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Hymenoptera Venom Immunotherapy: How to Safely Switch to the Same Venom From a Different Manufacturer
Bilò MB1, Martini M1, Berra D2, Scarpa A3, Losappio L4, Quercia O5, Lodi Rizzini F6, Bignardi D7, Cortellini G8, Zisa G9, Del Giudice A10, Manzotti G11, Marcotulli C12, Murzilli F13, Cilia M14, Pravettoni V15, Borrelli P16, Pastorello EA4
1Allergy Unit, Department of Internal Medicine, University
Hospital of Ancona - Allergy and Clinical Immunology School, Università Politecnica delle Marche, Ancona, Italy
2Allergology Service, Pneumology Unit, Busto Arsizio Hospital,
Varese, Italy
3Allergy Unit - Dermatology, Department of Surgery, Hospital of
Mirano, Mirano, Italy
4Department of Allergy and Immunology, Asst Grande Ospedale
Metropolitano Niguarda, University of Milano, Italy
5Allergology High Specialty Unit General Medicine, Faenza
Hospital Ravenna, Ravenna, Italy
6Allergy Unit, Spedali Civili Brescia, Department of Clinical
and Experimental Sciences, University of Brescia, Brescia, Italy
7Allergy Unit, Department of Internal Medicine, Ospedale
Policlinico San Martino of Genoa, Genoa, Italy
8Internal Medicine and Rheumatology Unit, Rimini Hospital,
Rimini, Italy
9Allergy Unit, Department of Internal Medicine, Azienda
Ospedaliero-Universitaria Maggiore della Carità, Novara, Italy
10Allergy Unit, Department of Internal Medicine, Hospital Martini
of Turin, Turin, Italy
11Allergy Unit, Department of Internal Medicine, Treviglio
General Hospital, ASST Bergamo Ovest, Treviglio, Italy
12Allergy Unit, Department of Pneumology, Asst Garda,
Desenzano, Italy
13Allergy Unit, Department of Internal Medicine, S.S. Filippo and
Nicola Hospital of Avezzano, Azienda Sanitaria Locale n. 1 dell’ Abruzzo, Avezzano, Italy
14Allergy Unit, Health Care Service, Scilla, Italy
15UOC General Medicine – Immunology and Allergology – IRCCS
Foundation Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy
16Allergy Unit, Department of Internal Medicine, U. Parini
Regional Hospital, Aosta, Italy
J Investig Allergol Clin Immunol 2018; Vol. 28(3): 205-208 doi: 10.18176/jiaci.0242
Key words: Extract switching. Hymenoptera. Immunotherapy. Mastocytosis. Safety.
Palabras clave: Cambio de extracto. Himenóptero. Inmunoterapia. Mastocitosis. Seguridad.
Venom immunotherapy (VIT) is a safe and effective treatment for hymenoptera venom allergy (HVA) [1,2]. It is also recommended in patients with underlying clonal mast cell disorders [2,3] and/or stabilized respiratory/cardiovascular diseases [2].
References
1. Fok JS, Smith WB. Hypersensitivity reactions to gadolinium-based contrast agents. Curr Opin Allergy Clin Immunol. 2017;17:241-6.
2. Carr T. Pathophysiology of Immediate Reactions to Injectable Gadolinium-based Contrast Agents Top Magn Reson Imaging. 2016;25:265-8.
3. Jung JW, Kang HR, Kim MH, Lee W, Min KU, Han MH, Cho SH. Immediate hypersensitivity reaction to gadolinium-based MR contrast media. Radiology. 2012;264:414-22.
4. Rosado Ingelmo A, Doña Diaz I, Cabañas Moreno R, Moya Quesada MC, García-Avilés C, García Nuñez I, et al. Clinical Practice Guidelines for Diagnosis and Management of Hypersensitivity Reactions to Contrast Media. J Investig Allergol Clin Immunol. 2016;26:144-55
5. Prince MR, Zhang H, Zou Z, Staron RB, Brill PW. Incidence of immediate gadolinium contrast media reactions. AJR Am J Roentgenol. 2011;196:W138-43.
