Discontinuation Of Immunosuppression Research Articles

An 8-month-old boy with infantile nephrotic syndrome caused by semaphorin 3B-associated membranous nephropathy.

We present a case of nephrotic syndrome caused by semaphorin 3B-associated membranous nephropathy. The patient was an 8-month-old male infant who presented with severe proteinuria and hypertension. He was treated with prednisolone (PSL) for nephrotic syndrome; however, remission was not achieved within 4weeks. He was diagnosed with steroid-resistant nephrotic syndrome and underwent kidney biopsy. Pathological examination revealed membranous nephropathy with IgG deposits on both the glomerular basement membrane (GBM) and the tubular basement membrane (TBM). He was treated with cyclosporine (CsA) in addition to PSL and achieved complete remission. However, frequent relapses occurred after the discontinuation or tapering of immunosuppressants. Two years after treatment initiation, a second biopsy was performed and showed worsening of the disease, which required treatment with several immunosuppressants to achieve complete remission. After that, we performed additional immunostaining for semaphorin 3B, which confirmed the diagnosis of semaphorin 3B-associated membranous nephropathy. Although extremely rare in infantile cases, semaphorin 3B-associated membranous nephropathy should be considered in the differential diagnosis, as strong treatment with immunosuppressants might be needed. In addition, mycophenolate mofetil showed an effective clinical response in this case, indicating that it can be considered for future treatment strategies.

Effect of Maintaining Immunosuppression After Kidney Allograft Failure on Mortality and Retransplantation.

We performed a single-center retrospective study of patients transplanted from October 2007 to May 2017 with AF. We collected data on demographics, immunosuppression, calculated panel reactive antibody (cPRA) levels, death, retransplantation, and dialysis. Cox regression models were used to evaluate factors associated with death and retransplantation. From October 2007 to May 2017, 1354 solitary ABO-compatible transplants were performed, of which 97 failed. Ten percent of patients received a preemptive retransplant. Among those who returned to dialysis (n = 87), 35% died, 25% received another transplant, and 30% remained on dialysis. After AF, 46% of patients discontinued immunosuppression. The cPRA was unchanged if immunosuppression was maintained, but immunosuppression discontinuation was associated with increased cPRA from a median (interquartile range) of 18 (0-99) to 96 (88.5-100.0; P = 0.003). Age at failure (hazard ratio, 1.1; confidence interval, 1.0-1.1) and cardiovascular disease were associated with death (hazard ratio, 2.9; confidence interval, 1.2-7.0) in multivariate analysis. Importantly, immunosuppression maintenance was not associated with increased death or retransplantation despite the increase in cPRA that occurred when immunosuppression was discontinued. Kidney transplant recipients with AF have a high mortality rate after dialysis initiation. Although immunosuppression withdrawal was associated with increased cPRA, it was not associated with reduced retransplantation. Therefore, it is reasonable to discontinue immunosuppression after AF despite sensitization if retransplantation is delayed.

Antibody response to a third SARS-CoV-2 vaccine dose in recipients of an allogeneic haematopoietic cell transplantation.

Allogeneic haematopoietic cell transplantation (allo-HCT) recipients show impaired antibody (Ab) response to a standard two-dose vaccination against severe acute respiratory syndrome coronavirus-2 and currently a third dose is recommended as part of the primary vaccination regimen. By assessing Ab titres 1 month after a third mRNA vaccine dose in 74 allo-HCT recipients we show sufficient neutralisation activity in 77% of the patients. Discontinuation of immunosuppression before the third vaccine led to serological responses in 50% of low responders to two vaccinations. Identifying factors that might contribute to better vaccine responses in allo-HCT recipients is critical to optimise current vaccination strategies.

G-CSF Improves Stable Engraftment in Adults with Sickle Cell Disease Undergoing Nonmyeloablative Hematopoietic Stem Cell Transplantation

