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Despite increasing evidence about the role of donor-specific human leukocyte antigen (HLA) antibodies in transplant outcomes, the incidence and impact of de novo donor-specific antibodies (dnDSA) after lung transplantation remains unclear. To describe the incidence, characteristics, and impact of dnDSA after lung transplantation. We investigated a single-center cohort of 340 lung transplant recipients undergoing transplant during 2008 to 2011. All patients underwent HLA-antibody testing quarterly pretransplant and at regular intervals over the first 24 months after transplant. The patients received modified immunosuppression depending on their pretransplant sensitization status. Risk factors for dnDSA development, as well as the associations of dnDSA with patient survival and chronic lung allograft dysfunction (CLAD), were determined using multivariable analysis. The cumulative incidence of dnDSA was 47% at a median of 86 days (range, 44-185 d) after lung transplantation. Seventy-six percent of recipients with dnDSA had DQ-DSA. Male sex and the use of ex vivo lung perfusion were associated with an increased risk of dnDSA, whereas increased HLA-DQB1 matching was protective. DQ-dnDSA preceded or coincided with the diagnosis of CLAD in all cases. Developing dnDSA (vs. no dnDSA) was associated with a twofold increased risk of CLAD (hazard ratio, 2.04; 95% confidence interval, 1.13-3.69). This association appeared to be driven by the development of DQ-dnDSA. dnDSA are common after lung transplantation, with the majority being DQ DSA. DQ-dnDSA are associated with an increased risk of CLAD. Strategies to prevent or treat DQ-dnDSA may improve outcomes for lung transplant recipients.

Background. Chronic lung allograft dysfunction (CLAD) is a major cause of allograft loss post-lung transplantation. Prior studies have examined the association between respiratory virus infection (RVI) and CLAD were limited by older diagnostic techniques, study design, and case numbers. We examined the association between symptomatic RVI and CLAD using modern diagnostic techniques in a large contemporary cohort of lung transplant recipients (LTRs). Methods. We retrospectively assessed clinical variables including acute rejection, cytomegalovirus pneumonia, upper and lower RVI, and the primary endpoint of CLAD (determined by 2 independent reviewers) in 250 LTRs in a single university transplantation program. Univariate and multivariate Cox models were used to analyze the relationship between RVI and CLAD in a time-dependent manner, incorporating different periods of risk following RVI diagnosis. Results. Fifty patients (20%) were diagnosed with CLAD at a median of 95 weeks post-transplantation, and 79 (32%) had 114 episodes of RVI. In multivariate analysis, rejection and RVI were independently associated with CLAD (adjusted hazard ratio [95% confidence interval]) 2.2 (1.2–3.9), P = .01 and 1.9 (1.1–3.5), P = .03, respectively. The association of RVI with CLAD was stronger the more proximate the RVI episode: 4.8 (1.9–11.6), P < .01; 3.4 (1.5–7.5), P < .01; and 2.4 (1.2–5.0), P = .02 in multivariate analysis for 3, 6, and 12 months following RVI, respectively. Conclusions. Symptomatic RVI is independently associated with development of CLAD, with increased risk at shorter time periods following RVI. Prospective studies to characterize the virologic determinants of CLAD and define the underlying mechanisms are warranted.

Emerging evidence suggests a restrictive phenotype of chronic lung allograft dysfunction (CLAD) exists; however, the optimal approach to its diagnosis and clinical significance is uncertain. To evaluate the hypothesis that spirometric indices more suggestive of a restrictive ventilatory defect, such as loss of FVC, identify patients with distinct clinical, radiographic, and pathologic features, including worse survival. Retrospective, single-center analysis of 566 consecutive first bilateral lung recipients transplanted over a 12-year period. A total of 216 patients developed CLAD during follow-up. CLAD was categorized at its onset into discrete physiologic groups based on spirometric criteria. Imaging and histologic studies were reviewed when available. Survival after CLAD diagnosis was assessed using Kaplan-Meier and Cox proportional hazards models. Among patients with CLAD, 30% demonstrated an FVC decrement at its onset. These patients were more likely to be female, have radiographic alveolar or interstitial changes, and histologic findings of interstitial fibrosis. Patients with FVC decline at CLAD onset had significantly worse survival after CLAD when compared with those with preserved FVC (P < 0.0001; 3-yr survival estimates 9% vs. 48%, respectively). The deleterious impact of CLAD accompanied by FVC loss on post-CLAD survival persisted in a multivariable model including baseline demographic and clinical factors (P < 0.0001; adjusted hazard ratio, 2.73; 95% confidence interval, 1.86-4.04). At CLAD onset, a subset of patients demonstrating physiology more suggestive of restriction experience worse clinical outcomes. Further study of the biologic mechanisms underlying CLAD phenotypes is critical to improving long-term survival after lung transplantation.

