Post-transplant Viral Infections Research Articles

Post-transplant malignancy: Focusing on virus-associated etiologies, pathogenesis, evidence-based management algorithms, present status of adoptive immunotherapy and future directions

Modern immunosuppression has led to a decrease in rejection rates and improved survival rates after solid organ transplantation. Increasing the potency of immunosuppression promotes post-transplant viral infections and associated cancers by impairing immune response against viruses and cancer immunoediting. This review reflects the magnitude, etiology and immunological characteristics of various virus-related post-transplant malignancies, emphasizing the need for future research. A multidisciplinary and strategic approach may serve best but overall literature evidence targeting it is sparse. However, the authors attempted to provide a more detailed update of the literature consensus for the prevention, diagnosis, management and surveillance of post-transplant viral infections and associated malignancies, with a focus on the current role of adoptive immunotherapy and the way forward. In order to achieve long-term patient and graft survival as well as superior post-transplant outcomes, collaborative research on holistic care of organ recipients is imperative.

Role of cytomegalovirus specific cell-mediated immunity in the monitoring of cytomegalovirus infection among living donor liver transplantation adult recipients: A single-center experience.

Cytomegalovirus (CMV) is one of the most common post-transplant viral infections causing significant morbidity and occasional mortality. Limited literature on the potential role of pre-transplant CMV-specific cell-mediated immunity (CMV-CMI) is available. This study aimed to evaluate the clinical utility of pre-transplant CMV-CMI monitoring in the occurrence of post-transplant CMV infection. This was a prospective, observational study where all adult CMV seropositive patients undergoing living donor liver transplantation at a tertiary care institute were enrolled. CMV-CMI was measured using QuantiFERON-CMV (Qiagen GmbH, Hilden, Germany) and interpreted as positive if the value was ≥0.2 IU/ml, 1-2 days prior to the transplant. Based on pre-transplant CMV-CMI, cases were classified into Group 1 (n=13, 43.3%) (positive) and Group 2 (n=17, 56.7%) (negative). CMV infection was defined as the detection of CMV-DNA > 2.7 log10 IU/ml in plasma specimens. The mean age was 43 years with male (n=29, 96.9%) predominance. Overall 40% of recipients developed post-transplant CMV infection, two (15.4%) in group 1 and 10 (58.8%) in group 2 (p-value=0.016). Recipients in group 2 had 87% higher odds (odds ratio 0.13, confidence interval [CI] 95) of developing post-transplant CMV infection compared to group 1. The overall median duration of occurrence of post-transplant CMV infection was 26 days with the median viral load being 2.8 log10 IU/ml. The treatment duration was 13 days in group 1 and 28 days in group 2 (p=0.003). Group 1 recipients showed rapid clearance of CMV-DNA within 7 days compared to group 2 in which it was 21 days (p=0.004, CI 95). Pre-transplant CMV-CMI may play a protective role against post-transplant CMV infection and can serve as an adjunct for pre-transplant risk stratification.

Generation of good manufacturing practice grade virus-specific T cells for the management of post-transplant CMV infections

Adoptive transfer of antigen-specific T cells has recently emerged as a successful strategy to treat viral infections following hematopoietic cell transplantation (HCT). Ex-vivo expanded donor-derived virus-specific T cells (VSTs) can be safe and effective, devoid of all the drug-related adverse effects. The study aimed to manufacture cGMP grade VSTs from healthy donors, characterize the VST product and demonstrate its safety and efficacy. Peripheral blood mononuclear cells (PBMCs) collected from six healthy donors were stimulated with pepmix that mimics the pp65 antigenic epitope of CMV and cultured for 14 days in G-Rex culture tubes. Post pepmix exposure and expansion the median CD3% was 98.8% (range:95.5% to 99.9%) while the median CD4% and CD8% were 49.1% (range:21.3% to 86.6%) and 43.9% (range:12.7% to 75.5%) respectively. The percentage of IFNγ+ cells was much higher among the CD8+ T cells (median - 18.47%; range 6.50% - 45.82%) when compared to CD4+ T cells (median − 2.74%; range 0.47% - 18.58%) and there was a switch from the CD45RA+ naive phenotype to CD45RA- effector memory phenotype in the 4 samples that achieved a >5 fold expansion. The VSTs were cytotoxic to the pepmix pulsed lymphoblasts (efficacy) while they did not induce cytolysis in the lymphoblasts that were not exposed to the pepmix (safety). This feasibility exercise helped us optimize the starting cell dose for the culture and clinical grade culture strategies, subset characterization and cytotoxicity assays. The approach could be applied to the clinical practice where virus-specific T cell infusions could be given for post-transplant viral infections.

