Revisiting the Biological Rationale for Cytomegalovirus Immune Globulin (CMVIG) in the Modern Era of Solid Organ Transplantation: Current State and Future Direction.

Cytomegalovirus (CMV) continues to be a significant challenge in solid organ transplantation (SOT), contributing to morbidity, mortality, and allograft rejection. Although CMV immune globulin (CMVIG; Cytogam®) has been shown to reduce the incidence of CMV disease, its precise mechanism of action and clear correlation between anti-CMV activity and disease attenuation remain unclear. Despite advances in antiviral therapies, CMV remains a persistent threat, with resistance complicating treatment strategies. This review revisits the biological rationale for CMVIG, highlighting its potential to improve patient outcomes through mechanisms such as virus neutralization, prevention of viral entry, complement-mediated cell lysis, and immune activation. Although CMVIG appears to mitigate CMV-related complications, further research is needed to establish therapeutic dosing based on anti-CMV antibody titers, pharmacokinetics (PK), and the desired thresholds of anti-CMV activity. Emerging factors, such as the role of co-stimulatory blocking immunosuppression in CMV risk, further emphasize the need for refining CMVIG's clinical application. Notably, CMVIG's in vitro effects on cellular immunity suggest its potential to improve outcomes, particularly in SOT recipients undergoing co-stimulation blockade. Unanswered questions remain, such as optimal IgG target levels for efficacy, the role of intracellular and extracellular immune responses to CMVIG and understanding the antibody dose-response relationship. Re-evaluating the CMV treatment paradigm, with a focus on CMVIG and antiviral agents, holds promise for more effective strategies in the modern era of SOT.