#18: Brincidofovir for the Treatment of Disseminated Human Adenovirus Infection in Pediatric Solid-organ Transplant Recipients

2021 ◽  
Vol 10 (Supplement_1) ◽  
pp. S3-S3
Author(s):  
Jackson Londeree ◽  
Rouba Garro ◽  
Rene Romero ◽  
Roshan George ◽  
Pamela Winterberg ◽  
...  
Keyword(s):  
Antiviral Treatment ◽  
Severe Disease ◽  
Treatment Options ◽  
Graft Loss ◽  
Clinical Specimen ◽  
Antiviral Drug ◽  
Solid Organ Transplantation ◽  
Kidney Injury ◽  
Human Adenovirus ◽  
Solid Organ

Abstract Background Human adenovirus (HAdV) viremia can cause significant morbidity among pediatric patients undergoing solid-organ transplantation (SOT). Currently, there are no US Food and Drug Administration (FDA)-approved treatments for HAdV infections, and historically the mainstay of treatment has been decreasing immunosuppression with antiviral therapies reserved for those with severe disease. Brincidofovir (BCV) is an investigational antiviral drug with potency against HAdV. We describe four cases of disseminated HAdV infection treated with (BCV) among pediatric SOT patients. Methods We retrospectively reviewed 4 cases of severe disseminated HAdV infection, which occurred between 2018 and 2019, in a tertiary pediatric transplant center. HAdV infection was defined as a positive HAdV PCR from a clinical specimen. Baseline clinical characteristics, disease course, treatment, and outcomes were reviewed. Results Four pediatric SOT patients (2 kidneys, 1 dual kidney/liver, and 1 liver) ranging in age from 9 months to 19 years were diagnosed with HAdV infection (Table 1). Patients presented with varied symptoms from 12 to 912 days post-transplant. Peak HAdV viral load ranged from 37,000 to >1,000,000 copies/mL. All patients had disseminated disease with evidence of graft involvement and varying degrees of acute kidney injury (AKI) making them candidates for BCV therapy over cidofovir to avoid nephrotoxicity. Three out of four patients received cidofovir prior to conversion to BCV. IRB-approved compassionate use of BCV was dosed at 2 mg/kg (max 100 mg) twice weekly PO along with reduced immunosuppression. Resolution of symptoms and HAdV viremia was seen at a mean of 21.5 days (range 15–32) of therapy. All patients had resolution of AKI with a return to baseline creatinine after therapy. Conclusions Though HAdV infection in pediatric SOT patients is uncommon, a subset of patients experience severe disease, morbidity, and graft loss. Currently, HAdV is not routinely monitored in pediatric SOT transplant patients. Although supportive care and decreased immunosuppression remain as the most important component of therapy, BCV was well tolerated and efficacious in our series. Further research is needed to better understand risk factors for HAdV infection and potential antiviral treatment options to improve patient outcomes.

scholarly journals How I treat EBV lymphoproliferation

Blood ◽  
2009 ◽  
Vol 114 (19) ◽  
pp. 4002-4008 ◽  
Author(s):  
Helen E. Heslop
Keyword(s):  
B Cells ◽  
Cytotoxic T Lymphocyte ◽  
Cytotoxic T Cells ◽  
Treatment Options ◽  
Solid Organ Transplantation ◽  
Solid Organ ◽  
Hematopoietic Stem ◽  
Serial Measurement ◽  
Barr Virus ◽  
Epstein Barr

Abstract Epstein-Barr virus (EBV)–associated B-cell lymphoproliferation is a life-threatening complication after hematopoietic stem cell or solid organ transplantation resulting from outgrowth of EBV-infected B cells that would normally be controlled by EBV-cytotoxic T cells. During the past decade, early detection strategies, such as serial measurement of EBV-DNA load in peripheral blood samples, have helped to identify high-risk patients and to diagnose early lymphoproliferation. Treatment options include manipulation of the balance between outgrowing EBV-infected B cells and the EBV cytotoxic T lymphocyte response and targeting the B cells with monoclonal antibodies or chemotherapy. Major challenges remain for defining indications for preemptive therapies and integrating novel and conventional therapies.

