Allergy ORIGINAL ARTICLE SKIN AND EYE DISEASES Diagnostic evaluation of patients with nonimmediate cutaneous hypersensitivity reactions to iodinated contrast media M. J. Torres1, F. Gomez1, I. Don˜ a1, A. Rosado2, C. Mayorga3, I. Garcia1, N. Blanca-Lopez4, G. Canto4 & M. Blanca1 1Allergy Service, Carlos Haya Hospital, Malaga; 2Allergy Service, Fundacion Alcorcon Hospital, Madrid; 3F-IMABIS, Carlos Haya Hospital, Malaga; 4Allergy Service, Infanta Leonor Hospital, Madrid, Spain To cite this article: Torres MJ, Gomez F, Don˜ a I, Rosado A, Mayorga C, Garcia I, Blanca-Lopez N, Canto G, Blanca M. Diagnostic evaluation of patients with nonimmediate cutaneous hypersensitivity reactions to iodinated contrast media. Allergy 2012; 67: 929–935. Keywords Abstract drug provocation test; hypersensitivity; Background: Nonimmediate hypersensitivity reactions to iodinated contrast media Iodinated contrast media; nonimmediate; skin tests. (CM) are common. Allergological evaluation is necessary to confirm the diagnosis and to find a tolerated alternative. The aim of this study was to establish the role Correspondence of skin testing and the drug provocation test (DPT) in the diagnosis of nonimme- Maria Jose´ Torres Jae´n, Carlos Haya diate reactions to CM. Hospital (Pabellon C), Allergy Service, Plaza Methods: Skin intradermal testing and patch testing with delayed readings were del Hospital Civil s/n, pabello´ n5,so´tano. carried out with different CM (iobitridol, iomeprol, iodixanol, iohexol, ioversol, 29009 Malaga, Spain. iopramide and ioxaglate). Single-blind placebo-controlled DPT was carried out in Tel.: +34 951290346 those cases with a negative skin test. In seven cases, a skin biopsy was obtained Fax: +34 951290302 from positive skin tests and positive DPT. E-mail: [email protected] Results: Of the 161 subjects evaluated, 34 (21.1%) were skin-test positive, 21 (50%) to Iomeprol, 7 (16.7%) to Iodixanol, 5 (11.9%) to Iobitridol, 4 (9.5%) to Accepted for publication 03 April 2012 Ioxaglate, 3 (7.1%) to Iohexol and 1 (2.4%) to Iopramide. DPT was positive in DOI:10.1111/j.1398-9995.2012.02840.x 44 cases (34.6%) that were skin-test negative, 38 (76%) to Iodixanol, 8 (16%) to Iomeprol and 4 (8%) to Iohexol. Of 78 cases (48.4%) with confirmed hypersensi- Edited by: Hans-Uwe Simon tivity, 34 (43.6%) were identified by skin testing and 44 (56.4%) by DPT. Skin biopsies showed a perivascular mononuclear cell infiltrate, mainly in the dermis, with higher levels of CD4 than CD8 T lymphocytes, with expression of activation markers and skin homing receptors. Conclusion: Patients with nonimmediate reactions to CM were identified by skin testing in 43.6% and by DPT in 56.4%. The method to confirm the diagnosis dif- fered depending on the CM involved. Hypersensitivity reactions to iodinated contrast media (CM) infiltrates of T cells in the affected skin lesions and in the can be classified according to the time interval between drug positive skin-test sites as well as lymphocyte proliferation administration and symptom appearance in two groups: tests to the culprit contrast media (5–8). immediate reactions, appearing within 1 h after CM adminis- Several reports have detected positive delayed intradermal tration, and nonimmediate reactions, appearing later than tests as well as positive patch tests to undiluted or diluted 1 h after CM administration (1). In the last decade, nonim- CM in patients with nonimmediate reactions to CM (9–18), mediate reactions to CM have been increasingly described, and general guidelines for this procedure have been published with the skin being the organ most frequently involved (1, 2). (1). A recent multicentre study found that 47% of the Reactions may vary from mild to severe, with maculopapular patients with nonimmediate reactions to CM were diagnosed exanthema being the clinical entity most frequently reported, by skin testing, although the negative predictive value of skin followed by nonimmediate urticaria, whether or not accom- testing was not assessed (16). panied by angioedema (1, 3, 4). T-cell involvement has been Only a few studies have examined the role of drug demonstrated with the presence of perivascular dermal provocation tests (DPT) in the diagnosis of patients with Allergy 67 (2012) 929–935 © 2012 John Wiley & Sons A/S 929 Nonimmediate reactions to iodinated contrast media Torres et al. nonimmediate hypersensitivity reactions to CM (9–11, 17). (Clarograf; Bayer, Barcelona, Spain) and ioxaglate (Hexa- One study evaluating patients with suggestive reactions to brix; Guerbet). CM and skin-test negative in both delayed reading intrader- Intradermal tests were performed in the volar forearm mal and patch testing showed that 41.6% of cases developed using 10-fold diluted and undiluted CM and a patch test with a positive reaction after DPT (11). It was therefore suggested undiluted CM. In the intradermal tests, the wheal area was that DPT should be considered to establish the diagnosis in marked initially and 20 min, 1-, 2- and 