Background: Balancing immunosuppression to prevent rejection and infection in solid organ transplant recipients (SOTx) remains a challenge. Torque teno virus (TTV), a commensal non-pathogenic virus, has been proposed as functional marker of immunity: higher loads reflect over-immunosuppression, while lower loads reflect under-immunosuppression. Here we present a systematic review and meta-analysis of the current literature and provide evidence on the association between TTV load and infection and rejection in SOTx recipients.

Methods: A systematic literature search strategy, deposited in PROSPERO, resulted in 548 records. After screening, 23 original and peer-reviewed articles were included in qualitative assessment, investigating the association between TTV load, and either infection or rejection in SOTx. The Quality in Prognosis Studies (QUIPS) tool was used to assess the risk of bias. Meta-analysis was performed on studies with similar outcomes measures and exposure using a joint modelling strategy.

Results: 23 studies were included, most involved retrospective cohorts in which the TTV load was measured within 1-2 years post-transplantation, once or longitudinally. Defined outcomes differed between studies, and included viral (CMV, BK, respiratory), bacterial, and fungal infections. Rejection outcomes included rejection treatment, with or without biopsy confirmation. QUIPS assessment showed varying risks of bias between studies. Twelve out of 17 studies reported an association between high TTV loads and infection (71%), and 13 out of 15 an inverse association between low TTV loads and rejection (87%). Meta-analysis showed an increased risk of infection (OR: 1.16, CI 1.04-1.30; HR: 1.05, CI 0.97-1.14) and decreased risk of rejection (OR: 0.90, CI 0.87-0.94, HR: 0.74, CI 0.71-0.76) per 1 log TTV load increase.

Conclusions: Systematic review of the current literature shows an association between TTV load and each outcome in most studies, and this association is supported by our meta-analysis. However, concerns on study quality and the risk of publication bias warrants careful interpretation. Externally validated prediction models using TTV load remain to be built, as these will offer individualized diagnostic or prognostic value to predict infection and rejection in SOTx recipients.