Mild Acute Cellular Rejection Research Articles

CLINICAL OUTCOMES OF INFLAMMATORY BOWEL DISEASE AFTER ORTHOTOPIC HEART TRANSPLANT

Abstract BACKGROUND Limited data are available on outcomes of patients with pre-existing inflammatory bowel disease (IBD) who undergo orthotopic heart transplantation (OHT) or develop de novo IBD post-OHT. We aimed to assess the incidence and disease outcomes of pre-existing and de novo IBD in OHT patients while evaluating the effect of IBD on OHT outcomes. METHODS A retrospective review of records was performed from a tri-site tertiary care system between July 2000 and July 2022. A total of 83 OHT receipients were concomitantly diagnosed with colitis of infectious or inflammatory etiology. Only patients with a diagnosis of IBD were included. Sub-analyses of the outcomes and immunosuppressive regimens of OHT recepients were done relative to those with pre-existing or de novo IBD. RESULTS A total of 8 OHT patients with concomitant IBD were identified. The median patient age (IQR) was 54 (23) with OHT and IBD onset at 50 (21.2) and 32.5 (15.7), respectively. Six patients were diagnosed with ulcerative colitis (UC) and 2 were diagnosed with Crohn’s disease. Five of the patients were female. All patients developed IBD within 11.5 (8) years within OHT. Only 1 patient developed de novo IBD 15 years after the first OHT and 7 years prior to a second OHT. OHT immunosuppressive regimens included a combination of tacrolimus (TAC) and prednisone (n=2), TAC and mycophenolate mofetil (MMF) (n=2), TAC, MMF, and sirolimus (n=2), TAC and sirolimus (n=1), and MMF with sirolimus (n=1). Therapy for pre-existing IBD included maintenance of 5-aminosalicylic (5-ASA) (n=3), escalation to vedolizumab (VD) (n=2), and discontinuation of IBD therapy (5-ASA and azathioprine) (n=3). De novo IBD consistent with UC (15 years post-OHT) was managed with 5-ASA (n=1). Six patients (including de novo IBD case) maintained clinical and endoscopic remission of IBD with no flares post-OHT while 2 patients (1 UC and 1 CD) with active disease flares responded clinically and endoscopically to VD escalation from 5-ASA and azathioprine. Among two UC patients with ileal J-pouch pre-OHT, 1 developed refractory pouchitis requiring diverting ileostomy (while on TAC and prednisone) with no pouchitis in the other (maintained on TAC and MMF). Good graft tolerance limited to mild acute cellular rejection episodes was noted in 6 patients, while multiple or no rejection episodes were noted in the remaining two. None of the patients developed CMV or MMF-induced colitis. One patient died due to progressive functional decline unrelated to graft failure or IBD. DISCUSSION The clinical course and treatment of IBD preceding OHT or de novo (though rare) is not significantly worsened or altered post-OHT. The majority of patients achieve clinical and endoscopic remission while on heart transplant-related immunosuppression. Biologic therapy escalation to VD resulted in clinical remission with no effect on graft tolerance. Table 1 Clinical outcomes of OHT patients with concomitant IBD

Anything But a Biopsy: The Quest for Noninvasive Alternatives in Heart Transplantation.

Anything But a Biopsy: The Quest for Noninvasive Alternatives in Heart Transplantation.

Benralizumab Used for Eosinophilic Inflammation in a Lung Transplant Patient

<h3>Introduction</h3> Eosinophilic inflammation in lung transplant (LTX) is challenging. Eosinophils may be found in transplant grafts during rejection episodes; however, it is unclear if they are bystanders or pathogenic. We did not find any prior use of biologics to disrupt the interleukin-5 (IL-5) pathway in the transplant literature. We discuss the novel use of benralizumab, a monoclonal antibody that targets IL-5 receptor. <h3>Case Report</h3> 19 year-old female with cystic fibrosis presented 18 months post-LTX with cough and chest pain and was treated with amoxicillin-clavulanate for community acquired pneumonia. She had mild leukocytosis and elevated absolute eosinophil count. She worsened and developed respiratory distress and fever, requiring bilevel positive airway pressure (BiPAP). Computed tomography showed total opacification of right lung. Bronchoscopy identified mild acute cellular rejection, low-grade small airway inflammation, chronic airway rejection, and marked eosinophilic inflammation in tissue and bronchoalveolar lavage (18%). Broad infectious work up was unrevealing. Peripheral eosinophils decreased to undetectable after methylprednisolone pulse, but rebounded one week later. She remained in intensive care unit on BiPAP. Due to favorable side effect profile and deteriorating clinical picture, we initiated benralizumab. Peripheral eosinophilia resolved, and she was weaned off respiratory support. Her two-year post-LTX surveillance bronchoscopy demonstrated resolution of eosinophilic inflammation. <h3>Summary</h3> Eosinophilic inflammation with acute respiratory failure justified the use of benralizumab, which successfully treated eosinophilic associated rejection. We selected benralizumab over other IL-5 disrupters because it theoretically targets IL-5 receptors in the tissue, thereby impacting tissue resident eosinophils. Further study of the role of eosinophils in LTX and the efficacy of IL-5 blockade should be considered.

