Research artide/Raziskovalni prispevek SAFETY OF VENOMENHAL® VENOM IN MAINTENANCE HYMENOPTERA VENOM IMMUNOTHERAPY VARNOST PRIPRAVKA VENOMENHAL® ZA VZDRŽEVALNO IMUNOTERAPIJO BOLNIKOV, ALERGIČNIH ZA STRUPE KOŽEKRILCEV Mitja Košnik,1 Ema Mušič,1 Angelika Sager2 1 University Clinic of Respiratory and Allergic Diseases, 4204 Golnik, Slovenia 2 HAL ALLERGIE GMBH, Düsseldorf, Germany Arrived 2001-04-23, accepted 2001-06-26; ZDRAV VESTN 2001; 70: 531-3 Key words: allergen extracts; Hymenoptera venom allergy; immunotherapy; safety Abstract - Background. Venomenhal® (V) is a new brand of Hymenoptera venom allergen for diagnosis and immunotherapy of venom allergy. We studied the safety of switching the patients treated with other brands of venom to V. Methods. We performed duplicate skin prick tests with V and ALKReless® (R) venom extract (100jg/ml) in 68patients (50 males, 42 ± 15years) on maintenance immunotherapy with honey bee (26) or wasp (42) venom. On two consecutive maintenance injection days 53 patients received in random order either 100 jg of R or V venom. Results. Weal diameter in skin prick tests (mean ± st.dev.) were 3.9 ± 1.1 mm (V) and 4.1 ± 1.0 mm (R) for bee venom (NS) and3.4 ± 1.0 mm (V) and3.9 ± 1.2 mm (R) for wasp venom (p < 0.01). Local reaction 30 minutes after maintenance injection were 6.1 ± 1.7 cm (V) and 5.4 ± 2.5 cm (R)for bee venom (NS) and5.1 ± 1.8 cm (V) and 6.1 ± 1.8 cm (R)for wasp venom (p < 0.05). Late local reactions (LLR) and tiredness (T) on the day of injection and 24 hours after injection were equally distributed among both groups and were mild (LLR on the day of injection: 38% of patients [V] vs. 43% [R]. LLR after 24 hours: 28% [V] vs. 28% [R]. Ton the day of injection: 21% [V] vs. 23% [R]. T after 24 hours: 0% [V] vs. 6% [R]). Conclusions. V was at least as safe as A. There were no adverse reactions due to switchingfrom one brand to another. Slightly but significantly smaller weal in skin prick tests and immediate local reactions might be due to lesser potency or better purification of V wasp extract. Ključne besede:pripravek alergena; alergija za strupe kože-krilcev; imunoterapija; varnost Izvleček - Izhodišča. Venomenhal® (V) je nov pripravek strupa kožekrilcev. Namenjen je za kožno testiranje in za imu-noterapijo bolnikov, alergičnih za strup kožekrilcev (čebel, os, sršenov). Zanimalo nas je, ali je varno bolnike, ki so bili zdravljeni z alergenskim pripravkom drugega proizvajalca, prevesti na pripravek V. Metode. 68 bolnikom (50 moških, starost 42 ± 15 let), ki so bili vsaj eno leto zdravljeni z imunoterapijo s pripravkom čebeljega (26 bolnikov) ali osjega (42 bolnikov) strupa ALK Reless® (R), smo v dvojniku naredili kožne vbodne teste s pripravki V in R (100 iig/ml). Pri dveh zaporednih vzdrževalnih odmerkih je 53 bolnikov v slučajnem vrstnem redu dobilo 100¡ugpripravka R ali V. Rezultati. Premer urtike v kožnem testu (srednja vrednost ± st.dev.) je bila 3,9 ± 1,1 mm (V) in 4,1 ± 1,0 mm (R) s strupom čebele (NS) ter 3,4 ± 1,0 mm (V) in 3,9 ± 1,2 mm (R) s strupom ose (p < 0,01). Premer lokalne reakcije 30 minut po vzdrževalnem odmerku je bil 6,1 ± 1,7 cm (V) in 5,4 ± 2,5 cm (R) po strupu čebele (NS) ter 5,1 ± 1,8 cm (V) in 6,1 ± 1,8 cm (R) po strupu ose (p < 0, 05). Pogostost kasne lokalne reakcije (KLR) in utrujenosti (U) na dan injekcije in 24 ur po injekciji je bila enakomerno razporejena med obema skupinama bolnikov (KLR na dan injekcije: 38% bolnikov [V] proti 43% [R]. KLR po 24 urah: 28% [V]proti 28% [R]. U na dan injekcije: 21% [V]proti 23% [R]. U 24 ur po injekciji: 0% [V] proti 6% [R]). Zaključki. V je vsaj toliko varen kot A. Pri prehodu iz ene vrste alergenskega pripravka na drugega ni bilo pomembnih zapletov. Nekoliko, vendar pomembno manjši premer urtike pri kožnem vbodnem testu in manjši premer takojšnje lokalne reakcije, je lahko posledica manjše moči ali boljše prečiščenos-ti pripravka osjega