Fibrotic progression from acute cellular rejection is dependent on secondary lymphoid organs in a mouse model of chronic lung allograft dysfunction.

Chronic lung allograft dysfunction (CLAD) remains one of the major limitations to long-term survival after lung transplantation. We modified a murine model of CLAD and transplanted left lungs from BALB/c donors into B6 recipients that were treated with intermittent cyclosporine and methylprednisolone postoperatively. In this model, the lung allograft developed acute cellular rejection on day 15 which, by day 30 after transplantation, progressed to severe pleural and peribronchovascular fibrosis, reminiscent of changes observed in restrictive allograft syndrome. Lung transplantation into splenectomized B6 alymphoplastic (aly/aly) or splenectomized B6 lymphotoxin-ß receptor-deficient mice demonstrated that recipient secondary lymphoid organs, such as spleen and lymph nodes, are necessary for progression from acute cellular rejection to allograft fibrosis in this model. Our work uncovered a critical role for recipient secondary lymphoid organs in the development of CLAD after pulmonary transplantation and may provide mechanistic insights into the pathogenesis of this complication.

Early extracorporeal photopheresis treatment is associated with better survival in patients with chronic or recurrent acute lung allograft dysfunction.

BACKGROUND: Due to development of chronic lung allograft dysfunction (CLAD), prognosis for patients undergoing lung transplantation (LTx) is still worse compared to other solid organ transplant recipients. Treatment options for slowing down CLAD progression are scarce with extracorporeal photopheresis (ECP) as an established rescue therapy. The aim of the study was to identify characteristics of responders and non-responders to ECP treatment, assess their survival, lung function development and by that define the subset of patients who should receive early ECP treatment. METHODS: We performed a retrospective study of all LTx patients receiving ECP treatment at the University Hospital Zurich between January 2010 and March 2020. Patients were followed-up for a maximum period of 5 years. Mortality and lung function development were assessed by CLAD stage and by CLAD subtype before initiation of ECP treatment. RESULTS: Overall, 105 patients received at least one ECP following LTx. A total of 57 patients (61.3%) died within the study period with a median survival of 15 months. Mortality was 57% for patients who started ECP at CLAD1, 39% for CLAD2, 93% for CLAD3, and 90% for CLAD4 (p < 0.001). Survival and lung function development was best in young patients at early CLAD stages 1 and 2. Response to ECP treatment was worst in patients with CLAD-RAS/mixed subtype (14.3%) and patients with ECP initiation in CLAD stages 3 (7.1%) and 4 (11.1%). Survival was significantly better in a subset of patients with recurrent acute allograft dysfunction and earlier start of ECP treatment (105 vs 15 months). CONCLUSION: In this retrospective analysis of a large group of CLAD patients treated with ECP after LTx, early initiation of ECP was associated with better long-term survival. Besides a subset of patients suffering of recurrent allograft dysfunction, especially a subset of patients defined as responders showed an improved response rate and survival, suggesting that ECP should be initiated in early CLAD stages and young patients. ECP might therefore prevent long-term disease progression even in patients with CLAD refractory to other treatment options and thus prevent or delay re-transplantation.

Restrictive allograft dysfunction rather than bronchiolitis obliterans syndrome had a major impact on the overall survival after living-donor lobar lung transplantation.

PURPOSE: Chronic lung allograft dysfunction (CLAD) is a known long-term fatal disorder after lung transplantation. In this study, we evaluated the CLAD classification of the International Society for Heart and Lung Transplantation (ISHLT) for living-donor lobar lung transplantation (LDLLT). METHODS: We conducted a single-center retrospective review of data from 73 patients who underwent bilateral LDLLT between 1998 and 2019. Factors related to opacity on computed tomography (CT) and restriction on pulmonary function tests (PFTs) were also analyzed. RESULTS: Overall, 26 (36%) patients were diagnosed with CLAD, including restrictive allograft syndrome (RAS), n = 10 (38.5%); bronchiolitis obliterans syndrome (BOS), n = 8 (30.8%); mixed, n = 1 (3.8%); undefined, n = 2 (7.7%); and unclassified, n = 5 (19.2%). The 5-year survival rate after the CLAD onset was 60.7%. The survival of patients with BOS was significantly better than that of patients with RAS (p = 0.012). In particular, patients with restriction on PFT had a significantly worse survival than those without restriction (p = 0.001). CONCLUSIONS: CLAD after bilateral LDLLT does not have a major impact on the recipient survival, especially in patients with BOS. Restriction on PFT may predict a particularly poor prognosis in patients with CLAD after bilateral LDLLT.

