Post-transplant Immunosuppression Research Articles

Vaccination for solid organ transplanted patients: Recommendations, efficacy, and safety.

Solid organ transplant recipients face unique challenges in managing their immunosuppressed status, making vaccination a critical consideration. This review aimed to comprehensively analyze current recommendations, evaluate the efficacy of vaccinations in this population, and assess safety concerns. We explored the latest evidence on vaccine types, timing, and potential benefits for transplant patients, highlighting the importance of individualized approaches for routinely used vaccines as well as coronavirus disease 2019 vaccines. By synthesizing available data, this review underscored the pressing need to optimize vaccination strategies, ensuring that transplant recipients can obtain the full protection against many pathogens while minimizing risks associated with their post-transplant immunosuppression.

Abstract 4139613: Orthotopic Heart Transplant in a Patient with Chronic Lymphocytic Leukemia: Challenges in Management

Description of Case: A 67-year-old female with a long-standing history of chronic lymphocytic leukemia (CLL, stage 0) on surveillance protocol, end stage heritable cardiomyopathy (titin mutation positive) with ejection fraction 15% and severe mitral regurgitation was referred to our center for advanced therapy evaluation. On evaluation, right heart catheterization showed normal filling pressures but decreased cardiac index (RA 4, PCWP 8, CI 1.6), so she was started on milrinone and listed for transplant as UNOS status 4 exception after extensive discussion regarding advanced therapies in the setting of her low-grade malignancy with favorable outcome. She underwent orthoptic heart transplantation (OHT) with DCD donor and ex-vivo perfusion. The preoperative total leukocytes count was 71,700/μl with mild anemia but no thrombocytopenia. Retrospective crossmatch was notable for flow cytometry crossmatch positive but CDC negative. The post-operative course was significant for an increase in total leukocyte count to 110,000/μl in absence of fever or infective source but was complicated with SVC stenosis at anastomotic site and thrombosis of the SVC and innominate vein necessitating thrombectomy and stent placement in the SVC. She also had bilateral pleural effusions for which she had bilateral chest tubes for three weeks post-transplant. Standard immunosuppression without induction was given and graft function was preserved with biopsies negative for rejection. Discussion: This case describes a successful OHT in a patient with long-standing chronic lymphocytic leukemia with a favorable outcome. OHT is the most effective therapy for end-stage heart disease, however historically cancer patients were considered ineligible for this therapy, given the increased risk with post-transplant immunosuppression. Though literature is limited, it is suggested that a careful selection of patients may have favorable outcome with slightly increased risk of cancer. These patients are at increased risk of infections and complications related to immunosuppression, which may exacerbate the immunocompromised state and potential rapid progression of underlying malignancy. Hematologic malignancies increase thromboembolism risk, as seen with this patient. A multi-disciplinary team approach involving oncology and infectious disease is integral for optimizing care in this complex population.

Characteristics of Inherited Metabolic Disorders Following Kidney Transplantation: A 13-Year Observational Study.

Background and Objectives: Inherited metabolic disorders (IMDs), primarily cystinosis, Fabry disease, and methylmalonic acidemia (MMA), are genetic conditions that typically result in multi-organ disease manifestations. Kidney function progressively deteriorates in many cases, with patients eventually reaching end-stage kidney disease (ESKD) and requiring renal replacement therapy. Kidney transplantation has been deemed the optimal renal replacement therapy option to achieve long-term survival in patients with IMD. Whilst improved long-term survival is expected, the patterns of clinical evolution for IMD after transplantation remain largely unknown. Methods: Our group conducted a retrospective observational study that included 37 adult patients with IMD (11 with cystinosis, 20 with Fabry disease, and 6 with MMA). The study evaluated the clinical status and progression of these patients following kidney transplantation between January 2010 and December 2023. Results: This generally resulted in good graft outcomes for patients with IMD. Standard immunosuppression regimes included tacrolimus, mycophenolate mofetil, and prednisolone. The mean graft survival duration was noted to be 12 years in patients with cystinosis, 11 years in patients with Fabry disease, and 7 years in patients with MMA. Suboptimal outcomes were noted with grafts of cadaveric origin and poor adherence to the prescribed post-transplant immunosuppression regime. A greater extra-renal morbidity burden was associated with a reduced duration of graft function and increased mortality in patients with IMD. Conclusions: Our findings emphasise the need for a multi-disciplinary approach in the care of IMD patients following kidney transplantation.

