Torque Teno Virus Load Research Articles

FC 106: Validation of the Optimal Torque Teno Virus Range for Risk Stratification of Graft Rejection and Infection in Kidney Transplant Recipients by TTV R-GENE®

Abstract BACKGROUND AND AIMS The nonpathogenic and ubiquitous Torque Teno virus (TTV) plasma load is associated with immunosuppression in solid organ transplant recipients. An optimal TTV range has been defined for risk stratification of graft rejection and infection in the first year post kidney transplant applying an in-house PCR. Recently, a commercial PCR—the TTV R-GENE® kit—has been CE certified for clinical use. The present study was designed to validate and refine the optimal TTV range applying the TTV R-GENE® kit. METHOD Patients and events were selected from the prospective TTV-POET trial, including all 628 consecutive adult recipients of a kidney allograft transplanted at the Medical University of Vienna, between January 2016 and July 2020. Patients were followed for 12 months post-transplant or until drop-out. TTV was quantified longitudinally by the TTV R-GENE® kit. The primary outcome was biopsy proven graft rejection and the secondary end-point was infection. RESULTS A total of 78 patients with 85 graft biopsies (rejection, n = 18) and 274 patients with 80 infectious events following TTV quantification after reaching steady state in month 3 post-transplantation were selected. TTV was quantified at a median of 17 days before rejection was diagnosed and 63 days before onset of infection. The risk for rejection decreased by 25% with every log level increase in TTV load [RR 0.75, 95% confidence interval (95% CI) 0.67–0.85; < 0.001]. For TTV loads < 5log10 c/mL a high specificity of 90% for rejection was calculated. The risk for an infection increased by 6% with every log level increase of TTV load (RR 1.06, IQR 1.00–0.12; = 0.047). For TTV loads > 7log10 c/mL a high specificity of 91% for infection was calculated. Multivariate modelling revealed an independent associated between TTV and rejection and infection, respectively. CONCLUSION These data support the value of TTV quantified by TTV R-GENE® for risk stratification of graft rejection and infection in the first year post kidney transplantation. The optimal TTV range defined within this study will be applied in an interventional randomized controlled trial to assess the safety of TTV-guided immunosuppression: the TTVguideIT trial.

TTV Load is Associated with SARS-CoV-2 Vaccination Response in Lung Transplant Recipients

PurposeAlthough the currently approved COVID-19 vaccines are highly effective, SARS-CoV-2-specific immune responses are diminished in lung transplant recipients (LTR), probably due to immunosuppression (IS). There is currently no marker of IS that can be used to predict vaccination responses. Here, we study if torque tenovirus (TTV) can be used as a predictive marker.MethodsThe humoral response to the mRNA-1273 vaccine was assessed in 103 LTR, who were vaccinated 4 to 237 months after Lung transplantation. Spike (S)-specific IgG levels were measured at baseline, 28 days after first, and 28 days after the second vaccination. TTV loads were determined by RT-PCR and Pearson's correlation coefficient was calculated to correlate serological responses to TTV load.ResultsHumoral responses to the vaccine COVID-19 vaccination were found in 41/103 (40%) LTR at 28 days after the second vaccination. 62 /103 (60%) had no detectable antibodies. TTV loads at baseline correlated with S-specific antibodies and the percentage of responders (=<0.001) (Fig 1). TTV loads also strongly correlated with the time since transplantation, indicating that participants with lower TTV loads were longer after transplantation.ConclusionThis study shows an association between baseline TTV load and mRNA-1273-induced S-specific antibodies. If the TTV load is indeed a predictor of vaccination responses, this can be used in the future as a potential guidance for optimizing vaccination regimens. Therefore, we recommend that TTV load measurements are included in further vaccination efficacy studies in immunocompromised cohorts.

High torque tenovirus (TTV) load before first vaccine dose is associated with poor serological response to COVID-19 vaccination in lung transplant recipients.

