Virus Viremia Research Articles

Intravenous Immunoglobulin G (IVIg) and Ganciclovir or Valganciclovir for the Treatment of Ebstein Barr Virus (EBV) Viremia and Prevention of Post-Transplant Lymphoproliferative Disease (PTLD) in Pediatric Heart Transplant Recipients

<h3>Purpose</h3> EBV viremia can progress to a potentially fatal PTLD. Data on the use of IVIg and antiviral agents such as ganciclovir or valganciclovir for the treatment (Rx) of this condition are limited. This study retrospectively evaluated the efficacy of IVIg with the combination of antiviral therapy in reducing EBV viral load and preventing PTLD in pediatric heart transplant patients (pts). <h3>Methods</h3> All pts transplanted since December 2007 were included. IVIg plus antiviral was implemented as empiric Rx in clinically significant EBV viremia polymerase chain reaction (PCR) > 100,000 copies/mL). Pts who were refractory to this tx and had EBV PCR > 250,000 copies/mL received rituximab. The pts were divided into two groups, those that received empiric Rx and those that did not. Pts who did not receive empiric Rx never had EBV viremia or only had EBV viremia at the time of PTLD diagnosis. The change from baseline EBV PCR values over time was evaluated, and the actuarial freedom from PTLD was compared between the two groups. <h3>Results</h3> There were 88 pts in the non-Rx group and 18 pts in the empiric Rx group. In the empiric Rx group, 9 pts received rituximab. The median time of initial EBV viremia incident was 27.7 months after transplantation. Pts on empiric Rx experienced an initial decrease in EBV viral load (p = 0.009) and maintain an acceptable EBV PCR level compared to baseline. None of the treated pts, including those who were refractory, developed PTLD. In the non-Rx group, 5 pts developed PTLD (p = 0.272). <h3>Conclusion</h3> A clinically important finding was observed when EBV viremia was identified with steps implemented to minimize viral load by utilizing IVIg, antivirals, and rituximab. It appeared that PTLD may be avoided though our data did not yet reach statistical significance. A large prospective clinical trial is indicated to support the use of this empiric Rx for the prevention of PTLD.

Optimal Active Anti-Thymocyte Globulin Exposure Associated with Minimum Risk of Virus Reactivation and Comparable Acute Graft-Versus-Host Disease Under Adult Myeloablative Haploidentical Peripheral Blood Stem Cell Transplantation

Anti-thymocyte globulin (ATG) is often included in the conditioning regimen to prevent graft-versus-host disease (GVHD) in allogeneic hematopoietic cell transplantation (allo-HCT). However, the risk of virus reactivation increases significantly. We conducted a single-center prospective study to identify the optimal ATG exposure that ensures engraftment, effectively prevents acute GVHD, and reduces the risk of virus reactivation without increasing relapse of malignant diseases in haploidentical peripheral blood stem cell transplantation (haplo-PBSCT). From September 2018 to June 2020, 106 patients (median age, 32 years) with malignant hematological diseases who received haplo-PBSCT for the first time were enrolled. All patients received 10 mg/kg rabbit ATG (thymoglobulin) divided for 4 days (days –5 to –2). Pre-transplant, post-transplant, and total areas under the concentration–time curve (AUCs) of active ATG were calculated. Total AUC of active ATG was shown to be the best predictor for virus reactivation and acute GVHD of grades II to IV or grades III and IV. The optimal total AUC range of active ATG was 100 to 148.5 UE/mL/day. The median time was 14 versus 13 days (P = .184) for neutrophil engraftment and 13 versus 13 days (P = .263) for platelet engraftment in the optimal and non-optimal AUC groups, respectively. The optimal AUC group showed a lower cumulative incidence of cytomegalovirus (CMV) reactivation and persistent CMV viremia than the non-optimal AUC group: 60.6% (95% confidence interval [CI], 48.3%–73.1%) versus 77.1% (95% CI, 64.5%–87.7%; P = .016) and 31.5% (95% CI, 21.2%–45.3%) versus 56.3% (95% CI, 42.9%–70.4%; P = .007), respectively. The cumulative incidence of persistent Epstein–Barr virus (EBV) viremia in the optimal AUC group was significantly lower than the non-optimal total AUC group: 33.1% (95% CI, 22.5%–46.8%) versus 52.6% (95% CI, 39.3%–67.2%; P = .048). However, there was no difference in EBV reactivation (P = .752). Similar outcomes were observed for grade II to IV and grade III and IV acute GVHD between the two groups: 48.6% (95% CI, 36.8%–62.0%) versus 37.0% (95% CI, 24.8%–52.5%; P = .113) and 10.4% (95% CI, 4.8%–21.7%) versus 4.2% (95% CI, 1.0%–15.6%; P = .234, respectively. Relapse, non-relapse mortality, and disease-free survival demonstrated no significant differences between the two groups. But, overall survival at 2 years tended to increase in the optimal AUC group: 75.7% (95% CI, 62.4%–84.8%) versus 57.8% (95% CI, 42.4%–70.4%; P = .061). These data support an optimal active ATG exposure of 110 to 148.5 UE/mL/day in haplo-PBSCT. Individualized dosing of ATG in allo-HCT might reduce the risk of virus reactivation and effectively prevent acute GVHD simultaneously.

