Cytomegalovirus

Background

Microbiology

• A dsDNA virus and the largest member of the human herpesvirus family
• DNA in the nucleoprotein core is embedded in matrix proteins and pp65 antigen, which is surrounded by lipid envelope
• UL54 encodes DNA polymerase and is highly conserved
• UL97 encodes a phosphotransferase enzymes required to phosphorylate (and therefore activate) ganciclovir
• May have four genotypes

Epidemiology

• Transferred by respiratory droplets and blood transfusions that lies dormant in white blood cells
• 80% of people are CMV-IgG positive

Risk Factors

• Crowding

Clinical Presentation

• Asymptomatic when young

Infectious mononucleosis syndrome

• CMV causes 21% of IM
• Fever, lymphadenopathy, and lymphocytosis

Stem cell transplantation

• Low risk until day 21 post-transplantation, when cell lines begin to return
• May presents as asymptomatic viremia
• Most common symptomatic presentation is pneumonitis
  • Can also present with GI involvement

Solid-organ transplantation

• Tends to reactivate within the transplanted organ
• However, all can have GI involvement

Investigations

• CBC showing leukopenia or pancytopenia
• Mild elevation in liver enzymes
• CMV-IgG positive
• Detectable CMV DNA in peripheral blood, though it can rise during intercurrent illness

Diagnosis

• Serology for IgG only useful for prior exposure (suggesting latent infection)
• Quantitative PCR is most useful for diagnosis and monitoring response to treatment
  • Can be done on blood, BAL, urine, saliva, etc.
  • Standards for reporting are defined by WHO
  • However, can shed CMV asymptomatically during an acute illness, so must be taken within the clinical context
  • Sensitivity/specificity for CMV disease depends on the laboratory methods and cutoff used
• Microscopy of tissue biopsy or cytology may demonstrate large nuclear inclusions, and can use immunofluorescence to pp65 antigen to confirm diagnosis
• Viral culture can be done with human fibroblast cells, but is slow

Management

• Antivirals
  • First-line: valganciclovir or ganciclovir
    • Measure baseline CBC first due to risk of cytopenias
  • Second-line, if cytopenias: foscarnet
  • Third-line: cidofovir, maribavir, letermovir
• At McMaster, expect 1-log drop within 2 weeks (lab-dependent)
• Continue treatment until PCR is negative

Resistance

• Inherent acyclovir resistance
• Tyrosine kinase mutation UL97? confers resistance to (val)ganciclovir
• Polymerase mutation U54? confers resistance to (val)ganciclovir and foscarnet
• Consider resistance if CMV DNA titres not decreasing despite appropriate treatment
• Resistance genotyping available

Prophylaxis

• Solid-organ transplant
  • Donor+/Recipient– high risk for reactivation, the the donor organ infecting the recipient
  • Donor–/Recipient+ intermediate risk
  • Donor+/Recipient+ intermediate risk
  • Donor–/Recipient– lowest risk
  • High and intermediate risk patients get prophylaxis with valganciclovir 900 mg po bid for some amount of duration...
• Hematologic stem cell transplant
  • Donor+/Recipient+ high risk for reactivation
  • Donor–/Recipient+ high risk
  • Donor+/Recipient– intermediate risk
  • Donor–/Recipient– lowest risk
  • Preemptive monitoring with weekly CMV DNA PCR starting week 2
• Treat if greater than threshold (1425 at McMaster) or if rising titre with symptoms

Complications

• Even when dormant, can cause mild immunosuppression that predisposes to fungal infections
• Asymptomatic shedding in lungs during intercurrent illness
• Viremia with influenza-like illness
• End-orgam damage
  • CMV colitis
  • Retinitis in AIDS patient (CD4 < 50-100)
  • Organ inflammation of solid-organ transplants
  • Pneumonitis in stem cell transplants