Penicillin Treatment in Infectious Mononucleosis May Lead to Persistent Drug Allergy in Adolescents and Adults Even after Years.

Introduction: Patients with infectious mononucleosis are often treated with penicillins, frequently resulting in maculopapular rashes resembling delayed drug hypersensitivity reactions (DHR). While traditionally considered self-limiting with no long-term consequences, some individuals develop persistent drug allergy. This study assessed the rate of persistent penicillin allergy in patients with a prior Epstein-Barr virus (EBV)-related penicillin-induced rash.

Methods: We retrospectively reviewed adolescent and adult patients, who developed an EBV-related rash after penicillin treatment and later underwent drug allergy testing between 2012 and 2023. Among 3,067 screened patients with suspected delayed DHR after penicillin, 15 fulfilled inclusion criteria (informed consent, confirmed EBV, and complete allergy workup). Clinical data, test results, and re-exposure history were extracted from a hospital record database.

Results: Fifteen patients were included (median age 18.5 years, 87% female). Skin tests were positive in 7 out of 15 subjects (47%). Four patients were re-exposed to penicillins before testing; 3 developed recurrent DHR, including 1 case with an acute generalized exanthematous pustulosis. Median time to allergy workup was 16 months. Positive skin tests were more common in those with prolonged DHR.

Conclusion: Nearly half of patients with EBV-related rashes after penicillin exposure showed evidence of persistent drug allergy, even years after the initial reaction. These findings emphasize the importance of allergy testing in patients with EBV-related DHR to prevent unnecessary antibiotic restrictions and avoid unintended re-exposures.