Dual Immunosuppression Research Articles

Successful medical management of septic pericardial effusion in a dog

AbstractA 5‐year‐old, male, neutered cocker spaniel diagnosed with presumed immune‐mediated haemolytic anaemia 9 weeks previously, and treated with immunosuppressive medications with subsequent resolution of anaemia was presented for hyporexia, lethargy and tachypnoea of 48‐hour duration. Point‐of‐care thoracic ultrasonography revealed pericardial effusion causing cardiac tamponade. Cytological examination of the pericardial fluid showed an exudate with intracellular cocci chains and degenerate neutrophils, consistent with septic pericardial effusion. The culture of the effusion revealed a profuse growth of Staphylococcus pseudintermedius. Antibiotic and supportive therapy were instituted, immunosuppressant medications were tapered and stopped, the patient's clinical status progressively improved, and a full recovery ensued without need of further surgical and interventional procedures. Dual immunosuppression with prednisolone and ciclosporin was considered to be the most likely cause for the patient's clinical condition.

Improved Gvhd-Relapse Free Survival of Ex Vivo αβtcr/CD19 Depleted Allo-Sct Combined with In Vivo T Cell Depletion with ATG When Compared to T Cell Replete Transplantations with or without the Addition of ATG

Introduction The aim of allogeneic stem cell transplantation (allo-SCT) is to reach graft-versus-host disease, relapse free survival (GRFS). To reduce the incidence of graft-versus-host disease (GVHD), we have developed an allo-SCT platform combining ex vivo αβTCR/CD19 depletion with in vivo T-cell depletion through administration of antithymoglobulin (ATG). Here we compare GRFS to historical cohorts of T-cell replete allo-SCT. Methods Adults with hematological malignancies and transplanted between 2011 and 2022 were included in this retrospective analysis. Written informed consent was obtained in accordance with the JACIE guidelines. Clinical data was extracted from the EBMT registry. 3 cohorts were identified. Cohort A: Allo-SCT of unmanipulated peripheral blood derived mononuclear cells (PBMCs) of matched related donors (MRD) after non-myeloablative (NMA) or myeloablative (MA) conditioning without ATG. Cohort B: Allo-SCT of unmanipulated PBMCs of 10/10 or 9/10 matched unrelated donors (MUD) after NMA or MA conditioning with ATG. Patients in cohorts A & B received dual immunosuppression with cyclosporin (CsA) and mycophenolic acid (MMF). Cohort C: Allo-SCT of αβTCR/CD19 depleted PBMCs of MRD and MUD (10/10 and 9/10) after ATG and a myeloablative conditioning as previously described[1]. Patients in cohort C received 28 days of MMF. Cumulative incidence (CI) of GVHD was defined as time to onset of GVHD, with relapse and death as competing events. Overall survival (OS) was defined as time to death from any cause. CI of relapse was defined as time to relapse, with death as a competing event. Non-relapse mortality (NRM) was defined as time to death, without relapse or progression. Event free survival (EFS) was defined as the time to relapse, graft failure or death. GRFS was defined as the time to relapse, aGVHD 3-4 or extensive cGVHD, graft failure or death. CI of CMV and EBV reactivations were calculated with relapse and death as competing events. Results 341 patients were included (cohort A: N=63; cohort B: N=150; cohort C: N=128) (table 1). In T cell replete allo-SCT (A&B) ATG was administered to recipients of MUD and MA conditioning was administered to patients < 40 years with acute leukemia. In cohort C, all patients received ATG and an MA conditioning, regardless of age or underlying malignancy. This explains differences donor types and intensity of conditioning between the cohorts (table 1). Other clinical characteristics were comparable. Two year OS (A=66.7%; B=58.7%; C=63.8%) and EFS (A=57.1%; B=52%; C=55.7%) was comparable between the cohorts. Two year CI of relapse was also comparable (A=30%; B=23%; C=28%). Two year NRM appeared higher in B, but this difference did not reach significance (A= 9.8%; B=24%; C=15%). The CI of aGVHD grade 2-4 and 3-4 at day 100 was significantly higher in T cell replete allo-SCT with MUD (2-4; A=23%; B=37%; C=20% (p=0.002); 3-4: A=5%; B=16%; C=4.7% (p=0.043)). The incidence of extensive cGVHD was significantly higher in T cell replete allo-SCT of MRD. (A= 25%; B=13%; C= 2.3% (p=< 0.001)). The low incidence of grade 3-4 aGVHD and extensive cGVHD without an increase in relapse or NRM, translated into a superior 2 year GRFS in patients receiving ATG combined with an αβTCR/CD19 allograft (C=55.6%) as compared to T cell replete allo-HSCT of MRD (A=38.1%) and MUD (B=40.8%) (Figure 1, p=0.04). This difference remained significant in a multivariate analysis. Conclusion We demonstrate that αβTCR/CD19 depletion combined with ATG, with a myeloablative conditioning and a very short course of immunosuppression results in very low incidences of life-threatening GVHD and an improved GRFS as compared to T cell replete allo-SCT for adult patients up to the age of 70. This is likely to positively impact the long term quality of life in survivors of allo-SCT[2]. In addition, this platform provides a window for additional early post allo-interventions to further improve the control of underlying hematological malignancies. 1. de Witte, M.A., et al., alphabeta T-cell graft depletion for allogeneic HSCT in adults with hematological malignancies. Blood Adv, 2021. 5(1): p. 240-249. 2. Oerlemans, S., et al. Relapse and severe Graft-versus-Host Disease have a negative impact on long-term symptoms and quality of life of patients three years after allogeneic haematopoietic stem cell transplantation. Annual meeting EBMT 2022.