Donor Derived Coccidioides in a Lung Transplant Recipient

<h3>Introduction</h3> There are no universal guidelines on screening donors for coccidioides. We describe a fatal case of coccidioides empyema from a donor previously residing in an endemic region. <h3>Case Report</h3> This is a 72 year old male, status post right single lung transplantation 3 weeks prior for chronic hypersensitivity pneumonitis, who presents to clinic with a productive cough. The donor was a 31 year old male with no medical history from the southern inland region of California. A chest X-ray in clinic demonstrated a right pleural effusion. He underwent thoracentesis and bronchoscopy on post-operative day (POD) 22. Pleural fluid was lymphocytic and exudative with negative cultures, and transbronchial biopsies showed mild acute cellular rejection. He was treated with pulse dose steroids. His symptoms worsened one week later when he was seen in the emergency department. Chest CT showed a large right loculated pleural effusion. The patient was started on broad spectrum antibiotics, and a thoracostomy tube was placed, demonstrating a neutrophil predominant exudate. Repeat chest CT showed the effusion extending through the chest wall, and an additional thoracostomy tube was placed. The patient became more hypoxemic requiring mechanical ventilation and VV-ECMO. Pleural cultures taken two-days prior demonstrated mold and the patient underwent irrigation with amphotericin in the operating room, along with intravenous amphotericin. Ultimately, the patient had multi-organ failure and cardiac arrest. Following his passing, pleural fluid cultures confirmed growth of Coccidioides immitis. <h3>Summary</h3> This case describes a patient with initial negative serologies to coccidioides and a donor from the southern inland region of California, where the incidence of coccidioides is increasing. Transmission of donor-derived coccidioides has been shown to be 43% within 30 days post-transplant, with a 29% mortality. Given the high mortality and treatment availability, screening donors in endemic areas with serologies may prevent post-transplant complications.

Human myocardial mitochondrial oxidative capacity is impaired in mild acute heart transplant rejection.

AimsAcute cellular rejection (ACR) following heart transplantation (HTX) is associated with long‐term graft loss and increased mortality. Disturbed mitochondrial bioenergetics have been identified as pathophysiological drivers in heart failure, but their role in ACR remains unclear. We aimed to prove functional disturbances of myocardial bioenergetics in human heart transplant recipients with mild ACR by assessing myocardial mitochondrial respiration using high‐resolution respirometry, digital image analysis of myocardial inflammatory cell infiltration, and clinical assessment of HTX patients. We hypothesized that (i) mild ACR is associated with impaired myocardial mitochondrial respiration and (ii) myocardial inflammation, systemic oxidative stress, and myocardial oedema relate to impaired mitochondrial respiration and myocardial dysfunction.Methods and resultsWe classified 35 HTX recipients undergoing endomyocardial biopsy according International Society for Heart and Lung Transplantation criteria to have no (0R) or mild (1R) ACR. Additionally, we quantified immune cell infiltration by immunohistochemistry and digital image analysis. We analysed mitochondrial substrate utilization in myocardial fibres by high‐resolution respirometry and performed cardiovascular magnetic resonance (CMR). ACR (1R) was diagnosed in 12 patients (34%), while the remaining 23 patients revealed no signs of ACR (0R). Underlying cardiomyopathies (dilated cardiomyopathy 50% vs. 65%; P = 0.77), comorbidities (type 2 diabetes mellitus: 50% vs. 35%, P = 0.57; chronic kidney disease stage 5: 8% vs. 9%, P > 0.99; arterial hypertension: 59% vs. 30%, P = 0.35), medications (tacrolimus: 100% vs. 91%, P = 0.54; mycophenolate mofetil: 92% vs. 91%, P > 0.99; prednisolone: 92% vs. 96%, P > 0.99) and time post‐transplantation (21.5 ± 26.0 months vs. 29.4 ± 26.4 months, P = 0.40) were similar between groups. Mitochondrial respiration was reduced by 40% in ACR (1R) compared with ACR (0R) (77.8 ± 23.0 vs. 128.0 ± 33.0; P < 0.0001). Quantitative assessment of myocardial CD3+‐lymphocyte infiltration identified ACR (1R) with a cut‐off of >14 CD3+‐lymphocytes/mm2 (100% sensitivity, 82% specificity; P < 0.0001). Myocardial CD3+ infiltration (r = −0.41, P < 0.05), systemic oxidative stress (thiobarbituric acid reactive substances; r = −0.42, P < 0.01) and myocardial oedema depicted by global CMR derived T2 time (r = −0.62, P < 0.01) correlated with lower oxidative capacity and overt cardiac dysfunction (global longitudinal strain; r = −0.63, P < 0.01).ConclusionsMild ACR with inflammatory cell infiltration associates with impaired mitochondrial bioenergetics in cardiomyocytes. Our findings may help to identify novel checkpoints in cardiac immune metabolism as potential therapeutic targets in post‐transplant care.