Allograft rejection remains the major hurdle in lung transplantation despite modern immunosuppressive treatment. As part of the alloreactive process, B cells are increasingly recognized as modulators of alloimmunity and initiators of a donor-specific humoral response. In chronically rejected lung allografts, B cells contribute to the formation of tertiary lymphoid structures and promote local alloimmune responses. However, B cells are functionally heterogeneous and some B cell subsets may promote alloimmune tolerance. In this review, we describe the current understanding of B-cell-dependent mechanisms in pulmonary allograft rejection and highlight promising future strategies that employ B cell-targeted therapies.

Purpose This study aimed to investigate the potential impact of tacrolimus (TAC) exposure on clinical outcomes after lung transplantation. Methods This retrospective observational study enrolled a total of 228 lung transplant recipients. TAC trough levels (C 0 ) were collected for 3 intervals: 0–3 months, 3–12 months, and 12–24 months. The intra-patient variability (IPV) was calculated using coefficient of variation. Genotyping of CYP3A5*3 (rs776746) was performed. Patients were further divided into groups based on the C 0 cut-off value of 8 ng/mL and IPV cut-off value of 30%. Cox proportional hazards regression models were used to explore the potential impact of C 0 and IPV on outcomes of interests, including de-novo donor-specific antibodies ( dn DSA), chronic lung allograft dysfunction (CLAD) and mortality. Results The influence of CYP3A5*3 polymorphism was only significant for C 0 and IPV during the first 3 months. Low C 0 (< 8 ng/mL) at 3–12 months increased the risk of dn DSA (hazard ratio [HR] 2.696, 95% confidence interval [CI] 1.046–6.953) and mortality (HR 2.531, 95% CI 1.368–4.685), while High IPV (≥ 30%) during this period was associated with an increased risk of mortality (HR 2.543, 95% CI 1.336–4.839). Patients with Low C 0 /High IPV combination had significantly higher risks for dn DSA (HR 4.381, 95% CI 1.279–15.008) and survival (HR 6.179, 95% CI 2.598–14.698), surpassing the predictive power provided by C 0 or IPV alone. Conclusion A combination of Low C 0 /High IPV might be considered in categorizing patients towards risk of adverse clinical outcomes following lung transplantation.

A growing number of patients with end-stage lung disease have benefited from lung transplantation (LT). Improvements in organ procurement, surgical techniques and intensive care management have greatly increased short-term graft survival. However, long-term outcomes remain limited, mainly due to the onset of chronic lung allograft dysfunction (CLAD), whose diagnosis is based on permanent loss of lung function after the development of irreversible lung lesions. CLAD is associated with high mortality and morbidity, and its exact physiopathology is still only partially understood. Many researchers and clinicians have searched for CLAD biomarkers to improve diagnosis, to refine the phenotypes associated with differential prognosis and to identify early biological processes that lead to CLAD to enable an early intervention that could modify the inevitable degradation of respiratory function. Donor-specific antibodies are currently the only biomarkers used in routine clinical practice, and their significance for accurately predicting CLAD is still debated. We describe here significant studies that have highlighted potential candidates for reliable and non-invasive biomarkers of CLAD in the fields of imaging and functional monitoring, humoral immunity, cell-mediated immunity, allograft injury, airway remodeling and gene expression. Such biomarkers would improve CLAD prediction and allow differential LT management regarding CLAD risk.

