Positive Recipients Research Articles

A new ICEEMDAN-based transfer entropy quantifying information flow between real estate and policy uncertainty

We quantify the dependence between real estate indices and global economic policy uncertainty for 12 top-advanced countries. Generally, real estate investments are found to be highly risky to information flow from global economic policy uncertainty. amidst policy uncertainty, we find diversification, safe haven, and hedging prospects – based on the market conditions – at short term frequencies only, for the pairs between (a) Japan and the US; (b) Singapore and the US; (c) China and Canada; (d) China and Hong Kong. Our findings underscore market efficiency (inefficiency) at mid-and long-term (short-term) frequencies. In the presence of policy uncertainty, our findings underscore the operability of ingrained market dynamics between real estate investments in the mid-and long-term horizons. It is prudent for investors to combine real estate investments with other asset classes that are less risky to (or are positive recipients of) information flow from global EPU to hedge against adverse market shocks from any asset in the portfolio based on market conditions. Practically, not only should legislations be flexible to the changing market trends in the short term, but they should also be strategically crafted to retain the fundamental market dynamics between real estate investments in the mid-and long-term economic horizons.

IFNL4 rs368234815 polymorphism does not predict risk of BK virus associated nephropathy after living‐donor kidney transplant: A case‐control study

BackgroundBK polyoma virus (BKPyV) associated nephropathy (BKPyVAN) is a major cause of kidney graft loss in renal transplant patients. Interferons (IFNs) are an important innate immune response against viral infections and genetic polymorphisms of the IFN‐pathways can affect susceptibility and mortality during viral infection. Here, we investigated whether the dinucleotide polymorphism rs368234815 (ΔG/TT) in the IFNL4 gene contributed to BKPyV reactivation or BKPyVAN after living‐donor kidney transplantation.MethodsThis retrospective case‐control study determines the prevalence of IFNL4 variants in a Caucasian population of living‐donor kidney transplant recipients and donors and explores its association with BKPyV infection and BKPyVAN development. We included 28 recipients with BKPyV reactivation, 10 of which developed BKPyVAN and 30 BKPyV negative controls. Targeted sequencing of the IFNL4 gene from both recipients and their respective donors was performed.ResultsWe found IFNL4 rs368234815 ΔG allele frequencies of 41.7% in BKPyV negative and 39.3% in BKPyV positive recipients (P = .85), and 41.7% and 40.4% (P>.99) in their respective donors. IFNL4 rs368234815 ΔG allele frequencies in BKPyVAN developing recipients and their respective donors were 50% and 43.7% (P = .60 and P>.99).ConclusionsOur results indicate that the IFNL4 rs368234815 ΔG allele is not associated with BKPyV reactivation, nor the manifestation of BKPyVAN.

Personal Protective Equipment for Liver Transplant in SARS-CoV-2 Polymerase Chain Reaction-Positive Convalescing Recipients

Personal protective equipment (PPE) comes in several variations, and is the principal safety gear during the COVID-19 pandemic. Unfortunately, the user is severely impacted by its serious nonergonomic features. What PPE is appropriate for labor-intensive cases, like liver transplant (LT), remains unknown. We describe our experience with 2 types of PPE used during 2 separate LT performed in COVID-19 positive recipients. We conclude that for the safety of both health care workers and patients, hospitals should designate a few PPE kits for labor-intensive surgical procedures. These kits should include powered air-purifying respirators, or a similar loose-fitting powered air hood.

Impact of utilization of hepatitis C positive organs in liver transplant: Analysis of united network for organ sharing database.

BACKGROUNDThe utility of hepatitis C virus (HCV) organs has increased after the Food and Drug Administration approval of direct acting anti-viral (DAA) medications for the HCV treatment. The efficacy of DAA in treating HCV is nearly 100%. AIMTo analyze the United Network for Organ Sharing (UNOS) database to compare the survival rates between the hepatitis C positive donors and negative recipients and hepatitis C negative donors and recipients. METHODSWe analyzed the adult patients in UNOS database who underwent deceased donor liver transplant from January 2014 to December 2017. The primary endpoint was to compare the survival rates among the four groups with different hepatitis C donor and recipient status: (Group 1) Both donor and recipient negative for HCV (Group 2) Negative donor and positive recipient for HCV (Group 3) Positive donor and negative recipient for HCV (Group 4) Both positive donor and recipient for HCV. SAS 9.4 software was used for the data analysis. Kaplan Meier log rank test was used to analyze the estimated survival rates among the four groups. RESULTSA total of 24512 patients were included: Group 1: 16436, Group 2: 6174, Group 3: 253 and Group 4: 1649. The 1-year (Group 1: 91.8%, Group 2: 92.12%, Group 3: 87%, Group 4: 92.8%), 2-year (Group 1: 88.4%, Group 2: 88.1%, Group 3: 84.3%, Group 4: 87.5%), 3-year (Group 1: 84.9%, Group 2: 84.3%, Group 3: 75.9%, Group 4: 83.2%) survival rates showed no statistical significance among the four groups. Kaplan Meier log rank test did not show any statistical significance difference in the estimated survival rates between Group 3 vs all the other groups. CONCLUSIONThe survival rates in hepatitis C positive donors and negative recipients are similar as compared to both hepatitis C negative donors and recipients. This could be due to the use of DAA therapy with cure rates of nearly 100%. This study supports the use of hepatitis C positive organs in the selected group of recipients with and without HCV infection. Further long-term studies are needed to further validate these findings.

