Acute Cellular Rejection Episodes Research Articles

Low Pre-Transplant Caveolin-1 Serum Concentrations Are Associated with Acute Cellular Tubulointerstitial Rejection in Kidney Transplantation.

Acute and chronic transplant rejections due to alloreactivity are essential contributors to graft loss. However, the strength of alloreactivity is biased by non-immunological factors such as ischemia reperfusion injury (IRI). Accordingly, protection from IRI could be favorable in terms of limiting graft rejection. Caveolin-1 (Cav-1) is part of the cell membrane and an important regulator of intracellular signaling. Cav-1 has been demonstrated to limit IRI and to promote the survival of a variety of cell types including renal cells under stress conditions. Accordingly, Cav-1 could also play a role in limiting anti-graft immune responses. Here, we evaluated a possible association between pre-transplant serum concentrations of Cav-1 and the occurrence of rejection during follow-up in a pilot study. Therefore, Cav-1-serum concentrations were analyzed in 91 patients at the time of kidney transplantation and compared to the incidence of acute and chronic rejection. Higher Cav-1 levels were associated with lower occurrence of acute cellular tubulointerstitial rejection episodes.

The respiratory microbiome after lung transplantation: Reflection or driver of respiratory disease?

With the introduction of high-throughput sequencing methods, our understanding of the human lower respiratory tract's inhabitants has expanded significantly in recent years. What is now termed the "lung microbiome" has been described for healthy patients, as well as people with chronic lung diseases and lung transplants. The lung microbiome of lung transplant recipients (LTRs) has proven to be unique compared with nontransplant patients, with characteristic findings associated with disease states, such as pneumonia, acute rejection, and graft failure. In this review, we summarize the current understanding of the lung microbiome in LTRs, not only focusing on bacteria but also highlighting key findings of the viral and the fungal community. Based on our knowledge of the lung microbiome in LTRs, we propose multiple opportunities for clinical use of the microbiome to improve outcomes in this population.

Cardiac Transplantation in Danon Disease

PurposeDanon disease is a rare X-linked dominant cardioskeletal myopathy caused by mutations in the lysosome-associated membrane protein-2 (LAMP-2) gene. Currently, there are no disease modifying therapies for Danon disease. The purpose of this study is to characterize individuals with Danon disease who undergo cardiac transplantation and describe their outcomes.MethodsRetrospective data of individuals with Danon disease who underwent cardiac transplantation (N=16) were obtained from 6 centers. Post-transplantation outcomes included survival, re-transplantation, and episodes of acute rejection within the first year. Analysis of preoperative patient characteristics was stratified by sex. Because the study was not limited to adults, z-scores were calculated for echocardiographic parameters to allow for comparisons between groups.ResultsMedian follow up time in this dataset was 2.35 years (IQR: 0.8 years - 8.3 years). Males had higher preoperative AST and ALT (p=0.02) compared to females and were more likely than females to have muscular symptoms (p=0.037). From a cardiac perspective, pre-transplant EF was lower in females compared to males (p=0.047), while left ventricular hypertrophy was more prominent in males compared to females (p<0.001). [TABLE] There was 1 death (female) in the entire cohort (occurred 5 days post-transplant) and no re-transplants. At 1 year, there were no episodes of antibody mediated rejection, and 5 episodes of acute cellular rejection (33%) in those who survived to discharge after transplantation.ConclusionDanon disease is a progressive multisystem disease. Understanding the individuals who undergo cardiac transplantation and their outcomes is critical for informing patient selection and guiding decisions regarding organ allocation. Short term post-transplant outcomes are acceptable in Danon disease and suggest that cardiac transplantation is a treatment option for these patients. Danon disease is a rare X-linked dominant cardioskeletal myopathy caused by mutations in the lysosome-associated membrane protein-2 (LAMP-2) gene. Currently, there are no disease modifying therapies for Danon disease. The purpose of this study is to characterize individuals with Danon disease who undergo cardiac transplantation and describe their outcomes. Retrospective data of individuals with Danon disease who underwent cardiac transplantation (N=16) were obtained from 6 centers. Post-transplantation outcomes included survival, re-transplantation, and episodes of acute rejection within the first year. Analysis of preoperative patient characteristics was stratified by sex. Because the study was not limited to adults, z-scores were calculated for echocardiographic parameters to allow for comparisons between groups. Median follow up time in this dataset was 2.35 years (IQR: 0.8 years - 8.3 years). Males had higher preoperative AST and ALT (p=0.02) compared to females and were more likely than females to have muscular symptoms (p=0.037). From a cardiac perspective, pre-transplant EF was lower in females compared to males (p=0.047), while left ventricular hypertrophy was more prominent in males compared to females (p<0.001). [TABLE] There was 1 death (female) in the entire cohort (occurred 5 days post-transplant) and no re-transplants. At 1 year, there were no episodes of antibody mediated rejection, and 5 episodes of acute cellular rejection (33%) in those who survived to discharge after transplantation. Danon disease is a progressive multisystem disease. Understanding the individuals who undergo cardiac transplantation and their outcomes is critical for informing patient selection and guiding decisions regarding organ allocation. Short term post-transplant outcomes are acceptable in Danon disease and suggest that cardiac transplantation is a treatment option for these patients.

