The Lung Microbiome Predicts Mortality and Response to Azithromycin in Lung Transplant Recipients with Chronic Rejection.

Rationale: Chronic lung allograft dysfunction (CLAD) is the leading cause of death after lung transplant, and azithromycin has variable efficacy in CLAD. The lung microbiome is a risk factor for developing CLAD, but the relationship between lung dysbiosis, pulmonary inflammation, and allograft dysfunction remains poorly understood. Whether lung microbiota predict outcomes or modify treatment response after CLAD is unknown. Objectives: To determine whether lung microbiota predict post-CLAD outcomes and clinical response to azithromycin. Methods: Retrospective cohort study using acellular BAL fluid prospectively collected from recipients of lung transplant within 90 days of CLAD onset. Lung microbiota were characterized using 16S rRNA gene sequencing and droplet digital PCR. In two additional cohorts, causal relationships of dysbiosis and inflammation were evaluated by comparing lung microbiota with CLAD-associated cytokines and measuring ex vivo P. aeruginosa growth in sterilized BAL fluid. Measurements and Main Results: Patients with higher bacterial burden had shorter post-CLAD survival, independent of CLAD phenotype, azithromycin treatment, and relevant covariates. Azithromycin treatment improved survival in patients with high bacterial burden but had negligible impact on patients with low or moderate burden. Lung bacterial burden was positively associated with CLAD-associated cytokines, and ex vivo growth of P. aeruginosa was augmented in BAL fluid from transplant recipients with CLAD. Conclusions: In recipients of lung transplants with chronic rejection, increased lung bacterial burden is an independent risk factor for mortality and predicts clinical response to azithromycin. Lung bacterial dysbiosis is associated with alveolar inflammation and may be promoted by underlying lung allograft dysfunction.

Center variability in the prognostic value of a cumulative acute cellular rejection "A-score" for long-term lung transplant outcomes.

The acute rejection score (A-score) in lung transplant recipients, calculated as the average of acute cellular rejection A-grades across transbronchial biopsies, summarizes the cumulative burden of rejection over time. We assessed the association between A-score and transplant outcomes in 2 geographically distinct cohorts. The primary cohort included 772 double lung transplant recipients. The analysis was repeated in 300 patients from an independent comparison cohort. Time-dependent multivariable Cox models were constructed to evaluate the association between A-score and chronic lung allograft dysfunction or graft failure. Landmark analyses were performed with A-score calculated at 6 and 12 months posttransplant. In the primary cohort, no association was found between A-score and graft outcome. However, in the comparison cohort, time-dependent A-score was associated with chronic lung allograft dysfunction both as a time-dependent variable (hazard ratio, 1.51; P < .01) and when calculated at 6 months posttransplant (hazard ratio, 1.355; P = .031). The A-score can be a useful predictor of lung transplant outcomes in some settings but is not generalizable across all centers; its utility as a prognostication tool is therefore limited.

Exosomal-miRNas expression and growth factors released by mononuclear cells of CLAD patients in response to extracorporeal photopheresis.

BACKGROUND: CLAD (Chronic Lung Allograft Dysfunction) remains a serious complication following lung transplantation. Some evidence shows that portions of Extracorporeal Photopheresis (ECP)-treated patients improve/stabilize their graft function. In spite of that, data concerning molecular mechanisms are still lacking. Aims of our study were to assess whether ECP effects are mediated by Mononuclear Cells (MNCs) modulation in term of microRNAs (miRNAs) expression and growth factors release. METHODS: Cells from leukapheresis of 16 CLAD patients, at time 0 and 6-months (10 cycles), were cultured for 48h ± PHA (10 ug/ml) or LPS (2 ug/ml). Expression levels of miR-146a-5p, miR-155-5p, miR-31-5p, miR181a-5p, miR-142-3p, miR-16-5p and miR-23b-5p in MNCs-exosomes were evaluated by qRT-PCR, while ELISA assessed different growth factors levels on culture supernatants. RESULTS: Our result showed miR-142-3p down-regulation (p = 0.02) in MNCs of ECP-patients after the 10 cycles and after LPS stimulation (p = 0.005). We also find miR-146a-5p up-regulation in cells after the 10 cycles stimulated with LPS (p = 0.03). Connective tissue growth factor (CTGF) levels significantly decreased in MNCs supernatant (p = 0.04). The effect of ECP is translated into frequency changes of Dendritic Cell (DC) subpopulations and a slight increase in T regulatory cells (Treg) number and a significant decrease in CTGF release. CONCLUSIONS: ECP might affect regulatory T cell functions, since both miR-142 and miR-146a have been shown to be involved in the regulation of suppressor regulatory T cell functions and DCs. On the other side ECP, possibly by regulating macrophage activation, is able to significantly down modulate CTGF release.