The Global Impact of COVID-19 on Solid Organ Transplantation: Two Years Into a Pandemic.

The coronavirus disease 2019 (COVID-19) pandemic has had a major global impact on solid organ transplantation (SOT). An estimated 16% global reduction in transplant activity occurred over the course of 2020, most markedly impacting kidney transplant and living donor programs, resulting in substantial knock-on effects for waitlisted patients. The increased severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection risk and excess deaths in transplant candidates has resulted in substantial effort to prioritize the safe restart and continuation of transplant programs over the second year of the pandemic, with transplant rates returning towards prepandemic levels. Over the past 2 y, COVID-19 mortality in SOT recipients has fallen from 20%–25% to 8%–10%, attributed to the increased and early availability of SARS-CoV-2 testing, adherence to nonpharmaceutical interventions, development of novel treatments, and vaccination. Despite these positive steps, transplant programs and SOT recipients continue to face challenges. Vaccine efficacy in SOT recipients is substantially lower than the general population and SOT recipients remain at an increased risk of adverse outcomes if they develop COVID-19. SOT recipients and transplant teams need to remain vigilant and ongoing adherence to nonpharmaceutical interventions appears essential. In this review, we summarize the global impact of COVID-19 on transplant activity, donor evaluation, and patient outcomes over the past 2 y, discuss the current strategies aimed at preventing and treating SARS-CoV-2 infection in SOT recipients, and based on lessons learnt from this pandemic, propose steps the transplant community could consider as preparation for future pandemics.

Safety, tolerability, and efficacy of monoclonal CD38 antibody felzartamab in late antibody-mediated renal allograft rejection: study protocol for a phase 2 trial

BackgroundAntibody-mediated rejection (ABMR) is a cardinal cause of renal allograft loss. This rejection type, which may occur at any time after transplantation, commonly presents as a continuum of microvascular inflammation (MVI) culminating in chronic tissue injury. While the clinical relevance of ABMR is well recognized, its treatment, particularly a long time after transplantation, has remained a big challenge. A promising strategy to counteract ABMR may be the use of CD38-directed treatment to deplete alloantibody-producing plasma cells (PC) and natural killer (NK) cells.MethodsThis investigator-initiated trial is planned as a randomized, placebo-controlled, double-blind, parallel-group, multi-center phase 2 trial designed to assess the safety and tolerability (primary endpoint), pharmacokinetics, immunogenicity, and efficacy of the fully human CD38 monoclonal antibody felzartamab (MOR202) in late ABMR. The trial will include 20 anti-HLA donor-specific antibody (DSA)-positive renal allograft recipients diagnosed with active or chronic active ABMR ≥ 180 days post-transplantation. Subjects will be randomized 1:1 to receive felzartamab (16 mg/kg per infusion) or placebo for a period of 6 months (intravenous administration on day 0, and after 1, 2, 3, 4, 8, 12, 16, and 20 weeks). Two follow-up allograft biopsies will be performed at weeks 24 and 52. Secondary endpoints (preliminary assessment) will include morphologic and molecular rejection activity in renal biopsies, immunologic biomarkers in the blood and urine, and surrogate parameters predicting the progression to allograft failure (slope of renal function; iBOX prediction score).DiscussionBased on the hypothesis that felzartamab is able to halt the progression of ABMR via targeting antibody-producing PC and NK cells, we believe that our trial could potentially provide the first proof of concept of a new treatment in ABMR based on a prospective randomized clinical trial.Trial registrationEU Clinical Trials Register (EudraCT) 2021-000545-40. Registered on 23 June 2021. ClinicalTrials.gov NCT05021484. Registered on 25 August 2021

Outcomes of Flow Cytometry Crossmatch-Positive Lung Transplants Using Peri-Operative Desensitization

