Immunosuppression In Lung Transplantation Research Articles

Immunosuppression in lung transplantation: a narrative review

Immunosuppression in lung transplantation: a narrative review

Review: immunosuppression for the lung transplant patient.

Lung transplantation (LTx) has evolved significantly since its inception and the improvement in LTx outcomes over the last three decades has predominantly been driven by advances in immunosuppression management. Despite the lack of new classes of immunosuppression medications, immunosuppressive strategies have evolved significantly from a universal method to a more targeted approach, reflecting a greater understanding of the need for individualized therapy and careful consideration of all factors that are influenced by immunosuppression choice. This has become increasingly important as the demographics of lung transplant recipients have changed over time, with older and more medically complex candidates being accepted and undergoing LTx. Furthermore, improved survival post lung transplant has translated into more immunosuppression related comorbidities long-term, predominantly chronic kidney disease (CKD) and malignancy, which has required further nuanced management approaches. This review provides an update on current traditional lung transplant immunosuppression strategies, with modifications based on pre-existing recipient factors and comorbidities, peri-operative challenges and long term complications, balanced against the perpetual challenge of chronic lung allograft dysfunction (CLAD). As we continue to explore and understand the complexity of LTx immunology and the interplay of different factors, immunosuppression strategies will require ongoing critical evaluation and personalization in order to continue to improve lung transplant outcomes.

Induction and maintenance immunosuppression in lung transplantation.

Immunosuppression for lung transplant recipients is a critical part of post-transplant care, to prevent acute and chronic rejection. Treatment protocols consist of induction and maintenance immunotherapy. Induction agents provide an immediate state of immunosuppression following transplantation and over time, and their use has become more commonplace. Several agents are available for clinical use, including anti-thymocyte globulin, alemtuzumab, and basiliximab, the latter being most commonly employed. Each induction agent has unique side effects and caveats to their use, of which we must be aware. Maintenance immunosuppression is initiated following transplant but requires multiple doses prior to reaching therapeutic levels. A calcineurin inhibitor, an anti-metabolite, and a corticosteroid are traditionally used, most commonly tacrolimus, mycophenolate mofetil, and prednisone. Dosing regimens and goal trough levels vary and are tailored to a patient's clinical status and duration post-transplant. Future clinical studies may be able to assist in determining the optimal induction and maintenance immunosuppression regimens. In the interim, we use cohort and registry data to guide our therapies.

Immunosuppression in Lung Transplantation.

Immunosuppression in lung transplantation is an area devoid of robust clinical data. This chapter will review the history of immunosuppression in lung transplantation. Additionally, it will evaluate the three classes of induction, maintenance, and rescue immunosuppression in detail. Induction immunosuppression in lung transplantation aims to decrease incidence of lung allograft rejection, however infectious risk must be considered when determining if induction is appropriate and which agent is most favorable. Similar to other solid organ transplant patient populations, a multi-drug approach is commonly prescribed for maintenance immunosuppression to minimize single agent drug toxicities. Emphasis of this review is placed on key medication considerations including dosing, adverse effects, and drug interactions. Clinical considerations will be reviewed per drug class given available literature. Finally, acute cellular, antibody mediated, and chronic rejection are reviewed.

Immunosuppression in lung transplantation: Changing perspectives

Lung transplantation is a definitive treatment option for select end-stage lung disease patients. Post lung transplantation, immunosuppression plays a significant role in a successful outcome. Rejection and infection are commonly encountered where immunosuppression plays an important role. Many immunosuppressive strategies have been designed and their protocols might vary from center to center. This review will focus on these perspectives as well as emerging perspectives during COVID times.

