Donor IL-17 receptor A regulates LPS-potentiated acute and chronic murine lung allograft rejection.

Chronic lung allograft dysfunction (CLAD) is a major complication after lung transplantation that results from a complex interplay of innate inflammatory and alloimmune factors, culminating in parenchymal and/or obliterative airway fibrosis. Excessive IL-17A signaling and chronic inflammation have been recognized as key factors in these pathological processes. Herein, we developed a model of repeated airway inflammation in mouse minor alloantigen-mismatched single-lung transplantation. Repeated intratracheal LPS instillations augmented pulmonary IL-17A expression. LPS also increased acute rejection, airway epithelial damage, and obliterative airway fibrosis, similar to human explanted lung allografts with antecedent episodes of airway infection. We then investigated the role of donor and recipient IL-17 receptor A (IL-17RA) in this context. Donor IL-17RA deficiency significantly attenuated acute rejection and CLAD features, whereas recipient IL-17RA deficiency only slightly reduced airway obliteration in LPS allografts. IL-17RA immunofluorescence positive staining was greater in human CLAD lungs compared with control human lung specimens, with localization to fibroblasts and myofibroblasts, which was also seen in mouse LPS allografts. Taken together, repeated airway inflammation after lung transplantation caused local airway epithelial damage, with persistent elevation of IL-17A and IL-17RA expression and particular involvement of IL-17RA on donor structural cells in development of fibrosis.

Donor Batf3 inhibits murine lung allograft rejection and airway fibrosis.

Chronic lung allograft dysfunction (CLAD) limits survival after lung transplantation. Noxious stimuli entering the airways foster CLAD development. Classical dendritic cells (cDCs) link innate and adaptive immunity and exhibit regional and functional specialization in the lung. The transcription factor basic leucine zipper ATF-like 3 (BATF3) is absolutely required for the development of type 1 cDCs (cDC1s), which reside in the airway epithelium and have variable responses depending on the context. We studied the role of BATF3 in a mouse minor alloantigen-mismatched orthotopic lung transplant model of CLAD with and without airway inflammation triggered by repeated administration of intratracheal lipopolysaccharide (LPS). We found that cDC1s accumulated in allografts compared with isografts and that donor cDC1s were gradually replaced by recipient cDC1s. LPS administration increased the number of cDC1s and enhanced their state of activation. We found that Batf3-/- recipient mice experienced reduced acute rejection in response to LPS; in contrast, Batf3-/- donor grafts underwent enhanced lung and skin allograft rejection and drove augmented recipient cluster of differentiation 8+ T-cell expansion in the absence of LPS. Our findings suggest that donor and recipient cDC1s have differing and context-dependent roles and may represent a therapeutic target in lung transplantation.

Predefined and data driven CT densitometric features predict critical illness and hospital length of stay in COVID-19 patients.

The aim of this study was to compare whole lung CT density histograms to predict critical illness outcome and hospital length of stay in a cohort of 80 COVID-19 patients. CT chest images on segmented lungs were retrospectively analyzed. Functional Principal Component Analysis (FPCA) was used to find the main modes of variations on CT density histograms. CT density features, the CT severity score, the COVID-GRAM score and the patient clinical data were assessed for predicting the patient outcome using logistic regression models and survival analysis. ROC analysis predictors of critically ill status: 87.5th percentile CT density (Q875)-AUC 0.88 95% CI (0.79 0.94), F1-CT-AUC 0.87 (0.77 0.93) Standard Deviation (SD-CT)-AUC 0.86 (0.73, 0.93). Multivariate models combining CT-density predictors and Neutrophil-Lymphocyte Ratio showed the highest accuracy. SD-CT, Q875 and F1 score were significant predictors of hospital length of stay (LOS) while controlling for hospital death using competing risks models. Moreover, two multivariate Fine-Gray regression models combining the clinical variables: age, NLR, Contrast CT factor with either Q875 or F1 CT-density predictors revealed significant effects for the prediction of LOS incidence in presence of a competing risk (death) and acceptable predictive performances (Bootstrapped C-index 0.74 [0.70 0.78]).

A B cell-dependent pathway drives chronic lung allograft rejection after ischemia-reperfusion injury in mice.

