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

Abstract

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.

Introduction

Infectious mononucleosis, caused by the Epstein-Barr virus (EBV), often presents with symptoms that mimic bacterial infections. As a result, patients are frequently treated with antibiotics, particularly penicillins. However, 80–100% of EBV-infected individuals who receive beta-lactam antibiotics develop a characteristic maculopapular rash [1, 2]. Recent studies suggest that this incidence may be overestimated [2].

While EBV-related rashes after penicillin treatment are often considered self-limiting with no long-term consequences, recent evidence – particularly in pediatric patients – indicates that some individuals develop persistent drug allergy [1, 3]. It has been hypothesized that viral infections can prime the immune system for drug hypersensitivity reaction (DHR) by enhancing immune reactivity to drugs [4]. However, data on the long-term incidence of persistent allergy remain limited, with studies estimating a prevalence of approximately 30% in children [1] and 26% in adults [3].

Previous studies have demonstrated persistent sensitization to penicillins through both skin tests and lymphocyte transformation tests (LTTs) [5, 6]. Nevertheless an allergy workup is not routinely performed or significantly delayed in patients with a history of EBV-associated rashes after penicillin exposure. This study aimed to assess the rate of persistent DHR to penicillins, the diagnostic delay in adult and adolescent patients with a prior EBV-related penicillin-induced rash and whether re-exposure to penicillins occurred before an allergy evaluation was done.

Methods

This retrospective study evaluated adolescent and adult patients who developed an EBV-related rash following penicillin treatment. Using a search tool in the hospital record database, we screened all patients who underwent a drug allergy workup between 2012 and 2023. Patients were included if they had documented evidence of EBV infection at the time of the initial DHR and had undergone a complete allergy evaluation, including skin tests for penicillin antibiotics.

Drug allergy skin tests were performed according to EAACI/ENDA guidelines [7], using intradermal skin test (IDT) and/or patch test (PT) with late readings at 48 h for IDT and at 48 and 72 h for PT. The tested drugs included amoxicillin, amoxicillin/clavulanate, ampicillin, penicillin G, and cefuroxime. Clinical data, including the characteristics of the initial DHR, the type and duration of the rash, the suspected triggering drug, and the results of skin tests and cellular assays, were retrieved from the medical records. A maculopapular rash was defined as a cutaneous eruption consisting of both macules and papules, typically erythematous and confluent, based on clinical documentation. Rashes involving more than 50% of the body surface and/or facial involvement and/or lasting at least 7 days or more were considered severe.

To assess the diagnostic delay, we analyzed the time interval between the EBV-related rash and the allergy workup. Additionally, we investigated whether patients were re-exposed to penicillins during this time period and whether re-exposure was tolerated. In two cases, in vitro testing was performed using a multiplex cyto-LTT, measuring cytokines IL-5, IL-13, IFN-gamma, granzyme B, and granulysin by ELISA. This retrospective study was conducted and reported in accordance with the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines.

Results

A total of 3,067 patients with delayed DHRs after penicillin treatment were retrospectively screened from our hospital record database, of whom 24 were identified as eligible. Among these, 15 provided written informed consent and were included in the study (Table 1). The median age was 18.5 (IQR 15.5; 24.0) years at the time of the EBV-related rash. The majority of patients were female (n = 13, 86.7%). The rash was described as maculopapular in 10 out of 15 patients, with 1 subject also presenting with facial swelling, and macular in 2 patients (Table 1). In the remaining three cases, the rash was not further specified. The most commonly suspected trigger was either amoxicillin alone or amoxicillin/clavulanate (n = 13, 86.7%). In 2 cases, the specific penicillin was not documented (Table 1).

Table 1.

Patient characteristics

Patient	Initial DHR	Penicillin re-exposition	Duration of initial rash, days	Time to reaction, days	Time to allergy workup, months	IDT	PT	LTT
1	MPE	n/a	7	3	14	+	+	n/a
2	MPE	n/a	>14	9	2	+	+	n/a
3	MPE	n/a	n/a	7	156	−	−	n/a
4	Macular rash	Tolerated	n/a	n/a	420	−	−	n/a
5	Macular rash	Macular rash, facial swelling	14	6	16	−	−	n/a
6	MPE	n/a	>14	3	120	+	+	n/a
7	MPE	n/a	7	7	2	−	−	−
8	Rash	AGEP, facial swelling	n/a	n/a	n/a	n/a	+	n/a
9	MPE, facial swelling	Tolerated after allergy workup	7	6	2	−	−	n/a
10	Rash	n/a	n/a	10	48	−	−	n/a
11	Rash	n/a	14	3–4	16	−	−	n/a
12	MPE	n/a	2	7	11	+	+	n/a
13	MPE	2× MPE	7	5	108	+	+	n/a
14	MPE	n/a	7	3	84	+	n/a	+
15	MPE	n/a	10	9	5	−	−	n/a

MPE, maculopapular exanthema; AGEP, acute generalized exanthematous pustulosis; n/a, not applicable; IDT, intradermal skin test; DHR, drug hypersensitivity reaction; LTT, lymphocyte transformation test.

Four of the 15 patients were re-exposed to penicillins before undergoing an allergy workup, three of whom experienced a recurrent DHR. Patient 5 exhibited a more severe DHR with macular rash and facial swelling, while patient 8 developed an acute generalized exanthematous pustulosis upon re-exposure. Patient 13 was even re-exposed twice and developed maculopapular exanthema (MPE) on both occasions. None of these patients had undergone an allergy evaluation directly after their initial EBV-related rash. The remaining one re-exposed patients tolerated penicillins without adverse reactions.

