S. Ivulich

Evolving experience of treating antibody-mediated rejection following lung transplantation.

BACKGROUND The importance of antibody-mediated rejection (AMR) following lung transplantation remains contentious. In particular, the diagnostic criteria suggested to define AMR, namely the presence of donor-specific antibodies (DSA), C4d immunoreactivity, histological features and allograft dysfunction are not always readily applicable or confirmatory in lung transplantation. METHODS In a retrospective single-center study of 255 lung transplant recipients (LTR), we identified 9 patients in whom a clinical diagnosis of AMR was made within 12months of transplant, and define the immunological, histological, clinical features, as well as the therapeutic response of this cohort. RESULTS Nine LTR with AMR underwent combination therapy with high-dose intravenous corticosteroid, intravenous immunoglobulin, plasmapheresis and rituximab. Following therapy, while the total number of the original DSA dropped by 17%, and the median value of the mean fluorescence intensity (mfi) of the originally observed DSA decreased from 5292 (IQR 1319-12,754) to 2409 (IQR 920-6825) (p<0.001), clinical outcomes were variable with a number of patients progressing to either chronic lung allograft dysfunction or death within 12month. CONCLUSION AMR in lung transplantation remains both a diagnostic and therapeutic challenge, but when clinically suspected is associated with a variable response to therapy and poor long-term outcomes.

Evolution to twice daily bolus intravenous tacrolimus: Optimizing efficacy and safety of calcineurin inhibitor delivery early post lung transplant

BACKGROUND Achieving therapeutic levels of cyclosporine (CSA) or Tacrolimus (TAC) early post lung transplantation (LTx) is challenging. Gut dysmotility, renal dysfunction and seizure risk are variably present and problematic. This study reports a single center. MATERIAL AND METHODS All adult LTx recipients from Aug 06-Aug 11 were divided into 4 cohorts: A) intravenous (IV) CSA twice daily (BD) 6 hr bolus then oral CSA, n=63; B) sub-lingual (SL) TAC BD then oral TAC, n=90; C) oral TAC BD, n=18; and D) IV TAC BD 4hr bolus then oral TAC, n=62. CSA/TAC trough levels were measured at days 1-7, 14 and 28 aiming for target trough levels >250 ng/ml and >8ng/ml respectively. RESULTS There were no differences in demographics, ICU and total length of stay between groups. Target trough levels were achieved in 13%*#, 26%*, 17% and 37%# of patients for Groups A-D respectively, (*#p<0.05) by day 7, increasing to 65%, 74%, 88% and 72% by day 14 (p=ns). Acute rejection at day 14 was seen in 3%*, 6%, 17%* and 5% respectively (*p<0.05) Acute rejection <90days was noted in 15%, 17%, 22% and 11% respectively (p=ns). No significant difference in neurotoxicity or acute nephrotoxicity was apparent across the groups. CONCLUSIONS Early post LTx, SL and oral routes of immunosuppressive administration are less efficacious than intravenous. BD bolus IV TAC achieved significantly higher target levels earlier, with correspondingly lower acute rejection rates and acceptable safety of administration.

Clinical effectiveness of early posaconazole suspension pre-emptive therapy in lung transplant recipients: The Alfred’s experience

Objectives This study describes the clinical outcomes and therapeutic drug monitoring (TDM) following posaconazole suspension pre-emptive therapy in lung transplant (LTx) recipients. Methods This was a single-centre, retrospective cohort study evaluating posaconazole suspension pre-emptive therapy in LTx recipients between January 2009 and December 2015. Results Forty-two LTx recipients were prescribed posaconazole suspension pre-emptively. Aspergillus fumigatus was the most commonly isolated fungal organism. Of the patients receiving posaconazole suspension as the initial antifungal post-LTx, 93% had eradication of colonization at 6 months after commencing therapy. In contrast, only 61% had eradication of fungal colonization when posaconazole suspension was administered following initial therapy with voriconazole. Posaconazole suspension appeared to be well tolerated, although one case was curtailed following concern about abnormal liver function and another due to nausea/vomiting. TDM was performed in 37 patients. The initial median (IQR) trough plasma concentration ( C min ) following 400 mg twice-daily posaconazole suspension was 0.78 (0.46-1.19) mg/L. Doses beyond 800 mg daily did not appear to result in a higher median C min. Conclusions Early initiation of posaconazole suspension pre-emptive therapy in LTx recipients appears to be well tolerated and may potentially afford favourable clinical outcomes.