The Impact of Grade 1R Endomyocardial Biopsies on Donor-Derived Cell-Free DNA, Higher-Grade Rejection and Development of Donor Specific Antibodies

<h3>Purpose</h3> Recurrent episodes of mild rejection early post-transplant may lead to subsequent higher severity rejections and adverse outcomes, but there is a paucity of data on the prognosis of these patients. Elevations in donor-derived cell-free DNA (dd-cfDNA) and the development of donor specific antibodies (DSA) in kidney, heart, and lung transplantation have been described. We evaluated the association of AlloSure (dd-cfDNA) during episodes of acute cellular rejection (ACR) ISHLT Grade 1R with subsequent development of higher-grade rejections and DSA in heart transplantation. <h3>Methods</h3> This is a retrospective analysis of 484 patients who developed ACR Grade 1R (< 365 days post-transplant) paired with dd-cfDNA in the <i>Surveillance HeartCare® Outcomes Registry</i> (SHORE). dd-cfDNA levels were divided into 4 quartiles (median dd-cfDNA; Q1 = 0.10%, Q2 = 0.12%, Q3 = 0.15%, Q4 = 0.32%). The number of recurrent rejections (ISHLT Grade 2R/3R) and DSA were compared across quartiles using the Cochran-Armitage test (p<0.05). <h3>Results</h3> There were 933 episodes of Grade 1R biopsies. The median dd-cfDNA in 72 for-cause biopsies was 0.16% and in 860 surveillance biopsies was 0.12%, p=0.8979. Grade 1R rejection was not associated with later development of higher grades of ACR or dd-cfDNA quartiles (Table). Sixty-seven patients developed DSA subsequent to a 1R rejection and a higher incidence of DSA was associated with increased dd-cfDNA (median dd-cfDNA in Q1=8.7%, Q2=10.9%, Q3=18.9%, Q4=18.3%) (p = 0.006). <h3>Conclusion</h3> Grade 1R biopsies did not progress to higher grade rejections. There was no significant elevation in dd-cfDNA with Grade 1R biopsies. With increasing dd-cfDNA there was a significant trend toward DSA development following Grade 1R biopsies. Further analysis with longer follow-up to assess recurrent rejection and larger sample size of DSA is warranted.

Successful Eradication of De Novo C1q-Binding Donor-Specific Antibodies with Rituximab Monotherapy

