Question 4

College answer

Discussion

Clinical manifestations of CMV:

CMV syndrome is defined as viraemia plus any two of the following:

• Fever ≥38°C for at least 2 days.
• New or increased malaise or  fatigue 
• Leukopenia or neutropenia 
• >5% atypical lymphocytes
• Thrombocytopenia 
• Elevation of aminotransferases

This definition is based on Ljungman et al (2016).

Diagnosis of CMV

• Positive CMV antibodies (IgM or IgG) - sensitive for recent or acute infection
  • However, this is obviously invalidated by IVIg infusion, plasmapheresis, and such other.
• Antigen assay (for pp65 antigen) is cheap and used to be the standard, but it requires a few neutrophils and cannot be performed in severe neutropenia. The blood needs to be fresh; one is better off sending this test during working hours.
• Qualitative PCR for CMV DNA- very sensitive for the presence of CMV, but they do not distingusih between active and latent infection.
• Quantitative PCR for CMV DNA - ideal test, as it provides a quantitative assessment of viral load, and allows the monitoring of therapy. The WHO have set up an international standard for this technique.
• Tissue histology: one cannot always have access to the tissue, but it does allow the identification of these characteristic cytomegalic cells.
• Viral cultures: These take some time; in vivo CMV is cultured in fibroblasts.

Management:

Extensive literature exists concerning CMV in the immunocompromised:

• Ganciclovir is first-line: a selective inhibitor of CMV DNA polymerase. Much more activity against CMV than aciclovir.
  • Valganciclovir usually follows: it is the orally bioavailable pro-drug.
  • Ganciclovir-soaked pellets can be sutured into the eye to treat retinitis
• Foscarnet is second-line: it is sodium phosphonoformate, and it also inhibits CMV DNA polymerase.
  • Unfortunately, it is hideously nephrotoxic and neurotoxic.
• Cidofovir is an alternative second-line: a nucleotide analogue, it also selectively inhibits CMV DNA polymerase.
  • It is also nephrotoxic
  • The major approved indication is the management of CMV retinitis
• CMV immunoglobulin is specific antibodies to CMV from immune hosts.
  • The specific purified immunoglobulin may not be available, but experience suggests that non-specific immunoglobulin might be just as good. In spite of little evidence for efficacy or influence on mortality, this seems to be a well-accepted adjunctive strategy to throw at the dying CMV patient; given that CMV pneumonitis (for instance) has a mortality approaching 80%, one can be forgiven for straying out of one's EBM practice norms.