Infectious Disease & Internal Medicine & Pediatrics & Family Medicine
Infectious mononucleosis
Infectious mononucleosis (IM) — commonly known as the «kissing disease» — is an acute infection caused by the Epstein-Barr virus (EBV — Human Herpesvirus 4, HHV-4), a ubiquitous double-stranded DNA herpesvirus belonging to the Herpesviridae family, subfamily Gammaherpesvirinae. EBV infects more than 95% of the global population, most often asymptomatically during childhood (before the age of 5 in low-income countries) or as clinically manifest infectious mononucleosis when primary infection occurs during adolescence or adulthood. Transmission occurs primarily through saliva (kissing, sharing utensils, coughing)—EBV persists for life in memory B cells and in the epithelial cells of the oropharynx following primary infection. The classic clinical triad of IIM combines fever + pharyngitis (pseudomembranous tonsillitis with exudate) + posterior cervical lymphadenopathy — accompanied by intense and prolonged fatigue + splenomegaly + hepatomegaly. Lymphocytosis with atypical lymphocytes (Downey cells—large activated lymphocytes with abundant blue-gray vacuolated cytoplasm) on the CBC is characteristic. The diagnosis is confirmed by the Monotest (heterophile test—sensitivity 85–90% + specificity >99%) plus specific EBV serology. The key rule to remember: amoxicillin and ampicillin are strictly contraindicated in infectious mononucleosis—they cause a confluent maculopapular rash in 80–90% of cases, which is NOT a true penicillin allergy and should not be recorded as such in the patient’s medical record.
Pathophysiology, clinical presentation, and diagnosis
- Pathophysiology of EBV infection and immune response: EBV infection cycle: EBV → oropharyngeal epithelial cells (primary infection) → then naive B cells via CD21 receptor (complement receptor CR2) → EBV uses surface protein gp350 to bind to CD21 → infection and transformation of B cells → proliferation of infected B cells → massive cytotoxic immune response: CD8+ T cells (cytotoxic T cells) are activated to control the proliferation of infected B cells → these are the atypical lymphocytes (Downey cells) visible on the CBC → CD8+ T cells express the activated phenotype and are 10-100 times more numerous than infected B cells → therefore, atypical lymphocytosis is a normal CYTOTOXIC RESPONSE → the virus persists for life in memory B cells in a latent state (EBV latency) → can reactivate → polyclonal activation of B cells → production of heterophile antibodies (IgM directed against sheep and horse antigens → basis of the monospot test) → incubation period: 4–8 weeks + contagiousness: persistent for several months in saliva even after clinical recovery
- Clinical presentation, complications, and biological diagnosis: Classic triad of MNI: fever (38–40°C — often lasting >1 week) + pseudomembranous pharyngitis (erythematous sore throat + grayish-white exudate + sometimes very painful + petechiae on the soft palate) + posterior cervical lymphadenopathy (bilateral + painful + mainly posterior cervical → distinguishes from bacterial tonsillitis with mainly submandibular lymph nodes) → + splenomegaly (50–80% of cases) → RISK OF SPLENIC RUPTURE + hepatomegaly (10–15% of cases) + jaundice (5–10% of cases) + intense and prolonged fatigue (most debilitating symptom — may last weeks to months) + spontaneous maculopapular skin rash (5% of cases without amoxicillin) + complications: upper airway obstruction (very enlarged tonsils) → emergency → IV corticosteroids + splenic rupture (rare — 0.1–0.3% of cases) → sudden left-sided abdominal pain → surgical emergency + macrophage activation syndrome (HLH) → fever + cytopenias + very high ferritin → etoposide + anakinra according to the HLH-2004 protocol + myocarditis + encephalitis + thrombocytopenic purpura + laboratory diagnosis: CBC: lymphocytosis (>4.5 × 10⁹/L + atypical lymphocytes >10% %) + characteristic CBC → frequent thrombocytopenia + hemolytic anemia (rare) + elevated transaminases (EBV hepatitis — in 80% of cases) + Monospot (heterophile test): EBV IgM heterophils → sensitivity 85–90% + specificity >99% → false negatives in the first 2 weeks (early seronegativity) → rare false positives (lupus + Burkitt’s lymphoma + autoimmune diseases) + EBV-specific serology if Monotest is negative: anti-VCA IgM (acute) + anti-VCA IgG + anti-EA (early antigen) + anti-EBNA → EBNA absent in the acute phase = recent infection
Treatment, complications, and long-term sequelae
| Appearance / treatment | Data, protocols and results | References and recommendations |
|---|---|---|
