A rare case of acute generalized exanthematous pustulosis induced by gadobutrol

We present a 50-year-old male, who was admitted to the hospital because of diffuse erythema with multiple non-follicular pustules beginning on the trunk and flexural areas with diffuse erythema and itching. The patient had undergone cerebral magnetic resonance imaging (cMRI) with gadolinium-based contrast medium (gadobutrol) because of glioblastoma 48 hours before the onset of first skin lesions. The patient's general practitioner had treated him with oral prednisolone (100 mg/day at day 1, tapered to 50 mg/day at day 2). The rash had initially improved rapidly after the first prednisolone dose. But, immediately upon dose reduction to prednisolone 50 mg/day at day 2 lesions again exacerbated which is why the patient was referred to our department. Physical examination showed diffuse erythema, numerous small, non-follicular pustules without mucosal involvement (Figure 1). Fever or other systemic symptoms were not observed. Laboratory findings showed leukocytosis, neutrophilia and elevation of c-reactive protein (Figure 2). Skin findings during this first episode exacerbated when reducing dexamethasone from 4 mg thrice daily to 2 mg thrice daily. Other new medications were not prescribed concomitantly. Pustular psoriasis was diagnosed clinically because of the clinical presentation and observed exacerbation during steroid tapering. Histopathological changes were consistent with pustular psoriasis or acute generalized exanthematous pustulosis (AGEP) (Figure 3). Following dose increase to dexamethasone 4 mg thrice daily with slower tapering (dose reduction of 1 mg every 3 days) and concurrent topical steroid and calcitriol therapy the rash fully disappeared. Four months later, the patient presented with the same rash. This time, it had appeared only 12 h after cMRI with gadobutrol. Because of this new information, AGEP was diagnosed clinically and could be correlated histopathologically (Figure 3). Because of clinical history and the current presentation of symptoms allergological skin tests were scheduled. Skin testing was performed 3 months after the second reaction including prick and patch testing. Testing was performed with iodine-based contrast media as well as gadolinium-based contrast media. Testing included iomeprol, iopromide, amidotrizoic acid, iopamidol, gadoteric acid, gadobutrol and disodium gadoxetate without dilutions. Positive control in prick testing was conducted with histamine hydrochloride 10 mg/mL, negative control was carried out with NaCl 0.9%. Negative control in patch testing was implemented with vaseline (See also online supplement). Patch testing was performed with 8 mm Finn Chamber® on Scanpor® Tape (SmartPractice®). All tested contrast media showed negative reactions in prick testing after 20 min, ruling out IgE-mediated type I allergies. Patch testing showed positive reaction with distinct palpable infiltrated erythema and pustules after 48 and 72 h for iomeprol and gadobutrol (Figure 4). According to the test results, delayed type IV hypersensitivity against iomeprol and gadobutrol could be verified. Since levetiracetam had been suspected as a trigger of the first episode, therefore we tested as well for levetiracetam type I and IV allergy. It could be ruled out via prick and patch testing, as well as uncomplicated oral provocation (Data not shown). AGEP was diagnosed through medical history, clinical presentation and typical histological findings (Figure 3). Gadobutrol could be identified as the allergic agent via patch testing. In the literature, most cases of contrast media related AGEP are attributed to iodinated contrast media.1 Bordel Gomez et al. reported the first case of AGEP induced by gadobutrol. Their methodology involved patch testing on the forearm with undiluted gadobutrol and gadoteric acid. It is notable that a limitation of their study was the use of undiluted contrast media at the thin skin of the forearm, potentially leading to higher doses in thin skin due to occlusion over 48 h, which could induce toxic reactions.2 At the moment there are only few reported cases of delayed hypersensitivity after exposure with gadolinium-based contrast media.2, 3 Moreover, sensitization to iomeprol remains to be elucidated. To our best of knowledge, so far, no cross-reaction due to structural similarity of gadobutrol and iomeprol has been reported. However, after careful anamnesis, the patient has not received iodinated contrast medium before. Notably, our case represents the first case of AGEP induced by gadobutrol exposure, demonstrating a more rapid onset of symptoms upon re-exposure. It emphasizes the need for elevated awareness of AGEP, even in cases involving agents rarely associated with such reactions. Katharina Fetzer: Writing – original draft; conceptualization; methodology; visualization; investigation. Stephan Forchhammer: Data curation; supervision; validation. Toni Silber: Data curation; validation; supervision. Sebastian Volc: Writing – review and editing; conceptualization; supervision; resources; project administration. Open Access funding enabled and organized by Projekt DEAL.