SUCCESSFUL CALCINEURIN-INHIBITOR-FREE IMMUNOSUPPRESSION REGIMEN WITH SIROLIMUS AND PREDNISONE IN LUNG TRANSPLANT RECIPIENTS: A CASE SERIES

SESSION TITLE: Fellows Transplantation Posters SESSION TYPE: Fellow Case Report Posters PRESENTED ON: October 18-21, 2020 INTRODUCTION: The current standard of care for immunosuppression after lung transplantation is the use of triple agents with a calcineurin inhibitor (CNI), cell cycle inhibitor (CCI), and corticosteroids (CS) with the calcineurin inhibitor (CNI) being the backbone of the regimen. However, the use of immunosuppressant drugs is frequently complicated by the development of malignancy, nephrotoxicity, cytopenias, and infection, usually requiring a reduction in immunosuppression. In cases where both CCIs and CNIs must be stopped, mTOR inhibitors are frequently used in an effort to maintain sufficient immunosuppression. A definitive role for mTOR inhibitors for immunosuppression post-lung transplant, however, remains unclear although there have been some studies in renal transplant recipients. There are challenges with transitioning to mTOR inhibitors due to concerns over wound healing in the first year, potential pulmonary toxicities, as well as the lack of data on efficacy. To our knowledge, there is no data on the outcomes of lung transplant patients maintained on dual immunosuppression with mTOR inhibitors and steroids alone. CASE PRESENTATION: We present a series of three lung transplant patients maintained on an immunosuppressant regimen of sirolimus and prednisone. All three patients remained free of acute cellular rejection and antibody-mediated rejection. Of the three patients, two remain alive and one patient died from multi-system organ failure secondary to sepsis. DISCUSSION: This small case series highlights the successful use of dual immunosuppression with mTOR inhibitors and corticosteroids in patients with contraindications to both calcineurin inhibitors and cell cycle inhibitors. CONCLUSIONS: More data is required to determine how mTOR-CS dual immunosuppression compares to traditional CCI-CNI-CS triple immunosuppression in regards to transplant rejection and the safest way to transition to this regimen when necessary. Reference #1: Ivulich S, Westall G, Dooley M, Snell G. The Evolution of Lung Transplant Immunosuppression. Drugs. 2018;78(10):965-982. doi:10.1007/s40265-018-0930-6 DISCLOSURES: No relevant relationships by Shambhu Aryal, source=Web Response No relevant relationships by Adam Cochrane, source=Web Response No relevant relationships by Margaret Fregoso, source=Web Response No relevant relationships by Vikramjit Khangoora, source=Web Response Consultant relationship with Veracyte Please note: $1001 - $5000 Added 04/03/2020 by Steven Nathan, source=Web Response, value=Honoraria Consultant relationship with United Therapeutics Please note: $5001 - $20000 Added 05/27/2020 by Steven Nathan, source=Web Response, value=Consulting fee Consultant relationship with Bellerophon Please note: $5001 - $20000 Added 05/27/2020 by Steven Nathan, source=Web Response, value=Consulting fee Speaker/Speaker's Bureau relationship with Roche-Genentech Please note: $5001 - $20000 Added 05/27/2020 by Steven Nathan, source=Web Response, value=Honoraria Speaker/Speaker's Bureau relationship with Boerhinger-Ingelheim Please note: $20001 - $100000 Added 05/27/2020 by Steven Nathan, source=Web Response, value=Honoraria

Survival in Lung Transplant Recipients on a Calcineurin Free Regimen: Is It Possible?