Single-Cell Analyses of Immune Microenvironment Informs Potential Benefits of Dual Macrophage-Targeted Therapy in Multiple Myeloma

Background: Multiple myeloma(MM) remains incurable as most patients endure multiple progressions. The complexity of tumor-associated environment(TME) in the progression of MM was not fully clarified. We investigated the atlas of TME during the process of disease progression and explored potential novel therapeutic target. Methods: We performed in-depth single-cell RNA sequencing(scRNAseq) analysis on the bone marrow(BM) cells from 14 MM patients at different disease stage and validate the findings from scRNAseq analysis by bulk RNAseq, flow cytometry analysis and in vitro & in vivo functional experiments. Results: We delineated a compromised TME during progression, characterized by abnormal enrichment of NK cells and exhausted-CD8+T cells, and reprogramming of macrophages(MΦs). A significant enrichment in NK cells and a decrease in CD34+ hematopoietic cells were observed, and the enrichment in NK cells was associated with the progression of disease stage. We found CD8+T cells expressing LAG3 and TIGIT were enriched in advanced disease stage. We further dissected the gene expression signatures of myeloid lineage cells and identified five monocyte/macrophage subsets, which were further divided into CD14+subsets (hm1, hm4, hm5) and CD16+subsets (hm3, hm6) （FigureA). In previous studies reported by other researchers, macrophages presenting M2 phenotype were highly enriched in the BM microenvironment and contributed to the progression of MM. We calculated M1/M2 polarization score for monocyte/macrophage clusters (Figure B). The gene expression signatures of the five macrophage clusters did not fit with either the canonical M1 or M2 classifications, demonstrating a reprogrammed phenotype rather than the M1/M2 paradigm. However, the two CD14+subsets (hm4 and hm5) only present in myeloma stage demonstrated high M2 score than other macrophage clusters (hm1, hm3 and hm6), implying the potential role of M2 polarization in myeloma progression. TAMs reprogramming was correlated with MM progression, mainly involving the CD14+subsets identified in late-stage-disease, featured by a prone-M2 phenotype and phagocytic dysfunction. Transcription factors associated with macrophage M2 polarization and immunosuppression were preferentially expressed in different TAMs clusters. We validate the reprogrammed phenotype of macrophages found in scRNAseq data by flow cytometry analysis and bulk RNAseq in patients samples and in vitro cell experiments. To interrogate global cell-cell interactions in myeloma during disease progression, we performed computational modeling using 'CellPhoneDB' to identify interactions between different monocyte/macrophage subclusters and plasma cells (PCs) in the BM microenvironment from different stage disease(Figure C). We identified two significantly enriched ligand-receptor pairs including the SIRPA-CD47 'don't eat me' pathway suppressing phagocytosis and the CD74-MIF(macrophage inhibitory factor) reshaping the MΦs phenotype. As CD47 and MIF molecules are linked with disease progression and adverse outcomes, we proposed the hypothesis that dual immunosuppression of TAMs by CD47 and MIF promotes disease progression in MM. Finally, we designed a dual-MΦs-targeted therapeutic strategy by combining anti-CD47 mAbs and MIF inhibitor to activate phagocytosis and repolarize MΦ to a functional phenotype, and proved the potent anti-tumor effect in vitro and in vivo. Conclusion: We identified compositional alterations in MM-TME during the disease progression and unraveled significant TAMs phenotype reprogramming and phagocytic dysfunction. We discovered critical dual cellular cross-talks (CD47 and MIF) between MΦs and PCs, and explored their function and clinical significance. Finally, we designed a dual MΦs-targeted therapeutic strategy and proved its anti-tumor effect and the potential clinical benefits. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