Chances and risks of sodium-glucose cotransporter 2 inhibitors in solid organ transplantation: A review of literatures.

Solid organ transplantation offers life-saving treatment for patients with end-organ dysfunction. Patient survival and quality of life have improved over the past few decades as a result of pharmacological development, expansion of the donor pool, technological advances and standardization of practices related to transplantation. Still, transplantation is associated with cardiovascular complications, of which post-transplant diabetes mellitus (PTDM) is one of the most important. PTDM increases mortality, which is best documented in patients who have received kidney and heart transplants. PTDM results from traditional risk factors seen in patients with type 2 diabetes mellitus, but also from specific post-transplant risk factors such as metabolic side effects of immunosuppressive drugs, post-transplant viral infections and hypomagnesemia. Oral hypoglycaemic agents are the first choice for the treatment of type 2 diabetes mellitus in non-transplanted patients. However, the evidence on the safety and efficacy of oral hypoglycaemic agents in transplant recipients is limited. The favourable risk/benefit ratio, which is suggested by large-scale and long-term studies on new glucose-lowering drug classes such as glucagon-like peptide 1 receptor agonists and sodium-glucose cotransporter 2 inhibitors, makes studies warranted to assess the potential role of these agents in the management of PTDM.

Pre-Transplant Pulmonary Function Test Parameters of FEF50% (Forced expiratory flow at 50% of forced vital capacity) and RV (residual volume) in Combination Can Predict the Risk for Development of Lung Gvhd after Allogeneic Transplantation

BackgroundChronic graft vs host disease (GVHD) of the lung is a significant post-transplant complication that impacts patients' quality of life and overall survival. It manifests as bronchiolitis obliterans syndrome (BOS), an irreversible progressive airflow obstruction. Risk factors identified include busulfan, peripheral blood stem cell source, post-transplant viral infections, history of lung disease, and acute GVHD. Diagnosis involves changes in pulmonary function tests (PFTs), ruling out infection and presence of chronic GVHD in other organ systems. Without routine monitoring patients can present with moderate to severe symptoms. The predictive value of pre-transplant PFTs has not been clearly elucidated. In this retrospective study, we examined the role of pre-transplant PFT parameters with respect to the development of lung GVHD.MethodsPatients receiving allogeneic HCT at Princess Margaret Cancer Centre between 2004 to 2013 were included in the analysis. Pre-HCT PFT results were routinely obtained within 30 days prior to transplant. PFT parameters included % predicted FEV1, DLCO, TLC, RV, RV/TLC, FRC, FVC, FEV1/FVC, FEF50% and FEF75%. After transplant, PFT was repeated around day 120, then annually, or when clinically indicated.Our definition of lung GVHD required at least the first two of the 2005 NIH consensus criteria for the diagnosis of chronic lung GVHD: 1) FEV1/forced vital capacity ratio <0.7 and FEV1<75% predicted, 2) evidence of airway obstruction on high-resolution computed tomography or a residual volume on PFTs >120%, 3) absence of infection in the respiratory tract, and 4) histologic diagnosis of BOS or at least 1 other manifestation of chronic GVHD in an additional organ system.The primary endpoint was cumulative incidence (CI) of lung GVHD at 3 years. The cut-off values in each PFT parameter with respect to development of lung GVHD were calculated using binary recursive partitioning (rpart) method provided by rpart package using R. Pearson's correlation test was used to look for relationship among the PFT parameters. The parameters with cut-offs identified by rpart were analyzed by factor analysis with Varimax rotation method.For multivariable analysis, Fine-Gray proportional hazard regression with competing risks was applied. The clinical variables included in the model were busulfan, acute GVHD, and stem cell source (peripheral vs bone marrow). All statistical tests were performed using EZR and SPSS.ResultsA total of 605 patients with available PFTs were reviewed. The CI of lung GVHD at 3 years was 10.6% (7.9 - 13.7) with a median onset at 12.6 months (range of 1.7 - 55.8).Univariate analysis of each PFT parameter as a continuous variable did not show an impact on development of GVHD. With recursive partitioning, cut-offs were identified for DLCO (68%), FEF50% (39%), FRC (130%) and RV (93%).In Pearson's correlation analysis, DLCO and FEF50% did not have a significant association with the other PFT parameters selected from rpart, while RV was significantly associated with TGV (r= 0.65). In the factor analysis, based on the factor loading, FEF50% and RV were selected for multivariate analysis.Multivariate analysis showed that FEF50% < 39% and RV ≥ 93% were independent risk factors of lung GVHD development. The patients with pre-transplant FEF50 ≥ 39% had significantly less risk compared to those with < 39% (p=0.025; HR 0.389), and RV ≥ 93% showed a 2 fold higher risk than those < 93% (p=0.036, HR 2.63).A risk score model was created using the cut-offs from FEF50% and RV. For FEF50%, score 0 was assigned to ≥ 39% while score 1 was < 39%. For RV, score 0 was assigned to < 93%, while score 1 was ≥ 93%. A risk score was summed from the two parameters. Risk scores of 2 were classified as high risk, scores of 1 intermediate risk and score of 0 low risk. The 3 year CIs of lung GVHD were then compared according to the new risk score. The high risk group had an incidence of 33.5% (11.8 - 57.0%; n=28, 4.6%), intermediate risk 11.4% (8.3 - 15.2%; n=445, 73.6%) and low risk 3.0% (0.8 - 8.2%; n=132, 21.8%; p = 0.003; Figure).Conclusions1) Pre-transplant PFT parameters can predict the risk of lung GVHD development.2) FEF50% and RV were predictive of lung GVHD development independent from the other clinical risk factors acute GVHD, busulfan and stem cell source which were not confirmed in our cohort.3) A risk score model using pre-transplant FEF50% and RV may help in prediction of lung GVHD. [Display omitted] DisclosuresKim:Paladin: Consultancy; Novartis: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy.