<h3>Purpose</h3> Successful outcomes among virtual crossmatch (VXM)-positive lung transplant recipients (LTRs) following peri-operative desensitization have been previously reported. However, the subset of flow cytometry crossmatch (FCXM)-positive LTRs, who may be at higher immunologic risk, has not been studied specifically. We conducted a retrospective cohort study to determine the impact of a positive FCXM on allograft survival (death/re-transplant) and chronic lung allograft dysfunction (CLAD)-free survival among LTRs in our program. <h3>Methods</h3> All adult, first-time LTRs from January 2014 to December 2019 with complete crossmatch data were divided into 3 cohorts based on sensitization status at the time of transplant: VXM-negative, VXM-positive/FCXM-negative, and VXM-positive/FCXM-positive. Patients were followed until October 2021. VXM-positive LTRs were routinely desensitized using plasma exchange, intravenous immune globulin, and anti-thymocyte globulin peri-operatively. Patient characteristics were compared using the chi-square test, and Kaplan Meier estimates of allograft survival and CLAD-free survival were compared using the log-rank test. <h3>Results</h3> A total of 902 LTRs were included: 765 (85%) VXM-negative, 63 (7%) VXM-positive/FCXM-negative, and 74 (8%) VXM-positive/FCXM-positive. VXM-positive/FCXM-positive LTRs were more likely to be female (p<0.001) and less likely to have cystic fibrosis/bronchiectasis (p=0.022), but age and urgency status at listing did not differ from the other cohorts. There was no significant difference in allograft survival (p=0.9805) or CLAD-free survival (p=0.9306) among VXM-negative, VXM-positive/FCXM-negative, and VXM-positive/FCXM-positive LTRs (Figure 1). <h3>Conclusion</h3> In the largest study to date of FCXM-positive LTRs, we demonstrate that with our peri-operative desensitization protocol, outcomes are equivalent to other LTRs. Our protocol may be used to facilitate VXM-positive and FCXM-positive lung transplants safely.

Initial Experience With SARS-CoV-2-Neutralizing Monoclonal Antibodies in Kidney or Combined Kidney-Pancreas Transplant Recipients.

Background: Antiviral drugs have shown little impact in patient infected with acute respiratory coronavirus 2 (SARS-CoV-2). Especially for immunocompromised persons positive for SARS-CoV-2, novel treatments are warranted. Recently, the U.S. FDA has granted an emergency use authorization (EUA) to two monoclonal antibodies (mAb) targeting the viral spike protein: bamlanivimab and casivirimab and imdevimab. As per the EUA, all SARS-CoV-2 positive organ transplant recipients can receive mAb treatment. Patients and methods: We queried our center’s transplant registry to identify SARS-CoV-2 infected recipients treated with single doses of either Bamlanivimab or casivirimab/imdevimab up to May 31, 2021. We analyzed clinical outcomes, renal function and virus-specific antibodies. The co-primary endpoints were hospitalization due to COVID-19 and SARS-CoV-2 RT-PCR negativity. Results: Thirteen patients at a median interval of 55 (IQR, 26-110) months from transplant were treated: 8 with bamlanivimab and 5 with casivirimab/imdevimab. In all, 4/13 (31%) patients were hospitalized at some time, while 11/13 (85%) achieved PCR negativity. 2/4 hospitalized patients received mAb as rescue treatment. Overall mortality was 23%, with one death attributable to transplant-associated lymphoma. All six patients infected with the B 1.1.7 variant were alive at last contact. Conclusion: mAb treatment appears effective when administered early to SARS-CoV-2-infected transplant recipients.

Effects and outcome of Direct Acting Antiviral Therapy for Eradication of Hepatitis C in Kidney Transplant patients

Aim: To look for effects and graft outcome of Direct Antiviral Agents on Hepatitis C positive Renal Transplant Patients Design: Prospective study Duration &amp; place of study: The study will be conducted in Shaikh Zayed Hospital’s Kidney Transplant Unit, Lahore, and will comprises of consecutive Hepatitis C positive Renal Transplant Recipients from January 2018 to January 2020 Methodology: The Hepatitis C Positive Renal Transplant Recipients will be selected after fulfilling Inclusion and Exclusion Criteria and we will follow the patient for 3 months after initiation of DAA regime. Result: The study included 50 patients average age was 36.1±10.5 years and 32(64%) of them were male and rest were females. Therapy for HCV was 100.0% successful. The total bilirubin levels, hemoglobin, platelet count, serum creatinine and eGFR had no significant change in averages over 12 weeks of treatment. The ALT and AST levels reduced significantly in first 4-week time and then stayed at a level while the ALP levels reduced significantly over all intervals of follow-ups. The albumin levels increased significantly at week 8 and stayed unchanged on week 12 as compared to baseline. The WBC count and blood glucose levels reduced significantly from baseline till end of study. 12th week was compared with baseline, it was observed that among 29 with eGFR &gt;90 at baseline 7(24.1%) had eGFR 60 – 90 and 3(10.3%) had eGFR even less (30 – 60). Conclusion: HCV is a well-recognised risk factor of poor graft survival in kidney transplant patients. In our study it was observed that DAA treatment can resolved HCV infection in kidney Transplant Recipients with significant improvement of liver function without loss of allograft function. Keywords: Hepatitis C, Direct Antiviral Agents, Sustained Virological Response