P21 The fly in the ointment: a rare cause of cytopaenia

Introduction/BackgroundThose working in Rheumatology frequently encounter cytopaenia both as adverse effects of many conventional and biological disease modifying drugs and as manifestations of autoimmune diseases. In cases where cytopaenia progresses, other explanations should be sought. Here we present an unusual cause of cytopaenia, seen in a patient with psoriatic arthritis on immunosuppression.Description/MethodAn 81-year-old woman with a diagnosis of psoriatic arthritis had been maintained on Infliximab (3mg/kg 8 weekly) and Methotrexate (7.5mg PO weekly) for 12 years. She then developed mild neutropaenia (1.52 x 109/L). Methotrexate was stopped and she continued on Infliximab monotherapy for several months, until ongoing neutropenia resulted in Infliximab being withheld. Sustained mild neutropenia and the development of thrombocytopenia (platelets 95 x 109/L) prompted a referral to Haematology, who suspected autoimmune neutropenia and advised checking haematinics and monitoring the FBC monthly. The neutropenia improved and Infliximab was restarted.Over 6 months she developed gradually worsening and persistent pancytopenia (neutrophils 1.36 x 109/L, platelets 134 x 109/L, Hb 91 g/L). There was no history of fevers, night sweats, bone pain, headaches, recurrent infections, lumps or bumps, chest symptoms, change in bowel habit or urinary symptoms. Examination revealed no pallor, jaundice, clubbing, peripheral lymphadenopathy or sternal tenderness. The chest was clear and the abdomen soft with no organomegaly.Repeat bloods showed microcytic hypochromic anaemia (Hb 86 g/L, MCV 73 fL, MCH 24.6 pg) with target cells on blood film. Iron was low (iron 5.1 umol/L, transferrin 1.52 g/L). Serum protein electrophoresis showed paraprotein bands with abnormal serum free light chain assay possibly consistent with myeloma, lymphoma or MGUS. Haematology suspected myelodysplasia, potentially secondary to previous long term Methotrexate therapy. A bone marrow biopsy was performed; the unexpected result was Leishmaniasis. Our patient was admitted to hospital and, following microbiology review, was treated with liposomal amphotericin (IV) for Visceral Leishmaniasis as an inpatient. Her Infliximab was suspended and her joints have remained quiescent.Discussion/ResultsLeishmania is an intracellular parasitic protozoan that is transmitted to humans by sandfly bites. It is endemic in Africa, America, Central Asia and the Mediterranean. It usually has an incubation period of 3-8 months. Those who are immunosuppressed, for example due to immunotherapy or HIV, are at increased risk of infection. The patient had only ever travelled to Portugal and Gibraltar. One trip to Gibraltar occurred whilst on dual immunosuppression with Infliximab and Methotrexate and prior to the development of neutropenia. She has no recollection of any insect bites.Visceral leishmaniasis is variable in the severity of symptoms experienced ranging from asymptomatic to a febrile illness with lymphadenopathy, hepatospenomegaly, night sweats, cutaneous pigmentation, appetite loss and weight loss, which can be drastic. Our patient indeed described significant weight loss in the preceding year.This case demonstrated the laboratory abnormalities which are typical of Visceral Leishmaniasis: pancytopenia and hypergammaglobulinaemia.Treatment for visceral Leishmaniasis has classically been with pentavalent antimonials (based on the heavy metal antimony) such as Sodium stibogluconate. Their toxicity profile and growing resistance however has meant amphotericin B is often used first line. This is given intravenously, with the liposomal form preferred as it has lower toxicity. Our patient received 4 mg per kg daily on days 1–5, 10, 17, 24, 31, and 38, following the FDA-approved regimen for immunosuppressed patients.Without treatment Leishmaniasis is usually fatal, with haemmorrhage, infection, cachexia and multiorgan failure as causes of death.Key learning points/ConclusionWhilst patients with Rheumatological conditions may have cytopaenia due to their disease or its treatment, persistent, progressive or unexplained results should be investigated further. In patients with cytopaenia of unclear aetiology, thorough investigation with Haematology involvement is mandatory. You may find an unexpected diagnosis … we did!

POS-075 ASSOCIATION OF CYP3A5 POLYMORPHISM WITH INFECTIONS IN KIDNEY TRANSPLANT RECIPIENTS

Kidney transplant recipients who are non-expressors (CYP3A5*3/*3 genotype) are known to have increased dose-adjusted trough concentrations of tacrolimus as compared with those who are CYP3A5 expressors (CYP3A5*1/*1 and CYP3A5*1/*3 genotypes), possibly delaying achievement of target concentrations. Also, tacrolimus increases the exposure of mycophenolate mofetil by 30%. Both these factors in patients who are non-expressors can increase the risk of infections. However, there is lack of data corelating CYP3A5 polymorphism with infections post-kidney transplant. We retrospectively evaluated 181 out of 260 kidney transplant recipients who were at regular follow up at the transplant clinic of a tertiary referral center in western India from 2018 to 2021. Recipients on tacrolimus for at least 3 months post-transplant were eligible for evaluation. They were categorized into non-expressors (CYP3A5*3/*3) and expressors (CYP3A5*1/*1 and CYP3A5*1/*3 genotype). The infectious burden was evaluated by the incidence of total infections and further classified according to etiologies such as bacterial, viral, parasitic, fungal and mycobacterial and specific system patterns such as diarrhea, urinary tract infections, tropical illnesses, infections of the skin, soft tissue and musculoskeletal system. The incidence of non-infectious diarrhea was evaluated as a measure of increased MMF exposure. Multivariate logistic regression was performed to evaluate the impact of genotype on the risk of infections. Out of 181 recipients, 103 (56.9%) were non-expressors and 78 (43%) were expressors. Mean (SD) age was 35±10 years with 128 (70.7%) being males. Their mean (SD) eGFR at enrollment was 57.72± 23.15 ml/min/1.73m2. Higher number of non-expressors received antibody induction at the time of transplant but this difference was not statistically significant (52.4% vs 42.3%, p= 0.177). New onset diabetes after transplant observed in the non-expressor group was higher, but did not reach statistical significance (37.2% vs 29.1%, p= 0.252). Overall incidence of infections was similar in both groups (85.4% vs 89.7%, p = 0.389), however tuberculosis was significantly more common in non-expressors (16.7 % vs 6.8%, p= 0.036). This association remained significant (p= 0.043) after controlling for factors such as history of tuberculosis before transplant, antibody induction, living vs deceased donor, triple or dual immunosuppression at time of transplant, and anti-rejection therapy. Infectious diarrhea, fungal infections, parasitic infections, were higher in non-expressors, but this difference was not statistically significant. Hospitalization for infectious diarrhea was significantly higher in non-expressors (20.5% vs 7.8%, p= 0.012). Non-infectious diarrhea attributed to MMF was significantly higher in non-expressors (32.1% vs 19.2%, p= 0.035). Viral infections were higher in non-expressors but were statistically insignificant (51.3% vs 40.8%, p= 0.160). Mortality due to infectious causes was higher in non-expressors but was not statistically significant (6.4% vs 3.9%, p= 0.439). Non-expressor CYP3A5 genotype in kidney transplant recipients is associated with a significant burden of infectious complications and a higher incidence of MMF induced diarrhea. A genotype-based approach may help individualizing dosing of tacrolimus in this population.

Monoclonal antibody-mediated immunosuppression enables long-term survival of transplanted human neural stem cells in mouse brain.