LIVER TRANSPLANTATION: TACROLIMUS BLOOD LEVELS VARIATION AND SURVIVAL, REJECTION AND DEATH OUTCOMES.

Immunosuppressive drugs have important role in transplant of solid grafts, it aim avoid episodes of acute and chronic rejection and improving graft survival and patient survival. In Brazil, in 2016, liver transplantation was the third most frequent, with 1,880 transplants performed, of which 150 in Rio Grande do Sul. Several studies evaluated the association between variability in blood levels of immunosuppressive tacrolimus and late acute cellular graft rejection. To investigate the association of tacrolimus blood levels with clinical outcomes late acute cellular rejection, death, patient survival and graft survival in patients undergoing liver transplantation. This is a retrospective longitudinal study including patients submitted to adult liver transplantation by the Liver Transplantation Group in the Santa Casa de Misericórdia Hospital of Porto Alegre, from January 2006 to January 2013, and who used tacrolimus as immunosuppressive therapy. Of the 127 patients included in the study, the majority were male (70.1%), 52-60 years old (33.9%) at the transplant. The most frequent causes of liver transplantation in this series were hepatitis C virus and hepatocellular carcinoma (24.4%) and alcohol (15.7%). Thirteen patients had late acute cellular rejection (10.2%); of these, three had two episodes. Regarding severity classification, seven patients had mild late acute cellular rejection. The mean time of rejection after liver transplantation was 14 months (ranging from 8 to 33 months). Overall survival was 8.98 years. Regarding tacrolimus blood levels, 52 patients with a variation ≥2 standard deviations were identified. Of these patients, eight had rejection; however, the association was not significant (P=0.146). A significant association was found between variation ≥2 standard deviations in tacrolimus blood levels and death (P=0.023) and survival (P=0.019). Regarding 5-year follow-up of graft survival, being two standard deviations above increases by 2.26 times the risk of transplanted graft loss, and for each unit of increase of standard deviation of tacrolimus blood levels there is a two-fold increase in the risk of graft loss in 5 years. Increased risk of graft loss associated with increased standard deviations of tacrolimus blood levels may indicate the need for more rigorous and prospective monitoring of tacrolimus blood levels.

Recurrent lymphangioleiomyomatosis in a lung allograft with COVID-19: autopsy case report and literature review

Lymphangioleiomyomatosis (LAM) is a rare neoplastic disease of the lung with a characteristic feature of diffuse cystic changes in bilateral lungs. Lung transplantation is considered to be one of the effective treatments in end stage disease. Patients with LAM who underwent lung transplant tend to have more favorable outcome compared to other end stage lung diseases. We report a case of a female patient who was diagnosed with LAM and received bilateral lung transplantation at 45 years of age. Subsequent allograft biopsies were significant for mild acute cellular rejection (Grade A2), for which the immunosuppressive regimen was adjusted accordingly. At 7 years post-transplant, she presented with shortness of breath, cough, and fatigue, and diagnosed with a viral infection. Her chest imaging was unremarkable. However, a transbronchial biopsy was performed to rule out rejection and revealed foci of spindle cells proliferation, with positive HMB-45 and smooth muscle actin immunohistochemical studies, confirming the diagnosis of recurrent LAM. After she was discharged, she was re-admitted 1 week later with severe COVID-19. Her clinical course was complicated by acute respiratory distress syndrome, respiratory failure, and gastrointestinal hemorrhage. The patient passed away on day 36 of hospital stay. Autopsy was requested and confirmed the pathology of recurrent LAM and diffuse alveolar damage from COVID-19.

Predictive Factors of De Novo Malignancies After Living-Donor Liver Transplantation: A Single-Center Experience

BackgroundDe novo malignancies are a major reason of long-term mortalities after liver transplantation. However, they usually receive minimal attention from most health care specialists. The current study aims to evaluate our experience of de novo malignancies after living-donor liver transplantation (LDLT). MethodsWe reviewed the data of patients who underwent LDLT at our center during the period between May 2004 and December 2018. ResultsDuring the study period, 640 patients underwent LDLT. After a mean follow-up period of 41.2 ± 25.8 months, 15 patients (2.3%) with de novo malignancies were diagnosed. The most common de novo malignancies were cutaneous cancers (40%), post-transplantation lymphoproliferative disorders (13.3%), colon cancers (13.3%), and breast cancers (13.3%). Acute cellular rejection (ACR) episodes occurred in 10 patients (66.7%). Mild ACR occurred in 8 patients (53.3%), and moderate ACR occurred in 2 patients (13.3%).All patients were managed with aggressive cancer treatment. The mean survival after therapy was 40.8 ± 26.4 months. The mean overall survival after LDLT was 83.9 ± 52.9 months. Twelve patients (80%) were still alive, and 3 mortalities (20%) occurred. The 1-, 5-, and 10-year overall survival rates after LDLT were 91.7%, 91.7%, and 61.1%, respectively. On multivariate regression analysis, smoking history, operation time, and development of ACR episodes were significant predictors of de novo malignancy development. ConclusionsLiver transplant recipients are at high risk for the development of de novo malignancies. Early detection and aggressive management strategies are essential to improving the recipients’ survival.