Occurrence of De novo Donor-Specific Antibodies After COVID-19 in Kidney Transplant Recipients Is Low Despite Immunosuppression Modulation

IntroductionDecreased immunosuppression has been proposed for kidney transplant recipients infected with coronavirus disease 2019 (COVID-19), but the impact on the alloreactive immune response during and after infection has been poorly investigated. We evaluated the occurrence of antihuman leukocyte antigen (HLA) donor-specific antibodies (DSAs) (post–COVID-19) and rejection episodes after COVID-19 with particular focus on immunosuppression modulation.MethodsKidney transplant recipients from 2 French institutions had anti-HLA antibody screening before and after COVID-19. Management of immunosuppression, rejection episodes, COVID-19 severity, inflammatory markers, and antiviral therapies were recorded.ResultsFrom 251 recruited patients, 72 were excluded because of COVID-19–related death (n = 25) and incomplete immunologic follow-up (n = 47). Among the remaining 179 included patients, almost half were hospitalized (49.2%). Antimetabolites were interrupted in 47% of patients (82% in hospitalized, median time of resumption of 23 days and in 15% nonhospitalized, median time of resumption of 7 days). Calcineurin inhibitors were interrupted in 12% of patients (all hospitalized, median time of resumption of 11 days). The incidence of post–COVID-19 DSA was 4% (8% and 0% in hospitalized and nonhospitalized, respectively). Allograft rejection occurred in 3 patients (1.7%) and all were hospitalized. Younger age, transplantation <1 year, and preexisting DSA were more frequently observed in patients with post–COVID-19 DSA, whereas inflammatory markers, lymphopenia, and use of antiviral therapies were not.ConclusionThe incidence of post–COVID-19 DSA among COVID-19–positive kidney transplant recipients was low (4%) despite a significant decrease in immunosuppression and was mainly restricted to high-risk immunologic patient’s status. COVID-19 severity was not associated with post–COVID-19 DSA and/or rejection.

Successful Liver Transplantation From a SARS-CoV-2 Positive Donor to a Positive Recipient: Potential Role of Monoclonal Antibodies.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic initially resulted in a decline in organ transplantation, including a 35.9% decrease in the United States.1 Although there are many factors contributing to this, potential donors who tested positive for SARS-CoV-2 have been largely excluded from donation. Simultaneously, there was uncertainty about safety of transplanting a recipient with coronavirus disease 2019 (COVID-19). Although there are emerging reports of liver transplantation from SARS-CoV-2-infected deceased donors,2 optimal risk mitigation strategies are unclear. Herein, we report a case of liver transplantation from a SARS-CoV-2 positive deceased donor to a SARS-CoV-2 positive recipient who was managed with anti spike monoclonal antibodies. This report did not require review board approval. Our patient was a 33 y-old female with adult-onset Still’s disease, treated previously with canakinumab, admitted for severe acute-on-chronic liver failure of unclear etiology. She had experienced several months of relapsing elevations in liver biochemistries attributed to lobular hepatitis of unclear etiology. She developed jaundice with progressive encephalopathy over 3 wk, culminating in a clinical scenario consistent with subacute liver failure, with a calculated Model for End-stage Liver Disease-Sodium score of 35. Concurrently, multiple household contacts developed mild upper respiratory symptoms and were diagnosed with COVID-19. She had not undergone SARS-CoV-2 vaccination. Upon admission, the patient was jaundiced, encephalopathic, and coagulopathic, although normoxic, and her chest radiograph did not show infiltrates. Urgent evaluation for liver transplantation was initiated. Nasopharyngeal SARS-CoV-2 polymerase chain reaction was positive (cycle threshold N 33.0, open reading frame 27.6; ARIES SARS-CoV-2 assay, Luminex Corp), and serum SARS-CoV-2 nucleocapsid antibody was negative. Because of high-risk comorbidities and likely impending transplantation, she received casirivimab and imdevimab on hospital day 1. She received an organ offer for liver transplantation on hospital day 4. The donor was incidentally found to have a positive SARS-CoV-2 polymerase chain reaction on routine donor screening without evidence of clinical disease. The donor had died from trauma, and the liver was normal. After shared decision-making, she proceeded with orthotopic liver transplantation and received a 5-d course of remdesivir after transplantation. She received induction immunosuppression with methylprednisolone and maintenance immunosuppression with tacrolimus, mycophenolate mofetil, and prednisone. She did receive augmented prophylactic anticoagulation with enoxaparin 30 mg twice per day; however, this was complicated by perihepatic hematoma requiring reoperation for evacuation and hemostasis on posttransplant day 8. She experienced no thrombotic complications. She was dismissed from the hospital 11 d following transplantation and remained in isolation for 20 d posttransplantation. She did not develop respiratory symptoms or abnormal lung imaging in 30 d of follow-up. There is currently little experience transplanting a SARS-CoV-2 positive donor to a SARS-CoV-2 positive recipient.3 We utilized anti spike monoclonal antibodies to mitigate the risk of progression to severe infection while awaiting transplantation. This treatment has been associated with good outcomes in solid organ transplantation4 and has been utilized as postexposure prophylaxis.5 We propose anti spike monoclonal antibodies may have a role in mitigating the risks of SARS-CoV-2 donor-derived infection and progression to severe disease posttransplantation. Our case highlights that donor SARS-CoV-2 positivity does not necessarily preclude nonlung organ transplantation, and risks of transmission must be balanced with the risk of death while remaining on the transplant waitlist. SARS-CoV-2-directed monoclonal antibody therapy and/or preemptive remdesivir administration may have roles in this setting; however, additional studies on strategies to mitigate donor-derived COVID-19 are necessary.