BackgroundAs the field of stem cell therapy advances, it is important to develop reliable methods to overcome host immune responses in animal models. This ensures survival of transplanted human stem cell grafts and enables predictive efficacy testing. Immunosuppressive drugs derived from clinical protocols are frequently used but are often inconsistent and associated with toxic side effects. Here, using a molecular imaging approach, we show that immunosuppression targeting costimulatory molecules CD4 and CD40L enables robust survival of human xenografts in mouse brain, as compared to conventional tacrolimus and mycophenolate mofetil.MethodsHuman neural stem cells were modified to express green fluorescent protein and firefly luciferase. Cells were implanted in the fimbria fornix of the hippocampus and viability assessed by non‐invasive bioluminescent imaging. Cell survival was assessed using traditional pharmacologic immunosuppression as compared to monoclonal antibodies directed against CD4 and CD40L. This paradigm was also implemented in a transgenic Alzheimer's disease mouse model.ResultsGraft rejection occurs within 7 days in non‐immunosuppressed mice and within 14 days in mice on a traditional regimen. The addition of dual monoclonal antibody immunosuppression extends graft survival past 7 weeks (p < .001) on initial studies. We confirm dual monoclonal antibody treatment is superior to either antibody alone (p < .001). Finally, we demonstrate robust xenograft survival at multiple cell doses up to 6 months in both C57BL/6J mice and a transgenic Alzheimer's disease model (p < .001). The dual monoclonal antibody protocol demonstrated no significant adverse effects, as determined by complete blood counts and toxicity screen.ConclusionsThis study demonstrates an effective immunosuppression protocol for preclinical testing of stem cell therapies. A transition towards antibody‐based strategies may be advantageous by enabling stem cell survival in preclinical studies that could inform future clinical trials.

SARS‑CoV‑2 vaccination in liver transplant recipients: factors affecting immune response and refusal to vaccine.

The effectiveness of SARS‑CoV‑2 vaccination in liver transplant (LT) recipients varies between reports. In this study, we analyzed the immune response to the SARS‑CoV‑2 vaccine, factors affecting the response, and reasons for the vaccine refusal. Among 300 consecutive LT recipients, 75% were vaccinated. The humoralresponse was assessed by the quantitative determination of antitrimeric spike protein‑specific IgG antibodies to SARS‑CoV‑2. Thirty‑four vaccinated patients with prior SARS‑CoV‑2 infection were analyzed separately. Among 192 LT recipients vaccinated without past natural infection, 69% developed the immune response (median time of 125 days after the second dose). Older age, worse kidney function, and dual immunosuppression negatively affected the humoral response. Mycophenolate mofetil increased the risk of nonresponse (odds ratio [OR], 2.99; 95% CI, 1.45-6.19). The antibody concentration was higher in the first 90 days from the second dose and stable as compared with 90-150 days and over 150 days. LT recipients with prior COVID‑19 presented with a robust immune response (100%). The female sex, living in a rural area, lower body mass index, and younger age (all P <0.05) were associated with the refusal of the vaccine. The lower immune response in the vaccinated LT recipients than in the general population justifies administering the third dose of the vaccine. However, more data are needed to recommend any therapy modification before the vaccination.

Monotherapy Immunosuppression in Pediatric Heart Transplant Recipients

<h3>Purpose</h3> Although dual-drug immunosuppression is standard for rejection prophylaxis in pediatric heart transplant (HT), single-drug immunosuppression (monotherapy) may be sufficient for certain patients. We describe the experience with monotherapy at a single institution. <h3>Methods</h3> Retrospective review of HT patients at a single pediatric transplant center who underwent HT between from 1/2001- 12/2020 and were treated with calcineurin-inhibitor monotherapy for > 1 month. Patients were transitioned to monotherapy per primary clinician due to concerns for over-immune suppression or post-transplant lymphoproliferative disorder (PTLD). Clinical characteristics and patient outcomes were analyzed. <h3>Results</h3> During the study period, 12/333 (3.6%) patients were placed on monotherapy at a median of 4.6 years post-HT [IQR 1.9-6.7 years]. Ten (83%) were transplanted as infants and 6 (50%) were transplanted for congenital heart disease. Nine (75%) were on tacrolimus monotherapy and 3 were on cyclosporine monotherapy. Indication for monotherapy was serious or chronic infection in 6 (50%), PTLD in 4 (33%), and neutropenia in 2 (16%). At a median follow-up of 1.5 years [IQR 1.1-2.2 years], 2 (16%) patients experienced grade 1B/1R cellular rejection, one of which required mechanical support and was transitioned back to dual therapy immunosuppression. All patients remain alive, with the remaining 11 (91%) still on monotherapy at time of last follow-up. <h3>Conclusion</h3> Monotherapy immunosuppression with calcineurin inhibitors can be safely used in a subset of pediatric HT patients with evidence of over-immune suppression without significant increase in rejection.

Left Ventricular Apical Hypertrophic Cardiomyopathy After Heart Transplant: Case Report.

