Mechanistic differences between phenotypes of chronic lung allograft dysfunction after lung transplantation

Distinct phenotypes of chronic lung allograft dysfunction (CLAD) after lung transplantation are emerging with lymphocytic bronchiolitis (LB)/azithromycin reversible allograft dysfunction (ARAD), classical or fibrotic bronchiolitis obliterans syndrome (BOS), and restrictive allograft syndrome (RAS) proposed as separate entities. We have additionally identified lung transplant recipients with prior LB, demonstrating persistent airway neutrophilia (PAN) despite azithromycin treatment. The aim of this study was to evaluate differences in the airway microenvironment in different phenotypes of CLAD. Bronchoalveolar lavage (BAL) from recipients identified as stable (control), LB/ARAD, PAN, BOS, and RAS were evaluated for differential cell counts and concentrations of IL‐1α, IL‐1β, IL‐6, IL‐8, and TNF‐α. Primary human bronchial epithelial cells were exposed to BAL supernatants from different phenotypes and their viability measured. BOS and RAS showed increased BAL neutrophilia but no change in cytokine concentrations compared with prediagnosis. In both LB/ARAD and PAN, significant increases in IL‐1α, IL‐1β, and IL‐8 were present. BAL IL‐6 and TNF‐α concentrations were increased in PAN and only this phenotype demonstrated decreased epithelial cell viability after exposure to BAL fluid. This study demonstrates clear differences in the airway microenvironment between different CLAD phenotypes. Systematic phenotyping of CLAD may help the development of more personalized approaches to treatment.     

BALF cytokines in different phenotypes of chronic lung allograft dysfunction in lung transplant patients

The long‐term success of lung transplantation (LT) is limited by chronic lung allograft dysfunction (CLAD). Different phenotypes of CLAD have been described, such as bronchiolitis obliterans syndrome (BOS) and restrictive allograft syndrome (RAS). The purpose of this study was to investigate the levels of cytokines and chemokines in bronchoalveolar lavage fluid (BALF) as markers of these CLAD phenotypes. BALF was collected from 51 recipients who underwent (bilateral and unilateral) LT. The study population was divided into three groups: stable (ST), BOS, and RAS. Levels of interleukin (IL)‐4, IL‐5, IL‐6, IL‐10, IL‐13, tumor necrosis factor alpha (TNF‐α), interferon‐gamma (IFN‐γ), and granulocyte‐macrophage colony‐stimulating factor (GM‐CSF) were measured using the multiplex technology. BALF neutrophilia medians were higher in BOS (38%) and RAS (30%) than in ST (8%) (P=.008; P=.012). Regarding BALF cytokines, BOS and RAS patients showed higher levels of INF ‐ γ than ST (P=.02; P=.008). Only IL‐5 presented significant differences between BOS and RAS (P=.001). BALF neutrophilia is as a marker for both CLAD phenotypes, BOS and RAS, and IL‐5 seems to be a potential biomarker for the RAS phenotype.     

Evolution of lung and kidney allograft function in patients receiving kidney after lung transplantation

Calcineurin inhibitor (CNI) toxicity leads to end‐stage renal disease in almost half of long‐term survivors after lung transplantation, some of them receiving kidney transplants. Little is known about the outcomes of kidney and lung allograft function following kidney after lung transplantation (KALTPL) in the modern era. We retrospectively analyzed a group of 13 consecutive patients who received a KALTPL with respect to their renal and pulmonary function and immunological evolution over 2 years. We documented a stable evolution of forced expiratory volume in 1 second (FEV1) after KALTPL in most patients as well as an excellent kidney graft during the 2‐year follow‐up period. In our small cohort, living donations showed a significantly higher estimated glomerular filtration rate compared to deceased donation (75.7 compared to 41.6 mL/min). Patients who received a preemptive KALTPL were more likely to improve their lung function after KALTPL. Four patients developed de novo donor‐specific antibodies (DSA) against the kidney graft. There were no DSA against shared antigens from the lung allograft. De novo DSA did not lead to graft loss in any patient. All 13 patients survived the first 24 months after KALTPL.     

