-effects during induction treatment.  Clin Exp Allergy. 2000;  30 1423-1429
• 7 Tabar A I, Garcia B E, Rodriguez A, Olaguibel J M, Muro M D, Quirce S. A prospective safety-monitoring study of immunotherapy with biologically standardized extracts.  Allergy. 1993;  48 450-453
• 8 Hansen I, Stuck B A, Schneider-Gêne S, Klimek L, Hörmann K, Klimek L. Cluster-Immuntherapie bei allergischer Rhino-Konjunktivitis - Therapieprinzip und Sicherheitsaspekte.  Allergologie. 2002;  (in Press)
• 9 Bousquet J, Hejjaoui A, Skassa Brociek W, Guerin B, Maasch H J, Dhivert H, Michel F B. Double-blind, placebo-controlled immunotherapy with mixed grass-pollen allergoids. I. Rush immunotherapy with allergoids and standardized orchard grass-pollen extract.  J Allergy Clin Immunol. 1987;  80 591-598
• 10 Bousquet J, Hejjaoui A, Soussana M, Michel F B. Double-blind, placebo-controlled immunotherapy with mixed grass-pollen allergoids. IV. Comparison of the safety and efficacy of two dosages of a high-molecular-weight allergoid.  J Allergy Clin Immunol. 1990;  85 490-497
• 11 Ariano R, Kroon A M, Augeri G, Canonica G W, Passalacqua G. Long-term treatment with allergoid immunotherapy with Parietaria. Clinical and immunologic effects in a randomised, controlled trial.  Allergy. 1999;  54 313-319
• 12 Kroon A M. A post-marketing survey of the safety and efficacy of PURETHAL, a glutaraldehyde-modified allergoid for immunotherapy.  Schw Med WSchr. 1991;  121 55
• 13 Tryba . et al . Akuttherapie anaphylaktoider Reaktionen.  Allergo-Journal. 1994;  3 211-224
• 14 Norman P S. Immunotherapy for nasal allergy (symposium).  J Allergy Clin Immunol. 1988;  81 992-996
• 15 Ohman J L. Allergen immunotherapy in asthma: evidence for efficacy.  J Allergy Clin Immunol. 1989;  84 133-140
• 16 Haugaard L, Dahl R, Jacobsen L. A controlled dose-response study of immunotherapy with standardized, partially purified extract of house dust mite: clinical efficacy and side effects.  J Allergy Clin Immunol. 1993;  91 709-722
• 17 Haugaard L, Dahl R. Immunotherapy in patients allergic to cat and dog dander. I. Clinical results.  Allergy. 1992;  47 249-254
• 18 Hedlin G, Graff-Lonnevig V, Heilborn H. et al . Immunotherapy with cat- and dog-dander extracts. V. Effects of 3 years treatment.  J Allergy Clin Immunol. 1991;  87 955-964
• 19 Hepner M J, Ownby D R, Anderson J A, Rowe M S, Sears Ewald D, Brown E B. Risk of systemic reactions in patients taking beta-blocker drugs receiving allergen immunotherapy injections.  J Allergy Clin Immunol. 1990;  86 407-411
• 20 Kelso J M, Jones R T, Tellez R, Yunginger J W. Oral allergy syndrome successfully treated with pollen immunotherapy.  Ann Allergy Asthma Immunol. 1995;  74 391-396
• 21 Bousquet J, Maasch H J, Martinot B, Hejjaoui A, Wahl R, Michel F B. Double blind, placebo-controlled immunotherapy with mixed grass-pollen allergoids. II. Comparison between parameters assessing the efficacy of immunotherapy.  J Allergy Clin Immunol. 1988;  82 439-446
• 22 Ewan P W, Alexander M M, Snape C, Ind P W, Agrell B, Dreborg S. Effective hyposensitization in allergic rhinitis using a potent partially purified extract of house dust mite.  Clin Allergy. 1988;  18 501-508
