Quantification of Torque Teno Virus Viremia as a Prospective Biomarker for Infectious Disease in Kidney Allograft Recipients

Straßl, Robert; Schiemann, Martin; Doberer, Konstantin; Görzer, Irene; Puchhammer‐Stöckl, Elisabeth; Eskandary, Farsad; Kikić, Željko; Gualdoni, Guido A.; Vossen, Matthias G.; Rasoul‐Rockenschaub, Susanne; Herkner, Harald; Böhmig, Georg A.; Bond, Gregor

doi:10.1093/infdis/jiy306

Cited by 105 publications

(164 citation statements)

References 25 publications

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“…In addition, we did not find any association between recipient CMV serology and pretransplant TTV DNA, in contrast with a previous report involving healthy individuals . After transplant, patients with negative serology (who presented a higher incidence of CMV infection) had a higher TTV DNA load, which was consistent with previous findings . Although a potential association with CMV primoinfection after transplant has previously been hypothesized, our results showed that this difference was only significant in those patients who received triple IS, the same group that also presented a higher incidence of CMV infection.…”

Section: Discussionsupporting

confidence: 77%

“…(18) In addition, Strassl et al recently showed that an MMF dose 1.5 g or higher was the only IS therapy associated with a higher TTV viremia in kidney transplant recipients. (19) In contrast, in our cohort, patients with triple therapy did not present fewer episodes of rejection as might have been expected in light of the higher state of IS suggested. Nevertheless, immune mechanisms that lead to graft rejection are different than those that protect a host from infections and thus these 2 complications are not mutually exclusive.…”

Section: Discussioncontrasting

confidence: 52%

“…(24) After transplant, patients with negative serology (who presented a higher incidence of CMV infection) had a higher TTV DNA load, which was consistent with previous findings. (19) Although a potential association with CMV primoinfection after transplant has previously been hypothesized, our results showed that this difference was only significant in those patients who received triple IS, the same group that also presented a higher incidence of CMV infection. These results support the notion that TTV replication is related to immune status and is not directly associated with CMV.…”

Section: Discussioncontrasting

confidence: 48%

“…This immunosuppressant has also been associated with a more severe course of CMV infection and organ involvement . In addition, Strassl et al recently showed that an MMF dose 1.5 g or higher was the only IS therapy associated with a higher TTV viremia in kidney transplant recipients . In contrast, in our cohort, patients with triple therapy did not present fewer episodes of rejection as might have been expected in light of the higher state of IS suggested.…”

Section: Discussionsupporting

confidence: 48%

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Torque Teno Virus Is Associated With the State of Immune Suppression Early After Liver Transplantation

et al. 2019

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The development of noninvasive biomarkers that reflect the state of immunosuppression (IS) remains an unmet need in liver transplantation (LT). Torque Teno virus (TTV) is a highly prevalent, nonpathogenic DNA virus whose plasma levels may be associated with the immune status of the host. The aim of this study was to assess the role of TTV as a biomarker of IS in LT recipients. TTV DNA in plasma was quantified by real‐time polymerase chain reaction at different time points during the first year after transplant in a prospectively followed cohort of 63 de novo LT recipients, and any correlation between TTV DNA and biopsy‐proven acute cellular rejection (ACR) and opportunistic infections was then evaluated. In addition, TTV DNA was studied in 10 longterm LT recipients in monotherapy with tacrolimus, 10 tolerant recipients, and 10 healthy controls. TTV was detected in the plasma of all patients. Among the 63 LT recipients, 20 episodes of ACR were diagnosed, and there were 28 opportunistic infections, 26 of them being cytomegalovirus (CMV) infections. TTV viremia was significantly lower during ACR (4.41 versus 5.95 log10 copies/mL; P = 0.002) and significantly higher during CMV infections (5.79 versus 6.59 log10 copies/mL; P = 0.009). The area under the receiver operating characteristic curve of TTV viral load for the diagnosis of moderate ACR was 0.869, with a sensitivity and negative predictive value of 100%, respectively, for a cutoff point of 4.75 log10 copies/mL. There were no statistically significant differences in TTV DNA in either longterm or tolerant patients and healthy controls. In conclusion, plasma TTV DNA levels are associated with immune‐related events after LT and could constitute a potential biomarker of the state of IS during the first months after transplant.

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Section: Discussionsupporting

confidence: 77%

Section: Discussioncontrasting

confidence: 52%

Section: Discussioncontrasting

confidence: 48%

Section: Discussionsupporting

confidence: 48%

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Torque Teno Virus Is Associated With the State of Immune Suppression Early After Liver Transplantation

et al. 2019

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“…28 The number of epitopes was significantly higher even after subtracting CMV epitopes, which echoes findings of several recently published studies in which torque-teno virus (a ubiquitous virus thought to be nonpathogenic, but serves as a marker of overall immunosuppression) and herpesvirus reactivation predicted reactivation of other viruses. 29,30 It may be that persons who reactivated CMV were also more likely to subclinically reactivate other viruses due to overall immunosuppression, leading to the observed expansion of non-CMV viral epitopes. Heterogeneity in CMV epitope recognition could potentially help explain why CMV-positive donors may not be able to adequately control reactivation of a recipient's specific CMV strain.…”

