Risk of CMV infection post transplant Cytomegalovirus (CMV) is a γ-herpes virus and is one of the most common infections encountered post-transplant. The likelihood of infection post-transplant is dependent on whether the recipient has had previous CMV infection and therefore has immunological memory of the virus. Immune memory is detected by looking for the presence of CMV-specific antibody (IgG).
Around 50% of adults in the UK are CMV immune (seropositive) and 50% seronegative. Seronegative transplant recipients (R–) who receive an allograft from a CMV seropositive donor (D+) are at risk of developing primary infection; in the absence of prophylaxis, 60% will develop symptomatic CMV infection post-transplant. Thus, most transplant centres would give CMV prophylaxis to this high-risk group of recipients in the form of oral valganciclovir. Many centres also offer ‘universal prophylaxis’ to all at risk patients (D+R–, D–R+, D+R+).
Clinical features of CMV infection
The presentation of post-transplant CMV is very variable; infection can be relatively asymptomatic in patients with immunological memory to the virus and is diagnosed only by routine screening by polymerase chain reaction (PCR). In others, particularly those who develop primary infection while immunosuppressed, it can be life-threatening. Systemic symptoms associated with CMV include fever, sweats, lethargy and weight loss. Abdominal pain may accompany gastrointestinal (GI) infection or pancreatitis. CMV can also present with organ-specific disease, including:
· colitis – symptoms include diarrhoea and weight loss
· retinitis – typical retinal appearance is of a ‘brush fire’
· pneumonitis – patients present with breathlessness, widespread alveolar infiltrates visible on chest radiograph or CT
· allograft – viral inclusions can be observed on renal transplant biopsy, and are usually associated with a decline in allograft function, even in the absence of rejection.
CMV is diagnosed by the detection of virus particles in the blood (viraemia) or in urine. PCR performed on blood/urine samples allows the identification of viral DNA. Alternatively, classical ‘owl eye’ inclusion bodies may be observed within the nuclei of infected cells isolated by biopsy or bronchi alveolar lavage by histology or cytology. CMV-specific antibodies can also be used in immunohistochemical staining of biopsy material.
CMV should be treated in the following ways.
· Reduction in immunosuppression – the development of a CMV infection suggests that the patient is relatively over-immunosuppressed. Usually the target trough level of calcineurin inhibitor (CNI) is reduced and the antiproliferative agent (azathioprine or mycophenolate) stopped.
· Specific treatment for CMV – intravenous ganciclovir is the treatment of choice for patients with life-threatening disease. Patients with low viral titres or with reactivation rather than primary disease can be treated with high-dose oral valganciclovir. Valganciclovir is a pro-drug which is converted in the liver to ganciclovir. Ganciclovir must be phosphorylated in order to generate its active metabolite ganciclovir triphosphate. Phosphorylation is dependent in part on a CMV-synthesised enzyme UL97 phos-photransferase. Thus, the virus may become resistant to ganciclovir if it mutates to produce a non-functional enzyme.
· Other agents used include foscarnet, cidofovir and intravenous CMV immune globulin, although these are usually reserved for patients with refractory or ganciclovir resistant disease.
Complications of CMV infection
Studies suggest that CMV infection (either symptomatic or asymptomatic) can have an adverse effect on both patient and allograft survival. CMV infection has been associated with:
· acute rejection
· chronic allograft nephropathy (CMV infection induces fibrosis and vascular thickening in animal models of transplantation). Such chronic changes together with an increase in acute rejection reduce long-term allograft survival
· cardiovascular complications, thus a reduced patient survival
· post-transplant diabetes mellitus.