Analysis of the QuantiFERON-CMV assay, CMV viraemia and antiviral treatment following solid organ transplantation in Western Australia

Pathology ◽  
2018 ◽  
Vol 50 (5) ◽  
pp. 554-561 ◽  
Author(s):  
Grace Thompson ◽  
Peter Boan ◽  
Jay Baumwol ◽  
Aron Chakera ◽  
Gerry MacQuillan ◽  
...  
Keyword(s):  
Organ Transplantation ◽  
Western Australia ◽  
Antiviral Treatment ◽  
Solid Organ Transplantation ◽  
Solid Organ

scholarly journals Acute Kidney Injury in Patients Undergoing Cardiac Transplantation: A Meta-Analysis

Medicines ◽  
2019 ◽  
Vol 6 (4) ◽  
pp. 108 ◽  
Author(s):  
Charat Thongprayoon ◽  
Ploypin Lertjitbanjong ◽  
Panupong Hansrivijit ◽  
Anthony Crisafio ◽  
Michael Mao ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Mortality Risk ◽  
Cardiac Transplantation ◽  
Patient Survival ◽  
Meta Analysis ◽  
Solid Organ Transplantation ◽  
Kidney Injury ◽  
Solid Organ ◽  
Short Term ◽  
Incidence And Mortality

Background: Acute kidney injury (AKI) is a common complication following solid-organ transplantation. However, the epidemiology of AKI and mortality risk of AKI among patients undergoing cardiac transplantation is not uniformly described. We conducted this study to assess the incidence of AKI and mortality risk of AKI in adult patients after cardiac transplantation. Methods: A systematic review of EMBASE, MEDLINE, and Cochrane Databases was performed until June 2019 to identify studies evaluating the incidence of AKI (by standard AKI definitions), AKI requiring renal replacement therapy (RRT), and mortality risk of AKI in patients undergoing cardiac transplantation. Pooled AKI incidence and mortality risk from the included studies were consolidated by random-effects model. The protocol for this study is registered with PROSPERO (no. CRD42019134577). Results: 27 cohort studies with 137,201 patients undergoing cardiac transplantation were identified. Pooled estimated incidence of AKI and AKI requiring RRT was 47.1% (95% CI: 37.6–56.7%) and 11.8% (95% CI: 7.2–18.8%), respectively. The pooled ORs of hospital mortality and/or 90-day mortality among patients undergoing cardiac transplantation with AKI and AKI requiring RRT were 3.46 (95% CI, 2.40–4.97) and 13.05 (95% CI, 6.89–24.70), respectively. The pooled ORs of 1-year mortality among patients with AKI and AKI requiring RRT were 2.26 (95% CI, 1.56–3.26) and 3.89 (95% CI, 2.49–6.08), respectively. Conclusion: Among patients undergoing cardiac transplantation, the incidence of AKI and severe AKI requiring RRT are 47.1% and 11.8%, respectively. AKI post cardiac transplantation is associated with reduced short term and 1-year patient survival.

scholarly journals Metformin Improves Relevant Disease Parameters in an Autosomal Dominant Polycystic Kidney Disease Mouse Model

2021 ◽  
Author(s):  
Nuria M Pastor-Soler ◽  
Hui Li ◽  
Jessica Pham ◽  
Daniel Rivera ◽  
Pei-Yin Ho ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Mouse Model ◽  
Polycystic Kidney Disease ◽  
Autosomal Dominant ◽  
Severe Disease ◽  
Treatment Options ◽  
Kidney Injury ◽  
Polycystic Kidney ◽  
Gene And Protein Expression ◽  
Autosomal Dominant Polycystic Kidney