Percentage of low attenuation area on computed tomography detects chronic lung allograft dysfunction, especially bronchiolitis obliterans syndrome, after bilateral lung transplantation.

INTRODUCTION: The percentage of low attenuation area (%LAA) on computed tomography (CT) is useful for evaluating lung emphysema, and higher %LAA was observed in patients with chronic lung allograft dysfunction (CLAD). This study investigated the relationship between the %LAA and the development of CLAD after bilateral lung transplantation (LT). METHODS: We conducted a single-center retrospective study of 75 recipients who underwent bilateral LT; the recipients were divided into a CLAD group (n = 30) and a non-CLAD group (n = 45). The %LAA was calculated using CT and compared between the two groups from 4 years before to 4 years after the diagnosis of CLAD. The relationships between the %LAA and the percent baseline values of the pulmonary function test parameters were also calculated. RESULTS: The %LAA was significantly higher in the CLAD group than in the non-CLAD group from 2 years before to 2 years after the diagnosis of CLAD (P < .05). In particular, patients with bronchiolitis obliterans syndrome (BOS) exhibited significant differences even from 4 years before to 4 years after diagnosis (P < .05). Significant negative correlations between the %LAA and the percent baseline values of the forced expiratory volume in 1 s (r = -.36, P = .0031), the forced vital capacity (r = -.27, P = .027), and the total lung capacity (r = -.40, P < .001) were seen at the time of CLAD diagnosis. CONCLUSION: The %LAA on CT was associated with the development of CLAD and appears to have the potential to predict CLAD, especially BOS, after bilateral LT.

Rescue Everolimus Post Lung Transplantation is Not Associated With an Increased Incidence of CLAD or CLAD-Related Mortality.

Everolimus (EVE) has been used as a calcineurin inhibitor (CNI) minimization/ elimination agent or to augment immunosuppression in lung transplant recipients (LTR) with CNI-induced nephrotoxicity or neurotoxicity. The long-term evidence for survival and progression to chronic lung allograft dysfunction (CLAD) is lacking. The primary aim was to compare survival outcomes of LTR starting EVE-based immunosuppression with those remaining on CNI-based regimens. The secondary outcomes being time to CLAD, incidence of CLAD and the emergence of obstructive (BOS) or restrictive (RAS) phenotypes. Single center retrospective study of 91 LTR starting EVE-based immunosuppression matched 1:1 with LTR remaining on CNI-based immunosuppression. On multivariate analysis, compared to those remaining on CNI-based immunosuppression, starting EVE was not associated with poorer survival [HR 1.04, 95% CI: 0.67-1.61, p = 0.853], or a statistically significant faster time to CLAD [HR 1.34, 95% CI: 0.87-2.04, p = 0.182]. There was no difference in the emergence of CLAD (EVE, [n = 57, 62.6%] vs. CNI-based [n = 52, 57.1%], p = 0.41), or the incidence of BOS (p = 0.60) or RAS (p = 0.16) between the two groups. Introduction of EVE-based immunosuppression does not increase the risk of death or accelerate the progression to CLAD compared to CNI-based immunosuppression.

Pharmacotherapy of chronic lung allograft dysfunction post lung transplantation.

BACKGROUND: Chronic lung allograft dysfunction (CLAD) remains the primary cause of death in lung transplant recipients (LTRs) despite improvements in immunosuppression management. Despite advances in knowledge regarding the pathogenesis of CLAD, treatments that are currently available are usuallyineffective and delay progression of disease at best.There are currently no evidence-based guidelines and minimal publications regarding the optimal treatment ofCLAD. OBJECTIVE: To complete a comprehensive review of the literature for the prevention and medical management of CLAD. METHODS: We identified the major domains of the medical management of CLAD and conducted a comprehensive search of PubMed and Embase databases to identify articles published from inception to December 2021 related to CLAD in LTRs. Studies published in English pertaining to the pharmacologic prevention and treatment of CLAD were included; highest priority was given to prospective, randomized, controlled trials if available. Prospective observational and retrospective controlled trials were prioritized next, followed by retrospective uncontrolled studies, case series, and finally case reports if the information was deemed to be pertinent. Reference lists of qualified publications were also reviewed to find any other publications of interest that were not found on initial search.In the absence of literature published in the aforementioned databases, additional articles were identified by reviewing abstracts presented at the International Society for Heart and Lung Transplantation and American Transplant Congress annual meetings between 2010-2021. CONCLUSION: CLAD should be identified as early as possible along with prompt intervention to optimize the possibility of stabilizing or improving lung function. More robust clinical data is needed to validate the use of all currently available and investigational treatment options for CLAD to identify the optimal pharmacotherapy management for this patient population.

