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Letters / Ann Allergy Asthma Immunol 111 (2013) 567e579

Late elicitation of maculopapular exanthemas to iodinated contrast media after first exposure Contrast media are known to elicit hypersensitivity reactions based on either an immediate- or delayed-type pathogenesis.1 The term late or delayed adverse reactions is used by radiologists for any adverse reaction occurring 1 hour to 1 week after the injection, including various rashes, nausea, headaches, muscular pain, and fever.2 Maculopapular exanthemas are often observed, and a Tcellemediated mechanism is often present as proven by delayed positive patch or intradermal tests.3 Allergologists use the term delayed more in the sense of reactions occurring 1 to 2 days after the last exposure to an allergen, which are typically mediated by T cells. An immunologically naive patient first exposed to a medication usually does not react on exposure to a single drug dose but requires repeated doses during a sensitization phase lasting typically 5 to 10 days, except after exposure to a cross-reactive molecule.4 In previously sensitized individuals, exanthemas typically occur within a period of 1 to 2 days on reexposure. Apparently for contrast media, a first single exposure is sufficient to induce sensitization and elicit a maculopapular exanthema. We describe 5 patients who were exposed to a particular contrast media and who developed typical maculopapular exanthemas within a period of 5 to 10 days. All received for the first time ever the culprit contrast media (iomeprol 4 times, iodixanol 1 time). In 2 patients, previous exposure to an unknown medium and to another contrast medium was documented. No previous adverse drug reactions to any medications were known. A typical macular, papular, or maculopapular exanthema occurred on day 5 (1 time), day 8 (3 times), and day 10 (1 time), respectively, and lasted for up to a week (Table 1). In all patients, an allergological workup within a period of 1 to 5 months after the reaction was performed. This workup included prick, intradermal, and patch tests with test series of contrast media and any other concomitantly taken drugs.3 T-cellemediated allergy to the contrast media in question was documented by positive skin test results in 3 patients with monosensitization and a cross-reactive pattern with positive skin test results to several contrast media in 2 patients (Table 1). All other concomitantly given drugs were later tolerated by the patients. One patient was later unintentionally reexposed to the culprit contrast medium and reacted within 2 days with the same clinical manifestation. Several cases mentioning this particular time pattern have been previously described.3,5,6 It has also been previously reported that, particularly in patients who had not been previously exposed to contrast media, the onset of exanthemas was often after 6 days or more, whereas previously exposed or skin tested patients reacted mainly within 1 day.3,7,8 A considerable percentage of these latter patients had positive delayed skin test results after the incident. In

another large study, approximately 5% of the patients had delayed reactions starting beyond day 5, and in some of those patients the delayed skin test results were positive.9 This finding implies that a single dose of a contrast medium, also in patients without risk factors such as renal insufficiency, may concurrently induce sensitization and then elicitation of an exanthema in the typical period of 5 to 10 days. Renewed exposure results, as expected, in an exanthema within few days, as demonstrated in one of the patients. This finding is unexpected because contrast media are thought to be chemically inert; however, antigen-processing dependent and independent pathways in delayed reactions to contrast media have been previously described.10 This finding suggests that direct interaction with T-cell receptors (pharmacological-interaction concept) or major histocompatibility complex molecules and classic activation by major histocompatibility complex II on antigen-presenting cells may be involved in these hypersensitivity reactions.10 It has been reported that 90% of intravascular applied contrast media are excreted unchanged by the renal route within 1 to 2 days.11 On the other hand, it has been reported that biliary and transmucosal excretion may take place through the small bowel.12,13 Traces of angiographic contrast media may remain for several days to weeks in the gastrointestinal tract, leading to unexpected contrast on further radiographic examinations of the abdomen (Prof. Lukas Degen, Gastroenterology University Hospital Basel, personal oral communication). Therefore, traces of contrast media may also reach the skin. In humans allergic contact dermatitis on first exposure to potent contact allergens has been observed.14 Allergen persistence in the skin, resulting in sensitization and elicitation, is suspected. In a mouse model, sensitization and elicitation to a single application of potent contact allergens (eg, dinitrofluorobenzene and fluorescein isothiocyanate) has also been demonstrated. The hapten fluorescein isothiocyanate persisted in the skin for up to 14 days, explaining contact dermatitis 6 to 7 days after single exposure.15 However, these are potent contact allergens and are highly immunogenic if applied to the skin. Case reports and series from the literature5e9 and our observations suggest that after a single dose of contrast medium prolonged exposure may be present, which can result in sensitization and elicitation of exanthemas. It can only be speculated whether the gut- or skin-associated immune system is involved in the sensitization process. We are not aware of any other systemic drugs for which this particular consecutive pattern of sensitization and elicitation of clinical symptoms from a single dose exposure has been reported.

