Reduction Of Immunosuppressive Therapy Research Articles

CARDIOVASCULAR INVOLVEMENT IN SYSTEMIC LUPUS ERYTHEMATOSUS

Abstract Background Cardiovascular involvement is frequent in systemic lupus erythematosus (SLE). Aortic insufficiency is a common valvular abnormality seen in patients with systemic lupus erythematosus (SLE), it may be caused by a primary valve pathology or by an aortitis One of the cardiac manifestations associated with SLE and antiphospholipid syndrome (APLS) is Libman–Sacks endocarditis, also known as non–bacterial thrombotic endocarditis Although rare, there are reported cases of lupus aortitis which has also been associated with dissection, aneurysm and thrombus. Case Report We present a case of a 40 –years–old lady with lupus glomerulonephritis requiring immunosuppression and dialysis, who presented to the emergency department with fever and dyspnea. She was first treated with dialysis. Blood cultures drawn from central venous catheter peripheral were positive for staphylococcus epidermidis, the cultures from peripheral blood was negative instead.Transthoracic and transesophageal Echocardiography showed severe aortic regurgitation (not present three month earlier) with doubt valvular vegetations and with a focal enlargement of the aortic root (figure 1, 2).The patient met one major criterion (blood culture) and two minor criteria (high risk and fever), implying possible infective endocarditis. The patient was then started on intravenous antibiotics (vancomycin) and immunosuppression was reduced. Given the hemodynamic instability due to the severe aortic insufficiency, an Heart CT scan was performed to planned the surgical intervention. The CT scan confirmed the presence of small, multiple vegetation attached to the aortic leaflet and an aortic dissection on the right coronary cusp (figure 3). She proceeded to urgent surgery with aortic valve and aortic root replacement, the histology revealed evidence of Libman–Sacks endocarditis and aortitis. Discussion Our patient showed two different cardiovascular complications of SLE: the more frequent Libman –Sack endocarditis and the rare lupus aortitis associated to aortic dissection.The patient had risk factors for infective endocarditis and she did fulfil the modified Duke’s criteria for infective endocarditis and was treated with antibiotics and with a reduction of immunosuppression therapy. In fact, it can be difficult to distinguish between infective endocarditis and Libman–Sacks endocarditis especially in the setting of risk factors for both. Antibiotics and immunosuppressants should be used both.

Management of Kidney Transplant Outpatients With COVID-19: A Single Center Experience.

Patients undergoing kidney transplant are at risk of severe COVID-19. Our single-center retrospective analysis evaluated the outcomes of kidney transplant outpatients with COVID-19 who were managed with reduced immunosuppression and treatment with molnupiravir. Between January 2022 and May 2023, we included 93 patients (62 men, average age 56years), serum creatinine 127 (101-153) µmol/L. Molnupiravir was administered, and immunosuppressive therapy was reduced immediately following the confirmation of SARS-CoV-2 infection by PCR, which was 2 (1-3) days after the onset of symptoms. Only three (3.2%) patients required hospitalization, and one patient died. Acute kidney injury was observed in two patients. During the follow-up period of 19 (15-22) months, there was no significant increase in proteinuria, no acute or new chronic graft rejection, and kidney graft function remained stable; serum creatinine was 124 (106-159) µmol/L post-COVID-19 infection and 128 (101-161) µmol/L at the end of the follow-up period. Our results demonstrate that early initiation of molnupiravir treatment combined with a temporary reduction in immunosuppressive therapy results in favorable clinical outcomes in patients with COVID-19, with preservation of good graft function and no episodes of graft rejection.

New advances in pediatric nephrology: ESPN 2023 results

On September 28 — October 1, 2023, the European Society for Paediatric Nephrology (ESPN) 55th Annual Meeting was held in Vilnius, Lithuania, where new achievements in the world of pediatric nephrology were presented. The program included 66 sessions with reports, continuing medical education courses, 117 invited speakers, meetings of working groups on various issues of pediatric nephrology were held, about 450 abstracts were printed and 292 poster presentations were discussed, inclu­ding two by authors from Ukraine. Courses for young doctors, preparing them for the international exam, and 5-minute reports by well-known specialists became interesting in the organization of continuing medical education, which significantly increased the amount of presented material. Among the innovative approaches in pediatric nephrology, the following drugs have been considered: finerenone (a selective non-steroidal mineralocorticoid receptor antagonist), sparsentan (an angiotensin/endothelin receptor antagonist) for Alport syndrome, focal segmental glomerulosclerosis, IgA nephropathy, dapagliflozin (a sodium-glucose cotransporter 2 inhibitor) for chronic kidney disease and pioglitazone for proteinuria. New approaches have been introduced: to IgA nephropathy — proteinuria control with angiotensin-converting enzyme inhibitors (ACEi), tonsillectomy, rituximab, eculizumab; to focal segmental glomerulosclerosis — plasmapheresis, rituximab (CD20), ofatumumab (CD20), abatacept (CD80/86), belatacept (CD80/86), daratumumab (CD38); to membranous nephropathy — proteinuria control with ACEi, rituximab, calcineurin inhibitors, glucocorticoids, cyclophosphamide; to membranoproliferative glomerulonephritis — proteinuria control with ACEi; to C3 glomerulopathy — proteinuria control with ACEi, eculizumab. Specific provisions of the BK polyomavirus (BKPyV) guidelines were considered, in particular, monthly screening for BKPyV-DNAemia in blood plasma is suggested until month 9, then every 3 months until month 24, after which additional screening every 3 months until the end of the third year after transplantation in pediatric kidney recipients (C, weak). In pediatric patients with stable renal function and high BKPyV-DNAemia, despite reduction in immunosuppressive therapy, we suggest consideration of renal allograft biopsy, as creatinine elevation may be decreased in children with significant renal involvement, including rejection (A, strong).

