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    Infectious Mononucleosis: Diagnosis and Treatment


    Last Updated Jul 12, 2021
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    By James Heilman, Neil Thurley


    • Infectious mononucleosis (IM) typically occurs between the ages of 15-24 (most often at 16-20 years).
    • 90% of IM cases are caused by Epstein-Barr virus (EBV); other causes include cytomegalovirus (CMV), human herpesvirus 6 (HHV-6), human immunodeficiency virus (HIV), adenovirus, and toxoplasmosis.
    • It spreads in saliva through direct contact and droplet spread.
    • IM typically resolves within 2-4 weeks of onset; 20% of people will have persistent symptoms (sore throat, fatigue) at 1 month.
    • Complications may include:
      • splenic rupture
      • airway obstruction
      • hepatitis
      • hemolytic anemia.

    Diagnostic Process

    Classic Signs and Symptoms

    • Fever.
    • Fatigue.
    • Pharyngitis with tonsillar enlargement.
    • Posterior and anterior cervical chain lymphadenopathy.
    • Other potential signs include:
      • Palatal petechiae.
      • Splenomegaly.
      • Liver Involvement: hepatomegaly, jaundice, or elevated aspartate aminotransferase (AST) and alanine aminotransferase (ALT).
      • Rash: Erythematous, maculopapular, or morbilliform.
      • Axillary and inguinal lymphadenopathy.
    • It can be difficult to distinguish from streptococcal pharyngitis. Predictors of IM in the presence of sore throat were palatal petechiae (specificity 0.95; positive LR, 5.3), lymphadenopathy (posterior cervical, axillary, or inguinal, specificity 0.82-0.91; positive LR, 3.0-3.1), and splenomegaly (specificity 0.71-0.99; positive LR, 1.9-6.6).

    Laboratory Investigations

    • Clinical diagnosis alone may be sufficient; consider the following investigations if a definitive diagnosis is desired.
    • Heterophile antibody test (Monospot test) and a CBC with diff.
      • Absolute lymphocytosis ≥4×109/L, relative lymphocytosis ≥50%, and/or atypical lymphocytes ≥10%, and a positive Monospot = IM due to EBV.
      • Positive hematological findings and negative Monospot: consider EBV Antibody Test.
      • Patients with negatives tests are unlikely to have IM.
    • EBV Antibody Test: Patients negative for anti-VCA IgM are highly unlikely to have EBV infection, and may require further testing for CMV, HHV-6, and HIV.

    Other Tests to Consider

    • Throat culture or rapid antigen detection test for streptococcal infection.
    • Liver function test: IM due to EBV typically have transient, mildly elevated AST and ALT.
    • Pregnant or high-risk patients (men who have sex with men, injection drug users, etc.) should receive initial testing for HIV, CMV, and toxoplasmosis in addition to EBV.


    • False Negative Monospot: within the first week of symptom onset and if age <5 years old.
    • False Positive Monospot: Autoimmune disease, toxoplasmosis, rubella, lymphoma, cytomegalovirus, and acute HIV.

    Recommended Treatment

    • Supportive care alone: rest, hydration, and symptomatic management.
    • Abstain from strenuous exercise for 3-4 weeks after symptom onset to limit risk of splenic rupture. However, splenic rupture reported to occur spontaneously.
    • Patients involved in contact sports, or activities involving high intra-abdominal pressure, require longer periods of rest.
    • Patients with IM presenting with upper airway obstruction often admitted to hospital or observed for several hours.

    Analgesia and Antipyretics

    • Acetaminophen
    • NSAIDs
    • Topical anaesthetic lozenges (over the counter)
    • Benzydamine (Tantum) Oral Gargle or similar (Prescription): How to Use Benzydamine Rinse – Oral (Source: HealthLinkBC).
      • Usually 30 cc q1.5-3 hours. Gargle for 30 seconds, and then spit it out. Do not swallow.


    • Often given but insufficient evidence to recommend the routine usage of glucocorticoids in the treatment of IM.
    • NNT Summary: Corticosteroids for Acute Pharyngitis.
    • Often single doses of either prednisolone or dexamethasone.
    •  Typically:
      • prednisone 60 mg po
      • prednisolone 30-60 mg po
      • dexamethasone up to 10 mg, PO/IM
    • An equivalent dose of IV corticosteroids may be used during the first few days of treatment if admitted.


    • Insufficient evidence to recommend the use of antiviral medications (acyclovir, valacyclovir, ganciclovir, etc.) in the treatment of IM.

    Quality Of Evidence?


    Recommendations based on evidence from low to moderate quality systematic reviews and clinical reviews. Findings primarily based on expert opinion and consensus guidelines.


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