CMV after solid organ transplantation

Clinical Manifestations

• Tends to reactivate in the transplanted organ

CMV Syndrome

• Detectable CMV viremia, plus at least two of:
  • Fever ≥38ºC for 2+ days
  • New or increased malaise or fatigue
  • Leukopenia or neutropenia on 2 separate measurements
  • 5% atypical lymphocytes
  • Thrombocytopenia
  • Hepatic aminotransferases ≥2 times the upper limit of normal (except non-liver transplant recipients)

Management

• Treated with ganciclovir 5 mg/kg IV q12h or valganciclovir 900 mg PO bid, depending on severity of illness
• Second-line treatment includes foscarnet and cidofovir
• Expect a 1-log decrease in viral level after 2 weeks
• Duration is for a minimum of 2 weeks, until resolution of symptoms, and until viral load falls below the negative cutoff
• While being treated, check CBC and creatinine weekly to monitor for toxicity

Refractory Disease

• Refractory CMV infection: viral load increases >1 log after 2 weeks of appropriate therapy
• Probable refractory CMV infection: viral load persists or increases <1 log after 2 weeks of appropriate therapy
• Lack of clinical improvement after 2 weeks is also concerning
• The causes of refractory disease include:
  • Over-immunosuppression resulting in a severe deficiency of CMV-specific T cells
  • Subtherapeutic antiviral drug levels
  • Antiviral resistance
    • Ganciclovir resistance occurs in 0-3% of patients, and foscarnet resistance in less
    • Risk factors include prolonged subtherapeutic levels, D+/R– serostatus, heavy immunosuppression, and lung transplantation
    • If suspected, send testing for UL97 kinase (ganciclovir) ± UL54 DNA polymerase (ganciclovir & foscarnet)

Prevention

• Two approaches are used, either ongoing antimicrobial prophylaxis following transplantation, or close monitoring of viral load with preemptive treatment (PET) of subclinical viremia
  • Prophylaxis: easier to coordinate, higher drug costs, greater drug toxicity (myelosuppression)
  • Preemptive therapy: harder to coordinate, viral load thresholds not well-defined, higher laboratory costs, lower drug toxicity
• Approach and duration depends on risk profile and organ transplanted
  • Intermediate and high risk patients should get either prophylaxis or PET
    • Prophylaxis (rather than PET) is preferred in lung, heart, and pancreas transplantations
  • Low risk should either be monitored for symptoms or be followed with PET (if there is other concern for CMV disease, such as frequent transfusions)
• Antimicrobial of choice is valganciclovir 900 mg po daily, starting within 10 days of transplantation

Serostatus	Risk profile	Approach	Prophylaxis regimen
D+/R-	High	Either prophylaxis or PET; prophylaxis preferred for lung, heart, and pancreas	3-6 months for most organs; 6 months for kidney; 6-12 months for lung
R+	Intermediate	Either prophylaxis or PET; prophylaxis preferred for lung, heart, and pancreas	3 months for most organs; 6 months for lung
D-/R-	Low	Clinical monitoring; consider PET if other risk factors for CMV

Further Reading

• The Third International Consensus Guidelines on the Management of Cytomegalovirus in Solid organ Transplantation. Transplantation. 2018;102:900–931. DOI: 10.1097/TP.0000000000002191