Posaconazole is widely used in lung transplant recipients as pre-emptive therapy or universal fungal prophylaxis. In this patient group, posaconazole is increasingly used instead of voriconazole due ...to the concerns of an increased risk of squamous cell carcinoma (SCC) with voriconazole, particularly with its long-term use. Dose dependent toxicity has not been identified for posaconazole in the registration trials of intravenous (IV) and modified-release tablet formulations. This is supported by post-marketing experience. We describe a lung transplant recipient who experienced dementia-like symptoms almost 3 years after commencing posaconazole for treatment of Aspergillus fumigatus complex and Lomentospora prolificans (formerly Scedosporium prolificans) fungal infections. Symptoms resolved upon discontinuation of posaconazole, but recurred when re-challenged at a lower dose more than a year later. To the best of our knowledge, this is the first case reporting a dementia-like state with posaconazole.
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.
Everolimus (EVE) provides an alternative to maintenance immunosuppression when conventional immunosuppression cannot be tolerated. EVE can be utilized with a calcineurin inhibitor (CNI) minimization ...or elimination strategy. To date, clinical studies investigating EVE after lung transplant (LTx) have primarily focused on the minimization strategy to preserve renal function. The primary aim was to determine the preferred method of EVE utilization for lung transplant recipients (LTR). To undertake this aim, we compared the safety and efficacy outcomes of EVE as part of minimization and elimination immunosuppressant regimens. Single center retrospective study of 217 LTR initiated on EVE (120 CNI minimization and 97 CNI elimination). Survival outcomes were calculated from the date of EVE commencement. On multivariate analysis, LTR who received EVE as part of the CNI elimination strategy had poorer survival outcomes compared to the CNI minimization strategy HR 1.61, 95% CI: 1.11-2.32,
=0.010. Utilization of EVE for renal preservation was associated with improved survival compared to other indications HR 0.64, 95% CI: 0.42-0.97,
=0.032. EVE can be successfully utilized for maintenance immunosuppression post LTx, particularly for renal preservation. However, immunosuppressive regimens containing low dose CNI had superior survival outcomes, highlighting the importance of retaining a CNI wherever possible.
Everolimus (EVE) has been used as a calcineurin inhibitor (CNI) minimization/ elimination agent or to augment immunosuppression in lung transplant recipients (LTR) with CNI-induced nephrotoxicity or ...neurotoxicity. The long-term evidence for survival and progression to chronic lung allograft dysfunction (CLAD) is lacking. The primary aim was to compare survival outcomes of LTR starting EVE-based immunosuppression with those remaining on CNI-based regimens. The secondary outcomes being time to CLAD, incidence of CLAD and the emergence of obstructive (BOS) or restrictive (RAS) phenotypes. Single center retrospective study of 91 LTR starting EVE-based immunosuppression matched 1:1 with LTR remaining on CNI-based immunosuppression. On multivariate analysis, compared to those remaining on CNI-based immunosuppression, starting EVE was not associated with poorer survival HR 1.04, 95% CI: 0.67-1.61,
= 0.853, or a statistically significant faster time to CLAD HR 1.34, 95% CI: 0.87-2.04,
= 0.182. There was no difference in the emergence of CLAD (EVE,
= 57, 62.6% vs. CNI-based
= 52, 57.1%,
= 0.41), or the incidence of BOS (
= 0.60) or RAS (
= 0.16) between the two groups. Introduction of EVE-based immunosuppression does not increase the risk of death or accelerate the progression to CLAD compared to CNI-based immunosuppression.
Summary
Lung transplant (LTx) recipients are at risk of lower respiratory tract infection (LRTI), while altered physiology may lead to difficulty clearing sputum. Mucoactive agents alter sputum ...properties and facilitate mucociliary clearance; however, there are no randomized controlled trials (RCTs) studying this post‐LTx. This RCT evaluated the safety and efficacy of nebulized dornase alfa during LRTI post‐LTx. Inpatient adults with LRTI and abnormal sputum following bilateral sequential LTx were eligible. Participants received 5 ml of isotonic saline, or 2.5 ml of dornase alfa, nebulized once daily for 1 month followed by 2 months symptom diary. Primary outcome was lung clearance index (LCI2%). Secondary outcomes included spirometry, quality of life, readmission, length of stay, self‐reported exacerbations, and adverse events at baseline, 1 and 3 months. Thirty‐two participated, 16 in each group, baseline mean (SD) FEV1% 58 (22), median (IQR) length of stay 7 (5) days, time since LTx 3.49 (6.80) years. There were no significant between‐group differences in LCI2% at any point (1 month mean difference −0.34, 95% confidence interval (CI) −1.57 to 0.89; 3 months −0.76, 95% CI −2.29 to 0.78, favoring dornase alfa). Secondary outcomes were not different between groups. These results do not support the routine use of dornase alfa during LRTI in LTx recipients.
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).
A single-centre, retrospective study evaluating posaconazole Cmin in LTx recipients receiving posaconazole suspension or MR tablets between January 2014 and December 2016.
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.
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.
Abstract 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 12 months 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 12 month. 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.
This study describes the clinical outcomes and therapeutic drug monitoring (TDM) following posaconazole suspension pre-emptive therapy in lung transplant (LTx) recipients.
This was a single-centre, ...retrospective cohort study evaluating posaconazole suspension pre-emptive therapy in LTx recipients between January 2009 and December 2015.
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.
Early initiation of posaconazole suspension pre-emptive therapy in LTx recipients appears to be well tolerated and may potentially afford favourable clinical outcomes.
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