慢性移植肺功能障碍的诊断与治疗现状

慢性移植肺功能障碍(CLAD)是影响肺移植受者远期生存的最大阻碍,代表了一系列术后移植肺功能显著且持续恶化的复杂临床表现。由于缺乏有效的早期诊断和预防策略,一半以上的肺移植受者在5年内会出现CLAD,且这一比例将在10年内提高到75%。目前没有任何药物可以完全阻止或逆转CLAD的进展。近年来,随着2019年国际心肺移植学会(ISHLT)更新了CLAD的定义、诊断和治疗,国际上对CLAD的认识有了较大提高。本文将对CLAD的综合诊断方式和潜在治疗策略进行详细总结,为CLAD发生、发展的早期监测和管理提供理论参考和见解。     

When tissue is the issue: A histological review of chronic lung allograft dysfunction

Although chronic lung allograft dysfunction (CLAD) remains the major life‐limiting factor following lung transplantation, much of its pathophysiology remains unknown. The discovery that CLAD can manifest both clinically and morphologically in vastly different ways led to the definition of distinct subtypes of CLAD. In this review, recent advances in our understanding of the pathophysiological mechanisms of the different phenotypes of CLAD will be discussed with a particular focus on tissue‐based and molecular studies. An overview of the current knowledge on the mechanisms of the airway‐centered bronchiolitis obliterans syndrome, as well as the airway and alveolar injuries in the restrictive allograft syndrome and also the vascular compartment in chronic antibody‐mediated rejection is provided. Specific attention is also given to morphological and molecular markers for early CLAD diagnosis or histological changes associated with subsequent CLAD development. Evidence for a possible overlap between different forms of CLAD is presented and discussed. In the end, “tissue remains the (main) issue,” as we are still limited in our knowledge about the actual triggers and specific mechanisms of all late forms of posttransplant graft failure, a shortcoming that needs to be addressed in order to further improve the outcome of lung transplant recipients.     

Humoral immunity in phenotypes of chronic lung allograft dysfunction: A broncho-alveolar lavage fluid analysis

BackgroundRecently, antibody mediated rejection (AMR) has been associated with a higher incidence of chronic lung allograft dysfunction (CLAD) and mortality after lung transplantation (LTx). We investigated markers related to AMR and matrix remodeling in CLAD, with special attention for its two phenotypes being bronchiolitis obliterans syndrome (BOS) and restrictive CLAD (rCLAD).MethodsImmunoglobulins (IgA, IgE, IgG₁–IgG₄, total IgG and IgM) and complement (C4d and C1q) were quantified in lung lavage samples at the moment of BOS (n = 15) or RAS (n = 16) diagnosis; and were compared to stable transplant patients who served as control (n = 14). Also, airway remodeling and metalloproteinases (MMPs) were investigated via zymography and gelatin degradation. The presence of DSA was additionally assessed in blood.ResultsTotal IgG, IgG₁-IgG₄ and IgM were increased in rCLAD versus control (p < 0.001) and BOS patients (p < 0.01). IgA and IgE were increased in rCLAD compared to control (respectively p < 0.05 and p < 0.01), but not to BOS. Total IgG and IgE were increased in BOS versus control (respectively p < 0.01 and p < 0.05). Complement proteins were exclusively present in rCLAD and correlated positively with immunoglobulins. Additionally, in blood, DSA were more present in rCLAD (p = 0.041). MMP-9 levels increased in RAS and BOS versus control (p < 0.001) and MMP-9 induced gelatin degradation was only increased in BOS compared to control (p < 0.01).ConclusionWe demonstrated increased levels of immunoglobulins and complement proteins dominantly present in rCLAD. This leads to the belief that antibodies and AMR might play a more important role in rCLAD compared to BOS. Therefore, anti B-cell therapy could offer beneficial therapeutic effects in patients diagnosed with rCLAD, which needs further research.