<h3>Introduction</h3> Antibody-mediated rejection (AMR) is an increasingly recognized cause of lung transplant allograft failure. Treatment of AMR involves combination therapy that is often poorly tolerated or unsuccessful with regimens involving the combination of intravenous immunoglobulins, plasmapheresis, and proteasome inhibitors, complement, or CD20 therapy. The development of DSAs alone, specifically complement activating C1q-binding DSAs, has been identified as an independent risk factor for solid organ transplant allograft dysfunction. Previous studies have examined the efficacy of combination therapy involving the anti-CD20 antibody rituximab to preemptively eliminate DSAs. Here we report on a case of successful eradication of de novo C1q-binding DSAs in a lung transplant recipient using rituximab. <h3>Case Report</h3> Our patient underwent double-lung transplantation for idiopathic pulmonary fibrosis in August 2019. His post-transplant course was notable for multiple episodes of acute cellular rejection (ACR) requiring burst-dose corticosteroids. DSA titers were monitored every three months post-transplant. At six months, de novo DSAs were detected (DQ7 with DQA1*05) at a mean fluorescence intensity (MFI) of 3623 (low-moderate) (Figure 1). These subsequently rose to an MFI of 11281 (strong) with development of C1q positivity that peaked at an MFI of 15038. Given his frequent episodes of ACR, the strong C1q positivity, and concerns regarding his ability to tolerate therapy for potential future AMR, he was preemptively treated with a single infusion of rituximab (375 mg per meter-squared body surface area). Follow-up DSA titers demonstrated near-total elimination of the C1q component (MFI 403). The patient tolerated the treatment without issue and continues to demonstrate improvement in his allograft function. <h3>Summary</h3> Rituximab monotherapy can be considered preemptively in patients with C1q-binding DSAs that may not tolerate traditional treatment of antibody-mediated rejection.

A Case of Unremitting Cellulitis in a Lung Transplant Recipient: What is the Infectious Etiology?

<h3>Introduction</h3> <i>Mycobacterium chelonae</i> is a rare, non-tuberculous mycobacterium that is highly pathogenic in immunosuppressed patients. Herein, we describe a chronic presentation of cellulitis which was later biopsy-proven as <i>M. chelonae</i> in a lung transplant recipient. <h3>Case Report</h3> A 61-year-old female bilateral lung transplant recipient presented 15-months post-transplant with multiple erythematous cutaneous lesions of the right arm. She had a 3-month history of waxing and waning cutaneous lesions that had not fully cleared despite antibiotic therapy. The first transplant year was eventful with two episodes of acute cellular rejection necessitating high-dose corticotherapy. Dermatological biopsy performed in a prior visit demonstrated features consistent with dermatitis. Autoimmune etiologies were ruled out, and the patient reported no history of trauma or other nidus of entry for infection. At the time of the current presentation, we observed nodular changes to the cutaneous lesions, which necessitated repeat biopsy, revealing granulomatous infiltrate (Figure 1). Acid-fast staining was positive, and <i>M. chelonae</i> was properly identified. Given her immunosuppressed state, the patient was started on multidrug antibiotic therapy, guided by antibiogram. Skin showed some improvement on observation, however, one large, nodular cutaneous lesion persisted. Decision was made to perform excision in effort to reduce bacterial growth burden. Subsequent biopsy findings were negative, likely a result of immunological phenomenon. She ultimately finished multidrug treatment with complete resolution of skin nodules. <h3>Summary</h3> This case underlines the role of corticotherapy and immunosuppression as a major risk factor for atypical infections, such as <i>M. chelonae</i>, in lung transplant recipients. Eradication can be difficult as demonstrated, and thus early recognition and multidrug antibiotic therapy are the cornerstone for management in this population.

Ex Situ Dual Hypothermic Oxygenated Machine Perfusion for Human Split Liver Transplantation.

After transport using static cold storage, a 51-year-old brain death donor liver underwent end-ischemic DHOPE. During DHOPE, the donor liver was maintained <10 °C and oxygenated with a Po2 of >106 kPa. An ex situ ERL/LLS split was performed with continuing DHOPE throughout the procedure to avoid additional ischemia time. Total cold ischemia times for the LLS and ERL were 205 minutes and 468 minutes, respectively. Both partial grafts were successfully transplanted at 2 different transplant centers. Peak aspartate aminotransferase and alanine aminotransferase were 172 IU/L and 107 IU/L for the LLS graft, and 839 IU/L and 502 IU/L for the ERL graft, respectively. The recipient of the LLS experienced an episode of acute cellular rejection. The ERL transplantation was complicated by severe acute pancreatitis with jejunum perforation requiring percutaneous drainage and acute cellular rejection. No device-related adverse events were observed. Liver splitting during continuous DHOPE preservation is feasible, has the potential to substantially shorten cold ischemia time and may optimize transplant logistics. Therefore liver splitting with DHOPE can potentially improve utilization of split liver transplantation.

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.

Phasing out the pre-transplant cytotoxicity crossmatch: Are we missing something?