BackgroundSerological responses to COVID-19 vaccination are diminished in recipients of solid organ transplants, especially in lung transplant recipients (LTR), probably as result of immunosuppressive treatment. There is currently no marker of immunosuppression that can be used to predict the COVID-19 vaccination response. Here, we study whether torque tenovirus (TTV), a highly prevalent virus can be used as an indicator of immunosuppression.MethodsThe humoral response to the mRNA 1273 vaccine was assessed in 103 LTR, who received a transplant between 4 and 237 months prior to vaccination, by measuring Spike (S)-specific IgG levels at baseline, 28 days after first, and 28 days after the second vaccination. TTV loads were determined by RT-PCR and Pearson's correlation coefficient was calculated to correlate serological responses to TTV load.ResultsHumoral responses to COVID-19 vaccination were observed in 41 of 103 (40%) LTR at 28 days after the second vaccination. Sixty-two of 103 (60%) were non-responders. Lower TTV loads at baseline (significantly) correlated with higher S-specific antibodies and a higher percentage of responders. Lower TTV loads also strongly correlated with longer time since transplantation, indicating that participants with lower TTV loads were longer after transplantation.ConclusionsThis study shows a better humoral response to the SARS-CoV-2 vaccine in subjects with a lower TTV load pre-vaccination. In addition, TTV load correlates with the time after transplantation. Further studies on the use of TTV load in vaccination efficacy studies in immunocompromised cohorts should provide leads for the potential use of this marker for optimizing vaccination response.

Association of post-transplantation anellovirus viral load with kidney transplant rejection in children.

Post-transplantation immunosuppressive therapy reduces the risk of graft rejection but raises the risk of infection and malignancy. A biomarker of the level of immunosuppression can be helpful in monitoring immunosuppressive therapy. Inverse correlation between Torque teno virus (TTV) from the Anelloviridae (AV) family load and immune competence was described in previous studies. The aim of this study was to analyze the association between AV family viruses' kinetics and the risk for graft rejection in the first year after kidney transplantation in children. The titers of three genera (TTV, TTMDV, and TTMV) from the AV family were monitored by real-time PCR in consecutive samples from children before and after kidney transplantation. Twenty-one children who underwent kidney transplantation were enrolled. Five out of 21 patients experienced acute graft rejection within a year from transplantation. We found that in patients who experienced graft rejection, the median titers of TTV and total AV titers at 5-6 months post-transplantation were lower than in those who did not. Using a threshold determined by ROC analysis, significant differences in TTV and total AV load were found between patients who had or did not have graft rejection (p = 0.002 and 0.004, respectively). No association was found between the dominance of any AV genus titer and the likelihood of rejection. This pilot study suggests that children after kidney transplantation with low TTV and total AV titers 5-6 months post-transplantation are at increased risk for graft rejection within a year after transplantation. A higher resolution version of the Graphical abstract is available as Supplementary information.

Quantification of torque teno virus (TTV) DNA in saliva and plasma samples in patients at short time before and after kidney transplantation

ABSTRACT Background Several reports have proposed that the viral load of torque teno virus (TTV) in plasma is a biomarker of immune function in solid organ transplantation (SOT) and in allogeneic hematopoietic stem cell transplantation. Additionally, for the latter one, TTV-DNA quantification in saliva has also been suggested. Aim to investigate the correlation between the TTV viral load and immune function in paired saliva and plasma samples in patients on kidney transplantation. Materials and Methods TTV-DNA viral load was quantified in paired samples of saliva and plasma from 71 patients before and a short-time after renal-transplantation by real-time PCR. Results The data obtained from 213 paired samples showed a slight consistency in the comparison between saliva and plasma, with prevalence of TTV-DNA being 58%, 52% and 60% in saliva samples and 60%, 73% and 90% in plasma samples before and at 15–20 and 45–60 days after transplantation, respectively. Additionally, a high TTV viral load was observed in plasma at 15–20 and 45–60 days after transplantation compared to that observed in saliva at the same time. Conclusions Overall, monitoring TTV-DNA in saliva samples could be an additional fast non-invasive option to assess the immune functionality in SOT populations.

Torque Teno Virus Load Is Associated With Subclinical Alloreactivity in Kidney Transplant Recipients: A Prospective Observational Trial.