Disseminated Toxoplasma Gondii Infection in a Deceased Donor Kidney Transplant Recipient: A Fatal Case Report

Abstract Introduction/Objective Post-transplant immunosuppression predisposes patients to severe complications from opportunistic infections, including Toxoplasma gondii. Typically asymptomatic and self-limited in immunocompetent individuals, Toxoplasma gondii can cause life-threatening disseminated disease in immunocompromised patients like solid organ transplant recipients. The challenge in diagnosing Toxoplasmosis is further exacerbated in patients receiving prophylactic therapy with agents such as Atovaquone, which may mask clinical suspicion. This case report describes a fatal presentation of disseminated Toxoplasmosis in a kidney transplant recipient. Methods/Case Report A 44-year-old male with a history of deceased donor kidney transplant presented to the emergency department two months post-transplant with symptoms of malaise, shortness of breath, hypoxemia, and hypotension. Despite medical interventions, the patient deteriorated rapidly, developing acute hypoxemic respiratory failure and septic shock requiring intubation. Subsequently, he succumbed to multisystem organ failure five days after admission. The autopsy revealed disseminated Toxoplasma gondii infection, with tachyzoites/bradyzoites identified in multiple organs, including the brain, bone marrow, and lymph nodes. Positive Toxoplasma immunohistochemical staining and PCR confirmed the diagnosis. Results (if a Case Study enter NA) NA Conclusion Toxoplasma infection in post-transplant patients can manifest as a severe and potentially fatal complication. Dissemination can arise from the reactivation of latent infection, donor transmission, or new acquisition. In this case, the infection likely resulted from the reactivation of latent infection in the donor, compounded by immunosuppression in the recipient. Notably, the patient received Atovaquone prophylaxis due to a sulfa allergy. Nonetheless, the case highlights the potential for delayed diagnosis due to atypical presentations in immunocompromised patients. Clinicians should maintain a high index of suspicion for Toxoplasma infection in post- transplant patients, particularly in those with unexplained clinical deterioration. This case emphasizes the importance of maintaining a high index of suspicion for T. gondii infection in post-transplant patients, even in those receiving prophylaxis.

S4527 A Post-Transplant Immunosuppression Complication: EBV-Positive Classic Hodgkin Lymphoma PTLD Mimicking as Cholangiocarcinoma

S4527 A Post-Transplant Immunosuppression Complication: EBV-Positive Classic Hodgkin Lymphoma PTLD Mimicking as Cholangiocarcinoma

Genitourinary tumors and liver transplantation: A comprehensive review.

Liver transplantation is as a crucial therapeutic option for patients with end-stage liver disease, but the persistent organ shortage emphasizes a need to explore unconventional donor sources, including individuals with a history of malignancies. This review investigates the viability of liver donation from individuals with current or past genitourinary malignancies, focusing on renal, prostate and urinary bladder cancers. The rising incidence of urogenital malignancies among potential donors is thought to result from increasing donor age. Analysis of transmission risks reveals low rates of donor-derived cancer transmission, particularly for early-stage renal and prostate cancers. Recipients with a history of genitourinary malignancy pose complex challenges regarding post-transplant immunosuppression and cancer recurrence. Nonetheless, the evidence suggests acceptable outcomes can be achieved with careful patient selection and tailored management strategies. Recommendations for pre-transplant evaluation and post-transplant surveillance are discussed, highlighting the need for individualized approaches in this patient population. Further prospective studies are warranted to refine guidelines and optimize outcomes in liver transplantation for patients with genitourinary malignancies.

Estimation of lifetime costs for patients receiving a transplant: the case of liver transplantation related to hepatitis B in Italy.

In Italy, post-liver transplant (LT) hepatitis B virus (HBV) reinfection prophylaxis is frequently based on a combined regimen of anti-HBV immunoglobulin (HBIG) and oral antivirals. However, little information is available at the national level on the cost of LT and the contribution of HBV prophylaxis. This study aimed to quantify the direct healthcare cost for adult patients undergoing LT for HBV-related disease over a lifetime horizon and from the perspective of a National Healthcare Service. A pharmaco-economic model was implemented with a 4-tiered approach consisting of 1) preliminary literature research to define the research question; 2) pragmatic literature review to retrieve existing information and inform the model; 3) micro-simulated patient cycles; and 4) validation from a panel of national experts. The average lifetime healthcare cost of LT for HBV-related disease was €395,986. The greatest cost drivers were post-transplant end-stage renal failure (31.9% of the total), immunosuppression (20.6%), and acute transplant phase (15.8%). HBV reinfection prophylaxis with HBIG and antivirals accounted for 12.4% and 6.4% of the total cost, respectively; however, lifetime HBIG prophylaxis was only associated with a 6.6% increase (~€422 k). Various sensitivity analyses have shown that discount rates have the greatest impact on total costs. This analysis showed that the burden of LT due to HBV is not only clinical but also economic.

Disseminated Histoplasmosis with Secondary Hemophagocytic Lymphohistiocytosis in a Renal Transplant Recipient on Belatacept-based Immunosuppression

