Viral infections post transplantation: Cytomegalovirus in transplantation

Dr Hooi Lai Seong

CMV is a herpesvirus. It is the most common opportunistic infection after solid organ transplantation. 20 – 60% of transplant recipients develop symptomatic infection without prophylaxis. CMV infection and disease contribute to post-transplant mortality and morbidity. Prophylactic regimens are associated with variable efficacy and expense. Antiviral therapy will either prevent disease or extend the incubation period. Treatment of established CMV costs USD 25,000 – 50,000.

CMV infection occurs primarily after the first month of transplantation and the risk is dependent on the serological status of the donor and recipient. CMV infection is the presence of CMV viremia with mild fever without evidence of tissue invasion. It may be asymptomatic. CMV disease refers to symptomatic or tissue-invasive acute CMV infection eg mononucleosis, pneumonitis, hepatitis, haematological, nervous system and gastrointestinal involvement. There are 3 sources of infection: latently infected allografts or leukocyte containing transfusions (D+), reactivation of endogenous virus in seropositive recipients and contact with people with replicating virus. Proinflammatory cytokines, particularly TNF, play a significant role in the reactivation of latent virus. Many of CMV's effects are due to the cytokines, chemokines, and growth factors that are produced in response to CMV replication and invasion. This accounts for the bidirectional effects between different viruses: e.g. CMV and HHV-6, CMV and HCV, CMV and EBV, etc.

There are 3 types of infection: Primary infection occurs when an allograft from a seropositive donor is transplanted into a seronegative recipient; ~60% become ill. Reactivation infection occurs when endogenous, latent infection is reactivated; ~15% become ill. Superinfection is when both donor and recipient are seropositive, but the virus that is reactivated is of donor origin; ~25% become ill. The risk of CMV infection is greatest in donor-positive, recipient-negative (D+R-) transplant patients, particularly after the use of anti-lymphocyte antibodies. Diagnosis is by direct early antigen fluorescent foci (monoclonal antibody against pp65, DEAFF), in urine, blood, throat washing, CMV DNA PCR, upper and lower GI endoscopy and biopsy, bronchio-alveolar lavage. Serology (IgM and IgG) is less helpful.

Treatment of CMV disease is with intravenous ganciclovir for at least 2 to 4 weeks, dosage according to renal function or oral valganciclovir (bioavailability 70%, prodrug of ganciclovir). Duration of therapy should be carefully considered and depends on viral load and intensity of immunosuppression. The side effects of these drugs include neutropenia, thrombocytopenia, abnormal LFTs, fever, rash, azoospermia. Foscarnet i.v. may be used instead of ganciclovir especially in ganciclovir resistant CMV or cidofovir (which is toxic). Acyclovir has no role in treating CMV disease while CMV hyperimmune globulin and intravenous immunoglobulin have uncertain value. The other experimental drugs include leflunomide and maribavir. Monitoring during treatment include daily full blood count, renal profile, liver enzymes, CMV DNA and repeat cultures for CMV.

Given that life threatening disease is difficult to treat (and mortality 90% if untreated), prevention by either prophylaxis or pre-emptive therapy is the most effective approach. The alternative is standard therapy where treatment is based on detection of CMV infection with signs and symptoms attributable to CMV.

Prophylaxis means that treatment is administered before and at transplantation to prevent CMV disease (prior to detection of CMV infection). This is easy to administer but there may be unnecessary exposure of low risk recipients to a drug. Prolonged exposure may result in development of resistance. The prophylaxis therapy used includes i.v. ganciclovir for at least 14 days, followed by oral, oral ganciclovir, oral valganciclovir, oral valacyclovir and oral acyclovir.

Pre-emptive therapy means early detection of CMV infection with treatment administered for a brief period if laboratory tests indicate a high risk for CMV disease before onset of symptoms. This gives rise to exposure of fewer individuals to drug, less toxicity, less cost. There is reduced duration of exposure and this may minimise emergence of resistant CMV. It requires a sensitive, predictive test to detect infection and depending on test sensitivity may not identify all individuals at risk of disease. This approach requires extreme vigilance. The test is usually one for PCR, Ag or other molecular diagnostic but it is not clear for how long it has to be done and how often.

CMV is associated with immunomodulatory derangements that can lead indirectly to opportunistic superinfections, allograft rejection, and development of post transplant lymphoproliferative disease. Other secondary effects include cardiac complications and diabetes. These could lead to graft loss and death. The evidence base supports the role of asymptomatic CMV viremia in the indirect effects and prophylaxis against CMV may impact on many of these effects.