Nonpathogenic torque teno viruses (TTVs) are highly prevalent in transplant recipients and associated with immunosuppression. Studies in kidney transplant patients have proposed assessment of TTV load for risk stratification of clinically overt graft rejection. The value of TTV quantification in the context of subclinical rejection has not been evaluated. In this prospective trial, 307 consecutive kidney transplant recipients were subjected to per-protocol monitoring of plasma TTV. TTV was analyzed in the context of protocol biopsies (n = 82), scheduled 1 year posttransplantation. TTV load at the time of biopsy was lower in recipients with rejection (n = 19; according to Banff, including borderline changes suspicious for acute T cell-mediated rejection) than those without rejection (n = 63) whereby each log increase in TTV copies/mL decreased the risk for rejection by 9% (risk ratio 0.91, 95% confidence interval, 0.85-0.97; P = 0.004). Development of chronic lesions (cg, cv, ci, ct, ah, ptcml) was associated with the number of days with a TTV load <1 × 106 copies/mL between months 3 and 12 posttransplant (β 0.07, 95% confidence interval, 0.01-0.14; P = 0.02). This trial demonstrates an association between TTV and subclinical graft rejection in kidney transplant recipients. A TTV load <1 × 106 copies/mL suggests suboptimal immunosuppression.

Torque Teno Virus load in lung cancer patients correlates with age but not with tumor stage.

BackgroundTorque teno virus (TTV) is a ubiquitous non-pathogenic virus, which is suppressed in immunological healthy individuals but replicates in immune compromised patients. Thus, TTV load is a suitable biomarker for monitoring the immunosuppression also in lung transplant recipients. Since little is known about the changes of TTV load in lung cancer patients, we analyzed TTV plasma DNA levels in lung cancer patients and its perioperative changes after lung cancer surgery.Material and methodsPatients with lung cancer and non-malignant nodules as control group were included prospectively. TTV DNA levels were measured by quantiative PCR using DNA isolated from patients plasma and correlated with routine circulating biomarkers and clinicopathological variables.Results47 patients (early stage lung cancer n = 30, stage IV lung cancer n = 10, non-malignant nodules n = 7) were included. TTV DNA levels were not detected in seven patients (15%). There was no significant difference between the stage IV cases and the preoperative TTV plasma DNA levels in patients with early stage lung cancer or non-malignant nodules (p = 0.627). While gender, tumor stage and tumor histology showed no correlation with TTV load patients below 65 years of age had a significantly lower TTV load then older patients (p = 0.022). Regarding routine blood based biomarkers, LDH activity was significantly higher in patients with stage IV lung cancer (p = 0.043), however, TTV load showed no correlation with LDH activity, albumin, hemoglobin, CRP or WBC. Comparing the preoperative, postoperative and discharge day TTV load, no unequivocal pattern in the kinetics were.ConclusionOur study suggest that lung cancer has no stage dependent impact on TTV plasma DNA levels and confirms that elderly patients have a significantly higher TTV load. Furthermore, we found no uniform perioperative changes during early stage lung cancer resection on plasma TTV DNA levels.

Torque teno virus loads after kidney transplantation predict allograft rejection but not viral infection.

The main challenge of immunosuppressive therapy after solid organ transplantation is to create a new immunological balance that prevents organ rejection and does not promote opportunistic infection. Torque teno virus (TTV), a ubiquitous and non-pathogenic single-stranded DNA virus, has been proposed as a marker of functional immunity in immunocompromised patients. Here we investigate whether TTV loads predict the risk of common viral infection and allograft rejection in kidney transplantation recipients. In a retrospective cohort of 389 kidney transplantation recipients, individual TTV loads in were measured by qPCR in consecutive plasma samples during one year follow-up. The endpoints were allograft rejection, BK polyomavirus (BKPyV) viremia and cytomegalovirus (CMV) viremia. Repeated TTV measurements and rejection and infection survival data were analysed in a joint model. During follow-up, TTV DNA detection in the transplant recipients increased from 85 to 100%. The median viral load increased to 107 genome copies/ml within three months after transplantation. Rejection, BKPyV viremia and CMV viremia occurred in 23%, 27% and 17% of the patients, respectively. With every 10-fold TTV load-increase, the risk of rejection decreased considerably (HR: 0.74, CI 95%: 0.71-0.76), while the risk of BKPyV and CMV viremia remained the same (HR: 1.03, CI 95%: 1.03-1.04 and HR: 1.01, CI 95%: 1.01-1.01). In conclusion, TTV load kinetics predict allograft rejection in kidney transplantation recipients, but not the BKPyV and CMV infection. The potential use of TTV load levels as a guide for optimal immunosuppressive drug dosage to prevent allograft rejection deserves further validation.