| Symptomatic treatment and absolute contraindications AMOXICILLIN AND AMPICILLIN ARE CONTRAINDICATED — maculopapular rash 80–90% % — not a true penicillin allergy — DO NOT record allergy — rest — analgesics — antipyretics — 3–4 weeks of restricted physical activity — splenic rupture — hydration — sore throat — acetaminophen, ibuprofen — antivirals are unnecessary — acute MNI |
Treatment of infectious mononucleosis — basic guidelines: ABSOLUTE RULE No. 1 — amoxicillin and ampicillin are STRICTLY CONTRAINDICATED in IM: amoxicillin + ampicillin (and to a lesser extent other aminopenicillins) cause a generalized confluent maculopapular rash (diffuse erythema + pruritus) in 80–90% of patients with IFM → mechanism: EBV-activated B cells produce anti-aminopenicillin IgM → non-allergic immune reaction → this rash IS NOT a true penicillin allergy → DO NOT record a penicillin allergy in the medical record → this may deprive the patient of an effective class of antibiotics for life → symptomatic treatment (the only validated treatment for uncomplicated MNI): bed rest + reduced activity during the acute phase + acetaminophen 500–1,000 mg PO every 6 hours for fever and pain + or ibuprofen 400 mg × 3/day → oral hydration + local anesthetics (viscous lidocaine or anesthetic mouthwash) for severe pharyngeal pain → restriction of physical activities and contact sports: for at least 3–4 weeks → until splenomegaly normalizes (clinical + ultrasound if in doubt) → risk of splenic rupture + antivirals (acyclovir, valacyclovir, ganciclovir): INEFFECTIVE in acute IMM → EBV is already disseminated in the lymph nodes at the time of diagnosis → antivirals have no demonstrable clinical effect → Luzuriaga 2010 — NEJM: acyclovir + IMM → no clinical benefit → Hamill 1988 — Pediatrics: acyclovir + IMM in children → no benefit | Luzuriaga 2010 — NEJM: MNI + acyclovir → no benefit → reference + Hamill 1988 — Pediatrics: acyclovir + MNI child → no benefit + Lennon 2019 — Pediatrics: MNI + amoxicillin + rash → reference + CPS (Canadian Paediatric Society) 2021: MNI + treatment + amoxicillin → contraindication + ASPC + INSPQ Quebec + INESSS Quebec + RAMQ: symptomatic treatment + paracetamol + ibuprofen → reimbursed + monotest + EBV serologies → reimbursed |
| Corticosteroids, serious complications, and SAM Corticosteroids prednisone airway obstruction — enlarged tonsils — stridor — dysphagia — splenic rupture left abdominal pain — surgical emergency — SAM HLH etoposide anakinra — thrombocytopenic purpura ITP — encephalitis — myocarditis — Guillain-Barré syndrome |
Corticosteroids and management of severe complications of MNI: corticosteroids — selective indications (do not use routinely): upper airway obstruction (very enlarged tonsils → dysphagia + stridor + respiratory distress) → prednisone 40–60 mg/day × 7–10 days → or IV methylprednisolone if severe obstruction → rapid effect on tonsil size → severe thrombocytopenia (<20 × 10⁹/L with bleeding) + or severe hemolytic anemia → splenic rupture (rare complication — 0.1–0.3% of cases): sudden left abdominal pain + radiation to the left shoulder (Kehr’s sign — diaphragmatic irritation) + hypotension + tachycardia → surgical emergency → urgent abdominal ultrasound → surgery (splenorrhaphy or splenectomy) → early restriction of physical activity is the best prevention → macrophage activation syndrome (MAS — HLH — Hemophagocytic Lymphohistiocytosis): rare but potentially fatal complication → HLH-2004 criteria: fever + splenomegaly + cytopenias (≥2 lineages) + very high ferritin (>500 µg/L + often >10,000 µg/L) + hypertriglyceridemia + low fibrinogen + hemophagocytosis on peripheral blood smear → treatment: etoposide + dexamethasone (HLH-2004 protocol) + or anakinra (anti-IL-1) in moderate cases + urgent consultation with a hematologist → other neurological complications: encephalitis + aseptic meningitis + Guillain-Barré syndrome + facial paralysis → treatment based on the complication + myocarditis: ECG + troponin + echocardiography + immune thrombocytopenic purpura (ITP): treatment if platelets <20–30 × 10⁹/L or hemorrhage → IVIG + or corticosteroids | Janka 2012 — Hematology ASH: SAM + HLH + treatment → etoposide + Henter 2007 — Pediatric Blood Cancer (HLH-2004): SAM protocol → reference + Luzuriaga 2010 — NEJM: EBV + complications + Baumgarten 2019 — Deutsches Ärzteblatt: EBV + splenic rupture + sports restriction → CPS 2021 + ASPC + INESSS Quebec + RAMQ: corticosteroids + IVIG → reimbursed if documented complication |
| EBV and associated long-term diseases EBV Burkitt lymphoma — Hodgkin lymphoma CD15 CD30 — nasopharyngeal carcinoma — multiple sclerosis MS — chronic fatigue — CAEBV active chronic infection — immunocompromised PTLD — EBV vaccine in development — return to sports — cure criteria |
