Post-transplant Cytomegalovirus Infection

Epidemiology

The seroprevalence of CMV is high in the general population of the United States, but has a greater risk of clinical consequences when the immune system is suppressed, such as during SOT or HSCT.^1,3,4

Nearly 40,000 solid organ transplants were performed in the US in 2020.⁵ Earlier studies estimate that the incidence of CMV disease ranges from 8-32% in heart, kidney, and liver recipients, and is as high as 75% in lung recipients.⁶ Risk factors for CMV disease in SOT include serological mismatch, intense immunosuppression, and lung transplant.^1,6 D+/R- transplants are associated with the highest risk of CMV disease (19.2% to 31.3%) because seronegative recipients lack cellular and humoral immunity to CMV.^7,8,9

There were about 22,000 HSCTs performed in the US in 2020.¹⁰ Estimates for the incidence of CMV disease range from 5% in autologous transplants to 30% in allogeneic transplant.⁶ Risk factors for CMV infection in HSCT include serological mismatch, treatment for GvHD, and treatment with anti-thymocyte globulin. Seropositive HSCT recipients have the highest risk of CMV reactivation. D-/R+ transplants are at highest risk for infection (36%) because the lack of CMV-specific memory T cells prolongs immunological anti-CMV reconstitution.^6,11

Diagnosis

CMV infection in transplant recipients is diagnosed through identification of viral replication, which is monitored post-transplant.^6,12,13 The most common method is quantitative nucleic acid testing (QNAT), which is a real-time polymerase chain reaction (RT-PCR) method. QNAT, which can be advantageous for standardization, provides quantification of CMV DNA.

Pathophysiology

CMV is a herpesvirus with double-stranded DNA.² CMV can lie dormant in cells and reactivate when the host is immunocompromised.^6,14,15

The seroprevalence of CMV is high in the general population, with transmission via saliva, sexual contact, placental transfer, breastfeeding, transfusion, and transplantation.¹⁵

Primary infection involves the lytic life cycle (lysis of the host cell), but is commonly asymptomatic in immunocompetent hosts.^14,15 CMV then enters a latent phase in which the virus lies dormant within a host cell, avoiding immune surveillance. Latency is normally asymptomatic. Reactivation is when the virus re-enters the lytic life cycle. This can be triggered by immunosuppression, inflammation, infection, and stress, and commonly occurs in immunocompromised hosts, such as transplant recipients.¹⁵

Navigating CMV

In the post-transplant setting, the transplant team must deploy a risk-based testing strategy to guide the approach to CMV prophylaxis, modulation of immunosuppressive regimen, and if necessary, treatment of CMV.⁶

Adding to the challenge of CMV management is the presence of refractory CMV, defined as a suboptimal response to antiviral therapy; and resistant CMV, a laboratory definition of a drug-resistant phenotype or the presence of mutations known to confer resistance to antiviral agents.¹⁶ CMV that is refractory and/or resistant to treatment can lead to high morbidity and mortality rates.^16,17 Ongoing and future research looks to improve sequencing and detection of mutations, and identification of optimal therapeutic strategies.¹⁶