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Kinetics of TTV-DNA Plasma Load

A Global Measure of Immune Suppression?

Mitchell, Alicia B., BMedSci1; Glanville, Allan R., MD, FRACP1

doi: 10.1097/TP.0000000000002437

1 The Lung Transplant Unit, St. Vincent’s Hospital, Sydney, Australia.

Received 16 August 2018. Revision received 27 August 2018.

Accepted 28 August 2018.

The authors declare no funding or conflicts of interest.

A.B.M. participated in the writing of the article and review of the source article. A.R.G. participated in the writing of the article and reviewed the source article.

Correspondence: Allan R Glanville, MD, FRACP, The Lung Transplant Unit St. Vincent’s Hospital, Sydney, NSW 2010, Australia. (

Torque teno viruses (TTV) have received attention in recent studies that have examined their presence and dynamics in the general population, and particularly after transplantation.1 The overall consensus is that TTV are nonpathogenic, resident members of the human virome which have been shown to be ubiquitous in the blood of healthy individuals.1 A range of studies has demonstrated divergent levels of TTV in different diseases and has suggested that TTV levels may correlate with levels of immunosuppression and immune response.2 As successful solid organ transplantation relies on a balance between these 2 factors, TTV load monitoring as a surrogate for effective immunosuppression is a promising avenue for research.

The ambient and optimum level of immune suppression likely varies between individuals and within the 1 individual at different time points after transplantation. Therapeutic drug monitoring is 1 tool to measure the levels of immune suppressive drugs achieved but has a poor relationship with overall burden of immune suppression partly due to the imprecision of single point surrogate measures when compared to area under the drug concentration curve monitoring.3 This is particularly relevant after lung transplantation where 1 target group is the cystic fibrosis population where absorption and metabolism are demonstrably different from the non–cystic fibrosis population.4,5 At divergent ends of the spectrum of immune suppression are the risks of opportunistic infection and rejection, including both acute cellular rejection (ACR) and antibody-mediated rejection.6 Both may contribute to adverse outcomes in the pulmonary allograft, specifically, as risk factors for chronic rejection, manifest as bronchiolitis obliterans syndrome, or restrictive allograft syndrome, both of which phenotypes fall under the umbrella term of chronic lung allograft dysfunction.7,8

The current single-center retrospective study by Frye et al,9 correlated kinetics of TTV-DNA plasma load with outcomes after lung transplantation and found reductions in load were predictive of the development of ACR. Patients with infections had higher TTV-DNA plasma loads from day 180 onward. Results presented are at variance with prior studies from Vienna, 1 explanation for which is the use of different protocols for TTV-DNA plasma load measurement.10 Quantitative polymerase chain reaction (PCR) for determining the load, or absolute amount of TTV virus within a sample, depends on a number of factors, which may explain the discrepancy in TTV levels found between the 2 studies.10 However, the retrospective nature of this study means that collected samples may not have been optimized for viral analysis with uniform processing and storage. Prospective analyses on recently collected and careful stored samples may yield slightly different results and as mentioned, utilization of the same PCR primers for TTV, across studies, may be important due to the large amount of genetic variation exhibited by this virus.11

As the authors state, therapeutic drug monitoring of immunosuppression was not correlated with TTV-DNA plasma load. Although there was a higher TTV-DNA plasma load in patients with infections, this cannot be implied directly to show a greater burden of immunosuppression. One plausible explanation for the apparent lack of association between TTV-DNA plasma load and immunosuppression levels is that calcineurin inhibitor trough levels may not be an accurate guide to total calcineurin inhibitor exposure. Also, the global burden of immunosuppression (including the cell cycle inhibiters and corticosteroids, especially pulse corticosteroid therapy) needs to be considered. In the cohort studied, TTV-DNA plasma load monitoring was more informative than drug trough level monitoring, which perhaps bespeaks the error signal in single point surrogates of area under the drug concentration curve.

Of interest, before transplant, the TTV-DNA plasma load was often not measurable which raises the question of whether the posttransplant load emanates from the donor lungs, related to blooms of virus in the mandatory ex vivo state after brain death.12 It is thought that TTV replication is under tight immunological control in immunocompetent individuals. Immunosuppressive drug therapy, particularly induction immune suppression, enables TTV to replicate at high levels which become detectable as the TTV-DNA plasma load. Although the bulk of TTV appears to be recipient-derived, graft-derived TTV may contribute to the overall viral load, as can exogenous virus from transfusion of blood products.

As mentioned in the article, an increase in TTV levels immediately post lung transplant has also been shown previously by Abbas et al,12 who correlated absolute and relative levels of serum TTV with perioperative transplant outcomes, namely primary graft dysfunction. This study also demonstrated that TTV load may be an important marker of immunosuppression, whereby lower levels lead to greater immune system activation and damage to the allograft. In combination with the current study, there is an increasing body of evidence to suggest that TTV may be a useful biomarker in monitoring the level of induction and maintenance immunosuppression and the risk of developing both primary graft dysfunction and ACR.

Further understanding of the potential real-time applicability of TTV-DNA plasma load monitoring will depend critically on cost, availability of trained personnel, equipment, and turnaround times. These are generic issues for all potential surrogate markers of immune suppression.13 However, development of a standardized protocol will allow more representative data to be generated in future studies. Once sufficient evidence has been collated, implementation of a quantitative PCR protocol into reference and hospital laboratories alongside or as part of current viral detection panels would be conceivable.

The current article, therefore, adds to the body of literature describing another potential marker of global immune suppression burden which has certain advantages over those described previously.14 Principal viral candidates that have been considered include cytomegalovirus, Epstein-Barr virus and other beta herpes viruses including human herpes virus type 6 and type 7. In comparison to these viruses, monitoring TTV-DNA plasma load assesses a ubiquitous “resident” virus rather than a “transient” and is likely not impacted by targeted antiviral therapies.

Integral to the current study is the longitudinal nature with repeated measures which facilitates assessment of load kinetics, which is the key to a noninvasive alert signal to the presence of ACR, specifically an individual 1 log decrease in TTV-DNA plasma load, which is independent of the absolute level. Confirmation of these viral dynamics in a larger cohort would allow further information to be determined regarding the potential clinical implications of TTV monitoring. The novel finding of this study was the ability of TTV-DNA plasma load monitoring to predict ACR, and given ACR remains a robust risk factor for chronic lung allograft dysfunction, it is a finding worthy of serious consideration. There are no well-validated sensitive methods for monitoring effective global immunosuppression at this point in time. TTV-DNA plasma load monitoring may be a promising alternative. It is important, therefore, to further examine this finding in future prospective studies of the richness and diversity of the human respiratory virome, especially in the immunosuppressed host. Whether perturbations of the virome are a reliable and clinically useful global measure of immune suppression remains to be elucidated but the tools are at hand.15

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