6. Hasdenteufel F, Luyasu S, Renaudin JM, Paquay JL, Carbutti G, Beaudouin E, et al. Anaphylactic shock after first exposure to gadoterate meglumine: two case reports documented by positive allergy assessment. J Allergy Clin Immunol. 2008;121:527-8.
7. Tepetam FM, Ciftaslan N, Oruc O, Duman D, Agca M, Bulut İ, et al. Should patients with risk factors be tested for hypersensitivity to contrast media: a prospective study. Radiol Med. 2016;121:660-7.
8. Nagai H, Nishigori C. A delayed reaction to the magnetic resonance imaging contrast agent gadobutrol. J Allergy Clin Immunol Pract. 2017;5:850-1.
9. Dillman JR, Ellis JH, Cohan RH, Strouse PJ, Jan SC. Allergic-like breakthrough reactions to gadolinium contrast agents after corticosteroid and antihistamine premedication. AJR Am J Roentgenol. 2008;190:187.
10. L Chiriac AM, Audurier Y, Bousquet PJ, Demoly P. Clinical value of negative skin tests to gadolinium contrast agents. Allergy. 2011;66:1504-6.
11. Romano A, Gaeta F, Valluzzi RL, Zaffiro A, Caruso C, Quaratino D. Natural evolution of skin-test sensitivity in patients with IgE-mediated hypersensitivity to cephalosporins. Allergy. 2014;69:806-9
Manuscript received August 13, 2017; accepted for publication February 13, 2018.
Peter Jandus Division of Immunology and Allergology Department of Medical Specialties University Hospital and Medical Faculty of Geneva Rue Gabrielle Perret-Gentil 4 1211 Geneva 14 Switzerland E-mail: peter.jandus@hcuge.ch
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Of the 531 cases recorded in 523 patients (8 patients underwent double VIT), 349 cases (Group A, 66%) switched to a new extract on a single day: their own maintenance dose, which was reached entirely with the new extract, was divided into 3 aliquots in 276 cases and 2 aliquots in 73 cases, with a 30-45 minute interval between injections. In 95 cases (Group B, 18%), the switch was performed on a single day by dividing the maintenance dose into 2 different aliquots injected at a 30-45 minute interval; however, only the old extract was used for the first injection (30% and 50% of the total maintenance dose in 31 and 64 cases, respectively), whereas at the second injection, only the new extract was injected. All the other switches (n=87) involved dose reduction by injecting different amounts of the new extract on the first day (ranging from 10% to 80% of the maintenance dose) and then gradual increases during subsequent visits until 100% of the maintenance The literature provides no clear approach to VIT-treated
patients if the allergenic extract is no longer available [1,2,4]. However, for safety reasons, current clinical practice discourages abrupt switching to the same venom extract from a different manufacturer without an induction phase.
In early 2016, a national shortage of aqueous VIT preparations led clinicians to switch to another extract based on their experience.
We prospectively collected data on VIT switching from 16 Italian centers with broad experience in management of VIT. Whenever discontinuation was not recommended, patients switched to a preparation of the same venom made by another manufacturer. Before VIT, all patients signed an informed consent form and underwent a medical examination. A venous access was also placed. The baseline characteristics of the patients are shown in the Table.