Pre-Emptive Use of Rituximab in Epstein-Barr Virus Reactivation: Incidence, Predictive Factors, Monitoring, and Outcomes.

Post-transplant lymphoproliferative disease (PTLD) is a fatal complication of hematopoietic cell transplantation (HCT) associated with the Epstein-Barr virus (EBV). Multiple factors such as transplant type, graft-versus-host disease (GVHD), human leukocyte antigens (HLA) mismatch, patient age, and T-lymphocyte-depleting treatments increase the risk of PTLD. EBV reactivation in hematopoietic cell transplant recipients is monitored through periodic quantitative polymerase chain reaction (Q-PCR) tests. However, substantial uncertainty persists regarding the clinically significant EBV levels for these patients. Guidelines recommend initiating EBV monitoring no later than four weeks post-HCT and conducting it weekly. Pre-emptive therapies, such as the reduction of immunosuppressive therapy and the administration of rituximab to treat EBV viral loads are also suggested. In this study, we investigated the occurrence of EBV-PTLD in 546 HCT recipients, focusing on the clinical manifestations and risk factors associated with the disease. We managed to identify 67,150 viral genomic copies/mL as the cutoff point for predicting PTLD, with 80% sensitivity and specificity. Among our cohort, only 1% of the patients presented PTLD. Anti-thymocyte globulin (ATG) and GVHD were independently associated with lower survival rates and higher treatment-related mortality. According to our findings, prophylactic measures including regular monitoring, pre-emptive therapy, and supportive treatment against infections can be effective in preventing EBV-related complications. This study also recommends conducting EBV monitoring at regular intervals, initiating pre-emptive therapy when viral load increases, and identifying factors that increase the risk of PTLD. Our study stresses the importance of frequent and careful follow-ups of post-transplant complications and early intervention in order to improve survival rates and reduce mortality.

Prevalence, management, and new treatment modalities of EBV-DNA-emia and EBV-PTLD after allo-HCT: survey of Infectious Diseases Working Party EBMT.

The aim of this study was to determine the current approach of EBV-driven post-transplant complications in context of monitoring, diagnosis, prevalence and treatment in EBMT transplant centers. Routine serology testing in patient and donor before HCT is performed in 95.5% centers. Pretransplant EBV-DNA is routinely tested in all patients in 32.7% centers. Monitoring for EBV infection is feasible in 98.2% centers: including 66.7% centers using standardized PCR. Post-HCT regular monitoring is performed in all patients in 80.5% centers. Anti-EBV prophylaxis with rituximab is used in 12.4% centers. Frequency of csEBV-DNA-emia was 7.4% (adults: 6.2%, children: 12.6%). The PCR threshold used to start preemptive treatment was differentiated among centers. Frequency of EBV-PTLD was 1.6% (adults: 1.3%; children: 3.5%). First-line therapy of EBV-driven complications was rituximab and reduction of immunosuppressive therapy. The rate of failure of first-line preemptive treatment was 12.0%. EBV-specific viral-specific T-lymphocytes were available in 46.0% centers. A number of new experimental therapies were given in 28 patients with resistant/refractory PTLD. In conclusion, the prevalence of EBV-DNA-emia and EBV-PTLD over the period 2020-2021 decreased in comparison to historical data. New trends (routine pretransplant screening for EBV-DNA, wider access to VST, new experimental therapies) are being observed in management of EBV infection after allo-HCT.

Cytopenias in pediatric kidney transplant recipients: preceding factors and clinical consequences.

