What is the cause of a rash following infectious mononucleosis (mono)?

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Last updated: April 30, 2025View editorial policy

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From the Guidelines

A rash after mononucleosis is typically a self-limiting condition that resolves on its own within 1-2 weeks without specific treatment. The rash, often triggered by antibiotics such as ampicillin, appears as flat, pink-to-red spots that may merge together, usually on the trunk and spreading to extremities 1. If you develop this rash, discontinuing any antibiotics, particularly amoxicillin or ampicillin, is recommended, as these medications can trigger the rash in about 90% of mono patients. For symptom relief, over-the-counter antihistamines like diphenhydramine (Benadryl) 25-50mg every 4-6 hours or cetirizine (Zyrtec) 10mg daily can be used, and calamine lotion can help with itching when applied to affected areas.

Key Considerations

  • The Epstein-Barr virus that causes mono alters the immune system's response to certain medications, leading to the rash 1.
  • If the rash is severe, spreads to mucous membranes, causes blistering, or is accompanied by difficulty breathing, seek immediate medical attention as this could indicate a more serious reaction.
  • The diagnosis of mononucleosis and associated rash can be supported by laboratory testing, including heterophile antibodies and EBV antibody testing for IgG and IgM to viral capsid antigen (VCA) and Epstein-Barr nuclear antigen (EBNA) 1.

Management

  • Discontinue antibiotics if possible
  • Use antihistamines for symptom relief
  • Apply calamine lotion to affected areas for itching
  • Monitor for severe reactions and seek medical attention if necessary

From the Research

Rash after Mononucleosis

  • A skin rash, which is usually widely scattered, erythematous, and maculopapular, occurs in approximately 10 to 45% of cases of infectious mononucleosis 2.
  • The incidence of rash after amoxicillin treatment in children with infectious mononucleosis was found to be 29.5% in a retrospective study, which is significantly lower than the 90% rate reported for ampicillin in past studies 3.
  • A review of case reports and epidemiological data found that the incidence of antibiotic-induced rash in patients with infectious mononucleosis was higher in the 1960s (55.6%, 45%, and 33%) than in 2013 (33% and 15%) 4.
  • The mechanism of antibiotic-induced rash in patients with infectious mononucleosis is thought to be a transient virus-mediated immune alteration that sets the stage for loss of antigenic tolerance and the development of a reversible, delayed-type hypersensitivity reaction to the antibiotic 4.

Antibiotic-Induced Rash

  • The top 3 reported drugs associated with antibiotic-induced rash in patients with infectious mononucleosis are ampicillin, azithromycin, and amoxicillin 4.
  • A reassessment of the long-held belief of the high incidence (80%-100%) of antibiotic-induced skin rash in patients with infectious mononucleosis seems prudent, as additional studies have found lower incidence rates 4.
  • Steroids have been used for their anti-inflammatory effects in infectious mononucleosis, but there is insufficient evidence to support their efficacy for symptom control, including rash 5.

References

Guideline

Guideline Directed Topic Overview

Dr.Oracle Medical Advisory Board & Editors, 2025

Research

Infectious Mononucleosis: An Updated Review.

Current pediatric reviews, 2024

Research

Steroids for symptom control in infectious mononucleosis.

The Cochrane database of systematic reviews, 2015

Professional Medical Disclaimer

This information is intended for healthcare professionals. Any medical decision-making should rely on clinical judgment and independently verified information. The content provided herein does not replace professional discretion and should be considered supplementary to established clinical guidelines. Healthcare providers should verify all information against primary literature and current practice standards before application in patient care. Dr.Oracle assumes no liability for clinical decisions based on this content.

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