Tumor necrosis factor α promotes clonal dominance of KIT D816V+ cells in mastocytosis: role of survivin and impact on prognosis.

ABSTRACT: Systemic mastocytosis (SM) is defined by the expansion and accumulation of neoplastic mast cells (MCs) in the bone marrow (BM) and extracutaneous organs. Most patients harbor a somatic KIT D816V mutation, which leads to growth factor-independent KIT activation and accumulation of MC. Tumor necrosis factor α (TNF) is a proapoptotic and inflammatory cytokine that has been implicated in the clonal selection of neoplastic cells. We found that KIT D816V increases the expression and secretion of TNF. TNF expression in neoplastic MCs is reduced by KIT-targeting drugs. Similarly, knockdown of KIT or targeting the downstream signaling cascade of MAPK and NF-κB signaling reduced TNF expression levels. TNF reduces colony formation in human BM cells, whereas KIT D816V+ cells are less susceptible to the cytokine, potentially contributing to clonal selection. In line, knockout of TNF in neoplastic MC prolonged survival and reduced myelosuppression in a murine xenotransplantation model. Mechanistic studies revealed that the relative resistance of KIT D816V+ cells to TNF is mediated by the apoptosis-regulator BIRC5 (survivin). Expression of BIRC5 in neoplastic MC was confirmed by immunohistochemistry of samples from patients with SM. TNF serum levels are significantly elevated in patients with SM and high TNF levels were identified as a biomarker associated with inferior survival. We here characterized TNF as a KIT D816V-dependent cytokine that promotes clonal dominance. We propose TNF and apoptosis-associated proteins as potential therapeutic targets in SM.

No evidence of asymptomatic monkeypox infection in a highly sexually active MSM population in Austria.

BACKGROUND: The 2022 outbreak of monkeypox virus (MPXV) revealed new transmission routes. Incidence declined sharply in September 2022, and it remains unclear whether MPXV is circulating in asymptomatic individuals because of increased immunity. OBJECTIVES: Our study aimed to assesss the number of asymtomatic MPXV carriers in individuals at high risk for STI. METHODS: We analysed anal samples from asymptomatic highly sexually active men who have sex with men for the presence of MPXV. RESULTS: We detected a high number of concomitant sexually transmitted infections but did not find a single sample with MPXV. CONCLUSIONS: Our results indicate that the general recommendation to implement screening for MPXV is not currently justified.

Scars are frequently found as late sequelae in individuals affected by the 2022 mpox outbreak.

BACKGROUND: The 2022 mpox outbreak continues, and while progress has been made in prevention strategies and potential treatment options, data on late sequelae following mpox are scarce. OBJECTIVE: This analysis aimed to assess the incidence of scar formation in individuals affected by the 2022 mpox outbreak. METHODS: All individuals diagnosed with mpox at the Department of Dermatology at the Medical University of Vienna in 2022 were included in this analysis. Follow-up data were collected throughout November 2023. 'Scar formation' was defined as having at least one scar at the former active mpox lesions. RESULTS: At our clinic, 28 cases of mpox presented between June 2022 and October 2022 and exclusively occurred in men who have sex with men (100%, 28/28), of whom 46% (13/28) were living with HIV, and 32% (9/28) were using pre-exposure prophylaxis (PrEP). Secondary bacterial infection of mpox lesions was suspected in six individuals, and all received systemic antibiotics. Overall, 26 were followed up in November 2023 after a median time of 15 months, and scar formations were found in 43% of cases. CONCLUSIONS: Our data provide insights into the late yet cumulating disease burden caused by the 2022 mpox outbreak. Highly effective prevention strategies are warranted to overcome the mpox epidemic and its potential late sequelae.

The kinetics of Torque Teno virus plasma load following calcineurin inhibitor dose change in kidney transplant recipients.