Table 1 Eliciting contrast media, period, and skin testepositive agents Patient No./Sex/Age, y

Contrast media/indication

Period, d

1/F/62 2/F/66 3/F/81 4/M/55

Iomeprol/coronarography Iomeprol/coronarography Iodixanol/coronarography Iomeprol/angiography

8 5 8 8

5/M/64

Iomeprol/coronarography

10

Abbreviations: ADR ¼ adverse drug reaction; CM ¼ contrast media.

Disclosures: Authors have nothing to disclose.

Positive skin test results

Exposure to CM

Iomeprol, iodixanol, ioversol, iopamidol Iomeprol Iodixanol Iomeprol, iopentol, iohexol, iodixanol, iotrolan

First exposure Previous exposure unknown CM, no ADR First exposure First exposure, later reexposure with iomeprol: exanthema within 20 h Previous exposure 2001: unknown CM, 2005 iopromide, no ADR

Iomeprol

Letters / Ann Allergy Asthma Immunol 111 (2013) 567e579

The recognition of this pattern is of clinical relevance because in clinical situations usually a drug is not considered the cause of an exanthema after a single dose and a time lag of more than 3 to 5 days until occurrence of allergic manifestations. This could result in wrongly suspecting other drugs as culprits (eg, in patients undergoing coronary stent procedures, where typically platelet aggregation inhibitors, b-blockers, angiotensin-converting enzyme inhibitors, and lipid-lowering agents are simultaneously given). This could result in the unnecessary withdrawal of relevant medications. Andreas J. Bircher, Professor* Knut Brockow, Professory Martine Grosber, MDy Kathrin Scherer Hofmeier, Assistant Professor* *Allergy Unit Dermatology Clinic University Hospital Basel Basel, Switzerland y Dermatology Clinic TU Munich Munich, Germany [email protected] References [1] Brockow K, Christiansen C, Kanny G, et al. Management of hypersensitivity reactions to iodinated contrast media. Allergy. 2005;60:150e158. [2] Bellin M-F, Stacul F, Webb J, et al. Late adverse reactions to intravascular iodine based contrast media: an update. Eur Radiol. 2011;21:2305e2310.

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[3] Brockow K, Romano A, Aberer W, et al. Skin testing in patients with hypersensitivity reactions to iodinated contrast media: a European multicenter study. Allergy. 2009;64:234e241. [4] Bircher AJ, Scherer Hofmeier K. Drug hypersensitivity reactions: Inconsistency in the use of the classification of immediate and nonimmediate reactions. J Allergy Clin Immunol. 2012;129:263e264. [5] Courvoisier S, Bircher AJ. Delayed-type hypersensitivity to a nonionic, radioopaque contrast medium. Allergy. 1998;53:1221e1224. [6] Christiansen C, Dreborg S, Pichler W, Ekeli H. Macular exanthema appearing 5 days after X-ray contrast medium administration. Eur Radiol. 2002;12: S94eS97. [7] Akiyama M, Nakada T, Sueki H, Fujisawa R, Iijima M. Drug eruption caused by nonionic iodinated X-ray contrast media. Acad Radiol. 1998;5(suppl 1): S159eS161. [8] Nakada T, Akiyama M, Iijima M, Kato A, Maibach HI. Drug eruptions to contrast media in Japan. Clin Exp Dermatol. 2006;31:361e364. [9] Hosoya T, Yamaguchi K, Akutsu T, et al. Delayed adverse reactions to iodinated contrast media and their risk factors. Radiat Med. 2000;18: 39e45. [10] Keller M, Lerch M, Britschgi M, et al. Processing-dependent and -independent pathways for recognition of iodinated contrast media by specific human T cells. Clin Exp Allergy. 2010;40:257e268. [11] Pasternak JJ, Williamson EE. Clinical pharmacology, uses, and adverse reactions of iodinated contrast agents: a primer for the non-radiologist. Mayo Clin Proc. 2012;87:390e402. [12] Rosati G. Clinical pharmacology of iomeprol. Eur J Radiol. 1994;18(suppl 1): S51eS60. [13] Bourin M, Jolliet P, Ballereau F. An overview of the clinical pharmacokinetics of X-ray contrast media. Clin Pharmacokinet. 1997;32:180e193. [14] Kanerva L, Tarvainen K, Pinola A, et al. A single accidental exposure may result in a chemical burn, primary sensitization and allergic contact dermatitis. Contact Dermatitis. 1994;31:229e235. [15] Saint-Mezard P, Krasteva M, Chavagnac C, et al. Afferent and efferent phases of allergic contact dermatitis (ACD) can be induced after a single skin contact with haptens: evidence using a mouse model of primary ACD. J Investig Dermatol. 2003;120:641e647.

