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').
Try two board-style Infectious Mononucleosis questions
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Question 1Infectious DiseaseMedium
A 17-year-old girl presents with a diffuse rash. One week ago she was seen for sore throat, fever, and fatigue; a rapid strep test was negative and she was prescribed amoxicillin for presumed bacterial pharyngitis. Five days into the course she developed a generalized pruritic maculopapular eruption involving the trunk, extremities, and face. Exam shows tonsillar exudates, posterior cervical lymphadenopathy, splenomegaly, and a symmetric morbilliform rash. Heterophile antibody (Monospot) test is positive. Which of the following best explains the rash?
AIgE-mediated penicillin anaphylaxis
BAminopenicillin rash in acute EBV
CGroup A streptococcal scarlet fever
DStevens-Johnson syndrome
Reveal answer & full explanation
Correct answer: B — Aminopenicillin rash in acute EBV
AIgE-mediated penicillin anaphylaxis
BAminopenicillin rash in acute EBV✓
CGroup A streptococcal scarlet fever
DStevens-Johnson syndrome
Why Aminopenicillin rash in acute EBV is correct
This patient has infectious mononucleosis (EBV) and developed the classic amoxicillin-associated morbilliform rash
When aminopenicillins are given during acute EBV, ~80–100% of patients develop a delayed, pruritic, symmetric maculopapular rash 7–10 days after starting therapy
The mechanism is a transient T-cell-mediated immune reaction driven by the EBV-altered immune state and is NOT a true IgE-mediated penicillin allergy; affected patients usually tolerate penicillins later in life
Why the others are wrong
IgE-mediated penicillin anaphylaxis — would present within minutes to hours with urticaria, angioedema, bronchospasm, or hypotension, not a delayed morbilliform eruption
Stevens-Johnson syndrome — involves mucosal erosions, painful targetoid lesions, and skin sloughing with systemic toxicity
Group A streptococcal scarlet fever — produces a sandpaper-textured erythematous rash with circumoral pallor and strawberry tongue, with positive group A strep testing
Question 2Infectious DiseaseMedium
A 22-year-old college student presents with 5 days of fever, severe sore throat, fatigue, and posterior cervical lymphadenopathy. Examination reveals tonsillar exudates and mild splenomegaly. A heterophile antibody (Monospot) test is positive, and the complete blood count shows atypical lymphocytes. Which of the following medications is most important to avoid in this patient?
AAcetaminophen
BAmoxicillin
CIbuprofen
DPrednisone
Reveal answer & full explanation
Correct answer: B — Amoxicillin
AAcetaminophen
BAmoxicillin✓
CIbuprofen
DPrednisone
Why Amoxicillin is correct
The fever, exudative pharyngitis, posterior cervical lymphadenopathy, splenomegaly, positive heterophile test, and atypical lymphocytes establish infectious mononucleosis from Epstein-Barr virus (EBV)
Amoxicillin and ampicillin precipitate a widespread, immune-complex-mediated maculopapular rash in roughly 80-90% of patients with acute EBV infection
This drug-virus reaction is not a true IgE-mediated penicillin allergy, but the eruption is striking enough that aminopenicillins are avoided when mononucleosis is suspected
The teaching point: confirm or exclude EBV before reflexively prescribing an aminopenicillin for sore throat
Why the others are wrong
Acetaminophen — a safe antipyretic/analgesic for symptomatic mononucleosis; chosen by a learner who assumes all medications are hazardous here (confused-with the EBV-aminopenicillin rule)
Ibuprofen — also safe for fever and pain; picked by anchoring on a vague "avoid NSAIDs" reflex that does not apply to uncomplicated mononucleosis
Prednisone — not contraindicated; it is reserved for specific complications (impending airway obstruction, severe thrombocytopenia, hemolytic anemia) rather than routine use, so "avoid" overstates the caution (right-concept-wrong-drug)
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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.
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
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
EBV serologic patterns for distinguishing acute, past, and reactivated infection.
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
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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