Effective post-transplant immunosuppression is essential to induce tolerance to allogeneic tissues and promote long-term graft survival. However, suppression of the immune system significantly increases the risk of opportunistic infections. In addition to the ongoing challenge of balancing graft survival and preventing infections, previous gold-standard calcineurin inhibitor-based immunosuppression also posed an increased risk of nephrotoxicity, cardiac disease, and diabetes. Belatacept is approved as an alternative to calcineurin inhibitor-based regimens. Although belatacept has improved cardiovascular and metabolic adverse events in renal transplant patients’ but it carries a notably higher risk of long-term graft survival and renal toxicity, similar to calcineurin inhibitor-based regimens. However, there may be an increased risk of infections with its mechanism of action. We present a case of a 62-year-old female who developed disseminated histoplasmosis 18 months after being on belatacept-based immunosuppression after a deceased donor renal transplant for end-stage renal disease secondary to focal segmental glomerulosclerosis. Grocott Methenamine Stain (GMS) of peripheral blood smear showed intracellular yeast in neutrophils, consistent with histoplasmosis. Disseminated histoplasmosis was confirmed with positive bronchoalveolar lavage (BAL) and urine culture. The patient later developed hemophagocytic lymphohistiocytosis (HLH) secondary to immunosuppression and disseminated histoplasmosis. The patient succumbed to the disease despite maximal medical therapy. To our knowledge, there is one other published report of disseminated histoplasmosis in a patient with belatacept-based immunosuppression. The unique feature of this case is the development of HLH secondary to disseminated histoplasmosis while on belatacept. Further research is needed to evaluate the need for antifungal prophylaxis in patients on belatacept therapy.

Disulfiram, an Anti-alcoholic Drug, Targets Macrophages and Attenuates Acute Rejection in Rat Lung Allografts.

Macrophages contribute to post-transplant lung rejection. Disulfiram (DSF), an anti-alcoholic drug, has an anti-inflammatory effect and regulates macrophage chemotactic activity. Here, we investigated DSF efficacy in suppressing acute rejection post-lung transplantation. Male Lewis rats (280-300g) received orthotopic left lung transplants from Fisher 344 rats (minor histocompatibility antigen-mismatched transplantation). DSF (0.75mg/h) monotherapy or co-solvent only (50% hydroxypropyl-β-cyclodextrin) as control was subcutaneously administered for 7 days (n = 10/group). No post-transplant immunosuppressant was administered. Grades of acute rejection, infiltration of immune cells positive for CD68, CD3, or CD79a, and gene expression of monocyte chemoattractant protein and pro-inflammatory cytokines in the grafts were assessed 7 days post-transplantation. The DSF-treated group had significantly milder lymphocytic bronchiolitis than the control group. The infiltration levels of CD68+ or CD3+ cells to the peribronchial area were significantly lower in the DSF than in the control groups. The normalized expression of chemokine ligand 2 and interleukin-6 mRNA in allografts was lower in the DSF than in the control groups. Validation assay revealed interleukin-6 expression to be significantly lower in the DSF than in the control groups. DSF can alleviate acute rejection post-lung transplantation by reducing macrophage accumulation around peripheral bronchi and suppressing pro-inflammatory cytokine expression.

Whole-Transcriptome Sequencing–Based Profiling of the Cutaneous Virome in Patients with Secondary Immunodeficiency

Most viral infections can be self-limited, with no requirement for medical intervention. However, the same viruses can cause severe diseases in patients with compromised immunity due to single-gene diseases, acquired immune deficiency syndrome, or hematologic malignancies or those receiving immunosuppressive drugs. Occasionally, these immunocompromised patients harbor >1 infectious agent, requiring several concomitant diagnostic tests. We have developed, to our knowledge, a previously unreported whole-transcriptome sequencing-based pipeline that allows virome profiling, quantitation, and expression pattern analysis of 926 distinct viruses by sequencing of RNA isolated from a single lesional skin biopsy. This pipeline can also explore host genetics if there is a Mendelian predisposition to infection. We applied this pipeline to 6 Iranian patients with viral-induced skin lesions associated with immune deficiency secondary to HIV, human T-lymphotropic virus 1, chronic lymphocytic leukemia, and post transplant immunosuppression. In 5 cases, definitive human papillomavirus infections were identified, some caused by multiple viral types. In addition to human papillomavirus, coinfection with other viruses (Merkle cell polyomavirus, cytomegalovirus, and human herpesvirus 4) was detected in some lesions. In 1 case, whole-transcriptome sequencing validated the clinical diagnosis of adult T-cell leukemia/lymphoma in a patient with an initial diagnosis of mycosis fungoides/Sézary syndrome. These findings attest to the power of whole-transcriptome sequencing in profiling the cutaneous virome in the context of compromised immunity.

Allogeneic Hematopoietic Stem Cell Transplantation for Adult Metachromatic Leukodystrophy (MLD): A Case Series

