What is the appropriate diagnosis and treatment approach for a young adult patient presenting with symptoms of mononucleosis and non-blanching red macules?

Diagnosis: Amoxicillin-Induced Rash in Infectious Mononucleosis

The presentation of non-blanching red macules in a patient with mononucleosis most likely represents an amoxicillin-induced maculopapular rash, which occurs in 80-100% of infectious mononucleosis patients who receive aminopenicillins, and should be managed by discontinuing the antibiotic immediately while continuing supportive care for the underlying EBV infection. 1, 2

Diagnostic Confirmation

Initial Laboratory Testing

• Obtain a heterophile antibody test (Monospot) as the first-line diagnostic test, which has 87% sensitivity and 91% specificity and typically becomes positive between days 6-10 after symptom onset 1, 3
• Review the complete blood count looking for lymphocytosis ≥50% of the white blood cell differential and atypical lymphocytosis ≥10% of total lymphocyte count, which strongly supports the diagnosis 1, 2
• Check for absolute lymphocytosis with at least 4,500 mononuclear cells/cu mm, which is an essential diagnostic feature 4

When Heterophile Testing is Negative

• Order EBV-specific serologic testing if clinical suspicion remains high despite negative heterophile test, including IgM antibodies to viral capsid antigen (VCA), IgG antibodies to VCA, and antibodies to Epstein-Barr nuclear antigen (EBNA) 1, 3
• Acute primary EBV infection is confirmed by the presence of VCA IgM (with or without VCA IgG) in the absence of EBNA antibodies 1, 3
• False-negative heterophile results are common in children younger than 10 years and during the first week of illness, occurring in approximately 10% of cases overall 1, 3

Differential Diagnosis of the Rash

Drug-Induced Rash (Most Likely)

• Amoxicillin/ampicillin-induced rash occurs in the vast majority of infectious mononucleosis patients who receive these antibiotics and presents as a widely scattered, erythematous, maculopapular eruption 2, 5
• This rash is NOT a true penicillin allergy and does not contraindicate future penicillin use after recovery from mononucleosis 5

EBV-Associated Rash

• Primary EBV rash occurs in approximately 10-45% of infectious mononucleosis cases without antibiotic exposure and is typically erythematous and maculopapular 2, 5

Serious Conditions to Exclude

• Stevens-Johnson syndrome/Toxic Epidermal Necrolysis must be ruled out if the rash is associated with mucosal involvement, blistering, or epidermal detachment, which presents with purpuric macules or flat atypical targets that are non-blanching 6
• SJS/TEN is characterized by tender skin, positive Nikolsky sign, and involvement of oropharynx, eyes, or genitourinary mucosa, requiring immediate specialist consultation 6

Management Approach

Immediate Actions

• Discontinue amoxicillin or any aminopenicillin immediately if the patient is currently taking these antibiotics 2, 5
• Avoid prescribing antibiotics unless there is documented bacterial co-infection, as infectious mononucleosis is viral and does not require antibiotic therapy 5

Supportive Care

• Provide adequate hydration, analgesics, and antipyretics as the mainstay of treatment 5
• Allow activity as tolerated based on the patient's energy level rather than enforcing strict bed rest 5
• Advise withdrawal from contact or collision sports for at least 4-8 weeks after symptom onset or while splenomegaly persists to prevent splenic rupture 2, 5

Medications to Avoid

• Corticosteroids should NOT be used routinely and should be reserved only for specific complications such as respiratory compromise or severe pharyngeal edema 1, 5
• Acyclovir has no proven benefit in immunocompetent patients with established infectious mononucleosis 1
• Antihistamines are not recommended for routine treatment 5

Critical Pitfalls to Avoid

Misdiagnosis Risks

• Do not assume penicillin allergy based on the amoxicillin-induced rash in mononucleosis, as this is a distinct phenomenon and does not represent true IgE-mediated hypersensitivity 5
• False-positive heterophile results may occur in patients with leukemia, pancreatic carcinoma, viral hepatitis, and CMV infection 1, 3

Alternative Diagnoses to Consider

• If heterophile and EBV testing are negative, consider testing for cytomegalovirus (CMV) infection, HIV infection, Toxoplasma gondii infection, adenovirus infection, and streptococcal pharyngitis 1, 3

Monitoring for Complications

• Splenic rupture occurs in 0.1-0.5% of infectious mononucleosis cases and is the most feared potentially fatal complication, requiring avoidance of abdominal trauma 2, 7
• Fatigue, myalgias, and need for sleep may persist for several months after acute infection resolves 5