Generation of Fungus-Specific T Lymphocytes for Use in HSCT Patients with Invasive Fungal Disease

Invasive fungal disease (IFD) is a major cause of morbidity and mortality in patients treated for haematological malignancies. The major determinants of outcome are the degree of the patient's immune incompetence, the fungal species and the presence of drug resistance in the infecting organism. As uncommon and drug resistant strains increase in frequency, effective alternative treatment strategies are needed to improve the dismal outcomes for IFD occurring after hematopoietic stem cell transplant (HSCT). Recent data provide strong evidence that a therapeutic benefit is seen using adoptive transfer of cryopreserved, partially human leukocyte antigen (HLA) matched 3rd party T-cells for post-transplant viral infections in HSCT recipients. We propose that a similar approach may be effective in IFDs.In the present study, we developed a method for rapid manufacture of large numbers of broadly reactive and highly specific antifungal T-cells starting with a stem cell product obtained from healthy donors as part of normal allogeneic transplant procedure. Water-soluble lysates of germinated conidia of Aspergillus and Candida species were used to stimulate 60.5 ± 21.7 x 106 mononuclear cells from the hematopoietic precursor cell (HPC) product. Reactive T-cells were selected using activation marker and magnetic bead isolation and expanded in culture with cytokines. After elution from the magnet, the enriched population measured 82.5±13.3 x103 cells of which 82.3±6.9% were CD4+ (n=6). All cultures were maintained for a total of 11 to 12 days, leading to 126.8±11.9x106 fungus-specific T cells, corresponding to approximately 1000 fold expansion within 12 days of culture initiation. At the end of culture greater than 97.3±0.9% of cells were CD3+, of which 91.7±1.2% were CD4+ cells and 3.6±0.7% were CD8+ cells.Responses against fungus were measured using cytokine flow cytometry after restimulation by specific fungal lysates. 59.4±0.9% of CD4+ cells were reactive against fungus-primed monocyte-derived dendritic cells (MoDCs). Production of the pro-inflammatory cytokines tumour necrosis factor (TNF)-α, interleukin (IL)-17 and interferon (IFN)-γ following challenge showed that the expanded T-cell populations had broad reactivity against Aspergillus fumigatus / flavus / terreus, Candida albicans / krusei, Fusarium oxysporum / solani and Leptosporum (Scedosporium) prolificans (Figure 1).We previously demonstrated that antifungal reactivity is mediated through HLA-DR and can occur through a single matching HLA-DR molecule. We calculated that in our HSCT population, donors with the seven highest frequency HLA-DR molecules (DRB1 1:01, 3:01, 4:01, 7:01, 11:01, 13:01 or 15:01) could be used to generate a bank of cryopreserved fungus-specific T lymphocytes to treat IFDs in HSCT recipients. Using a bank of this size, approximately 85% of HSCT recipients would have a fungus-specific T cell product in the bank matching at least 1 HLA-DR molecule. Increasing the bank to add donors with four additional HLA-DR types (DRB1 4:04, 11:04, 13:02 and 15:02) would increase the percentage of recipients with a banked product matching at least 1 of HLA-DR molecules to almost 95%.In conclusion, we have identified a GMP compliant method to rapidly manufacture fungal T-cell products to high number with specificity against a range of clinically relevant fungal pathogens including yeasts and moulds. Using these cells, we intend to construct a bank of fungus-specific T cells from donors with common HLA-DRB1 types and to test their efficacy in HSCT recipients with IFD. If effective in restoring immunity, adoptive cell therapy using 3rd party broadly reactive antifungal T-cells could be useful in improving outcomes for HSCT patients with IFDs.Figure 1: Cytokine expression profile of reactive antifungal T cells expanded with Aspergillus and Candida lysates following rechallenge with lysates of specific fungal pathogens or a mix of all lysates. Results are means of 6 experiments (±s.e.m) and shown as percentage of CD4+ T cells. [Display omitted] DisclosuresGottlieb:Indee: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees.