Allogeneic hematopoietic stem cell transplantation (HSCT) is curative in patients with sickle cell disease (SCD). HSCT using nonmyeloablative conditioning leads to a mixed chimerism that improves the SCD phenotype but may be complicated by the continued need for immunosuppression and graft loss. Granulocyte colony stimulating factor (G-CSF) may stimulate progenitor cells and is used post-HSCT to reduce the duration of neutropenia and the risk of neutropenic fever. G-CSF has been generally avoided in patients with SCD due to its risk of promoting vaso-occlusion (PMID 19513902). Starting in 7/2016, our institution administered G-CSF after day +5 post-HSCT on the days when the ANC was < 500 x103/µL. In this study, we evaluated whether G-CSF is safe and can improve the duration of neutropenia, infection risk, and donor chimerisms in adults with SCD undergoing non-myeloablative HSCT. We included 34 adults with SCD that underwent allogeneic HSCT from an HLA-matched sibling donor in our institution and were conditioned with alemtuzumab and total body irradiation (TBI) (PMID 33534948) between 11/2011 and 8/2021. Medical records were individually reviewed for data extraction. Linear and categorical outcomes were compared by G-CSF use with the Kruskal-Wallis and chi-square test, respectively. We also compared the Kaplan-Meier curves for discontinuation of immunosuppression with the log-rank method. Median and interquartile range (IQR) are provided. The median age of our cohort was 33 years (IQR, 26 - 45 years), 18 (53%) patients were female, and 30 (88%) had hemoglobin SS genotype. We did not observe statistically significant differences in baseline characteristics between the SCD patients that received G-CSF versus did not receive G-CSF for median age (37 years vs. 32 years), female gender (69% vs. 43%), hemoglobin SS genotype (85% vs. 90%) or median CD34+ dose (8.6 vs. 8.1 x 106/kg), respectively. In the 13 SCD patients that received G-CSF, the median day when it was initiated was day +10 (IQR, 7 - 17) and for a median of 3 days (IQR, 2 - 7 days). The maximum pain score during hospitalization was not significantly different in the SCD group that received G-CSF (median 8, IQR, 7 - 10) compared to those that did not receive G-CSF (median 10, IQR, 9 - 10). Median time to neutrophil engraftment (G-CSF: day 16 vs. no G-CSF: day 22) and duration of neutropenia (G-CSF: 7 days vs. no G-CSF: 9 days) were relatively similar between the 2 groups, while the incidence of neutropenic fevers trended lower with G-CSF treatment (8% vs. 29%, respectively, P=0.1). Whole blood or myeloid chimerism values were significantly higher in the SCD patients that received G-CSF at day +30, +90, +180, and 1 year post-HSCT (Figure 1A). Secondary graft loss was not observed after we implemented G-CSF while 4 out of 21 (19%) of patients experienced secondary graft failure who did not receive post-HSCT G-CSF. Furthermore, in those patients with stable engraftment, we observed a trend for more patients who received G-CSF being successfully tapered off immunosuppression (11/13, 85%) versus those that did not receive G-CSF (10/17, 59%) (Figure 1B). In conclusion, administration of G-CSF to patients with SCD undergoing HSCT conditioned with alemtuzumab/TBI was associated with significantly higher whole blood or myeloid donor chimerism values. This benefit was achieved without a significant increase in pain scores during the hospitalization for HSCT and was associated with trends for a greater proportion of patients discontinuing immunosuppression and less secondary graft loss. Future studies investigating the effects of G-CSF on donor myeloid progenitor cells and on T-cell clearance may guide strategies to improve outcomes for curative therapies in adults with SCD. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

FATAL CASE OF FULMINANT HEPATIC FAILURE DUE TO HERPES SIMPLEX VIRUS REACTIVATION IN SETTING OF IMMUNOSUPPRESSION FROM CHRONIC STEROID AND METHOTREXATE USE: A RARE PRESENTATION

FATAL CASE OF FULMINANT HEPATIC FAILURE DUE TO HERPES SIMPLEX VIRUS REACTIVATION IN SETTING OF IMMUNOSUPPRESSION FROM CHRONIC STEROID AND METHOTREXATE USE: A RARE PRESENTATION

A CASE OF LOMUSTINE-INDUCED PNEUMONITIS

A CASE OF LOMUSTINE-INDUCED PNEUMONITIS

Low dose interleukin-2 selectively expands circulating regulatory T cells but fails to promote liver allograft tolerance in humans