strupa V. Introduction About 0.4% of the population develop systemic allergic reactions after Hymenoptera insect stings (1). Specific immunotherapy is the treatment of choice for patients who experienced a severe systemic IgE mediated reaction after Hymenoptera insect sting (2). In different immunotherapy protocols a cumulative dose of 100 |jg of venom is reached in few hours or days. Thereafter most patients receive 100 |jg maintenance dose in 4-12 week intervals (3). Nearly complete tolerance was confirmed in sting challenge controlled study performed by Hunt (4). Immunotherapy is potentially dangerous because allergen material is injected into a sensitised person (5, 6). The number of producers of aqueous venom extracts is rising. Patients moving from one immunotherapy centre to other might present a problem if centres are using different brands of extracts. We studied clinical equipotency of two brands of aqueous venom extracts used for skin testing and specific immuno-therapy. Patients, material and methods Patients After informed consent 68 patients (50 males, 42 ± 15 years) were included into a prospective double blind crossover study. All patients were receiving venom immunotherapy with 100 |jg maintenance dose of R for at least 1 year. 26 patients were treated with honey bee and 42 with wasp venom. No patient experienced systemic side effect in previous 6 months of im-munotherapy. Allergens Commercial bee and wasp venom aqueous extracts Reless® (ALK) (R) and Venomenhal (HAL) (V) were used for skin prick testing and immunotherapy according to the instructions of the manufacturer. Procedure We performed duplicate skin prick tests with V and R venom extract (100 |jg/ml) in all 68 patients. Albumin diluent for venom (HAL) was used as a negative control and histamine di-hydrochloride 1 mg/ml (Allergopharma) as a positive control. Results were read after 20 minutes.The largest and perpendicular diameters of weal were measured and result expressed as a mean of 4 measurements (7). On two consecutive maintenance injection days 53 patients (42 males) received in a random order either 100 |jg of R or V venom. Patients were closely monitored for an hour for a possible immediate systemic reaction. Resuscitation equipment was stand by. After an hour a mean diameter of local reaction (redness) was measured. Patients were given a questionnaire, where they indicated local tenderness at injection site, tiredness and possible systemic reaction 6 and 24 hours after injection. Patients were also asked to measure the diameter of local oedema at injection site 24 hours after injection. Study was approved by State ethic committee of Slovenia. Statistical analysis Results are shown as mean ± standard deviation. Possible differences between two venom extracts were calculated using paired t-test. Results All patients finished the study. Mean weal diameters in skin prick tests were significantly smaller when using V wasp ve- nom compared to R wasp venom. There was no difference between both brands in skin tests with bee venom (Tab. 1). Also immediate local reaction 1 hour after maintenance injection were significantly smaller when using V wasp venom compared to R. There was no difference in immediate local reaction with bee venom (Tab. 1). Tab. 1. Results of skin prick tests and diameter of local reaction 1 hour after maintenance injection of 100 ug venom. R: Re-less venom, V: Venomenhal venom. Tab. 1. Rezultati kožnih testov in premer lokalne reakcije eno uro po vzdrževalnem odmerku 100 ug strupa. R: Reless, V: Venomenhal. Skin prick test weal diameter (mm) Premer urtike kožnega testa (mm) R V P Bee / Čebela Wasp / Osa 4.1 ± 1.0 3.9 ± 1.2 3.9 ± 1.1 3.4 ± 1.0 NS < 0,01 Local reaction 1 hour after injection (cm) Lokalna reakcija 1 uro po injekciji (cm) Bee / Čebela Wasp / Osa 5.4 ± 2.5 6.1 ± 1.8 6.1 ± 1.7 5.1 ± 1.8 NS < 0,05 Late local reactions and tiredness 6 