MINIREVIEW Role of the Laboratory in Diagnosis and Management of Cytomegalovirus Infection in Hematopoietic Stem Cell and Solid-Organ Transplant Recipients

Solid-organ and hematopoietic stem cell transplantation have become vital in the treatment of many illnesses that were previously considered fatal. In 1999, a total of 21,516 solidorgan transplant procedures were performed in the United States (Scientific registry, United Network for Organ Sharing). The use of immunosuppressive agents is essential in maintaining allograft function following organ transplantation. However, the use of these agents predisposes the transplant recipients to opportunistic infections (40). One of the most common complications following organ transplantation is infection with cytomegalovirus (CMV), a ubiquitous member of the -herpesvirus family. CMV infection occurs in the majority of humans, mainly during the first two decades of life. The main host defense against CMV is cell-mediated immunity; however, virus-specific antibodies may also modify the disease caused by this virus. Following primary infection, CMV is maintained in a latent state by integration within the host cell chromosome or by persistent low-level viral replication that is adequately controlled by a functioning immune system. Consequently, the dysfunction of the immune system will allow for increased levels of CMV replication; this is further amplified by circumstances that result in viral reactivation from latency, many of which are present following transplantation (1, 7, 33, 39, 40). The deleterious effects of CMV in transplant recipients result from direct viral invasion of various organ systems (resulting in, e.g., pneumonitis, enterocolitis, encephalitis, or retinitis) following dissemination of the virus in the blood (viremia). The most serious forms of CMV disease occur in CMV-seronegative recipients of solid organs obtained from CMV-infected donors (i.e., persons whose CMV serostatus is defined as CMV D / R , where D and R denote donor positive and recipient negative, respectively) and in CMV-seropositive hematopoietic stem cell transplant recipients (39). Additionally, CMV influences allograft dysfunction, accelerates graft coronary artery atherosclerosis, and increases opportunistic infections (33). Hence, CMV leads to increased resource utilization and total transplantation cost. Indeed, the impact of CMV on transplantation outcomes is so enormous that it is considered the most important infectious cause of posttransplant morbidity and mortality. There have been considerable efforts in improving posttransplant CMV disease prevention and management. Currently the treatment of CMV disease solid-organ transplant recipients consists of the administration of intravenous ganciclovir (5 mg/kg of body weight every 12 h, adjusted based on renal function) for 2 to 4 weeks. As will be discussed, the duration of treatment may be tailored as a function of the level of viral replication. In addition, CMV immunoglobulin or polyvalent immunoglobulin is used in hematopoietic stem cell transplant recipients. The strategies aimed at CMV prevention include the use of universal prophylaxis (directed to all transplant recipients or to predisposed individuals) and the use of preemptive therapy (guided by the detection of CMV viremia prior to onset of disease) (2, 11, 20, 32). With the widespread use of currently available antiviral agents (e.g., ganciclovir and valacyclovir), whether universally or preemptively, there has been a decrease in incidence of CMV disease during the early posttransplant period (11, 20). However, CMV disease still occurs after the completion of oral antiviral prophylaxis, particularly among solid-organ transplant recipients who develop allograft rejection (39) and was observed among hematopoietic stem cell transplant recipients who developed graft-versus-host disease or who required prolonged antiviral prophylaxis during the early posttransplant period (29). The success of CMV prevention during the early posttransplant period and the improvement of CMV disease management are partly attributed to the advancement in diagnostic virology. The development and the widespread implementation of sensitive, specific, and reliable diagnostic assays for CMV detection has been essential in achieving these goals. Moreover, the introduction of viral load quantification has greatly advanced the clinical utility of diagnostic virology. In this review, we will evaluate the clinical applications of the laboratory methods for the diagnosis of CMV infection, with particular emphasis on the recent availability of quantitative assays and the continued utility of conventional assays (Table 1). In addition, we will discuss future directions in the field of CMV diagnosis and assess their potential impact on CMV disease prevention and management following transplantation. * Corresponding author. Mailing address: Department of Pathology and Laboratory Medicine, Mayo Clinic, 200 First St. SW, Rochester, MN 55905. Phone: (507) 284-8146. Fax: (507) 284-4272. E-mail: tfsmith @mayo.edu.