Introduction Adult Metachromatic Leukodystrophy (MLD) is a rare neurological disorder leading to devastating and progressive cognitive impairment and motor impairment with ataxia, spasticity and neuropathy as well as incontinence resulting in complete disability and reduced life expectancy. MLD is caused by autosomal recessive mutations of the ARSA gene, resulting in reduced arylsulfatase A enzyme (ARSA) activity and consecutive accumulation of galactosylceramide-3-0-sulfate in the central nervous system (CNS). Potential therapies in infantile and juvenile MLD include allogeneic hematopoietic stem cell transplantation (allo-HCT), ex-vivo gene therapy (Atidarsagen autotemcel), and (intrathecal) enzyme replacement as tested in ongoing trials. Allo-HCT may slow down or stop MLD progression. However, the outcome in adult patients treated with allo-HCT has been only reported in a few case reports. In this case series, we report our experience of allogeneic transplantation in four patients with adult MLD. Methods Four patients (2 male and 2 female) with a genetically confirmed diagnosis of adult MLD, with enzyme deficiency detectable in peripheral blood (ARSA activity range 0.00-0.06 E514nm/10 -6), evidence of white matter lesions on MRI and demyelinating polyneuropathy in EMG were treated with allo-HCT. One patient was still clinically asymptomatic at the treatment timepoint. Allo-HCT was performed at an age between 18 and 37 years (mean 25.75 years) and within one year after diagnosis. Bone marrow (n=2) or mobilized peripheral blood stem cells (n=2) from 10/10 matched related (n=1) or unrelated (n=3) donors were infused at a dose of 2.2-7.82x10 6 CD34+/kg after a reduced intensity conditioning regime with Fludarabine (150 mg/m²) and Treosulfane (10 or 14 g/m²). Three patients received further infusions with allogeneic mesenchymal stem cells (MSCs) manufactured in the hospital´s own GMP laboratory around day 30 after transplantation. One patient received a second MSC infusion at day 182. MSCs are able to secrete ARSA and were used to consolidate enzyme levels. In case of transplant failure donor lymphocytes (DLI) were given. For posttransplant immunosuppression Tacrolimus, Methotrexate, Mycophenolate mofetil or Anti-thymocyte globulin (ATG, Grafalon®, Neovii 10 mg/kg) were used. Results All patients engrafted 16-21 days after HCT. Platelets regenerated within 14 to 21 days (mean 16 days), neutrophils recovered within 16 to 21 days (mean 18.5 days). In two patients hepatitis and exanthema associated with ATG administration were observed as transient adverse events. Other therapy-associated adverse events were innappetence, hyperkalemia and diarrhea. A mild Graft-versus-host disease of the skin occurred only in one patient with full resolution on a course of steroids and Tacrolimus. After allo-HCT, an increase in ARSA levels reaching normal range values within the first 12 months after treatment was already documented in 3 out of 4 patients; measurements are pending in the 4 th more recently transplanted patient. Three out of four patients developed consistent full donor chimerism within 11 (1-11 ) months after HCT. In the fourth 18-year-old patient autologous chimerism increased to 60-80%, while ARSA activity decreased from 1.05 to 0.61 E514nm/10 -6. Consequently, the patient received DLIs. However, an improvement in chimerism has not be achieved so far. Longer follow-up data will be reported at the meeting. Discussion and Conclusion Allo-HCT in patients with MLD can be used to restore normal range ARSA activity. Donor-derived macrophages with an adequate secretion of ARSA migrate to the central nervous system and release ARSA. To our knowledge, there have been only a few individual case reports on allo-HCT in adult MLD so far. Our case series indicates that allo-HCT can be performed with tolerable risks and evident efficacy in adult patients with MLD. Based on this experience and previously reported cohorts in juvenile and infantile MLD allo-HCT should be thus also considered as a therapeutic option for adult patients with MLD. Longer clinical follow-up, higher patient numbers and ultimately a prospective randomised trial containing an untreated group would be needed to evaluate allo-HCT as a treatment option for adult MLD.

Blinatumomab Redirects Donor Lymphocytes against CD19+ Acute Lymphoblastic Leukemia without Relevant Bystander Alloreactivity after Haploidentical Hematopoietic Stem Cell Transplantation.

Blinatumomab alone or with donor leukocyte infusions (DLI) has been used after allogeneic hematopoietic stem cell transplantation (HSCT) as a salvage therapy in relapsing patients with CD19+ hematological malignancies. It was effective in a fraction of them, with low incidence of Graft-versus-Host Disease (GvHD). Immunosuppressive drugs used as GvHD prophylaxis hinder T cell function and reduce the efficacy of the treatment. Because T cell-depleted haploidentical HSCT with donor regulatory and conventional T cells (Treg/Tcon haploidentical HSCT) does not require post-transplant immunosuppression, it is an ideal platform for the concomitant use of blinatumomab and DLI. However, the risk of GvHD is high because the donor is haploidentical. We treated two patients with CD19+ acute lymphoblastic leukemia (ALL) who had relapsed after Treg/Tcon haploidentical HSCT with blinatumomab and DLI. Despite the mismatch for one HLA haplotype, they did not develop GvHD and achieved complete remission with negative minimal residual disease. Consistently, we found that blinatumomab did not enhance T cell alloreactivity in vitro. Eventually, the two patients relapsed again because of their high disease risk. This study suggests that treatment with blinatumomab and DLI can be feasible to treat relapse after haploidentical transplantation, and its pre-emptive use should be considered to improve efficacy.