Influence of Induction Therapy Using Basiliximab With Delayed Tacrolimus Administration in Heart Transplant Recipients - Comparison With Standard Tacrolimus-Based Triple Immunosuppression.

Appropriate indications and protocols for induction therapy using basiliximab have not been fully established in heart transplant (HTx) recipients. This study elucidated the influence of induction therapy using basiliximab along with delayed tacrolimus (Tac) initiation on the outcomes of high-risk HTx recipients.Methods and Results:A total of 86 HTx recipients treated with Tac-based immunosuppression were retrospectively reviewed. Induction therapy was administered to 46 recipients (53.5%) with impaired renal function, pre-transplant sensitization, and recipient- and donor-related risk factors (Induction group). Tac administration was delayed in the Induction group. Induction group subjects showed a lower cumulative incidence of acute cellular rejection grade ≥1R after propensity score adjustment, but this was not significantly different (hazard ratio [HR]: 0.63, 95% confidence interval [CI]: 0.37-1.08, P=0.093). Renal dysfunction in the Induction group significantly improved 6 months post-transplantation (P=0.029). The cumulative incidence of bacterial or fungal infections was significantly higher in the Induction group (HR: 10.6, 95% CI: 1.28-88.2, P=0.029). These results suggest that basiliximab-based induction therapy with delayed Tac initiation may suppress mild acute cellular rejection and improve renal function in recipients with renal dysfunction, resulting in its non-inferior outcome, even in high-risk patients, when applied to the appropriate recipients. However, it should be carefully considered in recipients at a high risk of bacterial and fungal infections.

Clinicopathological features and outcomes of parenchymal rejection in liver transplant biopsies.

The aim of this study was to perform a comprehensive retrospective analysis of liver transplant biopsies with parenchymal rejection (PR) at our institution, including histological features, laboratory values and follow-up biopsies, and to compare PR with portal-based acute cellular rejection (ACR). Biopsies from 173 patients were evaluated (retrospective database search 1990-2017), including 49 isolated PR, 35 PR with portal ACR (PR/ACR), 34 mild ACR and 52 moderate ACR cases. The rise and fall of serum liver enzymes was calculated as a measure of acute liver injury and response to immunotherapy, respectively. Isolated PR was associated with delayed-onset acute rejection (P<0.001), as well as younger age (P=0.004), and showed a similar rise in liver enzymes to mild ACR. PR/ACR and moderate ACR showed the highest elevations in transaminases (P<0.05). Isolated PR on an initial biopsy was associated with recurrent episodes of PR (P=0.01), chronic ductopaenic rejection (P=0.002) and chronic vascular rejection (P=0.017). Immunohistochemistry for C4d was performed, and strong C4d staining of venules was only detected in one severe isolated PR case (one of three, 33%) and one moderate ACR case (one of 20, 5%). Isolated PR represents a form of late acute rejection with distinct clinical and histological features. There is value in reporting PR in liver transplant biopsies to identify patients at higher risk of developing recurrent PR and chronic rejection. Standardisation of terminology and histological criteria of PR can help in uniform reporting and ensure appropriate management.

SUN-302 EFFICACY AND SAFETY OF ANTI-HUMAN T-LYMPHOCYTE IMMUNOGLOBULIN IN SUPPRESSION ABSOLUTE LYMPHOCYTE, CD3, CD4 AND CD8 COUNTS IN PATIENTS UNDERGOING RENAL TRANSPLANT

