What are the initial steps to diagnose infectious mononucleosis?

Diagnostic Approach to Infectious Mononucleosis

The initial diagnostic approach for infectious mononucleosis should include a complete blood count with differential and a rapid heterophile antibody test (Monospot test), which has a sensitivity of 87% and specificity of 91%. 1

Clinical Presentation

• Infectious mononucleosis typically presents with the classic triad of fever, tonsillar pharyngitis, and lymphadenopathy, most commonly affecting adolescents and young adults aged 15-24 years 2, 1
• Posterior cervical or auricular lymphadenopathy is particularly characteristic 3
• Fatigue may be profound and can persist for several months after the acute infection resolves 2, 3
• Periorbital and/or palpebral edema, typically bilateral, occurs in approximately one-third of patients 2
• Splenomegaly occurs in approximately 50% of cases and hepatomegaly in about 10% 2
• A maculopapular rash may develop in 10-45% of cases, particularly in patients who have been treated with ampicillin or amoxicillin 2

Laboratory Evaluation

First-Line Testing

• Complete blood count (CBC) with differential:

  • Look for lymphocytosis (lymphocytes ≥50% of white blood cells) 2, 1
  • Atypical lymphocytes >10% of the total lymphocyte count is characteristic 2, 1

• Heterophile antibody test (Monospot):

  • Most widely used initial test for infectious mononucleosis 2, 4
  • Usually becomes positive between the sixth and tenth day after symptom onset 4
  • False-negative results may occur in children younger than 5 years and during the first week of illness in adults 1

Second-Line Testing (When Monospot is Negative)

• Epstein-Barr virus (EBV) serologic testing is recommended when clinical suspicion remains high despite a negative heterophile test 4, 2

• EBV-specific antibody panel should include:

  • IgM antibodies to viral capsid antigen (VCA) - indicates acute infection 4, 5
  • IgG antibodies to VCA - may be present in acute and past infection 4, 5
  • Antibodies to Epstein-Barr nuclear antigen (EBNA) - typically absent in acute infection, appears 1-2 months after primary infection 4, 5

• The presence of VCA IgM (with or without VCA IgG) antibodies in the absence of EBNA antibodies indicates recent primary EBV infection 4

• The presence of EBNA antibodies indicates infection more than 6 weeks prior and suggests EBV is not the cause of current symptoms 4

• Liver function tests may be helpful:

  • Elevated liver enzymes increase clinical suspicion for infectious mononucleosis when heterophile test is negative 1

Differential Diagnosis

• When rapid Monospot or heterophile tests are negative, consider other causes of mononucleosis-like illness:
  • Cytomegalovirus (CMV) infection 4, 3
  • HIV infection 4, 3
  • Toxoplasma gondii infection 4, 3
  • Adenovirus infection 4
  • Streptococcal pharyngitis 3

Common Pitfalls and Caveats

• False-positive heterophile antibody results may occur in patients with leukemia, pancreatic carcinoma, viral hepatitis, and CMV infection 4
• False-negative heterophile results are common early in the course of infection (first week) and in young children 3, 1
• Over 90% of normal adults have IgG antibodies to VCA and EBNA antigens, reflecting past infection, so these must be interpreted carefully 4
• Approximately 5-10% of patients who have been infected with EBV fail to develop antibodies to EBNA antigen 4
• Avoid ampicillin or amoxicillin in patients with suspected infectious mononucleosis as they can cause a non-allergic rash 2

By following this diagnostic approach, clinicians can efficiently diagnose infectious mononucleosis and differentiate it from other causes of similar symptoms, allowing for appropriate management and prevention of complications such as splenic rupture.