Acute kidney injury and chronic kidney disease after liver transplant: A retrospective observational study

Background and rationaleChronic kidney disease remains an important risk factor for morbidity and mortality among LT recipients, but its exact incidence and risk factors are still unclear. Material and methodsWe carried out a retrospective cohort study of consecutive adults who underwent liver transplant (January 2009–December 2018) and were followed (at least 6 months) at our institution. CKD was defined following the Kidney Disease: Improving Global Outcomes (KDIGO) 2012 Clinical Practice Guidelines. Long-term kidney function was classified into 4 groups: no CKD (eGFR, ≥60mL/min/1.73m2), mild CKD (eGFR, 30–59mL/min/1.73m2), severe CKD (eGFR, 15–29mL/min/1.73m2), and end-stage renal disease (ESRD). ResultsWe enrolled 410 patients followed for 53.2±32.6 months. 39 had CKD at baseline, and 95 developed de novo CKD over the observation period. There were 184 (44.9%) anti-HCV positive, 47 (11.5%) HBsAg positive, and 33 (8.1%) HBV/HDV positive recipients. Recipient risk factors for baseline CKD were advanced age (P=0.044), raised levels of serum uric acid (P<0.0001), and insulin dependent DM (P=0.0034). Early post-transplant AKI was common (n=95); logistic regression analysis found that baseline serum creatinine was an independent predictor of early post-LT AKI (P=0.0154). According to our Cox proportional hazards model, recipient risk factors for de novo CKD included aging (P<0.0001), early post-transplant AKI (P=0.007), and baseline serum creatinine (P=0.0002). At the end of follow-up, there were 116 LT recipients with CKD – 109 (93.9%) and 7 (6.1%) had stage 3 and advanced CKD, respectively. Only two of them are undergoing long-term dialysis. ConclusionThe incidence of CKD was high in our cohort of LT recipients, but only a slight decline in kidney function over time was recorded. Prevention of post-transplant AKI will improve kidney function in the long run. We need more studies to analyze the function of kidneys among LT recipients over extended follow-ups and their impact on mortality.

Promoting six-month exclusive breastfeeding: an examination of social norms messaging and outcome expectations

ABSTRACT Breast milk and breastfeeding bring considerable benefits to infants. A caveat in breastfeeding promotion efforts is the lack of emphasis on exclusive breastfeeding (EBF) for the first six months of a baby’s life. This research examined the relative effectiveness of descriptive and injunctive messaging on promoting 6-month EBF by employing a 3 (norms: descriptive norms vs. injunctive norms vs. no norms) X 2 (positive outcome recipient: baby vs. mother) factorial design and tested hypotheses with expecting women. Participants showed strong intention to exclusively breastfeed across experimental conditions. The results revealed that the descriptive normative message was more effective in promoting EBF than the control condition, whereas the injunctive normative message had no advantage over the control condition. Moreover, perceived outcome expectations for the baby and the mother attenuated the relationship between perceived descriptive norms and EBF intention. Theoretical and practical implications regarding how norms messaging can promote EBF are discussed.

