HHV-8/KSHV in Solid Organ Transplantation: Current Gaps of Knowledge and Future Directions

The incidence of HHV-8/KSHV-associated diseases (KADs) among solid organ transplant (SOT) recipients has shown a relative increase, likely reflecting the growing population of long-term SOT survivors and heightened recognition and reporting due to greater clinician awareness. The real impact of HHV-8/KSHV in the SOT setting remains difficult to determine due to regional variations in seroprevalence and non-universal screening practices. Neoplastic KAD reported in SOT includes Kaposi sarcoma (KS), multicentric Castleman disease (MCD), primary effusion lymphoma (PEL), and other rare lymphomas. Increasing attention has focused on Kaposi's Sarcoma-associated Herpesvirus Inflammatory Cytokine Syndrome (KICS), a non-malignant syndrome characterized by uncontrolled inflammation, fever, pancytopenia and elevated HHV-8/KSHV DNAemia, resembling viral sepsis that can progress to shock and multi-organ failure. A clinical protocol including testing donors and recipients, monitoring for DNAemia in recipients at risk, switching CNI to mTOR inhibitors, treatment with antivirals, and rituximab for KICS may mitigate the impact of HHV-8/KSHV infection in SOT recipients. However, standardized serological testing is not available and the role of monitoring, preemptive management and treatment of HHV-8/KSHV DNAemia should be studied in larger prospective studies. Severe donor-derived KICS and KS, often presenting without skin involvement, underscore the need for reliable serologic tests for identification of at-risk recipients (especially D+/R-), heightened clinical awareness to ensure timely diagnosis and prompt treatment. This review provides an updated overview of KADs with a particular focus on KICS in SOT, highlights knowledge gaps for future research, and summarizes recent advances in the screening and management of HHV-8/KSHV infection following transplantation.