Heterologous Challenge with PRRSV-1 MLV in Pregnant Vaccinated Gilts: Potential Risk on Health and Immunity of Piglets.

Simple SummaryModified live virus (MLV) vaccines are considered as the key component to control the Porcine Reproductive and Respiratory Syndrome Virus (PRRSV). The majority of pig farms apply the ‘mass’ vaccination strategy in breeding female animals. However, this PRRS MLV vaccination protocol involves the risk of inoculation of sows in the last stage of gestation, resulting in possible infection of the fetus as the virus can efficiently cross the placenta during the last period of pregnancy. Thus, we evaluated the ability of the vaccine virus to act as a pathogenic strain, to be transmitted to fetuses and to affect the health status of neonatal piglets. The results indicated that the study gilts transmitted the vaccine virus to their offspring, as well as that the PRRSV-infected piglets showed a poor clinical performance. Consequently, the pig farms that apply PRRS MLV vaccination in a routine blanket vaccination strategy must avoid inoculating pregnant gilts the last week before their parturition.The objective of the present study was to evaluate the potential risks of the four commercial PRRS-1 MLV vaccines in pregnant vaccinated gilts at the last stage of gestation under field conditions. The study was conducted at four pig farms, including 25 gilts from each farm (25 × 4 = 100 gilts), which were equally allocated to five different study groups. A PRRS-1 MLV vaccination was applied on the 100th day of their pregnancy with the different commercial vaccines that are available in the Greek market. The results indicated virus congenital infection and viremia in piglets (20/200 = 10% PRRSV infected piglets), and detection of PRRSV-specific antibodies (181/200 = 90.5% piglets found with PRRSV antibodies). The subsequent phylogenetic analyses revealed high percentages of similarity between the PRRSV-1 strain detected in infected litters and the PRRSV-1 vaccine strain to which the study gilts had been previously exposed to. Health status analyses of trial piglets resulted in differences between litters from vaccinated sows and litters from non-vaccinated sows at 110th day of gestation as regards the number of weak-born piglets, mummies, and piglets with splay-leg and/or respiratory symptoms. The current study’s results indicate several potential dangers of the PRRS MLV vaccination in late gestation.

Antiretroviral Refill Histories as a Predictor of Future Human Immunodeficiency Virus Viremia.

BackgroundThe use of adherence measures as markers for virologic failure (VF) has been studied. Yet, there is currently no single adherence metric recommended for VF. Antiretroviral prescription refill histories, for people living with human immunodeficiency virus (HIV), are readily accessible and can be easily quantified to an estimated adherence level.MethodsParticipants from a Midwestern US HIV clinic were retrospectively evaluated from 2018 to 2020. Refill histories (RH) and last HIV RNA for each participant were abstracted for each study year. RH were quantified as a percentage of days covered (PDC) and VF was defined as HIV RNA >200 copies/mL. PDC values were matched with subsequent year HIV RNA (matched pair). Sample t test were used to compare mean PDC level by viral suppression status and generalized estimating equations models were used to determine the predictability of PDC level for VF. An optimal PDC threshold for VF was determined using receiver operating characteristic curve analysis and Youden index.ResultsA total of 1056 participants contributed to 1923 matched pairs (PDC/HIV RNA); mean age was 48.3 years, 24% women, and 30.6% Black. PDC levels differed significantly based on dichotomized HIV RNA (2018–2019: >200: 40% [95% confidence interval {CI}, 33%–46%] vs ≤200: 85% [95% CI, 84%–87%], P < .0001; 2019–2020: >200: 45% [95% CI, 38%–51%] vs ≤200: 87% [95% CI, 86%–89%], P < .0001). Based on the Youden index value of 0.66 (sensitivity 0.77, specificity 0.89), the optimal PDC threshold predictive of VF was 52%.ConclusionsLower antiretroviral therapy (ART) adherence levels were predictive of future VF when PDC ≤52%.

