Infectious Diseases & Internal Medicine & Pediatrics & Family Medicine
Infectious mononucleosis (mono test)
Infectious mononucleosis (IM) is an acute clinical syndrome caused in 90 % of cases by the Epstein-Barr virus (EBV - Human Herpesvirus 4 - HHV-4), a double-stranded DNA virus of the Herpesviridae family that preferentially infects B lymphocytes and epithelial cells. NID is sometimes referred to as «kissing disease», due to its primary transmission via saliva. EBV infects over 95 % of the world's adult population over time - primary infection occurs in childhood in developing countries (often asymptomatic) or in adolescence/young adulthood in developed countries (more often symptomatic). The classic clinical triad of NID is: fever + exudative angina (often severe, pseudomembranous) + posterior cervical adenopathy ++ (+ sometimes generalized). Splenomegaly is present in 50-80 % of cases. Biological diagnosis is based on monotest (heterophilic test - heterophilic antibody agglutination test - sensitivity 85-90 %, specificity 99 %) and/or specific EBV serology (anti-VCA IgM + IgG + anti-EBNA). There is no curative antiviral treatment for NID - treatment is symptomatic. Avoidance of amoxicillin (and ampicillin) is imperative - they cause a maculopapular rash in 80-90 % of cases of NID (characteristic rash but no true allergic mechanism). Contact sports must be restricted for at least 3-4 weeks, due to the risk of splenic rupture.
Virology of EBV, pathophysiology, and clinical manifestations
- EBV Biology and Pathogenesis of Infectious Mononucleosis: EBV structure and tropism : double-stranded DNA virus + Herpesviridae family + Lymphocryptovirus genus → infects B lymphocytes (via CD21 - C3d complement receptor) and oropharyngeal epithelial cells → viral latency in host memory B lymphocytes (the virus persists for life in the host memory LB pool)pharyngeal epithelial cells → lifelong viral latency in memory B lymphocytes (virus persists lifelong in host memory LB pool - type III latency → type I in chronic latency phase) + periodic asymptomatic reactivations with salivary excretion → lytic cycle (viral replication) in epithelial cells + latent cycle (transformation program) in LB → EBV-1 and EBV-2 subtypes (geographically different) + pathophysiology of NIM : transmission via saliva → infection of tonsil epithelial cells → dissemination to LBs via CD21 → transformation and polyclonal activation of LBs → recognition of infected LBs by cytotoxic CD8+ LTs (= atypical lymphocytes in the blood smear) → considerable expansion of CD8+ LTs (atypical lymphocytosis) → responsible for most symptoms (exaggerated immune response) + massive release of cytokines (IFN-γ + IL-6 + IL-10) → inflammatory syndrome → EBV expresses oncogenic latency proteins (EBNA + LMP1 + LMP2) → potential LB transformation → association with lymphomas + carcinomas (Burkitt + Hodgkin + nasopharyngeal carcinoma + lymphoma of the immunocompromised) + epidemiology: almost universal worldwide prevalence (>90 % seropositive adults) → primary infection: child (developing countries - often asymptomatic) + adolescent-adult (developed countries - 50-75 % symptomatic) → incubation: 4-7 weeks + contagiousness: during acute phase + several months later (prolonged salivary excretion)
- Clinical manifestations of EBV infection and special forms: Classic NID triad: 1/ fever: 38-40°C + intense asthenia (profound fatigue +++) + myalgias + headaches → duration 1-3 weeks + 2/ angina: erythematous or exudative or pseudomembranous pharyngitis (bilateral grayish-white coating on tonsils ++) + very intense odynophagia + palatine macular erythema + sometimes palatine soft palate petechiae (little-known but very specific sign) + 3/ adenopathies: posterior cervical +++ (posterolateral - characteristic - posterior ADP in an adolescent with angina = MNI until proven otherwise) → often bilateral + diffuse (axillary + inguinal) → firm + tender → persisting 2-4 weeks + associated signs: splenomegaly (50-80 % of cases - risk of rupture ++) + hepatomegaly + jaundice (10-20 % - EBV hepatitis