Introduction: The anti-human globulin-enhanced complement-dependent cytotoxicity crossmatch (AHG-CDCXM) assay has been used to assess the presence of donor-specific antibodies (DSA) in recipient’s serum before kidney transplantation. The flow cytometric crossmatch (FCXM) assay was first introduced as an additional test. The aim of this study was to clinically validate the single use of the FCXM assay.Methods: This study compared the outcomes of a cohort of kidney transplant patients that underwent FCXM only (FCXM group) versus a cohort of kidney transplant patients that underwent AHG-CDCXM (control group).Results: Ninety-seven patients in the FCXM group and 98 controls were included. All crossmatches in the control group were negative. One patient in the FCXM group had a positive B cell crossmatch. One year after transplantation, there were no significant differences in patient survival (p = 0.591) and graft survival (p = 0.692) between the groups. Also, no significant difference was found in the incidence of Banff ≥ 1A acute cellular rejection episodes (p = 0.289). However, acute antibody-mediated rejections occurred in 3 controls (p = 0.028).Conclusion: The results showed that discontinuing the AHG-CDCXM assay does not modify the clinical outcomes in a 1-year follow-up.

Belatacept as salvage maintenance immunosuppression in a liver transplant recipient

Belatacept is a novel fusion protein that blocks signal two of T cell activation. Belatacept was approved in 2015 for the prevention of acute rejection in kidney transplant recipients. Results from a 2014 phase II clinical trial in liver transplant recipients was terminated early due to an increased risk of death and graft loss, leading to a black box warning for its use in liver transplant recipients. Here we describe the clinical course of a 55 year old male patient who underwent a liver transplant for cholestatic liver disease. His post-transplant course was complicated by multiple episodes of severe acute cellular rejection as well as multiple complications from maintenance immunosuppression including chronic kidney disease (CKD), steroid-induced diabetes, mycophenolate-associated colitis, and mammalian target of rapamycin (mTOR) inhibitor-induced lung injury. Belatacept was initiated 5 years post-transplant as a last-line option for maintenance immunosuppression. Six months post-initiation, the patient has had stabilization of his CKD, improvement in lung function, and remains without evidence of acute or chronic rejection.

Determinants of trajectories of cardiac allograft vasculopathy after heart transplantation: a population based study

Abstract Background Cardiac allograft vasculopathy (CAV) is a major contributor of heart transplant recipient's mortality. Little is known about determinants of CAV trajectories at a population level. Purpose We aimed to identify the respective contribution of immune and non-immune factors in the different evolutive profiles of CAV. Methods Heart transplant recipients receiving care at 2 academic centers (2004 to 2016) were included. Patients underwent prospective, protocol-based monitoring consisting of repeated coronary angiographies together with systematic assessment of clinical, functional, histological and immunological parameters. The outcome was CAV trajectories, identified with unsupervised latent class mixed models. The independent, predictive factors of CAV trajectories were investigated with multinomial regressions (NCT04117152). Results Overall, 815 patients were included. The median follow-up post-transplant was 7.7 years (IQR=5.14) with 2,742 coronary angiographies analyzed. We identified 4 distinct profiles of CAV trajectories over 10 years that were characterized by i) Patients without CAV at baseline and non-progression (n=459, 56.3%), ii) patients without CAV at baseline and late onset CAV progression (n=62, 7.6%), iii) patients with mild baseline CAV and mild progression (n=188 23.1%), iv) patients with mild baseline CAV and accelerated CAV progression (n=106, 13.0%, discrimination 0.92). Six early independent predictors of CAV trajectories were identified: donor age (p&amp;lt;0.001), donor male gender (p&amp;lt;0.001), donor tobacco consumption (p=0.001), recipient post-transplant dyslipidemia (p=0.009), preexisting or de novo class II anti-HLA donor-specific antibodies (p=0.004) and episode of acute cellular rejection ≥2R during the first year post transplantation (p=0.028). Conclusion In a large multicentric and highly phenotyped prospective cohort of heart transplant recipients, we identified 4 robust CAV trajectories and their respective immune and non-immune determinants. Our results provide the basis for a trajectory-based assessment of heart transplant patients for early patient risk stratification and patient monitoring. Factors associated CAV trajectories in multivariate analyses in the derivation cohort. This table shows the association of clinical, immunological, functional and structural parameters associated with CAV trajectories in multivariate multinomial regression analysis. The trajectory of reference was trajectory #1, including patients with no CAV at baseline and stable CAV grade over time. Funding Acknowledgement Type of funding source: None

Recipient risk factors for acute cellular rejection after orthotopic liver transplant - a single-center, retrospective study.