Pseudomonas aeruginosa infection correlates with high MFI donor-specific antibody development following lung transplantation with consequential graft loss and shortened CLAD-free survival.

BACKGROUND: Donor-specific antibodies (DSAs) are common following lung transplantation (LuTx), yet their role in graft damage is inconclusive. Mean fluorescent intensity (MFI) is the main read-out of DSA diagnostics; however its value is often disregarded when analyzing unwanted post-transplant outcomes such as graft loss or chronic lung allograft dysfunction (CLAD). Here we aim to evaluate an MFI stratification method in these outcomes. METHODS: A cohort of 87 LuTx recipients has been analyzed, in which a cutoff of 8000 MFI has been determined for high MFI based on clinically relevant data. Accordingly, recipients were divided into DSA-negative, DSA-low and DSA-high subgroups. Both graft survival and CLAD-free survival were evaluated. Among factors that may contribute to DSA development we analyzed Pseudomonas aeruginosa (P. aeruginosa) infection in bronchoalveolar lavage (BAL) specimens. RESULTS: High MFI DSAs contributed to clinical antibody-mediated rejection (AMR) and were associated with significantly worse graft (HR: 5.77, p < 0.0001) and CLAD-free survival (HR: 6.47, p = 0.019) compared to low or negative MFI DSA levels. Analysis of BAL specimens revealed a strong correlation between DSA status, P. aeruginosa infection and BAL neutrophilia. DSA-high status and clinical AMR were both independent prognosticators for decreased graft and CLAD-free survival in our multivariate Cox-regression models, whereas BAL neutrophilia was associated with worse graft survival. CONCLUSIONS: P. aeruginosa infection rates are elevated in recipients with a strong DSA response. Our results indicate that the simultaneous interpretation of MFI values and BAL neutrophilia is a feasible approach for risk evaluation and may help clinicians when to initiate DSA desensitization therapy, as early intervention could improve prognosis.

Late-Onset Exudative Pleural Effusions Without Concomitant Airway Obstruction or Lung Parenchymal Abnormalities: A Novel Presentation of Chronic Lung Allograft Dysfunction.

Restrictive allograft syndrome (RAS) is an aggressive variant of CLAD characterized by progressive restrictive ventilatory decline and persistent pleuro-parenchymal changes that can be seen on chest CT. We identified four lung transplant recipients with a progressive restrictive ventilatory defect due to lymphocyte-predominant exudative pleural effusions, but no pleuro-parenchymal abnormalities typical of RAS. Using molecular analysis, we also found increased levels of previously described immune markers of RAS, including NFkB, 20S proteasome, lipocalin, TNFα, and TGFß, within the circulating small extracellular vesicles of the remaining living lung transplant recipient. Despite the absence of lung parenchymal changes, these patients had a poor prognosis with rapid deterioration in allograft function and no response to pleural-based interventions such as thoracentesis, decortication, and pleurodesis. We hypothesize that these cases represent a distinct CLAD phenotype characterized by progressive restriction due to pleural inflammation, lymphocyte-predominant pleural effusion, resultant compressive atelectasis, and eventual respiratory failure in the absence of lung parenchymal involvement.

Lung Re-transplantation after prolonged veno-venous extracorporeal membrane oxygenation (ECMO) in a child with chronic lung allograft dysfunction.

BACKGROUND: Extracorporeal Membrane Oxygenation (ECMO) may be used as a bridge to lung transplantation in selected patients with end-stage respiratory failure. Historically, ECMO use in this setting has been associated with poor outcomes Puri V et.al, J Thorac Cardiovasc Surg, 140:427. More recently, technical advances and the implementation of rehabilitation and ambulation while awaiting transplantation on ECMO have led to improved surgical and post-transplant outcomes Kirkby S et.al, J Thorac Dis, 6:1024. METHODS: We illustrate the case of a 6-year-old child who received prolonged ECMO support as a bridge to lung re-transplantation secondary to Chronic Lung Allograft Dysfunction (CLAD). RESULTS: Early rehabilitation was key in improving the overall pre-transplant conditioning during ECMO. CONCLUSIONS: Despite challenges associated with awake/ambulatory ECMO, the use of this strategy as a bridge to lung transplantation is feasible and has resulted in improved pre-transplant conditioning and post-transplant outcomes.

