Bronchiolitis obliterans syndrome and restrictive allograft syndrome after lung transplantation: why are there two distinct forms of chronic lung allograft dysfunction?

Abstract

Bronchiolitis obliterans syndrome (BOS) had been considered to be the representative form of chronic rejection or chronic lung allograft dysfunction (CLAD) after lung transplantation. In BOS, small airways are affected by chronic inflammation and obliterative fibrosis, whereas peripheral lung tissue remains relatively intact. However, recognition of another form of CLAD involving multiple tissue compartments in the lung, termed restrictive allograft syndrome (RAS), raised a fundamental question: why there are two phenotypes of CLAD? Increasing clinical and experimental data suggest that RAS may be a prototype of chronic rejection after lung transplantation involving both cellular and antibody-mediated alloimmune responses. Some cases of RAS are also induced by fulminant general inflammation in lung allografts.However, BOS involves alloimmune responses and the airway-centered disease process can be explained by multiple mechanisms such as external alloimmune-independent stimuli (such as infection, aspiration and air pollution), exposure of airway-specific autoantigens and airway ischemia. Localization of immune responses in different anatomical compartments in different phenotypes of CLAD might be associated with lymphoid neogenesis or the de novo formation of lymphoid tissue in lung allografts. Better understanding of distinct mechanisms of BOS and RAS will facilitate the development of effective preventive and therapeutic strategies of CLAD.

Restrictive allograft syndrome after lung transplantation

“…Although RAS might be induced by cellular and/or antibody‐mediated rejection (AMR), that may not explain all cases of RAS. Pathologic findings in RAS, as discussed later, are quite broad and diverse 10 . Whatever the trigger or the cause of the lung injury is, it is evident that RAS shows a more intense inflammatory response in the lung compared with BOS.…”

“…Pathologic findings in RAS, as discussed later, are quite broad and diverse. 10 Whatever the trigger or the cause of the lung injury is, it is evident that RAS shows a more intense inflammatory response in the lung compared with BOS. Serum and bronchoalveolar lavage fluid (BALF) cytokines to predict CLAD are of interest to help understand the underlying pathophysiology and also to potentially identify a noninvasive biomarker to aid in diagnosis.…”

“…12,13 Higher levels of IL-5 were also detected in the BALF of RAS patients, which might be associated with the high number of eosinophils in the bronchoalveolar samples and lung tissues of RAS patients. 10,[14][15][16][17] Eosinophils may promote CLAD through the release of reactive oxygen species, promoting graft destruction, or transforming growth factorβ supporting aberrant remodeling. 18 Proinflammatory cytokines including IL-1, IL-6, and TNF-a are all upregulated in CLAD.…”

“…4 While there is one proposed grading system for RAS based on the degree and severity of fibrosis, no formal consensus currently exists. 10 It is currently recommended that all patients with CLAD and a decline in TLC, FVC, or persistent opacifications on CXR suggesting of RAS receive an inspiratory, thin section (maximum 3-mm thick sections), high-resolution chest CT without contrast media. More work focusing on such a grading system can potentially improve patients' outcomes and predict mortality, as studies have revealed those with nonclassical imaging have worse outcomes compared to those with the classic apical abnormalities on HRCT.…”

“…Alarmins also are released in response to proteins released from neutrophils including pentraxin‐3, neutrophil elastase, α‐defensins, and matrix metalloproteinase‐8 12,13 . Higher levels of IL‐5 were also detected in the BALF of RAS patients, which might be associated with the high number of eosinophils in the bronchoalveolar samples and lung tissues of RAS patients 10,14‐17 . Eosinophils may promote CLAD through the release of reactive oxygen species, promoting graft destruction, or transforming growth factor‐β supporting aberrant remodeling 18…”