A 19-year-old student presents with a one-week history of a sore throat, low-grade fever, and malaise. She states that a week ago she had a fine rash over her body that faded quickly. On examination you note the presence of mild splenomegaly.

1. What is the most likely diagnosis?

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This patient has a history and examination consistent with a diagnosis of infectious mononucleosis.

Clinical infection is most common in populations with large numbers of young adults, such as university students and active-duty military personnel.

The main clinical features of infectious mononucleosis are:

  • Low-grade fever
  • Fatigue and prolonged malaise
  • Sore throat (tonsillar enlargement and exudate are common)
  • Transient, fine, macular, non-pruritic rash
  • Lymphadenopathy (most commonly cervical)
  • Arthralgia and myalgia
  • Mild hepatomegaly and splenomegaly
  • Jaundice (<10% if young adults but more common in the elderly)

2. What is the commonest causative organism?

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Infectious mononucleosis is most commonly caused by the Epstein-Barr virus (EBV), which belongs to the human herpes virus family. Approximately 10% of cases are caused by cytomegalovirus (CMV) infection.

3. How can the diagnosis be confirmed?

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EBV infectious mononucleosis can be diagnosed using a variety of unrelated non-EBV heterophile antibodies and specific EBV antibodies.

  1. Heterophile antibodies:

70-90% of patients with EBV infectious mononucleosis produce heterophile antibodies (antibodies against an antigen produced in one species that react against antigens from other species). False positives can occur with hepatitis, malaria, toxoplasmosis, rubella, SLE, lymphoma and leukaemia. These antibodies can be detected by two main screening tests, both of which give rapid results within a day.

  • Paul-Bunnell test – sheep red blood cells agglutinate in the presence of heterophile antibodies
  • Monospot test – horse red blood cells agglutinate in the presence of heterophile antibodies


  1. EBV-specific antibodies:

Patients who remain heterophile-negative after six weeks are considered to be heterophile-negative and should be tested for EBV-specific antibodies. They are also helpful is a false positive heterophile antibody test is suspected.

4. Which other investigations should be organised?

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Other useful investigations include:

  • Full blood count – a raised white cell count with lymphocytosis and atypical lymphocytes occurs in > 20%
  • ESR – the ESR is elevated in most patients
  • LFTs – mild elevation of the serum transaminases is common
  • Throat swabs – to exclude group A streptococci pharyngitis as a differential diagnosis
  • Abdominal ultrasound – may be required if splenomegaly present


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