It's not too late: a proposal to standardize the terminology of “late‐onset” cytomegalovirus infection and disease in solid organ transplant recipients

Despite remarkable improvements in its diagnosis, prevention, and treatment, cytomegalovirus (CMV) remains the single most important pathogen after solid organ transplantation (SOT) (1). Its natural history is characterized by a predictable onset during the first 4 months after SOT, when the level of immune suppression is most intense. CMV may occur as a primary infection in CMV-na€ıve patients after SOT, or it can be reactivation of latent donor or recipient infection in CMV-seropositive SOT recipients. Primary CMV infection and disease occurs most commonly among CMV-uninfected and -seronegative patients who receive latently infected organs from CMV-seropositive donors (D+/R ), with the incidence ranging from 45% after kidney, liver, and heart transplantation (2–4) to 74% after heart-lung and lung transplantation in the absence of prophylaxis (5). CMV-seropositive (R+) SOT recipients are at a lower risk of disease, with an incidence between 6% and 18% after kidney and liver transplantation in the absence of antiviral prophylaxis (2, 3). The outcome of CMV infection after SOT is the result of the complex interplay between the virus causing damage, and the robustness of host immune response. In this framework, CMV may present as a subclinical infection among SOT recipients with sufficient pathogen-specific immunity that ably controls the virus (for example, CMV-seropositive SOT recipients with preexisting CMV-specific immunity) (2, 3); this is often diagnosed in asymptomatic SOT recipients undergoing surveillance for CMV by antigenemia or nucleic acid testing. In contrast, clinically apparent CMV-induced tissue damage, termed CMV disease, may be observed among SOT recipients without sufficient CMV-specific immunity (for example, CMV D+/R SOT patients and CMV R+ SOT patients who received lymphocytedepleting therapies) (5). CMV syndrome is manifested by fever and malaise, which may or may not be accompanied by laboratory findings of myelosuppression, atypical lymphocytosis, and/or elevated alanine aminotransferase (1). Tissue-invasive CMV disease requires evidence of end-organ involvement, with the gastrointestinal tract as the most common organ involved, either alone or as a component of multisystemic CMV disease (1). CMV shows a propensity for affecting the allograft, such as CMV hepatitis after liver (6), CMV carditis after heart (7), CMV nephritis after kidney (8), CMV pneumonitis after lung (9), and CMV pancreatitis after pancreas (10) transplantation. CMV is also associated with numerous indirect effects, such as an increased risk of acute and chronic rejection (2, 11, 12) and chronic allograft failure (13). Higher rates of allograft vasculopathy and bronchiolitis obliterans are observed, respectively, in heart and lung recipients with CMV (9, 14). CMV has also been associated with subsequent additional opportunistic infections caused by bacteria (15, 16), fungi (17, 18), and other viruses (19–21). New-onset diabetes mellitus after transplantation has also been associated with CMV (22). Finally, CMV has been associated with increased risk of death after transplantation (13, 23). Because of its negative impact on outcomes, CMV prevention is a major focus of post-transplant management (1), accomplished either by preemptive therapy or antiviral prophylaxis. Antiviral prophylaxis entails the administration of antiviral drug to “all patients” at risk of CMV disease during a defined high-risk period. In contrast, with preemptive therapy, an antiviral is given “selectively” to patients with asymptomatic CMV replication, as detected by serial laboratory measurements. Clinical trials have shown the efficacy of antiviral prophylaxis (2, 3, 24, 25) and preemptive therapy (26, 27). Only a limited number of studies have directly compared these two treatment strategies (28, 29), and results of meta-analysis suggest that they are similarly effective for preventing CMV disease (30, 31). A predictably higher rate of “traditional-onset” CMV infection (and disease) occurs among SOT patients undergoing surveillance and preemptive therapy, as, in