Kidney trans plantation is associated with secondary complications, including the risk of developing posttransplant cytopenias. This study aimed to evaluate the characteristics, identify predictors, and assess the management and consequences of cytopenias in the pediatric kidney transplant population. This is a single-center retrospective analysis of 89 pediatric kidney transplant recipients. Possible factors preceding cytopenias were compared with the goal of recognizing predictors for posttransplant cytopenias. Posttransplant neutropenias were analyzed for the total study period and separately for the period beyond 6months posttransplant (late neutropenias), to rule out confounding influences of induction and initial intensive therapy. Sixty patients (67%) developed at least one episode of posttransplant cytopenia. All episodes of posttransplant thrombocytopenias were mild or moderate. Posttransplant infections and graft rejection were found to be significant predictors for thrombocytopenia (HR 6.06, 95% CI 1.6-22.9, and HR 5.82, 95% CI 1.27-26.6, respectively). A total of 30% of posttransplant neutropenias were severe (ANC ≤ 500). Pretransplant dialysis and posttransplant infections were significant predictors for late neutropenias (HR 11.2, 95% CI 1.45-86.4, and HR 3.32, 95% CI 1.46-7.57, respectively). Graft rejection occurred in 10% of patients with cytopenia, all following neutropenia, within 3months from cytopenia appearance. In all such cases, mycophenolate mofetil dosing had been held or reduced prior to rejection. Posttransplant infections are substantial contributors to developing posttransplant cytopenias. Preemptive transplantation appears to reduce risk of late neutropenia, the accompanying reduction in immunosuppressive therapy, and the ensuing risk of graft rejection. An alternative response to neutropenia, possibly using granulocyte colony stimulating factor, may diminish graft rejection. A higher resolution version of the Graphical abstract is available as Supplementary information.

A132 A CASE OF COLONIC MALAKOPLAKIA PRESENTING AS A LARGE CECAL MASS : NOT EVERY POLYP HAS TO LOOK LIKE A NAIL

Abstract Background Malakoplakia is a rare inflammatory condition, commonly affecting the genitourinary system of immunocompromised patients. Gastrointestinal malakoplakia has been reported in the literature, with previous endoscopic findings mimicking mass lesions. Purpose To describe a case of colonic malakoplakia after referral for endoscopic management of a large non-pedunculated colorectal polyp. Method Case report and review of the literature. Result(s) Case Report An 80-year-old male with chronic kidney disease and remote renal transplant on immunosuppressive therapy (mycophenolate mofetil, tacrolimus, prednisone) was referred for endoscopic resection for a large non-pedunculated colorectal polyp in the cecum. Original presenting symptoms included chronic diarrhea, iron deficiency anemia, and fecal immunochemical test (FIT) positivity. A repeat colonoscopy demonstrated a 40mm Paris 0-IIA plaque-like lesion in the cecum with optical features not in keeping with adenomatous or serrated histopathology. Biopsies were performed with histopathology demonstrating normal colonic mucosa with confluent sheets of histiocytes with concentrically layered cytoplasmic inclusions, in keeping with malakoplakia. Literature review Malakoplakia, Greek for “soft plaque”, is a rare inflammatory condition characterized by impaired dysfunction in macrophages leading to the accumulation of incompletely degraded bacteria in phagolysosomes. Histologically, this appears as concentrically layered cytoplasmic inclusions, comprising the pathognomonic Michaelis-Gutmann bodies. Many bacterial organisms have been implicated in the development of malakoplakia, with E. coli being the most common; specifically in immunocompromised patients, whether from immunosuppressive medications, immunodeficiency syndromes, or clinical conditions precluding effective immune function. Malakoplakia commonly presents as a mass-like lesion and has been found in all organs, most commonly in the genitourinary system. Diagnosis is made by biopsy and allows for appropriate treatment, which is most commonly a reduction in immunosuppressive therapy and antibiotic therapy. Image Conclusion(s) Malakoplakia is rare but should be considered when a lesion with atypical optical evaluation features is found in immunocompromised individuals or those with recurrent infections. Please acknowledge all funding agencies by checking the applicable boxes below None Disclosure of Interest None Declared

A multivalent polyomavirus vaccine elicits durable neutralizing antibody responses in macaques.