Multiple early factors anticipate post-acute COVID-19 sequelae

SummaryPost-acute sequelae of COVID-19 (PASC) represent an emerging global crisis. However, quantifiable risk factors for PASC and their biological associations are poorly resolved. We executed a deep multi-omic, longitudinal investigation of 309 COVID-19 patients from initial diagnosis to convalescence (2–3 months later), integrated with clinical data and patient-reported symptoms. We resolved four PASC-anticipating risk factors at the time of initial COVID-19 diagnosis: type 2 diabetes, SARS-CoV-2 RNAemia, Epstein-Barr virus viremia, and specific auto-antibodies. In patients with gastrointestinal PASC, SARS-CoV-2-specific and CMV-specific CD8+ T cells exhibited unique dynamics during recovery from COVID-19. Analysis of symptom-associated immunological signatures revealed coordinated immunity polarization into four endotypes, exhibiting divergent acute severity and PASC. We find that immunological associations between PASC factors diminish over time, leading to distinct convalescent immune states. Detectability of most PASC factors at COVID-19 diagnosis emphasizes the importance of early disease measurements for understanding emergent chronic conditions and suggests PASC treatment strategies.

Hepatitis C re-treatment with first line direct acting antiviral drugs

Background and Aim: Sofosbuvir (S) in combination with daclatasvir [D], ledipasvir, or velpatasvir [V] cures hepatitis C virus (HCV) viremia in 90-95% patients. We report our experience of HCV retreatment using them in patients who had relapsed after their use.

Clinical Outcomes of B Cell Acute Lymphoblastic Leukemia Patients Treated with Haploidentical Stem Cells Combined with Umbilical Cord Blood Transplantation

Clinical outcomes of hematopoietic stem cell transplantation (HSCT) using a haploidentical stem cell graft and an unrelated umbilical cord blood unit (haplo-cord HSCT) for the treatment of B cell acute lymphoblastic leukemia (B-ALL) remain unclear. This study was conducted to explore the clinical outcomes of haplo-cord HSCT in patients with B-ALL. A total of 112 B-ALL patients who underwent haplo-cord HSCT and 64 B-ALL patients who underwent haploidentical HSCT (haplo-HSCT) at our center between 2010 and 2020 were retrospectively included in this study, and clinical outcomes and prognostic factors were further analyzed. Of the 112 haplo-cord HSCT recipients, 106 (94.6%) achieved complete haploidentical chimerism and 6 (5.4%) had mixed cord blood chimerism. No differences in neutrophil and platelet recovery or in the incidences of graft-versus-host disease, cytomegalovirus/Epstein-Barr virus viremia, bloodstream infection, or hemorrhagic cystitis were observed between the haplo-cord HSCT and haplo-HSCT groups. Compared with the haplo-HSCT group, the haplo-cord HSCT group had a higher absolute number of CD3+ cells (P=.029) and a lower ratio of CD3+CD4+ /CD3+CD8+ cells (P=.049) at 1 month post-transplantation. Moreover, the haplo-cord HSCT group had lower minimal residual disease (MRD) levels at 1 month (P=.020) and 100 days (P=.038) post-transplantation and a better 3-year prognosis (overall survival, P=.016; disease-free survival, P=.041; cumulative incidence of relapse [CIR], P=.016). The CIRs in patients with adverse genomic features (P=.040) or flow cytometry-based MRD (FCM-MRD) ≥1×10-4 (P=.033) were improved by haplo-cord HSCT. Multivariate analysis revealed that haplo-cord HSCT could independently improve the 3-year OS, DFS, and CIR of B-ALL patients (OS, P=.029; DFS, P=.024; CIR, P=.024). In addition, allo-HSCT at first complete remission was an independent parameter associated with 3-year OS for B-ALL patients (P=.014). An FCM-MRD ≥1×10-4 pre-HSCT could independently predict unfavorable 3-year DFS and CIR (DFS, P=.020; CIR, P=.036) in B-ALL patients. Our data suggest that the use of haplo-cord HSCT can independently improve survival in patients with B-ALL.

A case of VEXAS syndrome associated with EBV-associated hemophagocytic lymphohistiocytosis

Vacuoles, E1, X-linked, autoimmunity, somatic (VEXAS) syndrome is characterized by a pathogenic mutation in UBA1, which leads to protean complications including autoimmunity and myelodysplasia. A 56-year-old man with steroid-dependent, later steroid-refractory cutaneous polyarteritis nodosa and Sweet syndrome developed recurrent daily fever, macrocytic anemia, thrombocytopenia, acute hypoxic respiratory failure, and anasarca. He was eventually diagnosed with Epstein-Barr virus (EBV) viremia and hemophagocytic lymphohistiocytosis (HLH). He improved clinically with rituximab, ruxolitinib, and increased glucocorticoids before expiring from Pseudomonas sepsis. UBA1 exon 3 mutational analysis in myeloid enriched peripheral blood revealed a c.122T>C (p.Met41Thr) pathogenic variant, consistent with VEXAS syndrome. We describe the first case of EBV-associated HLH in a patient diagnosed with VEXAS syndrome. Early identification of this syndrome will be important in order to offer potential therapies before life-threatening complications arise.