The use of model for end-stage liver disease (MELD) score for liver allocation has resulted in transplanting sicker patients. As such, it is unclear whether the risk factors and severity of acute cellular rejection (ACR) have changed. To identify ACR characteristics where average MELD score at transplant is higher than previously published studies. This is a single-center, retrospective study designed to assess risk factors associated with ACR after adult orthotopic liver transplant (OLT) using a steroid sparing regimen. This study included 174 OLT patients transplanted from 2008 to 2013 at a single tertiary care center. Recipient demographics, preoperative clinical, and laboratory data were recorded for each transplant. Univariate and multivariate regression analyses were performed to identify variables that are significant predictors for ACR. The median MELD at transplantation was 29.5. The average time from transplant to ACR diagnosis was 283.9days and a majority of ACR episodes were mild to moderate. Serum creatinine, primary sclerosing cholangitis etiology, and tacrolimus use were significant predictors for ACR (P<0.05). This study confirmed a change in timing and severity of ACR in the MELD era. Recipient characteristics may affect the risk for developing ACR and should be considered when managing immunosuppression.

Serum Trough Concentration and Effects of Mycophenolate Mofetil Based on Pathologic Findings in Infants After Liver Transplantation

ObjectivesMycophenolate mofetil (MMF) is mainly used in conjunction with calcineurin inhibitors as an additional immunosuppressive for renal sparing after liver transplantation. However, few reports about MMF use in infants after living donor liver transplantation (LDLT) are available. The purpose of this study was to examine the efficacy and safety of MMF in infants. MethodsThis study enrolled infants younger than 1 year of age who received LDLT at our institution. Patients received oral MMF twice daily. The initial dose was 40 to 50 mg/kg/d, which was increased to a target mycophenolic acid (MPA) trough level of 2 mg/L. Body weight, height, MMF dose, MPA trough level, acute cellular rejection (ACR) episodes, pathologic findings, and adverse effects were analyzed. Allograft fibrosis was graded using the Meta-analysis of Histological Data in Viral Hepatitis score. ResultsPatients received MMF for refractory ACR (n = 2), fulminant hepatitis (n = 2), and pre-existing antibodies (n = 1). Original diseases were biliary atresia (n = 3) and fulminant hepatitis (n = 2). Mean age at transplant was 8 months (range 3-10 months). The last available mean trough level was 2.7 mg/L. The mean dose was 66 mg/kg/d or 1429 mg/m2/d at the time of the last available through level. The regression line for MMF dose and MPA trough level was y = 1.8 × 10-3x. The correlation coefficient was 0.65. All allografts showed F1 to F2 fibrosis. Two patients discontinued MMF because of infection and bone marrow suppression, respectively. Two patients converted to everolimus. One patient continued on MMF. ConclusionsAfter LDLT, infants require a higher MMF dose than older patients based on trough levels, but allograft fibrosis can progress.

Circulating miR-181a-5p as a new biomarker for acute cellular rejection in heart transplantation