Immunological Landscapes in Lung Transplantation: Insights from T Cell Profiling in BAL and PBMC.

Lung transplant recipients frequently encounter immune-related complications, including chronic lung allograft dysfunction (CLAD). Monitoring immune cells within the lung microenvironment is pivotal for optimizing post-transplant outcomes. This study examined the proportion of T cell subsets in paired bronchoalveolar lavage (BAL) and peripheral PBMC comparing healthy (n = 4) and lung transplantation patients (n = 6, no CLAD and n = 14 CLAD) using 14-color flow cytometry. CD4+ T cell proportions were reduced in CD3 cells in both PBMC and BAL, and positive correlations were discerned between T cell populations in peripheral PBMC and BAL, suggesting the prospect of employing less invasive PBMC sampling as a means of monitoring lung T cells. Furthermore, regulatory T cells (Tregs) were enriched in BAL when compared to peripheral PBMC for transplant recipients. A parallel positive correlation emerged between Treg proportions in BAL and peripheral PBMC, underscoring potential avenues for monitoring lung Tregs. Finally, the most promising biomarker was the Teff (CD8+Granzyme B+)-Treg ratio, which was higher in both the PBMC and BAL of transplant recipients compared to healthy individuals, and increased in the patients with CLAD compared to no CLAD and healthy patients. Conclusions: Distinct T cell profiles in BAL and peripheral PBMC underscore the significance of localized immune monitoring in lung transplantation. The Teff (CD8+granzyme B+)-Treg ratio, particularly within the context of CLAD, emerges as a promising blood and BAL biomarker reflective of inflammation and transplant-related complications. These findings emphasize the imperative need for personalized immune monitoring strategies that tailored to address the unique immunological milieu in post-transplant lungs.

Defining a natural killer cell-enriched molecular rejection-like state in lung transplant transbronchial biopsies.

In lung transplantation, antibody-mediated rejection (AMR) diagnosed using the International Society for Heart and Lung Transplantation criteria is uncommon compared with other organs, and previous studies failed to find molecular AMR (ABMR) in lung biopsies. However, understanding of ABMR has changed with the recognition that ABMR in kidney transplants is often donor-specific antibody (DSA)-negative and associated with natural killer (NK) cell transcripts. We therefore searched for a similar molecular ABMR-like state in transbronchial biopsies using gene expression microarray results from the INTERLUNG study (#NCT02812290). After optimizing rejection-selective transcript sets in a training set (N = 488), the resulting algorithms separated an NK cell-enriched molecular rejection-like state (NKRL) from T cell-mediated rejection (TCMR)/Mixed in a test set (N = 488). Applying this approach to all 896 transbronchial biopsies distinguished 3 groups: no rejection, TCMR/Mixed, and NKRL. Like TCMR/Mixed, NKRL had increased expression of all-rejection transcripts, but NKRL had increased expression of NK cell transcripts, whereas TCMR/Mixed had increased effector T cell and activated macrophage transcripts. NKRL was usually DSA-negative and not recognized as AMR clinically. TCMR/Mixed was associated with chronic lung allograft dysfunction, reduced one-second forced expiratory volume at the time of biopsy, and short-term graft failure, but NKRL was not. Thus, some lung transplants manifest a molecular state similar to DSA-negative ABMR in kidney and heart transplants, but its clinical significance must be established.

Risk of Bronchial Complications After Lung Transplantation With Respiratory Corynebacteria. Results From a Monocenter Retrospective Cohort Study.

Corynebacterium spp. are associated with respiratory infections in immunocompromised hosts. A link with bronchial complications after lung transplantation (LTx) has been suggested. We aimed to assess the link between respiratory sampling of Corynebacterium spp. and significant bronchial complication (SBC) after LTx. We performed a single center retrospective study. Inclusion of LTx recipients with at least one respiratory Corynebacterium spp. sample (July 2014 to December 2018). Subjects were matched to unexposed LTx recipients. Primary outcome was SBC occurrence after Corynebacterium spp. isolation. Secondary outcomes were Corynebacterium spp. persistent sampling, chronic lung allograft dysfunction (CLAD) onset and all-cause mortality. Fifty-nine patients with Corynebacterium spp. sampling with 59 without isolation were included. Corynebacterium spp. identification was not associated with SBC occurrence (32.4% vs. 21.6%, p = 0.342). Previous SBC was associated with further isolation of Corynebacterium spp. (OR 3.94, 95% CI [1.72-9.05]). Previous SBC and corticosteroids pulses in the last 3 months were the only factors associated with increased risk of Corynebacterium spp. isolation in multivariate analysis. Corynebacterium spp. sampling was significantly associated with CLAD onset (27.1% vs. 6.9%, p = 0.021). Corynebacterium spp. isolation was not associated with SBC but with higher risk of CLAD. Whether CLAD evolution is affected by Corynebacterium spp. eradication remains to be investigated.