Skin tests were positive in 46.7% of patients (7/15). Among these, 5 had positive results in both IDT and PT, 1 tested positive only in PT (IDT not done), and 1 only in IDT (PT not done). Notably, two of the four re-exposed patients had positive skin tests, while patient 5, despite experiencing a severe DHR upon re-exposure, showed no sensitization in skin testing (Table 1).

The allergy workup was performed a median of 16.0 months (IQR 4.3; 111.0) after the EBV-related rash, which reflects typical clinical practice patterns for evaluation of delayed DHRs. While some patients could not recall the duration of their initial reaction, 10 out of 15 reported a rash lasting 7 days or longer. Among those with positive skin tests, four out of seven reported a rash duration of at least 7 days.

In vitro testing was done in 2 patients. Patient 14 had a positive cyto-LTT, which correlated with the positive skin test, whereas patient 7 had negative results in both cyto-LTT and skin testing. No additional drug provocation tests were performed. Patient 9 was later re-exposed with amoxicillin and tolerated it.

Discussion

Our study substantiates the findings that penicillin associated EBV-related rashes can lead to persistent drug allergy in adolescents and adults, not only shortly after the reaction [8] but even years after the initial DHR [3]. Similar to previous studies in pediatric and adult populations [1, 3], a significant proportion of our patients exhibited a persistent drug allergy following penicillin treatment during EBV infection. Our rate with 47% is higher than in earlier reports. Possibly a selection bias might have increased our rate as patients with more severe DHR are more likely to be referred for an allergy workup.

A key finding of our study is the substantial diagnostic delay, with a median interval of 16 months between the EBV-related rash and the allergy evaluation. Current recommendations suggest that drug allergy testing should ideally be performed within 1 year of the initial reaction to ensure diagnostic accuracy. In our cohort, this was not achieved in over half of the patients. The common assumption that penicillin-induced EBV-related rashes are transient and self-limiting likely contributes to this delay. As a result, some patients were unnecessarily re-exposed to penicillins, leading to recurrent DHR, including more severe manifestations such as acute generalized exanthematous pustulosis. These findings highlight the importance of timely allergy testing in patients with a suspected EBV-related DHR.

Despite the well-known decline in skin test sensitivity over time, the rate of positive test results in our cohort remained relatively high even years after the DHR, particularly for PT. Such behavior in skin tests otherwise occurs primarily only in severe DHR, such as drug reaction with eosinophilia and systemic symptoms. Notably, PT yielded comparable results to IDT, further supporting their role in diagnosing persistent sensitization.

Certain clinical patterns appear to be associated with persistent drug allergy. Consistent with earlier studies, patients with a prolonged rash duration or more severe forms of DHR were more likely to have positive skin tests [9]. However, for patients with negative skin tests, the question remains whether they can safely tolerate penicillins in the future. Since drug provocation testing was not performed, this remains an open issue.

Limitations of our study include its retrospective design, the relatively small sample size, and the lack of drug provocation tests for patients with negative skin tests. A negative skin test does not necessarily mean that the patient does not have an allergy. It is, therefore, possible, that a minority of skin test negative cases would have reacted on rechallenge. In some cases, data are missing because the patients included in the study were unable to recall all details of their reaction. Additionally, a significant proportion of eligible patients declined to participate or could not be reached, which may have influenced our results. Future prospective studies should focus on systematically evaluating the long-term risk of persistent drug hypersensitivity after viral-associated DHR in a multicenter approach and should explicitly include drug provocation tests as a gold standard. Further research is also needed to better identify predictive factors for persistent allergy development.

Our findings underscore the importance of avoiding premature and uncritical labeling of patients as penicillin-allergic or not, solely based on a rash occurring during EBV infection. While it is well established that many EBV-related exanthems are parainfectious and non-allergic in nature, our data demonstrate that true drug hypersensitivity can persist in a relevant proportion of these cases. Therefore, clinicians should neither automatically assign an allergy label nor assume the rash was entirely non-allergic without further investigation.

Based on our findings and in line with recommendations by Cox et al. [3], we propose a more proactive approach to allergy evaluation in patients with a history of EBV-related rash following penicillin exposure. This is particularly relevant for individuals with prolonged or severe reactions, even if the initial event occurred years earlier or during childhood. Early allergy workup could help prevent unnecessary antibiotic restrictions and avoid potentially harmful re-exposures.

Statement of Ethics

This study was performed in accordance with the Declaration of Helsinki. This human study was approved by the Ethics Committee Berne, Approval Project-ID 2018-02192. All parents, guardians, or next of kin provided written informed consent for the minors to participate in this study. All adult participants provided written informed consent to participate in this study.

Conflict of Interest Statement

All authors declare no conflicts of interest relevant to this manuscript.

Funding Sources

This study was institutional funded. The funder had no role in the design, data collection, data analysis, and reporting of this study.

Author Contributions

L.C. and L.J. organized the study, recruited and included patients, analyzed and interpreted the data, wrote the manuscript, and critically revised the manuscript and gave approval for submission.

Funding Statement

This study was institutional funded. The funder had no role in the design, data collection, data analysis, and reporting of this study.

Data Availability Statement

All data generated or analyzed during this study are included in this published article. Further inquiries can be directed to the corresponding author.