Design and evaluation of Taqman low density array for monitoring post-transplant viral infections.

The majority of transplant recipients undergo immunosuppressive treatment to prevent organ or tissue rejection. Consequently, they are more susceptible to infection agents including a number of viruses causing a significant morbidity and mortality. Only a limited number of viruses are currently tested for in transplant donors and recipients due to the cost and complexity. Taqman low density array (TLDA) may provide a suitable format to address more systematic testing approach. One hundred and one liver transplant recipient samples were retrospectively tested for 48 viral targets including two controls (bovine viral diarrhea virus and MS2) and two common viruses (TTV and HPgV), using a custom designed TLDA. Eight samples were analysed simultaneously on 384-well TLDA. Samples giving a signal considered positive/indeterminant were re-tested by different individual confirmatory assays. Infections with six previously untested for viruses-EBV, HPIV3, HuPuV9, KIV, HMPV and HPV-were detected in fourteen patients. Previously detected HCV infections were also confirmed. These infections did not seem have an effect on 5 year post-transplant outcome. 55 of 79 and 17 of 87 samples available for confirmatory assays were positive for TTV and HPgV, included for the evaluation of the TLDA performance. The custom viral TLDA can be successfully used for simultaneous detection of a range of post-transplant viral infections. To fully exploit its potential for monitoring and intervention, a whole blood testing should be applied in a prospective setting.

Use of unapproved or off-label drugs in Japan for the treatment of graft-versus-host disease and post-transplant viral infection.

Many drugs are used for unapproved indications in Japan for post hematopoietic stem cell transplant (HCT) complications. To investigate unapproved or off-label drug usage for graft-versus-host disease (GVHD) and virus infections after allogeneic HCT, we analyzed the data of Japanese HCT registry. Between 2006 and 2017, 39,941 adults and children received HCT for a variety of disease and their transplant data were captured in the registry. Among them, 14,687 and 8914 patients receiving treatment for acute and/or chronic GVHD, 24,828 patients with cytomegalovirus (CMV) infection or receiving therapies for CMV, and 4943 who received treatment for other viral infections were included in the analyses of off-label or unapproved drugs. For GVHD, mycophenolate mofetil was the most frequently used off-label drug, followed by beclomethasone, infliximab, and etanercept. For viral infections other than CMV, foscarnet was the most frequently used off-label drug. Cidofovir, which is not approved for use in Japan, was mainly used for adenovirus infection. This study demonstrated that numerous off-label and unapproved drugs have been used as key drugs for GVHD and post-transplant viral infection, and the real world date in the transplant registry may serve as an important asset to regulatory purposes.

New blood-borne virus infections among organ transplant recipients: An Australian data-linked cohort study examining donor transmissions and other HIV, hepatitis C and hepatitis B notifications, 2000-2015.