Chronic lung allograft dysfunction (CLAD) limits long-term survival after lung transplant (LT). Ischemia-reperfusion injury (IRI) promotes chronic rejection (CR) and CLAD, but the underlying mechanisms are not well understood. To examine mechanisms linking IRI to CR, a mouse orthotopic LT model using a minor alloantigen strain mismatch (C57BL/10 [B10, H-2b ] → C57BL/6 [B6, H-2b ]) and isograft controls (B6→B6) was used with antecedent minimal or prolonged graft storage. The latter resulted in IRI with subsequent airway and parenchymal fibrosis in prolonged storage allografts but not isografts. This pattern of CR after IRI was associated with the formation of B cell-rich tertiary lymphoid organs within the grafts and circulating autoantibodies. These processes were attenuated by B cell depletion, despite preservation of allograft T cell content. Our observations suggest that IRI may promote B cell recruitment that drives CR after LT. These observations have implications for the mechanisms leading to CLAD after LT.

Lung Density Analysis Using Quantitative Chest CT for Early Prediction of Chronic Lung Allograft Dysfunction.

BACKGROUND: Chronic lung allograft dysfunction (CLAD) limits long-term survival after lung transplantation (LTx). Early detection or prediction of CLAD can lead to changes in patient management that, in turn, may improve prognosis. The purpose of this study was to investigate the utility of quantitative computed tomography (CT) lung density analysis in early prediction of CLAD. METHODS: This retrospective cohort was drawn from all consecutive adult, first LTxs performed between 2006 and 2011. Post-transplant monitoring included scheduled surveillance bronchoscopies with concurrent pulmonary-functions tests and low-dose chest CT. Quantitative density metrics (QDM) derived from CT scans obtained at the time of 10%-19% decline in forced expiratory volume in 1 second (FEV1) were evaluated: 114 bilateral LTx recipients (66 with CLAD and 48 stable) and 23 single LTx recipients (11 with CLAD, 12 stable) were included in the analysis. RESULTS: In both single and double LTx, at the time of 10%-19% drop in FEV1 from baseline, the QDM was higher in patients who developed CLAD within 3 years compared with those patients who remained stable for at least 3.5 years. The area under the receiver operating characteristic curve (AUC) was 0.89 for predicting CLAD in single LTx and 0.63 in bilateral LTx. A multipredictor AUC accounting for FEV1, QDM, presence of consolidation, and ground glass opacities increased the AUC to 0.74 in double LTx. CONCLUSIONS: QDM derived from a CT histogram at the time of early drop in FEV1 may allow prediction of CLAD in patients after single or double LTx.

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.

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.

Low-dose computed tomography volumetry for subtyping chronic lung allograft dysfunction.

BACKGROUND: The long-term success of lung transplantation is challenged by the development of chronic lung allograft dysfunction (CLAD) and its distinct subtypes of bronchiolitis obliterans syndrome (BOS) and restrictive allograft syndrome (RAS). However, the current diagnostic criteria for CLAD subtypes rely on total lung capacity (TLC), which is not always measured during routine post-transplant assessment. Our aim was to investigate the utility of low-dose 3-dimensional computed tomography (CT) lung volumetry for differentiating RAS from BOS. METHODS: This study was a retrospective evaluation of 63 patients who had developed CLAD after bilateral lung or heart‒lung transplantation between 2006 and 2011, including 44 BOS and 19 RAS cases. Median post-transplant follow-up was 65 months in BOS and 27 months in RAS. The median interval between baseline and the disease-onset time-point for CT volumetry was 11 months in both BOS and RAS. Chronologic changes and diagnostic accuracy of CT lung volume (measured as percent of baseline) were investigated. RESULTS: RAS showed a significant decrease in CT lung volume at disease onset compared with baseline (mean 3,916 ml vs 3,055 ml when excluding opacities, p < 0.0001), whereas BOS showed no significant post-transplant change (mean 4,318 ml vs 4,396 ml, p = 0.214). The area under the receiver operating characteristic curve of CT lung volume for differentiating RAS from BOS was 0.959 (95% confidence interval 0.912 to 1.01, p < 0.0001) and the calculated accuracy was 0.938 at a threshold of 85%. CONCLUSION: In bilateral lung or heart‒lung transplant patients with CLAD, low-dose CT volumetry is a useful tool to differentiate patients who develop RAS from those who develop BOS.