Results of the Astral Study: A Prospective Phase II Clinical Study of the German Lymphoma Alliance to Assess the Efficacy and Toxicity of High-Dose Chemotherapy Followed By Allogeneic Stem Cell Transplantation As Treatment of Primary Progressive and Relapsed Aggressive Non-Hodgkin Lymphoma

Introduction Patients with relapsed and refractory (r/r) aggressive B- or T-cell lymphoma have a dismal prognosis. Registry analyses as well as one preceding prospective clinical study demonstrated durable disease control through graft-versus-lymphoma activity conferred by allogeneic stem cell transplantation (alloSCT) in this population and suggests this modality being a preferred treatment option after failing of less toxic approaches. Recently, allogeneic SCT has been shown to result in long term PFS in r/r large B-cell lymphoma (LBCL) with preceding CAR-T treatment. Despite the current achievements in treatment of r/r LBCL by introducing anti CD19 CAR-T as a treatment modality appproximately 60% need further approaches to achieve long term progression free survival (PFS). Here we represent the results of a prospective clinical trial of allogeneic SCT in r/r aggressive B- and T-cell lymphoma using a thiotepa based conditioning regimen. Methods ASTRAL is a national, multicenter, prospective phase II study of the German Lymphoma Alliance (GLA). Eligible were patients aged 18 or older with relapsed or primary progressive aggressive B- or T-cell lymphoma who had a fully matched (10/10) related or unrelated donor available. Patients underwent myeloablative conditioning regimen with Fludarabine 125 mg/m², Thiotepa 15 mg/kg and Cyclophosphamide 120 mg/kg (FTC). GVHD prophylaxis and posttransplant immunosuppression was done by local standards. The primary objective was to determine the efficacy and toxicity of the defined conditioning therapy followed by allogeneic stem cell transplantation. The primary endpoint was progression free survival at 1 year. Key secondary efficacy endpoints included rate of complete remissions (CR), rate of partial remissions (PR), overall response rate (OR), rate of progressive disease (PD), relapse rate, event free survival (EFS) and overall survival (OS) at 1 year and non-relapse mortality (NRM). Results From June 2019 until December 2021 in total 60 patients were enrolled. The demographic data are presented in table 1. The majority of patients (70%) had B-cell lymphomas. Patients had received a median of 3 prior lines (range 1-6), including autoSCT in 42% of all patients and CAR-T in 29% of the B-cell patients. The rate of primary progressive disease before salvage therapy was 27% (29% B-cell and 22% T-cell). 83% (50/60) still had measurable disease (no CR) prior to FTC, thereof 81% with B-cell (34/42) and 89% with T-cell lymphoma (16/18) and 13 (22%) had high intermediate and high IPI. After alloSCT, CR was achieved in 45% of patients with B-cell and in 67% with T-cell lymphoma, respectively. The overall response rate was 53%, 48% for B-cell lymphoma and 67% T-cell lymphoma. After a median observation time of 30 months, 1-year PFS was 40% [95%-CI: 28%-52%] (38% [23%-53%] (B-cell) vs. 44% [21%-67%] (T-cell) (figure 1). EFS was identical to PFS. After one year 15 patients (25%) had progressive disease or relapse, thereof 13 patients (29%) with B-cell lymphoma and two with T-cell lymphoma (11%). Thirty-seven patients died. Main cause of death was treatment related 19/37 (51%), including 8/19 deaths due to toxicity of the conditioning therapy (6 infections, 1 respiratory failure and 1 neurotoxicity). 12/37 (32%) patients died lymphoma related, 4/37 (11%) patients died of a SARS-Cov-2 infection, and two causes of death were unknown. 1-year OS was 43% [31%-56%] (40% [26%-55%] (B-cell) vs. 50% [27%-73%] (T-cell)). 1-year NRM was 35% [23%-47%] (31% [17%-45%] (B-cell) vs. 44% [20%-68%] (T-cell)). Most of the patients with grade 3-5 adverse events had infections 40/60 (67%), renal disorders 17/60 (28%) and oral mucositis 14/60 (23%). Conclusions This is the second prospective trial on alloSCT for r/r aggressive lymphoma ever performed, demonstrating that alloSCT can provide sustained disease control in heavily pretreated patients. Also in the modern era, including patients who failed CARTs the strong anti-lymphoma activity of allogeneic SCT is shown in the low relapse/progression rate and the long term PFS. FTC conditioning avoids the toxicities of busulfan-based regimens but fosters neuro- and other toxicities, especially when given at 15mg/kg. Still, NRM remains a challenge and warrants exploration of novel transplant strategies, such as modulation of conditioning intensity and GVHD prophylaxis, e. g. post-transplant cyclophosphamide.

Dynamics of Immune Reconstitution after Unrelated Allogeneic Transplantation with Post-Transplantation Cyclophosphamide Compared to Classical Immunosuppression with ATG