Torque Teno virus (TTV) is nonpathogenic, highly prevalent, and reflects the immune status of its host. Thus, TTV plasma load was suggested for the guidance of immunosuppression post solid organ transplantation. The present study was designed to determine the kinetics of TTV following changes in calcineurin inhibitor (CNI) dose. A total of 48 adult recipients of a kidney graft transplanted at the Medical University of Vienna between 2018 and 2019 with isolated changes in CNI dose were selected from the prospective TTV-POET trial. TTV plasma load was quantified by in-house PCR. At Day 30 following CNI dose adaptation (median 33% of daily dose) no changes in TTV load were noted. However, at Day 60, following CNI dose reduction a lower TTV load of 6.4 log10 c/mL (median; interquartile range [IQR] 4.9-8.1) compared with the baseline of 7.1 log10 c/mL (IQR 5.3-8.9) was noted (p = 0.001); there was also a trend toward a higher TTV load following CNI increase (6.6 log10 c/mL, IQR 4.1-9.7 vs. 5.2 log10 c/mL, IQR 4.5-6.8; p = 0.09). The data suggested that TTV load changes become noticeable only 2 months after CNI dose adaptation, which might be the ideal time point for TTV load monitoring.

The natural killer cell-associated rs9916629-C allele is a novel genetic risk factor for fatal COVID-19.

The severity of COVID-19 is associated with individual genetic host factors. Among these, genetic polymorphisms affecting natural killer (NK) cell responses, as variations in the HLA-E- (HLA-E*0101/0103), FcγRIIIa- (FcγRIIIa-158-F/V), and NKG2C- (KLRC2wt/del ) receptor, were associated with severe COVID-19. Recently, the rs9916629-C/T genetic polymorphism was identified that indirectly shape the human NK cell repertoire towards highly pro-inflammatory CD56bright NK cells. We investigated whether the rs9916629-C/T variants alone and in comparison to the other risk factors are associated with a fatal course of COVID-19. We included 1042 hospitalized surviving and 159 nonsurviving COVID-19 patients as well as 1000 healthy controls. rs9916629-C/T variants were genotyped by TaqMan assays and were compared between the groups. The patients' age, comorbidities, HLA-E*0101/0103, FcγRIIIa-158-F/V, and KLRC2wt/del variants were also determined. The presence of the rs9916629-C allele was a risk factor for severe and fatal COVID-19 (p < 0.0001), independent of the patients' age or comorbidities. Fatal COVID-19 was more frequent in younger patients (<69.85 years) carrying the FcγRIIIa-158-V/V (p < 0.006) and in older patients expressing the KLRC2del variant (p < 0.003). Thus, patients with the rs9916629-C allele have a significantly increased risk for fatal COVID-19 and identification of the genetic variants may be used as prognostic marker for hospitalized COVID-19 patients.

Progressive cholestasis and associated sclerosing cholangitis are frequent complications of COVID-19 in patients with chronic liver disease.

BACKGROUND AND AIMS: Cholestasis is associated with disease severity and worse outcome in COVID-19. Cases of secondary sclerosing cholangitis (SSC) after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection have been described. APPROACH AND RESULTS: Hospitalized patients with COVID-19 between 03/2020 and 07/2021 were included. Patients were stratified as having (i) no chronic liver disease (CLD), (ii) non-advanced CLD (non-ACLD), or (iii) advanced CLD (ACLD). Patients with CLD and non-COVID-19 pneumonia were matched to patients with CLD and COVID-19 as a control cohort. Liver chemistries before (Pre) and at first, second, and third blood withdrawal after SARS-CoV-2 infection (T1-T3) and at last available time point (last) were recorded. A total of 496 patients were included. In total, 13.1% (n = 65) had CLD (non-ACLD: 70.8%; ACLD: 29.2%); the predominant etiology was NAFLD/NASH (60.0%). COVID-19-related liver injury was more common among patients with CLD (24.6% vs. 10.6%; p = 0.001). After SARS-CoV-2 infection, patients with CLD exhibited progressive cholestasis with persistently increasing levels of alkaline phosphatase (Pre: 91.0 vs. T1: 121.0 vs. last: 175.0 U/L; p < 0.001) and gamma-glutamyl transferase (Pre: 95.0 vs. T1: 135.0 vs. last: 202.0 U/L; p = 0.001). A total of 23.1% of patients with CLD (n = 15/65) developed cholestatic liver failure (cholestasis plus bilirubin ≥6 mg/dl) during COVID-19, and 15.4% of patients (n = 10/65) developed SSC. SSC was significantly more frequent among patients with CLD and COVID-19 than in patients with CLD and non-COVID-19 pneumonia (p = 0.040). COVID-19-associated SSC occurred predominantly in patients with NAFLD/NASH and metabolic risk factors. A total of 26.3% (n = 5/19) of patients with ACLD experienced hepatic decompensation after SARS-CoV-2 infection. CONCLUSIONS: About 20% of patients with CLD develop progressive cholestasis after SARS-CoV-2 infection. Patients with NAFLD/NASH and metabolic risk factors are at particular risk for developing cholestatic liver failure and/or SSC after COVID-19.