Autosomal dominant polycystic kidney disease (ADPKD), caused by mutations in the PKD1 or PKD2 genes encoding polycystins, presents with progressive development of kidney cysts and eventual end-stage kidney disease (ESKD) with limited treatment options. Previous work showed that metformin reduces cyst growth in rapid ADPKD mouse models via inhibition of CFTR-mediated fluid secretion, mTOR, and cAMP pathways. The present study importantly tested the effectiveness of metformin as a therapy for ADPKD in a more clinically relevant Pkd1RC/RC mouse model, homozygous for the R3277C knock-in point mutation in the Pkd1 gene. This mutation causes ADPKD in humans. Pkd1RC/RC male and female mice, which have slow progression to ESKD, received metformin (300 mg/kg/day in drinking water vs. water alone) from 3 to 9 or 12 months of age. As previously reported, Pkd1RC/RC females had a more severe disease phenotype than males. Metformin treatment reduced the ratio of total kidney weight to body weight relative to age- and sex-matched untreated controls at both 9 and 12 months and reduced cystic index in females at 9 months. Metformin also increased glomerular filtration rate (GFR), lowered systolic blood pressure, improved anemia, and lowered blood urea nitrogen levels relative to controls in both sexes. Moreover, metformin reduced gene expression of key inflammatory markers and both gene and protein expression of kidney injury marker-1 and cyclin-dependent kinase-1 vs. untreated controls. Altogether, these findings suggest several beneficial effects of metformin in this highly relevant slowly progressive ADPKD mouse model, which may help inform new ADPKD therapies in patients.

scholarly journals Epitope-Level Matching—A Review of the Novel Concept of Eplets in Transplant Histocompatibility

2021 ◽  
Vol 2 (3) ◽  
pp. 336-347
Author(s):  
André Renaldo ◽  
Adriel Roa-Bautista ◽  
Elena González-López ◽  
Marcos López-Hoyos ◽  
David San Segundo
Keyword(s):  
De Novo ◽  
Graft Loss ◽  
Solid Organ Transplantation ◽  
Human Leukocyte ◽  
Future Research ◽  
Solid Organ ◽  
Leukocyte Antigen ◽  
Definition Of ◽  
Novel Concept ◽  
Hla Compatibility

The development of de novo donor-specific antibodies is related to the poor matching of the human leukocyte antigen (HLA) between donor and recipient, which leads to dismal clinical outcomes and graft loss. However, new approaches that stratify the risks of long-term graft failure in solid organ transplantation have emerged, changing the paradigm of HLA compatibility. In addition, advances in software development have given rise to a new structurally based algorithm known as HLA Matchmaker, which determines compatibility at the epitope rather than the antigen level. Although this technique still has limitations, plenty of research maintains that this assessment represents a more complete and detailed definition of HLA compatibility. This review summarizes recent aspects of eplet mismatches, highlighting the most recent advances and future research directions.

scholarly journals M2 Macrophages Serve as Critical Executor of Innate Immunity in Chronic Allograft Rejection

2021 ◽  
Vol 12 ◽  
Author(s):  
Hanwen Zhang ◽  
Zhuonan Li ◽  
Wei Li
Keyword(s):  
Allograft Rejection ◽  
Chronic Rejection ◽  
Graft Loss ◽  
Solid Organ Transplantation ◽  
Innate Immune ◽  
Sterile Inflammation ◽  
Solid Organ ◽  
M2 Macrophages ◽  
Innovative Strategies ◽  
Chronic Allograft Rejection

Allograft functional failure due to acute or chronic rejection has long been a major concern in the area of solid organ transplantation for decades. As critical component of innate immune system, the macrophages are unlikely to be exclusive for driving acute or chronic sterile inflammation against allografts. Traditionally, macrophages are classified into two types, M1 and M2 like macrophages, based on their functions. M1 macrophages are involved in acute rejection for triggering sterile inflammation thus lead to tissue damage and poor allograft survival, while M2 macrophages represent contradictory features, playing pivotal roles in both anti-inflammation and development of graft fibrosis and resulting in chronic rejection. Macrophages also contribute to allograft vasculopathy, but the phenotypes remain to be identified. Moreover, increasing evidences are challenging traditional identification and classification of macrophage in various diseases. Better understanding the role of macrophage in chronic rejection is fundamental to developing innovative strategies for preventing late graft loss. In this review, we will update the recent progress in our understanding of diversity of macrophage-dominated innate immune response, and reveal the roles of M2 macrophages in chronic allograft rejection as well.