<h3>Background</h3> Apical hypertrophic cardiomyopathy (ApHCM) is a rare variant of HCM which predominantly involves the left ventricular apex, and therefore does not typically result in obstructive physiology. It has been infrequently reported in general, with a rarity in heart transplant patients, mostly due to a modest or delayed presentation with symptoms. We present a case of a heart transplant patient with a stable postoperative course who was incidentally found to have ApHCM during follow up non-invasive testing. <h3>Case presentation</h3> Patient is a 45-year-old gentleman with a history of cardiac transplantation in March 2013 for heart failure in the setting of arrhythmogenic right ventricular cardiomyopathy, on chronic dual immunosuppression therapy. He has maintained preserved allograft function with no treatable rejection. Mild donor-derived atherosclerotic disease was found on the first surveillance coronary angiogram with no progression over subsequent years. He has remained asymptomatic and extremely active. In September 2020, he underwent surveillance myocardial perfusion imaging, which showed a large area of moderately severe ischemia laterally extending from the mid ventricle to the apex, prompting coronary angiography which did not show significant epicardial coronary disease. A subsequent echocardiogram with contrast demonstrated normal biventricular function, with evidence of hypertrophy with classic spading of the apical myocardium, along with a corresponding reduction in longitudinal straining, consistent with ApHCM. Upon retrospective evaluation of prior echocardiograms, the finding was likely also present though less evident. Holter monitor detected no arrhythmia and treadmill exercise testing confirmed normal functional capacity, normal blood pressure response to exercise, and no arrhythmias.. Review of the details of the donor's death did not suggest cardiac etiology or arrhythmia. <h3>Conclusion</h3> In our literature search, we found only one similar presentation in a cardiac transplant patient with apical HCM. In general, familial ApHCM is known to follow an autosomal dominant inheritance, whereas sporadic forms are caused by acquired mutations of various sarcomeric and nonsarcomeric protein genes. Other associated factors include long-standing high-pressure states, as well as medications, with one case report suggesting a possible relation with tacrolimus. One literature review suggested a possible increase in mortality in ApHCM patients. Therefore, although it is usually a rare condition, pre and post transplant monitoring must take into account that this condition may clinically manifest post transplantation.

Disseminated nocardiosis and focal nontuberculous mycobacterial infection coexisting in a renal transplant recipient - A case report

Solid organ transplant (SOT) recipients are at increased risk of opportunistic infections, as they are on immunosuppressive drugs. The risk increases if the cumulative immunosuppression is high, especially when the patient is treated for acute rejection episodes. Multiple opportunistic infections in the same patient are reported in SOT recipients. We report a 43-year-old man, renal allograft recipient, 15 years posttransplant, on dual immunosuppression who presented with fever, generalized skin rashes, and altered sensorium. He was recently treated with pulse methylprednisolone injections for acute graft rejection episode. He had multiple pustules all over the body, predominantly over the face, eyelids, chest, and lower limbs. Pus from the facial lesion grew Nocardia, and tissue culture of skin ulcer from the leg grew nontuberculous mycobacteria. Combined infection with these organisms posed diagnostic challenge as both can present with cutaneous manifestation, both organisms are acid-fast bacilli, and both organisms were detected and grown from the sample taken from one of the large skin ulcers. It was important to identify both the organisms from the skin ulcer as the treatment options are different.

POS-695 INTESTINAL OBSTRUCTION COMPLICATING CAMPYLOBATER COLI ENTERITIS IN RENAL TRASNPLANTATION PATIENT

A 30 year old male, with cadaveric renal transplantation 2 years ago , his primary disease was anti-GBM disease diagnosed one year prior to transplantation and treated with 14 sessions of plasma exchange, steroids and cyclophosphamide shortly after that he was initiated on hemodialysis followed by renal transplantation. Two months post renal transplantation his course was complicated by biopsy proven mixed rejection (T-Cell mediated rejection type IA) and active Antibody medicated rejection , however ,C4d negative. The patient received pulsed steroids, 3 sessions Plasma-exchange and IVIG 2g/kg. He completed 2 doses of Rituximab and his serum creatinine was stable at 200-220 micromole/L. The patient was admitted after 3 weeks with persistent vomiting and abdominal pain and abdominal distention, his serum creatinine 304 micromole/L, abdominal x-ray showed multiple air fluid levels with dilatation of small bowel loops. CT scan with oral contrast showed multiple dilated small bowel loops down to the terminal ileum with caliber of 3.5 mm with multiple air-fluid levels and fecal loading in distal ileum loop with collapsed colon. The contrast media reached into the small bowel in left mid abdomen at mid jejunal loop. Stool culture grew campylobacter coli, BK PCR was positive of 371,000 copies. Other infectious causes of diarrhea were excluded. The patient completed 7 days of ciprofloxacin and treated with intravenous immunoglobulins (IVIG) . His mycophenolic acid was stopped, and he was maintained on dual immunosuppression therapy in form of tacrolimus and steroids. The patient was booked for upper endoscopy and colonoscopy in outpatient setting. View Large Image Figure ViewerDownload Hi-res image Download (PPT) Diarrhea is a common symptom in renal transplant patient population. The main causes of diarrhea after transplantation include infections, immunosuppressive drugs, antibiotics, and other drugs. Viral causes of diarrhea are the most frequently reported and usually last up to 3 days. Patients have tendency to develop Clostridium difficile after antibiotics. Other enteric bacteria responsible for diarrhea are Shigella, Salmonella typhi, Salmonella typhimurium and Campylobacter. CMV can cause enterocolitis, with or without fever, gastrointestinal bleeding, perforation, and toxic megacolon are possible complications. Incidence of diarrhea with mycophenolate mofetil dose of 2 g/day was higher than in other immunosuppressants like azathioprine. Campylobacter infection has prominent features like terminal ileitis, cecitis and mesenteric adenitis. Proton pump inhibitors are main risk factor for campylobacter enteritis as it lowers the gastric juice acidity allowing for pathogen survival. Campylobacter was detected in stool culture of a 31-year-old male patient diagnosed with immunoproliferative small intestinal disease (IPSID) and it was positive in tissue biopsy samples. Antibiotics treatment is enough to eradicate campylobacter and reduce the risk of IPSID. Diarrhea is a common symptom post renal transplantation, Campylobacter coli can be one of the main causes of ileocecal enteritis and may cause small bowel obstruction, treatment is usually conservative with antibiotics.

