Abstract
Bronchiolitis obliterans syndrome (BOS) is considered an airway-centered disease, with bronchiolitis obliterans (BO) as pathologic hallmark. However, the histologic spectrum of pure clinical BOS remains poorly characterized. We provide the first in-depth histopathologic description of well-characterized BOS patients and patients without chronic lung allograft dysfunction (CLAD), defined according to the recent consensus guidelines. Explant lung tissue from 52 clinically-defined BOS and 26 non-CLAD patients (collected 1993–2018) was analyzed for histologic parameters, including but not limited to airway lesions, vasculopathy and fibrosis. In BOS, BO lesions were evident in 38 (73%) patients and varied from concentric sub-epithelial fibrotic BO to inflammatory BO, while 10/14 patients without BO displayed ‘vanishing airways’, defined by a discordance between arteries and airways. Chronic vascular abnormalities were detected in 22 (42%) patients. Ashcroft fibrosis scores revealed a median of 43% (IQR: 23–69) of normal lung parenchyma per patient; 26% (IQR: 18–37) of minimal alveolar fibrous thickening; and 11% (IQR: 4–18) of moderate alveolar thickening without architectural damage. Patchy areas of definite fibrotic damage to the lung structure (i.e., Ashcroft score ≥5) were present in 28 (54%) patients. Fibrosis was classified as bronchocentric (n = 21/28, 75%), paraseptal (n = 17/28, 61%) and subpleural (n = 15/28, 54%). In non-CLAD patients, BO lesions were absent, chronic vascular abnormalities present in 1 (4%) patient and mean Ashcroft scores were significantly lower compared to BOS (p = 0.0038) with 78% (IQR: 64–88) normally preserved lung parenchyma. BOS explant lungs revealed evidence of various histopathologic findings, including vasculopathy and fibrotic changes, which may contribute to the pathophysiology of BOS.
Highlights
Long-term survival after lung transplantation is limited by chronic lung allograft dysfunction (CLAD), affecting >50% of patients within 5 years after transplantation [1,2].CLAD is clinically defined by a persistent decline in forced expiratory volume in one second (FEV1) of ≥20% compared to baseline, without another identifiable cause
Redo-transplant patients were younger compared to autopsy patients (p = 0.0077), had more cystic fibrosis and bronchiectasis as underlying disease (p = 0.0003) and underwent more bilateral lung transplant procedures (p = 0.016)
This study provides the largest in-depth histopathologic characterization of clinical Bronchiolitis obliterans syndrome (BOS) patients and the first to exclude restrictive allograft syndrome (RAS) and mixed phenotype patients
Summary
Long-term survival after lung transplantation is limited by chronic lung allograft dysfunction (CLAD), affecting >50% of patients within 5 years after transplantation [1,2].CLAD is clinically defined by a persistent decline in forced expiratory volume in one second (FEV1) of ≥20% compared to baseline, without another identifiable cause. Bronchiolitis obliterans syndrome (BOS) is characterized by an obstructive pulmonary function deficit and air trapping on computed tomography (CT) [3]. In 2011, restrictive allograft syndrome (RAS) was first described and later defined by a restrictive pulmonary function deficit and persistent radiological CT opacities [4,5]. Subsequent studies described BO in lung transplantation and BO became the hallmark of BOS [7,8,9,10]. The largest histological study on CLAD explant lungs hitherto was performed on 25 explant lungs by Saggar et al [12]. They reported pulmonary arteriopathy and venopathy in approximately 80% of investigated lungs. Martinu and colleagues examined 12 explant lungs from CLAD patients and found varying fibrosis and inflammation in BO, and several other lesions (e.g., cholesterol clefts, vascular injury) [11]
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