CD4+CD25+Foxp3+ regulatory T cells (Tregs) are essential to maintain immunological tolerance and have been shown to promote liver allograft tolerance in both rodents and humans. Low-dose IL-2 (LDIL-2) can expand human endogenous circulating Tregs invivo, but its role in suppressing antigen-specific responses and promoting Treg trafficking to the sites of inflammation is unknown. Likewise, whether LDIL-2 facilitates the induction of allograft tolerance has not been investigated in humans. We conducted a clinical trial in stable liver transplant recipients 2-6 years post-transplant to determine the capacity of LDIL-2 to suppress allospecific immune responses and allow for the complete discontinuation of maintenance immunosuppression (ClinicalTrials.gov NCT02949492). One month after LDIL-2 was initiated, those exhibiting at least a 2-fold increase in circulating Tregs gradually discontinued immunosuppression over a 4-month period while continuing LDIL-2 for a total treatment duration of 6 months. All participants achieved a marked and sustained increase in circulating Tregs. However, this was not associated with the preferential expansion of donor-reactive Tregs and did not promote the accumulation of intrahepatic Tregs. Furthermore, LDIL-2 induced a marked IFNγ-orchestrated transcriptional response in the liver even before immunosuppression weaning was initiated. The trial was terminated after the first 6 participants failed to reach the primary endpoint owing to rejection requiring reinstitution of immunosuppression. The expansion of circulating Tregs in response to LDIL-2 is not sufficient to control alloimmunity and to promote liver allograft tolerance, due, at least in part, to off-target effects that increase liver immunogenicity. Our trial provides unique insight into the mechanisms of action of immunomodulatory therapies such as LDIL-2 and their limitations in promoting alloantigen-specific effects and immunological tolerance. The study is registered at ClinicalTrials.gov (NCT02949492). The administration of low-dose IL-2 is an effective way of increasing the number of circulating regulatory T cells (Tregs), an immunosuppressive lymphocyte subset that is key for the establishment of immunological tolerance, but its use to promote allograft tolerance in the setting of clinical liver transplantation had not been explored before. In liver transplant recipients on tacrolimus monotherapy, low-dose IL-2 effectively expanded circulating Tregs but did not increase the number of Tregs with donor specificity, nor did it promote their trafficking to the transplanted liver. Low-dose IL-2 did not facilitate the discontinuation of tacrolimus and elicited, as an off-target effect, an IFNγ-orchestrated inflammatory response in the liver that resembled T cell-mediated rejection. These results, supporting an unexpected role for IL-2 in regulating the immunogenicity of the liver, highlight the need to carefully evaluate systemic immunoregulatory strategies with investigations that are not restricted to the blood compartment and involve target tissues such as the liver.

Setting up criteria for drug-induced autoimmune-like hepatitis through a systematic analysis of published reports.

Nitrofurantoin, minocycline, methyldopa and infliximab, have been found to induce autoimmune‐like hepatitis (DI‐AILH). Evidence for other drugs and herbal and dietary supplements (HDS) is unclear. The aims of the study were to establish criteria to define and review the published evidence of suspected DI‐AILH. Search was undertaken in Pubmed using search terms “drug‐induced liver injury,” “autoimmune hepatitis,” and “drug‐induced autoimmune hepatitis.” DI‐AILH was defined as (1) drug as a potential trigger of liver injury with autoimmune features and histological findings compatible with AIH; (2) no or incomplete recovery or worsening of liver tests after discontinuation of the drug; (3) corticosteroids requirement or spontaneous recovery; (4) follow‐up without immunosuppression (IS) and no relapse of AIH at least 6 months after discontinuation of IS; and (5) drugs potentially inducing AILH with a chronic course. Cases fulfilling the first four criteria were considered probable DI‐AILH with three possible DI‐AILH. A total of 186 case reports were identified for conventional drugs (n = 148; females 79%; latency 2.6 months) and HDS (n = 38; females 50%). The most commonly reported agents of DI‐AILH were interferons (n = 37), statins (n = 24), methylprednisolone (MPS) (n = 16), adalimumab (n = 10), imatinib (n = 8), and diclofenac (n = 7). Tinospora cordifolia and Khat were the only HDS with probable DI‐AILH cases. No relapses of AIH were observed when IS was stopped after interferons, imatinib, diclofenac, and methylprednisolone. Conclusion: Beyond well‐recognized nitrofurantoin, methyldopa, hydralazine, minocycline, and infliximab as causes of DI‐AILH, interferons, imatinib, adalimumab, and MPS were the best‐documented agents leading to probable DI‐AILH. Khat and Tinospora cordifolia were the only HDS found to be able to induce DI‐AILH. Long‐term immunosuppression appears to be rarely required in patients with DI‐AILH due to these drugs.

Rituximab Therapy in the Treatment of Juvenile Myasthenia Gravis: The French Experience.