A European Multi-Center Analysis of Extracorporeal Photopheresis as Therapy for Chronic Lung Allograft Dysfunction.

Extracorporeal photopheresis (ECP) is used by few lung transplant centers to treat chronic lung allograft dysfunction (CLAD). Although reported results suggest a beneficial effect on CLAD progression, evidence is limited to single center experiences. The aim of this study is to analyze outcomes of ECP in a large multicenter European cohort. The primary endpoint was patient survival after initiation of ECP. This study included 631 patients, 87% suffered from bronchiolitis obliterans syndrome (BOS), and 13% had restrictive allograft syndrome (RAS). Long-term stabilization was achieved in 42%, improvement in 9%, and no response in 26%. Within the first 12 months of therapy, 23% of patients died. Patients' survival after initiation of ECP at 5 years was 56% in stable, 70% in responders, and 35% in non-responders (p = 0.001). In multivariable Cox regression, both stabilization (HR: 0.48, CI: 0.27-0.86, p = 0.013) and response (HR: 0.11, CI: 0.04-0.35, p < 0.001) to ECP were associated with survival. Absolute FEV1 at baseline was also protective (HR: 0.09, CI: 0.01-0.94, p = 0.046). RAS phenotype was the only risk factor for mortality (HR: 2.11, 1.16-3.83, p = 0.006). This study provides long-term outcomes of ECP use in CLAD patients in the largest published cohort to date. Two-thirds of the cohort had a sustained response to ECP with excellent long-term results.

Surgical therapy of chronic lung allograft dysfunction.

Lung transplantation has become a standardized and widely accepted treatment modality for selected end-stage lung diseases. Many factors influ- ence the long-term survival of patients after lung transplantation. One of the most important is clearly the development of chronic lung allograft dysfunction (CLAD). This review summarizes current knowledge of the histopathology of CLAD and its clinical characteristics. It also describes lung re-transplantation as the only causal therapy, its possible complications, and outcomes in standard and high-urgency patients awaiting a suitable organ with extracorporeal membrane oxygenation support. Fundoplication is an important surgical modality potentially leading to an improvement of the patients' condition. The indications and outcomes of this surgical procedure are discussed in a separate chapter. In addition, several nonsurgical treatment options aimed at slowing the progression of CLAD are outlined, as well as ongoing research focused on extending the life of these patients.

Characteristics and outcomes among vaccinated lung transplant patients with breakthrough COVID-19.

BACKGROUND: Despite multiple studies evaluating the immunological responsiveness to vaccines, the clinical effectiveness of the two-dose mRNA vaccine schedule among lung transplant (LT) patients has not been evaluated. METHODS: We included LT patients who tested positive for SARS-CoV-2 on a nasopharyngeal swab between March 1, 2020, and August 25, 2021 (n = 70). The study group was divided based on their vaccination status. RESULTS: During the study period, 14 fully vaccinated LT patients with one of the mRNA vaccines tested positive for COVID-19 (median age 54, range 30-62 years, M:F 9:5). The vaccinated cohort was younger with bilateral LT, have suppurative conditions as the transplant indication, and present with milder symptoms. However, pulmonary parenchymal involvement was seen among all 12 patients where computed tomography (CT) of chest was available. The laboratory profile indicated a more subdued inflammatory response among the vaccinated group. A lower proportion of vaccinated patients developed respiratory failure, needed ICU admission or ventilator support, although none of the differences achieved statistical significance. None of the vaccinated patients succumbed to COVID-19 during the study period, while the 4-week mortality among unvaccinated patients was nearly 15% (8/56). CONCLUSIONS: In this cohort of vaccinated LT patients who developed breakthrough COVID-19, the clinical course, risk of complications, and outcomes trended better than unvaccinated patients. However, universal involvement of the allograft demonstrates the continued vulnerability of these patients to significant sequelae from COVID-19. Future studies may evaluate the incremental protection of vaccination after the completion of the third dose of mRNA vaccines among LT patients.