Results of Hematopoietic Stem Cells Transplantation with Tcrαβ and CD19-Depletion from Matched Related Donors and Infusions of CD45RA Depleted Donor Lymphocytes in Pediatric Severe Aplastic Anemia

IntroductionHSCT from matched family donors results in most favorable outcomes among children with severe aplastic anemia (SAA). Despite overall success, morbidity, associated with acute and chronic graft-versus-host disease (GVHD) is not completely prevented with current standard of pharmacologic prophylaxis. Depletion of ab T cells from the graft prevents GVHD, and improves outcome of hematopoietic stem cell transplantation from haploidentical donors, while infusions of donor memory lymphocytes (mDLI) (CD45RA-depleted) are able to transfer pathogen-specific immunity without the risk of GVHD. We evaluated the outcomes of ab T cell depletion and add-back of intermediate-dose mDLI among the pediatric SAA recipients of matched related grafts.Materials and methodsA total of 16 children with SAA (8 female, 8 male, median age 10,9 y) underwent allogenic HSCT from matched family donors (MFD) between february 2015 and may 2021. For 15 (94%) pts it was the first allo HSCT, for 1 pts it was the second HSCT. TCR αβ+/CD19+ depletion of HSCT with CliniMACS technology was implemented in all cases. The median dose of CD34+ cells was 7,1 x10 6/kg (range 2,6-13), αβ T cells - 28x10 3/kg (range 5,6-184). All pts received an additional injection of memory T-cell (CD45RA-depleted) on day 0 at 1 million T cells per kg.All patients received cyclophosphamide at 100 mg/kg, fludarabine at 100 mg/m 2, rituximab 100mg/m 2 and serotherapy with either rabbit ATG at 5 mg/kg (n-2) or horse ATG at 100 mg/kg (n-14).Post-transplant GVHD prophylaxis included calcineurin (CNI)-based regimen and abatacept 10mg/kg on days -1, +7, +14 and +28. All pts received a graft from a 10/10 HLA-matched sibling. Median time of follow-up for survivors was 1,1 years (range: 0.14 - 6.38).ResultsPrimary engraftment was achieved in all evaluable patients (100%) with full donor chimerism, and the median time to neutrophil and platelet recovery was 11 (10-20) and 14 (11-20) days, respectively. One patient had aGVHD grade I, there were no incidence of grade II-IV aGVHD and TRM. Event-free and overall survival were 100%. CMV viremia was detected among two patients after a median of 40 (35-73) days after HSCT. No cases of ADV and Epstein-Barr virus (EBV) viremia and EBV disease were recorded. The median recovery of T cells on day+60 was 0,26 (0,04-0,9).Conclusionab T cell-depleted transplantation with intermediate dose memory T cell add-back definitively prevents GVHD and provides a platform for safe HSCT from matched family donors in patients with SAA. DisclosuresMaschan: Miltenyi Biotec: Speakers Bureau.

PI3Kδ coordinates transcriptional, chromatin, and metabolic changes to promote effector CD8+ Tcells at the expense of central memory.

SUMMARYPatients with activated phosphatidylinositol 3-kinase delta (PI3Kδ) syndrome (APDS) present with sinopulmonary infections, lymphadenopathy, and cytomegalvirus (CMV) and/or Epstein-Barr virus (EBV) viremia, yet why patients fail to clear certain chronic viral infections remains incompletely understood. Using patient samples and a mouse model (Pik3cdE1020K/+ mice), we demonstrate that, upon activation, Pik3cdE1020K/+ CD8+ T cells exhibit exaggerated features of effector populations both in vitro and after viral infection that are associated with increased Fas-mediated apoptosis due to sustained FoxO1 phosphorylation and Fasl derepression, enhanced mTORC1 and c-Myc signatures, metabolic perturbations, and an altered chromatin landscape. Conversely, Pik3cdE1020K/+ CD8+ cells fail to sustain expression of proteins critical for central memory, including TCF1. Strikingly, activated Pik3cdE1020K/+ CD8+ cells exhibit altered transcriptional and epigenetic circuits characterized by pronounced interleukin-2 (IL-2)/STAT5 signatures and heightened IL-2 responses that prevent differentiation to memory-like cells in IL-15. Our data position PI3Kδ as integrating multiple signaling nodes that promote CD8+ T cell effector differentiation, providing insight into phenotypes of patients with APDS.