In 2019, there were about 100,000 kidney transplants globally, with more than a quarter of them performed in the United States. Unfortunately, some engrafted organs are lost to polyomavirus-associated nephropathy (PyVAN) caused by BK and JC viruses (BKPyV and JCPyV). Both viruses cause brain disease and possibly bladder cancer in immunosuppressed individuals. Transplant patients are routinely monitored for BKPyV viremia, which is an accepted hallmark of nascent nephropathy. If viremia is detected, a reduction in immunosuppressive therapy is standard care, but the intervention comes with increased risk of immune rejection of the engrafted organ. Recent reports have suggested that transplant recipients with high levels of polyomavirus-neutralizing antibodies are protected against PyVAN. Virus-like particle (VLP) vaccines, similar to approved human papillomavirus vaccines, have an excellent safety record and are known to induce high levels of neutralizing antibodies and long-lasting protection from infection. In this study, we demonstrate that VLPs representing BKPyV genotypes I, II, and IV, as well as JCPyV genotype 2 produced in insect cells elicit robust antibody titers. In rhesus macaques, all monkeys developed neutralizing antibody titers above a previously proposed protective threshold of 10,000. A second inoculation, administered 19weeks after priming, boosted titers to a plateau of ≥ 25,000 that was maintained for almost two years. No vaccine-related adverse events were observed in any macaques. A multivalent BK/JC VLP immunogen did not show inferiority compared to the single-genotype VLP immunogens. Considering these encouraging results, we believe a clinical trial administering the multivalent VLP vaccine in patients waiting to receive a kidney transplant is warranted to evaluate its ability to reduce or eliminate PyVAN.

Extracorporeal photopheresis in the treatment of chronic graft-versus-host-disease

Introduction. Chronic graft versus host disease (GVHD) is a frequently occurring complication after transplantation of allogeneic hematopoietic cells associated with a decrease in the quality of life and long-term administration of immunosuppressive drugs. Extracorporeal photopheresis (ECP) is a second line of therapy after treatment failure with glucocorticoids.Aim — to evaluate the effects of ECP treatment in patients with glucocorticosteroids (GCS)-refractory, GCS-dependent or GCS -intolerant chronic GVHD.Materials and methods. 24 patients with GCS-refractory, GCS-dependent or GCS-intolerant chronic GVHD were included in the therapy with ECP. Nine patients had moderate chronic GVHD, and 15 had a severe chronic GVHD. Skin and mucous membranes were the most frequently targeted organs, 21 and 20 of 24 patients respectively, liver damage was detected in 8 patients. The maximum duration of treatment was 33 months (median — 8.5 months). The number of procedures of ECP ranged from 6 to 48 (median — 22).Results. A response was determined in 23 patients with one patient being excluded from the assessment due to a relapse of acute leukemia. 16 (69.5 %) patients achieved an overall response to ECP treatment. Three patients had complete response and full reduction of immunosuppressive therapy. When assessing organ-specific response, the most notable improvement was observed in the mucous membranes of 17 patients (89.4 %), skin — 17 (85 %), and liver — 7 (75 %). Along with achieving a general overall response, 78.2 % of patients partly reduced or completely canceled immunosuppressive therapy.Conclusion. ECP is an effective and promising second line treatment method for chronic GVHD in patients with GCS-refractory, GCS-dependent or GCS-intolerant forms.

Perforin: An intriguing protein in allograft rejection immunology (Review).

Chronic kidney disease (CKD) is a worldwide public health problem. The constantly increasing prevalence of CKD requires further research into new additional strategies in its management. The preferred treatment of end-stage renal disease (ESRD) is renal transplantation. Kidney transplant patients benefit from substantial improvement in their quality and duration of life. For these to be feasible, the long-term graft and host survival optimization of the renal transplant recipient must be ensured and chronic allograft dysfunction (CAN) must be prevented. Once an equilibrium in the allograft tolerance is established, renal transplanted patients would benefit from the withdrawal or the reduction of immunosuppression therapy. Identification of early predictive biomarkers of CAN is essential. Recent publications have revealed that in long-term immune tolerance and graft survival several populations of immune cells are involved. Starting from the identification of perforin (PRF) in pathological renal glomeruli and following with the analysis of the molecular expression of PRF in renal biopsy samples, it appears that serum PRF is one of the potential biomarkers of graft dysfunction. Over the years, this protein has captured the attention of the medical world, conducting research that could potentially lead to the discovery of an innovative biomarker. Discovering and understanding the involvement of PRF in developing CAN may open up new therapeutic pathways that would ensure the survival of the kidney transplant. In this review the authors examined the structure, the role and the present understanding of the mechanisms by which serum PRF may be involved in chronic graft dysfunction as well as its role as an immune tolerance biomarker for chronic dysfunction of the renal graft.

Reducing Immunosuppression in Patients with De Novo Lung Carcinoma after Liver Transplantation Could Significantly Prolong Survival