Primary ciliary dyskinesia, with or without situs abnormalities, is a rare lung disease that can lead to an irreversible lung damage that may progress to respiratory failure. Lung transplant can be considered in end-stage disease. This study describes the outcomes of the largest lung transplant population for PCD and for PCD with situs abnormalities, also identified as Kartagener’s syndrome. Retrospectively collected data of 36 patients who underwent lung transplantation for PCD from 1995 to 2020 with or without SA as part of the European Society of Thoracic Surgeons Lung Transplantation Working Group on rare diseases. Primary outcomes of interest included survival and freedom from chronic lung allograft dysfunction. Secondary outcomes included primary graft dysfunction within 72 h and the rate of rejection ≥A2 within the first year. Among PCD recipients with and without SA, the mean overall and CLAD-free survival were 5.9 and 5.2 years with no significant differences between groups in terms of time to CLAD (HR: 0.92, 95% CI: 0.27–3.14, p = 0.894) or mortality (HR: 0.45, 95% CI: 0.14–1.43, p = 0.178). Postoperative rates of PGD were comparable between groups; rejection grades ≥A2 on first biopsy or within the first year was more common in patients with SA. This study provides a valuable insight on international practices of lung transplantation in patients with PCD. Lung transplantation is an acceptable treatment option in this population.

Long-term graft assessment in CARDS is essential to guide treatment and optimize resource use. Donor characteristics, including age, gender, and cause of death were comparable between groups and not associated with CLAD (Table 1). TABLE 1 Characteristics and outcomes of patients and multivariate cox proportional hazards regression analysis to predict CLAD. Variable No CARDS (n = 216) CARDS (n = 36) P Value Recipient factors Age, years 59.3 ± 12.4 52.4 ± 10.8 0.002 Female 88 (40.7%) 16 (44.4%) 0.72 Body Mass Index, kg/m2 25.8 ± 4.5 26.2 ± 4.6 0.56 Smoking history 116 (53.7%) 7 (19.4%) <0.001 Hypertension 112 (51.9%) 16 (44.4%) 0.47 Diabetes 64 (29.6%) 12 (33.3%) 0.70 Chronic Kidney Disease 12 (5.6%) 0 (0%) 0.23 Pre-operative ECMO use 9 (4.2%) 18 (50.0%) <0.001 Bilateral Transplantation 126 (58.3%) 34 (94.4%) <0.001 Lung Allocation Score 50.3 ± 15.8 77.9 ± 16.4 <0.001 Follow-Up Days 808 [538–1,327] 1,079 [935–1,208] 0.02 Laboratory Values Hemoglobin, g/dL 12.0 ± 2.4 9.1 ± 1.9 <0.001 BUN, mg/dL 16.0 ± 6.0 20.3 ± 12.8 0.001 Creatinine, mg/dL 0.80 ± 0.22 0.60 ± 0.21 <0.001 PRA 85 (39.4%) 18 (50.0%) 0.27 Donor-specific antibodies 20 (9.3%) 9 (25.0%) 0.007 Donor Age, years 32.6 ± 11.8 30.8 ± 12.5 0.41 Female 65 (30.1%) 14 (38.9%) 0.33 Donor cause of death Head trauma 84 (38.9%) 17 (47.2%) 0.36 Anoxia 81 (37.5%) 16 (44.5%) 0.46 Other 51 (23.6%) 3 (8.3%) 0.05 Intra-operative outcomes Operative time (hours) 5.8 (4.8–7.5) 8.2 (7.4–9.5) <0.001 Intra-op blood transfusion; pRBC 0 (0–2) 6 (2–11) <0.001 Ischemic time (hours) 4.9 (4.1–5.8) 5.6 (5.1–6.0) 0.001 VA ECMO use 123 (56.9%) 34 (94.4%) <0.001 VA ECMO time (hours) 1.7 (0–3.0) 3.1 (2.6–3.6) <0.001 Postoperative outcomes – Univariate Analysis PGD 82 (38.0%) 21 (58.3%) 0.03 PGD Grade 3 14 (6.5%) 7 (19.4%) 0.02 Acute rejection 58 (38.9%) 2 (6.1%) <0.001 post ECMO use 8 (3.7%) 13 (36.1%) <0.001 Acute Kidney Injury 79 (36.6%) 18 (50.0%) 0.14 PE 7 (3.2%) 0 (0%) 0.60 Dialysis 17 (7.9%) 8 (22.2%) 0.01 CMV infection 15 (10.1%) 6 (18.2%) 0.23 ICU stay (days) 7 (5–11) 16 (10–22) <0.001 Post-transplant ventilator (days) 2 (1–3) 4 (2–17) <0.001 Hospital stay (days) 15 (11–27) 23 (17–37) <0.001 Chronic Lung Allograft Dysfunction 46 (21.3%) 8 (22.2%) 1.00 BOS 36 (78.3%) 4 (50.0%) 0.18 RAS 6 (13.0%) 1 (12.5%) 1.00 Mixed 3 (6.5%) 3 (37.5%) 0.04 Undefined 1 (2.2%) 0 (0%) 1.00 Multivariable Analysis* HR P value 95% CI Recipient Factors Body Mass Index, kg/m2 1.07 0.03 1.01–1.14 Lung Allocation Score 0.99 0.18 0.97–1.01 Hemoglobin, g/dL 1.06 0.41 0.93–1.20 Continuous data are shown as means ± standard deviation (SD) for age and laboratory data, and as medians and interquartile ranges [Q1-Q3] for days. *Variables with biological plausibility and a p-value <0.10 on univariate analysis were included in multivariable analysis.