Viral infections in pediatric brain tumor patients treated with targeted therapies.

BACKGROUND: Brain tumors are the most common solid malignancies and the leading cause of cancer-related mortality in children. While numerous studies report on viral infections in children with hematologic malignancies and solid organ transplantation, epidemiologic data on the incidence and outcome of viral infections in pediatric patients with brain tumors treated with targeted therapies are still lacking. OBJECTIVES/STUDY DESIGN: We retrospectively reviewed all children with brain tumors receiving targeted therapies in a primary or recurrent setting at the Medical University of Vienna from 2006 to 2021. Demographic variables, quantitative and qualitative parameters of possible infections, and treatment outcomes were recorded. RESULTS: In our cohort (n = 117), 36% of the patients developed at least one PCR-proven viral infection. Respiratory and gastrointestinal tract infections were most common, with 31% and 25%, respectively. Central nervous system (CNS) infections occurred in approximately 10%, with an almost equal distribution of varicella-zoster virus, John Cunningham virus (JCV), and enterovirus. Two patients tested PCR-positive for SARS-CoV-2 infection, with one virus-related death caused by a SARS-CoV-2-related acute respiratory distress syndrome. Patients receiving bevacizumab or mTOR inhibitors seem to have a greater susceptibility to viral infections. CONCLUSION: Pediatric patients with brain tumors receiving targeted therapies have a higher risk of viral infections when compared to children receiving conventional chemotherapy or the general population, and life-threatening infections can occur. Fast detection and upfront treatment are paramount to prevent life-threatening infections in immunocompromised children suffering from brain tumors receiving targeted therapies.

HCV hotline facilitates Hepatitis C elimination during the COVID-19 pandemic.

The COVID-19 pandemic necessitates healthcare restrictions that also affected ongoing hepatitis C virus (HCV) elimination efforts. We assessed the value of a physician-operated HCV hotline on treatment and cure rates throughout the pandemic. All HCV patients undergoing HCV therapy at the Vienna General Hospital from 2019 to 2021 were included. An HCV hotline was established in 2019 and provided services including phone calls, text messages and voicemails. Patients were stratified by date of HCV therapy: 2019 (pre-COVID) vs. 2020/2021 (during-COVID) and use of the HCV hotline: users vs. non-users. Overall, 220 patients were included (pre-COVID: n = 91 vs. during-COVID: n = 129). The prevalence of intravenous drug use (60.5%) and alcohol abuse (24.8%) was high during COVID. During COVID, the number of DAA treatment starts declined by 24.2% (n = 69) in 2020 and by 34.1% (n = 60) in 2021 vs. pre-COVID (n = 91, 100%). Significantly more patients used the HCV hotline during-COVID (95.3%) vs. pre-COVID (65.9%; p < .001). Sustained virologic response (SVR) was 84.6% pre-COVID and 86.0% during-COVID. HCV hotline users achieved higher SVR rates during-COVID (88.2% vs. 33.3%, p = .004), but also pre-COVID (96.7% vs. 61.3%, p < .001) compared with non-users. Considering only patients with completed DAA treatments, SVR rates remained similarly high during-COVID (96.9%) versus pre-COVID (98.1%). HCV treatment initiations decreased during-COVID but importantly, nearly all DAA-treated HCV patients used the HCV hotline during the COVID pandemic. Overall, the SVR rate remained at 88.2% during COVID and was particularly high in HCV phone users-most likely due to facilitation of adherence.

Age-adjusted mortality and predictive value of liver chemistries in a Viennese cohort of COVID-19 patients.