Corticosteroids are the first-line immunosuppressants in the management of juvenile myasthenia gravis despite their adverse effects. The place of new immunosuppressive therapies is not clearly defined by the last international consensus held in March 2019 due to the lack of clinical trials. The aim of this study is to describe the use of rituximab and its efficacy and safety in 8 main pediatric centers of the French neuromuscular reference network to propose a new place in the therapeutic strategy of juvenile myasthenia gravis. We conducted a retrospective multicenter study from January 1, 2009, to April 30, 2020, including a large cohort of children with myasthenia gravis in 8 main French pediatric reference centers of the FILNEMUS network. The type of myasthenia, different lines of immunosuppressive treatment, and clinical course of the patients were collected. To evaluate the efficacy of rituximab, we studied the clinical course of patients on immunosuppressive therapy. Outcome was defined as the clinical and therapeutic status of patients at the last visit: stable without immunosuppressants, stable with immunosuppressants, or unstable. We included 74 patients: 18 children with ocular form and 56 children with generalized form. Of the 37 patients who required immunosuppressive therapy, 27 were treated with rituximab. Patients treated with rituximab had a better outcome than patients treated with conventional immunosuppressants (p = 0.006). The use of rituximab as a first-line immunosuppressant showed a better efficacy with a discontinuation of immunosuppressants in 75% of patients (vs 25%, p = 0.04) and results in cortisone sparing (42% vs 92%, p = 0.03) compared with rituximab treatment as a second- or third-line immunosuppression. Rituximab was well tolerated; no adverse effect was observed. The use of rituximab has increased in France over the last 10 years as a first-line immunosuppressant. This study suggests good tolerability and efficacy of rituximab in juvenile myasthenia gravis. Early use appears to improve outcomes and facilitate cortisone sparing in antibody-positive generalized juvenile myasthenia. This study provides Class III evidence that for children with MG, rituximab is effective and well tolerated.

Outcomes Following Intolerance to Tacrolimus/Sirolimus Graft-versus-Host Disease Prophylaxis for Allogeneic Hematopoietic Cell Transplantation

Although tacrolimus and sirolimus (TAC/SIR) is an accepted graft-versus-host disease (GVHD) prophylaxis regimen following allogeneic hematopoietic cell transplantation (HCT), toxicity from this regimen can lead to premature discontinuation of immunosuppression. There are limited studies reporting outcomes and subsequent treatment of patients with TAC/SIR intolerance. This study was conducted to assess the outcomes of patients with TAC/SIR intolerance and guide their subsequent management. We retrospectively analyzed transplantation outcomes of consecutive adult patients at Moffitt Cancer Center who underwent allogeneic HCT with TAC/SIR as GVHD prophylaxis between 2009 and 2018. TAC/SIR intolerance was defined as discontinuation of either TAC or SIR due to toxicity before post-transplantation day +100. A total of 777 patients met the inclusion criteria. The median duration of follow-up was 22 months (range, 0.2 to 125 months). Intolerance occurred in 13% (n = 104) of the patients at a median of 30 days (range, 5 to 90 days). The most common causes of intolerance were acute kidney injury (n = 53; 51%), thrombotic microangiopathy (n = 31; 28%), and veno-occlusive disease (n = 23; 22%). The cumulative incidence of grade II-IV acute GVHD at 100 days was 50% (95% CI, 39% to 64%) in the TAC/SIR-intolerant patients and 25% (95% CI, 22% to 29%) in patients tolerant to this regimen (P < .0001). In multivariate analyses, the incidence of grade II-IV 4 acute GVHD was significantly higher in the TAC/SIR-intolerant patients (hazard ratio [HR], 2.40; 95% CI, 1.59 to 3.61; P < .0001). Similarly, in multivariate analyses, the TAC/SIR-intolerant patients had a higher incidence of chronic GVHD (HR, 1.48; 95% CI, 1.03 to 2.12; P = .03). The nonrelapse mortality (NRM) at 1 year was 47% (95% CI, 38% to 59%) in the TAC/SIR-intolerant patients and 12% (95% CI, 10% to 15%) in those tolerant to the regimen (P < .0001). The 2-year relapse-free survival was 35% (95% CI, 25% to 44%) in the TAC/SIR-intolerant patients and 60% (95% CI, 57% to 65%) in the TAC/SIR-tolerant patients (HR, 2.30; 95% CI, 1.61 to 3.28; P < .0001). Intolerance stratified by early (≤30 days) versus late (31 to 100 days) significantly affected the cumulative incidence of acute GVHD at 75% (early; 95% CI, 59% to 94%) versus 33% (late; 95% CI, 21% to 50%) (P = .001), as well as the cumulative incidence of NRM at 61% (early; 95% CI, 48% to 77%) versus 35% (late; 95% CI, 24% to 51%) (P = .006). Most patients who developed TAC/SIR intolerance were switched to an alternative 2-drug regimen (71 of 104; 68%), most commonly mycophenolate mofetil in addition to continuing TAC or SIR (68 of 71; 96%). Overall, TAC/SIR intolerance was associated with poorer outcomes. Early intolerance contributed to a higher risk of acute GVHD, increased NRM, and inferior survival. Patients with early intolerance were often switched to an alternative agent, and patients with late intolerance tended to be continued on single-drug therapy without substitution. The use of single-drug versus 2-drug regimens after intolerance did not appear to affect outcomes. Management strategies to mitigate the risks of intolerance are warranted.

