VirusesHerpesviridae

Epstein-Barr virus

Epstein-Barr virus is a double-stranded DNA herpesvirus (HHV-4) of the Lymphocryptovirus genus that causes infectious mononucleosis and is associated with Burkitt lymphoma, nasopharyngeal carcinoma, and post-transplant lymphoproliferative disorder.

Organism Card

DomainMust know
Identity
  • dsDNA virus, family Herpesviridae (Human herpesvirus-4, HHV-4) [1]
  • Enveloped; linear dsDNA genome (~172 kb)
  • Acute infection → infectious mononucleosis; latent infection → virus hides in B-cells [1]
  • Up to 95% of the population may have latent EBV infection [1]
Reservoir / transmission
  • Humans are the only reservoir
  • Transmission via saliva ("kissing disease"), close contact
  • Also via blood products, organ transplant (rare)
  • EBV is endemic in Southern China / HK — relevant to NPC [3]
Key virulence
  • gp350 binds CD21 (CR2) on B-cells → B-cell entry and immortalisation
  • Latent membrane protein 1 (LMP1) mimics CD40 → constitutive NF-κB activation → B-cell proliferation
  • EBNA proteins maintain episomal latency in B-cells
  • Viral IL-10 homologue (BCRF1) → immune evasion
  • Different latency programmes (I/II/III) drive different malignancies
Clinical syndromes
  • Infectious mononucleosis: adolescents/young adults; fever, pharyngitis, LAD, splenomegaly, fatigue [1]
  • Atypical lymphocytosis on PBS (reactive CD8 T-cells; DDx: CMV, HIV, hepatitis, toxoplasma, drug reaction) [4]
  • Ampicillin/amoxicillin rash — classic exam trap
  • Splenic rupture risk (avoid contact sports 4–6 wks)
  • Nasopharyngeal carcinoma (NPC): endemic Southern China; IgA anti-VCA/EA; plasma EBV DNA for staging [1][3]
  • Burkitt lymphoma: endemic (African jaw); t(8;14) c-MYC/IgH
  • NK/T-cell (nasal-type) lymphoma: CD56+, EBV-associated [6]
  • Post-transplant lymphoproliferative disorder (PTLD): monitor EBV DNA in transplant recipients [2]
  • Hodgkin lymphoma (mixed cellularity subtype, EBV+ Reed-Sternberg cells)
  • Oral hairy leukoplakia (HIV/immunocompromised)
  • X-linked lymphoproliferative disease (Duncan syndrome; SH2D1A mutation)
Diagnosis
  • Monospot test (heterophile antibody): rapid screening for infectious mononucleosis [7]
  • EBV-specific serology: VCA-IgM (acute), VCA-IgG (past/current), EBNA-IgG (past infection)
  • EBV VCA-IgA and EA-IgA: screening for NPC (low specificity alone) [3]
  • Plasma EBV DNA by PCR: most sensitive tumour marker for NPC; monitors treatment response [3][8]
  • EDTA blood EBV DNA viral load: monitors PTLD in transplant recipients [2]
  • EBER in-situ hybridisation: gold standard for EBV in tissue (lymphoma, NPC)
  • PBS: atypical lymphocytes (DDx list is a favourite exam question) [4]
Treatment
  • Infectious mononucleosis: supportive (rest, analgesia, avoid contact sports)
  • Avoid ampicillin/amoxicillin → diffuse maculopapular rash
  • Short course corticosteroids: only if airway obstruction or severe thrombocytopenia
  • Antivirals (acyclovir/ganciclovir) have limited role in uncomplicated EBV
  • PTLD: reduce immunosuppression ± rituximab (anti-CD20) ± chemotherapy
  • NPC: concurrent chemoradiotherapy (cisplatin-based); advanced → immunotherapy
Prevention
  • No licensed EBV vaccine currently available
  • Transplant recipients: monitor EBV viral load for pre-emptive PTLD management [2]
  • NPC screening in high-risk populations (Southern China): EBV serology ± plasma EBV DNA [3]
Classic traps
  • Atypical lymphocytes DDx: EBV, CMV, HIV, acute viral hepatitis, toxoplasma, drug reaction — do NOT confuse with ALL blasts [4]
  • Monospot can be negative in children < 4 y → use EBV-specific serology
  • Plasma EBV DNA (not urine) is the most sensitive NPC tumour marker [8]
  • CMV mononucleosis: heterophile-negative, less prominent pharyngitis [5]
  • EBV VCA-IgA alone has low specificity for NPC; combine with plasma EBV DNA
  • NK/T-cell lymphoma is EBV-associated (not HPV or CMV) [6]

Exam Intelligence

  1. Molecular Pathology Seminar (EBV): EBV is a dsDNA herpesvirus; acute infection = infectious mononucleosis; latent infection = virus hides in B-cells; up to 95% of the population may carry latent EBV [1]. This is a direct slide point — expect a stem testing basic virology classification.

  2. GC 101 (Diagnosis of Infections): EDTA blood EBV DNA viral load monitoring is used in bone marrow transplant recipients specifically for detecting post-transplant lymphoproliferative disorder (PTLD) for pre-emptive treatment [2]. This is the GC-framed reason to order EBV PCR in transplant patients — contrasted with CMV pp65 antigenaemia for CMV in solid organ transplant.

  3. NPC and EBV (Surgery/Felix Lai notes): EBV is the primary etiological agent in NPC pathogenesis [3]. Key serological markers: IgA against VCA and EA. Plasma circulating EBV DNA by PCR is used for diagnosis, staging, prognosis, treatment response, and recurrence detection. Pre-treatment plasma EBV DNA levels correlate with outcomes [3].