Abstract 14116: Favorable Outcomes for Heart Transplantation in Barth Syndrome as Demonstrated by Multicenter/multiregistry Analysis

Introduction: Barth Syndrome (BTHS) is a rare (~1/350,000), X-linked mitochondrial disease characterized by cardioskeletal myopathy and neutropenia. Reported outcomes after heart transplant (HT) are limited to case reports. We sought to identify a large cohort of BTHS HT recipients to describe clinical outcomes. Hypothesis: HT in BTHS is associated with non-inferior survival, acute rejection (AR), infection, and vasculopathy (CAV) relative to non-BTHS dilated cardiomyopathy (DCM). Methods: We analyzed data from the Barth Syndrome Registry and Repository (BRR), Pediatric Heart Transplant Society (PHTS), and Scientific Registry of Transplant Recipients (SRTR). To avoid recounting patients occurring in &gt;1 source, we used years of birth, listing, and HT and listing/HT city to link records across registries. BTHS HT recipients were matched 1:4 on age, era, urgency status, and use of ECMO/VAD to male, non-BHTS, DCM HT recipients in PHTS. Survival was analyzed for all BTHS HT recipients. Because BRR and SRTR morbidity data are limited, AR, infection, malignancy, and CAV were analyzed only for those with PHTS data. Results: Forty-seven BTHS patients with 51 listings and 43 HTs (including 2 re-transplants) were identified; 29 BTHS HTs (1 re-transplant) had data in PHTS. Median age at HT was 1.9 yrs (IQR: 0.6-5.8) with 35% &lt;1 years-old at HT. Median follow up was 4.2 yrs (2.1-9.1). Mechanical circulatory support at HT was common (VAD 29%, ECMO 5%). We found no difference in survival between BTHS and non-BTHS HT recipients (HR 0.93, 95% CI 0.40-2.14). Freedom from infection (HR 0.63, 0.33-1.20), bacterial infection (HR 0.76, 0.29-1.99), malignancy (HR 0.22, 0.02-2.02), and CAV (HR 0.55, 0.15-1.97) were also similar between the groups. BTHS HT recipients had greater freedom from AR (HR 0.39, 0.17-0.87). Use of induction therapy (62 vs 74%, p=0.21), steroids at 30 days (76 vs 62%, p=0.17), and dual or triple immunosuppression at 1 year (80 vs 84%, p=0.58) were similar for BTHS and non-BTHS recipients. Conclusions: In this largest cohort yet reported, BTHS HT recipients show equivalent survival and freedom from infection, malignancy, and CAV, with a lower risk of acute rejection. Thus, individuals with BTHS should not be excluded from HT solely based on the diagnosis of BTHS.

Regulatory T cells for minimising immune suppression in kidney transplantation: phase I/IIa clinical trial

ObjectiveTo assess whether reshaping of the immune balance by infusion of autologous natural regulatory T cells (nTregs) in patients after kidney transplantation is safe, feasible, and enables the tapering of...

SUCCESSFUL CALCINEURIN-INHIBITOR-FREE IMMUNOSUPPRESSION REGIMEN WITH SIROLIMUS AND PREDNISONE IN LUNG TRANSPLANT RECIPIENTS: A CASE SERIES

SESSION TITLE: Fellows Transplantation Posters SESSION TYPE: Fellow Case Report Posters PRESENTED ON: October 18-21, 2020 INTRODUCTION: The current standard of care for immunosuppression after lung transplantation is the use of triple agents with a calcineurin inhibitor (CNI), cell cycle inhibitor (CCI), and corticosteroids (CS) with the calcineurin inhibitor (CNI) being the backbone of the regimen. However, the use of immunosuppressant drugs is frequently complicated by the development of malignancy, nephrotoxicity, cytopenias, and infection, usually requiring a reduction in immunosuppression. In cases where both CCIs and CNIs must be stopped, mTOR inhibitors are frequently used in an effort to maintain sufficient immunosuppression. A definitive role for mTOR inhibitors for immunosuppression post-lung transplant, however, remains unclear although there have been some studies in renal transplant recipients. There are challenges with transitioning to mTOR inhibitors due to concerns over wound healing in the first year, potential pulmonary toxicities, as well as the lack of data on efficacy. To our knowledge, there is no data on the outcomes of lung transplant patients maintained on dual immunosuppression with mTOR inhibitors and steroids alone. CASE PRESENTATION: We present a series of three lung transplant patients maintained on an immunosuppressant regimen of sirolimus and prednisone. All three patients remained free of acute cellular rejection and antibody-mediated rejection. Of the three patients, two remain alive and one patient died from multi-system organ failure secondary to sepsis. DISCUSSION: This small case series highlights the successful use of dual immunosuppression with mTOR inhibitors and corticosteroids in patients with contraindications to both calcineurin inhibitors and cell cycle inhibitors. CONCLUSIONS: More data is required to determine how mTOR-CS dual immunosuppression compares to traditional CCI-CNI-CS triple immunosuppression in regards to transplant rejection and the safest way to transition to this regimen when necessary. Reference #1: Ivulich S, Westall G, Dooley M, Snell G. The Evolution of Lung Transplant Immunosuppression. Drugs. 2018;78(10):965-982. doi:10.1007/s40265-018-0930-6 DISCLOSURES: No relevant relationships by Shambhu Aryal, source=Web Response No relevant relationships by Adam Cochrane, source=Web Response No relevant relationships by Margaret Fregoso, source=Web Response No relevant relationships by Vikramjit Khangoora, source=Web Response Consultant relationship with Veracyte Please note: $1001 - $5000 Added 04/03/2020 by Steven Nathan, source=Web Response, value=Honoraria Consultant relationship with United Therapeutics Please note: $5001 - $20000 Added 05/27/2020 by Steven Nathan, source=Web Response, value=Consulting fee Consultant relationship with Bellerophon Please note: $5001 - $20000 Added 05/27/2020 by Steven Nathan, source=Web Response, value=Consulting fee Speaker/Speaker's Bureau relationship with Roche-Genentech Please note: $5001 - $20000 Added 05/27/2020 by Steven Nathan, source=Web Response, value=Honoraria Speaker/Speaker's Bureau relationship with Boerhinger-Ingelheim Please note: $20001 - $100000 Added 05/27/2020 by Steven Nathan, source=Web Response, value=Honoraria