Fungal infections in solid organ transplantation

2017 ◽  
Author(s):  
Darius Armstrong James ◽  
Anand Shah ◽  
Anna Reed
Keyword(s):  
Organ Transplantation ◽  
Fungal Infections ◽  
Wide Spectrum ◽  
Treatment Options ◽  
Solid Organ Transplantation ◽  
Invasive Disease ◽  
Global Scale ◽  
Molecular Diagnostic ◽  
Individual Risk ◽  
Solid Organ

Fungal infections are a significant and life-threatening complication of organ transplantation, on a global scale. Risk varies according to transplant type, with liver, lung, and small bowel transplant recipients being at particular risk. Whilst invasive candidiasis is the most common fungal infection in organ transplantation overall, aspergillosis is a particular problem in lung transplantation. In addition, a wide spectrum of fungi may cause invasive disease in organ transplantation, consequently diagnosis and treatment can be challenging. Key challenges are to understand individual risk for infection, appropriate prophylactic strategies, and molecular diagnostic approaches. Treatment options are complicated by drug–drug interactions with transplant therapy, as well as intrinsic allograft dysfunction seen in many patients. In this chapter, we review the epidemiology, risk factors, diagnosis, and management of fungal infections in solid organ transplantation.

Anti-CD20 Monoclonal Antibody (rituximab) for Refractory PTLD after Pediatric Solid Organ Transplantation: Multicenter Experience from a Registry and from a Prospective Clinical Trial.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 746-746 ◽  
Author(s):  
Steven Webber ◽  
William Harmon ◽  
Albert Faro ◽  
Michael Green ◽  
Minnie Sarwal ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Monoclonal Antibody ◽  
B Cell ◽  
Organ Transplantation ◽  
Graft Loss ◽  
Solid Organ Transplantation ◽  
Solid Organ ◽  
Refractory Disease ◽  
First Line

Abstract Background: Anti B cell antibodies have been proposed as a treatment for post-transplant lymphoproliferative disorders (PTLD). Experience in children is limited. Methods and Results: We report experience (n=40) with use of the chimeric mouse/human antiCD20 monoclonal antibody (rituximab) in pediatric PTLD patients with refractory disease (no response to reduced immunosuppression, progressive or relapsed disease, or concomitant allograft rejection). Initial experience was through a voluntary registry (n=26), and most recent experience is from an onging prospective, non-randomized clinical trial (n=14). Use of chemotherapy or other experimental therapies were an exclusion criteria for both studies. All PTLD were of B cell origin and expressed CD20 and all but 2 (both in registry cohort) were EBV positive. The first cohort (registry) comprised 26 solid organ recipients from 12 centers (heart 11, kidney 6, lung 4, other 5) with mean age of 12.5 years, 29 months (range 2–132) from transplant. Histology revealed these lesions: polymorphic 17, monomorphic 7 (including 1 Burkitts-like), Hodgkins-like 1, unspecified 1. 21/26 received 375mg/m2 x 4 doses. There were no SAE’s. 18 pts (69%) showed CR, and 4 (16%) showed PR. The 4 non-responders comprised the 2 EBV negative cases, the Burkitts-like disease and the earliest onset case (fulminant disease at 2 months post-transplant). At latest follow-up (mean 41 months), 73% survive with one graft loss (kidney). In the prospective clinical trial, 14 patients (to date) with refractory disease were enrolled. The protocol comprises 4 doses of 375mg/m2 (weeks 1–4) with no further treatment for patients with CR or for those with no response. Patients with PR receive 4 further doses (weeks 5–8). The 14 patients were from 5 centers (lung 5, kidney 5, heart 4) with mean age of 6.5 years, 41 months (range 4–120) from transplant. Histology revealed the following: polymorphic 10, monomorphic 3, Hodgkin-like 1. There were no SAE’s. Two are still recieving therapy. Of the other 12, 9 (75%) acheived CR and 10 pts (83%) are alive with one graft loss (kidney) at mean follow-up of 1.5 years. The two deaths were due to fungal pneumonia and complications of elective surgery in a patient in CR (both lung recipients). Conclusions: These results suggest that rituximab may have an important role to play in management of refractory PTLD in solid organ recipients (CR rate approx. 70–75% with low incidence of graft loss). This group of patients traditionally has high mortality and has been treated with chemotherapy. Rituximab should be considered as first line treatment for refractory polymorphic PTLD in children after solid organ transplantation. Role in monomorphic disease requires further investigation. Use of rituximab as first line therapy is under investigation.

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