Multicenter evaluation of parametric response mapping as an indicator of bronchiolitis obliterans syndrome after hematopoietic stem cell transplantation.

Parametric response mapping (PRM) is a novel computed tomography (CT) technology that has shown potential for assessment of bronchiolitis obliterans syndrome (BOS) after hematopoietic stem cell transplantation (HCT). The primary aim of this study was to evaluate whether variations in image acquisition under real-world conditions affect the PRM measurements of clinically diagnosed BOS. CT scans were obtained retrospectively from 72 HCT recipients with BOS and graft-versus-host disease from Fred Hutchinson Cancer Research Center, Karolinska Institute, and the University of Michigan. Whole lung volumetric scans were performed at inspiration and expiration using site-specific acquisition and reconstruction protocols. PRM and pulmonary function measurements were assessed. Patients with moderately severe BOS at diagnosis (median forced expiratory volume at 1 second [FEV1] 53.5% predicted) had similar characteristics between sites. Variations in site-specific CT acquisition protocols had a negligible effect on the PRM-derived small airways disease (SAD), that is, BOS measurements. PRM-derived SAD was found to correlate with FEV1% predicted and FEV1/ forced vital capacity (R = -0.236, P = .046; and R = -0.689, P < .0001, respectively), which suggests that elevated levels in the PRM measurements are primarily affected by BOS airflow obstruction and not CT scan acquisition parameters. Based on these results, PRM may be applied broadly for post-HCT diagnosis and monitoring of BOS.

Ventilatory capacity in CLAD is driven by dysfunctional airway structure.

BACKGROUND: Chronic lung allograft dysfunction (CLAD) encompasses three main phenotypes: bronchiolitis obliterans syndrome (BOS), restrictive allograft syndrome (RAS) and a Mixed phenotype combining both pathologies. How the airway structure in its entirety is affected in these phenotypes is still poorly understood. METHODS: A detailed analysis of airway morphometry was applied to gain insights on the effects of airway remodelling on the distribution of alveolar ventilation in end-stage CLAD. Ex vivo whole lung µCT and tissue-core µCT scanning of six control, six BOS, three RAS and three Mixed explant lung grafts (9 male, 9 female, 2014-2021, Leuven, Belgium) were used for digital airway reconstruction and calculation of airway dimensions in relation to luminal obstructions. FINDINGS: BOS and Mixed explants demonstrated airway obstructions of proximal bronchioles (starting at generation five), while RAS explants particularly had airway obstructions in the most distal bronchioles (generation >12). In BOS and Mixed explants 76% and 84% of bronchioles were obstructed, respectively, while this was 22% in RAS. Bronchiolar obstructions were mainly caused by lymphocytic inflammation of the airway wall or fibrotic remodelling, i.e. constrictive bronchiolitis. Proximal bronchiolectasis and imbalance in distal lung ventilation were present in all CLAD phenotypes and explain poor lung function and deterioration of specific lung function parameters. INTERPRETATION: Alterations in the structure of conducting bronchioles revealed CLAD to affect alveolar ventilatory distribution in a regional fashion. The significance of various obstructions, particularly those associated with mucus, is highlighted. FUNDING: This research was funded with the National research fund Flanders (G060322N), received by R.V.

Bronchial artery revascularization in lung transplantation: a systematic review and meta-analysis.

Background: Bronchial artery revascularization (BAR) during lung transplantation has been hypothesized to improve early tracheal healing and delay the onset of bronchiolitis obliterans syndrome (BOS). We aimed to assess the outcomes of BAR after lung transplantation. Methods: Electronic search in Ovid Medline, Cumulative Index of Nursing and Allied Health Literature (CINAHL), Scopus, and Cochrane Controlled Trials Register (CCTR) databases was performed to identify all relevant studies published about lung transplantation with BAR. Studies discussing lung transplantation utilizing BAR were included while those without outcome data such as BOS and survival were excluded. Cohort-level data were extracted and pooled for analysis. A binary outcome meta-analysis of proportions with logit transformation was conducted. Newcastle-Ottawa scale was used for risk of bias assessment. Results: Seven studies were selected for the analysis comprising 143 patients. Mean patient age was 47 (95% CI: 40-55) years. Sixty-one percent (48-72%) were male. Seventy-three percent (65-79%) of patients underwent double lung transplant while 27% (21-25%) underwent single lung transplant. In patients with postoperative angiography, successful BAR was demonstrated in 93% (82-97%) of all assessed conduits. The 30-day/in-hospital mortality was 6% (3-11%). Seventy-nine percent (63-89%) of patients were free from rejection at three months. Eighty-three percent (29-98%) of patients were free from signs of airway ischemia at three and six months. Pooled survival at one year and five years was 87% (78-92%) and 71% (46-87%), respectively, with a mean follow-up time of 21 (3-38) months. Pooled freedom from bronchiolitis obliterans was 86% (77-91%) at two years. Conclusions: While this systematic review and meta-analysis is limited by the available surgeons, institutions, and papers discussing a highly specialized technique, it does show that BAR is a viable technique to minimize BOS and early anastomotic intervention following lung transplantation.

