What are the diagnosis and treatment of infectious mononucleosis?

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Diagnosis and Treatment of Infectious Mononucleosis

The diagnosis of infectious mononucleosis is primarily made using heterophile antibody testing (Monospot test), while treatment is mainly supportive with adequate hydration, analgesics, and rest, as there is no specific antiviral therapy recommended for routine cases. 1

Diagnostic Approach

Initial Clinical Evaluation

  • Infectious mononucleosis should be suspected in patients 10-30 years old presenting with the classic triad of fever, tonsillar pharyngitis, and lymphadenopathy 2
  • Additional suggestive findings include periorbital/palpebral edema (in one-third of patients), splenomegaly (50%), hepatomegaly (10%), and maculopapular rash (10-45%) 2
  • Fatigue, which may be profound, is a common symptom that can persist for several months 3

Laboratory Testing

  • First-line test: Heterophile antibody test (Monospot) becomes positive between the sixth and tenth day after symptom onset 4, 1
  • Complete blood count typically shows:
    • Peripheral blood leukocytosis with lymphocytes making up at least 50% of white blood cells
    • Atypical lymphocytes constituting more than 10% of the total lymphocyte count 2
  • An atypical lymphocytosis of at least 20% or atypical lymphocytosis of at least 10% plus lymphocytosis of at least 50% strongly supports the diagnosis 3

Additional Testing When Heterophile Test Is Negative

  • When clinical suspicion remains high despite a negative heterophile test, EBV-specific serologic testing is recommended 1
  • EBV antibody testing should include:
    • IgM antibodies to viral capsid antigen (VCA)
    • IgG antibodies to VCA
    • Antibodies to Epstein-Barr nuclear antigen (EBNA) 4, 1
  • Interpretation of EBV serology:
    • Presence of VCA IgM (with or without VCA IgG) antibodies in the absence of EBNA antibodies indicates recent primary EBV infection
    • Presence of EBNA antibodies indicates infection more than 6 weeks prior 4

Differential Diagnosis

  • Consider other causes of mononucleosis-like illness when heterophile tests are negative:
    • Cytomegalovirus (CMV) infection
    • HIV infection
    • Toxoplasma gondii infection
    • Adenovirus infection 1, 5
    • Streptococcal infection
    • Other viral infections 3

Treatment Approach

Supportive Care

  • Treatment is mainly supportive and includes:
    • Adequate hydration
    • Analgesics for pain relief
    • Antipyretics for fever
    • Adequate rest guided by the patient's energy level 2, 3
  • Bed rest should not be enforced, but activity should be guided by the patient's energy level 3

Activity Restrictions

  • Patients should be withdrawn from contact or collision sports for at least 4-8 weeks after symptom onset or while splenomegaly is present to reduce the risk of splenic rupture 2, 3

Medications

  • Corticosteroids are not recommended for routine treatment but may benefit patients with:
    • Respiratory compromise
    • Severe pharyngeal edema 1, 3
  • Acyclovir and antihistamines are not recommended for routine treatment of infectious mononucleosis 3

Complications and Prognosis

Potential Complications

  • Splenic rupture is the most feared complication, occurring in 0.1-0.5% of patients 2
  • Other potential complications involve:
    • Pulmonary system
    • Ophthalmologic system
    • Neurologic system
    • Hematologic system 6
  • Infectious mononucleosis is a risk factor for chronic fatigue syndrome 2

Prognosis

  • Most patients have an uneventful recovery 2
  • Fatigue, myalgias, and increased need for sleep may persist for several months after the acute infection has resolved 3

Common Pitfalls and Caveats

  • False-negative heterophile antibody results are common early in the course of infection and in young children under 10 years 4, 1
  • False-positive heterophile antibody results may occur in patients with leukemia, pancreatic carcinoma, viral hepatitis, and CMV infection 4, 1
  • Approximately 5-10% of patients who have been infected with EBV fail to develop antibodies to EBNA antigen 4, 1
  • Over 90% of normal adults have IgG antibodies to VCA and EBNA antigens, reflecting past infection 1

References

Guideline

Diagnostic Approach to Infectious Mononucleosis

Praxis Medical Insights: Practical Summaries of Clinical Guidelines, 2025

Research

Infectious Mononucleosis: An Updated Review.

Current pediatric reviews, 2024

Research

Epstein-Barr virus infectious mononucleosis.

American family physician, 2004

Guideline

Guideline Directed Topic Overview

Dr.Oracle Medical Advisory Board & Editors, 2025

Research

Diagnostic evaluation of mononucleosis-like illnesses.

The American journal of medicine, 2007

Research

Diagnosis and treatment of infectious mononucleosis.

American family physician, 1994

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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