Associations Between Sputum Torque Teno Virus Load and Lung Function and Disease Severity in Patients With Chronic Obstructive Pulmonary Disease

Purpose: Viral load of Torque Teno virus (TTV) is elevated in immunosuppressed patients. The weakened immune response is typical in chronic obstructive pulmonary disease (COPD) patients. However, the relationship between TTV and COPD is still unknown.Patients and Methods: We enrolled 91 patients admitted to hospitals with acute exacerbation of COPD (AECOPD) between January 2017 and August 2017 (ClinicalTrials.gov ID, NCT03236480). Sputum samples were gathered during hospitalization and the 120-day follow-up. TTV distribution and genogroups were assessed, and the associations between viral loads and clinical parameters were analyzed.Results: TTV DNA was detected in 95.6% of COPD patients, and the viral load was nearly invariable at the stable and exacerbation states. Most TTV DNA-positive patients carried four distinct genotypes. Sputum load of TTV was positively associated with RV/TLC (r = 0.378, p = 0.030), and negatively correlated with FEV1/pre and FEV1/FVC (r = −0.484, −0.432, p = 0.011, 0.024, respectively). Neutral correlation between the TTV DNA load and COPD assessment test (CAT) scores (r = 0.258, p = 0.018) was observed.Conclusion: Sputum loads of TTV DNA could be a novel indicator for lung function and disease severity assessment in COPD patients.

Torque Teno Virus Does Not Predict Cytomegalovirus Infection Post-Lung Transplantation

Purpose Torque teno virus (TTV) is a highly prevalent, non-pathogenic DNA virus that has been shown to correlate with immunosuppression post-transplantation. Cytomegalovirus (CMV) is the most common opportunistic infection to occur post-lung transplantation and is associated with morbidity and mortality. We evaluated the association between plasma TTV load and subsequent occurrence of CMV infection in lung transplant recipients at moderate risk for a CMV infection. Methods All adult, first-time lung and heart-lung transplant patients with moderate risk serotype for CMV infection [donor positive (D+) / recipient positive (R+)] transplanted between September 2005 and December 2013 in our program were included in the study. During this period, our program's CMV prophylaxis strategy was to use valganciclovir for 3 months post-transplant. Existing stored blood samples were retrieved and TTV DNA was quantified using real-time polymerase chain reaction (PCR), measured at 3, 4 and 5 months after lung transplantation, as well as at the time of detection in those who developed a CMV infection. Paired t-tests were used for serial data comparisons and Cox regression was performed to determine an association between log TTV PCR levels and CMV infection within 6 months of discontinuing antiviral prophylaxis. Results During the study period 297 patients were transplanted. Of these patients, 89 patients had D+/R+ serostatus, of which blood samples for TTV PCR testing were available for 76 patients. Only 1 patient did not have any detectable TTV PCR post-transplant. Within this cohort, 34/75 patients (45%) developed a CMV infection within 6 months of discontinuing antiviral prophylaxis. Baseline mean log TTV PCR levels one week after discontinuation of CMV prophylaxis was no different between those that went on to develop a CMV infection and those that did not (6.80 ± 1.08 vs 7.08 ± 0.75, p=0.20). For those developing CMV infection, mean log TTV PCR levels were slightly lower at the time of CMV infection compared to baseline levels (6.45 ± 1.36 vs 6.98 ± 0.72, p=0.04). TTV viral load was not associated with time to CMV infection, HR 0.76 (95% CI 0.55 - 1.05, p=0.09). Conclusion TTV PCR levels at the time of discontinuation of CMV prophylaxis in CMV D+/R+ lung transplant recipients were not associated with subsequent CMV infection. TTV's role in predicting future infection requires further study.