Acute cellular rejection (ACR) is a major complication in heart transplantation (HTx). Endomyocardial biopsy is the reference method for early detection of ACR, but a new non-invasive approach is needed. Tentative candidates could be circulating microRNAs. This study aimed to discover and validate microRNAs in serum for ACR detection after HTx. This prospective, observational, single-center study included 121 HTx patients. ACR was graded according to International Society of Heart and Lung Transplantation classification (0R-3R). First, in the discovery phase, microRNA expression profile was carried out in serum samples from patients at pre-rejection, during, and post-rejection time (0RS1 → 2RS2` → 0RS3). Relative expression (2-∆Cq) of 179 microRNAs per sample was analyzed by reverse transcription quantitative polymerase chain reaction. Second, a microRNA with a significant rise and fall pattern during ACR was selected for the next validation phase, where it was analyzed (reverse transcription quantitative polymerase chain reaction) in serum samples from 2 groups of patients: the no-ACR group (0R grade) and the ACR group (≥2R grade). Finally, a sensitivity analysis (receiver operating characteristic curve) was done to assess microRNA accuracy for ACR detection in HTx. A total of 21 ACR episodes (0RS1 → 2RS2 → 0RS3) with their respective serum samples (n = 63) were included in the discovery phase. Among the 179 microRNAs analyzed, only miR-181a-5p met the rise and fall criteria. In the validation phase, miR-181a-5p relative expression (2-∆Cq) in the ACR group (n = 45) was significantly overexpressed (p < 0.0001) vs the no-ACR group (n = 45). miR-181a-5p showed an area under the curve of 0.804 (95% confidence interval: 0.707-0.880); sensitivity and specificity of 78% and 76%, respectively; and a negative predicted value of 98%. miR-185a-5p in serum is a candidate as a non-invasive ACR biomarker (area under the curve = 0.80 and negative predicted value = 98%). Thus, this biomarker could reduce the need for endomyocardial biopsies and the associated risks and costs of this invasive procedure.

Long-term survival of the transplanted kidney and the clinical relevance of donor-specific antibodies

The aim of our study was to evaluate the relevance of donor-specific antibodies (DSA) as defined by solid-phase single-antigen (SA) assays for predicting long-term graft survival after kidney transplantation. Sera from 132 kidney transplant recipients were retrospectively tested before, 3, 6 and 12 months after transplantation. The incidence of rejection and graft survival was followed up for 7 years. We found 29 episodes of acute cellular rejection (CR), 21 cases of antibody-mediated rejection (AMR) and 18 graft failures due to immunological reasons. Pre-transplant DSA and DSA three months after transplantation correlated with an increased rate of AMR and impaired graft function. After the fourth year, recipients with persistent DSA were at a higher risk of graft failure (p = 0.0317). Antibody specificity was prevailingly to HLA class I antigens (66.6% DSA, 75% non-DSA). During the first year after transplantation, the number of patients with non-DSA decreased (30.3% to 10.7%), while, due to de novo production of antibodies, the number of DSA positive patients remained constant. Conclusion: Detection of antibodies to HLA antigens using solid-phase assays, especially single-antigen bead technology before and three months after transplantation is predictive for increased incidence of antibody-mediated rejection and impaired long-term kidney graft survival.

Risk factors for recurrent autoimmune liver diseases after liver transplantation: A meta-analysis.

Background:Autoimmune liver disease (ALD) is a chronic liver disease caused by immune dysfunction in the body. However, no causative or curative medical treatment with proven efficacy exists to cure ALDs, and liver transplantation (LT) remains the only effective treatment available. However, the problem of recurrence of ALDs (rALDs) still remains after LT, which seriously affects the survival rate of the patients. Therefore, clinicians need to be aware of the risk factors affecting rALDs after LT. Therefore, this meta-analysis aims to define the risk factors for rALDs, which include the recurrence of primary biliary cirrhosis, primary sclerosing cholangitis and autoimmune hepatitis.Methods:A systematic search in Pubmed, Embase, Cochrane library and Web of Science databases was performed from 1980 to 2019. The inclusion criteria were risk factors for developing rALDs after LT. However, case series, case reports, reviews, meta-analysis and studies only including human immunodeficiency virus cases, children, and pregnant patients were excluded.Results:The electronic database search yielded 1728 results. Sixty-three retrospective cohort studies met the inclusion criteria and 13 were included in the meta-analysis. The final cohort included 5077 patients, and among them, 21.96% developed rALDs. Colectomy before LT, HR 0.59 (95% confidence interval [CI]: 0.37-0.96), cholangiocarcinoma, HR 3.42 (95% CI: 1.88–6.21), multiple episodes of acute cellular rejection, HR 2.07 (95% CI: 1.27–3.37), model for end-stage liver disease score, HR 1.05 (95% CI: 1.02–1.08), use of mycophenolate mofetil, HR 1.46 (95% CI: 1.00–2.12) and the use of cyclosporin A, HR 0.69 (95% CI: 0.49–0.97) were associated with the risk of rprimary sclerosing cholangitis. In addition, the use of tacrolimus, HR 1.73 (95% CI: 1.00–2.99) and cyclosporin A, HR 0.59 (95% CI: 0.39–0.88) were associated with the risk of rALD.Conclusions:Multiple risk factors for rALDs were identified, such as colectomy before LT, cholangiocacinoma, multiple episodes of acute cellular rejection, model for end-stage liver disease score, and especially the use of mycophenolate mofetil, cyclosporin A and tacrolimus.

