Late Diagnosis of Anaphylactic Reaction to Gadolinium-Based

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Conflicts of Interest Late Diagnosis of Anaphylactic Reaction to The authors declare that they have no conflicts of interest. Gadolinium-Based Contrast Media by Skin Tests 10 Years After Onset References Harr T, Jandus P 1. Di Bona D, Albanesi M, Giliberti LA, Nico A, Rossi MP, Caiaffa Division of Immunology and Allergology, Department of Medical MF, et al. Desensitization for immediate hypersensitivity to Specialties, University Hospital and Medical Faculty, Geneva, oral dimethyl fumarate (Tecfidera). J Allergy Clin Immunol Switzerland Pract. 2017;5(3):821-2. 2. Linker RA, Gold R. Dimethyl fumarate for treatment of multiple J Investig Allergol Clin Immunol 2018; Vol. 28(3): 203-205 sclerosis: mechanism of action, effectiveness, and side effects. doi: 10.18176/jiaci.0240 Curr Neurol Neurosci Rep. 2013;13(11):394. 3. Bomprezzi R. Dimethyl fumarate in the treatment of Key words: Gadolinium-based contrast agents. Magnetic resonance relapsing–remitting multiple sclerosis: an overview. Ther Adv imaging. Skin prick tests. Intradermal tests. Neurol Disord. 2015;8(1):20-30. Palabras clave: Gadolinio. Resonancia magnética. Pruebas cutáneas 4. Pichler WJ, Tilch J. The lymphocyte transformation test in the prick. Pruebas intracutáneas. diagnosis of drug hypersensitivity. Allergy. 2004;59:809-20. 5. Jurado-Palomo J, Cabañas R, Prior N, Bobolea ID, Fiandor- Román AM, López-Serrano MC, et al. Use of the lymphocyte transformation test in the diagnosis of DRESS syndrome induced by ceftriaxone and piperacillin-tazobactam: two case Gadolinium-based contrast agents (GBCAs) have reports. J Investig Allergol Clin Immunol. 2010;20(5):433-6. paramagnetic properties that are used to enhance the 6. Qiao HL, Gao N, Jia LJ, Yang J, Tian X. Specific IgG antibodies diagnostic value of MRI studies. Iodinated contrast media were in sera in patients with penicillin allergy. Clin Exp Med. introduced in the 1920s; however, gadolinium-based contrast 2009;9(2):105-11. agents were first approved for use by the United States Food 7. Fallahi P, Ferrari SM, Ruffilli I, Elia G, Biricotti M, Vita R, et al and Drug Administration (FDA) in 1988 [1]. The association of other autoimmune diseases in patients with A 36-year-old white woman presented with sudden onset of autoimmune thyroiditis: Review of the literature and report of dyspnea and reduced consciousness shortly after the application a large series of patients. Autoimmun Rev. 2016;15(12):1125- of paramagnetic contrast media (product unknown) during a 8. cerebral MRI in summer 2007. Her condition improved 8. Seidel P, Roth M. Anti-inflammatory dimethylfumarate: a rapidly after treatment with antihistamines, corticosteroids, potential new therapy for asthma? Mediators Inflamm. and intravenous hydration. She has not undergone MRI since 2013;2013:875403. then. The patient had been diagnosed with ulcerative colitis 9. Stingeni L, Neve D, Tondi V, Bacci M, Lisi P. Immunological and nonallergic asthma. In the following years, she developed contact urticaria caused by dimethyl fumarate. Contact Behçet disease and bronchiectasis. She changed physicians Dermatitis. 2014;71(3):180-3. several times, with loss of her documentation. In summer 2017, an allergy work-up was performed without documentation to assess the reaction she experienced in 2007. At that time, her Behçet disease and ulcerative colitis were in remission under treatment with colchicine and azathioprine, and her asthma Manuscript received November 26, 2017; accepted for was controlled with budesonide and formoterol. publication February 13, 2018. Ten years after reacting to paramagnetic contrast media, the patient was found to have positive results in skin prick tests Darío Antolín-Amerigo (SPT, 1:1) (Figure) and intradermal tests (IDT, 1:100) with Servicio de Enfermedades del Sistema Inmune-Alergia gadobutrol (Gadovist) and gadoterate meglumine (Artirem, Hospital Universitario Príncipe de Asturias Carretera de Alcalá-Meco s/n Dotarem) and negative intradermal test results (IDT, 1:10) 28085 Alcalá de Henares, Spain with gadobenate dimeglumine (Multihance) and gadopentetate E-mail: [email protected] dimeglumine (Magnograf). SPTs (1:1) and IDTs (1:10) for iodinated contrast media (ioxithalamate, ioxaglate, iohexol, iomeprol, iobitridol, iopromide, iodixanol) were all negative. The basal tryptase level was in the normal range (3.4 μg/L, N<11; Thermo Fisher). There were no other signs of cutaneous or systemic mastocytosis. Prick tests for atopy were negative with inhalant allergens. Based on the skin test results, hypersensitivity to macrocyclic GBCAs was suspected. GBCAs have been used in more than 100 million patients worldwide [1]. Immediate hypersensitivity reactions to GBCAs