BACKGROUND AND AIMS: The coronavirus disease of 2019 (COVID-19) causes considerable mortality worldwide. We aimed to investigate the frequency and predictive role of abnormal liver chemistries in different age groups. METHODS: Patients with positive severe acute respiratory distress syndrome-coronavirus-2 (SARS-CoV-2) polymerase chain reaction (PCR) test between 03/2020-07/2021 at the Vienna General Hospital were included. Patients were stratified for age: 18-39 vs. 40-69 vs. ≥70 years (y). Aspartate aminotransferase (AST), alanine-aminotransferase (ALT), alkaline phosphatase (ALP), gamma-glutamyl transferase (GGT) and total bilirubin (BIL) were recorded. RESULTS: 900 patients (18-39 years: 32.2%, 40-69 years: 39.7%, ≥70 years: 28.1%) were included. Number of comorbidities, median D-dimer and C-reactive protein increased with age. During COVID-19, AST/ALT and ALP/GGT levels significantly increased. Elevated hepatocellular transaminases (AST/ALT) and cholestasis parameters (ALP/GGT/BIL) were observed in 40.3% (n  = 262/650) and 45.0% (n  = 287/638) of patients respectively. Liver-related mortality was highest among patients with pre-existing decompensated liver disease (28.6%, p < .001). 1.7% of patients without pre-existing liver disease died of liver-related causes, that is consequences of hepatic dysfunction or acute liver failure. Importantly, COVID-19-associated liver injury (16.0%, p < .001), abnormal liver chemistries and liver-related mortality (6.5%, p < .001) were most frequent among 40-69 years old patients. Elevated AST and BIL after the first positive SARS-CoV-2 PCR independently predicted mortality in the overall cohort and in 40-69 years old patients. CONCLUSIONS: Almost half of the COVID-19 patients exhibit abnormal hepatocellular and cholestasis-related liver chemistries with 40-69 years old patients being at particularly high risk for COVID-19-related liver injury and liver-related mortality. Elevated AST and BIL after SARS-CoV-2 infection are independent predictors of mortality, especially in patients aged 40-69 years.

Results of a SARS-CoV-2 virus genome detection external quality assessment round focusing on sensitivity of assays and pooling of samples.

OBJECTIVES: Results of earlier external quality assessment (EQA) rounds suggested remarkable differences in the sensitivity of SARS-CoV PCR assays. Although the test systems are intended to detect SARS-CoV-2 in individual samples, screening is often applied to sample pools to increase efficiency and decrease costs. However, it is unknown to what extent these tests actually meet the manufacturer's specifications for sensitivity and how they perform when testing sample pools. METHODS: The sensitivity of assays in routine use was evaluated with a panel of positive samples in a round of a SARS-CoV-2 virus genome detection EQA scheme. The panel consisted of samples at or near the lower limit of detection ("weakly positive"). Laboratories that routinely test sample pools were asked to also analyze the pooled EQA samples according to their usual pool size and dilution method. RESULTS: All participants could detect a highly positive patient-derived sample (>106 copies/mL). Most (96%) of the test systems could detect at least 1,000 copies/mL, meeting the minimum acceptable benchmark, and many (94%) detected the vRNA in a sample with lower concentration (500 copies/mL). The false negative ratio increased to 16 and 26% for samples with 100 and 50 copies/mL, respectively. CONCLUSIONS: The performance of most assays met or exceeded their specification on sensitivity. If assays are to be used to analyze sample pools, the sensitivity of the assay and the number of pooled samples must be balanced.

Adult Respiratory Syncytial Virus Infection and Hypoxic Cardiac Arrest-Coexistent or Causal? A Hypothesis-Generating Case Report.

Respiratory syncytial virus (RSV) is a well-known pathogen in paediatric patients. However, it also causes substantial morbidity and mortality in adults, posing a major healthcare problem. We present a patient with chronic pulmonary conditions and an acute RSV infection, thus leading to cardiac arrest (CA). We speculate that RSV as the causative agent for CA should be considered in post-resuscitation care. From a wider public health perspective, immuno-naivety for RSV caused by the coronavirus disease 2019 pandemic may induce a severe rise in cases, morbidity, and mortality in the future.

Epidemiological trends of HBV and HDV coinfection among Viennese HIV+ patients.