Simple SummaryLong-term immunosuppressive therapy following liver transplantation is associated with an increased risk for the development of de novo lung carcinoma. However, data on the management of the immunosuppression following the diagnosis of lung cancer are missing to the present day. In this retrospective analysis, we investigate factors associated with improved survival of liver transplant recipients with diagnosis of de novo lung carcinoma with a particular emphasis on the impact of immunosuppression. Our findings suggest that strict reduction of immunosuppression has a beneficial effect on survival in this particular situation and, thus, should be an early intervention following diagnosis. Liver transplant recipients with the diagnosis of de novo lung cancer should be offered surgical treatment if technically feasible as a potential curative therapeutic option to improve limited prognosis. Further investigations concerning dosage findings and reduction of immunosuppression in organ recipients should be the targets of subsequent studies.(1) Background: Liver transplantation (LT) is an established treatment for selected patients with end-stage liver disease resulting in a subsequent need for long-term immunosuppressive therapy. With cumulative exposure to immunosuppression (IS), the risk for the development of de novo lung carcinoma increases. Due to limited therapy options and prognosis after diagnosis of lung cancer, the question of the mode and extent of IS in this particular situation is raised. (2) Methods: All patients diagnosed with de novo lung cancer in the follow-up after LT were identified from the institution’s register of liver allograft recipients (Charité—Universitätsmedizin Berlin, Germany) transplanted between 1988 and 2021. Survival analysis was performed based on the IS therapy following diagnosis of lung cancer and the oncological treatment approach. (3) Results: Among 3207 adult LTs performed in 2644 patients at our institution, 62 patients (2.3%) developed de novo lung carcinoma following LT. Lung cancer was diagnosed at a median interval of 9.7 years after LT (range 0.7–27.0 years). Median survival after diagnosis of lung carcinoma was 13.2 months (range 0–196 months). Surgical approach with curative intent significantly prolonged survival rates compared to palliative treatment (median 67.4 months vs. 6.4 months). Reduction of IS facilitated a significant improvement in survival (median 38.6 months vs. 6.7 months). In six patients (9.7%) complete IS weaning was achieved with unimpaired liver allograft function. (4) Conclusion: Reduction of IS therapy after the diagnosis of de novo lung cancer in LT patients is associated with prolonged survival. The risk of acute rejection does not appear to be increased with restrictive IS management. Therefore, strict reduction of IS should be an early intervention following diagnosis. In addition, surgical resection should be attempted, if technically feasible and oncologically meaningful.

Akutní infekce u pacientů po transplantaci ledviny

Immunosuppressed kidney transplant recipients have a high risk of infectious complications. A variety of infections of viral, bacterial, or mycotic etiology, including opportunistic infections, occur in this group of patients, but bacterial infections are primarily responsible for the high infection-related mortality. Of the bacterial infections, urinary tract infections and pneumonia are the most common, often requiring hospitalization and temporary reduction of immunosuppressive therapy after consultation of the transplant center. In addition to symptoms due to the location of the infection, fever is often present. The differential diagnosis of fever and/or high inflammatory activity is specific to patients after kidney transplantation. In addition to infectious causes, we consider drug-related fever, a rejection episode, a relapse of systemic disease or in patients with graft failure in dialysis treatment graft intolerance syndrome (“symptomatic graft”). Saving the patients life, which often requires a significant reduction in immunosuppressive therapy, always takes precedence over preventing a rejection episode. Infection prevention is an integral part of the care of transplant patients, including the recommendation of vaccination where possible.

MO971LYMPHOPROLIFERATIVE DISEASE AFTER KIDNEY TRANSPLANTATION: DESCRIBING OUR EXPERIENCE

Abstract Background and Aims Post-transplant lymphoproliferative disorders (PTLD) are one of the most common malignancies in kidney transplant (KT) recipients. Immunosuppressive therapy and Epstein Barr Virus (EBV) play a main role in their pathogenesis. Method In this study we retrospectively analyze the characteristics, clinical evolution and treatments of a group of KT recipients performed between 1986 and 2020 in a single center. Results We included 31 patients (64.5% males). Polycystic kidney disease was the most frequent cause of renal failure. Before KT a 6.5% of the patients presented another malignancy, 10% were EBV seronegative and one received immunosuppressive therapy secondary to his primary disease. Mean age at KT was 43±12 years. 68% of the KT came from brain-dead donors. The most frequent immunosuppressive regime consisted in tacrolimus, mycophenolic acid and prednisone (61.3%). Basiliximab and Timoglobulin were used in the same proportion for the induction therapy (22.6%). Before PTLD appearance the immunosuppressive therapy was reduced in the 54.8% of the recipients. 13% of them presented acute allograft rejection. The majority of PTLD were diagnosticated between 2016 and 2020. Median time to develop PTLD was 13 years. 54.3% of the patients presented with extranodal involvement. Although all the patients positivized EBV serology, 60% of them had undetectable EBV viral load. The main therapeutical strategy after PTLD consisted in a reduction of the immunosuppressive therapy. In this way, 28.6% of the recipients was treated with monotherapy with a calcineurin inhibitors and 21.5% with monotherapy with a mTOR inhibitor. In other hand 16.7% received a combination of tacrolimus with a mTOR inhibitor. Rejections were not observed in our group and all the patients presented a preserved kidney function at the end of follow up. Four recipients died because of PTLD. The remaining 27 presented a complete response or stabilization of the disease. Conclusion Most of the PTLD were detected between 2016-2020. The time from transplantation to PTLD appearance was long, being EBV viral load negative in the majority of the cases. Graft survival after chemotherapy and reduction of immunosuppressive therapy was excellent, with a low risk of rejection and a good prognosis for hematologic disease. It is possible that a reduction in immunosuppression in selected patients could prevent the development of PTLD.