Vogt–Koyanagi–Harada Is a Curable Autoimmune Disease

Purpose:It is crucial to subdivide Vogt–Koyanagi–Harada (VKH) disease into two subentities, initial-onset disease versus chronically evolving disease. For early diagnosis and precise follow-up of VKH choroiditis, the “Revised criteria for VKH” are no more sufficient for the appraisal of VKH and new biomarkers for disease activity are needed. It has been shown that, if initial-onset disease is treated promptly within the “therapeutic window of opportunity” and long enough with dual steroidal and non-steroidal immunosuppression, the disease can be cured in a large proportion of cases, an approach still contested. The proportion of chronic evolution and/or sunset-glow fundus (SGF) following steroidal monotherapy versus dual steroidal and non-steroidal immunosuppression was compared.Methods:A literature search was performed, identifying studies on initial-onset VKH treated either by steroidal monotherapy or dual immunosuppression. Evolution toward chronicity and/or SGF was compared in both groups.Results:Twenty studies were identified with reported long-term outcomes. In 16 studies, 802 patients received steroidal monotherapy, while in 4 studies, 172 patients received dual steroidal and non-steroidal immunosuppression. Chronic evolution and SGF occurred, respectively, in 44% and 59% in the corticosteroid-alone group versus 2.3% and 17.5% in the dual therapy group with no chronic evolution in three studies and no SGF in two studies.Conclusions:Chronic evolution and SGF are significantly less frequent in initial-onset VKH when treated with immediate dual steroidal and non-steroidal immunosuppression with a high proportion of healed cases. This combined approach seems recommended in the management of initial-onset VKH disease.

Subcutaneous panniculitis-like T-Cell lymphoma in a child presenting as an abdominal wall mass

Abstract Childhood panniculitides are not common. Histopathological diagnostic approach is vital to differentiate this group of pathologies that commonly present with inflammation of the subcutaneous adipose tissue. Pediatric subcutaneous panniculitis-like T-cell lymphomas are rare. Treatment modalities include observation, surgical excision, radiotherapy, immunosuppression, and chemotherapy. The case of an 18-month female who presented with a flank mass that was diagnosed as a subcutaneous panniculitis-like T-cell lymphoma and successfully managed with intensity-reduced, dual agent immunosuppression is described.

A97 TACROLIMUS-ASSOCIATED HEMOLYTIC UREMIC SYNDROME IN A PEDIATRIC LIVER TRANSPLANT RECIPIENT

Abstract Background Tacrolimus associated hemolytic uremic syndrome (HUS) has been reported in renal and pediatric cardiac transplantation. Furthermore, in adults receiving liver transplant, there are reports of multiorgan failure, death, and end stage renal failure secondary to tacrolimus induced HUS [J NEPHROL 2003; 16: 580–585]. Although tacrolimus is commonly used in pediatric liver transplantation, there are no reports of the same entity. Aims To describe a case of tacrolimus induced HUS in a pediatric liver transplant patient and subsequent re-initiation of tacrolimus. Methods The patient was followed during his hospital admission and after discharge. Results An 8-year-old male with Progressive Familial Intrahepatic Cholestasis (PFIC) Type III, diagnosed at age 2, presents for living unrelated donor liver transplantation. He was previously well compensated but began to deteriorate in the months leading up to transplant with rising liver enzymes, ascites, and mild encephalopathy after presumed viral gastroenteritis. He receives a left lateral segment liver transplantation and is started on tacrolimus immunosuppression post liver transplant as per protocol. On initiation of tacrolimus, the patient’s hemoglobin trends downward to a trough of 59 g/L four days post transplantation. Concurrently, his haptoglobin is &amp;lt;0.10g/L, total bilirubin peaks at 708 umol/L, creatinine rises to a peak of 71 umol/L, urea peaks at 23.0 mmol/L. Platelets reach a nadir at 27x10^9/L, seven days post transplantation. Direct antibody test was negative, and blood cultures remained negative. Given the constellation of hemolytic anemia, thrombocytopenia, and acute kidney injury following initiation of tacrolimus, a diagnosis of atypical HUS is made. Tacrolimus is discontinued, intravenous methylprednisolone is started and the patient is switched to cyclosporine immunosuppression. Both the hemolysis and kidney injury resolve gradually. The patient develops side effects from cyclosporine including hypertension and excessive hair growth. One month post discontinuation of tacrolimus, he is started on sirolimus, while weaning steroids and cyclosporine. Seven weeks post discontinuation of tacrolimus, he is restarted on tacrolimus and is currently tolerating dual immunosuppression with no signs of HUS recurrence. Conclusions Atypical HUS secondary to tacrolimus post liver transplant in children is a rare entity. In the acute period, discontinuation of tacrolimus is essential to preserve renal function given potentially devastating outcomes seen in adults. Cyclosporine is an alternative immunosuppressive agent used in pediatric solid organ transplantation, although it has also been implicated in causing HUS. Funding Agencies None