BACKGROUND AND AIMS: Despite vaccination recommendations, hepatitis B (HBV) and D (HDV) coinfections are common in HIV+individuals. METHODS: HBV immunization status (anti-HBs) as well as HBV (HBsAg/HBV-DNA) and HDV (anti-HDV) coinfection rates were assessed in 1870 HIV+individuals at HIV diagnosis (baseline, BL) and last follow-up (FU). RESULTS: Sixty-eight (3.6%) HIV patients were never tested for HBV. At BL, 89/1802 (4.9%) HIV patients were HBV coinfected. Four hundred and fifteen (23.0%) showed virological HBV clearance [HBsAg(-)/anti-HBc(+)/anti-HBs(+)] and 210 (11.7%) presented with anti-HBc(+) only. Seven hundred and ten (39.4%) were HBV naïve [HBsAg(-)/anti-HBs(-)/anti-HBc(-)/HBV-DNA(-)], but only 378 (21.0%) received vaccinations with detectable anti-HBs(+) titres. Among the 89 HBV/HIV-coinfected patients, only 52 (58.4%) were tested for HDV: 11/49 (22.4%) had anti-HDV(+) and 3/12 (25.0%) showed HDV-RNA viraemia. During a median FU of 6.5 (IQR 7.2) years, 44 (4.6%) of the 953 retested BL HBV-negative patients acquired new HBV infection (including 15/304, 4.9% of vaccinated patients). Of the 89 patients, 22 (24.7%) patients cleared their HBsAg, resulting in 60/1625 (3.7%) HIV/HBV individuals at FU: 34 (56.7%) showed HBV-DNA suppression and 15 (25.0%) were HBV viraemic, while 12/89 (13.5%) remained without a FU test. Vaccinations induced anti-HBs(+) in 137 of the retested 649 (21.1%) BL HBV-naïve patients. CONCLUSION: HBV testing is well established among Viennese HIV+patients with HBV coinfection rates around 4%-5%. HBV vaccinations are insufficiently implemented since anti-HBs titres were detected in only 21.1% of HBV-naive HIV(+) patients and new HBV infections occurred in previously vaccinated patients. HDV testing is not systematically performed despite up to 25% of HIV/HBV patients may show HDV coinfection.

Recent outbreaks of severe hepatitis A virus infections in Vienna.

To explore the epidemiology and clinical course of hepatitis A virus (HAV) infections at the Vienna General Hospital. We retrospectively identified patients who were tested positive for HAV-IgM at the Vienna General Hospital form Q1/2008 to Q3/2018. Our definition of severe HAV infection was AST and/or ALT > 5 × above the upper limit of normal (ULN); and liver dysfunction as (i) hepatic encephalopathy or ammonia > 100 µmol/L, (ii) coagulopathy with INR > 1.5, or (iii) jaundice with bilirubin > 5 mg/dL. A total of 578 HAV-IgM (+) were identified, including 31 (5.4%) and 38 (6.6%) without and with liver dysfunction, respectively. A proportional increase in severe HAV cases with and without liver dysfunction occurred in 2016/2017 with (21.5% (vs. 8.0% in the years before; p < 0.001). Thirty-seven (53.6%) patients with severe HAV were hospitalized, 6 (9%) required ICU support, and one patient received liver transplantation within 30 days. Patients with severe HAV and liver dysfunction were more often male (60.5 vs. 43.1%, p = 0.055) and younger (31.5 vs. 63 years, p < 0.001) as compared with other HAV-IgM (+) cases. The observed increase of severe HAV infections in Vienna in 2017 among young males, coincided with a multinational HAV outbreak among MSM. Our data suggests a higher likelihood of severe courses of hepatitis A in MSM. Vaccination against HAV should be recommended for risk groups.

Cytomegalovirus in urinary sediment in patients with acute kidney injury.

BACKGROUND: Immunosuppression in solid organ transplantation is associated with frequent infections. Renal allograft recipients are susceptible to opportunistic infections and can acquire human cytomegalovirus (HCMV) infections even within the allograft. There, HCMV can be found in both the glomerulus and tubular cells, but is mostly restricted to specific and circumscribed sites. Therefore, not all organ infections are identifiable by immunohistology for HCMV proteins in fine needle core biopsies. Thus, we performed a urinalysis study to search for HCMV-specific RNA transcripts in the urine sediment of patients with acute kidney injury. METHODS: Urinary sediment of 90 patients with acute kidney injury (AKI), including 48 renal transplant recipients (RTX) and 42 non-transplant recipients (nRTX), was collected from morning urine for RNA extraction and reverse transcription. The copy number of HCMV transcripts was evaluated using a UL132 HCMV-specific probe set and by real-time quantitative polymerase chain reaction (RT-qPCR). RESULTS: Of the 48 RTX patients, ten showed HCMV copies in their urine sediment cells. Within this group, three recipients had negative HCMV serology and received an allograft from an HCMV-seropositive donor. In addition, all three RTX patients on a belatacept-based immunosuppressive regimen had HCMV transcripts in their urine. Of the 42 nRTX patients, only two had detectable HCMV transcripts in urine sediment cells and both were under immunosuppression. CONCLUSIONS: Ten immunosuppressed renal allograft recipients and two immunosuppressed non-transplant patients with AKI showed HCMV copies in urine sediment. Thus, HCMV positivity in urinary sediment appears to be associated with immunosuppression. This study describes a novel noninvasive method for detection of HCMV in urinary sediment. Whether all HCMV infections can be detected or only those with viral replication warrants further investigation.

