VirusesHerpesviridae

Cytomegalovirus

A double-stranded DNA herpesvirus (HHV-5) that causes opportunistic infections in immunocompromised hosts and congenital disease, characterized by cells with large intranuclear "owl-eye" inclusions.

Organism Card

DomainMust know
Identity
  • HHV-5; enveloped dsDNA virus; Herpesviridae (Betaherpesvirinae) [1]
  • Largest human herpesvirus; establishes lifelong latency in myeloid progenitor cells
  • HK seroprevalence > 90% — most blood products CMV +ve [2][3]
  • Reactivation in immunocompromised (T-cell deficiency) is the major clinical concern
Reservoir / transmission
  • Humans only reservoir
  • Transmission: saliva, genital secretions, breastmilk, blood products, organ transplant, transplacental [4]
  • Leukodepleted blood components reduce transfusion-transmitted CMV when CMV-seroneg products unavailable [3]
Key virulence
  • Immune evasion: downregulates MHC-I, encodes IL-10 homologue, Fc receptor decoy
  • Cytopathic effect: characteristic "owl-eye" nuclear inclusions (enlarged cells with intranuclear + cytoplasmic inclusions)
  • Latency in CD34+ myeloid progenitors → reactivation with immunosuppression
Clinical syndromes
  • Immunocompetent: mostly asymptomatic; mononucleosis-like syndrome (heterophile-negative) — less prominent than EBV [4]
  • Immunocompromised (transplant/HIV): retinitis, pneumonitis, colitis/esophagitis, hepatitis, encephalitis, BM failure [4][5]
  • Post-liver-transplant CMV colitis: low-grade fever + diarrhoea + inclusion bodies on biopsy [6][7]
  • Congenital CMV: IUGR, microcephaly, periventricular calcification, sensorineural hearing loss, hepatosplenomegaly, petechiae ("blueberry muffin baby")
  • CMV retinitis: classical in AIDS with CD4 < 50; "pizza pie" fundoscopy (haemorrhages + exudates) [8]
Diagnosis
  • PBS: atypical lymphocytes (DDx: EBV, HIV, acute viral hepatitis, Mycoplasma, toxoplasmosis, drug reaction) [4][9]
  • CMV pp65 antigenaemia: buffy coat immunostaining; semi-quantitative; used in solid organ transplant recipients [1]
  • CMV viral load by PCR (EDTA whole blood): used in BMT recipients with low WBC for preemptive therapy [1]
  • Histology: "owl-eye" intranuclear inclusion bodies on biopsy (e.g. colonic biopsy) [6][7]
  • Serology: IgM/IgG seroconversion (limited value in I/C; useful for congenital CMV in neonate)
  • "Students did poorly since they did not understand the difference between CMV antigenemia and CMV seropositivity" [3]
Treatment
  • First-line: IV ganciclovir (or PO valganciclovir) — nucleoside analogue requiring viral UL97 kinase for phosphorylation
  • Second-line: foscarnet (pyrophosphate analogue; nephrotoxic) — for ganciclovir-resistant CMV (UL97 mutation)
  • Cidofovir: alternative if both above fail; dose-limiting nephrotoxicity
  • Key SE of ganciclovir: myelosuppression (neutropenia, thrombocytopenia)
  • Preemptive strategy in transplant: monitor viral load → treat when rising above threshold before clinical disease
Prevention
  • CMV-seronegative blood products indicated for: CMV-seroneg pregnant women, neonates, CMV-seroneg transplant recipients [3]
  • If CMV-seroneg blood unavailable → use leukodepleted blood components [3]
  • Prophylaxis in high-risk transplant (D+/R−): valganciclovir
  • No licensed vaccine currently available
  • Universal screening for congenital CMV: hearing screening in newborns
Classic traps
  • CMV mono vs EBV mono: CMV = heterophile-Ab NEGATIVE (monospot −), less pharyngitis/LAP [4]
  • CMV antigenemia ≠ CMV seropositivity: antigenemia = active viral replication; seropositivity = past exposure (> 90% in HK) [3]
  • Post-transplant diarrhoea with inclusion bodies on colonic biopsy → CMV, NOT Streptococcus mitis or Talaromyces [6][7]
  • Congenital CMV vs congenital toxoplasmosis: CMV = periventricular calcification; Toxo = diffuse/scattered calcification
  • NK-cell lymphoma (nasal) is associated with EBV, NOT CMV [10]
  • Neutropenic fever at day 10 post-chemo: think bacteria (Strep viridans) or fungi, NOT CMV [11]

Exam Intelligence

  1. CMV pp65 antigenaemia (buffy coat immunostain) is the key monitoring test for solid organ transplant recipients; CMV PCR viral load (EDTA whole blood) is used for BMT recipients — GC 101 explicitly distinguishes these two modalities [1]. The transfusion lecture warns: "students did poorly since they did not understand the difference between CMV antigenemia and CMV seropositivity" [3].

  2. > 90% of the HK population is CMV seropositive — therefore eliminating all CMV-seropositive blood donations is impractical. Only a select group receives CMV-seronegative products; otherwise leukodepleted blood components are used as an alternative [3].

  3. Classic AOS EMQ stem: post-liver-transplant patient on tacrolimus + MMF + prednisolone → low-grade fever, diarrhoea, abdominal pain → sigmoid biopsy shows inclusion bodies → Answer: CMV [6][7]. This exact stem appeared in both AOS Microbio material and the 2022 Fourth Summative EMQ.