Section: Non-cmv Epitopesmentioning

confidence: 99%

Comprehensive viromewide antibody responses by systematic epitope scanning after hematopoietic cell transplantation

Ignacio

Dasgupta

Stevens-Ayers

et al. 2019

Blood

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K E Y P O I N T S l VirScan highlights both donor and recipient contributions to the viral antibody repertoire, and acquisition of new viral epitopes after HCT. l Age, CMV serostatus, and receipt of glucocorticoids correlate with recognition of viral epitopes after HCT.Further insight into humoral viral immunity after hematopoietic cell transplantation (HCT) could have potential impact on donor selection or monitoring of patients. Currently, estimation of humoral immune recovery is inferred from lymphocyte counts or immunoglobulin levels and does not address vulnerability to specific viral infections. We interrogated the viral antibody repertoire before and after HCT using a novel serosurvey (VirScan) that detects immunoglobulin G responses to 206 viruses. We performed VirScan on cryopreserved serum from pre-HCT and 30, 100, and 365 days after myeloablative HCT from 37 donor-recipient pairs. We applied ecologic metrics (a-and b-diversity) and evaluated predictors of metrics and changes over time. Donor age and donor/recipient cytomegalovirus (CMV) serostatus and receipt systemic glucocorticoids were most strongly associated with VirScan metrics at day 100. Other clinical characteristics, including pre-HCT treatment and conditioning, did not affect antiviral repertoire metrics. The recipient repertoire was most similar (pairwise b-diversity) to that of donor at day 100, but more similar to pre-HCT self by day 365. Gain or loss of epitopes to common viruses over the year post-HCT differed by donor and recipient pre-HCT serostatus, with highest gains in naive donors to seropositive recipients for several human herpesviruses and adenoviruses. We used VirScan to highlight contributions of donor and recipient to antiviral humoral immunity and evaluate longitudinal changes. This work builds a foundation to test whether such systematic profiling could serve as a biomarker of immune reconstitution, predict clinical events after HCT, or help refine selection of optimal donors. (Blood.

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Comparative evaluation of molecular methods for the quantitative measure of torquetenovirus viremia, the new surrogate marker of immune competence

Macera

Spezia

Medici³

et al. 2019

Journal of Medical Virology

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Background: Torquetenovirus (TTV) viremia is emerging as a promising tool to assess functional immune competence, to predict posttransplant immune-related complications, and eventually to customize immunosuppression.Methods: In this study, 327 blood samples were tested using two real-time PCR (rtPCR) assays both targeted to the untranslated region of the TTV genome. The first assay was an in-house rtPCR developed by our group, the second one was the recently marketed TTV R-GENE assay.Results: In the validation study, the TTV R-GENE showed good performances in precision and reproducibility, and sensitivity as low as 12 TTV DNA copies/mL, like previously reported for the in-house rtPCR. The Bland-Altman analysis showed that the mean difference between the two methods was −0.3 log copies/mL. In the comparison study, 69% and 72% of samples were detected positive by rtPCR and TTV R-GENE, respectively (94% concordance, κ = 0.88). Performances did not differ between the two rtPCRs by type of TTV group examined. When a newly-developed in-house digital droplet PCR was applied for TTV quantification and used as an alternative method of comparison on 94 samples, the results strongly correlated with those obtained by the two rtPCR methods (99% concordance). Conclusion:In summary, all the molecular methods assayed are highly sensitive and accurate in quantitation of TTV DNA in blood samples.digital droplet PCR, methods comparison, real-time PCR, torquetenovirus | INTRODUCTIONSoon after its discovery, 1 it became clear that torquetenovirus (TTV) was just one of a vast group of related, previously unrecognized viral agents, all of which were characterized by small, circular singlestranded DNA genomes with negative polarity. 2 Presently, all these viruses are classified within the family Anelloviridae. 3 TTV is currently attracting considerable interest due to a number of specific features. Among these, the most intriguing is probably the extremely high prevalence of chronic plasma viremia in more than 80% of the general population, regardless of disease status, age, sex, socioeconomic conditions, geographic location, risk factors, and other variables. 4,5 Individual viremia levels have been shown to vary between 10 1 to 10 9 genome copies per milliliter (mL) of blood, with

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Quantification of Torque Teno Virus Viremia as a Prospective Biomarker for Infectious Disease in Kidney Allograft Recipients

Abstract: TTV quantification predicts infection after kidney transplantation and might be a potential tool to tailor immunosuppressive drug therapy.

Cited by 105 publications

References 25 publications

Torque Teno Virus Is Associated With the State of Immune Suppression Early After Liver Transplantation

Torque Teno Virus Is Associated With the State of Immune Suppression Early After Liver Transplantation

Comprehensive viromewide antibody responses by systematic epitope scanning after hematopoietic cell transplantation

Comparative evaluation of molecular methods for the quantitative measure of torquetenovirus viremia, the new surrogate marker of immune competence

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