Karaciğer nakli alıcılarında herpes simpleks virüs viremisinin tanısı, klinik görünümleri ve tedavi yönetimi

Aim: We aimed to evaluate the clinical variations, possible risk factors and results of diagnostic procedures in liver transplant (LT) recipients who suffered from Herpes Simplex Virus (HSV) viremia in the post-transplant period, despite Cytomegalovirus (CMV) prophylaxis.&#x0D; Material and methods: The data of 1100 LT recipients were evaluated retrospectively. HSV DNA RT-PCR detected in blood and vesicular fluid samples of the patients with active painful mucocutaneous vesicular lesions and patients with organ involvement who had biopsy and confirmed HSV viremia were included in the study. The 110 recipients diagnosed with HSV viremia were included.&#x0D; Results: In 110 recipients, total 130 HSV viremia episodes were observed over sixty months. HSV viremia rate was 11.8%. Of the 130 HSV episodes, 120 (92.3%) were mucocutaneous form of the disease. In 10 cases, there was a specific organ involvement. HSV-1 was detected in all of viremia episodes. Sixty-four (49.2%) episodes developed six months after the LT, 41 (31.5%) episodes developed between the 1st and 6th months after LT, and 25 (20.3%) episodes were observed within the first postoperative month. All episodes were treated successfully with different antiviral therapy modalities.&#x0D; Conclusion: Despite CMV prophylaxis performed, HSV viremia may be occurred as a wide range of clinical presentation in LT recipients. It can be seen at any time point after the LT. HSV DNA RT-PCR from serum samples may not be sufficient for diagnosis of viremia, therefore the analysis of the vesicular fluid or the biopsy from the organs may be necessary for supporting the diagnosis.

A Novel STK4 Mutation Impairs T Cell Immunity Through Dysregulation of Cytokine-Induced Adhesion and Chemotaxis Genes

PurposeHuman serine/threonine kinase 4 (STK4) deficiency is a rare, autosomal recessive genetic disorder leading to combined immunodeficiency; however, the extent to which immune signaling and host defense are impaired is unclear. We assessed the functional consequences of a novel, homozygous nonsense STK4 mutation (NM_006282.2:c.871C > T, p.Arg291*) identified in a pediatric patient by comparing his innate and adaptive cell-mediated and humoral immune responses with those of three heterozygous relatives and unrelated controls.MethodsThe genetic etiology was verified by whole genome and Sanger sequencing. STK4 gene and protein expression was measured by quantitative RT-PCR and immunoblotting, respectively. Cellular abnormalities were assessed by high-throughput RT-RCR, RNA-Seq, ELISA, and flow cytometry. Antibody responses were assessed by ELISA and phage immunoprecipitation-sequencing.ResultsThe patient exhibited partial loss of STK4 expression and complete loss of STK4 function combined with recurrent viral and bacterial infections, notably persistent Epstein–Barr virus viremia and pulmonary tuberculosis. Cellular and molecular analyses revealed abnormal fractions of T cell subsets, plasmacytoid dendritic cells, and NK cells. The transcriptional responses of the patient’s whole blood and PBMC samples indicated dysregulated interferon signaling, impaired T cell immunity, and increased T cell apoptosis as well as impaired regulation of cytokine-induced adhesion and leukocyte chemotaxis genes. Nonetheless, the patient had detectable vaccine-specific antibodies and IgG responses to various pathogens, consistent with a normal CD19 + B cell fraction, albeit with a distinctive antibody repertoire, largely driven by herpes virus antigens.ConclusionPatients with STK4 deficiency can exhibit broad impairment of immune function extending beyond lymphoid cells.

Epstein-Barr virus oral shedding and viremia and their association with oral hairy leukoplakia in HIV+ individuals.

To assess the oral shedding and viremia of Epstein-Barr virus (EBV) in HIV-positive patients and their relationship with oral hairy leukoplakia (OHL). A total of 94 HIV-positive patients were included in the study, in which blood and saliva samples were collected for EBV quantification. Data on gender, age, time of HIV seropositivity, combined antiretroviral therapy (cART), CD4+ T-cell counts, and HIV viral load were collected. OHL diagnosis was based on histopathological examination and EBV in situ hybridization. The EBV load in the 94 HIV-positive patients was higher in saliva than in blood (2.4 and 1.6, respectively), and there was a positive correlation between EBV oral shedding and viremia (p=0.001). Twenty (21.27%) patients had OHL and also a higher EBV load in saliva (mean log10 =3.11) compared to those who had no OHL (p=0.045). Presence of OHL was only associated with age (p=0.030). In HIV-positive patients, the presence of OHL was associated with EBV oral shedding but not with viremia, regardless of the amount of circulating CD4+ T cells.

Isolation and Genetic Characterization of Canine Parvovirus in a Malayan Tiger.

