Toward the Individualization of Cytomegalovirus Control after Solid‐Organ Transplantation: The Importance of the “Individual Pathogenic Balance”

Despite improved treatment, surveillance, and prevention, cytomegalovirus (CMV) is still regarded as an important infectious pathogen after solid-organ transplantation. More than 50% of solid-organ transplant recipients may have evidence of CMV replication, and 10%–50% can develop symptomatic CMV disease. Throughout the years the risk of developing CMV replication or disease has been based on clinical risk markers. The most important are the type of organ transplantation, the CMV serostatus of the donor and recipient, the type and intensity of the immunosuppression (eg, use of antibodies to T cell receptors), and coinfection with other herpesvirus (eg, herpesvirus 6) [1]. According to these criteria, prevention and treatment strategies for CMV infection after solid-organ transplantation have been defined without taking into account variables that allow personalizing this management through the identification of the individual risk markers for every patient. Many of these classic risk markers are subrogated indicators of the 2 factors involved in the pathogenesis of this infection: the virus' capacity to produce damceptor's defensive capacity (immune response). In this issue of Clinical Infectious Diseases, Manuel et al [1] discuss the importance of the virus in this pathogenesis. I would like to emphasize that both pathogenic factors may have individual peculiarities. Both CMV replication and disease depend on their interaction. Without underestimating the importance of well-defined clinical situations, pointing out a general scenario of risk, we are currently gathering evidence that allows us to hypothesize that in the future the risk of CMV replication could be personalized according to the definition of an “individual pathogenic balance.” It seems obvious that pharmacologic immunosuppression plays an essential role in patients who have undergone solid-organ transplantation. The possibility of monitoring the levels of numerous drugs has been a remarkable advance in individual management of immunosuppression. Nevertheless, immunologic control of CMV, including factors that allow for replication in the solid-organ transplant recipient, is complex and should be individualized. Ideally, immune CMV monitoring should help to predict the risk of CMV for each particular patient with the aim of guiding prophylaxis and preemptive therapy. Both innate and adaptive immunity play a role in the control of CMV [2]. Individual innate immunity factors, such as Toll-like receptors (TLRs), especially polymorphisms of TLR2 and TLR4, have been related to CMV disease [3]. An association between deficiency of the mannose-binding lectin and CMV disease has been proven [4]. Individual peculiarities in natural killer cell response may also be important. Adaptive immunity also plays an important role in CMV disease development. B cells are important in the humoral response to CMV and produce neutralizing antibodies targeted at glycoprotein B (gB) and glycoprotein H. Hypogammaglobulinemia is a risk factor for CMV infection, particularly in heart and lung transplant recipients [5]. T cell response, including both CD4+and CD8+T cells, seems to be critical in the control of CMV. CD8+T cell reactivity has been shown to be directed toward a wide range of epitopes, including gB [2]. It is known that T cell response may show great differences, depending on (1) the eventual contact with CMV before transplantation, (2) the patient's age (immunosenescence), (3) the immunosuppression used, and (4) other individual peculiarities. Control of CMV by T cells can currently be put into clinical practice by using a wide variety of assays. Interferon-γ response is a useful marker of CMV immunity and can be measured with different assays (eg, Quantiferon-CMV assay (Cellestis), Elispot assay, flow cytometry, or intracellular cytokine staining). The individual quantitation of CMV-specific CD4+and CD8+T cell response is also possible (eg, major histocompatibility complex-multimer assay or Cylex Immuknow assay) [2]. Nevertheless, little is known regarding the clinical influence of viral virulence factors on the pathogenesis of the CMV infection. With the introduction of quantitative methods of virus detection (antigenemia and polymerase chain reaction), the importance of viral replication kinetics in each particular patient has been proven [6]. Thus, it has been observed that high viral load is related to higher risk of CMV. It has also been suggested that low-degree persistent viral replication may be associated with indirect effects, such as rejection. The VICTOR study (A Study of Valcyte [Valganciclovir] Compared with Ganciclovir in Patients with CMV Disease Who Are Solid Organ Transplant Recipients) has concluded that the response to ganciclovir depends on the peak viral load before treatment and the kinetic decrease in viral load within the first week of therapy [7]. Although the biodiversity of CMV has long been known, it had not been taken into account in large clinical studies of therapy. In this issue of Clinical Infectious Diseases , Manuel et al [1] present a secondary outcome analysis of the VICTOR study to assess the influence of the gB genotype on the outcome of CMV disease. The results of previous studies assessing the role of gB genotypes in CMV pathogenesis have been inconsistent. The authors observe that a mixed genotype infection occurs in nearly one-half of the patients, more likely occurring in donor-seropositive/recipient-seropositive patients. No specific gB genotype is associated with a specific CMV virulence advantage. However, mixed gB genotype infections are associated with higher viral loads and delayed viral clearance. As the authors indicate, these findings currently have little clinical utility. However, new scenarios are opened for future research on the “individual pathogenic balance” from the viewpoint of the study of viral virulence factors. If the technique aimed at detecting these genotypes becomes standardized in clinical laboratories, it may influence the management of CMV infection (as it occurred with hepatitis C). In addition, in the future, knowing the viral load and the genotypes that infect seropositive donors may have great importance [8]. Notably, in the study conducted by Manuel et al [1], 12% of donor-seropositive/recipient-seronegative patients showed mixed infection. Patients with mixed asymptomatic replications may require a specialized preventive management. It is possible that in the future we could monitor not only the pharmacologic immunosuppression but also the immunologic peculiarities and viral biodiversity of each patient, permitting a better definition of the “individual pathogenic balance.” It may allow the individualization of the management of CMV infection after solid-organ transplantation. Financial support. Spanish Ministry for Health, the Carlos-III Health Institute, FEDER, Spanish Network for Research in Infectious Diseases (REIPI RD06/0008). Potential conflicts of interest. J.T.C. has received unrestricted grants from Roche Pharmaceuticals.