1 patient developed mild urticaria upon administration [7]. Thus, screening of individuals with risk factors does not seem to be effective. The pathophysiological mechanism of immediate Histamine hypersensitivity reactions is not always clear. However, an IgE-mediated mechanism has been suggested based on positive skin test results in patients with immediate reactions to GBCAs [2]. GBCAs have been implicated in the Gadovist development of nephrogenic systemic fibrosis, particularly in patients with kidney disease. Nonimmediate hypersensitivity reactions to GBCAs are rare and should also be considered [8]. Hypersensitivity reactions to GBCAs should be investigated Artirem using SPTs with undiluted GBCAs followed by IDTs at dilutions of 1:1000-1:10 [4]. In patients who have experienced a reaction to GBCAs in the past, recommendations regarding subsequent use of paramagnetic contrast agents are often needed. However, Dotarem premedication with antihistamines and corticosteroids was not systematically studied in larger patient groups. Furthermore, premedication with antihistamines and corticosteroids was not effective in a small cohort of patients with documented Magnograf breakthrough reactions [9]. The decision to administer an alternative agent might be facilitated by skin testing. If the responsible agent shows a positive result and a skin test– negative alternative can be found, repeated reaction to the skin test-negative GBCA is unlikely to occur [9]. In this context, Multihence the classification of GBCAs into linear and macrocyclic agents based on their molecular structure might facilitate choice [4]. However, alternatives should be assessed with challenge tests to verify tolerance. In studies of patients with immediate hypersensitivity to drugs, skin tests are more likely to be positive the shorter the time elapsed since the clinical reaction. Figure. Positive prick test results with gadolinium-based contrast agents. Arrows indicate areas of skin testing with a negative control and negative In addition, skin tests are more likely to turn negative the skin testing test results for Multihance and Magnograf. longer the time after the reaction (67.8% in a 5-year follow-up in cephalosporin hypersensitivity [11]). Diagnostic criteria are mostly empiric, and consensus guidelines are primarily based on limited case series, have an estimated adverse event rate of 0.07% to 2.4% [2]. observational studies, and expert opinions. GBCAs have Urticaria is the most common manifestation, occurring in up received little attention in randomized controlled trials [7]. to 90% of hypersensitivity reactions [3]. With a frequency of Here, we report the first case with positive skin test results 0.004%-0.01% of cases, GBCA-induced anaphylaxis is rare [3]. 10 years after an anaphylactic reaction to GBCAs in Patients who have experienced prior immediate reactions to an immunosuppressed patient. This case illustrates that GBCAs have the highest risk for a recurrent reaction upon hypersensitivity with positive IDT and SPT results might subsequent readministration, with an estimated frequency of persist over several years. We stress that an undiluted positive reaction of 30% [3]. Reactions have been reported to be more SPT result should be considered a true positive. IDT should frequent after administration of gadobenate dimeglumine and only be carried out by experienced personnel after negative gadoteridol and after abdominal scans (0.01%) than brain scans prick testing, since it entails a risk for the patient and is not (0.005%) or spine scans (0.003%) [4]. Patients are at a higher necessary after positive SPT results. risk of experiencing adverse reactions if they have concomitant A classification of GBCAs into linear and macrocyclic atopic diseases, multiple allergies, and prior anaphylactic structures might facilitate identification of cross-reactivity. reactions, as well as after multiple exposures to GBCAs [5]. This approach needs to be validated in larger studies. However, anaphylaxis may occur upon first exposure with no known risk factors, as shown in a case report by Hasdenteufel Funding et al [6]. A mortality rate of 0.0019% (3 of 158 796 cases) has been estimated [5]. The FDA reported an overall mortality rate The authors declare that no funding was received for the of 0.00008% from 2004 to 2009 (40 deaths per 51 million MRI present study. contrast medium doses administered) [5]. In a recent prospective study, 151 patients at risk for Conflicts of Interest reactions were evaluated by skin testing before administration of GBCAs. No positive skin test results were detected, and only The authors declare that they have no conflicts of interest.