Association between MRSA Colonization and Chronic Lung Allograft Dysfunction in Lung Transplantation for Cystic Fibrosis

Incidence of and risk factors for chronic lung allograft dysfunction (CLAD) in lung transplantation for cystic fibrosis (CF) are not established. Methicillin resistant staphylococcus aureus (MRSA) is associated with CF morbidity but its association with CLAD is unclear. We aimed to describe CLAD incidence and assess if pre-transplant MRSA colonization is associated with CLAD. Retrospective cohort analysis of patients receiving a lung transplant for CF from 6/2005-3/2018 at the University of Pittsburgh Medical Center. Patients with Burkholderia species were excluded. Colonization was defined as at least one positive culture in the year before transplant. CLAD was defined by ISHLT criteria. We used competing risks methods to estimate CLAD incidence and assess associations between MRSA and CLAD. Of 101 patients 34% were colonized with MRSA (n=34), 87% with Pseudomonas (n=88), and 31% with Aspergillus (n=31). Median post-transplant survival was 10.8 years and did not differ by MRSA colonization (p=0.50). CLAD incidence was 25% (95% CI 16-35%) at 5 years and 37% (95% CI 27-52%) at 10 years. BOS accounted for 74% (n=20/27) of cases, RAS 22% (n=6/27), and there was 1 mixed phenotype. CLAD incidence at 5 years was 45% (95% CI 25-62%) for MRSA colonized vs 18% (95% CI 9-29%) for non-colonized patients (Figure 1). Adjusting for established CLAD risk factors and co-colonization with Pseudomonas and Aspergillus, MRSA was associated with increased incidence of CLAD (SDH 2.53, 95% CI 1.16-5.51). Among 6-month survivors, MRSA colonization was associated with increased incidence of CLAD (SDH 2.66, 95% CI 1.03-6.88) adjusting for episodes of acute cellular rejection and recurrence of pre-transplant organisms. Incidence of CLAD in our cohort of CF recipients is low and varies by pre-transplant microbiota. MRSA colonization may be a risk factor for CLAD, perhaps reflecting differences in microbiome composition and associated host-microbiome interactions.

Prolonged Survival Following Lung Transplantation in the Absence of Conventional Immunosuppression

The modern era of lung transplantation (LTx) coincided with the discovery of the calceneurin inhibitors and the ability to limit the the immune response to LTx. Most LTx recipients are maintained on triple immunosuppression. Prolonged survival without conventional immunosuppression has not been reported. We report extended survival following LTx in a recipient who has not received oral immunosuppression for over 2 years and is only maintained on 4-weekly extracorporeal photophoresis (ECP) and intravenous immunoglobulin (IVIg). The index case is a 13 year old male with cystic fibrosis who underwent LTx in 2015. He was colonized with mycobacterium abscessus pre-LTx and despite combinational antibiotics peri-operatively and antimicrobial washes of the chest cavities, soft tissue infections developed along the operative site. Wound swabs confirmed infection with mycobacterium abscessus and treatment included escalating doses of combinational intravenous (iv) antibiotics. Despite reduced immunosuppression and toxicity from the combinational antibiotics, the wound infection progressed (Figure 1. PET scan) He underwent surgical rib resection on two occasions separated by 6 months. At the time of initial surgery in 2017, a decision was made to cease his oral triple immunosuppression. To create a potential immunomodulatory environment he has been maintained on 4-weekly IVIg and ECP, and two years on he maintains stable allograft function (FEV1 47% predicted). There have been no episodes of acute cellular rejection. HLA class II donor specific antibodies (mfi 19025) have been chronically present but are not associated with allograft dysfunction. We report the first case of prolonged survival following lung transplantation in the absence of conventional immunosuppression. We speculate that the combination of IVIg and ECP is maintaining a tolerogenic environment for the transplanted lung allograft.