Blood-borne viral infections can complicate organ transplantation. Systematic monitoring to distinguish donor-transmitted infections from other new infections post transplant is challenging. Administrative health data can be informative. We aimed to quantify post-transplant viral infections, specifically those transmitted by donors and those reactivating or arising new in recipients. We linked transplant registries with administrative health data for all solid organ donor-recipient pairs in New South Wales, Australia, 2000-2015. All new recipient notifications of hepatitis B (HBV), C (HCV), or human immunodeficiency virus (HIV) after transplant were identified. Proven/probable donor transmissions within 12months of transplant were classified using an international algorithm. Of 2120 organ donors, there were 72 with a viral infection (9/72 active, 63/72 past). These 72 donors donated to 173 recipients, of whom 24/173 already had the same infection as their donor, and 149/173 did not, so were at risk of donor transmission. Among those at risk, 3/149 recipients had proven/probable viral transmissions (1 HCV, 2 HBV); none were unrecognized by donation services. There were no deaths from transmissions. There were no donor transmissions from donors without known blood-borne viruses. An additional 68 recipients had new virus notifications, of whom 2/68 died, due to HBV infection. This work confirms the safety of organ donation in an Australian cohort, with no unrecognized viral transmissions and most donors with viral infections not transmitting the virus. This may support targeted increases in donation from donors with viral infections. However, other new virus notifications post transplant were substantial and are preventable. Data linkage can enhance current biovigilance systems.

Availability of Multiple HLA-Matched Unrelated Donors for Allogeneic HCT Recipients

Introduction Success of allogeneic hematopoietic cell transplantation (HCT) is marred by adverse outcomes that include relapse of underlying malignancy, graft versus host disease (GVHD), and post-transplant viral infections. An ideal approach to minimize these adverse outcomes is to select an immunogentically ideal donor for each HCT recipient that not only has minimum allogeneic disparity with the recipient but also possesses an immunogenetic predisposition for strong anti-leukemic and anti-viral immune responses. In addition to human leukocyte antigen (HLA) compatibility, several other immunogenetic systems like killer Immunoglobulin-like receptors (KIRs) and variants in cytokine genes have shown promise in reducing HCT adverse outcomes. Their clinical utility in improving donor selection can only be assessed if for every patient there are more than one HLA matched donors available. Objectives In this study, a retrospective analysis of World Marrow Donor Association (WMDA) Search & Match Service search reports were performed for potential HCT recipients from a single center to assess how many allele level HLA matched donors were available for each recipient. Methods A retrospective, manual review of WMDA (formerly Bone Marrow Donors Worldwide) search reports for recipients seeking unrelated allogeneic HCT at Alberta Blood and Marrow Transplant Program in 2017 was performed (n=110). Patients were predominantly Caucasians. Allele-level match at HLA-A, HLA-B, HLA-C, and HLA-DRB1 was considered in determination of match level (n/8). The number of potential 8/8 and 7/8 matched unrelated donors were recorded. Donor prospects were categorized as ‘potential donor': total number of donors presented in WMDA search report; ‘high-probability donors': subset of donors known or highly-favored to match the patient; and ‘optimal donors': subset of high probability donors who were male and age ≤ 35. Results When 8/8 HLA matching was considered, more than one ‘potential', ‘high-probability' and ‘optimal' unrelated donors were available for 93%, 67% and 57% recipients respectively. When 7/8 HLA matching was considered, more than one ‘potential', ‘high-probability' and ‘optimal' unrelated donors were available for 100%, 98% and 94% recipients respectively. Conclusions Multiple HLA-matched unrelated donors are available for majority of HCT recipient of Caucasian ethnicity in BMDW search. These findings provide an ideal platform for prospective studies/clinical trials on unrelated HLA-matched HCTs to assess other non-HLA immunogenetic systems for finding an immunogenetically ideal donor (e.g., HLA matched and possessing favorable KIR or cytokine variants) for every HCT recipient.

