Chronic Lung Allograft Dysfunction: Evolving Concepts and Therapies

Abstract

The primary factor that limits 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 continues to evolve. Consensus definitions of CLAD and the major CLAD phenotypes were recently updated and clarified, but it remains to be seen whether the current definitions will lead to advances in management or impact care. Understanding the potential differences in pathogenesis for each CLAD phenotype may lead to novel therapeutic strategies, including precision medicine. Recognition of CLAD risk factors may lead to earlier interventions to mitigate risk, or to avoid risk factors all together, to prevent the development of CLAD. Unfortunately, currently available therapies for CLAD are usually not effective. However, novel therapeutics aimed at both prevention and treatment are currently under investigation. We provide an overview of the updates to CLAD-related terminology, clinical phenotypes and their diagnosis, natural history, pathogenesis, and potential strategies to treat and prevent CLAD.

Chronic Lung Allograft Dysfunction Is Associated with Increased Levels of Cell-Free Mitochondrial DNA in Bronchoalveolar Lavage Fluid of Lung Transplant Recipients

“…The concentration of IL8 was also significantly elevated in CLAD stage 3/4 patients compared to non-CLAD patients ( Figure 3 B). Both IL6 and IL8 are known to increase in the early post-transplant period and to be associated with adverse outcomes such as primary graft dysfunction and extracorporeal membrane oxygenation (ECMO) intervention [ 28 , 29 , 30 , 31 , 32 ]. IL6 is an early biomarker for inflammatory complications such as infection or acute rejection and might, therefore, not be a suitable candidate for predicting long-term complications [ 33 ].…”

“…IL6 is an early biomarker for inflammatory complications such as infection or acute rejection and might, therefore, not be a suitable candidate for predicting long-term complications [ 33 ]. However, IL8 is a known neutrophilic inflammatory indicator expressed in a donor’s lungs during CLAD and is associated with gastric regurgitation, making it a potential therapeutic target [ 32 , 34 , 35 ]. MIP1⍺ is another pro-inflammatory cytokine that has yet to be evaluated as a biomarker for CLAD detection.…”

“…This study did not explore the underlying mechanisms, but its findings are nonetheless explainable. CLAD is an umbrella term for different etiologies that decrease graft function and have heterogeneous pathologies [ 32 ]. Many immunologic biomarkers depend on distinct inflammatory origins, explaining their varying concentrations in CLAD patients [ 12 ].…”

Graft dysfunction and rejection of lung transplant, a review on diagnosis and management

“…In addition, peribronchovascular lymphocytes aggregation was accompanied by the presence of macrophages and B cells as their immune‐related presentation. 50 Pulmonary function tests are often difficult to perform in patients with progressive RAS. Therefore, imaging features play an integral role to assist in the diagnosis of this disease.…”

Why Cell-Free DNA Can Be a “Game Changer” for Lung Allograft Monitoring for Rejection and Infection

“…Wisdom would dictate that earlier detection and treatment of complications such as AR and allograft infection may result in less morbidity and mortality and a decreased incidence of CLAD [ 13 , 14 ]. Although our understanding of the pathobiology and risk factors for CLAD has broadened with time, no analyte in blood or bronchoalveolar lavage BAL fluid has yet been validated as a viable clinical biomarker [ 13 , 15 – 19 ].…”