The newborns Torque teno virus dynamics depending on the term, feeding type and maternal viral load.

The first weeks of life are extremely important for the development of the immunity-virome interaction that affects human health in adulthood. In this study we analyzed Torque teno virus (TTV) dynamics during the first weeks of life in the full-term/premature infants in relation with the maternal TTV load and the type of feeding. 152 infants aged 1-14 weeks (63 full-term and 89 premature) and 33 mother-child pairs were analyzed for the whole blood TTV load by qPCR with test sensitivity of 1000 viral copies/ml. 50 infants were retested (at 2-11 time points) for TTV dynamics data. All one-week babies (n=71) from TTV-positive mothers were TTV-negative, consistently with the previous findings of the lack of transplacental transmission of the virus. TTV was not detectable in newborns under two weeks of age. Most infants are TTV-positive by 14 weeks of age. Whole blood TTV load does not show significant correlation with full-term/prematurity, maternal TTV load, or feeding type. Keywords: Torque teno virus; transfusion-transmitted virus; commensal virus; TTV; viral load dynamics; TORCH infections; full-term and premature babies; breastfeeding; virome.

Torque teno virus microRNA detection in cerebrospinal fluids of patients with neurological pathologies.

Torque teno virus (TTV) is a widespread anellovirus that establishes persistent infections in humans and represents the most abundant component of the human virome. TTV encodes microRNAs (miRNA) which are found both in viremic and not viremic subjects being potentially ideal tools for the virus to evade the immune system response and to maintain chronic infection in the host. To investigate TTV-DNA loads and TTV-miRNAs expression in cerebrospinal fluids (CSF) from subjects under analysis for the assessment of neurological diseases. Detection of TTV-DNA and TTV-miRNAs (e. g. miRNA t1a, t3b, and tth8) were carried out from CSF samples of 93 subjects with neurological diseases by using universal real-time PCR, real-time RT-PCR, and next-generation sequencing (NGS) analyses. TTV-DNA was detected in 11 of 93 (12 %) CSFs with a mean TTV load of 155 copies/mL. Conversely, 29 CSF samples (31 %) were positive for at least one TTV-miRNA, while 15 (16 %) CSFs contained all the TTV-miRNAs examined. Overall, TTV-miRNA tth8 was detected in 62 % of samples, followed by TTV miRNA t3b (56 %), and t1a (29 %). Interestingly, TTV-miRNAs were found in CSF samples that were negative for the presence of TTV-DNA. Next-generation sequencing analysis carried out from 4 TTV-DNA negative CSF samples detected reads mapped in TTV-miRNA sequences region. These results shed novel light on the relationship between TTV and the central nervous system and make compelling furthered studies for investigating the potential role of TTV-miRNAs in neurological disorders.

Occurrence and quantification of Anelloviruses and Herpesviruses in gingival tissue in Chinese Shanghai sub-population

BackgroundHerpesviruses and bacteria and their interplay have long been believed to play important roles in the pathogenesis of periodontitis, but other microbial entities in the oral environment might also be involved. Anelloviruses are commonly detected in human, including in oral samples. The aim of the present study was to explore the occurrence and co-occurrence of human cytomegalovirus (HCMV), Epstein–Barr virus (EBV), and human anelloviruses (HTTVs) in gingival tissue samples collected from participants recruited in Shanghai, China.MethodsGingival tissues were collected from 159 participants (57 with aggressive periodontitis (AP), 59 with chronic periodontitis (CP) and 43 with healthy periodontal status). The presence of HCMV, EBV, torque teno virus (TTV), torque teno mini virus (TTMV) and torque teno midi virus (TTMDV) DNA was detected by nested-PCR. The virus loads were quantified by real-time PCR.ResultsThe detection rates of EBV, TTV, TTMV and TTMDV were significantly higher in the AP and CP groups compared to the healthy group (all P < 0.01). A statistically significant association was found between EBV, TTV and TTMV virus load and periodontitis (all P < 0.05). Participants infected with EBV showed significantly higher infection rates and higher virus loads of TTV and TTMV than the EBV-negative group (all P < 0.05). The coexistence rates of EBV and anelloviruses and the coexistence of three HTTVs were significantly higher in AP and CP groups (all P < 0.01).ConclusionsCollectively, results obtained in this study suggest that HTTVs and the coexistence of EBV and HTTVs in particular, may be associated with periodontitis. Possible mechanisms of the interaction between herpesviruses and anelloviruses in the context of periodontitis require further investigation.