Ruxolitinib as an Effective and Steroid-Sparing First-Line Treatment in Newly Diagnosed BOS Patients After Hematopoietic Stem Cell Transplantation.

Bronchiolitis obliterans syndrome (BOS) is a life-threatening pulmonary complication of chronic graft-versus-host disease (cGVHD) after allogeneic hematopoietic stem cell transplantation (HSCT). In this study, we retrospectively identified seven patients newly diagnosed with BOS post HSCT and analyzed the outcomes in those patients treated with ruxolitinib as a first-line treatment. All seven patients achieved symptom responses within 2 weeks after ruxolitinib administration. Three months after treatment, five patients (71.43%) achieved a CR, and two (28.57%) achieved a PR. The overall response rate (ORR) was 100%. In addition, the steroid therapy was determined within 2 months after ruxolitinib treatment, indicating ruxolitinib as a steroid-sparing agent. We also found that ruxolitinib was well-tolerated and safe in treating newly diagnosed BOS. According to our results, ruxolitinib would be a promising and safe option in newly diagnosed BOS post HSCT.

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

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.

Efficacy and safety of high-dose budesonide/formoterol in patients with bronchiolitis obliterans syndrome after allogeneic hematopoietic stem cell transplant.

BACKGROUND: Bronchiolitis obliterans syndrome (BOS) is a rare, progressive and irreversible airway disease associated with significant mortality after allogeneic hematopoietic stem-cell transplantation (HSCT). In this study, we investigated the therapeutic effect of high-dose budesonide/formoterol (320/9 µg bid) in patients with BOS after HSCT already using low-dose budesonide/formoterol (160/4.5 µg bid). METHODS: After a retrospective chart review, patients who were initially treated with budesonide/formoterol 160/4.5 µg bid and increased their dose to 320/9 µg bid between March 2009 and February 2019 were enrolled. Pulmonary function test (PFT) and COPD assessment test (CAT) were performed before and after changing the drug dose. Efficacy was assessed within 3 months after increasing the drug dose; the primary variable was changes in forced expiratory volume in 1 second (FEV1) and CAT score. Safety was assessed as the incidence of pneumonia within 3 months after increasing the drug dose. RESULTS: Seventy-seven patients were treated with budesonide 160 µg plus formoterol 4.5 µg twice a day for more than 3 months and the dose was increased to budesonide 320 µg plus 9.0 µg twice a day. After treatment with high-dose ICS/LABA (budesonide 320 µg plus formoterol 9.0 µg twice a day for 12 weeks), there were no significant differences in FEV1 (before treatment 1.59 L vs. after treatment 1.65 L, P=0.182) or FVC (before treatment 2.93 L vs. after treatment 2.96 L, P=0.519) compared to before starting the high dose treatment. There were no significant differences in the total CAT score. Of all patients, 34.2% of patients had an increase in FEV1 ≥100 mL and 35.3% of patients showed a decrease ≥2 points in CAT score. In safety assessment, there were no significant differences between the two periods. CONCLUSIONS: Our study failed to show superior effect of high-dose budesonide/formoterol (320/9 µg) compared with low-dose. However, high-dose budesonide/formoterol was safe and there was no lung function deterioration.

Lung transplantation for bronchiolitis obliterans syndrome after allogenic hematopoietic stem cell transplantation.

Bronchiolitis obliterans syndrome (BOS) after hematopoietic stem cell transplantation (HSCT) is a major cause of morbidity and mortality with limited treatment options. Lung transplantation (LTX) has been rarely reported as a treatment option for selected HSCT recipients with this problem. In the present study, we reported six patients who underwent LTX due to BOS after HSCT (two females, four males) from January 2012 to December 2014 in our center. The median time from HSCT to diagnosis of BOS was 2.5 years (ranging from 1 to 5 years). At a median time of 4 years (ranging from 2 to 5 years) after diagnosis of BOS, four patients received bilateral sequential LTX, and two patients received single LTX. One of the recipients suffered from mild acute rejection after LTX, another suffered from primary lung graft dysfunction on post-operation day 2, and three experienced fungal infections. The median time for follow-up after LTX was 19.5 months (ranging from 12 to 39 months). At present, all patients are alive with good functional capacity and no relapse of BOS and hematologic malignancy conditions. Patients who received bilateral LTX have better pulmonary functions than patients who received single LTX.

A novel model for dissecting roles of IL-17 in lung transplantation.