with elevated transaminases) + maculopapular rash (5-10 % without amoxicillin) → rash if amoxicillin given: 80-90 % of NMIs under amoxicillin → confluent + diffuse + pruritic → DO NOT attribute to penicillin allergy + bilateral palpebral edema (Hoagland's sign - highly suggestive of NMI) → CBC: leukocytosis (10,000-30,000/µL) + lymphocytosis ++ + atypical lymphocytes (Downey cells - activated CD8+ LT) ≥10-20 % → diagnosis often clinical + biological; special clinical forms: severe NIM: upper airway obstruction (very large tonsils affecting uvula + urgent corticosteroids) + splenic rupture (rare but surgical emergency) + macrophagic activation syndrome (MAS - very rare - severe) + autoimmune hemolytic anemia (anti-i) + thrombocytopenia + encephalitis + Guillain-Barré syndrome + pericarditis + myocarditis + NMI in the immunocompromised (HIV + transplant patients + chemotherapy) : severe forms + EBV-associated lymphomas
Diagnosis and management
| Appearance / treatment | Data, modalities and protocols | References and recommendations |
|---|---|---|
| Diagnostic - monotest, NFS and EBV serology Monotest heterophile antibodies — sensitivity 85–90% % — false negative first weeks — atypical lymphocytes CBC — EBV serology anti-VCA IgM IgG anti-EBNA — EBV PCR viral load — transaminases hepatitis — LDH — HIV serology primary infection |
Diagnosis of infectious mononucleosis - stepwise approach: clinical diagnosis: adolescent or young adult + triad (fever + exudative angina + posterior cervical adenopathies) + splenomegaly + atypical lymphocytes on smear → highly probable NIM → monotest (heterophilic test - Monospot): principle: heterophilic antibodies produced in NMI agglutinate sheep or horse red blood cells → result in 5-15 min → sensitivity 85-90 % + specificity >99 % → false negatives in the first 2 weeks (heterophilic antibodies not yet produced in sufficient quantity) + false negatives more frequent in children <4 years (lower rate of heterophilic antibodies in pediatric NIDs) → if Monospot negative + very suggestive clinic → repeat at 1-2 weeks OR proceed to specific EBV serology → specific EBV serology (anti-EBV ANTIBODIES) : anti-VCA (Viral Capsid Antigen) IgM : become positive at the start of NMI → marker of acute infection → disappear in 3 months → anti-VCA IgG: become positive at the start of NMI and persist for life → anti-EA (Early Antigen): present in the acute phase + anti-EBNA (Epstein-Barr Nuclear Antigen) IgG: absent in acute phase + appear 3-6 weeks after onset → their presence confirms an old infection → ABSENT at onset = recent infection + if EBNA positive → old infection → confirmed (old) NMI or asymptomatic past infection → CBC + blood smear: leukocytosis with lymphocytosis ++ + atypical lymphocytes (Downey cells) ≥10 % + thrombocytopenia possible + liver workup: ASAT + ALAT elevated (10× N in 80 % of cases) → self-limited benign EBV hepatitis + LDH elevated + CRP + VS elevated → HIV serology: primary HIV infection may mimic NMI → screen systematically + EBV PCR: useful in the immunocompromised to quantify viral load | Cohen 2000 — NEJM : Mononucleosis + diagnostic + treatment → review + Luzuriaga 2010 — NEJM : EBV + mononucleosis + immunopathology → reference + Dunmire 2018 — Current Biology : EBV + biology + mononucleosis → review + Candy 2019 — BMJ : Mononucleosis + diagnostic + management → + Henle 1968 — Journal of Bacteriology : EBV serology description → historical reference + ASPC + INSPQ Quebec : Mononucleosis + epidemiology + INESSS Quebec + RAMQ : monotest + CBC + EBV serology + liver panel → reimbursed if indicated |
| Treatment, amoxicillin, and sports restriction Symptomatic treatment — DO NOT give amoxicillin — rash 80–90 % — no true penicillin allergy — corticosteroids for upper airway obstruction — rest — pain relievers — restriction from contact sports 3–4 weeks — splenic rupture — return to school — prolonged fatigue — antivirals not indicated — acyclovir ganciclovir useless EBV |