Single-centre study of therapeutic drug monitoring of posaconazole in lung transplant recipients: Factors affecting trough plasma concentrations

Objectives This study describes therapeutic drug monitoring (TDM) of posaconazole suspension and modified release (MR) tablets in lung transplant (LTx) recipients and evaluates factors that may affect posaconazole trough plasma concentration (Cmin). Methods A single-centre, retrospective study evaluating posaconazole Cmin in LTx recipients receiving posaconazole suspension or MR tablets between January 2014 and December 2016. Results Forty-seven LTx patients received posaconazole suspension, and 78 received the MR tablet formulation; a total of 421 and 617 Cmin measurements were made, respectively. Posaconazole was concurrently administered with proton pump inhibitor in ≥ 90% of patients. The median (IQR) of initial posaconazole Cmin following 300 mg daily of posaconazole tablet was significantly higher than that of 800 mg daily of posaconazole suspension [1.65 (0.97-2.13) mg/L versus 0.81 (0.48-1.15) mg/L, P < 0.01]. Variability in posaconazole Cmin was apparent regardless of the formulations prescribed and dose adjustments were routinely undertaken to maintain therapeutic Cmin. A clear dose-response relationship was observed in patients receiving posaconazole MR tablets. Non-specific adverse events (fatigue, tremor, lethargy, sweating, nausea/vomiting and weight loss) were reported in 3/78 (4%) patients receiving posaconazole MR tablets. Posaconazole Cmin in these three patients was determined to be 9.6, 6.2 and 2.3 mg/L. Conclusions The current study has provided clinically important insights into the TDM of posaconazole in LTx recipients. Routine TDM should be undertaken in LTx recipients receiving posaconazole suspension and/or MR tablets.

The Evolution of Lung Transplant Immunosuppression

Advances in immunosuppression have been a key component to the ongoing success of lung transplantation. The demographics of patients receiving a lung transplant have evolved with older, more critically ill patients and those with previously contraindicated indications, now becoming recipients. Despite the lack of new classes of maintenance immunosuppression drugs becoming available, advances have been made in the prescribing of traditional immunosuppressive therapies. Developments in immunosuppressive regimens have seen changes in the route of administration, approaches to monitoring and combinations used. Long-term complications of immunosuppression, such as nephrotoxicity and malignancy can limit the success of lung transplantation, and strategies have evolved in recent years to minimise their long-term impact. Although survival outcomes have been steadily improving, chronic lung allograft dysfunction remains a barrier to long-term success. However, treatments for antibody-mediated rejection are emerging as a potential new therapeutic target to decrease the incidence of chronic lung allograft dysfunction. This article provides an update on the current status of immunosuppression after lung transplantation and reviews the evidence for immunosuppressive regimens and the implications for practice.

Clinical Challenges of Tacrolimus for Maintenance Immunosuppression Post–Lung Transplantation

Lung transplantation (LTx) is a successful treatment option for end-stage lung disease, and immunosuppressant regimens, utilized to prevent rejection of the transplanted graft, are paramount to maintaining long-term graft survival. Immunosuppression can be classified as induction, maintenance, and antirejection therapy. This article focuses on maintenance immunosuppression that includes a combination of a calcineurin inhibitor (CNI), cell cycle inhibitor, and corticosteroid. CNIs remain the cornerstone of immunosuppression following LTx, and tacrolimus is now the preferred CNI, based on a better adverse effect profile and some limited evidence for enhanced efficacy. Tacrolimus is associated with a number of unique challenges post-LTx, with erratic and highly variable absorption making it difficult to achieve and maintain therapeutic levels. Current methods of therapeutic drug monitoring are extrapolated from models in liver and kidney transplants and are not validated in the LTx population. Alternative methods of delivering tacrolimus can address some of the issues associated with their use and can be utilized in particular clinical scenarios. Long-term toxicities attributed to tacrolimus, such as nephrotoxicity and neurotoxicity, can limit the long-term success of tacrolimus in preventing allograft rejection. This article emphasizes the current clinical challenges faced when managing LTx recipients with tacrolimus, offers strategies to manage these issues, and highlights the areas that need further research.