Hypersensitivity and Cross-Reactivity References

60 Practitioner's Corner

Funding Paramagnetic Contrast Media: Hypersensitivity and The authors declare that no funding was received for the Cross-Reactivity present study.

Conflicts of Interest Moreno Escobosa MC, Cruz Granados S Allergy Unit, Hospital Torrecárdenas, Almería, Spain The authors declare that they have no conflicts of interest. J Investig Allergol Clin Immunol 2018; Vol. 28(1): 60-62 doi: 10.18176/jiaci.0210 References Key words: Gadobutrol. Gadolinium-based contrast hypersensitivity. 1. Scheurer S, Lauer I, Foetisch K, San Miguel Moncin M, Retzek Cross-reactivity between gadolinium contrast media. Gadoteridol. M, et al. Strong allergenicity of Pru av 3, the lipid transfer Paramagnetic contrast media. protein from cherry, is related to high stability against thermal Palabras clave: Gadobutrol. Hipersensibilidad a contrastes de gadolinio. processing and digestion. J Allergy Clin Immunol. 2004 Reactividad cruzada entre contrastes de gadolinio. Medios de contraste Oct;114(4):900-7. paramagnéticos. 2. Asero R, Mistrello G, Roncarolo D, Vriesc S, Gautierd MF, Ciuranae C, et al. Lipid Transfer Protein: A Pan-Allergen in Plant-Derived Foods That Is Highly Resistant to Pepsin Digestion. Int Arch Allergy Immunol. 2000;122:20-32. 3. Pastorello EA, Robino AM. Clinical role of lipid transfer Gadolinium-based contrast media have been used for proteins in food allergy. Mol Nutr Food Res. 2004;48:356-62. 25 years for contrast-enhanced magnetic resonance imaging 4. Fernández Rivas M. Food Allergy in Alergológica-2005. J (MRI) because of their safety and low rates of adverse effects Investig Allergol Clin Immunol. 2009;19:S2:37-44. (0.3%) [1]. The incidence of immediate hypersensitivity 5. Fernández-Rivas M, González-Mancebo E, Rodríguez-Pérez reactions to magnetic resonance contrast media is 0.079% in R, Benito C, Sánchez-Monge R, Salcedo G, et al. Clinically adults and 0.04% in children [2]. Reactions have been reported relevant peach allergy is related to peach lipid transfer protein, more frequently for abdominal explorations (0.01%) than Pru p 3, in the Spanish population. J Allergy Clin Immunol. for explorations of the brain (0.005%) and spine (0.003%). 2003;112:789-95 The most common reaction is urticaria (50%-90% of cases), 6. Egger M, Hauser M, Mari A, Ferreira F, Gadermaier G. The while anaphylaxis has an incidence of 0.004% to 0.01%. role of lipid transfer proteins in allergic diseases. Curr Allergy These contrast media can be classified based on their net Asthma Rep. 2010 Sep;10(5):326-35. charge as ionic or nonionic and on their structure as linear or 7. Wangorsch A. Molecular cloning of plane pollen allergen Pla macrocyclic [1,2]. a 3 and its utility as diagnostic marker for peach associated A 45-year-old man diagnosed with astrocytoma was plane pollen allergy. Clin Exp Allergy. 2016;46(5):764-74. sent to our Allergy Unit because he developed facial edema, 8. Pascal M, Muñoz-Cano R, Reina Z, Palacín A, Vilella R, Picado generalized erythema, dyspnea, rhinitis, and edema in his hands C, et al. Lipid transfer protein syndrome: clinical pattern, and feet 5 minutes after starting an infusion with gadobutrol. cofactor effect and profile of molecular sensitization to plant- The infusion was stopped immediately, and he was treated with foods and pollens. Clin Exp Allergy. 2012:42;1529-39. parenteral methylprednisolone and dexchlorpheniramine. He 9. Goikoetxea MJ, Berroa F, Cabrera-Freitag P, Ferrer M, Núñez- had received this contrast media previously without adverse Córdoba JM, Sanz ML, et al. Do Skin Prick Test and In Vitro reactions. An allergy study was programmed once informed Techniques Diagnose Sensitization to Peach Lipid Transfer consent was obtained. Since the patient did not wish to Protein and Profilin Equally Well in Allergy to Plant Food and undergo tests involving gadobutrol, we carried out prick and Pollen? J Investig Allergol Clin Immunol. 2015;25(4):283-7. intradermal tests with other gadolinium-based contrast media 10. Palacín A, Gómez-Casado C, Rivas LA, Aguirre J, Tordesillas L, (Table). The patient had to receive a gadolinium contrast Bartra J, et al. Graph based study of allergen cross-reactivity media for disease control; therefore, we proposed a challenge of plant lipid transfer proteins (LTPs) using microarray in a test with gadoteridol, because the results of the prick and multicenter study. PLoS One. 2012;7(12);e50799. intradermal tests were negative and positive with other agents. Twenty-five minutes after administration, the patient began to experience facial erythema, palmar pruritus, tinnitus, urticaria on his arms and knees, and mild dyspnea. He was treated Manuscript received June 28, 2017; accepted for publication immediately with parenteral epinephrine, methylprednisolone, October 17, 2017. and dexchlorpheniramine. Hypersensitivity reactions with gadolinium-based contrast Maria Basagaña Torrentó agents are very rare, with very few cases reported in the Allergy Unit literature. In 2007, Kalogeromitros et al [3] reported a case Hospital Universitari Germans Trias i Pujol Crta/ Del Canyet, s/n of anaphylaxis after infusion of gadobenate with a positive 08916 Badalona, Spain intradermal test result. Hasdenteufel et al [4] reported 2 cases E-mail: [email protected] of anaphylactic shock with positive results in skin tests with