Treatment of infectious mononucleosis - basic principles: symptomatic treatment (no effective curative antiviral in clinical practice): rest (avoid exhaustion - asthenia can be prolonged) + analgesics and antipyretics: paracetamol 1 g × 3-4/d + or ibuprofen 400 mg × 3/d if severe pain → ASPIRIN: avoid in children (risk of Reye's syndrome) → oral hydration ++ (for very painful angina) → throat lozenges + mouthwash → corticoids: indicated if : upper airway obstruction (very large tonsils almost touching the uvula + stridor) → prednisone 40-60 mg/d × 5-7 days → or methylprednisolone IV if severe obstruction → severe thrombocytopenia + or severe autoimmune hemolytic anemia → no systematic indication to shorten duration of illness → AMOXICILLIN AND AMPICILLIN - FORMALLY CONTRAINDICATED: amoxicillin and ampicillin cause a confluent + diffuse + pruritic + bright red maculopapular rash in 80-90 % of patients with NID → mechanism: not a true allergy to penicillin → complex immune mechanism / activated LB + drug → DO NOT conclude penicillin allergy following this rash → rash resolves in a few days on discontinuation of antibiotic → if superadded bacterial angina suspected → use amoxicillin-clavulanate is also to be avoided → prefer cefuroxime or azithromycin if antibiotic needed → restriction of physical and sporting activities: risk of splenic rupture ++ → spleen increases in volume and becomes fragile + at risk of traumatic rupture + sometimes spontaneous → formal restriction of contact sports (soccer + rugby + field hockey + martial arts + basketball) + intense abdominal exertion → for at least 3-4 weeks after onset of symptoms → or until normalization of splenomegaly on ultrasound → return to sport must be gradual and discussed with the doctor → antivirals (acyclovir + ganciclovir + valacyclovir): ineffective on symptoms of acute IM → not routinely prescribed → some indications in immunocompromised forms (transplant + HIV) | Cohen 2000 — NEJM: IMN + treatment + amoxicillin + rash → reference + Candy 2019 — BMJ: IMN + management + sports restriction + Hamill 1988 — Pediatrics: splenic rupture + IMN + sports + Cohen 2000 — NEJM: antivirals + IMN + ineffectiveness + Ebell 2004 — American Family Physician: IMN + diagnostic criteria + Hoagland 1952: eyelid edema + IMN → Hoagland's sign → classic reference + CPS (Canadian Paediatric Society) 2021: IMN + pediatrics + treatment + return to sports + ASPC + INESSS Québec + RAMQ: acetaminophen + NSAIDs + corticosteroids → reimbursed |
| Complications, chronic MNI and oncological associations Splenic rupture surgical emergency — macrophage activation syndrome — anti-i hemolytic anemia — encephalitis — Guillain-Barré — chronic fatigue — EBV Burkitt Hodgkin lymphoma — nasopharyngeal carcinoma — immunocompromised lymphoma — PTLD — EBV and multiple sclerosis |
Complications of infectious mononucleosis and oncological associations: haematological complications: thrombocytopenia (frequent - often moderate - rarely severe) + autoimmune haemolytic anaemia (AHAI): anti-i antibodies (cold IgM) → haemolysis → Coombs direct positive (IgM + complement) → resolving → corticosteroids if severe + agranulocytosis + macrophagic activation syndrome (MAS - rare but very serious): fever + pancytopenia cytopenias + hyperferritinemia + hypertriglyceridemia + hemophagocytosis on osteomedullary biopsy → hematological emergency → immunosuppressants (anakinra + etoposide + ciclosporin) → neurological complications (rare): encephalitis + aseptic meningitis + Guillain-Barré syndrome + facial paralysis + cranial nerve involvement + splenic complications: splenic rupture (0.1-0.5 % of MNI) → surgical emergency → rupture may be spontaneous or traumatic → sudden left abdominal pain + hypotension + defense → call 911 → CBC + typing + arteriography → splenectomy or splenorrhaphy → rupture often within the first 2 weeks + prolonged fatigue and post-MNI syndrome: intense asthenia persisting several weeks to months after resolution of acute IM → may last 3-6 months → different from chronic fatigue syndrome (CFS/ME) → progressive rest + gradual resumption of activities; EBV oncologic associations: EBV is oncogenic and associated