Acute liver injury following methylprednisolone pulse therapy: 13 cases from a prospectively collected cohort.

Drug-induced liver injury (DILI) remains a challenging diagnosis requiring exclusion of other causes of liver injury, concise medical history taking to identify potential causative medication and creation of a plausible temporal relation to attribute said liver injury to a potentially hepatotoxic agent. In spite of corticosteroids being considered an effective treatment for DILI in some patients, methylprednisolone (MPS) has been associated with liver injury of varying severity. We analyzed data of our prospective study on potentially hepatotoxic drugs (NCT02353455), identified 13 cases of MPS-associated liver injury and performed an analysis of clinical, laboratory and histopathological characteristics. For all available liver biopsy specimens, expert histopathological analysis was performed. Thirteen patients with a variety of primarily neurologic autoimmune diseases treated with MPS developed subsequent liver injury with a median latency of 5 weeks. Liver injury was severe or required transplantation in six patients. Injury typically occurred after repeated pulsing was hepatocellular and responded swiftly to prednisolone administration. For those patients who received in house-follow up, relapse after discontinuation of immunosuppression was not observed. Histopathological features of MPS-DILI comprised both interface and periportal hepatitis with mixed inflammatory infiltrates, similar to autoimmune hepatitis (AIH) features. MPS-related liver injury can be life-threatening, occurs with considerable latency and after repeat dosing. Regular surveillance of hepatic biochemistry should therefore be routinely performed also after discharge to avoid further MPS-related liver injury during repeat application. Swift response to prednisolone but not histologic features can be helpful to discriminate MPS-DILI from AIH.

Changes in Beliefs About Post-Transplant Immunosuppressants Over Time and Its Relation to Medication Adherence and Kidney Graft Dysfunction: A Follow-Up Study.

PurposeThe main aim was to evaluate the changes in beliefs about immunosuppressants over a 3-year period in patients after kidney transplantation. The second aim was to investigate the relationship between beliefs, medication adherence, and selected clinical outcomes such as graft functioning.Patients and MethodsThis observational follow-up study was conducted in the outpatient post-transplant clinic at the University Hospital Hradec Kralove in the Czech Republic. Adult patients, at least 4 weeks after kidney transplantation, were invited for the structured interview, which was followed by a self-administered questionnaire survey during their regularly scheduled visits at the clinic. Appropriate paired tests were used to compare two measurements of beliefs about immunosuppressants by BMQ-CZ© in 2016 (baseline) and in 2019 (follow-up). Self-reported adherence was measured by two validated tools (MARS-CZ© and BAASIS©) capturing implementation and discontinuation phases. A generalized linear model was used to investigate the relation between beliefs and the consecutive estimated glomerular filtration rate.ResultsThe study involved 134 patients. Over time, their perceived treatment necessity beliefs of immunosuppressants decreased, while their treatment-related concerns increased. Overall self-reported non-adherence (ie, taking, dosing and discontinuation of immunosuppressants) was reported by 12% of the patients in both observation periods. In the follow-up period, timing non-adherence was reported by 52 (38.8%) patients. Higher baseline treatment concerns were associated with poor adherence whereas higher baseline treatment necessity beliefs corresponded with better kidney functioning, even after adjusting for age.ConclusionHigher treatment necessity beliefs corresponded with better kidney functioning, whereas higher treatment concerns were related to non-adherence to immunosuppressants at the beginning of the observed period. Still, most patients accepted their medicines that do not come without risk. Nevertheless, decreasing treatment necessity beliefs on one hand, and increasing treatment concerns on the other, should be considered in clinical practice.

The incidence, clinical characteristics, and outcome of COVID-19 in a prospectively followed cohort of patients with Behçet's syndrome.

