Key Facts

CMV is a major pathogen in immunocompromised individuals and the leading cause of congenital viral infection. In transplant medicine, CMV reactivation is one of the most important complications.

Epidemiology

• Seroprevalence: 50–60% in UK (higher in lower socioeconomic groups); >90% in some developing countries
• Congenital CMV: ~1 in 200 live births (UK); ~10% symptomatic; ~12% of asymptomatic develop sequelae
• Post-transplant: CMV disease in 20–60% of D+/R– solid organ transplant recipients without prophylaxis
• HIV: CMV retinitis in ~30% of AIDS patients pre-ART era; now rare with effective ART

Aetiology

• CMV (HHV-5): double-stranded DNA, Herpesviridae (Betaherpesvirinae)
• Transmission: saliva, urine, sexual contact, blood transfusion, organ transplant, vertical (in utero, perinatal, breast milk)
• Lifelong latency in myeloid progenitor cells; reactivation with immunosuppression

Pathophysiology

• CMV infects epithelial cells, endothelial cells, monocytes/macrophages, fibroblasts
• Latent in CD34+ haemopoietic stem cells and monocytes
• Immunosuppression → viral reactivation → cytopathic effect on target organs
• CMV immune evasion: downregulates MHC class I, produces viral IL-10 homologue, expresses Fc receptor
• Congenital CMV: transplacental transmission during maternal viraemia → widespread fetal organ damage

Immunocompetent

• Usually asymptomatic (90%)
• CMV mononucleosis: fever, malaise, lymphocytosis, mild hepatitis — pharyngitis less prominent than EBV; heterophile antibody negative

Immunocompromised (HIV CD4 <100, Transplant)

• CMV retinitis: painless visual loss, floaters; 'pizza-pie' fundoscopy (haemorrhages + exudates)
• CMV colitis: diarrhoea (often bloody), abdominal pain, fever
• CMV oesophagitis: odynophagia, large shallow ulcers (vs HSV small deep ulcers)
• CMV pneumonitis: interstitial pneumonia (especially post-BMT); high mortality
• CMV encephalitis/ventriculitis: confusion, cranial nerve palsies

Congenital CMV

• 10% symptomatic at birth: petechiae, hepatosplenomegaly, jaundice, microcephaly, periventricular calcification, chorioretinitis
• 90% asymptomatic at birth: ~12% develop late sequelae (sensorineural deafness most common)

Red Flags

• Visual symptoms in immunocompromised (retinitis emergency)
• Persistent diarrhoea in transplant/HIV patient
• Rising CMV viral load post-transplant
• Microcephaly or intracranial calcification in neonate

Bloods

• CMV PCR (quantitative viral load): gold standard for diagnosis and monitoring
• CMV IgM/IgG: useful for determining immune status; IgM for acute/recent infection
• FBC: atypical lymphocytes (monocyte-predominant); leucopenia
• LFTs: raised transaminases

Imaging

• Fundoscopy: CMV retinitis — haemorrhages, exudates, 'pizza-pie' appearance
• CT/MRI brain: periventricular calcification (congenital); ventriculitis/encephalitis (immunocompromised)
• CXR: interstitial infiltrates (pneumonitis)

Special Tests

• Tissue biopsy: owl-eye inclusion bodies (large intranuclear + smaller cytoplasmic inclusions) — diagnostic on colonic/oesophageal biopsy
• BAL PCR: CMV pneumonitis (distinguish colonisation from disease)
• Neonatal CMV: CMV PCR on urine or saliva (within 3 weeks of birth to confirm congenital vs perinatal)
• Audiology: all congenital CMV cases — serial hearing assessments

Non-pharmacological

• Hygiene education: hand washing (especially around young children — main source of CMV for pregnant women)
• CMV-negative blood products: for CMV-seronegative transplant recipients and pregnant women (leucodepleted products reduce risk)

Pharmacological

CMV disease in immunocompromised:

• Induction: ganciclovir 5mg/kg BD IV for 14–21 days, OR valganciclovir 900mg BD oral for 21 days
• Maintenance: valganciclovir 900mg OD until immune reconstitution (e.g. CD4 >100 on ART for 6 months)
• CMV retinitis: valganciclovir 900mg BD for 21 days then 900mg OD maintenance; intravitreal ganciclovir for immediate sight-threatening disease
• Second-line: foscarnet 90mg/kg BD IV (if ganciclovir-resistant or neutropenic) — nephrotoxic, electrolyte disturbance
• Third-line: cidofovir (nephrotoxic — co-prescribe probenecid and IV saline)

Transplant prophylaxis:

• Valganciclovir 900mg OD for 3–6 months post-transplant (D+/R– highest risk)
• OR pre-emptive strategy: monitor CMV PCR weekly; treat if viraemia detected

Congenital CMV:

• Symptomatic: valganciclovir 16mg/kg BD oral for 6 months — improves hearing and neurodevelopmental outcomes
• Monitoring: FBC weekly (neutropenia risk), LFTs, serial audiology

Side effects of ganciclovir/valganciclovir:

• Neutropenia (most common — up to 40%): monitor FBC weekly; may need G-CSF
• Thrombocytopenia, anaemia
• Teratogenic: effective contraception required

Referral Criteria

• Ophthalmology: CMV retinitis (urgent)
• Transplant team: CMV viraemia/disease post-transplant
• Fetal medicine: maternal CMV seroconversion in pregnancy
• Paediatrics: congenital CMV — multidisciplinary (audiology, ophthalmology, neurology)

• Immunocompetent primary CMV: excellent prognosis; self-limiting in 2–6 weeks
• CMV retinitis (with treatment): vision stabilised in ~80%; relapse common if immune reconstitution incomplete
• CMV pneumonitis post-BMT: mortality 30–50% even with treatment
• Congenital CMV (symptomatic): mortality ~5%; 50–60% develop long-term sequelae (deafness, intellectual disability)
• Congenital CMV (asymptomatic): ~12% develop late sensorineural deafness
• Valganciclovir for congenital CMV: significant improvement in hearing and neurodevelopment (Kimberlin et al.)
• Post-transplant CMV disease: mortality 5–20% depending on organ and level of immunosuppression

CMV Disease by Organ

CMV Risk in Transplant (D/R Serostatus)