with several malignancies: Burkitt's lymphoma: t(8;14) + myc → LB EBV+ → endemic in sub-Saharan Africa + sporadic everywhere → Hodgkin's lymphoma (HL): Reed-Sternberg CD15+ CD30+ → EBV+ in 40-50 % of cases in developed countries → nasopharyngeal carcinoma (NPC): EBV+ almost universally → Southeast Asia ++ → specific IgA anti-VCA + EBV lymphoma of the immunocompromised (PTLD - Post-Transplant Lymphoproliferative Disease): in transplant recipients under immunosuppression → EBV+ proliferation of LBs → treatment: immunosuppressive reduction + rituximab + multiple sclerosis: strong epidemiological association EBV and MS → EBV necessary but not sufficient to trigger MS | Cohen 2000 — NEJM: Mononucleosis, Complications, Associations, Review Luzuriaga 2010 — NEJM: EBV, Pathophysiology, Lymphomas Dunmire 2018 — Current Biology: EBV, Oncogenesis Hjalgrim 2003 — NEJM: EBV, Hodgkin Lymphoma, Association Bjornsson 2020 — NEJM (Ascherio): EBV, Multiple Sclerosis, Necessary Cause, Reference 2022 Hamill 1988 — Pediatrics: Splenic Rupture, Mononucleosis, CPS 2021: Mononucleosis, Pediatrics, Complications, ASPC INSPQ Quebec: EBV, Mononucleosis, Lymphomas INESSS Quebec + RAMQ: Hematology-Oncology, Reimbursed, CHU EBV-associated Oncology |
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Amoxicillin and ampicillin are formally contraindicated in infectious mononucleosis — they cause a maculopapular rash in 80 to 90 % of cases, without this constituting a true penicillin allergy: Never conclude a penicillin allergy based on this characteristic rash. The Monospot test can be falsely negative in the first two weeks—repeat or use EBV serology if the clinical presentation is suggestive. Restriction from contact sports is mandatory for a minimum of 3–4 weeks due to the risk of splenic rupture.
Situations requiring a 911 call or urgent care
Patient with known IBD + sudden, severe left abdominal pain + hypotension + pallor + tachycardia + abdominal guarding → splenic rupture → call 911 → CBC + blood typing crossmatch urgently → abdomino-pelvic CT scan → urgent vascular surgery (splenectomy or splenorrhaphy) → do not mobilize patient unnecessarily.
Adolescent with mono + very enlarged tonsils + «muffled» voice + stridor + difficulty swallowing + difficulty opening mouth → Upper airway obstruction + or peritonsillar abscess → Emergency → prednisone 40–60 mg IV or PO immediately → ENT on call → possible intubation if severe obstruction → DO NOT give amoxicillin if angina is due to EBV.
Patient with MNI + prolonged fever >3 weeks + pancytopenia + very high ferritin + hypertriglyceridemia + massive splenomegaly + marked deterioration in general condition → Macrophage Activation Syndrome (MAS) → hematologic emergency → bone marrow aspirate (hemophagocytosis) → hematology consultation → immunosuppressive treatment (anakinra + etoposide + cyclosporine according to the HLH-2004 protocol).
Consult at Clinique Omicron
Doctors at Clinique Omicron diagnose infectious mononucleosis (IMN) clinically (fever + sore throat + posterior lymphadenopathy + splenomegaly triad) and biologically (Monospot test + CBC + EBV serology if necessary). They prescribe appropriate symptomatic treatment (paracetamol + rest + hydration), strictly prohibit amoxicillin, prescribe corticosteroids for tonsillar obstruction, provide recommendations for sports restrictions (minimum 3-4 weeks + gradual return), screen for complications (splenic rupture + acute respiratory distress syndrome + hemolytic anemia), and refer patients to the emergency room if alarming signs appear. Consultations are available at several service locations in Quebec and via telemedicine. To book an appointment, visit cliniqueomicron.ca.
The content of this page is for informational purposes only and does not substitute medical advice. A rash occurring with amoxicillin in a patient with EBV is NOT a true penicillin allergy—never chart this without verification. Any sudden left-sided abdominal pain in a patient with EBV is splenic rupture until proven otherwise.
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