Quantification of Torque Teno Virus and Epstein-Barr Virus Is of Limited Value for Predicting the Net State of Immunosuppression After Lung Transplantation

Abstract

Background: Major hurdles for survival after lung transplantation are rejections and infectious complications. Adequate methods for monitoring immune suppression status are lacking. Here, we evaluated quantification of torque teno virus (TTV) and Epstein-Barr virus (EBV) as biomarkers for defining the net state of immunosuppression in lung-transplanted patients.

Methods: This prospective single-center study included 98 patients followed for 2 years after transplantation. Bacterial infections, fungal infections, viral respiratory infections (VRTI), cytomegalovirus (CMV) viremia, and acute rejections, as well as TTV and EBV levels, were monitored.

Results: The levels of torque teno virus DNA increased rapidly after transplantation, likely due to immunosuppressive treatment. A modest increase in levels of Epstein-Barr virus DNA was also observed after transplantation. There were no associations between either TTV or EBV and infectious events or acute rejection, respectively, during follow-up. When Tacrolimus was the main immunosuppressive treatment, TTV DNA levels were significantly elevated 6-24 months after transplantation as compared with Cyclosporine treatment.

Conclusions: Although replication of TTV, but not EBV, appears to reflect the functionality of the immune system, depending on the type of immunosuppressive treatment, quantification of TTV or EBV as biomarkers has limited potential for defining the net state of immune suppression.

Keywords: Epstein-Barr virus; biomarker; immunosuppression; infection; lung-transplantation; rejection; torque teno virus.

Figure 1.

Kinetics of torque teno virus (TTV)– and Epstein-Barr virus (EBV)–DNA levels, in serum and whole blood respectively, before and during the follow-up period after lung transplantation. TTV-DNA levels in serum starting pre–lung transplantation (LTx) were determined by real-time polymerase chain reaction (PCR). Individual TTV levels are indicated by dots. EBV-DNA levels in whole blood post-LTx were determined by real-time PCR, and individual EBV levels are indicated by dots. Patients receiving either Tacrolimus treatment (n = 19) or Cyclosporine treatment (n = 79) are indicated by red and blue dots, respectively. The mean levels of TTV and EBV in Tacrolimus-treated patients are indicated by red lines in their respective graphs. The mean levels of TTV and EBV in Cyclosporine-treated patients are indicated by blue lines in their respective graphs. Infectious events and acute rejections are indicated by black dots. Statistical calculations were done using Mann-Whitney U (P values are indicated by ^*<.05, ^**<.01, and ^***<.001). ⁺⁺The levels of EBV-DNA pre-LTx were determined in serum samples. Abbreviations: CMV, cytomegalovirus, reject: acute rejection of which all but 3 were biopsy-verified; LOQ, level of quantification; viral RI, viral respiratory tract infection.