Table. Characteristics of Patients and VIT Switching
Total Group A Group B Group C
Patients, No. 523 342 (65.39%) 94 (17.97%) 87 (16.63%)
Male/Female 391/132 258/84 70/24 63/24
Mean age (range), y 55.5 (8-90) 55.5 (11-90) 54.6 (8-85) 48.9 (11-82)
Reaction typea
Grade I 38 (7.27%) 15 (39.47%) 14 (36.84%) 9 (23.68%)
Grade II 70 (13.38%) 40 (57.14%) 13 (18.57%) 17 (24.29%)
Grade III 185 (35.37%) 128 (36.68%) 31 (16.49%) 29 (15.43%)
Grade IV 230 (43.98%) 166 (70.64%) 37 (15.74%) 32 (13.62%)
Mastocytosis and/or high bSTC 62 (11.68%) 44 (70.97%) 11 (17.74%) 7 (11.29%)
Patients with double VIT, No. 8 7 1 0
Type of VIT
Apis mellifera 58 (10.92%) 36 (62.07%) 12 (20.69%) 10 (17.24%)
Polistes species/P dominulab 83 (15.63%) 54 (65.06%) 9 (10.84%) 20 (24.10%)
Vespula species 389 (73.26%) 258 (66.32%) 74 (19.02%) 57 (14.65%)
Vespa crabro 1 (0.19%) 1 (100%) 0 (0.00%) 0 (0.00%)
Mean (SD) administration interval, wk 8 (2.6)
Mean (SD) VIT period, y 7 (5.6)
Switches, No. 531 349 (65.73%) 95 (17.89%) 87 (16.38%)
Switch protocol / Full dose Full dose Reduced dose
1 day 1 day 1 dayc
Extract / N N + Od N
Type of new extract
Aqueouse 357 (67.23%) 227 (63.59%) 64 (17.93%) 66 (18.49%)
Depotf 174 (32.77%) 122 (70.11%) 31 (17.82%) 21 (12.07%)
Systemic reaction 1 (0.19%) 0 0 1
Abbreviations: N, new extract; O, old extract; bSTC, serum baseline tryptase concentration; VIT, venom immunotherapy.
aMueller grading system [6].
bForty-four patients (46%) were treated with mixed American Polistes extract (Polistes annularis, fuscatus, and exclamans species), and all the
others were treated with Polistes dominula extracts.
c100% of new extract was used during the following visits.
dThe dose was gradually increased to the full dose during the following visits. ePurified, nonpurified, or capillary extracted extracts.
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dose was reached (Group C, 16%). The extracts used were both aqueous (purified aqueous, 10%; nonpurified aqueous, 51%; capillary extracted aqueous, 6%) and depot (purified aluminium hydroxide adsorbed, 16%; tyrosine adsorbed, 17%). All the Polistes-allergic patients were switched to the new Polistes dominula extracts. The switch protocols and the extracts used are reported in the Table. Subsequent administration of maintenance VIT doses was scheduled with a timeframe similar to that followed before the switch (8 [2.6] weeks).
The switch was well tolerated in all but 1 patient. One grade I systemic reaction (SR) [5] was reported in an 82-year-old man who had been receiving 100 µg of Vespula VIT for 3.8 years (Group C). The patient had mastocytosis and ischemic heart disease treated with a ß-blocker and a sartan. He experienced generalized pruritus a few hours after the injection (60 µg) and recovered spontaneously in 4 days. His nonpurified Vespula aqueous extract was switched to a purified aluminium hydroxide adsorbed preparation. He tolerated subsequent injections at the same total dose after 1 week and at a dose of 100 µg after a further week, with no SRs. Local reactions were not taken into consideration, as they are very common.
No SRs were reported in the other patients with mastocytosis and/or elevated serum baseline tryptase concentration (n=61), even though 44 (71%) followed the Group A protocol. Similarly, SRs were not observed in patients with cardiovascular comorbidity (19% of patients) or respiratory comorbidity (3%) or in patients treated with ß-blockers (4%), ACE-inhibitors (5%), or sartans (9%). In addition, adverse effects were not reported in any bee venom–allergic patients (n=58) or in patients with a long interval between injections (more than 8 weeks) (35%) before switching. Moreover, patients previously treated with a mix of American Polistes venom tolerated the switch to P dominula extracts. None of the patients reported any subsequent SRs during a mean follow-up period of 18 (4.9) months.