Initial case series of small number of patients at the beginning of the pandemic reported a rather guarded prognosis for Behçet’s syndrome (BS) patients infected with SARS-CoV-2. In this prospective study, we describe the incidence, clinical characteristics, disease course, management, and outcome in a large cohort of BS patients with laboratory-confirmed infection of SARS-CoV-2. We defined a cohort of 1047 registered BS patients who were aged between 16 and 60 years and seen routinely before the pandemic at the multidisciplinary outpatient clinic. We followed prospectively this cohort from beginning of April 2020 until the end of April 2021. During 13 months of follow-up, of the 1047 (599 M/448 F) patients, 592 (56.5%) were tested for SARS-CoV-2 PCR at least once and 215 (20.5%; 95% CI 0.18–0.23) were tested positive. We observed 2 peaks which took place in December 2020 and April 2021. Of the 215 PCR positive patients, complete information was available in 214. Of these 214, 14 (6.5%) were asymptomatic for COVID-19. In the remaining, the most common symptoms were anosmia, fatigue, fever, arthralgia, and headache. A total of 40 (18.7%) had lung involvement, 25 (11.7%) were hospitalized, 1 was admitted to the intensive care unit while none died. Favipiravir was the most prescribed drug (74.3%), followed by colchicine (40.2%), and hydroxychloroquine (20.1%) in the treatment of COVID-19. After COVID-19, 5 patients (2.3%) were given supplemental O2 and 31 (14.5%) antiaggregant or anticoagulants. During COVID-19, of the 214 PCR positive patients, 116 (54.2%) decreased the dose of their immunosuppressives or stopped taking completely; 36 (16.8%) experienced a BS flare which was mostly oral ulcers (10.3%). None of the patients reported a thrombotic event. A total of 93 (43.5%) patients reported BS flares after a median 45 days of COVID-19 infection and this was found to be significantly associated with immunosuppressive drug discontinuation. Multiple regression analysis adjusted for age and gender indicated that smoking and using interferon-alpha decreased the likelihood of getting COVID-19. The incidence and severity of COVID-19 did not differ between those who were using colchicine or not. The cumulative incidence of COVID-19 in this prospectively followed cohort of BS patients was almost two folds of that estimated for the general population living in Istanbul, Turkey, however, the clinical outcome of COVID-19 was not severe and there was no mortality. The protective effect of smoking and interferon deserves further investigation. On the other hand, colchicine did not have any positive or negative effect against COVID-19. Significant number of patients flared after COVID-19, however, this was significantly associated with immunosuppressive discontinuation during the infection. Contrary to our previous observations, COVID-19 did not seem to exacerbate thrombotic events during or after the infection.Supplementary InformationThe online version contains supplementary material available at 10.1007/s00296-021-05056-2.

Belatacept in Kidney Transplant Recipients With Failed Allografts for the Prevention of Humoral Sensitization: A Pilot Randomized Controlled Trial.

Belatacept in Kidney Transplant Recipients With Failed Allografts for the Prevention of Humoral Sensitization: A Pilot Randomized Controlled Trial.

Long-term Persistence of Allosensitization After Islet Allograft Failure.

Allosensitization has been reported after discontinuation of immunosuppression following graft failure in islet transplantation (ITx) recipients, though duration of its persistence is unknown. We evaluated 35 patients with type 1 diabetes who received ITx, including 17 who developed graft failure (ITx alone, n = 13; ITx plus bone marrow-derived hematopoietic stem cells, n = 4) and 18 with persistent graft function. Panel-reactive antibody (PRA) was measured yearly for the duration of graft function within 1 y after graft failure at enrollment and yearly thereafter. In ITx alone graft failure patients, 61% (8/13) were PRA-positive at 6 y postgraft failure, and 46% (6/13) developed donor-specific anti-HLA antibodies (DSA to 2 ± 1 donors) during follow-up. The degree of sensitization was variable (cPRA ranging between 22% and 100% after graft failure). Allosensitization persisted for 7-15 y. Three subjects (3/13) were not allosensitized. In ITx plus bone marrow-derived hematopoietic stem cell recipients, cPRA-positivity (88%-98%) and DSA positivity persisted for 15 y in 75% (3/4) of subjects. Allosensitization was minimal while subjects remained on immunosuppression, but after discontinuation of immunosuppressive therapy, the majority of subjects (77%) became allosensitized with persistence of PRA positivity for up to 15 y. Persistence of allosensitization in this patient population is of clinical importance as it may result in longer transplant waiting list times for identification of a suitable donor in the case of requiring a subsequent transplant.

S2841 Autoimmune Hepatitis: Possible Relation to the Pfizer-BioNTech COVID-19 Vaccine?