• 23 Büchner K, Siepe M. Nutzen der Hyposensibilisierung unter wirtschaftlichen Aspekten.  Allergo Journal. 1995;  4 156-163
• 24 Saloga J, Renz H, Lack G. et al . Development and transfer of immediate cutaneous hypersensitivity in mice exposed to aerosolized antigen.  J Clin Invest. 1993;  91 133-140
• 25 Bellinghausen I, Enk A H, Mohamadzadeh M, Lohmann S, Knop J, Saloga J. Epidermal cells enhance interleukin 4 and immunoglobulin E production after stimulation with protein allergen.  J Invest Dermatol. 1996;  107 582-588
• 26 Secrist H, DeKruyff R H, Umetsu D T. Interleukin 4 production by CD4+ T cells from allergic individuals is modulated by antigen concentration and antigen-presenting cell type.  J Exp Med. 1995;  181 1081-1089
• 27 Secrist H, Chelen C J, Wen Y, Marshall J D, Umetsu D T. Allergen immunotherapy decreases interleukin 4 production in CD4+ T cells from allergic individuals.  J Exp Med. 1993;  178 2123-2130
• 28 Rocklin R E, Sheffer A L, Greineder D K, Melmon K L. Generation of antigen-specific suppressor cells during allergy desensitization.  New Engl J Med. 1980;  302 1213-1219
• 29 Kesarwala H H, Maccia C, Amaram N, Szep R, Papageorgiu P. Suppressor T cells and soluble suppressor factors in allergy: effect of immunotherapy.  Clin Allergy. 1984;  14 519-524
• 30 Rocklin R E, Pence H, Kaplan H, Evans R. Cell-mediated immune response of ragweed-sensitive patients to ragweed antigen E: In vitro lymphocyte transformation and elaboration of lymphocyte mediators.  J Clin Invest. 1974;  53 735-744
• 31 Jutel M, Pichler W J, Skrbic D, Urwyler A, Dahinden C, Müller U R. Bee venom immunotherapy results in decrease of IL-4 and IL-5 and increase of IFN-gamma secretion in specific allergen-stimulated T cell cultures.  J Immunol. 1995;  154 4187-4194
• 32 Creticos P S, van Metre T E, Mardiney M R, Rosenberg G L, Norman P S, Adkinson N F, Jr. Dose response of IgE and IgG antibodies during ragweed immunotherapy.  J Allergy Clin Immunol. 1984;  73 94-104
• 33 Gleich G J, Zimmermann E M, Henderson L L, Yunginger J W. Effect of immunotherapy on immunoglobulin E and immunoglobulin G antibodies to ragweed antigens: a six-year prospective study.  J Allergy Clin Immunol. 1982;  70 261-271
• 34 Sadan N, Rhyne M B, Mellits E D, Goldstein O, Levy D A, Lichtenstein L M. Immunotherapy of pollinosis in children. Investigation of the immunologic basis of clinical improvement.  N Engl J Med. 1969;  280 623
• 35 Van Metre T E, Adkinson N F, Kagey-Sobotka A. et al . Immunotherapy decreases skin sensitivity to ragweed extract: demonstration by midpoint skin test titration.  J Allergy Clin Immunol. 1990;  87 299
• 36 Durham S R, Varney V A, Gaga M, Jacobson M R, Frew A J, Kay A B. Immunotherapy suppresses T lymphocyte infiltration in the cutaneous late phase reaction.  J Allergy Clin Immunol. 1991;  88 299
• 37 Iliopoulos O, Proud D, Adkinson N F, Jr. Effects of immunotherapy on the early, late, and rechallenge reaction to provocation with allergen: changes in inflammatory mediators and cells.  J Allergy Clin Immunol. 1991;  87 855
• 38 Varney V A, Hamid Q A, Gaga M, Ying S, Jacobson M, Frew A J, Kay A B, Durham S R. Influence of grass pollen immunotherapy on cellular infiltration and cytokine mRNA expression during allergen-induced late-phase cutaneous responses.  J Clin Invest. 1993;  92 644-651
