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. A complete blood count shows lymphocytosis with 20% atypical lymphocytes. Which of the following best explains the rash?
AIgE-mediated penicillin allergy
BAmoxicillin-induced DRESS
CStevens-Johnson syndrome
DAminopenicillin rash in acute EBV
ESerum sickness-like drug reaction
Reveal answer & full explanation
Correct answer: D — Aminopenicillin rash in acute EBV
AIgE-mediated penicillin allergy
BAmoxicillin-induced DRESS
CStevens-Johnson syndrome
DAminopenicillin rash in acute EBV✓
ESerum sickness-like drug reaction
Why Aminopenicillin rash in acute EBV is correct
This patient has infectious mononucleosis (EBV) and developed the classic amoxicillin-associated morbilliform rash
Exudative pharyngitis, posterior cervical lymphadenopathy, splenomegaly, and atypical lymphocytosis identify infectious mononucleosis; a positive heterophile antibody (Monospot) test would confirm it
When aminopenicillins are given during acute EBV, a delayed, pruritic, symmetric maculopapular rash develops, usually 5–10 days after starting therapy; modern series report it in roughly 30% of amoxicillin-treated patients (the classic 80–100% figure comes from older ampicillin data)
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 allergy — IgE-mediated reactions begin within minutes to hours of a dose with urticaria, angioedema, bronchospasm, or hypotension, not a delayed morbilliform eruption on day 5 of therapy during acute EBV infection
Serum sickness-like drug reaction — usually begins 1 to 3 weeks after starting a drug such as cefaclor or amoxicillin, with fever, an urticarial or polycyclic rash, and prominent arthralgias; it would not explain the exudative pharyngitis that preceded the antibiotic or the splenomegaly and atypical lymphocytosis of acute EBV
Stevens-Johnson syndrome — involves mucosal erosions, painful targetoid lesions, and skin sloughing with systemic toxicity
Amoxicillin-induced DRESS — tempting because DRESS also causes fever, a morbilliform rash, lymphadenopathy, and atypical lymphocytes, but it usually begins 2 to 8 weeks after starting the drug with eosinophilia, facial edema, and internal organ involvement such as hepatitis; it would not explain the sore throat, fever, and fatigue that began before the antibiotic
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?
AIbuprofen
BAcetaminophen
CAmoxicillin
DPrednisone
EBenzocaine
Reveal answer & full explanation
Correct answer: C — Amoxicillin
AIbuprofen
BAcetaminophen
CAmoxicillin✓
DPrednisone
EBenzocaine
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 maculopapular rash, a transient T-cell-mediated drug-virus reaction, in a substantial minority of patients with acute EBV infection (about 30% in modern amoxicillin series; the classic 80-100% figure comes from older ampicillin data)
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)
Benzocaine — a topical anesthetic in sore-throat lozenges and sprays that is a reasonable symptomatic option for throat pain in adults with mononucleosis; the FDA methemoglobinemia warning bars its use in children younger than 2 years and stresses label dosing in others, so it is not a drug to avoid here (anchoring on a vague drug-safety warning)
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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 aminopenicillins given during acute EBV can cause a delayed morbilliform rash (~30% in modern series; the classic 80-100% figure comes from older ampicillin data)
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 — reduce oral viral shedding but give no clinical benefit and are not recommended; EBV-driven PTLD is managed by reducing immunosuppression plus rituximab, and EBV-associated HLH with HLH-directed therapy, not antivirals
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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