Radiographic Graft Surveillance in Lung Transplantation: Prognostic Role of Parametric Response Mapping.

Rationale: Chronic lung allograft dysfunction (CLAD) results in significant morbidity after lung transplantation. Potential CLAD occurs when lung function declines to 80-90% of baseline. Better noninvasive tools to prognosticate at potential CLAD are needed. Objectives: To determine whether parametric response mapping (PRM), a computed tomography (CT) voxel-wise methodology applied to high-resolution CT scans, can identify patients at risk of progression to CLAD or death. Methods: Radiographic features and PRM-based CT metrics quantifying functional small airway disease (PRMfSAD) and parenchymal disease (PRMPD) were studied at potential CLAD (n = 61). High PRMfSAD and high PRMPD were defined as ⩾30%. Restricted mean modeling was performed to compare CLAD-free survival among groups. Measurements and Main Results: PRM metrics identified the following three unique signatures: high PRMfSAD (11.5%), high PRMPD (41%), and neither (PRMNormal; 47.5%). Patients with high PRMfSAD or PRMPD had shorter CLAD-free median survival times (0.46 yr and 0.50 yr) compared with patients with predominantly PRMNormal (2.03 yr; P = 0.004 and P = 0.007 compared with PRMfSAD and PRMPD groups, respectively). In multivariate modeling adjusting for single- versus double-lung transplant, age at transplant, body mass index at potential CLAD, and time from transplant to CT scan, PRMfSAD ⩾30% or PRMPD ⩾30% continue to be statistically significant predictors of shorter CLAD-free survival. Air trapping by radiologist interpretation was common (66%), was similar across PRM groups, and was not predictive of CLAD-free survival. Ground-glass opacities by radiologist read occurred in 16% of cases and were associated with decreased CLAD-free survival (P < 0.001). Conclusions: PRM analysis offers valuable prognostic information at potential CLAD, identifying patients most at risk of developing CLAD or death.

MiR-21 in Lung Transplant Recipients With Chronic Lung Allograft Dysfunction.

Background: Micro-RNA-21 (miR-21) is a post-translational regulator involved in epithelial-to-mesenchymal transition (EMT). Since EMT is thought to contribute to chronic lung allograft dysfunction (CLAD), we aimed to characterize miR-21 expression and distinct EMT markers in CLAD. Methods: Expression of miR-21, vimentin, Notch intracellular domain (NICD) and SMAD 2/3 was investigated in explanted CLAD lungs of patients who underwent retransplantation. Circulating miR-21 was determined in collected serum samples of CLAD and matched stable recipients. Results: The frequency of miR-21 expression was higher in restrictive allograft syndrome (RAS) than in bronchiolitis obliterans syndrome (BOS) specimens (86 vs 30%, p = 0.01); Vimentin, NICD and p-SMAD 2/3 were positive in 17 (100%), 12 (71%), and 7 (42%) BOS patients and in 7 (100%), 4 (57%) and 4 (57%) RAS cases, respectively. All four markers were negative in control tissue from donor lungs. RAS patients showed a significant increase in serum concentration of miR-21 over time as compared to stable recipients (p = 0.040). Conclusion: To the best of our knowledge this is the first study highlighting the role miR-21 in CLAD. Further studies are necessary to investigate the involvement of miR-21 in the pathogenesis of CLAD and its potential as a therapeutic target.

Restrictive allograft syndrome after lung transplantation.