Medical Management of Transplant Patients

Kidney transplant is the best form of renal replacement therapy for most end-stage kidney disease patients due to improved quality of life and superior patient survival compared to chronic maintenance dialysis. Long-term outcome of kidney allograft recipients depends on the longevity of the allograft and optimal management of their comorbidities such as cardiovascular disease risk factors. According to organ procurement and transplant data in the United States, 14.5% of the deceased donor kidney wait list comprised patients who failed their first allograft and were awaiting second kidney transplant. Optimal immunosuppression management is key to both short- and long-term outcomes of allograft transplant by preventing rejection while avoiding or minimizing risk of over immunosuppression such as with infections and neoplasia. Cardiovascular disease is the leading cause of mortality after kidney transplant. It accounts for approximately 50% of deaths in the post transplant period and 30% of deaths among patients with preserved renal allograft function. Hence, it is crucial to optimally manage cardiovascular risk factors such as hypertension and diabetes post transplant. In this chapter, we review medical management of kidney transplant recipients, including commonly used induction therapies, maintenance immunosuppressive agents, and posttransplant medical complications such as posttransplant diabetes mellitus, hypertension, cardiovascular disease, bone disease, and BK viral infection. This review contains 1 table and 47 references Key Words: kidney transplantation, immunosuppression, rejection, post transplant diabetes mellitus (PTDM), BK viral infection, calcineurin inhibitors,

Medical Management of Transplant Patients

Kidney transplant is the best form of renal replacement therapy for most end-stage kidney disease patients due to improved quality of life and superior patient survival compared to chronic maintenance dialysis. Long-term outcome of kidney allograft recipients depends on the longevity of the allograft and optimal management of their comorbidities such as cardiovascular disease risk factors. According to organ procurement and transplant data in the United States, 14.5% of the deceased donor kidney wait list comprised patients who failed their first allograft and were awaiting second kidney transplant. Optimal immunosuppression management is key to both short- and long-term outcomes of allograft transplant by preventing rejection while avoiding or minimizing risk of over immunosuppression such as with infections and neoplasia. Cardiovascular disease is the leading cause of mortality after kidney transplant. It accounts for approximately 50% of deaths in the post transplant period and 30% of deaths among patients with preserved renal allograft function. Hence, it is crucial to optimally manage cardiovascular risk factors such as hypertension and diabetes post transplant. In this chapter, we review medical management of kidney transplant recipients, including commonly used induction therapies, maintenance immunosuppressive agents, and posttransplant medical complications such as posttransplant diabetes mellitus, hypertension, cardiovascular disease, bone disease, and BK viral infection. This review contains 1 table and 47 references Key Words: kidney transplantation, immunosuppression, rejection, post transplant diabetes mellitus (PTDM), BK viral infection, calcineurin inhibitors,

The impact of alternative donor types on viral infections in pediatric hematopoietic stem cell transplantation.

Viral infections remain one of the most important complications following allogeneic HSCT. Few reports compare virus infection between different donor types in pediatric patients. We retrospectively analyzed viral infections and the outcome of one hundred and seventy‐one pediatric patients (median 7.38 years) who underwent allogeneic HSCT from matched related donor (MRD, n = 71), 10 of 10 HLA allele‐matched unrelated donors (MUD1; n = 29), 9 of 10 HLA allele‐matched unrelated donors (MUD2; n = 40), and haploidentical donors (n = 31). PCR screening for BK virus, adenovirus, Epstein‐Barr virus, parvovirus B19, human herpesvirus 6, and CMV were performed routinely weekly. Infections between 0‐30, 31‐100, and 101 days‐2 years were identified separately. BK virus and CMV reactivations were significantly low in MRD transplant patients (P = .046 and P < .0001, respectively), but incidences of all virus infections between MUD1, MUD2, and haplo‐HSCT were found statistically not different. The OS was found to be affected by having one or multiple virus infection (P = .04 and P = .0008). Despite antiviral prophylaxis and treatments, post‐transplant viral infections are associated with reduced overall survival. Haplo‐HSCT is comparable with MUD transplantation in the setting of viral infections. A larger study group and prospective studies are needed to confirm this observation.

De novo glomerular diseases after renal transplantation: How is it different from recurrent glomerular diseases?