Minimization of Immunosuppressive Therapy Is Associated with Improved Survival of Liver Transplant Patients with Recurrent Hepatocellular Carcinoma.

Simple SummaryLiver transplantation is a curative treatment option for a subset of patients with hepatocellular carcinoma (HCC). However, about twenty percent of patients develop recurrence in the graft or at extrahepatic sites, which is associated with limited therapeutic options and poor survival. To date, management of the immunosuppressive regimen after recurrence and its impact on survival are unknown. In this retrospective study, we analyzed a cohort of liver recipients with HCC recurrence. Our findings indicate that reduction of immunosuppressive therapy after diagnosis of recurrence has a beneficial impact on patient survival. Therefore, we propose further investigation into the management of immunosuppressive therapy following recurrence.Introduction: Recurrence of hepatocellular carcinoma (rHCC) after liver transplantation (LT) is associated with limited survival. Therefore, identification of factors that prolong survival in these patients is of great interest. Surgical resection, radiotherapy, and transarterial chemoembolization (TACE) are established interventions to improve outcomes in these patients; however, the impact of immunosuppression is unknown. Methods: All patients diagnosed with rHCC in the follow-up after LT were identified from a database of liver recipients transplanted between 1988 and 2019 at our institution (Charité Universitätsmedizin Berlin, Germany). Based on the immunosuppressive regimen following diagnosis of rHCC and the oncological treatment approach, survival analysis was performed. Results: Among 484 patients transplanted for HCC, 112 (23.1%) developed rHCC in the follow-up. Recurrent HCC was diagnosed at a median interval of 16.0 months (range 1.0–203.0), with the majority presenting early after transplantation (63.0%, <2 years). Median survival after rHCC diagnosis was 10.6 months (0.3–228.7). Reduction of immunosuppression was associated with improved survival, particularly in patients with palliative treatment (8.4 versus 3.0 months). In addition, greater reduction of immunosuppression seemed to be associated with greater prolongation of survival. Graft rejection after reduction was uncommon (n = 7, 6.8%) and did not result in any graft loss. Patients that underwent surgical resection showed improved survival rates (median 19.5 vs. 8.7 months). Conclusion: Reduction of immunosuppressive therapy after rHCC diagnosis is associated with prolonged survival in LT patients. Therefore, reduction of immunosuppression should be an early intervention following diagnosis. In addition, surgical resection should be attempted, if technically feasible and oncologically meaningful.

Monitoring of hepatitis E virus RNA during treatment for chronic hepatitis E virus infection after renal transplantation.

BackgroundRecently, chronic hepatitis E virus (HEV) infections gained increasing attention as a possible cause for elevated liver enzymes of unknown origin and liver cirrhosis in solid organ transplant recipients. Reduction of immunosuppressive therapy and/or use of antiviral drug ribavirin have been established as possible treatment strategies.MethodsThe efficacy of dose reduction of mycophenolic acid (MPA) and ribavirin therapy was retrospectively analyzed in eight renal transplant patients of our outpatient clinic who were diagnosed with HEV infection by detection of specific antibodies (immunoglobulin M and immunoglobulin G) and/or positive RNA in blood and stool. In four patients serial HEV viral loads in blood were measured.ResultsOnly one patient reached HEV clearance after reduction of immunosuppressive therapy (predominantly reduction of MPA daily dose) alone, whereas six patients were treated with ribavirin after reduction of immunosuppressive therapy due to persistent virus replication. Four of six patients reached HEV clearance after 3 months of ribavirin therapy. HEV clearance was observed after 34–42 days. Two patients, both treated with rituximab within the last 12 months before diagnosis of HEV infection, needed prolonged ribavirin therapy due to persistent viral replication.ConclusionReduction of daily dose of MPA therapy alone in transplant patients with chronic HEV infection may not be sufficient to control viral replication. HEV clearance under ribavirin therapy shows interindividual variability. Therefore, serial viral monitoring may be useful to personalize treatment duration. Rituximab therapy is a risk factor for complicated‐to‐treat chronic HEV infection.

The Role of HLA and KIR Immunogenetics in BK Virus Infection after Kidney Transplantation.