Introduction: Post-transplant cyclophosphamide (PTCY), in hematopoietic stem cell transplantation (HSCT), is responsible for the success of haploidentical stem cell transplantation and is also being used in matched transplants such as unrelated transplants, with promising outcomes in graft versus host disease (GVHD). However, we lack data on immune reconstitution with this type of immunosuppression, especially in unrelated transplantation. Immune reconstitution is directly involved with post-transplant morbidity and mortality, being related to GVHD, relapses and infections, such as cytomegalovirus (CMV). Objectives: To evaluate global and CMV-specific immune reconstitution after unrelated donor HSCT, comparing the use of thymoglobulin (ATG) or PTCY protocol. Methods: We prospectively included patients undergoing first unrelated donor HSCT with ATG, methotrexate and tacrolimus or PTCY (50mg/Kg D+3 and D+4), mycophenolate mofetil (MMF) and tacrolimus with patient and/or donor CMV IgG positive. Immune reconstitution analyzes were performed by flow cytometry and CMV-specific recovery by ELISPot technique on days +30, +60, +90 and +180 post HSCT. Results: Thirty-six patients were included in this study, 20 in the ATG group and 16 in the PTCY group (table 1). Only 2 patients were 9x10 match, and the others were 10x10 match. All patients were submitted to preemptive strategy of CMV treatment, without the use of letermovir. Regarding clinical outcomes, neutrophilic engraftment was earlier with ATG (median of 12 days), compared to PTCY (median of 16 days) (p=0.0001). There was no difference between the groups in terms of length of hospital stay (median 33 days in both groups), CMV reactivation (70% in ATG and 75% PTCY, p=0.98), acute GVHD grades II to IV (p=0.26) or grades III-IV (p=0.56), and chronic GVHD (p=0.45), as well as relapse (p=0.3), non relapse mortality (p=0.77) and overall survival (p=0.4). Regarding immune reconstitution we observed an initial expansion of monocytes and NK lymphocytes in both groups and a higher increase in CD8+ T lymphocytes was evidenced, with an inversion of the CD4/CD8 ratio (CD4 14.9% vs 15.5% p=0.9 and CD8 49.7% vs 54.5%p=0.5 in ATG and PTCY respectively). We identified a CD4+/CD8+ double-positive T cell (DP) population, which was higher in PTCY group compared to ATG on days +30 (3.5% vs 10.2%, p=0.009), +90 (3.1% vs 12% p= 0.01) and +180 (5.2% vs 13%, p=0.007, in ATG and PTCY respectively ). On day +30 there were higher proportion of T cells (19.9% vs 9.6% p=0.004), B cells (0.76% vs 0.2%, p=0.006) and NK cells (19.2% vs 8.6% p=0.006) in ATG group compared to PTCY and monocytes were higher in PTCY (31.7 vs 44.5%, p=0.02). On day +180 the proportion of B cell were higher in PTCY (6.1% vs 16.6% p=0.014) and the NK cells were higher in the ATG (22.4% vs 14.7% p=0.021) (Figure 1), with higher CD56dim population in ATG group (46% vs 33.6% p=0.0079), while in PTCY there were a higher NK population CD56high on day +60 (40.3% vs 61%, p=0.014). We identified a peripheral expansion of a CD56negCD16posNKG2Dpos NK cell population, which was higher in the PTCY group on day +180 (3.7% vs 13.2% p=0.017). Regarding CMV-specific immune response, we found no difference between the groups on days +30 (5 vs 5 spots/10 4 PBMC p=0.41), +60 (10 vs 6 spots/10 4 PBMC p=0.38), +90 (13 vs 4 spots/10 4PBMC p=0.33) or +180 (7 vs 6 spots/10 4 PBMC p=0.57). Conclusions: In the context of unrelated HSCT, we found no difference in CMV-specific immune response with the use of PTCY or ATG protocol. Post-transplant immunosuppression with PTCY compared to ATG protocol is related to lower levels of T cells, NK cells and B cells on day +30 and later neutrophil engraftment, but with a higher proportion of double positive T cells on days +30, +90 and +180 and a higher proportion of B cells on day +180. At 6 months after transplantation, a proportionately lower number of NK cells, but higher proportion of CD56negCd16posNKG2D NK population was observed in the PTCY group.

FRI677 Analysis Of Characteristics Associated With Osteoporosis In Solid Organ Transplant Recipients - Results Of Phoenix VA Based Quality Improvement Project

Abstract Disclosure: T. Shah: None. K. Vinales: None. Introduction: Solid organ transplants are increasingly performed for multiple end-stage organ failures, that increase longevity and quality of life, but can be complicated with osteoporosis, which is associated with increased morbidity and mortality. Determining the risk factors, diagnostic and treatment related characteristics will facilitate improvement in care of patients with this condition. Design: This was part of a quality improvement project at single institution to identify male veterans, 65 years and older, who were at risk for or osteoporosis. In this analysis, we focused on those with solid-organ transplant who developed post-transplant osteoporosis over the past 10 years. Various parameters were obtained, along with the most recent DXA scan, quantifying the T-scores at various sites, trabecular bone score (TBS) and treatment modalities. Results: From initial cohort of male veterans at risk for osteoporosis (n=1676), 26 (1.5%) were identified as post-transplant osteoporosis. Baseline characteristics (mean±SD) included: age = 72.9±3.0 years-old, BMI =26.0±3 kg/m2. 26.9% patients were noted to have history of smoking, while 7.6% had rheumatoid arthritis, 65% had history of diabetes mellitus, 54% were noted to be on prednisone as part of post-transplant immunosuppression regimen with dosages varying between 5-10mg daily. 61.5% of patients had GERD, whereas 57.1% were treated with proton pump inhibitors and H2-blockers. Analysis of DXA parameters revealed the lowest T-score average to be -1.88±0.5 with 88% having low BMD at the femoral neck site. Average TBS in the group was noted to be 1.37±0.1, while vertebral compression fractures were noted in 21% of these patients. Only 76% of patients were on osteoporosis treatment, where 65% were treated with Alendronate, 25% were treated with Denosumab and 20% with Zolendronic acid. Sub group analysis based on the solid organ transplanted reported liver transplant in 46%, renal transplant in 30%, lung transplant in 15%, heart transplant in 7% of the patients. Patients in the liver transplant group had a lower TBS of 1.26 (vs. 1.46 in the renal, 1.45 in the heart and 1.33 in the lung transplant groups). Incidence of vertebral compression fractures was highest in this subgroup and noted in 27% patients. Notably 25% of liver transplant were diagnosed with osteoporosis solely based on presence of vertebral compression fractures. Conclusion: Our quality improvement study highlights the fact that lowest DEXA scan T-scores are most commonly found at the femoral neck site in solid organ transplant recipients and high incidence of fragility fractures. Thorough assessment for vertebral fractures should be routinely incorporated while evaluating DXA scans in post-transplant osteoporosis cases, especially recipients of liver transplants as vertebral compression fractures can be the sole determinant of osteoporosis in this group of patients. Presentation: Friday, June 16, 2023