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.

Side-by-Side Comparison of Three Fully Automated SARS-CoV-2 Antibody Assays with a Focus on Specificity.

BACKGROUND: In the context of the COVID-19 pandemic, numerous new serological test systems for the detection of anti-SARS-CoV-2 antibodies rapidly have become available. However, the clinical performance of many of these is still insufficiently described. Therefore, we compared 3 commercial CE-marked, SARS-CoV-2 antibody assays side by side. METHODS: We included a total of 1154 specimens from pre-COVID-19 times and 65 samples from COVID-19 patients (≥14 days after symptom onset) to evaluate the test performance of SARS-CoV-2 serological assays by Abbott, Roche, and DiaSorin. RESULTS: All 3 assays presented with high specificities: 99.2% (98.6-99.7) for Abbott, 99.7% (99.2-100.0) for Roche, and 98.3% (97.3-98.9) for DiaSorin. In contrast to the manufacturers' specifications, sensitivities only ranged from 83.1% to 89.2%. Although the 3 methods were in good agreement (Cohen's Kappa 0.71-0.87), McNemar tests revealed significant differences between results obtained from Roche and DiaSorin. However, at low seroprevalences, the minor differences in specificity resulted in profound discrepancies of positive predictive values at 1% seroprevalence: 52.3% (36.2-67.9), 77.6% (52.8-91.5), and 32.6% (23.6-43.1) for Abbott, Roche, and DiaSorin, respectively. CONCLUSION: We found diagnostically relevant differences in specificities for the anti-SARS-CoV-2 antibody assays by Abbott, Roche, and DiaSorin that have a significant impact on the positive predictive values of these tests.

Longitudinal assessment of the CXCL10 blood and urine concentration in kidney transplant recipients with BK polyomavirus replication-a retrospective study.

In kidney transplant recipients (KTRs), BK polyomavirus (BKPyV) replication may progress to polyomavirus-associated nephropathy (PVAN). In this retrospective study, we assessed the chemokine CXCL10 in urine and blood samples consecutively acquired from 85 KTRs who displayed different stages of BKPyV replication and eventually developed PVAN. In parallel to progression toward PVAN, CXCL10 gradually increased in blood and urine, from baseline (prior to virus replication) to BKPyV DNAuria (median increase in blood: 42.15 pg/ml, P = 0.0156), from mere DNAuria to low- and high-level BKPyV DNAemia (median increase: 52.60 and 87.26 pg/ml, P = 0.0010 and P = 0.0002, respectively) and peaked with histologically confirmed PVAN (median increase: 145.00 pg/ml, P < 0.0001). CXCL10 blood and urine levels significantly differed among KTRs with respect to simultaneous presence of human cytomegalovirus (P < 0.001) as well as in relation to the clinical severity of respective BKPyV DNAemia episodes (P = 0.0195). CXCL-10 concentrations were particularly lower in KTRs in whom BKPyV DNAemia remained without clinical evidence for PVAN, as compared to individuals who displayed high decoy cell levels, decreased renal function and/or biopsy-proven PVAN (median blood concentration: 266.97 vs. 426.42 pg/ml, P = 0.0282). In conclusion, in KTRs CXCL10 rises in parallel to BKPyV replication and correlates with the gradual development of PVAN.

Immunoadsorption Combined with Membrane Filtration to Counteract Early Treatment-Refractory Antibody-Mediated Rejection.