BK virus (BKV) is a polyomavirus with high seroprevalence in the general population with an unremarkable clinical presentation in healthy people, but a potential for causing serious complications in immunosuppressed transplanted patients. Reactivation or primary infection in kidney allograft recipients may lead to allograft dysfunction and subsequent loss. Currently, there is no widely accepted specific treatment for BKV infection and reduction of immunosuppressive therapy is the mainstay therapy. Given this and the sequential appearance of viruria-viremia-nephropathy, screening and early detection are of utmost importance. There are numerous risk factors associated with BKV infection including genetic factors, among them human leukocyte antigens (HLA) and killer cell immunoglobulin-like receptors (KIR) alleles have been shown to be the strongest so far. Identification of patients at risk for BKV infection would be useful in prevention or early action to reduce morbidity and progression to frank nephropathy. Assessment of risk involving HLA ligands and KIR genotyping of recipients in the pre-transplant or early post-transplant period might be useful in clinical practice. This review summarizes current knowledge of the association between HLA, KIR and BKV infection and potential future directions of research, which might lead to optimal utilization of these genetic markers.

T cell and antibody responses to SARS-CoV-2: Experience from a French transplantation and hemodialysis center during the COVID-19 pandemic.

Immunosuppressed organ‐transplanted patients are considered at risk for severe forms of COVID‐19. Moreover, exaggerated innate and adaptive immune responses might be involved in severe progression of the disease. However, no data on the immune response to SARS‐CoV‐2 in transplanted patients are currently available. Here, we report the first assessment of antibody and T cell responses to SARS‐CoV‐2 in 11 kidney‐transplanted patients recovered from RT‐PCR–confirmed (n = 5) or initially suspected (n = 6) COVID‐19. After reduction of immunosuppressive therapy, RT‐PCR–confirmed COVID‐19 transplant patients were able to mount vigorous antiviral T cell and antibody responses, as efficiently as two nontherapeutically immunosuppressed COVID‐19 patients on hemodialysis. By contrast, six RT‐PCR–negative patients displayed no antibody response. Among them, three showed very low numbers of SARS‐CoV‐2–reactive T cells, whereas no T cell response was detected in the other three, potentially ruling out COVID‐19 diagnosis. Low levels of T cell reactivity to SARS‐CoV‐2 were also detected in seronegative healthy controls without known exposure to the virus. These results suggest that during COVID‐19, monitoring both T cell and serological immunity might be helpful for the differential diagnosis of COVID‐19 but are also needed to evaluate a potential role of antiviral T cells in the development of severe forms of the disease.

Post-Transplant Lymphoproliferative Disorder after Liver Transplant in the Pediatric Population: A Systematic Review

Background: Post-transplant lymphoproliferative disease (PTLD), a group of lymphoid disorders ranging from indolent polyclonal proliferation to aggressive lymphomas is a known complication following solid organ transplantation. The aim is to study the characteristics, predictive factors, management, and outcomes of PTLD among pediatric groups after liver transplantation in particular. Methods: Following the PRISMA guideline, we performed a comprehensive literature search on PubMed, Cochrane Library, Embase, and clinicaltrials.gov from the past ten years on May 04, 2020. We used the MeSH terms of organ transplantation and lymphoproliferative disorders. Initial search revealed 1741 articles. We excluded all case reports, case series, pre-clinical trials, review articles, and meta-analysis. We found five retrospectives observational, one observational cohort study, and one multicenter cohort in the pediatric population. We extracted the data for baseline characteristics, the reason for transplantation, recipient &amp; donor EBV status, immunosuppression used, type &amp; stage of PTLD, organ system involved, duration between transplant and PTLD diagnosis, treatment, response to therapy, adverse effects of therapy and mortality. Results: We included seven retrospective observational studies with a total (n) number of 3116 post-liver transplant pediatric patients, out of which 135 (4.33%) patients who developed PTLD as a complication of transplantation were studied. The male to female ratio was 41: 55 with the gender of 6 patients unknown. In five studies, with 118 PTLD patients, 34 recipients and 24 donors were positive for EBV at the time of liver transplantation. In addition to EBV, CMV status of patients in 5 studies showed 11/25 (44%) PTLD patients positive for CMV at the time of transplant. Post-transplant immunosuppression was achieved among these seven cohorts with cyclosporine, tacrolimus, OKT3, mycophenolate mofetil, prednisone, and basiliximab. The diagnosis was made via biopsy, showing all histopathological types including early lesions 14/46 (30.4%), polymorphic 13/46 (28.3%), monomorphic 18/46 (39.1%), and classic Hodgkin's lymphoma PTLD 1/46 (2.1%). Diffuse large B-cell lymphoma was the most common subtype in 6/18 (33.3%) of samples with monomorphic PTLD. Hsu, et al. in their study showed a five-year survival rate of 33.3% for St. Jude's classification stage IV lymphoma compared to 88.9% for stage I-III. The median age for 36 patients from three studies at the diagnosis of PTLD was 39.6 months (range 24-48 months). The median duration from transplantation to the diagnosis of PTLD was 13.48 months (range 8-24 months) in 54 patients from four studies. PTLD treatment was achieved with a combination of reduction or withdrawal of the immunosuppressive drugs with antiviral prophylaxis, chemotherapy, irradiation &amp; the use of monoclonal antibodies in a total of 57 PTLD patients for which post-transplant immunosuppression data was available. Study by Hsu, et al. reported that 5/16 (31.3%) patients had acute graft rejection and 2 had a chronic rejection in a group of 16 PTLD patients undergoing treatment for PTLD with a reduction in immunosuppressive therapy. The overall mortality in patients who developed PTLD was 15/54 (27.8%) in four of the studies. Conclusions: Pre-transplant EBV-naive status in patients was associated with a higher incidence of PTLD. Advanced stage (Stage IV) lymphoma was associated with poor survival outcomes. Monomorphic histopathology may be most commonly associated with PTLD post-liver transplant. The main approach for the treatment of PTLD is the reduction or complete withdrawal of immunosuppressive drugs, administration of antiviral drugs (ganciclovir/valganciclovir),and lymphoma treatment with chemotherapy or irradiation, and monoclonal antibody therapy such as rituximab. Management of PTLD with reduction or withdrawal of post-transplant immunosuppressive drugs in one cohort was associated with an increased risk of graft rejection. Thus immunosuppressive therapy maintaining a fine balance between the risk of graft rejection and risk of developing PTLD may be associated with better patient outcomes post-liver transplant. Disclosures Anwer: Incyte, Seattle Genetics, Acetylon Pharmaceuticals, AbbVie Pharma, Astellas Pharma, Celegene, Millennium Pharmaceuticals.: Honoraria, Research Funding, Speakers Bureau.