hours after injection and 24 hours after injection were equally distributed among both groups and were mild (Tab. 2). Tab. 2. Presence of local tenderness, tiredness and oedema 6 and 24 hours after maintenance injection of 100 ug venom. R: Reless venom, V: Venomenhal venom. Tab. 2. Prisotnost občutljivosti na mestu injekcije, utrujenosti in otekline 6 in 24 ur po vzdrževalnem odmerku 100 ug strupa. R: Reless, V: Venomenhal. Bee / Čebela Wasp / Osa Symptoms after 6 hours Simptomi po 6 urah R V p R V p Tenderness at the site of injection Občutljivost na mestu injekcije 45% 32% NS 49% 42% NS Tiredness Utrujenost 9% 9% NS 32% 29% NS Symptoms after 24 hours Simptomi po 24 urah Tenderness at the site of injection Občutljivost na mestu injekcije 23% 23% NS 32% 32% NS Tiredness Utrujenost 9% 0% NS 3% 0% NS Local oedema Oteklina 14% 27% NS 39% 42% NS There were no immediate systemic reactions, and no patients reported signs of systemic allergic reaction during next 24 hours. Discussion Immunotherapy with standardised extracts is relatively safe procedure (6). Before standardisation was accepted as a necessary procedure in allergen extract production, patients experienced systemic and even fatal reaction when switching from one batch of allergen extract to another and a diminish of a dose was proposed when changing from one batch to another. Nowadays the concentrations of allergen epitopes are held on the same level in every batch (8). As a concentration of purified venom allergen is the same in the products of different pharmaceutical companies, we speculated that switching from one brand to another is possible and safe. This is important as some patients move during immunotherapy to another immunotherapy centre, where allergen extract of different pharmaceutical company is used. Even in one center problem may arise as sometimes a pharmaceutical company is temporary unable to provide adequate supply of allergen. To show biological equipotency of two venom extracts we performed comparative skin prick tests. Bee venom extracts were shown to be of identical biologic activity as they elicited weals of the same diameter. On the other hand, V wasp venom elicited slightly but significantly smaller weal diameter than R. After getting information, that V doesn't have greater biological activity as R, we switched patients receiving R in a double blind manner to V. Patients were injected a single 100 jag dose. Dividing of the dose would diminish the risk of side effects and hide a possible disadvantage of V over R. Similarly as in skin prick tests we didn't notice any difference in diameter of immediate local reaction after bee venom, but slightly and significantly smaller reactions after wasp venom. No patient experienced clinically significant immediate side effect when switching from a single injection of V back to R. A good tolerance might be due to equipotency of both venoms. On the other hand, most patients tolerate maintenance injection even if a single dose is skipped (9). The design of the study allowed us only to detect unsafety of switching to V in the case that V contained much more relevant allergen epitopes or other relevant epitopes than R. To conclude, we showed that V was at least as safe as R in maintenance venom immunotherapy. In patients on stable maintenance immunotherapy there were no adverse reactions due to switching from R to V. Slightly but significantly smaller weals in skin prick tests and immediate local reactions might be due to lesser potency or better purification of V wasp extract. References 1. Settipane GA, Chafee FH. Natural history of allergy to Hymenoptera. Clin Allergy 1979; 9: 385-90. 2. Müller U, Mosbech H. Position paper: Immunotherapy with Hymenoptera venoms. Allergy 1994; 48: Suppl 14: 36-46. 3. Birnbaum J, Charpin D, Vervioet D. Rapid Hymenoptera venoms immunotherapy: Comparative safety of three protocols. Clin Exp Allergy 1992; 23: 226-30. 