P210 Clostridium difficile infection in pre-existing inflammatory bowel disease: Management and outcomes

Abstract Background Inflammatory bowel disease (IBD) is a recognised risk factor for clostridium difficile infection (CDI), and CDI in an IBD patient is associated with higher morbidity and mortality. It is thought that factors including alterations in the gut microbiome, mucosal disruption and immunosuppression provide a synergistic environment for CDI to complicate an IBD flare. Despite this, there is conflicting evidence available on management. Our aim was to examine a series of recent cases to assess our own practice and subsequent outcomes. Methods A retrospective analysis was carried out of hospitalised cases of CDI in IBD patients in Greater Glasgow and Clyde from 2017 to 2018. Patients were identified via the CDI database held by the microbiology department; those with co-existing IBD were extrapolated. Data collected included demographics, IBD subtype and presence of other CDI risk factors. Severity of symptoms was assessed using Truelove and Witts Criteria. Initial management and changes following the diagnosis of CDI were noted. Outcomes were measured by the length of stay, survival to discharge, and requirement for surgical intervention. One year outcomes were assessed by recording mortality, treatment escalation and re-admission to hospital. Results 29 patients in total were identified (61% female, 39% male). Twenty-one had a diagnosis of ulcerative colitis, 7 Crohn’s disease, and 1 IBD unclassified. Twenty-four were on immunosuppressive therapy at the time of CDI, 11 were on dual or triple immunosuppression. This was continued during admission in all but three cases. Once the diagnosis of CDI was established, metronidazole was given in 16 cases and vancomycin in 13. Steroid treatment varied - 13 received oral steroids, 5 IV steroids and 11 no steroids. There was no clear correlation between steroid management and outcome. Assessment with the Travis criteria on day 3 indicated a high chance of colectomy in 12 patients, however only one required surgical intervention. No patients received a faecal transplant. The median length of stay was 15 days (range 3–169). One patient did not survive to discharge. In those surviving to discharge, a further 6 had died at one year, bringing the one-year mortality to 24%. Three had CDI as a contributory factor listed on the death certificate. 31% of surviving patients had their IBD treatment escalated in the year following admission, 17% were treated for CDI relapse, and 28% had readmission to hospital. Conclusion Managing CDI in patients with co-existing IBD is challenging. This case series highlights the lack of consensus on how this should be approached, even within a single health board. Morbidity and mortality are high. This suggests that a wider body of work is required to establish guidelines and provide better outcomes.

Hand transplantation in the United States: A review of the Organ Procurement and Transplantation Network/United Network for Organ Sharing Database.

Hand transplantation is the most common application of vascularized composite allotransplantation (VCA). Since July 3, 2014, VCAs were added to the definition of organs covered by federal regulation (the Organ Procurement and Transplantation Network (OPTN) Final Rule) and legislation (the National Organ Transplant Act). As such, VCA is subject to requirements including data submission. We performed an analysis of recipients reported to the OPTN to have received hand transplantation between 1999 and 2018. Forty-three patients were identified as having been listed for upper extremity transplantation in the United States. Of these, 22 received transplantation prior to July 3, 2014 and 10 from then to December 31, 2018. Of patients transplanted after 2014, posttransplant functional scores included a decrease in Disabilities of the Arm, Shoulder and Hand questionnaire in 3 of 10 patients, Carroll test scores ranging from 9 to 60 of 99, and monofilament testing with protective sensation achieved in 4 of 6 patients. Complications included rejection in nine recipients with Banff scores from II-IV. One patient experienced graft failure 5days after transplantation. Of the remaining patients, two were reported as receiving monotherapy and seven receiving dual or triple immunosuppression therapy. The inclusion of VCA in the OPTN Final Rule standardized parameters for safe implementation and data collection.

Kaposi Sarcoma in HIV-positive Solid-Organ Transplant Recipients: A French Multicentric National Study and Literature Review.

Kaposi sarcoma is a vascular tumor related to herpesvirus-8 and is promoted by immunosuppression. For the last 15 years, human immunodeficiency virus (HIV) patients have had access to organ transplantation. The dual immunosuppression of HIV and immunosuppressive treatments might increase the risk and severity of Kaposi sarcoma. We conducted a multicentric retrospective study by collecting cases from French databases and society members of transplanted patients, among which 7 HIV-infected patients who subsequently developed Kaposi sarcoma were included. In the CRISTAL database (114 511 patients) and the DIVAT (Données Informatisées et VAlidées en Transplantation) database (19 077 patients), the prevalence of Kaposi sarcoma was 0.18% and 0.46%, respectively, in transplanted patients; these values compare with 0.66% and 0.50%, respectively, in transplanted patients with HIV. The median time from HIV infection to Kaposi sarcoma was 20 years. Kaposi sarcoma occurred during the first year after transplantation in most cases, whereas HIV viral load was undetectable. Only 2 patients had visceral involvement. Five patients were treated with conversion of calcineurin inhibitor to mammalian target of rapamycin inhibitor, and 5 patients were managed by decreasing immunosuppressive therapies. At 1 year, 4 patients had a complete response, and 3 had a partial response. In our study, Kaposi sarcoma in transplanted patients with HIV did not show any aggressive features and was treated with the usual posttransplant Kaposi sarcoma management protocol.