BACKGROUND: The long-term success of lung transplantation is limited by the development of chronic lung allograft dysfunction (CLAD) in which IL-17 plays an important role. Direct evidence of IL-17-mediated allograft rejection has been observed when T-bet is absent. However, lack of T-bet also leads to failure in production of IFN-γ which is required for tolerance induction and allograft acceptance, as T-bet deficiency results in IL-17-expressing CD8+ T cells mediated costimulation blockade-resistant allograft rejection. Our previous research demonstrated that additional STAT6 deficiency to T-bet deficiency resulted in Th17-dominant immune responses, and importantly, restored IFN-γ production. Here we investigated whether T-bet/STAT6 double knout-out (DKO) mice as allograft recipients could provide a useful model to study IL-17 and Th17 in lung transplantation. METHODS: Murine orthotopic allogeneic lung transplants were performed in C57BL/6 wild type (WT) or T-bet/STAT6 DKO (C57BL/6 background) mice using MHC fully mismatched BALB/c donors. Syngeneic transplants were also performed in WT C57BL/6 mice using C57BL/6 donors. At day 10, histopathologic characteristics and rejection status of transplanted grafts were assessed; graft-infiltrating cells were isolated and real-time RT-PCR was performed for IL-17, IFN-γ and IL-4 expressions. RESULTS: Isografts showed no apparent rejection as anticipated. Allografts of both WT and DKO recipients displayed vigorous acute rejection and expressed comparable levels of IFN-γ; while T-bet/STAT6 double deficiency resulted in much more IL-17 and less IL-4 production. Histopathologic examination demonstrated that allografts of both WT and DKO recipients have marked inflammatory cell infiltration and pulmonary parenchyma lesion. In contrast to lymphocyte-predominant inflammation observed in WT recipients, allografts of DKO recipients displayed obvious polymorphonuclear cell infiltration and severer obliterative airway inflammation. Compared to WT recipients, the ratio of graft-infiltrating CD8+ versus CD4+ T cells increased significantly with much higher numbers of neutrophils in allografts of DKO recipients. CONCLUSIONS: T-bet/STAT6 DKO recipients of lung allografts result in IL-17-dominant transplant immunity, retain IFN-γ responses, and develop neutrophilia, obliterative airway inflammation and acute transplant rejection. Our results indicate that T-bet/STAT6 DKO mice serving as allograft recipient could be utilized as a new viable model to study the roles of IL-17 in lung transplantation.

Chronic lung allograft dysfunction phenotypes and treatment.

Chronic lung allograft dysfunction (CLAD) remains a major hurdle limiting long-term survival post lung transplantation. Given the clinical heterogeneity of CLAD, recently two phenotypes of CLAD have been defined [bronchiolitis obliterans syndrome (BOS) vs. restrictive allograft syndrome (RAS) or restrictive CLAD (rCLAD)]. BOS is characterized by an obstructive pulmonary function, air trapping on CT and obliterative bronchiolitis (OB) on histopathology, while RAS/rCLAD patients show a restrictive pulmonary function, persistent pleuro-parenchymal infiltrates on CT and pleuroparenchymal fibro-elastosis on biopsies. Importantly, the patients with RAS/rCLAD have a severely limited survival post diagnosis of 6-18 months compared to 3-5 years after BOS diagnosis. In this review, we will review historical evidence for this heterogeneity and we will highlight the clinical, radiological, histopathological characteristics of both phenotypes, as well as their risk factors. Treatment of CLAD remains troublesome, nevertheless, we will give an overview of different treatment strategies that have been tried with some success. Adequate phenotyping remains difficult but is clearly needed for both clinical and scientific purposes.

Multivariate modeling using quantitative CT metrics may improve accuracy of diagnosis of bronchiolitis obliterans syndrome after lung transplantation.

BACKGROUND: To assess how quantitative CT (qCT) metrics compare to pulmonary function testing (PFT) and semi-quantitative image scores (SQS) to diagnose bronchiolitis obliterans syndrome (BOS), manifestation of chronic lung allograft dysfunction after lung transplantation (LTx), according to the type of LTx (unilateral or bilateral). METHODS: Paired inspiratory-expiratory CT scans and PFTs of 176 LTx patients were analyzed retrospectively, and separated into BOS (78) and non-BOS (98) cohorts. SQS were assessed by 2 radiologists and graded (0-3) for features including mosaic attenuation and bronchiectasis. qCT metrics included lung volumes and air trapping volumes. Multivariate logistic regression (MVLR) and support vector machines (SVM) were used for the classification task. RESULTS: MVLR and SVM models using PFT metrics demonstrated highest accuracy for bilateral LTx (max AUC 0.771), whereas models using qCT metrics-only outperformed models using SQS or PFTs in unilateral LTx (max AUC 0.817), to diagnose BOS. Adding PC (principal components) from qCT on top of PFT improved model diagnostic accuracy for all transplant types. CONCLUSIONS: Combinations of qCT metrics augment the diagnostic performance of PFTs, are superior to SQS to predict BOS status, and outperform PFTs in the unilateral LTx group. This suggests that latent information on paired volumetric CT may allow early diagnosis of BOS in LTx patients, particularly in unilateral LTx.