The objective of our study was to assess changes in absolute lymphocyte, CD3, CD4, CD8 counts, CD4:CD8 ratio, serum creatinine levels and incidence of viral and other infections in renal transplant patients receiving anti-human T-lymphocyte globulin (ATLG). In a single-center, retrospective, observational study, data of renal transplant patients was screened to identify patients treated with ATLG. ATLG was administered with a mean dose 5 mg/kg in three divided doses on a day before transplant and day 1 and day 2 post-transplant with. Blood samples were collected in EDTA vial on day 1 and day 5 for immunodeficiency panel testing. Changes in absolute lymphocytes count (aLC), absolute CD3 (aCD3), absolute CD4 (aCD4), absolute CD8 (aCD8) counts, CD4:CD8 ratio and serum creatinine were noted. Also, the incidence of bacterial, viral or any other infections as well as graft dysfunction or rejection were noted. In 30 patients treated with ATLG, mean age was 42.0±14.1 years and 80% were males. Etiology of chronic kidney disease was unknown in majority (86.7%) patients. HLA mismatch of 3 or more was seen in 61% patients. Significant reductions in aLC (1068.9±488.4 to 472.6±443.2, p<0.0001), aCD3 (790.8±405.8 to 249.5±305.4, p<0.0001), aCD4 (476.8±293.6 to 141.4±168.3, p<0.0001) and aCD8 (282.2±145.8 to 102.0±134.2, p<0.0001) counts were seen in post-transplant period. Change in CD4:CD8 ratio was also significant (p=0.046). Mean serum creatinine at discharge was 0.98±0.36 mg/dL, which changed to 1.06±0.31 at 1 month (n=29, p=0.109), 1.1±0.39 at 2 month (n=24, p=0.210), 1.26±0.49 at 3 months (n=18; p=0.040) and 1.33±0.31 at 6 months (n=8; p=0.081). Urinary tract infection (majority due to Escherichia coli) was observed in 30% patients. One patient each had delayed graft function and mild acute cellular rejection (at 5th month). No complications of viral infections were noted. Pre-transplant use of ATLG is associated with significant reduction in absolute counts of lymphocytes, CD3, CD4, CD8 cells, change in CD4:CD8 ratio and with preservation graft function over 6 months. There is no increase in incidence of viral infections. Larger, prospective studies are necessary to confirm the findings.

Surveillance for acute cellular rejection after lung transplantation.

Acute cellular rejection (ACR) is a common complication following lung transplantation (LTx), affecting almost a third of recipients in the first year. Established, comprehensive diagnostic criteria exist but they necessitate allograft biopsies which in turn increases clinical risk and can pose certain logistical and economic problems in service delivery. Undermining these challenges further, are known problems with inter-observer interpretation of biopsies and uncertainty as to the long-term implications of milder or indeed asymptomatic episodes. Increased risk of chronic lung allograft dysfunction (CLAD) has long been considered the most significant consequence of ACR. Consensus is lacking as to whether this applies to mild ACR, with contradictory evidence available. Given these issues, research into alternative, minimal or non-invasive biomarkers represents the main focus of research in ACR. A number of potential markers have been proposed, but none to date have demonstrated adequate sensitivity and specificity to allow translation from bench to bedside.

Mild acute cellular rejection and development of cardiac allograft vasculopathy assessed by intravascular ultrasound and coronary angiography in heart transplant recipients-a SCHEDULE trial substudy.

To evaluate the association between mild acute cellular rejection (ACR) and the development of cardiac allograft vasculopathy (CAV) after heart transplantation (HTx). Substudy of the SCHEDULE trial (n=115), where de novo HTx recipients were randomized to (i) everolimus with early CNI elimination or (ii) CNI-based immunosuppression. Seventy-six patients (66%) were included based on matched intravascular ultrasound (IVUS) examinations at baseline and year 3 post-HTx. Biopsy-proven ACR within year 1 post-HTx was recorded and graded (1R, 2R, 3R). Development of CAV was assessed by IVUS and coronary angiography at year 3 post-HTx. Median age was 53years (45-61), and 71% were male. ACR was recorded in 67%, and patients were grouped by rejection profile: no ACR (33%), only 1R (42%), and ≥2R (25%). Median ∆MIT (maximal intimal thickness)BL-3Y was not significantly different between groups (P=0.84). The incidence of CAV was 49% by IVUS and 26% by coronary angiography with no significant differences between groups. No correlation was found between number of 1R and ∆MITBL-3Y (r=-0.025, P=0.83). The number of 1R was not a significant predictor of ∆MITBL-3Y (P=0.58), and no significant interaction with treatment was found (P=0.98). The burden of mild ACR was not associated with CAV development.