4. HuntJK et al. A controlled trial of immunotherapy in insect hypersensitivity. N Engl J Med 1978; 299: 157-61. 5. Youlten LJF, Atkinson BA, Lee TH. The incidence and nature of adverse reactions to injection immunotherapy in bee and wasp venom allergy. Clin Exp Allergy 1995; 25: 159-65. 6. Mosbech H, Müller U. Side effects of insect venom immunotherapy: Results from an EAACI multicenter study. Allergy 2000; 55: 1005-10. 7. Dreborg S. Skin tests used in type I allergy testing. Position paper. Allergy 1989; 44: Suppl 10: 11-59. 8. Bousquet J. Allergen immunotherapy: therapeutic vaccines for allergic diseases. WHO position paper. J Allergy Clin Immunol 1998; 102: 558-62. 9. Kochuyt AM, Stevens EAM. Safety and efficacy of a 12-week maintenance interval in patients treated with Hymenoptera venom immunotherapy. Clin Exp Allergy 1994; 24: 35-41. V tej številki so sodelovali: mag. Marija Cesar-Komar, dr. med., specialistka anesteziologinja, Oddelek za anesteziologijo, Splošna bolnišnica, Slovenj Gradec prof. dr. Andrej Debeljak, dr. med., specialist internist, Klinični oddelek za pljučne bolezni in alergijo, Bolnišnica Golnik prim. doc. dr. Jurij Dobovišek, dr. med., specialist internist, Klinični oddelek za hipertenzijo, Bolnišnica dr. Petra Držaja, Klinični center, Ljubljana asist. Damjan Eržen, dr. med., specialist internist, Klinični oddelek za pljučne bolezni in alergijo, Bolnišnica Golnik prim. Jurij Fürst, dr. med., Zavod za zdravstveno zavarovanje Slovenije, Ljubljana mag. Željko Jakelič, dr. stom., Zasebna ordinacija Jakelič, Jesenice prim. dr. Igor Japelj, dr. med., specialist ginekolog in porodničar, Služba za ginekologijo in perinatologijo, Splošna bolnišnica, Maribor asist. Peter Kecelj, dr. med., specialist internist, Klinični oddelek za pljučne bolezni in alergijo, Bolnišnica Golnik asist. Izidor Kern, dr. med., specialist patolog, Klinični oddelek za pljučne bolezni in alergije, Bolnišnica Golnik prof. dr. Miloš F. Kobal, dr. med., specialist psihiater, Ljubljana doc. dr. Mitja Košnik, dr. med., specialist internist, Klinični oddelek za pljučne bolezni in alergijo, Bolnišnica Golnik doc. dr. Mojca Kržan, dr. med., Inštitut za farmakologijo in eksperimentalno toksikologijo, Medicinska fakulteta, Ljubljana mag. Anton Lopert, dr. med., specialist internist, Pnevmološki oddelek, Splošna bolnišnica, Murska Sobota Ljubica Lovišček, mag. farm., Lekarna Glavni trg, Maribor prof. dr. Helena Meden-Vrtovec, dr. med., specialistka ginekologinja in porodničarka, Ginekološka klinika, Klinični center, Ljubljana prof. dr. Aleš Mrhar, mag. farm., Fakulteta za farmacijo, Ljubljana prof. dr. Ema Mušič, dr. med., specialistka internistka, Klinični oddelek za pljučne bolezni in alergije, Bolnišnica Golnik mag. Ksenija Ogrizek-Pelkič, dr. med., specialistka ginekologinja in porodničarka, Služba za ginekologijo in perinatologijo, Splošna bolnišnica, Maribor Katarina Osolnik, dr. med., specialistka internistka, Klinični oddelek za pljučne bolezni in alergijo, Bolnišnica Golnik Matjaž Pavlišič, dr. med., Krka d.d., Ljubljana prof. dr. Ivo Pavšič, dr. stom., specialist ortodont, Ljubljana asist. mag. Barbara Požlep, dr. med., specializantka ginekologije in porodništva, Ginekološka klinika, Klinični center, Ljubljana Stanko Pšeničnik, Oddelek za biomedicinsko tehniko, Splošna bolnišnica, Maribor Angelika Sager, dr. med., Hal Allergie GmbH, Düsseldorf, Nemčija Vladimir Senekovič, dr. med., specialist kirurg, Klinični oddelek za travmatologijo, Klinični center, Ljubljana Valdet Šaciri, dr. med., Klinični oddelek za travmatologijo, Klinični center, Ljubljana prim. spec. akad. st. Janez Šuštaršič, dr. med., specialist internist, Ljubljana prim. Nadja Triller, dr. med., specialistka internistka, Klinični oddelek za pljučne bolezni in alergijo, Bolnišnica Golnik prim. Andrej Žmitek, dr. med., specialist psihiater, Psihiatrična bolnišnica, Begunje