Auto-inflammation and auto-immunity pathways are associated with emergence of BOS in pediatric lung transplantation.

BACKGROUND: Long-term survival after lung transplantation (LTx) is limited by chronic lung allograft dysfunction (CLAD). METHODS: We report an analysis of cytokine profiles in bronchoalveolar lavage samples collected during a prospective multicenter non-interventional trial primarily designed to determine the impact of community-acquired respiratory viral infections (CARV) in outcomes after pediatric LTx. In this analysis, we identify potential biomarkers of auto-inflammation and auto-immunity associated with survival and risk of bronchiolitis obliterans (BOS) after LTx with cytokine analysis of bronchoalveolar lavage fluid (BALF) from 61 pediatric recipients. RESULTS: Higher IL-23 (p = .048) and IL-31 (p = .035) levels were associated with the risk of BOS, and lower levels of epithelial growth factor (EGF) (p = .041) and eotaxin (EOX) (p = .017) were associated with BOS. Analysis using conditional inference trees to evaluate cytokines at each visit associated with survival identified soluble CD30 (p < .001), pro-inflammatory cytokine IL-23 (p = .02), and sTNFRI (p = .01) below cutoff levels as associated with BOS-free survival. CONCLUSIONS: Our results indicate that post-LTx survival in children may be linked to activation of alternate pathways of the immune system that affect airway remodeling in addition to activation of "classical" pathways that have been described in adult LTx recipients. These may indicate pathways to target for intervention.

Immunosuppression in Lung Transplantation.

Immunosuppression in lung transplantation is an area devoid of robust clinical data. This chapter will review the history of immunosuppression in lung transplantation. Additionally, it will evaluate the three classes of induction, maintenance, and rescue immunosuppression in detail. Induction immunosuppression in lung transplantation aims to decrease incidence of lung allograft rejection, however infectious risk must be considered when determining if induction is appropriate and which agent is most favorable. Similar to other solid organ transplant patient populations, a multi-drug approach is commonly prescribed for maintenance immunosuppression to minimize single agent drug toxicities. Emphasis of this review is placed on key medication considerations including dosing, adverse effects, and drug interactions. Clinical considerations will be reviewed per drug class given available literature. Finally, acute cellular, antibody mediated, and chronic rejection are reviewed.

Activation of Humoral Immunity during the Pathogenesis of Experimental Chronic Lung Allograft Dysfunction.

Alloreactive and autoreactive antibodies have been associated with the development of chronic lung allograft dysfunction (CLAD), but their pathogenic role is disputed. Orthotopic left lung transplantation was performed in the Fischer-344 to Lewis rat strain combination followed by the application of ciclosporine for 10 days. Four weeks after transplantation, lipopolysaccharide (LPS) was instilled into the trachea. Lungs were harvested before (postoperative day 28) and after LPS application (postoperative days 29, 33, 40, and 90) for histopathological, immunohistochemical, and Western blot analyses. Recipient serum was collected to investigate circulating antibodies. Lung allografts were more strongly infiltrated by B cells and deposits of immunoglobulin G and M were more prominent in allografts compared to right native lungs or isografts and increased in response to LPS instillation. LPS induced the secretion of autoreactive antibodies into the circulation of allograft and isograft recipients, while alloreactive antibodies were only rarely detected. Infiltration of B cells and accumulation of immunoglobulin, which is observed in allografts treated with LPS but not isografts or native lungs, might contribute to the pathogenesis of experimental CLAD. However, the LPS-induced appearance of circulating autoreactive antibodies does not seem to be related to CLAD, because it is observed in both, isograft and allograft recipients.

Post-infection pulmonary sequelae after COVID-19 among patients with lung transplantation.