P1624TORQUE TENO VIRUS FOR RISK STRATIFICATION OF GRAFT REJECTION AND INFECTION IN KIDNEY TRANSPLANT RECIPIENTS - A PROSPECTIVE OBSERVATIONAL TRIAL

Abstract Background and Aims The non-pathogenic and ubiquitous Torque Teno virus (TTV) is associated with immunosuppression in solid organ transplant recipients. Studies in kidney transplant patients proposed TTV quantification for risk stratification of graft rejection and infection. This prospective observational trial was designed to assess the potential of TTV load for risk prediction of both, infection and rejection in the first year after transplantation. The objective of this trial was to provide TTV cut-off level to define an optimal TTV range as a basis for a randomised controlled interventional trial to test the efficacy of TTV-guided immunosuppression. Method Within this trial (DRKS00012335) all 386 adult (≥18 years of age) consecutive kidney graft recipients transplanted at the Medical University Vienna, Austria, between January 1st 2016 and June 31st 2018. were subjected to longitudinal per protocol TTV monitoring. In total 3265 TTV measurements were taken and 71 biopsy proven graft rejections (defined by BANFF classification) and 472 clinically relevant infections were documented in the first year post-transplant. After reaching steady state at the end of post-transplant month 3, peripheral TTV plasma load was analyzed in the context of subsequent rejection and infection by rt-PCR. Results Patients with allograft rejection had lower levels of TTV compared to patients without rejection (median 3.5x106 c/mL, IQR 1.7x105-1.3x108 c/ml vs. median 2.5x108 c/mL, IQR 5.8x106-9.3x108 c/mL; P = .028) in subsequent biopsies. TTV load in individuals experiencing an infectious event in the subsequent observation period was higher compared to patients without infection (median 3.9x108 c/mL, IQR 7.9x106-3.3x109 c/mL vs. median 2.6x107 c/mL, IQR 1.3x106-9.2x108 c/mL; P &amp;lt; .001). Of note, TTV was quantified several weeks before rejection diagnosis and infection onset. Each log increase in TTV load decreased the odds for rejection by 22% (OR 0.78, 95% CI 0.62-0.97; P = .027) and increased the odds for infection by 11% (OR 1.11, 95% CI 1.06-1.15; P &amp;lt; .001). The association of TTV and infection and rejection, respectively was not altered by confounding or effect modification. A TTV load between 106 and 108 copies/mL was defined as optimal range to minimize the risk for rejection and infection. Conclusion These data support the initiation of an interventional trial assessing the efficacy of TTV-guided immunosuppression to reduce infection and graft rejection in kidney transplant recipients.

Torque Teno Virus DNA Load after Heart Transplantation and Its Association with the Strength of Immunosuppression: Preliminary Data of a Prospective Single Center Study