Risk Factors for Early Cytomegalovirus Reactivation and Impact of Early Cytomegalovirus Reactivation on Clinical Outcomes after T Cell-Replete Haploidentical Transplantation with Post-Transplantation Cyclophosphamide

Risk factors for cytomegalovirus (CMV) reactivation and the impact of CMV reactivation on patient outcomes have been extensively investigated after matched related or unrelated donor transplantation, but little is known in the setting of haploidentical stem cell transplantation (Haplo-SCT) with post-transplantation cyclophosphamide (PT-Cy), in which recipients are considered more severely immunocompromised. We retrospectively analyzed a cohort of 554 consecutive patients undergoing Haplo-SCT with PT-Cy at 3 different centers. Early CMV reactivation (occurring within the first 120 days post-transplantation) occurred in 242 patients, for an estimated cumulative incidence of 44%. Among those patients, 74 (30%) had recurrent CMV and 20 (8%) had CMV disease. On multivariable analysis, positive recipient CMV serostatus (hazard ratio [HR] >2.5; P < .001), disease histology (lymphoid versus myeloid: HR, 0.66; P=.003) and increasing recipient age (HR, 1.01; P=.015) were independent predictors of CMV reactivation. At a 4-month landmark analysis, CMV reactivation was associated with higher 1-year and 5-year cumulative incidence of nonrelapse mortality (NRM) relative to patients without reactivation: 13% versus 5% and 22% versus 9%, respectively (P < .001). On multivariable analysis, CMV reactivation was an independent negative predictor of NRM (HR, 2.69; P < .001) and was close to statistically significant for overall survival (HR, 1.38; P=.062). Our results suggest that CMV reactivation plays an important role at determining NRM. Because patient CMV serostatus is the main predictor of CMV reactivation, it should be considered when evaluating strategies for preventing CMV reactivation. 2022 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc.

B Cell-Derived Extracellular Vesicles Reveal Residual B Cell Activity in Kidney Graft Recipients Undergoing Pre-Transplant Desensitization.

Background: Living-donor kidney transplant (LDKT) recipients undergoing desensitization for Human Leukocyte Antigen (HLA)-incompatibility have a high risk of developing antibody-mediated rejection (ABMR). The purpose of the study is to evaluate if residual B cell activity after desensitization could be estimated by the presence of circulating B cell-derived extracellular vesicles (BEVs).Methods: BEVs were isolated by Sepharose-based size exclusion chromatography and defined as CD19+ and HLA-II+ extracellular vesicles. We analyzed stored serum samples from positive crossmatch LDKT recipients before and after desensitization at first post-transplant biopsy and at 12-month protocol biopsy (n = 11). Control groups were formed by hypersensitized patients who were not submitted to desensitization (n = 10) and by low-risk recipients (n = 9). A prospective validation cohort of 11 patients also included the analysis of B cells subpopulations in recipients' blood and lymph nodes recovered upon graft implantation, along with BEVs analysis before and after desensitization.Results: We found out that CD19+ and HLA-II+BEVs dropped significantly after desensitization and relapse in patients who later developed ABMR was evident. We validated these findings in a proof-of-concept prospective cohort of 6 patients who received the same desensitization protocol and also in a control group of 5 LDKT recipients. In these patients, B cell subpopulations were also studied in recipients' blood and lymph nodes that were recovered before the graft implantation. We confirmed the significant drop in BEVs after desensitization and that this paralleled the reduction in CD19+cells in lymph nodes, while in peripheral blood B cells, this change was almost undetectable.Conclusions: BEVs reflected B cell residual activity after desensitization and this could be a valid surrogate of humoral alloreactivity in this setting.

Are Hepatitis C Positive Female Liver Transplant Recipients Still at Increased Risk for Graft Failure? Reexamining the Disparity in the Modern Era of Direct-acting Antiviral Agents.

