Chronic Lung Allograft Dysfunction: Evolving Concepts and Therapies

Abstract

Lung transplantation has become an established therapeutic option for a variety of end-stage lung diseases. Technical advances in graft procurement, implantation, perioperative care, immunosuppression, and posttransplant medical management have led to significant improvements in 1-year survival, but outcomes after the first year have improved minimally over the last two decades. The main limitation to better long-term survival after lung transplantation is chronic lung allograft dysfunction (CLAD). CLAD also impairs quality of life and increases the costs of medical care. Our understanding of CLAD manifestations, risk factors, and mechanisms is rapidly evolving. Recognition of different CLAD phenotypes (e.g., bronchiolitis obliterans syndrome and restrictive allograft syndrome) and the unique pathogenic mechanisms will be important for developing novel therapies. In addition to alloimmune-mediated rejection, we now recognize the importance of alloimmune-independent mechanisms of injury to the allograft. CLAD is the consequence of dysregulated repair of allograft injury. Unfortunately, currently available therapies for CLAD are usually not effective. However, the advances in knowledge, reviewed in this manuscript, should lead to novel strategies for CLAD prevention and treatment, as well as improvement in long-term outcomes after lung transplantation. We provide an overview of the evolving terminology related to CLAD, its varying clinical phenotypes and their diagnosis, natural history, pathogenesis, and potential treatments.

Increased frequency of CD4+CD25highCD127lowT cells early after lung transplant is associated with improved graft survival – a retrospective study

“…Finally, the EPV ratios were slightly lower than 15 [41]. However, further reduction of covariate number might have implied the exclusion of covariates which had been previously demonstrated as risk factors for the outcomes considered in this study [1,2,[25][26][27][28]33,34,[36][37][38][39][40].…”

Bronchiolitis and Bronchiolar Disorders

“…Pharmacokinetic optimization of immunosuppressive therapy via therapeutic drug monitoring of immunosuppressive agents is important for prevention of acute rejection. 104 Long-term azithromycin benefits pulmonary function and survival in BOS patients, particularly in those with increased lavage neutrophilia. 103 Bronchoalveolar neutrophilia should be assessed, and azithromycin may be initiated in patients with increased neutrophilia.…”

“…106 The acceptance of this dichotomy in the clinical spectrum of BOS (with neutrophilic reversible allograft dysfunction responding to azithromycin and fibroproliferative BOS not responding) can improve the current understanding of the heterogeneous pathological conditions that constitute BOS, thus encouraging a more accurate diagnosis and, ultimately, an improved treatment that can be tailored for each individual BOS patient. When BOS is established, pharmacokinetic optimization of immunosuppression may result in BOS stabilization, 104 but increasing the level of immunosuppression is generally unsuccessful and may be associated with increased risk of infections. Lung re-transplantation may be considered in some patients, although survival is lower than after the first transplantation.…”

Recent advances in lung transplantation

“…The greatest threat to long-term survival for recipients who survive beyond one year post-transplant is the onset and progression of CLAD 74 – 76 . This syndrome was initially termed bronchiolitis obliterans syndrome (BOS) in the 1990s 77 , 78 and diagnosed on the basis of a persistent ≥20% decline from best post-transplant forced expiratory volume in one second (FEV1) without other identifiable cause, and BOS was assumed to be a consequence of chronic rejection and the cause of persistent decline in the surrogate marker of FEV1.…”