  4. DDx of atypical lymphocytes / infectious mononucleosis-like syndrome: EBV, CMV, HIV, acute viral hepatitis, Mycoplasma, Legionella, Salmonella, Rickettsia, disseminated TB, Talaromyces, Toxoplasma, drug reactions. Acute lymphoblastic leukaemia blasts can mimic atypical lymphocytes on blood film [9].

  5. CMV is NOT a typical cause of neutropenic fever at day 10 post-chemotherapy — that setting points to bacterial (Strep viridans/mitis) or fungal causes. CMV disease occurs later, typically post-engraftment (day 28+), especially in patients not taking antiviral prophylaxis [5][11][12].

  6. Congenital CMV is the commonest congenital infection worldwide and the leading non-genetic cause of sensorineural hearing loss in children — periventricular calcifications on imaging are the discriminating feature vs toxoplasmosis (diffuse calcifications) [4].

  • CMV vs EBV mononucleosis: CMV = heterophile-negative (monospot −), less exudative pharyngitis, less prominent lymphadenopathy. EBV = heterophile-positive, ampicillin/amoxicillin rash, possible splenic rupture.
  • CMV colitis vs C. difficile colitis: Both cause diarrhoea in immunosuppressed patients. Pseudomembranes → C. diff; inclusion bodies on biopsy → CMV. The 2020 MCQ Q8 stem specifically tests this: patient on azathioprine with bloody diarrhoea and pseudomembranes → answer is C. difficile (from prior antibiotics), NOT CMV [11].
  • Nasal NK-cell lymphoma (CD56+) is associated with EBV, not CMV — a classic pathology trap [10].
  • Post-BMT timeline: Day 10 neutropenic fever = bacteria/fungi; Day 28+ post-engraftment with fever + diarrhoea + CXR infiltrates + LFT derangement and missed prophylaxis = think CMV (and Aspergillus, Pneumocystis) [12].

2020 Fourth Summative MCQ Q82 [11]:

"What is MORE LIKELY to be the microbial cause of neutropenic fever at day 10 post-chemotherapy? A. Aspergillus fumigatus B. Candida albicans C. Cytomegalovirus D. Streptococcus viridans"

  • Answer: D. Streptococcus viridans. Rationale: Day 10 post-chemo = early neutropenic period → bacterial causes predominate, especially oral streptococci (Strep viridans/mitis group) due to mucositis. CMV disease typically occurs later. Aspergillus is more likely with prolonged neutropenia ( > 7–10 days).

2020 Fourth Summative MCQ Q8 [11]:

"A 25-year-old woman… ulcerative colitis on oral mesalazine and azathioprine… bloody diarrhoea… Six weeks ago, she had an episode of UTI which was resolved upon treatment. Colonoscopy showed multiple yellow plaques and pseudomembranes. What is the MOST LIKELY cause? A. Cefuroxime B. Ciprofloxacin C. Cytomegalovirus infection D. Smoking"

  • Answer: B. Ciprofloxacin (penicillin-allergic patient treated with fluoroquinolone for UTI → antibiotic-associated C. difficile colitis with pseudomembranes). CMV colitis is a trap answer here — pseudomembranes point to C. diff, whereas CMV colitis shows inclusion bodies on biopsy.

2022 Fourth Summative EMQ Q21 [7]:

"A 60-year-old woman with HBV-related cirrhosis received living donor liver transplantation 3 months ago. She is now on prednisolone 5 mg daily, tacrolimus 5 mg BD, and MMF 500 mg BD. She presented with low-grade fever, abdominal pain, and diarrhoea for 5 days. There is no recent travel or contact history. Endoscopic biopsy of the inflamed sigmoid showed the presence of inclusion bodies."

  • Answer: C. Cytomegalovirus. Rationale: Post-solid-organ transplant on triple immunosuppression + GI symptoms + inclusion bodies on biopsy = classic CMV colitis. This exact stem also appears in AOS Microbio material [6].

2021 Fourth Summative SAQ Q12(b) [12]:

"On day 28 after neutrophil engraftment, he developed fever, impaired LFT, persistent diarrhoea and CXR infiltrates. The patient admitted that he did not take the antimicrobial prophylaxis. List 4 organisms which may account for his symptoms."

  • Expected answers include: CMV, Aspergillus fumigatus, Pneumocystis jirovecii, and other opportunistic organisms. CMV is a key answer here because post-engraftment (day 28) in BMT patients off prophylaxis is the classic window for CMV reactivation causing hepatitis, colitis, and pneumonitis.

[1] Lecture slides: GC 101. Diagnosis of infections [Handouts].pdf [2] Lecture slides: GC 102. Fever after chemotherapy infections in immunocompromised hosts.pdf [3] Senior notes: Block A - Fever after a blood transfusion_ transfusion and related problems.pdf [4] Senior notes: Adrian Lui Pediatrics Notes.pdf [5] Lecture slides: GC 102. Fever after chemotherapy infections in immunocompromised hosts [Handout].pdf [6] AOS material: AOS - Microbio.pdf [7] Past papers: 2022 Fourth Summative MCQ.pdf [8] Senior notes: Ryan Ho Opthalmology.pdf [9] Senior notes: Block A - Generalised Lymphadenopathy_ Differential diagnosis and principle of management.pdf [10] AOS material: AOS - Pathology.pdf [11] Past papers: 2020 Fourth Summative Assessment MCQ paper.pdf [12] Past papers: 2021 Fourth Summative SAQ.pdf

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