TABLE 4.

Research recommendations regarding prevention.

Future research recommendations: prevention
Azithromcyin	⁃ Optimal timing of initiation after lung transplantation ⁃ Whether treatment should be applied universally or targeted to specific risk groups ⁃ Patient-reported outcome measures ⁃ Evaluation of long-term effects, including impact on graft and overall survival
Tacrolimus vs. cyclosporine	⁃ Long-term data on overall survival and graft survival; updated results from the ScanCLAD study are anticipated ⁃ Comparative effects of once-daily, extended release vs. twice-daily, immediate-release dosing and of different tacrolimus formulations on renal outcomes and other side effects ⁃ Management of unacceptable side effects, including thrombotic microangiopathy, posterior reversible encephalopathy syndrome ⁃ Comparative quality of life outcomes with tacrolimus vs. cyclosporine in lung transplantation; follow-up reports from the ScanCLAD study are expected ⁃ Optimal trough levels for CNI at different time points after transplantation, including feasibility and safety of dose reduction ⁃ Adjustment of CNI target levels based on kidney function, immunological risk, risk factors, and drug–drug interactions ⁃ CNI-reduction or CNI-free immunosuppressive strategies, such as mTOR inhibitor-based quadruple low CNI maintenance immunosuppressive regimen vs. standard triple maintenance immunosuppressive regimen ⁃ Best practices for therapeutic drug monitoring, including frequency, methodology, and dose adjustment ⁃ Cost-effectiveness of tacrolimus compared with cyclosporine in lung transplantation
MMF vs. AZA	⁃ Optimal dosing, considering pharmacogenetic factors beyond lymphopenia ⁃ Definition of patient subgroups (e.g., those with telomeropathies) that may benefit preferentially from one agent ⁃ Development of DSAs in patients receiving MMF vs. AZA ⁃ Long-term effects of each cell cycle inhibitor ⁃ Alternatives of cell cycle inhibitors, such as the use of mTOR inhibitors instead of MMF or AZA ⁃ Timing and management of MMF discontinuation during infections and its impact on CLAD incidence ⁃ Guidance on pausing cell cycle inhibitors around vaccinations
Other	⁃ Clinical trials with novel drugs for preventing CLAD are an unmet need, and the Task Force recommends conducting well-designed RCTs (ideally multicenter RCTs and the use of CLAD adjudication) for CLAD prevention, in accordance with the recent ISHLT consensus statement on Lung Transplant Clinical Trials [105] ⁃ Further studies on long-term outcomes of organ preservation strategies are needed to inform about the effects on CLAD incidence ⁃ The use of specific HLA antibody/DSA-directed treatments and whether they reduce the risk of later CLAD development ⁃ In patients with AMR, more data are needed on the efficacy of AMR treatments as a prevention of CLAD ⁃ The role of inhaled immunosuppressive drugs, such as inhaled cyclosporine and mTOR inhibitors, in the prevention of CLAD ⁃ Whether the addition of other immunomodulating or immunosuppressive drugs, such as belumosudil, ECP or tocilizumab, to standard triple immunosuppression has an impact on CLAD incidence

AMR, antibody-mediated rejection; AZA, azathioprine; CLAD, chronic lung allograft dysfunction; CNI, calcineurin inhibitor; DSA, donor-specific antibody; ECP, extracorporeal photopheresis; HLA, human leukocyte antibody; MMF, mycophenolate mofetil; mTOR, mammalian target of rapamycin.