The glomerular diseases after renal transplantation can occur de novo, i.e., with no relation to the native kidney disease, or more frequently occur as a recurrence of the original disease in the native kidney. There may not be any difference in clinical features and histological pattern between de novo glomerular disease and recurrence of original glomerular disease. However, structural alterations in transplanted kidney add to dilemma in diagnosis. These changes in architecture of histopathology can happen due to: (1) exposure to the immunosuppression specifically the calcineurin inhibitors (CNI); (2) in vascular and tubulointerstitial alterations as a result of antibody mediated or cell-mediated immunological onslaught; (3) post-transplant viral infections; (4) ischemia-reperfusion injury; and (5) hyperfiltration injury. The pathogenesis of the de novo glomerular diseases differs with each type. Stimulation of B-cell clones with subsequent production of the monoclonal IgG, particularly IgG3 subtype that has higher affinity to the negatively charged glomerular tissue, is suggested to be included in PGNMID pathogenesis. De novo membranous nephropathy can be seen after exposure to the cryptogenic podocyte antigens. The role of the toxic effects of CNI including tissue fibrosis and the hemodynamic alterations may be involved in the de novo FSGS pathophysiology. The well-known deleterious effects of HCV infection and its relation to MPGN disease are frequently reported. The new concepts have emerged that demonstrate the role of dysregulation of alternative complement pathway in evolution of MPGN that led to classifying into two subgroups, immune complex mediated MPGN and complement-mediated MPGN. The latter comprises of the dense deposit disease and the C3 GN disease. De novo C3 disease is rather rare. Prognosis of de novo diseases varies with each type and their management continues to be empirical to a large extent.

Post-transplant Viral Respiratory Infections in the Older Patient: Epidemiology, Diagnosis, and Management.

Organ and stem cell transplantation has been one of the greatest advances in modern medicine, and is the primary treatment modality for many end-stage diseases. As our population ages, so do the transplant recipients, and with that comes many new challenges. Respiratory viruses have been a large contributor to the mortality and morbidity of solid organ transplant (SOT) and hematopoietic stem cell transplant (HSCT) recipients. Respiratory viruses are generally a long-term complication of transplantation and primarily acquired in the community. With the emergence of molecular methods, newer respiratory viruses are being detected. Respiratory viruses appear to cause severe disease in the older transplant population. Influenza vaccine remains the mainstay of prevention in transplant recipients, although immunogenicity of current vaccines is suboptimal. Limited therapies are available for other respiratory viruses. The next decade will likely bring newer antivirals and vaccines to the forefront. Our goal is to provide the most up to date knowledge of respiratory viral infections in our aging transplant population.

16 - Early Post-Transplant Viral Infections and the Incidence of Acute and Chronic Noninfectious Pulmonary Complications Following Hematopoietic Stem Cell Transplantation (HSCT)

16 - Early Post-Transplant Viral Infections and the Incidence of Acute and Chronic Noninfectious Pulmonary Complications Following Hematopoietic Stem Cell Transplantation (HSCT)

Influence of Lower Dose Antithymocyteglobulin As Conditioning Regimen on Viral Infection after Haploidentical Allogeneic Stem Cell Transplantation

▪Background: Antithymocyteglobulin (ATG), used as conditioning regimen, can reduce graft-versus-host disease (GVHD) in haploidentical hematopoietic stem cell transplantation (haplo-HSCT). Notwithstanding, immunosuppressive effect of ATG may increase the risk of viral infections after HSCT. To evaluate the effect of different doses of ATG on post-transplant viral infection, we conducted a multicenter prospective study to compare EBV and CMV infection in haplo-HSCT recipients receiving 7.5 mg/kg or 10 mg/kg ATG.MethodsBetween May 2013 and November 2015, 350 consecutive patients with hematological malignancies undergoing haplo-HSCT were randomized in 5 hospitals. One hundred and seventy-two patients received ATG with a total dosage of 7.5 mg/kg and 175 received 10 mg/kg ATG. Three patients did not received allocated intervention and transplantation due to leukemia relapse before transplant or toxicity of conditioning regimens.ResultsThe cumulative incidence of EBV viremia on day 180 was 23.3±3.2% in 7.5 mg/kg ATG arm which was lower than that in 10 mg/kg arm (34.6±3.7%, P=0.037). CMV viremia were comparable in the two arms (7.5 mg/kg arm: 79.0±3.1% vs. 10 mg/kg arm: 76.9±3.2%, P=0.950). The incidences of CMV diseases were 0.6±0.6% and 2.4±1.2% in 7.5 mg/kg and 10 mg/kg arms, respectively (P=0.093). No difference in the incidence of post-transplant lymphoproliferative disorder (PTLD) was found between the two arms (2.4±1.2% in 7.5 mg/kg arm vs. 5.4±1.8% in 10 mg/kg arm, P=0.150). Besides, acute GVHD grade II to IV within 100 days occurred in 55 recipients with the incidence of 31.4% in 7.5mg/kg ATG arms and 45 recipients in 10 mg/kg arms with the incidence of 26.2% (P=0.279). The incidences of aGVHD grade III to IV were similar in the two arms (8.0% in 7.5 mg/kg arm: vs. 4.7% in 10 mg/kg arm, P=0.196). The 2-years overall survival were 69.5±4.7% and 69.4±3.9% for 7.5 mg/kg and 10 mg/kg group (P=0.540).ConclusionCompared with 10 mg/kg of ATG, the application of 7.5 mg/kg might reduce the risk of EBV infection after haplo-HSCT and not increase aGVHD. DisclosuresLin:National Natural Science Foundation of China 81270647: Research Funding; Science and technology planning project of Guangdong Province 2014B020226004: Research Funding; The project of health collaborative innovation of Guangzhou City 201400000003-4: Research Funding; National Natural Science Foundation of China 81400141: Research Funding.

