CMV in Transplant (BSH 2013)

 

Leucodepleted blood products means CMV product selection no longer indicated for stem cell transplant

 

CMV

 

CMV is a herpes virus

Causes a primary infection followed by life-long latency

 

Primary CMV infection = infection occurring in a CMV IgG-negative patient

CMV Reactivation = infection occurring when patient or donor is known to be CMV IgG positive

Uncomplicated CMV infection = Infection + non-specific signs/symptoms without end organ dmg

CMV Disease = CMV infection + signs/symptoms of end organ damage

 

CMV disease most commonly affects the lung, GI tract, eye, liver or CNS

CMV pneumonia is the most serious complication with a 50% mortality.

CMV also has indirect immunosuppressive effects —> increased susceptibility to other fungal and bacterial infections, and an increased risk of acute and chronic GvHD.

 

Risk Factors for CMV infection

 

Preventing CMV reactivation post transplant is dependent on T-cell immune response

Therefore, RF include:

  • Unrelated / HLA-mismatched donor transplants as increased immunosuppression used

  • ATG or Alemtuzumab use

  • Prolonged use of immunosuppression to treat GvHD

 

Impact of host and donor CMV serology

 

CMV IgG-negative donor-recipient pairs (R-/D-)

  • Rarely develop major CMV-related complications

  • CMV- donors should be sought for CMV- recipients wherever possible

  • CMV status may be more important for transplant outcome than HLA DQ or DP matching

  • CMV- recipients should be re-screened pre-transplant to look for passive antibody transfer from blood products (IgM-, PCR-) or seroconversion following primary infection

  • CMV infection occurring in R-/D- pairs must be reported to SHOT

 

CMV IgG-positive donor or recipient

  • CMV+ in either donor or recipient associated with increased non-relapse mortality

  • CMV+ donor into a CMV- recipient results in CMV infection in 20-30%

  • CMV+ recipients are at greater risk of reactivation (80%) irrespective of donor status, but complications are greater if CMV- donor

management

Primary Prophylaxis

Aciclovir or valaciclovir

  • Both used but efficacy in T-cell depleted transplants is limited

Letermovir

  • Indicated for first 100 days in recipients who are CMV IgG positive prior to transplant

  • No activity against HSV or VZV —> use in combination with aciclovir

  • Hepatic metabolism, sensitive to enzyme inducers

  • Interacts w/ calcineurin inhibitors (ciclosporin, tacrolimus, sirolimus)

Ganciclovir

  • Used in solid organ transplants but myelosuppressive SE preclude use in HSCT

Secondary Prophylaxis

 

Consider for patients with previous CMV disease prior to transplant or with recurrent episodes of CMV infection post-transplant. Use valganciclovir or valaciclovir.

 

Pre-Emptive Therapy

 

Principle of CMV management post transplant is rapid introduction of therapy based on CMV viral loads detected by real time quantitative PCR.

 

CMV PCR can be performed on plasma or whole blood.

Should be tested weekly for first 3-6 months post-transplant

Threshold for treatment must be decided at each centre because of Inter-lab variability

Similarly, same lab should be used each time for an individual patient.

 

Anti-Viral Agents

 

Ganciclovir

  • Virustatic. Inhibits viral replication by competing with deoxyguanosine triphosphate (a required substrate for viral DNA polymerase)

  • 5mg/kg IV BD for 14 days

  • SE: Myelosuppression

 

Valganciclovir

  • Valine ester of ganciclovir

  • 900mg BD

  • SE: Haemolysis, Nausea, Fever, Rash, Mental state change, Urinary Sx

 

Foscarnet

  • Virustatic. Inhibits viral DNA polymerase

  • 90mg/kg BD

  • SE: Electrolyte abnormalities, Renal impairment, Nausea, GU symptoms

 

Cidofovir

  • Nucleotide analogue

  • 5mg/kg weekly

  • SE: Renal impairment, nausea, ocular

 

Drug resistance

 

Uncommon in transplant patients

Resistance estimated at 2-8% of patients after 2-3 months of prolonged therapy

 

De Novo CMV Disease

 

MDT approach required (Resp, ophthalmology)

Ganciclovir or Foscarnet for 2 weeks followed by maintenance

Immunosuppression should be reduced or stopped, particularly steroids.