References Hymenoptera Venom Immunotherapy: How to 1. Fok JS, Smith WB. Hypersensitivity reactions to gadolinium- Safely Switch to the Same Venom From a Different based contrast agents. Curr Opin Allergy Clin Immunol. Manufacturer 2017;17:241-6. 2. Carr T. Pathophysiology of Immediate Reactions to Injectable Bilò MB1, Martini M1, Berra D2, Scarpa A3, Losappio L4, Gadolinium-based Contrast Agents Top Magn Reson Imaging. Quercia O5, Lodi Rizzini F6, Bignardi D7, Cortellini G8, Zisa G9, 2016;25:265-8. Del Giudice A10, Manzotti G11, Marcotulli C12, Murzilli F13, Cilia 3. Jung JW, Kang HR, Kim MH, Lee W, Min KU, Han MH, Cho SH. M14, Pravettoni V15, Borrelli P16, Pastorello EA4 Immediate hypersensitivity reaction to gadolinium-based MR 1Allergy Unit, Department of Internal Medicine, University contrast media. Radiology. 2012;264:414-22. Hospital of Ancona - Allergy and Clinical Immunology School, 4. Rosado Ingelmo A, Doña Diaz I, Cabañas Moreno R, Moya Università Politecnica delle Marche, Ancona, Italy Quesada MC, García-Avilés C, García Nuñez I, et al. Clinical 2Allergology Service, Pneumology Unit, Busto Arsizio Hospital, Practice Guidelines for Diagnosis and Management of Varese, Italy Hypersensitivity Reactions to Contrast Media. J Investig 3Allergy Unit - Dermatology, Department of Surgery, Hospital of Allergol Clin Immunol. 2016;26:144-55 Mirano, Mirano, Italy 5. Prince MR, Zhang H, Zou Z, Staron RB, Brill PW. Incidence 4Department of Allergy and Immunology, Asst Grande Ospedale of immediate gadolinium contrast media reactions. AJR Am J Metropolitano Niguarda, University of Milano, Italy Roentgenol. 2011;196:W138-43. 5Allergology High Specialty Unit General Medicine, Faenza 6. Hasdenteufel F, Luyasu S, Renaudin JM, Paquay JL, Carbutti Hospital Ravenna, Ravenna, Italy G, Beaudouin E, et al. Anaphylactic shock after first exposure 6Allergy Unit, Spedali Civili Brescia, Department of Clinical to gadoterate meglumine: two case reports documented and Experimental Sciences, University of Brescia, Brescia, Italy by positive allergy assessment. J Allergy Clin Immunol. 7Allergy Unit, Department of Internal Medicine, Ospedale 2008;121:527-8. Policlinico San Martino of Genoa, Genoa, Italy 7. Tepetam FM, Ciftaslan N, Oruc O, Duman D, Agca M, Bulut 8Internal Medicine and Rheumatology Unit, Rimini Hospital, İ, et al. Should patients with risk factors be tested for Rimini, Italy hypersensitivity to contrast media: a prospective study. Radiol 9Allergy Unit, Department of Internal Medicine, Azienda Med. 2016;121:660-7. Ospedaliero-Universitaria Maggiore della Carità, Novara, Italy 8. Nagai H, Nishigori C. A delayed reaction to the magnetic 10Allergy Unit, Department of Internal Medicine, Hospital Martini resonance imaging contrast agent gadobutrol. J Allergy Clin of Turin, Turin, Italy Immunol Pract. 2017;5:850-1. 11Allergy Unit, Department of Internal Medicine, Treviglio 9. Dillman JR, Ellis JH, Cohan RH, Strouse PJ, Jan SC. Allergic-like General Hospital, ASST Bergamo Ovest, Treviglio, Italy breakthrough reactions to gadolinium contrast agents after 12Allergy Unit, Department of Pneumology, Asst Garda, corticosteroid and antihistamine premedication. AJR Am J Desenzano, Italy Roentgenol. 2008;190:187. 13Allergy Unit, Department of Internal Medicine, S.S. Filippo and 10. L Chiriac AM, Audurier Y, Bousquet PJ, Demoly P. Clinical value Nicola Hospital of Avezzano, Azienda Sanitaria Locale n. 1 dell’ of negative skin tests to gadolinium contrast agents. Allergy. Abruzzo, Avezzano, Italy 2011;66:1504-6. 14Allergy Unit, Health Care Service, Scilla, Italy 11. Romano A, Gaeta F, Valluzzi RL, Zaffiro A, Caruso C, Quaratino 15UOC General Medicine – Immunology and Allergology – IRCCS D. Natural evolution of skin-test sensitivity in patients with Foundation Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy IgE-mediated hypersensitivity to cephalosporins. Allergy. 16Allergy Unit, Department of Internal Medicine, U. Parini 2014;69:806-9 Regional Hospital, Aosta, Italy

J Investig Allergol Clin Immunol 2018; Vol. 28(3): 205-208 doi: 10.18176/jiaci.0242

Manuscript received August 13, 2017; accepted for publication February 13, 2018. Key words: Extract switching. Hymenoptera. Immunotherapy. Mastocytosis. Safety. Peter Jandus Palabras clave: Cambio de extracto. Himenóptero. Inmunoterapia. Division of Immunology and Allergology Mastocitosis. Seguridad. Department of Medical Specialties University Hospital and Medical Faculty of Geneva Rue Gabrielle Perret-Gentil 4 1211 Geneva 14 Switzerland E-mail: [email protected] 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].