2456 Fibrosing Cholestatic Hepatitis Following Transplantation of a Hepatits C Virus Positive Donor Liver

INTRODUCTION: Fibrosing cholestatic hepatitis (FSC) is a rare disorder, typically seen in immunosuppressed patients with a history of chronic hepatitis B and C infections. We present a case of a 67-year-old recipient of a hepatitis C virus positive donor liver with subsequent development of FSC. CASE DESCRIPTION/METHODS: We present a case of a 67 year-old gentleman, with a past medical history of HCV cirrhosis and multifocal hepatocellular carcinoma (HCC), who underwent orthotopic liver transplantation (OLT). Prior to transplantation, the patient was treated for HCV with Vosevi/ribavirin with sustained viral response. His course was complicated by multifocal HCC, for which he received treatments with DEB-TACE and Y90. He subsequently underwent OLT with a HCV positive (RNA quantitative positive) donor liver. The patient's post-operative course was complicated by marked elevation in AST and ALT (1610 and 647 respectively) and HCV RNA quantitative (1.5 million), concerning for fibrosing cholestatic hepatitis. A liver biopsy was performed and showed both mild acute cellular rejection (ACR) and cholestasis. The patient was treated with Epclusa for HCV and immunosuppression (prednisone, tacrolimus) for ACR with improvement in his liver enzymes. DISCUSSION: Fibrosing cholestatic hepatitis (FSC) is a rare disorder, typically seen in immunosuppressed patients with a history of chronic hepatitis B and C infections. It is particularly seen in patients following transplantation, namely recipients of donor liver and kidneys. Patients with FSC present with a number of symptoms including malaise, fatigue, jaundice, abdominal pain and progressive liver failure, which may occur over a period of weeks to months. The pathophysiology is related to direct cytotoxic effect of viral antigens on hepatocytes in the setting of immunosuppression. High viral titers and elevated liver enzymes in an immunosuppressed patient should raise concern for FSC. The diagnosis is established with a liver biopsy, which typically reveals hepatocyte ballooning, bridging fibrosis, pericellular and sinusoidal fibrosis as well as intracellular and canalicular cholestasis. This ultimately leads to acute liver failure and may result in rapid graft loss. Given the high rates of mortality associated with FSC, prompt diagnosis and treatment with direct-acting antiviral regimens may be effective in treatment, even in severe cases.

Use of His-Bundle Pacing for the Treatment of Left Bundle Branch Block-Induced Cardiomyopathy Following Orthotopic Heart Transplantation: A Case Report

A 70-year-old male with a past medical history significant for ischemic cardiomyopathy, status post uncomplicated orthotopic heart transplant 8 years prior, developed a new-onset left bundle branch block (LBBB) with a QRS of 170 milliseconds (ms) (Figure 1A). He subsequently developed pronounced new-onset left ventricular systolic dysfunction (LVSD) 6 months later, with an ejection fraction (LVEF) of 10-15%. Left heart catheterization demonstrated normal coronary arteries and endomyocardial biopsy revealed mild acute cellular rejection (1R). He was treated with intravenous diuretics, steroids and induction with thymoglobulin. Repeat endomyocardial biopsy was negative for cellular rejection and interval transthoracic echocardiography (TTE) showed only minimal improvement in LVEF to 20%. Guideline-directed medical therapy for heart failure was titrated to maximally tolerated doses with no improvement in LVEF. He subsequently underwent His-bundle pacing (HBP) with defibrillator placement. ECG after showed non-selective His bundle pacing with a QRS duration of 142 ms (Figure 1B). TTE at one month post-HBP revealed an LVEF of 42% and by four months his LVEF had normalized to 60%. Left ventricular end diastolic diameter decreased from 5.5 cm to 4.7 cm and left ventricular end systolic diameter decreased from 4.8 cm to 3.2 cm after HBP. Our patient developed persistent LBBB 8 years after cardiac transplantation with the development of LVSD 6 months after. To our knowledge, this is the first reported case of LVSD with LBBB in a post heart transplant patient treated successfully with HBP with normalization of LVEF. We believe that this temporal relationship in the onset of LBBB concurrent with the development of LVSD, followed by hyper-response to CRT with HBP, is demonstrative of LBBB-induced cardiomyopathy.

Mild Acute Cellular Rejection is Not Associated with Development of Cardiac Allograft Vasculopathy Assessed by Intravascular Ultrasound and Coronary Angiography in Heart Transplant Recipients - A Substudy of the SCHEDULE Trial

Purpose The impact of mild (1R) acute cellular rejection (ACR) on the development of cardiac allograft vasculopathy (CAV) after heart transplantation (HTx) remains unclear. We aimed to investigate the association between mild ACR within 1 year of HTx and development of CAV at 3 years post HTx. Methods This is a substudy of the SCHEDULE trial (n=115) in which de novo HTx recipients were randomized to either (i) everolimus or (ii) conventional CNI-based immunosuppression. 76 patients (66%) were eligible for inclusion based on matched intravascular ultrasound (IVUS) examinations at baseline (BL) and 3 years post HTx. Biopsy proven ACR within year 1 was recorded and graded according to ISHLT criteria (1R, 2R, 3R). Development of CAV was assessed by IVUS and coronary angiography at year 3 post HTx. Results Median age was 53 years (45-61) and 71% were male. In 67% of patients ACR was recorded during year 1 (1R in 63%, 2R in 24%, and 3R in 3% of patients, respectively). Patients were grouped by rejection profile: no ACR (33%), only 1R (42%), at least one 2R/3R (25%). At 3 years post HTx 49% of patients had CAV on IVUS (maximal intimal thickness, MIT ≥ 0.5 mm) with no difference in the incidence of IVUS-CAV between groups (p=0.43). Median ∆MITBL-3Y was 0.09 mm (0.05-0.15) with no significant difference among groups (p=0.84) (figure 1). At 3 years post HTx angiographic CAV was present in 26% of patients with no significant between group difference (no ACR: 40%, only 1R: 24%, at least one 2R/3R: 7%; p=0.06). No correlation was found between number of 1R and ∆MITBL-3Y (r=-0.03, p=0.83). Number of 1R did not predict ∆MITBL-3Y in an adjusted linear regression model (p=0.69). No significant interaction with treatment regimen (everolimus/CNI) was found (p=0.84). Conclusion Mild ACR within 1 year of HTx was not associated with development of CAV assessed by IVUS and coronary angiography at year 3 post HTx.