Long-term survival after heart transplant is still limited due to immunological and drug related adverse events. Immunosuppressive therapy is solely managed via pharmacokinetic analysis and clinical events. TTV (Torque Teno Virus) is a small single-stranded DNA virus associated with increasing viral load under immune compromising conditions. Studies in both kidney and lung transplantation have already shown that the level of plasma TTV - DNA load is associated with the magnitude of immunosuppression. The aim of this prospective observational study was to analyze TTV viral load in patients after heart transplantation (HTX). We prospectively determined the TTV load in 50 heart transplant patients. Samples were collected at pre-transplant and each HTX visit in the out-patient clinic. Viral load analysis was performed by PCR from plasma or serum on the Department of Virology. TTV viral load was compared between pre-transplant and peak levels post transplant. Pre-TX TTV load was compared between different patient groups and between different immunosuppressive protocols after transplantation. Patients were transplanted between 1/2016-6/2018. Median age at transplant was 60 (42-67) years and 38% were female. 50%(n=25) of patients were transplanted due to ischemic disease, 44% (n=22) due to dilative Cardiomyopathy and 6% (n=3) due to other disease. 16% of patients were bridged with a mechanical assist device (n=8). Pretransplant TTV levels were 4.4E+00±2.03E+00 cps/ml and significantly increased to 9.39E+00 ±0.75E+00 (p<0.001) at the TTV peak levels at a median time of 121 (92-185) days post-transplant. Pretransplant, VAD bridged patients had significantly higher TTV loads than non-bridged patients (4,02±1,97E+00 vs. 5,93±0,63 E+00, p=0.023). This difference disappeared after 90-120 days post transplant (120d: VAD: 8.72±0,74 E+00 vs. no VAD: 8,49±1,17 E+00, p=n.s.). TTV viral load increases significantly after heart transplantation and reaches its peak after 90-120 days. VAD pretransplant has an influence of TTV viral load and the choice of calcineurin inhibitor drug seems to be associated with differences in TTV viral load. TTV viral load might be useful as a biomarker for the state of immunosuppression.

Torque teno virus for risk stratification of graft rejection and infection in kidney transplant recipients-A prospective observational trial.

The nonpathogenic and ubiquitous torque teno virus (TTV) is associated with immunosuppression in solid organ transplant recipients. Studies in kidney transplant patients proposed TTV quantification for risk stratification of graft rejection and infection. In this prospective trial (DRKS00012335) 386 consecutive kidney transplant recipients were subjected to longitudinal per‐protocol monitoring of plasma TTV load by polymerase chain reaction for 12 months posttransplant. TTV load peaked at the end of month 3 posttransplant and reached steady state thereafter. TTV load after the end of month 3 was analyzed in the context of subsequent rejection diagnosed by indication biopsy and infection within the first year posttransplant, respectively. Each log increase in TTV load decreased the odds for rejection by 22% (odds ratio [OR] 0.78, 95% confidence interval [CI] 0.62‐0.97; P = .027) and increased the odds for infection by 11% (OR 1.11, 95% CI 1.06‐1.15; P < .001). TTV was quantified at a median of 14 days before rejection was diagnosed and 27 days before onset of infection, respectively. We defined a TTV load between 1 × 106 and 1 × 108 copies/mL as optimal range to minimize the risk for rejection and infection. These data support the initiation of an interventional trial assessing the efficacy of TTV‐guided immunosuppression to reduce infection and graft rejection in kidney transplant recipients.

Role of BK polyomavirus (BKV) and Torque teno virus (TTV) in liver transplant recipients with renal impairment.

Renal impairment is a common complication after liver transplantation (LT). While BK polyomavirus (BKV) has been linked to renal failure in kidney transplant recipients, Torque teno virus (TTV) is a surrogate marker for immunosuppression that does not have a clear association with any human disease. The impact of BKV and TTV on renal impairment after LT is unknown. In this retrospective study, urine and serum samples from 136 liver transplant recipients were screened for BKV and TTV by quantitative PCR. In addition, serum was screened for BKV-specific antibodies and the VP1 typing region was sequenced for BKV genotyping. All parameters were correlated with clinical data.Results/Key findings. BK viruria was detected up to 21 years after transplantation in 16.9 % of cases. BK viraemia was detected in 8.7 % of patients with BK viruria up to 4 years after LT. BKV-specific antibodies were detected in 93.6 % of all LT recipients and correlated with BKV viral load in urine. There was no correlation between renal impairment and the detection of BK DNA in urine (OR 0.983). TTV DNA was detected in 84.6 % of serum samples and in 66.6 % of urine samples. The TTV viral load in serum correlated with the BKV viral load but had no impact on renal impairment. Our data indicate that the detection of BKV and TTV is not a risk factor for renal impairment after LT. A correlation of TTV and BKV viral load seems to be an indicator for the immune status of the host.

