Infectious DiseasesTier 1Disease (DEADMAN)

Epstein–Barr virus (EBV)

Description

Human herpesvirus 4 - lifelong latency in B lymphocytes after primary infection
Primary infection in adolescence/adulthood -> infectious mononucleosis (glandular fever)
- Primary infection in childhood is usually asymptomatic - which is why IM is a disease of teenagers and young adults

Infectious mononucleosis - the classic triad

Fever + pharyngitis (exudative, often severe) + lymphadenopathy (posterior cervical especially)
Profound fatigue and malaise - out of proportion to signs, and the slowest feature to resolve
Splenomegaly ~50%, hepatomegaly ~10%, transaminitis in ~80-90% (usually mild), jaundice ~5%
Palatal petechiae, periorbital oedema, tonsillar exudate
*Widespread maculopapular rash after amoxicillin or ampicillin in ~80-90%*
- Not a true penicillin allergy - a transient virus-drug interaction; do not label the patient penicillin-allergic
Incubation 4-6 weeks; transmitted in saliva ("kissing disease"), shedding for months

>90% of adults worldwide are EBV seropositive
Peak IM incidence 15-24 years; M=F
Seroconversion occurs earlier in lower socioeconomic and developing-country settings (mostly asymptomatic in childhood)
Transmission: saliva; also sexual, transfusion and transplantation

Entry via oropharyngeal epithelium -> infects B lymphocytes via CD21 (the C3d complement receptor)
Drives polyclonal B cell proliferation and immortalisation (latent membrane protein 1, EBNA)
*The "atypical lymphocytes" on the film are reactive CD8+ cytotoxic T cells responding to the infected B cells - NOT the infected B cells themselves*
- The symptoms of IM are the T cell response, not the virus - which is why the illness is worse in adults with a robust immune system
Latency in memory B cells for life, with intermittent oropharyngeal shedding
Heterophile antibodies - IgM antibodies against unrelated animal red cell antigens produced by the polyclonal B cell activation (the basis of the Monospot test)
Oncogenesis where immune control fails or a co-factor exists
- Burkitt lymphoma (c-myc t(8;14); endemic African form with malaria as co-factor)
- Nasopharyngeal carcinoma (Southern Chinese populations)
- Hodgkin lymphoma, post-transplant lymphoproliferative disorder, CNS lymphoma in HIV, gastric carcinoma, NK/T-cell lymphoma
- Oral hairy leukoplakia in HIV

A. Bloods

Lymphocytosis with >10% atypical lymphocytes on the film (large, abundant basophilic cytoplasm moulding around adjacent red cells - "Downey cells")
FBE: absolute lymphocytosis; mild thrombocytopenia and neutropenia are common
LFTs raised in ~80-90%

B. Serology

Test	Meaning
Heterophile antibody (Monospot/Paul-Bunnell)	Specific but insensitive - false negative in the first week (~25%) and in children under 12; stays positive for months
VCA IgM	Acute/recent primary infection
VCA IgG	Appears early, persists for life
EBNA IgG	*Appears 6-12 weeks after onset and persists for life*
Anti-EA	Reactivation or active disease

*The key pattern: VCA IgG positive + EBNA IgG NEGATIVE = recent primary infection. VCA IgG positive + EBNA positive = past infection*
EBV DNA PCR (viral load) - for immunocompromised patients, PTLD monitoring and CNS disease; not useful for diagnosing IM in the immunocompetent

C. Differential of a "glandular fever-like illness"

*Always test for HIV - acute HIV seroconversion is the diagnosis you cannot afford to miss*
CMV (less pharyngitis and lymphadenopathy, heterophile-negative), toxoplasmosis, acute hepatitis A/B, rubella, HHV-6, adenovirus
Streptococcal pharyngitis (can coexist; ~30% of IM patients carry group A strep)
Acute leukaemia or lymphoma - a very high or very low white cell count, blasts, or lymphadenopathy that does not settle
Drug reaction (DRESS)

A. Uncomplicated infectious mononucleosis - supportive only

Rest, fluids, paracetamol or NSAIDs, salt-water gargles
No antiviral therapy - aciclovir reduces oropharyngeal shedding but does not improve symptoms
Avoid amoxicillin and ampicillin; if bacterial tonsillitis needs treatment, use phenoxymethylpenicillin

B. Splenic rupture precautions - the safety message

Avoid contact and collision sport, heavy lifting and vigorous exercise for at least 3-4 weeks from symptom onset (4-8 weeks for contact sport)
Splenic rupture occurs in <0.5%, is usually atraumatic, and is most likely in the first 3 weeks
*New left upper quadrant, left shoulder tip pain or haemodynamic instability -> urgent imaging*
Routine ultrasound is not needed to clear return to sport; splenomegaly regresses over weeks

C. Corticosteroids - narrow indications only

Not for routine symptom control (no lasting benefit, theoretical concern about immune modulation)
Indicated for: impending airway obstruction from tonsillar hypertrophy, severe haemolytic anaemia or thrombocytopenia, myocarditis, or neurological complications
- Airway obstruction is the emergency - ENT review, steroids, and occasionally intubation or tonsillectomy

D. Complications to recognise

Airway obstruction, dehydration from odynophagia
Haematological: autoimmune haemolytic anaemia (cold agglutinins, anti-i), immune thrombocytopenia, aplastic anaemia, HLH
Neurological: Guillain-Barre syndrome, encephalitis, transverse myelitis, cranial nerve palsies, "Alice in Wonderland" syndrome (metamorphopsia)
Myocarditis, pericarditis, interstitial nephritis, pneumonitis
Fulminant infection in X-linked lymphoproliferative syndrome (SH2D1A/SAP mutation - Duncan syndrome)

E. Immunocompromised and transplant patients

Post-transplant lymphoproliferative disorder - EBV-seronegative recipient of a seropositive organ is the highest-risk group
- Monitor EBV viral load; first-line management is reduction of immunosuppression, then rituximab, then chemotherapy
HIV: oral hairy leukoplakia, CNS lymphoma, lymphoid interstitial pneumonitis
EBV-specific cytotoxic T cell therapy in refractory cases

Malignancy: Burkitt lymphoma, Hodgkin lymphoma, nasopharyngeal carcinoma, post-transplant lymphoproliferative disorder, CNS lymphoma in HIV, gastric carcinoma, NK/T-cell lymphoma
Oral hairy leukoplakia (HIV)
Haemophagocytic lymphohistiocytosis - EBV is the commonest infective trigger
Multiple sclerosis - EBV infection is now regarded as a necessary (though not sufficient) precondition
Chronic active EBV infection; X-linked lymphoproliferative syndrome
Post-viral fatigue; association with autoimmune disease (SLE, Sjogren)
Amoxicillin/ampicillin rash

Acute illness 2-4 weeks; fever settles in ~10-14 days, pharyngitis in ~1 week, lymphadenopathy and splenomegaly over 3-4 weeks
*Fatigue is the last symptom to go - ~10-20% remain fatigued at 6 months*; counsel about this at the outset to prevent repeated investigation
Full recovery is the rule; lifelong latency with asymptomatic shedding follows
Complications occur in <5%; death is very rare (splenic rupture, airway obstruction, HLH, fulminant hepatitis)
Recurrent or persistent symptoms with a high EBV viral load in an immunocompetent patient = chronic active EBV infection, a rare and serious entity requiring haematology referral

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