Efficacy and safety of sofosbuvir-based therapy in hepatitis C virus recurrence post living donor liver transplant: A real life egyptian experience.

Direct acting antiviral has offered treatment of hepatitis C virus (HCV) recurrence post liver transplantation (LT) with an all-oral regimen for short duration, excellent safety profile, and high sustained virological response (SVR). The aim of this study was to evaluate the efficacy and safety of sofosbuvir (SOF)-based regimens in the real world among a cohort of Egyptian patients with recurrent HCV post living donor LT (LDLT). Patients with HCV-G4 recurrence post-LDLT were recruited from National Committee of Control of Viral Hepatitis, Egypt, from November 2014 to May 2017. They received different SOF-based regimens according to the treatment protocols available during this period. Patients' outcome and Adverse effects (AE) were evaluated. One hundred ninety patients (170 males, mean age 56.8 ± 7.9 years) were included. Calcineurin inhibitors were the main immunosuppression used (173 patients). Out of 190, 119 (62.6%) received SOF/ribavirin (RBV), 38 (20%) SOF/simeprevir (SMV), 22 (11.6%) SOF/daclatasvir (DSV)/ ± RBV, and 11 (5.8%) received SOF/LDV/ ± RBV. Overall SVR12 was 89.5%, 84.9% in SOF/RBV group, 94.7% in SOF/SMV, 100% in SOF/DCV, and 100% in SOF/LDV with no statistically significant difference ( P = 0.104). The AE reported were as follows: anemia (n = 65, 34.4%) mainly in SOF/RBV group, transient hyperbilirubinemia during SOF/SMV in 13 patients (34%), mild Acute cellular rejection in eight patients (4.2%), and hepatocellular carcinoma in two patients (1%) mainly driven by underlying liver condition. Two deaths were unlikely related to HCV therapy. Different SOF-based regimens were effective with high SVR12 rates in a difficult-to-treat population, recurrent HCV post LDLT.

OR53 Post transplant monitoring to include donor derived cell free DNA (%ddcfDNA): Steps toward personalized medicine

Aim Elevated %ddcfDNA levels have been shown to correlate with allograft injury and acute rejection in lung transplantation. This case highlights how conventional post-transplant monitoring may underestimate the complex interactions between infection, injury, and de novo donor specific antibody (DSA) development. Methods Quantitation of %ddcfDNA via next generation sequencing was performed as part of the Genomic Research Alliance for Transplantation (GRAfT) consortium. DSA monitoring utilized Luminex phenotype and single bead immunoassays. Spirometry was used to assess pulmonary function and transbronchial biopsies to assess rejection. Bronchoalveolar lavage, blood samples and sputum cultures were used to diagnose infections. Results A 60 year old male with interstitial lung disease received a single lobe lung transplant. This patient was entered into GRAfT, a blinded prospective trial to investigate the use of %ddcfDNA to monitor allograft injury and predict long term outcomes. Immediately after transplant, high %ddcfDNA was detected in the recipient’s plasma which declined over several weeks. A biopsy on post-operative day (POD) 192 indicated mild acute cellular rejection concomitant with an infection and a spike in %ddcfDNA. The elevated %ddcfDNA ( > 1% threshold) suggested substantial injury to the allograft despite stable lung function. The patient experienced several infections prior to the detection of HLA-DQB1 de novo DSA. The second %ddcfDNA spike was concurrent with an increase in DSA and loss in lung function. Therapeutic plasma exchange reduced DSA with corresponding %ddcfDNA regression and improved lung function. An infection on POD 338 correlated with a third %ddcfDNA spike (last available measurement). The patient experienced further infections with a diminishing trend in lung function. Conclusion %ddcfDNA monitoring to detect cumulative clinical and subclinical injury may aid in assessing de novo DSA risk and in the development of interventions to prevent chronic allograft loss. Download : Download high-res image (141KB) Download : Download full-size image A.M. Jackson: 3. Speaker’s Bureau; Company/Organization; Thermo Fisher Scientific. DRB4*01:03:01 DQA1*03:01:01 DQB1*03:02:01 DPA1*01:03:01 DPB1*04:02:01 (HF = 0.03). A new DPA1*02:07:01_5407G > A was found. Conclusions As we published previously, the DRB1*04-DQA1*03-DQB1*03 association is strong but it is shown for the first time, that A*, B*, C* DQA1* and DPB1* alleles of Mexican AMI ancestry are strongly associated. The genetics of VKH is undoubtedly of Oriental origin, and present therefore in AMI, admixed groups such as Hispanics, Mediterranean and Asians. The shared epitope at S57-LLEQRRAA 67-74 in DR β 1 chain and the new class I associations are the basis to look for immunological intervention to block the T-cell response vs. the antigens that trigger the autoimmune response in VKH.