Despite recent advances over the past decade in lung transplantation including improved surgical technique and immunotherapy, the diagnosis and treatment of chronic lung allograft dysfunction remains a significant barrier to recipient survival. Aside from bronchiolitis obliterans syndrome, a restrictive phenotype called restrictive allograft syndrome has recently been recognized and affects up to 35% of all patients with CLAD. The main characteristics of RAS include a persistent and unexplained decline in lung function compared to baseline and persistent parenchymal infiltrates on imaging. The median survival after diagnosis of RAS is 6 to 18 months, significantly shorter than other forms of CLAD. Treatment options are limited, as therapies used for BOS are typically ineffective at halting disease progression. Specific medications such as fibrinolytics are lacking large, multicenter prospective studies. In this manuscript, we discuss the definition, mechanism, and characteristics of RAS while highlighting the similarities and differences between other forms of CLAD. We also review the diagnoses along with current and potential treatment options that are available for patients. Finally, we discuss the existing knowledge gaps and areas for future research to improve patient outcomes and understanding of RAS.

Identification and characterization of chronic lung allograft dysfunction patients with mixed phenotype: A single-center study.

RATIONALE: Patients can change chronic lung allograft dysfunction (CLAD) phenotype, especially from BOS to mixed phenotype. Our aim was to further characterize these patients. METHOD: Mixed CLAD was defined as a restrictive physiology with persistent CT opacities, after initial bronchiolitis obliterans syndrome (BOS) diagnosis. The incidence, prognosis, pulmonary function, radiology, pathology, and airway inflammation were compared between patients with restrictive allograft syndrome (RAS) and mixed CLAD. RESULT: A total of 268 (44%) patients developed CLAD of which 47 (18%) were diagnosed with RAS "ab initio," 215 (80%) with BOS, and 6 (2%) an undefined phenotype. Twenty-five patients developed a mixed CLAD phenotype (24 BOS to mixed and 1 RAS to mixed). Survival after mixed phenotype diagnosis was comparable (P = .39) to RAS. More emphysema patients developed a mixed phenotype (P = .020) compared to RAS ab initio, while mixed CLAD patients had a lower FEV1 (P < .0001) and FEV1 /FVC (P = .0002) at diagnosis compared to RAS ab initio. CT scans in patients with the mixed phenotype demonstrated apical predominance of the opacities (P = .0034) with pleuroparenchymal fibroelastosis on histopathology. CONCLUSION: We further characterized patients with a mixed phenotype of CLAD. Although the survival after diagnosis was comparable to RAS ab initio patients, there was a difference in demography, pulmonary function, radiology, and pathology.

Total lymphoid irradiation in progressive bronchiolitis obliterans syndrome after lung transplantation: a single-center experience and review of literature.

Limited results about treatment with total lymphoid irradiation (TLI) in lung transplant (LTx) recipients suffering from progressive bronchiolitis obliterans syndrome (BOS) have been reported. We performed a retrospective analysis of all LTx recipients undergoing TLI for progressive BOS in our center, focusing on long-term outcomes regarding overall survival and lung allograft function. Treatment with TLI (2004-2017, n = 20, 1 BOS stage 1, 6 BOS stage 2, and 13 BOS stage 3) resulted in significant attenuation of the FEV1 -decline in the majority of patients, mainly in those with a rapid decline (P = 0.0005). This allowed bridging to redo-transplantation in five patients. However, three patients progressed from BOS to RAS following prior TLI. Overall patient survival was 44% at 2 years post-TLI and 38% after 17 years. Generally, TLI was well tolerated, with limited side effects and no serious adverse events. TLI may attenuate the decline in FEV1 of LTx recipients with rapid progressive BOS and could thus help to bridge selected patients to redo-transplantation.

Impact of chronic lung allograft dysfunction, especially restrictive allograft syndrome, on the survival after living-donor lobar lung transplantation compared with cadaveric lung transplantation in adults: a single-center experience.