3-day after testing. In the case of a negative skin test as well as for choosing an the immediate reading (20 min), an increase in diameter alternative CM in those with a positive skin test. >3 mm surrounded by erythema was considered positive, and Given this background, we considered it necessary to in delayed readings (1- to 3-day), an erythematous induration establish the role of skin testing and DPTs in the diagnosis at the skin-test site was considered positive. Patch tests were of nonimmediate reactions to CM. Accordingly, we evaluated removed and read at 48 h with an additional reading at 72 h a group of patients with nonimmediate reactions to CM and considered positive according to the European Society of using a well-defined protocol that included skin testing and a Contact dermatitis (19). DPT. Drug provocation test Methods Single-blind placebo-controlled DPT was carried out in those cases with a negative skin test as described by the ENDA Patients and controls group (20). CM was administered intravenously diluted in A group of patients were evaluated in the Allergy Service of saline at different doses at 1-h intervals. To control any Carlos Haya Hospital because of a clinical history indicative adverse effect and to avoid severe systemic reactions, this of a nonimmediate hypersensitivity cutaneous reaction after was performed in two runs separated with sufficient time to administration of a CM. This was considered when symp- detect reactions appearing later than 48 h. In the first run, 5, toms appearing more than 1 h after CM administration. 10 and 15 cc of CM were administered and, if this was well The clinical categories included were exanthema and non- tolerated, 1 week later CM was administered at 20, 30 and immediate urticaria. The criteria for urticaria were when the 50 cc (cumulative dose = 100 cc). manifestations were limited exclusively to the skin and con- sisted of pruritic, erythematous cutaneous nonpersistent ele- Skin biopsy vations that blanched with pressure at various sites of the body, whether or not associated with angioedema. Maculo- Skin biopsies were obtained with a 6-mm punch from skin- papular exanthema was considered to be the presence of test positive and DPT-positive reactions and were processed small confluent erythematous maculae or papules dissemi- as described (21) for haematoxylin–eosin and immunohisto- nated over different parts of the body, whether or not fol- chemical staining with the following monoclonal antibodies: lowed by desquamation. Patients with severe CM reactions CD4, CD69, CD25, Granz-B, and perforin (Novocastra like Stevens–Johnson syndrome, acute generalized pustulosis Lab., Newcastle upon Tyne, UK), CD8, and HLA-DR or drug reaction with eosinophilia and systemic symptoms (Dako, Ely, Cambridgeshire, UK) and CLA (BD Pharmin- were not included in this study. gen, San Diego, CA, USA). The binding of these primary Severity was graded according to Brockow (16) as mild antibodies (mouse IgG) was detected using an anti-mouse when no treatment was required, moderate when the patient IgG conjugated to peroxidase-labelled dextran polymer (Zy- responded to appropriate treatment and no hospitalization med Lab., San Francisco, CA, USA) and a 3-3′-diam- was needed, and severe when the reaction required hospital- inobenzidine substrate kit (Sigma, St. Louis, MI, USA). ization. Patients with at least one skin-test positive to common and Statistical studies prevalent inhalant or food allergens were considered atopics. A group of 25 subjects with good tolerance to CM were Comparisons for qualitative variables were carried out using included as controls. Chi-squared analysis. All reported P values represent two- The study was approved by the relevant institutional tailed tests, with values <0.05 considered statistically signifi- review boards, and informed consent for the diagnostic pro- cant. cedures was obtained from the patients and controls. Results Skin test A total of 161 subjects with a history of a nonimmediate Skin testing was carried out as previously described (1, 16) reaction imputable to at least one CM were evaluated. One using the following CM: iobitridol (Xenetix; Guerbet, patient who developed Stevens–Johnson syndrome was not Madrid, Spain), iomeprol (Iomeron; Rovi, Madrid, Spain), included. The median age was 58.5 years (IR: 48.85–66.5) iodixanol (Visipaque; GE Healthcare Biosciences, Madrid, with 82 men (50.9%). According to the information obtained Spain), iohexol (Omnipaque; GE Healthcare Biosciences), from the clinical history, the CM involved in the reaction ioversol (Optiray; Covidien, Barcelona, Spain), iopramide were iomeprol in 53 (32.9%), iodixanol in 46 (28.6%), 930 Allergy 67 (2012) 929–935 © 2012 John Wiley & Sons A/S Torres et al. Nonimmediate reactions to iodinated contrast media iohexol in 27 (16.8%), iobitridol in 4 (2.5%), ioversol in 3 reported by the patients although with a lower intensity (data (1.9%), iopramide in 3 (1.9%), ioxaglate in 2 (1.2%) and not shown).