Calcineurin inhibitors (CNI) are the cornerstone of immunosuppression in lung transplantation. The International Heart and Lung Transplant registry data estimates that almost 99% of patients are on a CNI-based immunosuppression regimen. The population of lung transplant (LTx) recipients not on a calcineurin inhibitor is exceedingly rare and their outcomes have not been previously examined in a systematic way. An IRB-approved, retrospective, observational, cohort study of LTx recipients who received CNI-free, everolimus (EVR)-based immunosuppression at the University of Colorado from January 1, 1995 - October 1, 2019. The health system's electronic medical records was queried to identify and collect data on eligible LTx recipients. All continuous variables are presented as median(range). Seven of 12 were single LTx (ILD, COPD), five were bilateral LTx,(ILD, COPD, CF) and one was a re-transplant. The majority (8/12) of patients were transitioned to CNI-free, EVR-based immunosuppression due to renal insufficiency, 3/12 due to metastatic cancer, and 1/12 due to both renal failure and cancer. Five of 12 were maintained on three agents (EVR, corticosteroid, and either methotrexate or azathioprine) and the others were on corticosteroids with EVR alone. The median time to transition to CNI-free immunosuppression was 8.8 (2.3 to 21.3) years. Median age at CNI cessation was 67 years old (40-72 years old). Median survival on CNI-free immunosuppression for all comers was 1.6 years with median survival in the deceased cohort (n=8) of 1 year (4 days to 4.6 years) and median survival in the living cohort (n=4) of 2.1 years (1.2 years to 8.2 years). At least three patients were treated with high dose steroids for presumed acute rejection after stopping the CNI. This review demonstrates that in certain situations withdrawal of CNI and transition to CNI-free, EVR- based immunosuppression may result in durable patient survival. Larger multicenter cohort analysis may be the next step in understanding the safety, efficacy and role of CNI-free immunosuppression, as equipoise would be impossible to achieve in a randomized controlled trial.

Quantiferon®-Monitor: A Potential Biomarker of Immunosuppression in Lung Transplantation

Purpose Determining the optimal level of immunosuppression in lung transplant (LT) recipients is challenging. The Quantiferon®-Monitor (QFM) is a novel immune function assay that measures interferon-γ after stimulation with ligands for the innate & adaptive immune system. The aim of this prospective cohort study was to assess the relationships between immunosuppression and QFM results, and the clinical utility of QFM as a predictor of infection/rejection in LT. Methods QFM was tested pre & at 2, 6, 12, 24 & 52 weeks post-LT. Standard immunosuppression included tacrolimus , azathioprine , prednisone & basiliximab in patients with limited renal reserve. Patients were assessed over 1yr for rejection & infection. Results 80 LT patients were recruited from 2015-17 (median age 61, 60% male, 86% bilateral LT and 50% received basiliximab). Pre-transplant QFM results were lower in patients receiving glucocorticoids (median 67 IU/mL, IQR 9-244 vs. 314, 67-499, p=0.01) and those testing cytomegalovirus (CMV) seronegative (71, 5-262 vs. 230, 58-499, p=0.01). QFM values decreased significantly post-transplant then progressively increased (Figure). Trough tacrolimus levels & prednisone doses were associated with post-transplant QFM levels (p viremia occurred in 44% (>1000 copies/mL in 15%), respiratory viral infections in 40% & positive BAL bacterial cultures in 64%. 9 patients (11%) experienced rejection, 4 within 30 days post-transplant. 76% were readmitted & 5 died within 1 yr. QFM results at 2 & 6 weeks were not associated with any of these outcomes. Conclusion Our study demonstrated an association between tacrolimus levels, prednisolone dose & QFM results but was underpowered to detect differences in clinical outcomes. CMV serostatus appeared to have an impact on QFM results both pre- & post-transplant.

Immunosuppression for Lung Transplantation: Current and Future.

The number of lung transplantations performed worldwide continues to increase. There is a growing need in these patients for more effective immunosuppressive medications with less toxicity. This review article summarizes the recent studies and developments in lung transplant immunosuppression. Novel immunosuppressive medications and strategies used in other solid organ transplantations are being trialed in lung transplantation. This includes the use of co-stimulation blockers like belatacept and mTOR inhibitors like everolimus. Calcineurin sparing regimens have been described in an attempt to minimize nephrotoxicity. Assays to measure the bioactivity of immunosuppressive medications to determine the global immune competence, such as Immuknow assay and Gamma interferon response are gaining traction. Immunosuppression in lung transplant is evolving with the development of newer drugs and promising strategies to optimize immunosuppression. Further studies with multicenter randomized trials are required to increase the strength of the evidence.

Suppressed calcineurin-dependent gene expression identifies lung allograft recipients at increased risk of infection.

