Infectious Mononucleosis (EBV)
Acute viral syndrome caused by Epstein-Barr virus — fever, pharyngitis, posterior cervical lymphadenopathy, fatigue, and atypical lymphocytosis.
Also known as: mono, EBV, Epstein-Barr virus, mononucleosis, glandular fever
Overview
Acute infection by Epstein-Barr virus (HHV-4), a gamma-herpesvirus that infects B-lymphocytes via CD21 receptor binding. Lifelong latency in memory B cells follows primary infection.
Epidemiology
Most US adults are EBV-seropositive by age 35. Symptomatic mononucleosis peaks in adolescents and young adults (15-24 years); primary infection in childhood is usually asymptomatic or mild. Transmitted via oral secretions (the 'kissing disease').
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Risk factors
- Adolescence/young adulthood (delayed primary infection)
- Close personal contact, sharing of utensils/drinks
- College/military barracks settings
- Immunocompromise → severe/atypical disease or PTLD
Pathophysiology
EBV enters via oropharyngeal epithelium, infects B-cells, and induces polyclonal B-cell activation. The clinical syndrome reflects an exuberant cytotoxic T-cell response (the 'atypical lymphocytes' are activated reactive CD8 T-cells, not infected B-cells). EBV establishes lifelong latency and is implicated in Burkitt lymphoma, nasopharyngeal carcinoma, Hodgkin lymphoma, primary CNS lymphoma in HIV, and post-transplant lymphoproliferative disease.
Clinical presentation
Symptoms
- Prodrome (1-2 weeks): malaise, low-grade fever, headache, anorexia
- Classic triad: fever, exudative pharyngitis (often with palatal petechiae), lymphadenopathy (posterior cervical chain prominent)
- Profound fatigue lasting weeks to months
- Abdominal discomfort from splenomegaly
Signs / physical exam
- Tonsillar enlargement with white-gray exudate; palatal petechiae at hard-soft palate junction
- Posterior > anterior cervical lymphadenopathy; may have generalized adenopathy
- Splenomegaly (~50%); hepatomegaly (~10%); jaundice in ~5%
- Maculopapular rash after amoxicillin/ampicillin exposure (highly suggestive)
- Periorbital edema, soft palate edema
Classic findings
An adolescent with sore throat, fatigue, posterior cervical adenopathy, and a diffuse maculopapular rash after a course of amoxicillin given for presumed strep is EBV until proven otherwise.
Differential diagnosis
- Streptococcal pharyngitis — Centor criteria; rapid antigen test; can coexist with EBV — but penicillin/amoxicillin in EBV causes a maculopapular rash (~80-95%)
- CMV mononucleosis — Heterophile-negative; pharyngitis and adenopathy less prominent; older patients; CMV PCR or IgM
- Acute HIV (retroviral syndrome) — Trunk rash, oral ulcers, recent high-risk exposure; obtain HIV RNA
- Toxoplasmosis — Lymphadenopathy without pharyngitis; cat exposure or undercooked meat; toxo IgM/IgG
- Lymphoma — Persistent painless adenopathy >4 weeks, B symptoms, mediastinal mass; lymph node biopsy
- Acute leukemia — Cytopenias, blasts on smear, bone pain; flow cytometry
- Viral hepatitis A/B — Right upper quadrant pain, jaundice, marked transaminitis; viral hepatitis serologies
Diagnostic workup
Diagnostic criteria
Clinical syndrome + positive heterophile antibody OR positive EBV VCA IgM with negative EBNA-1 IgG.
Labs
- CBC with differential: lymphocytic predominance with ≥10% atypical lymphocytes (Downey cells)
- Heterophile antibody (Monospot) — positive in ~85% of adolescents/adults; may be falsely negative in the first week and in young children (<4 yo)
- EBV-specific serology if heterophile-negative or atypical course: VCA IgM (acute), VCA IgG (lifelong), EBNA (appears 6-12 weeks; absence supports recent infection)
- AST/ALT often 2-3x elevated (mild hepatitis nearly universal)
- Throat swab for strep if pharyngitis prominent (coinfection possible)
Imaging
- Abdominal ultrasound only if splenic enlargement clinically suspected and would change activity counseling (most evidence does not support routine imaging)
Diagnostic algorithm
| EBV Antibody | Acute Infection | Past Infection | Reactivation |
|---|---|---|---|
| VCA IgM | Positive | Negative | Variable |
| VCA IgG | Positive (rises) | Positive (stable) | Positive (rises) |
| EBNA-1 IgG | Negative | Positive | Positive |
| Early antigen (EA) IgG | Often positive | Negative | Often positive |
| Heterophile | Positive (~85%) | Negative | Negative |
Treatment
First-line
- Supportive care: hydration, NSAIDs/acetaminophen, rest, throat lozenges/saltwater gargles
- Avoid contact sports/heavy exertion for at least 3 weeks (and until splenomegaly resolves) due to splenic rupture risk
- Avoid amoxicillin/ampicillin — high rate of maculopapular rash (immune-mediated, not true allergy)
Second-line / adjunct
- Corticosteroids (prednisone) — reserved for airway compromise from tonsillar/lymph node swelling, autoimmune hemolytic anemia, severe thrombocytopenia
- Acyclovir/ganciclovir — no clinical benefit in routine immunocompetent mononucleosis; reserved for severe disease in immunocompromised (PTLD, hemophagocytic lymphohistiocytosis)
Complications
- Splenic rupture (rare, ~0.1%) — usually weeks 2-4; can be spontaneous
- Airway obstruction from tonsillar/lymph node hypertrophy
- Autoimmune hemolytic anemia (cold agglutinin, anti-i), immune thrombocytopenia, aplastic anemia
- Hepatitis (usually mild and self-resolving); rarely fulminant
- Neurologic: Guillain-Barre, encephalitis, transverse myelitis, optic neuritis, cranial neuropathies
- Chronic active EBV, hemophagocytic lymphohistiocytosis (HLH) in immunocompromised
- Long-term association with Hodgkin lymphoma, Burkitt lymphoma, nasopharyngeal carcinoma, multiple sclerosis
PANCE pearls
- The amoxicillin-EBV rash is NOT a true penicillin allergy and does not preclude future beta-lactam use — but document and counsel.
- Heterophile antibody can be falsely negative in the first week of symptoms; repeat in 5-7 days if clinical suspicion remains.
- Splenic rupture is the feared complication — avoid contact sports/heavy lifting for at least 3 weeks; return-to-play guided by symptoms (imaging not required in routine cases).
- Suspect EBV in any young adult with prolonged fatigue, mild transaminitis, and lymphocytosis with atypical lymphocytes.
- Recent landmark data (Bjornevik 2022, Science) supports EBV as a necessary causal factor in multiple sclerosis.
References
- CDC — About Epstein-Barr Virus (EBV) — laboratory testing for EBV infection
- AAFP — Womack & Jimenez, Common Questions About Infectious Mononucleosis (Am Fam Physician 2015)
- Bjornevik 2022 — Longitudinal analysis reveals high prevalence of EBV associated with multiple sclerosis (Science 2022)
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