Immunotherapy for hepatocellular carcinoma in liver transplant patients (Literature review)

Hepatocellular carcinoma (HCC) is the third cause of cancer-related mortality worldwide, accounting for more than 800,000 deaths annually. Surgical removal of the neoplasm remains the most effective treatment option. Partial liver resection is an adequate solution for patients without cirrhosis or with well-compensated cirrhosis, orthotopic liver transplantation is necessary in patients with early stage HCC on the background of cirrhosis. Tumor recurrence remains a major limitation of long-term survival of patients after liver transplantation. Posttransplant immunosuppression reduces the body's antitumor defense, which is provided by natural immunity. This contributes to the development and progression of the tumor process. Purpose of the study: to analyze domestic and foreign publications that present treatment options for HCC recurrence after liver transplantation. Literature sources were searched in PubMed, Scopus, Web of Science, MEDLINE, eLibrary databases. The search was conducted in Russian and English by keywords: hepatocellular carcinoma, tyrosine kinase inhibitors, immune checkpoint inhibitors, therapy of HCC relapse, orthotopic liver transplantation, RETREAT index, regorafenib, nivolumab. The authors presented a review of the data on the use of tyrosine kinase inhibitors and immune checkpoint inhibitors to prevent HCC recurrence. The results of the analysis of literature sources showed that the issue of post-transplant immunosuppression is relevant. The large number of studies and clinical case reviews leaves hope that an effective way of immunosuppression for recurrent HCC patients after liver transplantation will soon be found.

Hyperinflammatory syndrome in a paediatric patient with a recent diagnosis of HIV/AIDS infection: hemophagocytic lymphohistiocytosis or immune reconstitution syndrome?

IntroductionHaemophagocytic lymphohistiocytosis is a rare and life-threatening condition caused by uncontrolled immune activation leading to excessive inflammation and tissue destruction. It could either be due to a primary genetic defect or be triggered by secondary causes such as infections, autoimmune diseases, rheumatological diseases or post-transplant immunosuppression. We here report the case of a 4-year-old child with a recent AIDS diagnosis who developed a severe systemic inflammation.Case reportWe here report the case of a 4-year-old child with a recent AIDS diagnosis who was admitted to the ER with acute respiratory failure due to Pneumocystis jiroveci infection and Aspergillosis; the following microbiological assessment also showed a CMV, HSV, EBV and HHV-7 coinfection. On the 51st day after she’d started antiretroviral therapy, 39th after she’d followed a course of Bactrim and Caspofungin for PJI and Ambisome for pulmonary Aspergillosis, she started presenting fever, unresponsive to broad-spectrum antibiotic therapy. She also presented worsening of her clinical conditions, with evidence at the laboratory assessments of progressive raise in inflammatory indexes, coagulopathy, trilinear cytopenia and hyperferritinemia. To perform the differential diagnosis between IRIS and HLH, HLA-DR on T cells was studied, turning out negative for IRIS. Therefore, in the suspicion of HLH, a bone marrow aspirate and biopsy were performed with evidence of trilinear cytopenia, prevalence of T-cells and macrophages with signs of phagocytosis. She was started on high-dose steroids and Anakinra for a total of 29 days, resulting in prompt apyrexia and progressive improvement of her clinical conditions and laboratory results.ConclusionTo the best of our knowledge there is poor literature available about the differential diagnosis of HLH and IRIS, therefore medical management in the concurrence of these two conditions needs to be further investigated, especially in a setting where immunological testing is not quickly available. The clinical differences between these pathologies are blurred and the bone marrow biopsy within marker for IRIS helped us to distinguish these two entities.