This study aimed to compare the outcomes of hepatitis C virus (HCV) positive (+) female liver transplant recipients to HCV negative (-) female and HCV+ male recipients before and after the direct-acting-antiviral (DAA) era. The United Network for Organ Sharing liver transplant database was retrospectively reviewed from 2002 to 2017. The DAA era was defined as ≥2014. In the pre-DAA era, HCV+ female recipients had greater risk for graft failure compared with HCV+ male (hazard ratio [HR], 1.06; 95% confidence interval [CI], 1.01-1.11; P = 0.03) and HCV- female (HR, 1.51; 95% CI, 1.43-1.60; P < 0.001) recipients. In the post-DAA era, HCV+ female recipients had lower risk for graft failure compared with HCV+ male recipients (HR, 0.82; 95% CI, 0.70-0.97; P = 0.02) and equivalent outcomes to HCV- female recipients. HCV+ female recipients with graft failure had increased likelihood of graft failure due to disease recurrence compared with HCV+ male recipients in the pre-DAA era (odds ratio, 1.23; 95% CI, 1.08-1.39; P = 0.001) but not in the post-DAA era. Although historically HCV+ female recipients were at disproportionately increased risk for graft failure and disease recurrence, this disparity has been eliminated in the DAA era.

A multicenter evaluation of hepatitis B reactivation with and without antiviral prophylaxis after kidney transplantation.

Hepatitis B virus (HBV) reactivation in hepatitis B surface antigen (HBsAg)-negative and hepatitis B core antibody (anti-HBc)-positive kidney transplant recipients ranges between 1.4% and 9.6%. Limited evidence is available regarding routine antiviral prophylaxis and identifiable risk factors for HBV reactivation in this population. In this multicenter retrospective study, we evaluated the prevalence of HBV reactivation in HBsAg-negative anti-HBc-positive kidney transplant recipients who did or did not receive antiviral prophylaxis. The primary outcome assessed the prevalence of HBV reactivation, defined as a positive HBV DNA by PCR of any viral load at or above the minimal detection level. The principal safety outcomes assessed 1-year graft survival, 1-year all-cause mortality, biopsy-proven acute rejection, and antibody-mediated rejection. One hundred and sixty-one patients met inclusion criteria and comprised two groups, antiviral prophylaxis (n=14) and no antiviral prophylaxis (n=147). Of patients who did not receive prophylaxis, only five (3.4%) experienced HBV reactivation, whereas one (7.1%) patient in the prophylaxis group experienced reactivation over a median follow-up of 1103 days (p=.43). Furthermore, there were no differences with respect to all secondary outcomes. Statistical analysis demonstrated delayed graft function to be a significant factor associated with HBV reactivation. These study results suggest that the prevalence of HBV reactivation in HBsAg-negative anti-HBc-positive kidney transplant recipients is low, regardless of antiviral prophylaxis. Furthermore, there were no significant graft-related outcomes among those that did experience reactivation.

276. SARS-CoV-2 Infection in Solid Organ Transplant Candidates and Recipients at Texas Children’s Hospital: A Retrospective Review

BackgroundTexas Children’s Hospital (TCH) is the largest pediatric solid organ transplant (SOT) program in the US, performing heart, kidney, liver, and lung transplants. Limited data exists about SARS-CoV-2 infection (COVID-19) in the pediatric SOT populations. We evaluated the impact of COVID-19 in a cohort of PCR positive SOT candidates and recipients. We hypothesized that COVID-19 would more severely impact SOT recipients compared to transplant candidates. MethodsPatients with SOT or transplant candidates at TCH with a positive SARS-CoV-2 RT-PCR test since March 1, 2020 to April 12, 2021 were included in the cohort. Retrospective medical record review was performed, and descriptive statistics were used. ResultsA total of 103 SOT patients were identified, 13 candidates and 90 recipients. Of the SOT candidates, there were 1 heart, 3 kidney, and 9 liver transplant candidates. The SOT recipient cohort included 33 heart, 6 lung, 20 kidney, 33 liver and 2 multi-visceral recipients. A significant difference in age was observed between candidates and recipients with candidates being younger with median age of 4.5 years as opposed to recipient’s median age of 12.8 years (p=0.0003). The majority of patients, 70 of 101 (69%), were symptomatic. Most common symptoms reported were fever in 34/70 (49%), cough in 31/70 (44%), and headache in 19/70 (27%). A higher percentage of candidates (31%, 4 of 13) were hospitalized for acute COVID-19 infection compared to (17%, 15 of 90) of recipients. A transplant candidate who ultimately died from underlying illness and COVID-19 was the only patient in the cohort who required mechanical ventilation. More deaths (2/13, 15%) occurred in transplant candidates with COVID-19 compared to transplant recipients with COVID-19 (1/90, 1%, p=0.04); however, 2 of the deaths occurred after recovery from acute COVID-19 illness.ConclusionOur study suggests that pediatric candidates who are actively listed for transplant with underlying conditions have more severe acute COVID-19 illness than pediatric SOT recipients despite their immunosuppression based on the higher mortality observed in the transplant candidates. Prospective studies are needed to better understand which specific patients are at increased risk for mortality from COVID-19.Disclosures Leanne Petters, MSN, APRN, CPNP-AC, Pfizer (Scientific Research Study Investigator) Flor M. Munoz, MD, Biocryst (Scientific Research Study Investigator)Gilead (Scientific Research Study Investigator)Meissa (Other Financial or Material Support, DSMB)Moderna (Scientific Research Study Investigator, Other Financial or Material Support, DSMB)Pfizer (Scientific Research Study Investigator, Other Financial or Material Support, DSMB)Virometix (Other Financial or Material Support, DSMB) Elizabeth A. Moulton, MD, PhD, Pfizer (Scientific Research Study Investigator)