Lung transplant immunosuppression regimens generally include the calcineurin inhibitor tacrolimus. We hypothesized that mean residual expression (MRE) of calcineurin-dependent genes assesses rejection and infection risk better than does tacrolimus trough. We prospectively followed 44 lung allograft recipients at 2 to 18months posttransplant and measured changes in whole blood interleukin-2, interferon-γ, and granulocyte-macrophage colony-stimulating factor gene expression following a tacrolimus dose. Posttransplant duration, immunosuppressive medication levels, and bronchoscopic rejection and infection assessments were compared with MRE by using generalized-estimating equation-adjusted models. Prednisolone effect on MRE was assessed ex vivo in blood samples from nontransplanted controls. Tacrolimus concentration inhibiting 50% of cytokine production (IC50 ) was measured in a pretransplant subset. Results showed that MRE did not change with diagnosis of rejection but that airway infection was associated with a 20% absolute decrease (95% confidence interval 11%-29%). MRE increased with time after transplant but was not associated with tacrolimus trough. Interestingly, MRE correlated inversely with corticosteroid dose in the study cohort and ex vivo. Pretransplant tacrolimus IC50 depended on the cytokine measured and varied between individuals, suggesting a range in baseline responses to tacrolimus. We conclude that MRE identifies infection risk in lung allograft recipients, potentially integrating calcineurin inhibitor and steroid effects on lymphocyte effector function.

Individualizing immunosuppression in lung transplantation.

Immunosuppression management after lung transplantation continues to evolve, with an increasing number of agents available for use in various combinations allowing for more choice and individualization of immunosuppressive therapy. Therapeutic developments have led to improved outcomes including lower acute rejection rates and improved survival. However, a one size fits all approach for any immunosuppressive strategy may not be best suited to the individual patient and ultimately patient specific factors must be considered when designing the immunosuppressive regimen. Recipient factors including age, race, co-morbidities, immunologic risk, genetic polymorphisms, concomitant and previous pharmacotherapy, and overall immunosuppression burden should be considered. There are several significant drug-drug interactions with select immunosuppressive agents utilized in lung transplant pharmacotherapy that must be considered when choosing and devising a dosing strategy for an individual immunosuppressive agent. Herein, considerations for immunosuppression management in the individual patient will be reviewed.

Future direction of immunosuppression in lung transplantation.

Immunosuppression regimens have helped improve rejection episodes following lung transplantation, but long-term outcomes are still not comparable with cardiac, hepatic, or renal transplantation. This review summarizes the immunobiology that contributes to rejection events and future opportunities in outcomes on the basis of providing optimized delivery of the immunosuppression based on immune-monitoring techniques, taking into account individual patient pharmacokinetics and phenotypic variance. Drug toxicities, narrow therapeutic drug monitoring windows, and current immunoassays currently do not assist in detecting the global degree of immunosuppression. The currently available randomized control trials for induction therapy or maintenance therapies do not provide additional benefits compared with previously reported retrospective trials. To push beyond the current barriers, transplant teams are focusing on the role of pharmacokinetics, assessing phenotypic variable to potentially modify to quadruple therapy and using extracorporeal photopheresis. Conventional practice for the choices of immunosuppression is being evaluated on the basis of randomized control trials as opposed to retrospective studies or single-center trials. The future direction of immunosuppression will be continued by dynamic processes taking into consideration measures to improve tolerance, reducing treatment burden, and providing the best level of evidence while accounting for rejection, infections, renal function, and other comorbidities.

Immunosuppression in lung transplantation.