This is the first real-life multicenter study showing the safety of switching VIT to the same venom from another manufacturer in a large number of patients. No severe SRs were reported. No significant differences were observed between 1-day protocols (Group A and B) and the dose reduction protocols (Group C), suggesting that there is no need for an induction phase using lower doses of venom. We propose 3 explanations for our encouraging safety results. First, even though 79% of patients developed a class III-IV SR [6] at baseline and 27% had a comorbid condition, the venom was switched mainly after a maintenance phase of several years without adverse effects. Second, patients were managed by clinicians with specific expertise in VIT. Third, the comorbidities and treatments analyzed do not seem to be risk factors for severe adverse effects, individually. Interestingly, the only SR reported occurred in a mastocytosis patient with ischemic heart disease treated with a ß-blocker and a sartan. Even though the SR was mild and affected only the skin, we cannot rule out the possibility that the combination of mastocytosis with cardiovascular disease could have played a role in the case we report. In clinical practice, special attention should be paid in patients with comorbidities, especially when mastocytosis occurs with other severe comorbidities.
Although bee venom is considered a risk factor for adverse effects during VIT and different allergen compositions have been demonstrated for bee venom extracts [7], our results showed that bee venom allergy does not seem to be related to a higher risk of SRs during switching. Similarly, switching from American Polistes species to P dominula venom did not cause any SRs, despite the incomplete cross-reactivity between American and European Polistes venom [8,9].
Notwithstanding the pitfalls normally associated with multicenter real-life studies, such as the different protocols and extracts used in this study, no differences in safety were observed between aqueous extracts and depot preparations or between the purified and nonpurified aqueous formulations.
Before switching, no patients in our study experienced severe SRs to the old extract, although we believe that, in this case, VIT should be restarted with a rush/ultrarush protocol in centers with broad experience in HVA and VIT [10], or with a conventional protocol in less experienced centers.
The unexpected and accidental shortage of some extracts was the only reason that made the VIT switch necessary in our study.
In conclusion, our results showed that switching VIT, if strictly necessary, is a safe option in patients who previously tolerated VIT, even without reducing the maintenance dose already reached by the patient and when performed in an appropriate environment by experienced staff.
Funding
The authors declare that no funding was received for the present study.
Conflicts of Interest
MBB has received speaker’s honoraria and/or travel support from ALK-Abelló and Thermo Fisher Scientific. She has also received consultancy fees from ALK-Abelló for participation in an advisory board.
AS has received reimbursement for symposia from ALK Abelló and Stallergenes.
The other authors declare that they have no conflict of interests.
References
1. Bonifazi F, Jutel M, Bilo BM, Birnbaum J, Muller U, EAACI Interest Group on Insect Venom Hypersensitivity. Prevention and treatment of hymenoptera venom allergy: guidelines for clinical practice. Allergy. 2005;60:1459-70.
2. Sturm GJ, Varga E-M, Roberts G, Mosbech H, Bilò MB, Akdis CA, et al. EAACI Guidelines on Allergen Immunotherapy: Hymenoptera venom allergy. Allergy. 2018;73:744-64. 3. Bonadonna P, Gonzalez-de-Olano D, Zanotti R, Riccio A, De
Ferrari L, Lombardo C et al. Venom immunotherapy in patients with clonal mast cell disorders: efficacy, safety, and practical considerations. J Allergy Clin Immunol Pract. 2013;1:474-8. 4. Wolf BL, Hamilton RG. Near-fatal anaphylaxis after
Hymenoptera venom immunotherapy. J Allergy Clin Immunol. 1998;102:527-8.
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Urticaria Induced by Ingestion of Anemonia sulcata De Aramburu Mera T1, Labella Álvarez M1, Baynova K1, Bartolomé Zavala B2, Prados Castaño M1
1Department of Allergology, University Hospital Virgen del Rocío,
Seville, Spain
2Roxall, R&D Department, Bilbao, Spain
J Investig Allergol Clin Immunol 2018; Vol. 28(3): 208-209 doi: 10.18176/jiaci.0244
Key words: Urticaria. Anemonia sulcata. “Ortiguilla” allergy. IgE-binding bands.