Paneth and Intestinal Stem Cells are Differentially Affected during Worsening of Acute Cellular Rejection in Small Bowel Transplantation compared to Intestinal Ischemia Reperfusion Injury and Graft versus Host Disease

Instituto de Estudios Inmunológicos y Fisiopatológicos, UNLP-CONICET, La Plata, Argentina. Introduction Acute cellular rejection (ACR) is one of the leading causes of graft loss after small bowel transplantation (SBTx). Although crypt epithelial cell apoptosis is used as histopathological criteria for ACR diagnosis, it is not clear which of epithelial lineages are the target of ACR. It was shown that the number of enteroendocrine progenitor cells in intestinal crypts was reduced during mild ACR, however, no results on other cell types of the crypt have been depicted so far. The aim of our work was to elucidate integrity and functionality of Paneth and stem cells during different degrees of ACR, in comparison with other clinical conditions such as graft vs. host disease (GVHD) and ischemia reperfusion injury (IRI). Material and Methods 44 patients of SBTx and controls treated in our center between 2006 and 2016 were included in the study. Rejection diagnosis was established by an experienced pathologist according to the recommendations of the pathology workshop of the VIII Small Bowel Transplantation Symposium. We compared small biopsies from SBTx patients with no, mild, moderate or severe ACR by immunohistochemistry and quantitative PCR (n=10 per group as average) for different cell markers (Lgr5, lysozyme, defensin5, IL22R, Ki67). Other conditions such as different degree of intestinal GVHD and IRI were included as separate groups. Comparisons among groups of data were performed with the Kruskal-Wallis test and the Dunn`s post-test when more than two groups were analyzed, whereas the Mann-Whitney U test was chosen to compare data from two groups. Results and Discussion Using differential immunofluorescence counting of different markers we observed that numbers of Paneth and stem cells remain constant in all ACR groups, whereas the transit-amplifying zone is the region that concentrates most of the apoptotic bodies during ACR (p<0.05). We detected unchanged level of antimicrobial peptides in Paneth cells and similar numbers of Ki-67+IL-22R+ stem cells revealing cell functionality in moderate ACR samples. Oppositely, in GVHD of moderate to severe, as well as IRI, Paneth cell number and markers were diminished (p<0.05), indicating differential mechanism that operate to trigger epithelial cell apoptosis in different situations. Conclusion Paneth and stem cells are not primary target cells during ACR. IL-22R + Ki-67+ stem cells might be an interesting target cell population for protection and regeneration of the epithelial monolayer during/after a severe ACR in ITx patients.

Histological findings to five years after early conversion of kidney transplant patients from cyclosporine to everolimus: an analysis from the randomized ZEUS study

BackgroundConversion from calcineurin inhibitor (CNI) therapy to everolimus within 6 months after kidney transplantation improves long-term graft function but can increase the risk of mild biopsy-proven acute cellular rejection (BPAR). We performed a post-hoc analysis of histological data from a randomized trial in order to further analyze histologic information obtained from indication and protocol biopsies up to 5 years after transplantation.MethodsBiopsy samples obtained up to 5 years post-transplant were analyzed from the randomized ZEUS study, in which kidney transplant patients were randomized at month 4.5 to switch to everolimus (n = 154) or remain on cyclosporine (CsA)-based immunosuppression (n = 146). All patients received mycophenolate and steroids.ResultsAt least one investigator-initiated biopsy was undertaken in 53 patients in each group between randomization and year 5, with a mean (SD) of 2.6 (1.7) and 2.2 (1.4) biopsies per patient in the everolimus and CsA groups, respectively. In the everolimus and CsA groups, investigator-initiated biopsies showed (i) BPAR in 12.3 and 7.5% (p = 0.182) of patients, respectively, with episodes graded mild in 22/24 and 18/20 cases (ii) CsA toxicity lesions in 4.5 and 10.3% of patients (p = 0.076) (iii) antibody-mediated rejection in 0.6 and 2.7% of patients (p = 0.204), respectively.ConclusionsThis analysis of histological findings in the ZEUS study to 5 years after kidney transplantation shows no increase in antibody-mediated rejection under everolimus-based therapy with a lower rate of CNI-related toxicity compared to a conventional CsA-based regimen, and confirms the preponderance of mild BPAR seen in the main study after the early switch to CsA-free everolimus therapy.Trial registrationClinicalTrials.gov NCT00154310. Date of registration: September 12, 2005.