Introduction: Autoimmune Hepatitis (AIH) is a rare liver injury known to cause approximately 13% of acute liver failure cases in the United States. Drug-induced AIH has similar clinical, serological and histological features of AIH but is less likely to require long term immunosuppression or to relapse after discontinuation of immunosuppressants. It is mostly associated with nitrofurantoin, minocycline, hydralazine, and methyldopa, however other medications may be culprits. Herein, we present a patient with drug-induced AIH with possible relation to Pfizer-BioNTech COVID-19 vaccine. Case Description/Methods: A 38-year-old female with a history of Helicobacter pylori treated with amoxicillin and pantoprazole three months ago and recent COVID-19 vaccination presented with two weeks of right upper quadrant pain and diarrhea. Patient received second dose of vaccination two weeks prior to symptom onset. Five days post-symptom onset, she developed a pruritic rash with vomiting and yellowing of her skin. Physical examination was notable for normal mentation, scleral icterus, jaundice, and a maculopapular rash. Initial blood workup showed international normalized ratio 2.4, alkaline phosphatase 212 U/L, ALT 3769 U/L, AST 1572 U/L and total bilirubin of 23.8 mg/dL. Viral hepatitis serologies, chronic liver disease workup and autoimmune serologies were normal. Imaging demonstrated no intra- or extra-hepatic biliary ductal dilation. Liver biopsy showed portal inflammation with interface activity, diffuse lobular inflammation, and perivenulitis with abundant lymphocytes and plasma cells consistent with seronegative AIH or drug induced AIH. The patient developed altered mental status meeting the criteria of acute liver failure, she was started on corticosteroids as well as supportive care with resolution of encephalopathy and was discharged home on prednisone. Discussion: Several etiologies of drug-induced AIH are well-established, however cases secondary to COVID-19 vaccination have been minimally reported. Common adverse events for COVID-19 vaccination have been noted such as fever, chills, fatigue, headache, and muscle pain. Several rare side effects have occurred including immune thrombocytopenia and one other suspected case of Pfizer-BioNTech COVID-19 vaccination-induced AIH reported in the literature. In that case the patient developed symptoms within one week of the first dose. This case serves to report a potential association and not necessarily causation between the Pfizer-BioNTech COVID-19 vaccination and AIH.Figure 1.: Severely active lymphoplasmacytic hepatitis with frequent apoptotic hepatocytes with confluent necrosis.

Impact of COVID-19 Pandemic on Management of Pediatric Kidney Transplant Recipients.

Children appear to be less commonly and less severely affected by COVID-19 than adults, accounting for 1% to 5% of all COVID-19 cases. The COVID-19 pande mic has challenged pediatric kidney transplant programs to provide safe and consistent care during this difficult and unprecedented time. So far during this pandemic, best practices being delivered to pediatric kidney transplant patients are based on available information from published literature and expert opinions. The key areas of pediatric kidney transplant care that may be affected by the COVID-19 pandemic include transplant activity, outpatient clinic activity, monitoring, multidisciplinary care, medications (immunosuppression and others), patient/family education/support, school and employment, and care of pediatric kidney transplant patients who are COVID-19 positive. It has been presumed that children with chronic kidney disease and/or those who take immunosuppressants may be at increased risk for complications from COVID-19 infection; however, available evidence has now suggested that immunosuppressed children with kidney transplant are not at increased risk of severe COVID-19 disease. Clinicians should remain aware that transplant recipients may present with atypical symptoms. In addition, because evidence-based reports to support specific adjustments to immunosuppressive medications in relation to COVID-19 are not yet available, decisions on reduction or discontinuation of immunosuppression should be on a case-by-case basis for kidney transplant recipients who are COVID-19 positive. Reports to support evidence-based management of pediatric kidney transplant patients during the COVID-19 pandemic are lacking; therefore, expert opinion and available knowledge and experience remain subject to biases.

Successful treatment of refractory pure red cell aplasia with eltrombopag after ABO-incompatible allogeneic hematopoietic stem cell transplantation

Pure red cell aplasia (PRCA) is a well-recognized complication of ABO major mismatched allogeneic hematopoietic stem cell transplantation (allo-HSCT), with a reported incidence of 10%-20% (Zhidong et al., 2012; Busca et al., 2018). It is clinically characterized by anemia, reticulocytopenia, and the absence of erythroblasts in a normal-appearing bone marrow biopsy (Shahan and Hildebrandt, 2015). The mechanism for PRCA has been presumed to be persistence of recipient isoagglutinins, produced by residual host B lymphocytes or plasma cells, which can interfere with the engraftment of donor erythroid cells (Zhidong et al., 2012). Several risk factors of PRCA at presentation are known, such as presence of anti-A isoagglutinins before transplantation, reduced intensity conditioning, absence of acute graft-versus-host disease (GVHD), sibling donors, and cyclosporin A (CsA) as GVHD prophylaxis (Hirokawa et al., 2013). PRCA is not considered to be a barrier to HSCT, as some patients can recover spontaneously or benefit from various approaches including high-dose steroids, erythropoietin (EPO), plasma exchange, immunoadsorption, donor lymphocyte infusion (DLI), treatment with rituximab, bortezomib, or daratumumab, and tapering or discontinuation of immunosuppression (Hirokawa et al., 2013; Bathini et al., 2019). However, there are still some patients who fail to respond even to aggressive treatment; they become red cell transfusion-dependent and iron-overloaded, and their life quality is impaired.