Lung transplantation can be a life-saving procedure for those with end-stage lung diseases. Unfortunately, long term graft and patient survival are limited by both acute and chronic allograft rejection, with a median survival of just over 6 years. Immunosuppressive regimens are employed to reduce the rate of rejection, and while protocols vary from center to center, conventional maintenance therapy consists of triple drug therapy with a calcineurin inhibitor (cyclosporine or tacrolimus), antiproliferative agents [azathioprine (AZA), mycophenolate, sirolimus (srl), everolimus (evl)], and corticosteroids (CS). Roughly 50% of lung transplant centers also utilize induction therapy, with polyclonal antibody preparations [equine or rabbit anti-thymocyte globulin (ATG)], interleukin 2 receptor antagonists (IL2RAs) (daclizumab or basiliximab), or alemtuzumab. This review summarizes these agents and the data surrounding their use in lung transplantation, as well as additional common and novel therapies in lung transplantation. Despite the progression of the management of lung transplant recipients, they continue to be at high risk of treatment-related complications, and poor graft and patient survival. Randomized clinical trials are needed to allow for the development of better agents, regimens and techniques to address above mentioned issues and reduce morbidity and mortality among lung transplant recipients.

(810) - Halting BOS in Lung Transplant: Is Cyclosporine Conversion the Answer?

Calcineurin inhibitors are considered the backbone of lung transplant immunosuppression regimens. When used de novo, tacrolimus has been shown to be associated with fewer acute rejection episodes compared to cyclosporine. However, conflicting evidence exists regarding the superiority of tacrolimus or cyclosporine in preventing bronchiolitis obliterans syndrome (BOS). Furthermore, the effect of these drugs on fibroproliferation ultimately leading to BOS remains to be investigated.

Immunosuppressive therapy in lung transplantation: state of the art

The coming of age of lung transplantation is accompanied by an immunosuppressive armamentarium that has been brought forward from other transplant indications. Widely employed on the basis of few small randomized studies, and mostly single-center experience or empirical expert knowledge, anti-rejection therapeutic strategies in pulmonary transplantation have hardly been rigorously evaluated in large-scale prospective international trials. This review compiles the available findings on the use of current immunosuppressants in clinical lung transplantation, accentuating high level-of-evidence study results. Reporting on recent meeting and registry data, and assembling ongoing relevant trials from international databases, this article serves as an update on the state of the art of immunosuppression in lung transplantation.

Basiliximab as an Alternative to Antithymocyte Globulin for Early Immunosuppression in Lung Transplantation

Objective Basiliximab (BAS), an interleukin-2 monoclonal antibody, has shown promising results as induction therapy in liver and kidney transplantation. We compared the efficacy and patient tolerability of BAS and antithymocyte globulin (ATG) in lung transplantation (LTx). Patients and Methods The study included 37 patients in two groups (ATG and BAS, respectively). The indication for LTx was emphysema in 62.6% of patients in group 1 and 57.1% of patients in group 2. Mean (SD) patient characteristics compared in the two groups included age (52.0 [9.8] vs 54 [10.6] years), height (172.0 [10.1] vs 169 [7.55] cm), and weight (73.9 [15.3] vs 64.4 [14.2] kg) ( P = .049). Induction therapy after LTx in the two groups was as follows: in 16 transplantation procedures (eight single and eight bilateral) performed between April 1998 and December 2002, ATG, 3 mg/kg/d for 3 days, was administered, and in 21 transplantation procedures (15 single and 6 bilateral) performed between January 2003 and July 2005, BAS, 20 mg on days 0 and 4, was given. Dosages of cyclosporine, azathioprine, and steroids for maintenance therapy were equivalent in the two groups. We retrospectively compared patient tolerability, occurrence of acute rejection or infection (from bacteria, cytomegalovirus [CMV], or Aspergillus), and outcomes between the two groups during 2 years of follow-up. Results No cytokine-mediated reaction was observed in either group; however, there was a difference in hematologic effects. On day 2, mean (SD) platelet count was significantly lower in the ATG group at 113,500 (56,400)/mm 3 vs 151,900 (57,300)/mm 3 ( P = .046). Because of severe thrombocytopenia, three patients could not be given ATG on day 3. The overall incidence of aspergillosis (18.8% vs 19.0%) and CMV infection (31% vs 57%) was similar in the two groups. However, when the recipient was CMV-positive and the donor was CMV-negative, the there was a clear trend (33.3% vs 88.9%). The number of acute rejection episodes was similar (43.8% vs 52.4%). Survival increased by 20% in the BAS group ( P = .03). Conclusion In LTx, safety of BAS use is as good as or better than that of ATG, with no difference in acute rejection episodes or infections, with the possible exception of increased reactivation of CMV infection. Thus, BAS could be an alternative to ATG as induction therapy in LTx; however, further studies are necessary.