  4. Generalised lymphadenopathy lecture: Atypical lymphocytosis DDx = EBV, CMV, HIV, acute viral hepatitis, Mycoplasma, Legionella, disseminated TB, Talaromyces marneffei, Toxoplasma gondii, drug reactions [4]. Acute lymphoblastic leukaemia blasts can mimic atypical lymphocytes — classic trap to mention in SAQ.

  5. AOS Pathology: A case of bilateral nasal tumour with CD56+ malignant lymphoid cells (NK-cell lymphoma) — the answer is Epstein-Barr virus (not CMV, HIV, or HPV) [6]. This tests the EBV–extranodal NK/T-cell lymphoma association.

  6. 2021 Fourth Summative MCQ Q19: 4-year-old girl with low-grade fever, sore throat, generalised maculopapular rash, atypical lymphocytes → answer = Monospot test (D) [7]. This is the direct past-paper test of EBV diagnosis in paediatrics.

  • EBV vs CMV mononucleosis: Both cause atypical lymphocytes. EBV → exudative pharyngitis, splenomegaly, heterophile +ve. CMV → heterophile −ve, less prominent pharyngitis, more hepatitis [5]. In post-transplant: CMV = GI/retinitis/pneumonitis with inclusion bodies; EBV = PTLD.
  • Ampicillin rash: Virtually pathognomonic vignette clue for EBV infectious mononucleosis. Not a true allergy — do not label patient as penicillin allergic.
  • Monospot false negatives: Children < 4 years may not produce heterophile antibodies → must use EBV VCA-IgM for definitive acute diagnosis.
  • EBV-associated malignancies spectrum: Burkitt lymphoma (endemic + sporadic), NPC, Hodgkin lymphoma (mixed cellularity), NK/T-cell lymphoma, PTLD, gastric carcinoma, leiomyosarcoma (in immunocompromised children). Exams love asking which virus is associated with each.
  • NPC screening trap: EBV VCA-IgA has low specificity alone for NPC. Plasma EBV DNA is the most sensitive tumour marker [8] — this was directly tested in 2025 MCQ Q66.

2021 Fourth Summative MCQ Q19 [7]:

A 4-year-old girl presented with a low-grade fever, sore throat and a generalised, blanchable, erythematous, maculopapular rash. Her blood count revealed presence of atypical lymphocytes. [Select the MOST USEFUL test in patient diagnosis.]

  • Answer: D. Monospot test
  • Rationale: Classic infectious mononucleosis presentation with atypical lymphocytes. Monospot (heterophile antibody test) is the most useful rapid diagnostic test. Note: in young children, monospot sensitivity is lower, but it remains the best answer from the option list.

2025 Fourth Summative MCQ Q66 [8]:

Which of the following is the MOST SENSITIVE tumour marker for nasopharyngeal carcinoma? A. IgA against EA of EBV / B. IgA against VCA of Epstein-Barr virus (EBV) / C. Plasma EBV DNA / D. Urine EBV DNA

  • Answer: C. Plasma EBV DNA
  • Rationale: Plasma circulating EBV DNA detected by PCR is the most sensitive marker — used for diagnosis, staging, treatment response monitoring, and recurrence detection. IgA anti-VCA/EA are used for screening but have lower sensitivity and specificity. Urine EBV DNA is not a standard clinical test.

AOS Pathology EMQ [6]:

A 55-year-old man presents with bilateral nasal obstruction and on-and-off epistaxis for six months... Biopsy shows malignant lymphoid cells that are CD56 positive, compatible with NK-cell lymphoma. Which viral infection is most strongly associated with this disease?

  • Answer: B. Epstein-Barr virus
  • Rationale: Extranodal NK/T-cell lymphoma (nasal type) is strongly associated with EBV. EBER in-situ hybridisation is characteristically positive. Not HPV (oropharyngeal SCC), not CMV, not HIV.

2022 Fourth Summative MCQ Q21 [9]:

A 60-year-old woman with HBV-related cirrhosis received living donor liver transplantation 3 months ago... low-grade fever, abdominal pain, and diarrhoea for 5 days... Endoscopic biopsy of the inflamed sigmoid showed the presence of inclusion bodies.

  • Answer: C. Cytomegalovirus (not EBV)
  • Rationale: This is a discriminator question. Post-transplant GI disease with inclusion bodies = CMV colitis. EBV in post-transplant setting presents as PTLD (lymphoproliferative masses), not colitis with inclusion bodies. Know the difference.

2023 Fourth Summative MCQ Section B (Haematopoietic Neoplasms) [10]: The EMQ list includes "Post-transplant lymphoproliferative disease" as an option. While no specific stem in the indexed text directly describes a PTLD scenario, the inclusion signals this is examinable — expect a transplant patient with rising EBV viral load and lymphadenopathy/mass lesion → answer = PTLD.

[1] Lecture slides: Molecular Pathology Seminar 4_EPSTEIN-BARR VIRUS.pdf [2] Lecture slides: GC 101. Diagnosis of infections [Handouts].pdf [3] Senior notes: MBBS Final MB (Surgery) (Felix PY Lai).pdf (NPC section) [4] Senior notes: Block A - Generalised Lymphadenopathy_ Differential diagnosis and principle of management.pdf [5] Senior notes: Adrian Lui Pediatrics Notes.pdf (CMV section) [6] AOS material: AOS - Pathology.pdf [7] Past papers: 2021 Fourth Summative Assessment MCQ.pdf (Section B, Q19) [8] Past papers: 2025 Fourth Summative MCQ.pdf (Q66) [9] Past papers: 2022 Fourth Summative MCQ.pdf (Q21) [10] Past papers: 2023 Fourth Summative MCQ.pdf (Section B, Haematopoietic Neoplasms EMQ)

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