Occupational rhinitis, asthma, and contact urticaria caused by hydrolyzed wheat protein in hairdressers Hydrolyzed wheat protein (HWP) is a common ingredient in food and cosmetic products. Immediate hypersensitivity to HWP has been reported,1,2 and HWP present in foods may cause severe allergic reactions.3 HWP in cosmetic products has been reported to cause allergic contact urticaria (CU)1,4 and even to induce wheatdependent exercise-induced anaphylaxis (WDEIA) in consumers.5 We describe 2 hairdressers in whom the use of HWP-containing hairdressing products at work led to the development of HWP hypersensitivity, occupational rhinitis (OR), and occupational CU. One of them also developed occupational asthma (OA). In addition, both hairdressers developed symptoms consistent with WDEIA. Hairdresser 1 had milk allergy during infancy, with no allergies or atopic symptoms thereafter. After working as a hairdresser for 2 years, she developed watery rhinitis, conjunctivitis, asthma-like symptoms at work, and CU associated with the use of a sprayable hair conditioner (product 1). Her work-related rhinitis was associated with the use of product 1 and another hairspray (product 2), both of which contained HWP (laurdimonium hydroxypropyl HWP). She also experienced asthma symptoms at work when using these products or hair dyes. At the same time, she had several attacks of dyspnea, angioedema of the eyelids, and burning and tingling of the hands and soles when exercising after having eaten wheat-containing foods. She was diagnosed as having asthma and WDEIA and referred for further examinations because suspected OR, OA and CU. Hairdresser 2 had a history of atopic eczema. Having worked as a hairdresser for 6 months, she started developing urticarial wheals from skin contact with 2 hairdressing products she used in her work: a sprayable hair conditioner (product 1) and another hair Disclosures: Authors have nothing to disclose.

conditioner (product 3), which contained laurdimonium hydroxypropyl HWP. After 4 years of hairdressing work, the patient developed work-related sneezing, nasal itching, and watery rhinitis. Rhinitis was associated with the use of products 1 and 3. At the same time, the patient experienced generalized urticaria and eyelid edema twice while exercising after having eaten wheat-containing food. The exercise-induced symptoms ceased after she switched to a grain-free diet. She was referred for further examinations because of suspected OR and CU. Skin prick tests (SPTs) with a series of common aeroallergens (tree and grass pollen, mugwort, animal dander, house dust mites, and environmental molds) and natural rubber latex were performed with standardized extracts (ALK, Copenhagen, Denmark, and Stallergenes SA, Antony, France), histamine hydrochloride (10 mg/mL), and diluent controls. In addition, wheat, oat, barley and rye flours, gliadin, hair-bleaching agents, and paraphenylenediamine, hairdressing products 1 through 3 as is and their ingredients obtained from the manufacturer were skin prick tested (Table 1). In the open skin application test, the test substance was applied on a 5  5-cm area of healthy skin on the forearm. The test area was inspected at 20 minutes, and if the result was negative, application was repeated for another 20 minutes and the area interpreted again. A positive reaction was defined as urticarial wheals appearing on the test area (Table 1). Specific inhalation challenge or nasal provocation tests were performed to confirm suspected OA and/or OR. To assess asthma, peak expiratory flow (PEF) and forced expiratory volume in 1 second (FEV1) measurements were performed before, during, and after the challenge, until the next morning.6 A decrease of 15% or greater in PEF or FEV1 within 1 hour after the challenge (immediate reaction)

Late elicitation of maculopapular exanthemas to iodinated contrast media after first exposure.

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