Guillain-Barré Syndrome Following Primary Cytomegalovirus Infection in a Patient with Liver Transplantation: a Case Report (P10-5.002)

<h3>Objective:</h3> To report the case of a patient who underwent liver transplantation and developed Guillain-Barré syndrome (GBS) as a result of primary cytomegalovirus (CMV) infection. <h3>Background:</h3> GBS is the most common etiology of paralysis worldwide and it is an autoimmune-mediated neuropathy that is frequently caused by a preceding infection. Although the relationship between CMV and GBS is well known, only about 4% of cases are specifically attributable to this infection. Likewise, few cases of GBS have been reported in the context of liver transplant recipients, and in the majority of cases, it is not ascribable to the CMV infection. <h3>Design/Methods:</h3> Not applicable. <h3>Results:</h3> A 66-year-old male patient with a 5-month medical history of liver transplantation secondary to hepatocellular carcinoma, is seen in the emergency room with a progressive ascending limb weakness and foot dysesthesias for the past eight days. Interestingly, three days before the onset of the symptoms, he presented a self-resolved gastrointestinal infection. Neurological examination revealed decreased strength and areflexia in all extremities, especially in the lower limbs. Nerve conduction studies and electromyography showed an acute inflammatory demyelinating polyneuropathy (AIDP) consistent with the diagnosis of GBS. Lumbar puncture ruled out any potential neuro infections and revealed the typical albuminocytologic dissociation. Additionally, a FilmArray panel was negative for other gastrointestinal pathogens. However, a significant CMV serum viral load indicated an active infection. Therapy with IV immunoglobulin and valganciclovir was started, with symptoms considerably improving after five days. <h3>Conclusions:</h3> GBS can be a rare complication after solid organ transplantation. Although post-transplant immunosuppression is known to increase the likelihood of contracting CMV opportunistic infections, GBS has not been frequently linked to this condition. Also, to our knowledge, this is one of few reports where it occurs after a primary CMV infection in the context of a liver transplant recipient, while other frequent etiologies were ruled out. <b>Disclosure:</b> Dr. Toro has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Watch Neurology . Dr. Gaitan Alfonso has nothing to disclose. Thomas Medina has nothing to disclose. Dr. Reyes has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for Merck. Dr. Reyes has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for Roche. Dr. Reyes has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for BIIB. Dr. Reyes has received personal compensation in the range of $0-$499 for serving on a Speakers Bureau for Merck. Dr. Reyes has received personal compensation in the range of $0-$499 for serving on a Speakers Bureau for Novartis. Dr. Reyes has received personal compensation in the range of $0-$499 for serving on a Speakers Bureau for Biogen.

Merkel Cell Carcinoma in Kidney Transplant Recipients

Merkel cell carcinoma (MCC) is an uncommon form of skin neoplasm with poor histological differentiation and an aggressive disease process, leading to high recurrence and mortality. There are multiple risk factors in which being in an immunocompromised state is a significant factor, and the discovery of Merkel cell polyomavirus (MCPyV) since 2008 has strengthened causal associations between MCC and immunosuppression. Individuals who have undergone kidney transplantation are therefore more susceptible to having MCC, secondary to post-transplant immunosuppression which plays a vital role in reducing the risk of transplant kidney rejection. Over recent years a rise in the incidence of MCC following kidney transplantation is noted, with increased reporting of such cases. Whilst localized MCC is observed, MCC metastasis to the lymphatic system, brain, bone, liver, lung, and heart has been previously observed in patients with transplanted kidneys. Kidney metastasis is less common and has been only reported in recent years with greater frequency. The management of aggressive, metastatic MCC has historically been palliative, and prognosis is poor. Recently, the use of immune checkpoint inhibitors for metastatic MCC in multi-center phase II clinical trials have shown promising survival outcomes and have been approved for use in countries such as the United States as a first-line treatment. In this review we will explore the potential pathophysiological processes of MCC manifesting post-kidney transplantation. We will then evaluate the epidemiology of MCC within the context of kidney transplantation, before discussing the various clinical presentations, diagnostic measures, surveillance strategies, and current treatment options as well as future directions to best manage MCC in kidney transplant recipients.

Tumors after kidney transplantation: a population study

One of the main causes of post-transplant-associated morbidity and mortality is cancer. The aims of the project were to study the neoplastic risk within the kidney transplant population and identify the determinants of this risk. A cohort of 462 renal transplant patients from 2010 to 2020 was considered. The expected incidence rates of post-transplant cancer development in the referenced population, the standardized incidence ratios (SIR) taking the Italian population as a comparison, and the absolute risk and the attributable fraction were extrapolated from these cohorts of patients. Kidney transplant recipients had an overall cancer risk of approximately three times that of the local population (SIR 2.8). A significantly increased number of cases were observed for Kaposi’s sarcoma (KS) (SIR 195) and hematological cancers (SIR 6.8). In the first 3 years post-transplant, the risk to develop either KS or hematological cancers was four times higher than in the following years; in all cases of KS, the diagnosis was within 2 years from the transplant. Post-transplant immunosuppression represents the cause of 99% of cases of KS and 85% of cases of lymphomas, while only 39% is represented by solid tumors. Data related to the incidence, the percentages attributable to post-transplant immunosuppression, and the time of onset of neoplasms, particularly for KS and hematological tumors could help improve the management for the follow-up in these patients.