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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.

In 2009, the International Society for Heart and Lung Transplantation recognized the importance and challenges surrounding generic drug immunosuppression. As experience with generics has expanded and comfort has increased, substantial issues have arisen since that time with other aspects of immunomodulation that have not been addressed, such as access to medicines, alternative immunosuppression formulations, additional generics, implications on therapeutic drug monitoring, and implications for special populations such as pediatrics and older adults. The aim of this consensus document is to address critically each of these concerns, expand on the challenges and barriers, and provide therapeutic considerations for practitioners who manage patients who need to undergo or have undergone cardiothoracic 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.

Purpose Calcinuerin inhibitor (CNI) based immunosuppression (IS) regimens remain the cornerstone of IS protocols post lung transplantation (LTx). Everolimus (EVE) has been used to augment IS in LTx patients or as a CNI minimization/ elimination agent in those with renal impairment or recurrent CMV infection. There is limited evidence to support EVE based IS regimens and the impact on progression to chronic lung allograft dysfunction (CLAD). The primary aim was to compare patients who remained on CNI-based IS to those who switched to EVE-based IS and assess the impact of EVE-based IS on time to CLAD and ultimately survival. Methods Single centre retrospective study of 91 patients who were initiated on EVE from 1550 consecutive LTx recipients between 1993 and 2018. Each EVE patient was matched with a patient who remained on CNI-based IS. Criteria for matching included indication for LTx, gender, LTx procedure and age at LTx. A survival analysis was performed in the EVE cohort. Results 182 LTx recipients [91 EVE & 91 CNI-based IS, mean age 51 ±15 years, 70% male, 82% BSLTx, LTx diagnosis: COPD 35%, ILD 22%, CF 22%, PAH 8%]. The incidence of CLAD was similar across the groups (51% EVE-based vs 48% CNI-based). Patients with CLAD at initiation of EVE had a 3.6 times higher risk of death than those without CLAD [HR 3.60, 95% CI: 2.16 - 6.01, p = 0.0001]. However there was no significant difference in the risk of developing CLAD between EVE-based IS and CNI-based IS [HR 1.05, 95% CI: 0.65 - 1.71]. The incidence of the RAS phenotype of CLAD was higher in the EVE-based group (56% EVE-based vs 39%- CNI-based) but not significant. The risk of death is not significant between EVE-based IS and CNI-based IS from time of switch [HR 1.22, 95% CI: 0.77 - 1.88]. The median days from CLAD to death was significantly higher (p = 0.01) in the EVE-based IS group (1127, IQR: 504 - 2210) compared to the CNI-based group (427, IQR: 236 - 1229). The survival analysis noted a higher mortality with 1) Earlier initiation post LTx (2% / month closer to LTx, 95% CI 1.0 - 3.0%, p = 0.001), 2) Increasing age at initiation (3% /year of age, 95% CI, 0 - 5%, p = 0.029). 3) Diabetes at the time of initiating EVE (HR 2.74 [1.48 - 5.09], p = 0.001). Conclusion EVE-based IS can be successfully utilized for second-line IS for CNI minimization / elimination and was not associated with an increase in CLAD incidence or CLAD related mortality.

Purpose EVE has proven benefits when prescribed post heart or kidney transplantation. The role of EVE is less well defined in LTx. We reported our experience with EVE over a 14-year period. Methods Single-center retrospective cohort study evaluating 124 adult LTx recipients initiated on EVE between 2005 and 2018 for calcineurin inhibitor (CNI) minimization / elimination. Data collected include demographics, prescribing patterns, mean EVE dose/ trough levels, adverse events and clinical parameters. Results 124 LTx recipients [mean age 51 ±15 years, 70% male, 82% BSLTx, mean days post LTx = 1059 ± 1374 days (range 12 - 7289)]. 38% patients switched less than 12 months post LTx. Patients were followed for a mean of 1415 ± 1282 days after initiation (range = 49 - 4826 days). LTx diagnosis: COPD 35%, ILD 22%, CF 22%, PAH 8%. Main indications: renal impairment (79%), malignancy (8%), neurotoxicity (5%), rejection (4%). Initiation of EVE allowed significant reduction of CNI levels. 121/124 patients (98%) of patients utilised CNIs at the time of switch, 78/124 (63%) one-week post initiation, 49/124 (39%) 3 months’ post switch and 34/124 (27%) at last follow up. TAC levels were reduced from a mean level of 9.0 ± 2.5 mg/L (one-month pre-switch) to 7.0 ± 2.4 mg/L (time of switch) to 5.0 ± 2.2 mg/L (3 months’ post switch). Median (range) EVE dose: 2.5 mg (0.25 - 10.0 mg) and mean (±SD) trough level: 5.9 ± 2.9 mg/L at 1 week and 5.08 ± 1.94 mg/L at 3 months. Pre-switch to EVE, there was a significant fall in mean creatinine clearance (CrCL) of 22 mL/min (p Conclusion Conversion of CNI-based IS to EVE-based IS is generally safe and efficacious for improving renal outcomes and neurotoxicity but not CLAD or malignancy.

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.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.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) (p0.001), clinical outcomes were variable with a number of patients progressing to either chronic lung allograft dysfunction or death within 12month.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.

Purpose Aspergillus or other molds are commonly isolated pre or post lung or heart-lung transplantation. Voriconazole is administered pre-emptively to eradicate the isolate and prevent invasive fungal infection (IFI). An association between blood trough levels of voriconazole, therapeutic outcomes and adverse events has been reported. We aimed to examine the impact of TDM to guide voriconazole dosing on clinical outcomes and adverse events. Methods and Materials Lung or heart-lung transplant recipients on pre-emptive voriconazole between 1 Jun 2011 and 17 Aug 2012 were prospectively followed for 3 months. Plasma voriconazole trough levels were measured using a validated high-performance liquid chromatography method. Voriconazole dose was adjusted according to the plasma trough level measured 5 days after initiation or dose adjustment to achieve a target level of 1.0-5.5 mg/L. Clinical outcomes and voriconazole-related adverse events were assessed 3 months after initiation. The study was approved by the institutional review board. Results 25 patients had 84 trough voriconazole levels performed. In 13/25 (52%) the initial trough voriconazole level was within target range. Of the 12 that were initially sub-therapeutic ( Aspergillus or other mold was eradicated whereas in 3 (12%) the isolate was persistent at the 3 months follow-up time-point. Voriconazole was discontinued in 5 (20%) a median (range) of 17 (2-73) days after initiation due to adverse events. Conclusions TDM appears to have a role in the eradication of Aspergillus or other mold and prevention of IFI but a larger, multi-center study needs to be performed for confirmation. Funding:[/bold] Investigator-initiated grant from Pfizer.