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

Drug-induced immunosuppression following kidney transplantation is crucial to prevent allograft rejection, but increases risk for infectious disease. Tailoring of drug dosing to prevent both rejection and infection is greatly desirable. The apathogenic and ubiquitous torque teno virus (TTV) reflects immunocompetence of the host and might be a potential candidate for immunologic monitoring. To assess TTV as an infection biomarker, virus load was prospectively quantified in peripheral blood of 169 consecutive renal allograft recipients at the Medical University Vienna. Patients with infection showed higher TTV levels compared to patients without infection (4.2 × 108 copies/mL [interquartile range, IQR, 2.7 × 107-1.9 × 109] vs 2.9 × 107 [IQR 1.0 × 106-7.2 × 108]; P = .006). Differences in TTV load became evident almost 3 months before infection (median 77 days, IQR 19-98). Each log level of TTV copies/mL increased the odds ratio for infection by 23% (95% confidence interval 1.04-1.45; P = .014). TTV >3.1 × 109 copies/mL corresponded to 90% sensitivity to predict infections. Logistic regression demonstrated independent association between TTV levels and infection. TTV quantification predicts infection after kidney transplantation and might be a potential tool to tailor immunosuppressive drug therapy.

High-dose zinc oral supplementation after stem cell transplantation causes an increase of TRECs and CD4+ naïve lymphocytes and prevents TTV reactivation

IntroductionZinc plays an important role in thymic function and immune homeostasis. We performed a prospective clinical trial using a high-dose zinc oral supplementation to improve the immune reconstitution after hematopoietic stem cell transplant (HSCT). Patients and methodsWe enrolled 18 patients undergoing autologous HSCT for multiple myeloma. Nine patients were randomized to receive only a standard antimicrobial prophylaxis; whereas, nine patients received in addition 150 mg/day of zinc from day +5 to day +100 after transplant. ResultsCD4+ naïve lymphocytes and TRECs showed a significant increase from day +30 until day +100 only in the zinc-treated group. Moreover, the load of Torquetenovirus, a harmless virus that replicates in course of immunedepression, increased at day +100 only in the control group. No severe adverse events were reported during the zinc consumption. ConclusionFirst data from the ZENITH trial suggest that high-dose zinc supplementation is safe and may enhance the thymic reconstitution after HSCT. Registered: http://Clinicaltrials.gov (NCT03159845); and EUDRACT: 2014-28 004499-47.

Dynamics of Torque Teno virus viremia could predict risk of complications after allogeneic hematopoietic stem cell transplantation.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an established treatment option for several hematological diseases. However, the first year post-transplantation is often complicated by infections and graft-versus-host disease (GVHD). Improvements in immunological monitoring could reduce such post-transplant complications. Torque Teno virus (TTV), a chronically persisting DNA virus, is reported to be a marker for immune function in immunocompromised patients. In the present study, the TTV kinetics were analyzed to investigate the potential role of TTV viremia as immune-competence read-out after allo-HSCT. Twenty-three monocentric allo-HSCT recipients were retrospectively tested for TTV-DNA in whole blood at given day post-transplant. Dynamics of TTV viremia was analyzed with respect to episodes of non-TTV viral reactivations (CMV, EBV, and BKPyV), acute GVHD, and recovery of immune cells. Recipients affected by persisting viral infections and/or GVHD during the first 100days after allo-HSCT showed a significantly higher median TTV load at day +30 than patients with a less complicated clinical course (p=0.005). This was also associated with a total lymphocyte count <5.5E+08 cells/L in this high-risk group (p=0.039). These findings suggest that TTV could represent an additional parameter to identify patients at higher risk for complications in the first 100days following allo-HSCT. Prospective studies, including the monitoring of lymphocyte subsets, are required to define the potential use of TTV in immunological monitoring after allo-HSCT.