Table. Results of the Allergy Work-up

Commercial Name Agent Chemical Structure Prick Test (Undiluted) Intradermal Test (1/10)

MultiHance Gadobenate Linear ionic chelate Negative Positive Omniscan Gadodiamide Linear nonionic chelate Negative Positive Dotarem Gadoterate Macrocyclic ionic chelate Negative Positive ProHance Gadoteridol Macrocyclic nonionic chelate Negative Negative

gadopentetate in 2008. In 2010, Galera et al [5] reported suggested the role of transmetallation and competition between 2 cases of anaphylactic shock following the administration Gd3+ with Ca2+ for cellular processes. Gd3+ is very similar to of gadoteridol and gadobenate, respectively. In both patients, Ca2+ in size, thus resulting in competition with Ca2+ in cellular intradermal tests were positive to the contrast media involved and biochemical processes. It is capable of inhibiting voltage- and negative to the remaining agents studied. In 2012, Tomás gated calcium channels [10]. Although the immediate reaction et al [6] reported a case of urticaria in a 17-year-old girl suggests an IgE-mediated mechanism, another explanation and a generalized rash in a 4-year-old girl after exposure to could be that gadoteridol had led to cellular degranulation gadopentetate and gadoteridol, respectively. Skin test results with release of a mediator that had been able to produce an were negative in the first case, and a challenge with gadoteridol anaphylactoid reaction in the present case. yielded a negative result. In the second case, prick tests were In conclusion, we present a case of anaphylaxis to negative for all the agents tested and intradermal tests were gadobutrol. Given that a gadolinium-based contrast medium positive for gadoteridol, gadobutrol, and gadoxetate and was an essential part of the patient’s management, an allergy negative for gadopentetate and gadobenate. The result of work-up was performed with other available contrast media. the challenge test with gadobenate was negative. In 2015, Skin test results were positive to all the agents studied except Takahashi et al [7] reported a case of fatal anaphylaxis gadoteridol. A challenge test with this agent yielded a positive associated with the use of gadoteridol. Autopsy revealed result, and the patient experienced an immediate reaction; widespread skin rash and severe laryngeal edema, which are however, we were unable to demonstrate an IgE-mediated typical findings of anaphylaxis, in addition to a very high pathway. We think that there may be cross-reactivity between concentration of serum tryptase. macrocyclic agents and between linear and macrocyclic Gadobutrol, the gadolinium-based contrast medium contrast media, although the few published reports do not responsible for the initial symptoms in the present case, is address this issue. Therefore, more studies are necessary to included in the macrocyclic nonionic group. As skin tests assess cross-reactivity. We considered that the challenge test were positive for linear chain agents and although gadoteridol must be performed using an alternative gadolinium-based was a macrocyclic agent, the negative results in the prick and contrast medium that yielded a negative skin test result because intradermal tests led us to perform a challenge test with this of the possibility of false-negative results and the implication agent, as indicated in the report by Tomás et al [6]. Although of other immunologic and nonimmunologic reactions. the skin test results were negative in the present case (as with Tomás et al), the challenge test result—surprisingly—was Funding positive, ie, the patient developed an anaphylactic reaction. The authors declare that no funding was received for the According to the study published by Chiriac et al [8] in 2011, present study. the negative predictive value of gadolinium skin tests was excellent and although the data reported are based on a small sample and the severity of the initial reactions was mild, we Conflicts of Interest thought that the patient would tolerate this contrast medium. The authors declare that they have no conflicts of interest. The negative skin test results with gadoteridol did not allow us to rule out the possible involvement of the macrocyclic structure as being responsible for the reaction with gadoteridol, References because the patient had a positive skin test result to gadoterate, another macrocyclic chelate, as reported by Galera et al [5]. 1. Granata V, Cascella M, Fusco R, Aprovitola N, Catalano O, Furthermore, Ideé and Corot [9] reported that gadoteridol Filice S, et al. Immediate adverse reactions to gadolinium- and gadoterate are both tetra-aza macrocyclic ligands that based MR contrast media: A retrospective analysis on 10,608 differ in the presence of an isopropanol moiety in the case of examinations. BioMed Research International. 2016. http:// gadoteridol. Therefore, we believe that the skin test results dx.doi.org/10.1155/2016/3918292. could be related to this difference in structure. We put forward 2. Rosado Ingelmo A, Doña Díaz I, Cabañas Moreno R, Moya the hypothesis that another common epitope is present in all Quesada MC, García-Avilés C, García Núñez I, et al. Clinical the gadolinium contrast media tested in the present study and practice guidelines for diagnosis and management of that this may have been responsible for the positive skin test hypersensitivity reactions to contrast media. J Investig Allergol results to linear and macrocyclic agents. Various studies have Clin Immunol. 2016;26(3):144-55.