Naïve Felidae in the wild may harbor infectious viruses of importance due to cross-species transmission between the domesticated animals or human–wildlife contact. However, limited information is available on virus shedding or viremia in the captive wild felids, especially in Malaysia. Four infectious viruses of cat, feline herpesvirus (FHV), feline calicivirus (FCV), canine distemper virus (CDV), and canine parvovirus (CPV), were screened in leopards, feral cats, and tigers in Malaysia based on virus isolation in Crandell-Rees feline kidney (CRFK) cells, PCR/RT-PCR, and whole-genome sequencing analysis of the positive isolate. From a total of 36 sera collected, 11 samples showed three consecutive cytopathic effects in the cell culture and were subjected to PCR using specific primers for FHV, FCV, CDV, and CPV. Only one sample from a Malayan tiger was detected positive for CPV. The entire viral genome of CPV (UPM-CPV15/P. tigris jacksoni; GenBank Accession number MW380384) was amplified using the Sanger sequencing approach. Genome sequencing of the isolate revealed 99.13, 98.65, and 98.40% close similarity to CPV-31, CPV-d Cornell #320, and CPV-15 strains, respectively, and classified as CPV-2a. Time-scaled Bayesian Maximum Clade Credibility tree for the non-structural (NS) genes of CPV showed a close relationship to the isolates CPV-CN SD6_2014 and KSU7-SD_2004 from China and USA, respectively, while the capsid gene showed the same ancestor as the FPV-BJ04 strain from China. The higher evolution rate of the capsid protein (CP) (VP 1 and VP2) [1.649 × 10−5 (95% HPD: 7.626 × 10−3 to 7.440 × 10−3)] as compared to the NS gene [1.203 × 10−4 (95% HPD: 6.663 × 10−3 to 6.593 × 10−3)] was observed in the CPV from this study, and fairly higher than other parvovirus species from the Protoparvovirus genus. Genome sequencing of the isolated CPV from a Malayan tiger in the present study provides valuable information about the genomic characteristics of captive wild felids, which may add information on the presence of CPV in species other than dogs.

Incidence and Risk Factors of Epstein-Barr Virus Viremia in Patients Undergoing Haploidential Transplantation with Post Translant Cyclophosphamide

INTRODUCTIONHaploidentical stem cell transplants are increasingly performed for a wide variety of malignant and non-malignant hematological conditions. Epstein - Barr virus (EBV) viremia and subsequent development of Post-Transplant Lymphoproliferative Disorder (PTLD) are potential adverse sequelae of the transplantation process and associated immunosuppression. Traditionally, haploidentical transplants have been associated with increased risk of EBV reactivation and subsequent PTLD. This was largely due to graft versus host disease (GVHD) prophylaxis protocols using intense immunosuppression with either Ex-vivo T-cell depletion or in-vivo T- cell depletion with anti-thymocyte globulin (ATG) and Alemtuzumab. However, most haploidentical transplants in recent years have utilized post-transplant cyclophosphamide (PTCy) for GVHD prophylaxis. Rituximab has been used for preemptive treatment of EBV viremia/PTLD, but there is scarce data on its use in this setting, as well as the risk factors and outcomes of EBV viremia associated with haploidentical transplants with PTCy. RESULTSA total of 63 patients with hematological malignancies received haploidentical transplant at our institution from 2013 from 2016. Patient characteristics are summarized in Table 1.All patients received EBV monitoring using plasma viral copies once weekly starting 20 days post-transplant. EBV monitoring continued for 6 months after immunosuppression ended or when CD4 count >200. Among these 63 patients, 18 (28.5%) became EBV DNA positive upon follow-up. Per institutional protocol, EBV titer was confirmed by repeat testing when viral load was 1000 copies/mL and treatment with Rituximab was initiated if repeat titer was >1000 copies/ml.The median time to detection of EBV viremia from the time of transplant was 99 days (range: 20-277). The median peak level for the EBV reactivation cohort was 7650 viral copies /ml. The median time from detection of viremia to peak viremia was 1.5 days (range 0-253).8 of the 18 (44.4%) patients that developed EBV viremia required Rituximab due to rising or persistent EBV viremia. The median EBV level at initiation of therapy was 31,000 copies/ml for the 8 patients that received Rituximab treatment. EBV seronegativity was achieved in 6 patients (75%) with treatment at a median of 13.5 days (range 3-26). The median number of Rituximab cycles administered was 1.5 (range: 1-16). None of the patients in either cohort developed PTLD or other EBV associated diseases.A univariate analysis was performed comparing EBV reactivation cohort and no EBV reactivation cohort to look for risk factors predisposing to EBV reactivation (Table 1) There were no statistically significant differences seen in the variables studied other than patients not in complete remission at the time of transplant were statistically more likely to develop EBV viremia. 9 out of 18 patients (50%) that developed EBV viremia were not in complete remission at the time of transplant, whereas 11 out of the 45 patients (24.44 %) that did not develop EBV viremia were in an incomplete remission at the time of transplant (p value: 0.05) (Table 1).With a median follow up of469 days, there were a total of 22 deaths among the 45 (48.9 %) patients that had no viremia, and 8 deaths amongst the 18 (44.4 %) patients that had viremia (p value: 0.75). There was no statistically significant difference in graft versus host disease (GVHD) incidence (p value: 0.79) or overall survival (555 days for patients with EBV reactivation versus not reached for patients without EBV reactivation, p value: 0.45) between these two groups (p value: 0.79) CONCLUSIONSIn this retrospective study assessing risk factors and outcomes of EBV viremia in patients following haploidentical transplants, we observed a 28.5 percent incidence of EBV viremia. Rituximab was effective in preemptive treatment of EBV viremia. However, no cases of PTLD were observed, even in those patients with sustained elevation in EBV titers. It is unclear how to manage asymptomatic elevations in viral titers after allogeneic transplantation in patients who are otherwise at low risk for development of PTLD. Previous data suggests that even high levels of EBV viremia lacks specificity for prediction of PTLD in post-transplant setting. Given these results, the utility of routine monitoring of EBV viral load after haploidentical transplant should be questioned in those who have received PTCy. [Display omitted] DisclosuresLin:Jazz Pharmaceuticals: Consultancy. Ganguly:Amgen: Other: Advisory Board; Seattle Genetics: Speakers Bureau.