EBV and long-term associated diseases — oncology and neurology: EBV and malignant lymphoproliferative disorders: Burkitt lymphoma: t(8;14) (c-Myc/IgH translocation) → transformed B cells → endemic in Africa (jaw + orbit) + sporadic (abdomen + ileum) → often EBV-positive → intensive chemotherapy + Hodgkin lymphoma: CD15+ CD30+ → Reed-Sternberg cells → EBV detectable in 40–70% of cases → excellent prognosis with ABVD + nasopharyngeal carcinoma: EBV+ in nearly 100% of cases → populations of Southeast Asia and North Africa ++ → treatment: chemoradiotherapy → post-transplant lymphoproliferative disorder (PTLD): in immunocompromised transplant recipients → EBV+ LB proliferate uncontrollably → reduction of immunosuppression + rituximab + EBV and multiple sclerosis (MS): Bjornsson 2020 — NEJM + Mokry 2022 — NEJM: EBV is a necessary (but not sufficient) cause of MS → 32-fold increased risk of MS following primary EBV infection → mechanism: molecular mimicry (EBNA1 protein vs. GlialCAM protein) + activation of anti-myelin autoreactive T cells → chronic active EBV infection (CAEBV): rare + children + adults + persistent detectable EBV + cytopenias + chronic fever + treatment: allogeneic stem cell transplant → return to sports after MNI: current recommendations: wait at least 3–4 weeks + confirm resolution of clinical splenomegaly + or via abdominal ultrasound before returning to contact sports → no strict laboratory criteria → individualized decision + EBV vaccine: mRNA-1189 (Moderna) — Phase 1–2 clinical trials ongoing → results expected 2025–2026 | Bjornsson 2020 — NEJM: EBV + SEP → risk × 32 → reference + Mokry 2022 — NEJM: EBV + SEP + molecular mimicry EBNA1 GlialCAM → Luzuriaga 2010 — NEJM: EBV + MNI + complications + Henter 2007 — PBC (HLH-2004) + Baumgarten 2019: return to sport + splenomegaly + CPS 2021 + ASPC + SCNC + Canadian Cancer Society + INESSS Quebec + RAMQ: EBV serologies + abdominal imaging → reimbursed |
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Amoxicillin and ampicillin are STRONGLY CONTRAINDICATED in infectious mononucleosis—they cause a rash in 80–90% of cases. This rash is NOT a true penicillin allergy—never record it in the medical record as an allergy: Antivirals (acyclovir) are also ineffective in acute EBV. Any sudden left abdominal pain in a patient with EBV should raise suspicion for splenic rupture—a surgical emergency. Restriction of physical activities and contact sports is mandatory for at least 3–4 weeks.
Situations requiring urgent care
Patient with MNI + very enlarged tonsils + stridor + difficulty swallowing saliva + or liquids + muffled voice + or oxygen desaturation → Upper airway obstruction → Emergency → Methylprednisolone IV 1 mg/kg → Monitor saturation → Intubation if severe obstruction → ENT + Anesthesia emergency → DO NOT tonsillectomy in the acute phase.
Patient with PLN + sudden and severe left abdominal pain + or pain radiating to the left shoulder (Kehr's sign) + tachycardia + hypotension + or syncope → ruptured spleen → call 911 → emergency room → urgent abdominal ultrasound → surgery (splenorrhaphy or splenectomy) → transfusion if hemorrhagic shock → life-threatening emergency.
Patient with PNH + persistent fever >2 weeks despite rest + progressive pancytopenia (anemia + leukopenia + thrombocytopenia) + very high ferritin (>500 µg/L) + large splenomegaly + hypertriglyceridemia + general health decline → Macrophage activation syndrome (MAS — HLH) → hematologic emergency → HLH-2004 criteria + BM → etoposide + dexamethasone → urgent hematologist consultation.
Consult at Clinique Omicron
Clinique Omicron physicians diagnose infectious mononucleosis clinically and biologically (CBC + monospot test + EBV serologies), prescribe appropriate symptomatic treatment, systematically remind patients of the absolute contraindication to amoxicillin and ampicillin, prescribe sports restriction for 3-4 weeks, verify the resolution of splenomegaly before returning to sports, recognize and quickly direct patients for complications (upper airway obstruction + splenic rupture + male infertility), and ensure follow-up for post-mono fatigue. Consultations are available at several service locations in Quebec and via telemedicine. To make an appointment, visit cliniqueomicron.ca.
The content of this page is for informational purposes only and does not substitute for the advice of a doctor or infectious disease specialist. Infectious mononucleosis is generally a benign illness but can have complications—restricting contact sports and the absolute contraindication of amoxicillin/ampicillin are the two key takeaways.
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