Complement C3F allotype synthesized by liver recipient modifies transplantation outcome independently from donor hepatic C3.

Complement component 3 (C3) presents both slow (C3S) and fast (C3F) variants, which can be locally produced and activated by immune system cells. We studied C3 recipient variants in 483 liver transplant patients by RT-PCR-HRM to determine their effect on graft outcome during the first year post-transplantation. Allograft survival was significantly decreased in C3FF recipients (C3SS 95% vs C3FS 91% vs C3FF 83%; P=.01) or C3F allele carriers (C3F absence 95% vs C3F presence 90%, P=.02). C3FF genotype or presence of C3F allele independently increased risk for allograft loss (OR: 2.38, P=.005 and OR: 2.66, P=.02, respectively). C3FF genotype was more frequent among patients whose first infection was of viral etiology (C3SS 13% vs C3FS 18% vs C3FF 32%; P=.04) and independently increased risk for post-transplant viral infections (OR: 3.60, P=.008). On the other hand, C3FF and C3F protected from rejection events (OR: 0.54, P=.03 and OR: 0.63, P=.047, respectively). Differences were not observed in hepatitis C virus recurrence or patient survival. In conclusion, we show that, independently from C3 variants produced by donor liver, C3F variant from recipient diminishes allograft survival, increases susceptibility to viral infections, and protects from rejection after transplantation. C3 genotyping of liver recipients may be useful to stratify risk.

Monitoring for Viral Infections in Transplant Patients

Monitoring of transplant patients for viral infections allows individualized treatment regimens based on the risk for severe viral disease and quantification of viral loads in patient samples. Depending on the transplant type (solid-organ versus hematopoietic stem cell transplant), donor/recipient serostatus, degree of immunosuppression, and time from transplant, a variety of strategies can be used to manage the risk of post-transplant viral infections. They include empiric suppressive therapy, viral load monitoring, and diagnostic testing algorithms. Since the majority of transplant-associated viral infections are due to reactivation of latent infection, monitoring for viremia can allow early detection and initiation of antiviral therapy or a decrease of immunosuppressive medication in an attempt to limit progression to severe disease. Viral load tests using quantitative-PCR methods are a standard method for monitoring viremia, allowing early detection and tracking of viral infections in this immunocompromised patient population, yet there is limited standardization of testing methods between laboratories.

Intravenous Immunoglobulin in BK Virus Nephropathy

The incidence of post transplant viral infections has increased with the use of more potent immunosuppressive regimens. Consequently, BK virus nephropathy (BKVN) has arisen as a significant cause of graft dysfunction and loss. Reduction of immunosuppression is the first line management of post-transplant viral infections. Other therapies such as intravenous immunoglobulin (IVIg), cidofovir, leflunomide and fluoroquinolones have been tried with varying degrees of success. We report our experience with IVIg in three pediatric renal transplant recipients who presented with allograft dysfunction. First, we describe two cases of biopsy proven BKVN, one diagnosed with undetectable viral titers in plasma, demonstrating that BKVN can occur even at low viral loads. We also present a pediatric renal transplant recipient with persistent BK viremia and allograft dysfunction who responded to therapy with recovery of renal function and clearance of viremia. Therefore we conclude that IVIg is efficacious in the treatment of persistent BK viremia and BKVN. The appropriate dose, frequency and duration of therapy require further study.