Malignancy after lung transplantation

Lung transplantation has become asuccessful life-saving treatment for patients with end-stage pulmonary disorders. Long-term survival outcomes after lung transplantation have been improving with increasing experience. Malignancies occupy the third position among the causes of death, particularly between years 5 to 10 from lung transplantation. The risk factors include predominantly high doses of immunosuppressive therapy, older age, infections caused by oncogenic viruses and smoking history. We retrospectively evaluated all patients undergoing lung transplantation between 2010 and 2019. The aim of this study was to analyze the incidence, type and location of tumors, time from detection, survival time and cause of death in patients with malignant tumors after lung transplantation. In total, 308 lung transplantations were performed at the 3rd Department of Surgery of the 1st Faculty of Medicine, Charles University and University Faculty Hospital in Motol between 2010 and 2019. Posttransplant malignancy was diagnosed in 32 patients; atumor was detected in the explanted lung in 5 patients. Lung cancer was the most frequent tumor in our study and was found in 13 patients (37%); 6 patients (17%) had anonmelanoma skin cancer; and posttransplant proliferative disease developed in 4 patients (12.5%). The incidence rate of other types of malignancy was low. Mean of survival after diagnosis was 152 days. Life time administration of immunosuppressive therapy in lung transplanted patients plays akey role in the prevention of rejection but on the other hand it represents arisk factor for cancer development. Oncological management of posttransplant cancer is based on reduction of immunosuppressive therapy, combined with surgical resection of solid organ tumors and other types of cancer therapy. Oncology screening tests should be done regularly as amethod of prevention, and for an early detection of any tumor.

Evidence of potent humoral immune activity in COVID-19-infected kidney transplant recipients.

Whether kidney transplant recipients are capable of mounting an effective anti‐severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) adaptive immune response despite chronic immunosuppression is unknown and has important implications for therapy. Herein, we analyzed peripheral blood cell surface and intracellular cytokine phenotyping by flow cytometry along with serum antibody testing in 18 kidney transplant recipients with active coronavirus disease 2019 (COVID‐19) infection and 36 matched, transplanted controls without COVID‐19. We observed significantly fewer total lymphocytes and fewer circulating memory CD4+ and CD8+ T cells in the COVID‐19 subjects. We also showed fewer anergic and senescent CD8+ T cells in COVID‐19 individuals, but no differences in exhausted CD8+ T cells, nor in any of these CD4+ T cell subsets between groups. We also observed greater frequencies of activated B cells in the COVID‐19 patients. Sixteen of 18 COVID‐19 subjects tested for anti‐SARS‐CoV‐2 serum antibodies showed positive immunoglobulin M or immunoglobulin G titers. Additional analyses showed no significant correlation among immune phenotypes and degrees of COVID‐19 disease severity. Our findings indicate that immunosuppressed kidney transplant recipients admitted to the hospital with acute COVID‐19 infection can mount SARS‐CoV‐2‐reactive adaptive immune responses. The findings raise the possibility that empiric reductions in immunosuppressive therapy for all kidney transplant recipients with active COVID‐19 may not be required.