PURPOSE: The differences in chronic lung allograft dysfunction (CLAD) between living-donor lobar lung transplantation (LDLLT) and cadaveric lung transplantation (CLT) remain unclear. We conducted this study to compare the impact of CLAD on the outcomes after LDLLT vs. CLT. METHODS: We conducted a retrospective review of the data of 97 recipients of bilateral lung transplantation, including 51 recipients of LDLLT and 46 recipients of CLT. RESULTS: The CLAD-free survival and overall survival after LDLLT were similar to those after CLT. CLAD and restrictive allograft syndrome (RAS), but not bronchiolitis obliterans syndrome (BOS), developed significantly later after LDLLT than after CLT (p = 0.015 and p = 0.035). Consequently, patients with CLAD and RAS, but not those with BOS, after LDLLT had a significantly better overall survival than those after CLT (p = 0.037 and p = 0.0006). Furthermore, after the diagnosis of CLAD, the survival of patients with RAS after LDLLT tended to be better than that after CLT (p = 0.083). CONCLUSION: CLAD, especially RAS, appears to develop later after LDLLT than after CLT and seems to have a lower impact on the overall survival after LDLLT than that after CLT.

Quantitative chest CT for subtyping chronic lung allograft dysfunction and its association with survival.

Chronic lung allograft dysfunction (CLAD) is a major cause of mortality in lung transplant recipients. CLAD can be sub-divided into at least 2 subtypes with distinct mortality risk characteristics: restrictive allograft syndrome (RAS), which demonstrates increased overall computed tomography (CT) lung density in contrast with bronchiolitis obliterans syndrome (BOS), which demonstrates reduced overall CT lung density. This study aimed to evaluate a reader-independent quantitative density metric (QDM) derived from CT histograms to associate with CLAD survival. A retrospective study evaluated CT scans corresponding to CLAD onset using pulmonary function tests in 74 patients (23 RAS, 51 BOS). Two different QDM values (QDM1 and QDM2) were calculated using CT lung density histograms. Calculation of QDM1 includes the extreme edges of the histogram. Calculation of QDM2 includes the central region of the histogram. Kaplan-Meier analysis and Cox regression analysis were used for CLAD prognosis. Higher QDM values were significantly associated with decreased survival. The hazard ratio for death was 3.2 times higher at the 75th percentile compared to the 25th percentile using QDM1 in a univariate model. QDM may associate with CLAD patient prognosis.

High-Resolution CT Findings of Obstructive and Restrictive Phenotypes of Chronic Lung Allograft Dysfunction: More Than Just Bronchiolitis Obliterans Syndrome.

OBJECTIVE: The purpose of this article is to review the high-resolution CT characteristics of individual obstructive and restrictive chronic lung allograft dysfunction (CLAD) phenotypes to aid in making accurate diagnoses and guiding treatment. CONCLUSION: Long-term survival and function after lung transplant are considerably worse compared with after other organ transplants. CLAD is implicated as a major limiting factor for long-term graft viability. Historically thought to be a single entity, bronchiolitis obliterans syndrome, CLAD is actually a heterogeneous group of disorders with distinct subtypes.

Restrictive allograft syndrome and idiopathic pleuroparenchymal fibroelastosis: do they really have the same histology?

AIMS: Restrictive allograft syndrome (RAS) and idiopathic pleuroparenchymal fibroelastosis (IPPFE) are two different diseases reported to share the same histology. RAS relates to chronic allograft dysfunction in lung transplantation, with IPPFE being a rare condition in native lungs. Our aim is to compare their histologies alongside biopsies of usual interstitial pneumonia (UIP), to determine if there are differences that might help to elucidate the pathogenesis. METHODS AND RESULTS: We selected four postmortem allograft lungs from patients who developed a clear clinical RAS pattern, five biopsies diagnosed as IPPFE, five UIP biopsies and five sections of normal lung. Histopathological features were described without knowledge of clinical and radiological features. Both RAS allografts and IPPFE biopsies showed intra-alveolar fibrosis and elastosis (IAFE), but RAS allografts also showed concomitant obliterative bronchiolitis, vascular lymphoplasmacytic inflammation within fibrointimal thickening, less fibroblastic foci (FF) at the advancing edge of the fibrosis (one against 14.4 FF in 2 mm2 ) and a slight reduction of the capillary network compared to UIP (P = 0.07) and controls (P = 0.06). The main differences seen in UIP were the lack of IAFE and the presence of honeycomb change. CONCLUSIONS: RAS and PPFE histopathology both show IAFE, but display various differences, particularly in their vascular morphology that may allow further understanding of pathogenesis.

The role of biomechanical anatomical modeling via computed tomography for identification of restrictive allograft syndrome.