Evidence for immunosuppression in lung transplantation

Historically, most lung transplant recipients have received triple-drug maintenance immunosuppression consisting of a calcineurin inhibitor, azathioprine, and prednisolone. The introduction of mycophenolate mofetil, mammalian target of rapamycin (mTOR) inhibitors, and antibody-based induction therapy has broadened immunosuppressive options. The purpose of this review is to summarize the evidence for immunosuppressive regimens in the prevention and treatment of lung allograft rejection. In clinical practice there has been a shift towards the de-novo use of more potent immunosuppressive regimens incorporating tacrolimus and mycophenolate post-transplant. The available evidence, however, suggests that such protocols do not lessen the risk of development of chronic allograft rejection [bronchiolitis obliterans syndrome (BOS)] compared with more traditional therapy. The role of antibody-based induction therapy remains controversial, with no survival benefit demonstrated in trials to date. The mTOR inhibitors have marked antifibroproliferative activity and are being rigorously evaluated in large, multicenter, randomized trials focused on the prevention of both acute and chronic lung rejection. Combination therapy with a calcineurin inhibitor, antimetabolite, and a corticosteroid derivative remains the backbone of lung transplant immunosuppression. Induction therapy (in whatever form) may reduce acute rejection, but does not lower the incidence of chronic rejection or improve survival. New strategies utilizing mTOR inhibitors may herald a more promising era.

Evolving Immunosuppressive Regimens for Lung Transplant Recipients

In organ transplantation, the key tenet remains the maintenance of graft function through the induction of allograft tolerance. Immunosuppression has been the mainstay of therapy to maintain graft function and induce tolerance. Immunosuppression for lung transplant and indeed all solid organ transplantation has greatly evolved in the past decade. Although calcineurin inhibitors, corticosteroids, and azathioprine remain the foundation of immunosuppression in lung transplantation, the arsenal of effective immunosuppression is ever expanding to include biological agents and newer drugs that are directed against increasingly specific targets of the immune cascade. This review examines the characteristics of both traditional and new pharmacological agents, describes a patient-centered approach to their use following lung transplantation, and discusses the controversies surrounding immunosuppression in the lung transplant recipient.

A novel approach to immunosuppression: targeting the alloimmune mechanisms of graft rejection

Purpose of review Lung transplantation has demonstrated both a survival and quality of life benefit for selected patients with end-stage lung disease. Allograft rejection is common. Chronic allograft rejection is the major life-limiting factor after lung transplantation. The mechanisms of graft rejection are reviewed, providing an insight into the possible targets for therapeutic intervention. Clinical trials of immunosuppression in lung transplantation are reviewed, highlighting the evolving evidence base for the use of the increasing number of immunosuppressive drugs. Recent findings An increasing number of immunosuppressive drugs with different characteristics are available to treat graft rejection. It is possible to tailor immunosuppression to individual clinical scenarios. Different routes of drug administration and drug monitoring have been evaluated, together with other immunomodulatory strategies. The role of anti-human leukocyte antigen antibodies in graft rejection is being evaluated. The role of environmental triggers to graft rejection has been highlighted. Summary The lack of evidence of improvements in long-term survival has led to wide variations in the interpretation of the relevance of clinical trials. The small volume of lung transplants undertaken in individual centres hampers research efforts. Continued collaborative research into the prevention of chronic allograft rejection is essential.

Clinical Trials of Immunosuppression in Lung Transplantation: A Coming of Age

Clinical Trials of Immunosuppression in Lung Transplantation: A Coming of Age