3. Kalogeromitros DC, Makris MP, Aggelides XS, Spanoudaki N, Gregoriou SG, Avgerinou G, et al. Anaphylaxis to gadobenate Acquired Angioedema With Anti–C1-inhibitor dimeglumine (Multihance®): A case report. Int Arch Allergy Autoantibodies During Assisted Reproduction Immunol. 2007;144:150-4. Techniques 4. Hasdenteufel F, Luyasu S, Renaudin JM, Paquay JL, Carbutti G, Beaudouin E, et al. Anaphylactic shock after first exposure Marbán Bermejo E1, Caballero T2,3, López-Trascasa M4, Caballero to gadoterate meglumine: Two case reports documented Peregrín P1, Gil Herrera J1 by positive allergy assessment. J Allergy Clin Immunol. 1Clínica Tambre, Madrid, Spain 2008;121:527-8. 2Servicio de Alergia, Hospital La Paz Health Research Institute 5. Galera C, Pur Ozygit L, Cavigioli S, Bousquet PJ, Demoly P. (IdiPaz), Madrid, Spain Gadoteridol-induced anaphylaxis -not a class allergy. Allergy. 3BiomedicalResearch Network on Rare Diseases (CIBERER, 2010;65(1):132-4. U754), Madrid, Spain 6. Tomás M, Fuentes Aparicio V, Zapatero Remón L, Alonso 4Unidad Inmunología, Hospital La Paz Health Research Institute Lebrero E, Infante Herrero S. Skin reactions to gadolinium- (Idipaz), Madrid, Spain based contrast media. J Investig Allergol Clin Immunol. 2012;22(4):292-3. J Investig Allergol Clin Immunol 2018; Vol. 28(1): 62-64 7. Takahashi S, Takada A, Saito K, Hara M, Yoneyama K, Nakanishi doi: 10.18176/jiaci.0213 H. Fatal anaphylaxis associated with the gadolinium-based contrast agent gadoteridol (ProHance®). J Investig Allergol Key words: Acquired angioedema. C1-Inhibitor deficiency. Autoimmunity. Clin Immunol. 2015;25(5):366-7. Assisted reproduction techniques. 8. Chiriac AM, Audurier Y, Bousquet PJ, Demoly P. Clinical value Palabras clave: Angioedema adquirido. Déficit de C1-Inhibidor. of negative skin tests to gadolinium contrast agents. Allergy. Autoinmunidad. Técnicas de reproducción asistida. 2011;66:1504-6. 9. Ideé JM, Corot C. Anaphylactic shock after first exposure to a macrocyclic gadolinium chelate: A few comments. J Allergy Clin Immunol. 2008;122(1):215-6. 10. Rogosnitzky M, Branch S. Gadolinium-based contrast agent C1-inhibitor (C1-INH) deficiency activates the contact toxicity: a review of known and proposed mechanism. system, resulting in increased bradykinin, vascular Biometals. 2016;29:365-76. hyperpermeability, and recurrent, localized, and self-limiting acute angioedema attacks [1]. Angioedema is classified as hereditary (C1-INH-HAE) or acquired (C1-INH-AAE) [1]. C1-INH-HAE is an autosomal dominant inherited disorder Manuscript received June 21, 2017; accepted for publication caused by mutations in the C1-INH gene, with an estimated October 20, 2017. prevalence of approximately 1/50 000 inhabitants [1]. C1-INH- AAE is much less prevalent (around 1/500 000) and is often M Carmen Moreno Escobosa associated with the presence of anti-C1-INH autoantibodies Unidad de Alergia and/or lymphoproliferative disorders [1,2]. Hospital Torrecárdenas Estrogens and pregnancy can worsen the clinical C/ Hermandad de Donantes de Sangre, s/n expression of C1-INH-HAE [3-5], whereas the fertility rate 04009 Almería, Spain is similar in patients with C1-INH-HAE and in the general E-mail: [email protected] population [3]. However, to our knowledge, there are no previous reports on pregnancy and C1-INH-AAE. We present the case of a 38-year-old woman who attended our clinic wishing to become pregnant. She underwent 3 intrauterine insemination cycles with sperm from a donor, which were unsuccessful. Five months after having initiated assisted fertilization techniques, she experienced a first episode of nonerythematous, nonpruriginous angioedema affecting her feet. The patient had previously tolerated oral contraceptives containing estrogens (drospirenone/ ethinylestradiol). Thereafter, she underwent ovarian stimulation with recombinant human luteinizing hormone, recombinant human follicle-stimulating hormone, recombinant human chorionic gonadotropin, and micronized natural progesterone for in vitro fertilization (IVF). The embryos were cryopreserved owing to her high progesterone levels. During this period, she experienced several self-limiting acute edema episodes affecting the upper/lower limbs. One of these episodes also affected the glottis and required admission