BACKGROUND: There is limited data on outcomes among lung transplant (LT) patients who survive Coronavirus disease 2019 (COVID-19). METHODS: Any single or bilateral LT patients who tested positive for SARS-CoV-2 between March 1, 2020, to February 15, 2021 (n = 54) and survived the acute illness were included (final n = 44). Each patient completed at least 3 months of follow-up (median: 4.5; range 3-12 months) after their index hospitalization for COVID-19. The primary endpoint was a significant loss of lung functions (defined as > 10% decline in forced vital capacity (FVC) or forced expiratory volume in 1 s (FEV1 ) on two spirometries, at least 3 weeks apart compared to the pre-infection baseline). RESULTS: A majority of the COVID-19 survivors had persistent parenchymal opacities (n = 29, 65.9%) on post-infection CT chest. Patients had significantly impaired functional status, with the majority reporting residual disabilities (Karnofsky performance scale score of 70% or worse; n = 32, 72.7%). A significant loss of lung function was observed among 18 patients (40.9%). Three patients met the criteria for new chronic lung allograft dysfunction (CLAD) following COVID-19 (5.6%), with all three demonstrating restrictive allograft syndrome phenotype. An absolute lymphocyte count < 0.6 × 103 /dl and ferritin > 150 ng/ml at the time of hospital discharge was independently associated with significant lung function loss. CONCLUSIONS: A significant proportion of COVID-19 survivors suffer persistent allograft injury. Low absolute lymphocyte counts (ALC) and elevated ferritin levels at the conclusion of the hospital course may provide useful prognostic information and form the basis of a customized strategy for ongoing monitoring and management of allograft dysfunction. TWEET: Twitter handle: @AmitBangaMD Lung transplant patients who survive COVID-19 suffer significant morbidity with persistent pulmonary opacities, loss of lung functions, and functional deficits. Residual elevation of the inflammatory markers is predictive.

Effect of Powder Particle Size and Spray Parameters on the Ni/Al Reaction During Plasma Spraying of Ni-Al Composite Powders.

It was known for long that Ni-Al composite powders can be used to deposit self-bonding coating as a bond coat for common ceramic coatings due to the exothermic reaction between Ni and Al. However, it was found that with commercial Ni-Al composite powders with a large particle size, it is difficult to ignite the self-propagating reaction between Ni and Al to form Ni-Al intermetallics by plasma spraying. In this study, Ni-Al composite powder particles of different sizes were used to prepare Ni-Al intermetallics-based coatings by plasma spraying. The dependencies of the exothermic reaction between Ni and Al and the coating microstructure on powder particle size and spray parameters were investigated. The phase composition, microstructure, porosity and oxide content of the coatings were characterized by x-ray diffraction, scanning electron microscope and image analyzing. The results show that particle size of Ni-Al composite powders is the dominant factor controlling the exothermic reaction for the formation of Ni-Al intermetallics during plasma spraying. When the powders larger than about 50 µm are used, the reaction forming aluminide cannot complete even by heating of plasma flame generated at high plasma arc power. However, when smaller powders less than 50 µm are used, the exothermic reaction can completely occur rapidly in plasma spraying, contributing to heating of Ni-Al droplets to the highest temperature for development of the self-bonding effect. The positive relationship between molten droplet temperature and tensile adhesive strength of the resultant coatings is recognized to confirm the contribution of high droplet temperature to the adhesive or cohesive strength.

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.

The fraction of sensitization among lung transplant recipients in a transplant center in Japan.

BACKGROUND: Anti-human leukocyte antigen (HLA) antibody testing was approved by the Japanese government in 2018. As such, there was no longitudinal data regarding the HLA-sensitization of lung transplant (LTX) patients in Japan. We therefore set out to measure anti-HLA antibodies from all our LTX patients during their annual follow-up to characterize the sensitization status in the Japanese population. METHODS: The cross-sectional study was conducted for consecutive LTX recipients who underwent transplantation from January 2000 to January 2020 at Tohoku University Hospital (TUH). The serum from the recipients was screened for anti-HLA antibody with the panel-reactive assay (PRA) and the donor-specific antibodies (DSA). RESULTS: Sensitization was reviewed in 93 LTX recipients, showing 23 positive (24.7%) and 70 negative (75.3%) PRA. More sensitized recipients were found in recent transplantations (60.9% (14/23), ≤5 years post LTX) than in older transplantations (17.4% (4/23), 5-10 years or 21.7% (5/23), ≥10 years post LTX) (p = 0.04). Even fewer recipients had DSA (5.4%, 5/93), among whom 4/5 (80%) were recently transplanted. CONCLUSION: The rate of PRA positive LTX recipients in our population was lower compared with those in previous reports from US and Europe. More sensitized LTRs were found in recent transplantations than the older cohort, and DSA was identified primarily in the recent recipients. Due to several limitations, it is still unclear whether the sensitization would be related the development of CLAD or survival, yet this study would be fundamental to the future anti-HLA body study in Japanese population.