Chronic lung allograft dysfunction (CLAD) reduces long-term graft survival. It is important to distinguish CLAD subtypes: bronchiolitis obliterans syndrome (BOS) and restrictive allograft syndrome (RAS) as RAS has a worse prognosis and accurate subtyping could facilitate targeted treatments. However, the current diagnosis of CLAD subtypes is based on pulmonary function test (PFT) results that reflect global estimates of lung function; anatomical modeling based on computed tomography (CT) has the potential to provide detailed analysis of global and regional lung function. The purpose of this study is to evaluate the utility of CT-based anatomical modeling for the identification of RAS. This retrospective study included 51 patients (CLAD: 17 BOS and 17 RAS, control: 17 No-CLAD). CT data were assessed using a biomechanical model-based platform (MORFEUS) to characterize changes in lung deformation between baseline and disease onset. Lung deformation demonstrated high sensitivity and specificity (>80%) in differentiating RAS from BOS (P<.0001) and No-CLAD (P<.0001). There were matching radiological reading and inward deformation abnormalities in 79% of lung sections in patients with RAS. Anatomical modeling is complementary to conventional assessment in the diagnosis of RAS and potentially provides quantitative data that can help in the characterization and detailed assessment of heterogeneous lung parenchymal disease.

Current views on chronic rejection after lung transplantation.

Chronic lung allograft dysfunction (CLAD) was recently introduced as an overarching term mainly to classify patients with chronic rejection after lung transplantation, although other conditions may also qualify for CLAD. Initially, only the development of a persistent and obstructive pulmonary function defect, clinically identified as bronchiolitis obliterans syndrome (BOS), was considered as chronic rejection, if no other cause could be identified. It became clear in recent years that some patients do not qualify for this definition, although they developed a chronic and persistent decrease in FEV1 , without another identifiable cause. As the pulmonary function decline in these patients was rather restrictive, this was called restrictive allograft syndrome (RAS). In the present review, we will further elaborate on these two CLAD phenotypes, with specific attention to the diagnostic criteria, the role of pathology and imaging, the risk factors, outcome, and the possible treatment options.

Spectrum of chronic lung allograft dysfunction pathology in human lung transplantation.

BACKGROUND: Long-term survival after lung transplantation (LTx) remains limited by chronic lung allograft dysfunction (CLAD), which includes 2 main phenotypes: bronchiolitis obliterans syndrome (BOS) and restrictive allograft syndrome (RAS), with possible overlap. We aimed to detail and quantify pathological features of these CLAD sub-types. METHODS: Peripheral and central paraffin-embedded explanted lung samples were obtained from 20 consecutive patients undergoing a second LTx for CLAD, from 3 lobes. Thirteen lung samples, collected from non-transplant lobectomies or donor lungs, were used as controls. Blinded semi-quantitative grading was performed to assess airway fibrotic changes, parenchymal and pleural fibrosis, and epithelial and vascular abnormalities. RESULTS: CLAD lung samples had higher scores for all airway- and lung-related parameters compared to controls. There was a notable overlap in histologic scores between BOS and RAS, with a wide range of scores in both conditions. Parenchymal and vascular fibrosis scores were significantly higher in RAS compared to BOS (p = 0.003 for both). We observed a significant positive correlation between the degree of inflammation around each airway, the severity of epithelial changes, and airway fibrosis. Immunofluorescence staining demonstrated a trend toward a lower frequency of club cells in CLAD and a higher frequency of apoptotic club cells in BOS samples (p = 0.01). CONCLUSIONS: CLAD is a spectrum of airway, parenchymal, and pleural fibrosis, as well as epithelial, vascular, and inflammatory pathologic changes, where BOS and RAS overlap significantly. Our semi-quantitative grading score showed a generally high inter-reader reliability and may be useful for future CLAD histologic assessments.

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.

Pirfenidone: a potential new therapy for restrictive allograft syndrome?

This case report describes the evolution of pulmonary function findings (FVC, FEV1 and TLC) and CT features with pirfenidone treatment for restrictive allograft syndrome following lung transplantation. Furthermore, we herein report hypermetabolic activity on (18) F-FDG PET imaging in this setting, which could indicate active fibroproliferation and pleuroparenchymal remodeling. These findings may warrant further investigation.