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This is a clinician-written, evidence-based summary aligned to the USMLE Step 2 CK Content Outline. It is intended for medical students preparing for USMLE Step 2 CK. Management reflects current ACC/AHA, USPSTF, and APA guidelines. Always cross-reference with UpToDate, institutional protocols, and clinical judgment.
The Bottom Line
- Classic triad: fever, pharyngitis, posterior cervical lymphadenopathy; fatigue and splenomegaly are common
- CBC shows lymphocytosis with atypical lymphocytes; heterophile antibody test supports diagnosis but can be negative early
- Treatment is supportive: hydration, NSAIDs/acetaminophen, rest; avoid contact sports due to splenic rupture risk
- Do not give amoxicillin/ampicillin for presumed strep without testing; EBV often causes a diffuse maculopapular rash after aminopenicillins
- Corticosteroids are not routine; reserve for airway obstruction, severe hemolytic anemia, severe thrombocytopenia, or CNS complications
- Differential includes acute HIV, CMV, toxoplasmosis, strep pharyngitis, viral hepatitis, and lymphoma
Overview
Infectious mononucleosis is most commonly caused by Epstein-Barr virus, a herpesvirus transmitted through saliva. EBV infects B cells and triggers a cytotoxic T-cell response responsible for atypical lymphocytosis and systemic symptoms. Adolescents and young adults classically develop fever, exudative pharyngitis, posterior cervical lymphadenopathy, profound fatigue, and splenomegaly. Management is supportive, with attention to airway compromise and splenic rupture prevention.
Epidemiology
EBV infection is common worldwide. Childhood infection is often asymptomatic, while primary infection in adolescence or young adulthood is more likely to cause mononucleosis. Transmission occurs via saliva and close contact. EBV is also associated with Burkitt lymphoma, Hodgkin lymphoma, nasopharyngeal carcinoma, post-transplant lymphoproliferative disorder, oral hairy leukoplakia in HIV, and some gastric cancers.
Clinical Features
Symptoms
Fever, malaise, profound fatigue lasting weeks
Sore throat with tonsillar enlargement or exudates
Posterior cervical lymphadenopathy, often bilateral
Left upper quadrant pain or referred shoulder pain suggests splenic enlargement or rupture
Jaundice or dark urine can occur from hepatitis or hemolysis
Rash after ampicillin or amoxicillin exposure
Signs
Posterior cervical, generalized, or epitrochlear lymphadenopathy
Tonsillar exudates, palatal petechiae, uvular edema
Splenomegaly and sometimes hepatomegaly
Airway compromise from massive tonsillar hypertrophy
Diffuse maculopapular rash after aminopenicillin exposure
Investigations
First-line
CBC with differentialLymphocytosis with >10% atypical lymphocytes supports EBV mono
Heterophile antibody testSpecific and rapid; can be falsely negative in first week and in young children
Rapid strep test / throat culture when indicatedEBV can mimic group A strep; avoid unnecessary antibiotics
Second-line
EBV-specific serologyVCA IgM indicates acute infection; useful when heterophile negative but suspicion high
Liver enzymesMild transaminitis is common; marked hepatitis should broaden differential
HIV testingAcute HIV can mimic mono and should be tested when exposure risk or atypical features exist
Specialist
Abdominal ultrasoundNot routine; may be used if splenic size/rupture concern or unclear abdominal pain
Hematology evaluationIf persistent massive lymphadenopathy, B symptoms, cytopenias, or concern for lymphoma/HLH
1
Supportive care
- Hydration, rest, NSAIDs or acetaminophen for fever/throat pain
- Avoid aspirin in children/adolescents due to Reye syndrome risk
- Avoid alcohol and hepatotoxic medications while transaminitis present
- Do not use routine antivirals; acyclovir reduces shedding but does not meaningfully improve symptoms
2
Activity restriction
- Avoid contact sports and heavy lifting during acute illness and for at least 3 weeks from symptom onset
- Return to play only when clinically well and afebrile; individualized if splenomegaly persists or athlete is high risk
- Educate on urgent evaluation for LUQ pain, dizziness, syncope, or shoulder pain
3
When to use corticosteroids
- Not for routine sore throat or fatigue
- Use for impending airway obstruction, severe autoimmune hemolytic anemia, severe thrombocytopenia, or selected neurologic complications
4
Differential management
- If group A strep confirmed, treat appropriately but avoid aminopenicillins when EBV likely
- If acute HIV possible, order HIV Ag/Ab and HIV RNA as needed
Complications
- Splenic rupture: Rare but life-threatening; LUQ pain, shoulder pain, hypotension
- Airway obstruction: Massive tonsillar hypertrophy
- Autoimmune hemolytic anemia or thrombocytopenia: Immune-mediated cytopenias
- Hepatitis: Usually mild transaminitis, rarely severe
- Chronic active EBV/HLH: Rare severe immune dysregulation
USMLE Step 2 CK Exam Tips
- 1Fever + pharyngitis + posterior cervical lymphadenopathy = EBV mono
- 2Atypical lymphocytes are reactive CD8 T cells, not malignant B cells
- 3Heterophile test can be negative early; use EBV VCA IgM if suspicion remains
- 4Amoxicillin rash after pharyngitis is a classic EBV clue
- 5Avoid contact sports because of splenic rupture risk
- 6Steroids are only for severe complications such as airway obstruction, not routine fatigue
- 7Acute HIV can mimic mono; test when exposure risk, rash/ulcers, diarrhea, or negative heterophile with high suspicion
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