Torque teno virus load as marker of rejection and infection in solid organ transplantation – A systematic review and meta‐analysis

Abstract

Balancing immunosuppression to prevent rejection in solid organ transplant (SOT) recipients remains challenging. Torque teno virus (TTV), a commensal non-pathogenic virus, has been proposed as marker of functional immunity: higher loads correspond to over-immunosuppression, and lower loads to under-immunosuppression. This review offers an overview of the current evidence of the association between TTV-load and infection and rejection after SOT. A systematic literature search strategy, deposited in the PROSPERO registry, resulted in 548 records. After screening, 23 original and peer-reviewed articles were assessed investigating the association between TTV-load, infection and/or rejection in SOT. The Quality in Prognostic Studies (QUIPS)-tool was used to assess the risk of bias. Meta-analysis with random-effects was performed on results with similar outcomes and exposure measures. Most of the included studies involved retrospective cohorts in which the TTV-load was measured longitudinally, within the first 2 years post-transplantation. Infection outcomes differed between studies and included viral, bacterial, parasitic and fungal infections. Rejection was defined by biopsy confirmation or initiation of rejection treatment. Twelve out of 16 studies reported an association between high TTV-load and infections, whereas 13 out of 15 reported an association between low TTV-load and rejection. Meta-analysis showed an increased risk of infection (OR: 1.16, 95% CI:1.03-1.32; HR: 1.05, 95% CI: 0.97-1.14) and a decreased risk of rejection (OR: 0.90, 95% CI: 0.87-0.94; HR: 0.74, 95% CI: 0.71-0.76) per 1 log TTV-load increase. The qualitative assessment showed varying risks of bias in the included studies. This systematic review and meta-analysis indicates that blood TTV-load measured within the first 2 years after SOT is associated with the risk of infection or allograft rejection, although substantial risk of bias in the studies included warrant cautious interpretation. The results in this review provide a rationale for larger, prospective, studies into TTV as marker of infection and rejection after SOT.

Torque Teno Virus load predicts opportunistic infections after kidney transplantation but is not associated with maintenance immunosuppression exposure.

“…We found no relationship between any of these tacrolimus exposure variables and TTV burden. We also did not find that the mean tacrolimus levels were related to TTV load as in other studies in kidney transplantation [13,19,25], unlike Gorzer et al in lung transplants [24]. Moreover, different from previous studies, we analyzed the relationship between TTV load and exposure to mycophenolic acid by measuring the gold standard AUC-MPA.…”

“…So far, it is not known precisely which immunosuppressive-related variables influence TTV levels. Some studies have linked higher doses of antimetabolite or CNI drugs or higher CNI blood levels to higher blood TTV loads, but this has not been demonstrated in all studies [13,19,[24][25][26]. Van Rijn et al reported that patients treated with tacrolimus showed higher TTV loads than those under cyclosporine [21].…”

Torque teno virus (TTV): A gentle spy virus of immune status, predictive marker of seroconversion to COVID‐19 vaccine in kidney and lung transplant recipients

“…15 The literature also contains evidence that TTV may serve as a SOT prediction marker for infection and rejection. 8,16,17 This study's primary goal is to confirm and gather new knowledge of the idea that TTV load may be identified as measure of functional immunity, also known as response to vaccination against SARS-CoV-2.…”

“… 15 The literature also contains evidence that TTV may serve as a SOT prediction marker for infection and rejection. 8 , 16 , 17 …”

Assessment of the potential value of plasma Torque Teno virus DNA load monitoring to predict Cytomegalovirus DNAemia in patients with hematological malignancies treated with small molecule inhibitors: A proof-of-concept study

“…The TTV DNA load in the systemic compartment behaved as a surrogate marker of the net state of immunosuppression in a pivotal study recruiting solid organ transplant recipients (SOT) 4 , which largely reflected the crucial role of adaptive T cell immunity in the ultimate control of TTV replication 2 . A large body of experimental evidence gathered in the SOT setting supports the assumption that either high or increasing blood TTV DNA levels after transplantation associate with the occurrence of certain infectious events, whereas the opposite holds true for acute rejection [7][8][9] . In the allogeneic hematopoietic stem cell transplantation setting (allo-HSCT), the plasma TTV DNA load appears to correlate with the degree of T cell reconstitution early after transplantation (<day 100), whereas it correlates with the level of immunosuppression afterward [10][11][12] .…”