Background Telomere shortening has been associated with several lung diseases. However, telomere length is generally measured in peripheral blood leucocytes rather than in lung tissue, where disease occurs. Consequently, telomere dynamics have not been established for the normal human lung nor for diseased lung tissue. We hypothesized an age- and disease-dependent shortening of lung tissue telomeres. Methods At time of (re-)transplantation or autopsy, 70 explant lungs were collected: from unused donors (normal, n  = 13) and patients with cystic fibrosis (CF, n  = 12), chronic obstructive pulmonary disease (COPD, n  = 11), chronic hypersensitivity pneumonitis (cHP, n  = 9), bronchiolitis obliterans syndrome (BOS) after prior transplantation (n = 11) and restrictive allograft syndrome (RAS) after prior transplantation ( n  = 14). Lungs were inflated, frozen and then scanned using CT. Four tissue cores from distinct lung regions were sampled for analysis. Disease severity was evaluated using CT and micro CT imaging. DNA was extracted from the samples and average relative telomere length (RTL) was determined using real-time qPCR. Results The normal lungs showed a decrease in RTL with age ( p  < 0.0001). Of the diseased lungs, only BOS and RAS showed significant RTL decrease with increasing lung age ( p  = 0.0220 and p  = 0.0272 respectively). Furthermore, we found that RTL showed considerable variability between samples within both normal and diseased lungs. cHP, BOS and RAS lungs had significant shorter RTL in comparison with normal lungs, after adjustment for lung age, sex and BMI ( p  < 0.0001, p  = 0.0051 and p  = 0.0301 respectively). When investigating the relation between RTL and regional disease severity in CF, cHP and RAS, no association was found. Conclusion These results show a progressive decline in telomere length with age in normal, BOS and RAS lungs. cHP, BOS and RAS lungs demonstrated shorter RTL compared to normal lungs. Lung tissue RTL does not associate with regional disease severity within the lung. Therefore, tissue RTL does not seem to fully reflect peripheral blood telomere length.

Allograft failure remains a major barrier in the field of lung transplantation and results primarily from acute and chronic rejection. To date, standard-of-care immunosuppressive regimens have proven unsuccessful in achieving acceptable long-term graft and patient survival. Recent insights into the unique immunologic properties of lung allografts provide an opportunity to develop more effective immunosuppressive strategies. Here we describe advances in our understanding of the mechanisms driving lung allograft rejection and highlight recent progress in the development of novel, lung-specific strategies aimed at promoting long-term allograft survival, including tolerance.