INTRODUCTION: Immunoadsorption (IA) represents a therapeutic option for acute antibody-mediated rejection (ABMR) after kidney transplantation. The addition of membrane filtration (MF) to enhance elimination of macromolecular components that potentially contribute to rejection, such as key complement component C1q and alloreactive IgM, may be an effective strategy to further improve its therapeutic efficiency. RESULTS: Here we present 4 consecutive patients with episodes of HLA donor-specific antibody-positive ABMR nonresponsive to cycles of 6-16 sessions of IA treatment. Rejection episodes were characterized by severe microvascular injury (high-grade microcirculation inflammation and/or signs of thrombotic microangiopathy) and evidence of intense complement activation in peritubular capillaries (diffuse C4d-positivity). IA combined with MF led to substantial morphologic improvement (follow-up biopsies: g + ptc and C4d scores ≤1) and stabilization of allograft function. CONCLUSIONS: Our findings provide evidence for an effect of combination of IA + MF in refractory early acute/active ABMR in kidney transplant recipients.

Torque Teno Virus for Risk Stratification of Acute Biopsy-Proven Alloreactivity in Kidney Transplant Recipients.

BACKGROUND: Drug-induced immunosuppression in kidney transplant recipients is crucial to prevent allograft rejection, but increases risk for infectious disease. Immunologic monitoring to tailor immunosuppressive drugs might prevent alloreactivity and adverse effects simultaneously. The apathogenic torque teno virus (TTV) reflects the immunocompetence of its host and might act as a potential candidate for a holistic monitoring. METHODS: We screened all 1010 consecutive patients from the prospective Vienna Kidney Transplant Cohort Study for availability of allograft biopsies and adequately stored sera for TTV quantification by polymerase chain reaction. RESULTS: Patients with acute biopsy-proven alloreactivity according to the Banff classification (n = 33) showed lower levels of TTV in the peripheral blood compared to patients without rejection (n = 80) at a median of 43 days before the biopsy. The risk for alloreactivity decreased by 10% per log level of TTV copies/mL (risk ratio, .90 [95% confidence interval, .84-.97]; P = .005). TTV levels >1 × 106 copies/mL exclude rejection with a sensitivity of 94%. Multivariable generalized linear modeling suggests an independent association between TTV level and alloreactivity. CONCLUSIONS: TTV is a prospective biomarker for risk stratification of acute biopsy-proven alloreactivity in kidney transplant recipients and might be a potential tool to tailor immunosuppressive drug therapy.

High seroprevalence of anti-Hepatitis E antibodies in Austrian patients with autoimmune hepatitis.

BACKGROUND & AIMS: Increasing numbers of autochthonous hepatitis E virus infections have been reported in Europe. Chronic infections have been shown in immune-compromised patients after solid organ transplantation. Hepatitis E virus might be a possible trigger for autoimmune hepatitis and might cause disease flares or relapses in the further course of disease. Aim of this study was to investigate the presence of hepatitis E virus antibodies and hepatitis E virus RNA, and to analyse their impact on immunosuppressive treatment in patients with autoimmune hepatitis. METHODS: Sera from 92 autoimmune hepatitis patients (73/79.3% female, age: 42.2 ± 16.3 years [mean ± SD]) were tested. Patients were scored according to the simplified and revised scoring systems of the International Autoimmune Hepatitis Group. The prevalence of anti- hepatitis E virus antibodies (Beijing Wantai Biological Pharmacy Enterprises Co., Ltd, Beijing, China) and hepatitis E virus RNA was determined. RESULTS: 19/20.7% autoimmune hepatitis patients tested positive for hepatitis E virus-IgG, which was higher than in previous reports of healthy Austrian individuals (12.4%, P = 0.031); hepatitis E virus RNA was not detectable in any patient. Anti-hepatitis E virus positive patients were older (49.5 ± 9.5 vs 40.4 ± 17.2 years [mean ± SD], P = 0.033) but did not differ in laboratory findings at diagnosis (AST: 14.6 [1.3-70.6] vs 9.5 [0.7-62.7] × ULN [median/range]; P = 0.387, alanine aminotransferase: 18.3 [1.6-62.7] vs. 12.9 [0.8-62.6] × ULN; P = 0.511; IgG: 1.4 [1.0-2.5] vs 1.3 [0.6-3.8] g/dL × ULN; P = 0.278) nor in alanine aminotransferase levels after six months (0.7 [0.5-2.4] vs 1.0 U/L × ULN [0.1-22.4]; P = 0.077). CONCLUSIONS: No chronic hepatitis E virus infection was observed in our cohort of autoimmune hepatitis patients. Anti- hepatitis E virus-IgG positive patients were older and the seroprevalence was nearly twice as high as reported previously in healthy Austrian individuals, suggesting that hepatitis E virus-infection might act as trigger for the development of autoimmune hepatitis.