Auxiliary liver transplantation for acute liver failure

Contents 1. What is auxiliary LT (ALT)? 2. When does ALT need? 3. What are issues of ALT for acute liver failure (ALF)? 4. Who can be a good candidate for ALT? 5. How to carve out a niche of technical challenges 6. How to manage Post-ALT patients 7. A SNUH case: A video clip 8. Reappraisal of ALT for ALF for Expanding Organ Utility. An APOLT (auxiliary partial orthtopic liver transplantation) for ALF has a benefit of immunosuppressant discontinuation in 60%-100% without compromising patients' survival outcome. This can also provide to expand the donor pool in some aspect. However, it's technically challenging as well as graft function and native liver regeneration is usually unpredictable. Thus, selection of good candidates (young, biopsy guided, hemodyenamically stable) and delicate surgical modification are important to lead a successful APOLT for ALF. In addition, this should be supported by careful postoperative monitoring and slow/steady immunosuppressant withdrawal after confirmation of native liver function restoration.

HBV Care Map for Patients Receiving Anti-CD20 Therapy

Background:Chronic Hepatitis B Virus (HBV) and so-called “resolved” HBV infections (HBsAg negative and anti-HBc positive) can be reactivated secondary to anti-CD20 therapy mediated immunosuppression used in the treatment of cancer and many non-malignant conditions. HBV reactivation can lead to delays in curative chemotherapy as well as HBV specific complications including liver failure and death. Appropriate screening, monitoring and treatment of HBV is integral to the safe administration of anti-CD20 therapies. However, current available guidelines for the management of HBV in patients receiving anti-CD20 therapies rely on a weak body of evidence and provide recommendations that do not adequately address all aspects of care.Objective:To provide a unified care map for the management of HBV in patients undergoing treatment with anti-CD20 therapies.Methods:A Delphi consensus technique was applied to a multidisciplinary panel of 10 North American experts in HBV or anti-CD20 therapy. The processed occurred over a 20-month period culminating in November 2014. To achieve a comprehensive overview, pharmacists, physicians and a nurse practitioner were included as team members. A preliminary HBV care map was generated based on literature review in conjunction with iterative questionnaires completed by panel members. Panelists were asked to rate their level of agreement across multiple domains of HBV care including screening, treatment and monitoring of patients. Consensus was achieved when there was greater than 75% agreement for all HBV care map elements. The HBV care map was subsequently revised and approved by all members at a face-to-face panel meeting.Results:The HBV care map recommends universal screening for all patients receiving anti-CD20 therapy. Patients with positive screening results are stratified into parallel, chronic and resolved HBV tracks. Both patients with chronic and resolved HBV should be started on antiviral treatment (or prophylaxis) prior to beginning anti-CD20 therapy. Entecavir is recommended as first line therapy over tenofovir disoproxil fumarate or lamuvidine. Where cost is a major factor, lamuvidine may be acceptable with close monitoring for viral resistance. Patients require routine monitoring for HBV reactivation (q3-6 months depending on care approach) from the initiation of anti-CD20 therapy until at least one year following discontinuation of immunosuppression. HBV DNA is recommended as the optimal test for HBV reactivation status as it is sensitive and can identify early reactivation events. Monitoring for HBsAg reverse seroconversion can also be used in resolved HBV but is not prioritized in the care map due to limited data demonstrating the safety of this approach.Conclusion:The HBV care map incorporates best available evidence and expert consensus building to provide clear and pragmatic guidance to clinicians managing HBV in patients receiving anti-CD20 therapies. In the rapidly changing clinical environment there is a need to quickly respond to growing risks associated with the development of new immunosuppressive treatments. The development of specific and valid guidelines in areas with limited published studies is an i2mportant step in improving the safe delivery of cancer care. This will also serve as the foundation for current and future prospective studies in the care of HBV among immunosuppressed patients. [Display omitted] DisclosuresCrump:Servier: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen Ortho: Consultancy, Membership on an entity's Board of Directors or advisory committees. Hwang:Gilead Sciences: Research Funding; Merck: Research Funding. Yim:Gilead Sciences: Consultancy, Honoraria. Zelenetz:Celgene: Consultancy; Amgen: Consultancy. Feld:Gilead Sciences: Research Funding. Hicks:Gilead Sciences: Research Funding.