Torque Teno Virus (TTV) Kinetics Can Predict Complications after Lung Transplantation

New biomarkers reflecting the degree of immunosuppression in transplant recipients are needed to provide an optimal balance between risk for rejection and risk of severe infections. We prospectively measured plasma TTV-DNA dynamics in 365 lung transplant recipients (LuTR) transplanted between 1/2013 and 12/2020. Severe infections, acute cellular and humoral rejection, incidence of CLAD and malignancies were recorded and correlated with dynamic changes in TTV levels. Patient demographics are summarized in Table 1. 95% of patients had detectable TTV levels pre-transplant with a mean log value of 4.0±1.6. Post-transplant, all LuTR became TTV positive with a peak value of log9.6±0.6 (range 5.9-10.9). TTV peaked at a mean of 143±109 days after transplantation. Mean TTV PCR values after 3, 4 and 5 years were log6.9±1,4, log6,4±1,4 and log6.0±1.2, respectively. TTV loads were significantly lower in LuTR who had episodes of acute cellular rejection (TTV PCR <log7.0 for more than 3 months[K1]; p=0.001) or who later developed chronic lung allograft dysfunction (CLAD) (p<0.05). Furthermore, TTV loads higher than log9.5 for a longer time [K2] correlated with episodes of severe infections (p<0.05) or the development of malignancies (p<0.05). No correlation between TTV load and episodes of acute/chronic antibody mediated rejection was found[K3]. FK levels were in 95% of all patients within the target levels and didn't correlate with infectious episodes or incidence of CLAD. TTV PCR measurement is a potent tool to predict acute cellular rejection episodes, infectious complications and CLAD. It represents a promising tool to monitor individualized immunosuppressive therapy in near future.

Persistence of Increased Type-1 Alloeffector CD4+ T Cell Responses from ACR into CLAD in Lung Transplant Recipients

Chronic lung allograft dysfunction (CLAD) significantly limits long-term survival in lung transplant recipients (LTRs) and episodes of acute cellular rejection (ACR) are the major risk factor for CLAD. To study the immune mechanisms leading to ACR/CLAD, we have characterized donor-specific alloreactive effector lung T (bronchoalveolar lavage; BAL) cells and peripheral blood mononuclear cells (PBMC) via indirect/direct allorecognition responses in LTRs with/without histologic evidence of ACR and into those who developed CLAD. Understanding these mechanisms may lead to new therapies to prevent CLAD. To assess alloeffector T cell responses from LTRs cells in BAL and PBMC, we used an ex vivo flow cytometric assay and donor alloantigen. LTRs with/without ACR (median 4 months), and a subset who developed CLAD (median 20 months) were studied. The effector responses (IFN-γ, TNF-α, CD107a, IL-17a, IL-13, IL-2 and the costimulation surface molecule, CD154) to donor alloantigen were measured using either donor lysate or irradiated cells in a 6 h in vitro re-stimulation assay. We also used single cell RNAseq analysis to analyze the transcriptome in response to alloantigen in isolated BAL T cells from LTRs with CLAD. The predominant BAL alloeffector responses during active ACR were similar between CD8+ and CD4+ T cells, with a Type-1 effector profile and IFN-γ responses predominant. The CD4+ T cells alloeffector responses were higher in BAL>PBMC (p<0.02), but similar in CD8+ cells between tissue compartments. Only CD4+ T cells expressed significant surface CD154 expression in response to donor lysate and segregated to IFN-γ+, TNF-α+, IL-2+ and CD107a+, but not IL-17+ or IL-13+ cells. BAL alloeffector responses persisted in CD4+ cells from active ACR into CLAD but decreased in CD8+ T cells (p<0.05). Preliminary data using single cell RNAseq data analysis on isolated BAL CD4+ allospecific from CLAD LTRs revealed differential transcriptomic CD4+ T cell clusters, including an NKG7+IFN-γ+ cluster consistent with CD4+ cytotoxic T cells. Type-1 alloeffector responses during ACR are similar between CD8+ and CD4+ T cells, with the latter predominant in BAL. Progression into CLAD is associated with persistently elevated CD4+ alloeffector responses with a potential cytotoxic CD4+ subset playing an important role.