Identification of a T-bethi Quiescent Exhausted CD8 T Cell Subpopulation That Can Differentiate into TIM3+CX3CR1+ Effectors and Memory-like Cells.

Persistent Ag induces a dysfunctional CD8 T cell state known as "exhaustion" characterized by PD-1 expression. Nevertheless, exhausted CD8 T cells retain functionality through continued differentiation of progenitor into effector cells. However, it remains ill-defined how CD8 T cell effector responses are sustained in situ. In this study, we show using the mouse chronic lymphocytic choriomeningitis virus infection model that CX3CR1+ CD8 T cells contain a T-bet-dependent TIM3-PD-1lo subpopulation that is distinct from the TIM3+CX3CR1+PD-1+ proliferative effector subset. The TIM3-CX3CR1+ cells are quiescent and express a low but significant level of the transcription factor TCF-1, demonstrating similarity to TCF-1hi progenitor CD8 T cells. Furthermore, following the resolution of lymphocytic choriomeningitis virus viremia, a substantial proportion of TCF-1+ memory-like CD8 T cells show evidence of CX3CR1 expression during the chronic phase of the infection. Our results suggest a subset of the CX3CR1+ exhausted population demonstrates progenitor-like features that support the generation of the CX3CR1+ effector pool from the TCF-1hi progenitors and contribute to the memory-like pool following the resolution of viremia.

Antibody-dependent enhancement representing in vitro infective progeny virus titer correlates with the viremia level in dengue patients

Dengue virus (DENV) causes dengue fever (DF) and dengue hemorrhagic fever in humans. Some DF patients suddenly develop severe symptoms around the defervescent period. Although the pathogenic mechanism of the severe symptoms has not been fully elucidated, the viremia level in the early phase has been shown to correlate with the disease severity. One of the hypotheses is that a phenomenon called antibody-dependent enhancement (ADE) of infection leads to high level of viremia. To examine the plausibility of this hypothesis, we examined the relationship between in vitro ADE activity and in vivo viral load quantity in six patients with dengue diseases. Blood samples were collected at multiple time points between the acute and defervescent phases, and the balance between neutralizing and enhancing activities against the autologous and prototype viruses was examined. As the antibody levels against DENV were rapidly increased, ADE activity was decreased over time or partially maintained against some viruses at low serum dilution. In addition, positive correlations were observed between ADE activity representing in vitro progeny virus production and viremia levels in patient plasma samples. The measurement of ADE activity in dengue-seropositive samples may help to predict the level of viral load in the subsequent DENV infection.