Invasive Mold Infections in Allogeneic Hematopoietic Cell Transplant Recipients in 2020: Have We Made Enough Progress?

BackgroundDespite progress in diagnostic, prevention, and treatment strategies, invasive mold infections (IMIs) remain the leading cause of mortality in allogeneic hematopoietic cell transplant (allo-HCT) recipients.MethodsWe describe the incidence, risk factors, and mortality of allo-HCT recipients with proven/probable IMI in a retrospective single-center 10-year (01/01/2010–01/01/2020) cohort study.ResultsAmong 515 allo-HCT recipients, 48 (9.3%) patients developed 51 proven/probable IMI: invasive aspergillosis (IA; 34/51, 67%), mucormycosis (9/51, 18%), and other molds (8/51, 15%). Overall, 35/51 (68.6%) breakthrough IMIs (bIMIs) were identified: 22/35 (62.8%) IA and 13/35 (37.1%) non-IA IMI. One-year IMI cumulative incidence was 7%: 4.9% and 2.1% for IA and non-IA IMI, respectively. Fourteen (29.2 %), 10 (20.8%), and 24 (50.0%) patients were diagnosed during the first 30, 31–180, and >180 days post-HCT, respectively. Risk factors for IMI included prior allo-HCT (sub hazard ratio [SHR], 4.06; P = .004) and grade ≥2 acute graft-vs-host disease (aGvHD; SHR, 3.52; P < .001). All-cause 1-year mortality was 33% (170/515): 48% (23/48) and 31.5% (147/467) for patients with and without IMI (P = .02). Mortality predictors included disease relapse (hazard ratio [HR], 7.47; P < .001), aGvHD (HR, 1.51; P = .001), CMV serology–positive recipients (HR, 1.47; P = .03), and IMI (HR, 3.94; P < .001). All-cause 12-week mortality for patients with IMI was 35.4% (17/48): 31.3% (10/32) for IA and 43.8% (7/16) for non-IA IMI (log-rank P = .47). At 1 year post–IMI diagnosis, 70.8% (34/48) of the patients were dead.ConclusionsIA mortality has remained relatively unchanged during the last 2 decades. More than two-thirds of allo-HCT recipients with IMI die by 1 year post–IMI diagnosis. Dedicated intensified research efforts are required to further improve clinical outcomes.

Combined Analysis of Early CD4+ T Cell Counts and CMV Serostatus May Improve CMV Risk Assessment after Allogeneic Hematopoietic Cell Transplantation.

The incidence and severity of viral complications after cellular therapy are highly variable. Recent publications describe relevant interactions between the human Cytomegalovirus (CMV) and host immunity in recipients of allogeneic hematopoietic cell transplantation (HCT). Although immune monitoring is routinely performed in HCT patients, validated cut-off levels correlating with transplant outcomes such as survival or CMV reactivation are mostly limited to day +100, which is later than the median time for CMV reactivation in the absence of medical prophylaxis. To address this gap in early risk assessment, we applied an unsupervised machine learning technique based on clustering of day +30 CD4+ helper T cell count data, and identified relevant cut-off levels within the diverse spectrum of early CD4+ reconstitution. These clusters were stratified for CMV recipient serostatus to identify early risk groups that predict clinical HCT outcome. Indeed, the new risk groups predicted subsequent clinical events such as NRM, OS, and high CMV peak titers better than the most established predictor, i.e., the positive CMV recipient serostatus (R+). More specifically, patients from the R+/low CD4+ subgroup strongly associated with high CMV peak titers and increased 3-year NRM (subdistribution hazard ratio (SHR) 10.1, 95% CI 1.38–73.8, p = 0.023), while patients from the R-/very high CD4+ subgroup showed comparable NRM risks (SHR 9.57, 95% CI 1.12–81.9, p = 0.039) without such an association. In short, our study established novel cut-off levels for early CD4+ T cells via unsupervised learning and supports the integration of host cellular immunity into clinical risk-assessment after HCT in the context of CMV reactivation.