• 39 Rak S, Löwenhagen O, Venge P. The effect of immunotherapy on bronchial hyperresponsiveness and eosinophil cationic protein in pollen-allergic patients.  J Allergy Clin Immunol. 1988;  82 470-480
• 40 Klimek L, Wolf H, Mewes T, Dormann D, Reske-Kunz A B, Schnitker J, Mann W. The effect of short-term immunotherapy with molecular standardized grass and rye allergens on eosinophil cationic protein and tryptase in nasal secretions.  J Allergy Clin Immunol. 1999;  103 47-53
• 41 Yssel H, Fasler S, Lamb J, de Vries J E. Induction of non-responsiveness in human allergen-specific type 2 T helper cells.  Curr Opin Immunol. 1994;  6 847-852
• 42 J Council on Scientific Affairs (AMA). In vivo diagnostic testing and immunotherapy for allergy.  JAMA. 1987;  258 1363-1367
• 43 Zenner H P, Baumgarten C, Rasp G. et al . Short-term immunotherapy: A prospective, randomized, double-blind, placebo-controlled multicenter study of molecular standardized grass and rye allergens in patients with grass pollen-induced allergic rhinitis.  J Allergy Clin Immunol. 1997;  100 23-29
• 44 Marsh D G, Alexander J F, Norman P S. Boosting of patients with high and low doses of allergoid.  J Allergy Clin Immunol. 1982;  69 99
• 45 Norman P S, Marsh D G, Ishizaka K, Lichtenstein L M. New immunologic methods of treatment in IgE mediated allergies. Allergy and Clinical Immunology. Amsterdam, Oxford; Excerpta Medica 1977: 483-486
• 46 Norman P S, Lichtenstein L M, Marsh D G. Studies on allergoids from naturally occuring allergens. IV. Efficacy and safety of long-term allergoid treatment of ragweed hay fever.  J Allergy Clin Immunol. 1981;  68 460-470
• 47 Bousquet J, Calvayrac P, Guerin B. Immunotherapy with a standardized Dermatophagoides pteronyssinus extract. I. In vivo and in vitro parameters after a short course of treatment.  J Allergy Clin Immunol. 1985;  76 734-744
• 48 Horst M, Hejjaoui A, Horst V, Michel F-B, Bousquet J. Double-blind, placebo-controlled rush immunotherapy with a standardized Alternaria extract.  J Allergy Clin Immunol. 1990;  85 460-472
• 49 Bousquet J, Hejjaoui A, Skassa Brociek W. Double blind, placebo-controlled immunotherapy with mixed grass-pollen allergoids. I. Rush immunotherapy with allergoids and standardized orchard grass-pollen extract.  J Allergy Clin Immunol. 1987;  80 591-598
• 50 Maasch H J, Marsh D G. Standardized Extracts. Modified Allergens - Allergoids.  Clin Rev Allergy. 1987;  5 89-106
• 51 Baumgarten C, Kunkel G, Rudolph R. Vergleichende Untersuchungen von Graspollen-Allergikern behandelt mit Graspollenallergoid sowie an Aluminiumhydroxid adsorbierten Graspollen-Allergenen.  Allergologie. 1982;  5 89-96
• 52 Grammer L C, Shaughnessy M A, Finkle S M, Shaughnessy J J, Patterson R. A double-blind placebo-controlled trial of polymerized whole grass administered in an accelerated dosage schedule for immunotherapy of grass pollinosis.  J Allergy Clin Immunol. 1986;  78 1180-1184
• 53 Pichler C E, Maryuardsen A, Sparholt S, Løwenstein H, Bircher A, Bischof M, Pichler W J. Specific immunotherapy with Dermatophagoides pteronyssinus and D. farinae in decreased bronchial hyperreactivity.  Allergy. 1997;  52 274-283