TREATMENT AND OUTCOMES OF PATIENTS WITH POST‐TRANSPLANT LYMPHOPROLIFERATIVE DISORDER: A SINGLE CENTRE EXPERIENCE

Background: Post-transplant lymphoproliferative disorder (PTLD) is a potentially severe complication that takes place after solid (SOT) or allogeneic hematopoietic stem cell transplant (HSCT). To date, its treatment is not standardised, and choice of therapy depends on histology and clinical presentation. We report the results of a 10 years (yrs) single-centre retrospective study assessing presentation, treatment patterns and outcomes of patients with PTLD. Methods: Patients ≥18 yrs diagnosed with a PTLD between 2011 and 2020 were identified in our medical records database. Primary endpoints were 2 yrs progression-free survival (PFS), overall survival (OS), and relapse incidence (RI) estimated with Kaplan-Meier and comparison between HSCT and SOT group. Secondary endpoints were the overall response rate (ORR) and complete response rate (CRR) at the end of first line treatment. Exploratory univariate analysis for OS, PFS were investigated using Cox regression model. Results: A total of 38 patients were included. Patient's characteristics and treatment strategies are presented in Table 1. HCST patients present a significantly higher prevalence of early onset PTLD (90% in HCST group vs 0% in SOT group), positive EBER immunostaining (100% vs 22%) and detectable Epstein Bar Virus (EBV) viremia (100% vs 28%), higher LDH (95% vs 66%), IPI score 3-5 (50% vs 33%), with a remarkable higher use of single agent Rituximab as first line therapy in HSCT patients (65% vs 11%). 2 yrs PFS was 54% (95%CI 36-73%) for the entire cohort, 42% (95%CI 16-67%) for HSCT and 67% (95%CI 41-92) for SOT; p-value 0.23. 2 yrs OS was 53% (95%CI 41-66%) for the entire cohort, 42% (95% CI 16-67%) for HSCT and 65% (95% CI 39-91) for SOT; p-value 0.22. 2 yrs RI was 9% (95% CI: 0-21%) for the entire cohort, 0% for HSCT and 14% (95% CI 0-33%) for SOT; p-value 0.26. ORR and CRR were similar with 82% (75% for HSCT, 89% for SOT, p-value 0.41) at the end of first line treatment. High IPI score (3-5) demonstrated worse outcome for PFS (HR: 2.5, 95%CI 0.95-6.65, p-value 0.063) and OS (HR: 2.4, 95%CI 0.92-6.48, p-value 0.07). A total of 17 patients died during follow-up: 7 during first line treatment of PTLD complication and multiorgan failure (5 in the HSCT group, 2 in the SOT group; p-value 0.41); 2 following PTLD relapse after first CR (0 in the HSCT group, 2 in the SOT group; p-value 0.22). Conclusion: This study highlights the clinical and therapeutic heterogeneity of PTLD. We observe a worse 2 yrs PFS and OS in patients with high IPI score. CRR after first line treatment is almost 90% in the SOT group, with a 2 yrs OS of 53%, consistent with previous studies (Trappe et al, JCO 2017). The higher mortality observed in the HSCT group suggests that serious treatment-related toxicities remain main challenges in this fragile patient population. New tools to guide therapeutic approaches in PTLD patients are warranted. Keywords: Lymphoid Cancers - Other No conflicts of interests pertinent to the abstract.

Antiviral therapy after curative treatment of hepatocellular carcinoma in patients with chronic hepatitis B infection: Is tenofovir or entecavir preferred?

Antiviral therapy after curative treatment of hepatocellular carcinoma in patients with chronic hepatitis B infection: Is tenofovir or entecavir preferred?

Reduction in the population prevalence of hepatitis C virus viraemia among people who inject drugs associated with scale-up of direct-acting anti-viral therapy in community drug services: real-world data.

There has been little empirical evidence to show the 'real-world' impact of scaling-up direct-acting anti-viral (DAA) treatment among people who inject drugs (PWID) on hepatitis C virus (HCV) viraemia at a population level. We aimed to assess the population impact of rapid DAA scale-up to PWID delivered through community services-including drug treatment, pharmacies, needle exchanges and prisons-in the Tayside region of Scotland, compared with Greater Glasgow and Clyde (GGC) and the Rest of Scotland (RoS). Natural experiment, evaluated using data from national biennial surveys of PWID and national clinical data. Services providing injecting equipment (2010-18) and HCV treatment clinics (2017-18) across Scotland. A total of 12 492 PWID who completed a questionnaire and provided a blood spot (tested for HCV-antibodies and RNA); 4105 individuals who initiated HCV treatment. The intervention was rapid DAA scale-up among PWID, which occurred in Tayside. The comparator was GGC/RoS. Trends in HCV viraemia and uptake of HCV therapy over time; sustained viral response (SVR) rates to therapy by region and treatment setting. Uptake of HCV therapy (last year) among PWID between 2013-14 and 2017-18 increased from 15 to 43% in Tayside, 6 to 16% in GGC and 11 to 23% in RoS. Between 2010 and 2017-18, the prevalence of HCV viraemia (among antibody-positives) declined from 73 to 44% in Tayside, 67 to 58% in GGC and 64 to 55% in RoS. The decline in viraemia was greater in Tayside [2017-18 adjusted odds ratio (aOR)=0.47, 95% confidence interval (CI)=0.30-0.75, P = 0.001] than elsewhere in Scotland (2017-18 aOR=0.89, 95% CI=0.74-1.07, P = 0.220) relative to the baseline of 2013-14 in RoS (including GGC). Per-protocol SVR rates among PWID treated in community sites did not differ from those treated in hospital sites in Tayside (97.4 versus 100.0%, P = 0.099). Scale-up of direct-acting anti-viral treatment among people who inject drugs can be achieved through hepatitis C virus (HCV) testing and treatment in community drug services while maintaining high sustained viral response rates and, in the Tayside region of Scotland, has led to a substantial reduction in chronic HCV in the population.