Palabras clave: Urticaria. Anemonia sulcata. Alergia a “ortiguilla”. Bandas IgE.
The anemone Anemonia sulcata is a species of anthozoan cnidarian belonging to the Actiniidae family. It is found in the Mediterranean Sea and the Atlantic Ocean, mainly near the province of Cadiz in the south of Spain, where it is commonly called “ortiguilla” [1]. It lives on rocks in areas of intense sunlight, up to a depth of 20 meters, and is harvested for human consumption. A sulcata is commercially available. This nettle-like anemone has toxic organelles called cnidocysts, which can inject venom with their microscopic harpoon-like structures and cause toxic reactions [2,3]. It is generally prepared by marinating in vinegar (with the nettles remaining attached) and then fried. The ability to sting disappears after this process. Toxic reactions have been reported after contact with A sulcata, although, to date, none have been documented after ingestion when it is prepared in this manner [3]. A sulcata is commercially available as a labeled product in our area.
We report a case of a patient who experienced urticaria after ingestion of fried “ortiguillas”. We detected IgE-reactive proteins of 69, 55, 40, 37, and 35 kDa, thus potentially explaining the symptoms observed.
The patient was a 47-year-old man, who was a cook by profession. He had a medical history of mild allergic rhinitis due to mite allergy. He was referred to our allergy department from the emergency room after presenting with hives on his torso, facial erythema, and pharyngeal pruritus. His urticaria occurred a few minutes after he had eaten an “ortiguilla” fried in olive oil. In the emergency room, the patient was treated with parenteral methylprednisolone and dexchlorpheniramine and recovered within 2 hours. No cofactors were identified in the episode. He has since tolerated fish and seafood. He reported having handled “ortiguillas” at work with gloves and never having experienced these symptoms. He had previously eaten “ortiguillas” with good tolerance.
We performed prick-by-prick tests with raw and fried “ortiguilla”. The results were positive, with wheals measuring 14 mm and 10 mm, respectively. Skin tests with raw and fried “ortiguillas” were also carried out in 10 healthy controls, whose results were negative.
The patient underwent skin prick tests (SPTs) for the most common aeroallergens in our area (mites, pollens, fungi, latex, Anisakis simplex, and dander from cat, dog, and horse) and
Manuscript received December 12, 2017; accepted for publication February 16, 2018.
Maria Beatrice Bilò Allergy Unit, Department of Internal Medicine University Hospital of Ancona Via Conca 71, 60126 Ancona, Italy E-mail: MariaBeatrice.Bilo@ospedaliriuniti.marche.it 5. Cox L, Larenas-Linnemann D, Lockey RF, Passalacqua G.
Speaking the same language: The World Allergy Organization Subcutaneous Immunotherapy Systemic Reaction Grading System. J Allergy Clin Immunol. 2010;125:569-74.
6. Mueller HL. Diagnosis and treatment of insect sensitivity. J Asthma Res. 1966;3:331-3
7. Blank S, Seismann H, Michel Y, McIntyre M, Cifuentes L, Braren I, et al. Api m 10, a genuine A. mellifera venom allergen, is clinically relevant but underrepresented in therapeutic extracts. Allergy. 2011;66:1322-9.
8. Severino MG, Campi P, Macchia D, Manfredi M, Turillazzi S, Spadolini I, et al. European Polistes venom allergy. Allergy. 2006 Jul;61(7):860-3.
9. Schiener M, Eberlein B, Moreno-Aguilar C, Pietsch G, Serrano P, McIntyre M, et al. Application of recombinant antigen 5 allergens from seven allergy-relevant Hymenoptera species in diagnostics. Allergy. 2017;72:98-108.
10. Birnbaum J, Ramadour M, Magnan A, Vervloet D. Hymenoptera ultra-rush venom immunotherapy (210 min): a safety study and risk factors. Clin Exp Allergy. 2003;33:58-64.
