Lung Allograft Research Articles

Transition from Transbronchial Forceps to Cryobiopsy After Lung Transplantation: A Single-Centre Experience

The gold standard for histological acute cellular rejection diagnosis is transbronchial forceps biopsy (FB), but in recent years, transbronchial cryobiopsy (CB) has been increasingly used. This study aims to compare the diagnostic rate and safety of FBs and CBs performed in two different periods. We retrospectively reviewed our case history for the two biopsy procedures: 251 FBs (223 for surveillance purposes and 28 for clinical indication) and 218 consecutive CBs (159 for surveillance purposes and 59 for clinical indication). All biopsies were scored according to the ISHLT criteria. Diagnostic yield was higher in the CB group for all the parameters considered: a grade of acute rejection (AR) was detected in 95.0% vs. 84.5% in the CB vs. FB groups (p < 0.001). The diagnostic rate of airway inflammation was 65.1% vs. 51.8% (p = 0.005), and 89.0% vs. 64.9% (p < 0.001) for chronic rejection. Pneumothorax requiring chest drainage occurred in 4% of the CB group and 3% of the FB group. Moderate and severe bleeding complicated CB and FB procedures in seven (3%) and three cases (1%), respectively. Transbronchial cryobiopsies improved the diagnostic yield in the monitoring of the lung allograft. The complication rate did not increase significantly in CBs vs. FBs.

Diagnostic value and safety of transbronchial cryobiopsy in postoperative complications after lung transplantation

Objective: To compare the diagnostic rate and safety of postoperative complications between transbronchial cryobiopsy (TBCB) and transbronchial lung biopsy (TBLB) in patients with lung transplantation. Methods: A retrospective analysis of patients who underwent TBCB or TBLB in the Department of Lung Transplantation in China-Japan Friendship Hospital from June 2017 to June 2024 was conducted to determine the postoperative complications and analyze clinical characteristics, procedures, diagnostic rates and safety. Results: Thirty-five and 153 patients with lung transplantation received TBCB and TBLB, respectively. Patients who received TBCB had lower preoperative oxygenation index (t'=2.4, P<0.01). Meanwhile, the pathological diagnosis rate (85.7% vs. 45.7%, χ²=18.27, P<0.01) and clinical diagnosis rate (94.2% vs. 69.9%, χ²=8.80, P<0.01) of patients who received TBCB were significantly higher than those who received TBLB. There was no significant difference in the incidence of severe bleeding (2.9% vs. 0.7%, χ²=1.3, P=0.86) and pneumothorax (0 vs. 3.9%, χ²=0.43, P=0.24) between patients receiving TBCB and TBLB. The most common complications after lung transplantation in the group of TBCB were chronic lung allograft dysfunction (45.4%, 15/33), antibody mediated rejection (18.2%, 6/33) and organizing pneumonia (12.2%, 4/33). While antibody mediated rejection (29.9%, 32/107), chronic lung allograft dysfunction (16.8%, 18/107), and pneumonia (16.8%, 18/107) were more frequent in the patients who received TBLB. Conclusions: TBCB has a high diagnostic value for postoperative complications after lung transplantation, with an acceptable complication rate of bleeding and pneumothorax.

Efficacy of a Standardized Regimen of Therapeutic Plasma Exchange and IVIG for Treatment of Antibody-Mediated Rejection in Lung Transplant Recipients.

Antibody-mediated rejection (AMR) in lung transplantation has been associated with poor long-term clinical course and is a risk factor for chronic lung allograft dysfunction and graft loss. Appropriate management of AMR is necessary to improve graft survival in lung transplant recipients. There is currently no standardized approach to the treatment of lung AMR, and practices vary by institution. We sought to examine the efficacy of a standardized protocol of plasma exchange (PLEX) and IVIG in decreasing donor-specific antibodies (DSAs) and improving AMR in lung transplant recipients. A retrospective chart review was conducted on all lung transplant recipients who completed a course of PLEX per UT Southwestern AMR protocol between January 2012 and December 2019 for diagnosis of AMR. Data were collected on the patient clinical course, treatment regimen, pre-PLEX DSA, post-PLEX DSA, follow-up (> 1-month post-PLEX) DSA, and pre-and post-PLEX biopsy, when available. Of 527 patients who underwent lung transplantation during the study period, 56 (11%) received an acute course of PLEX every other day per protocol for AMR of lung transplant. Forty (71%) of 56 patients had one episode of AMR requiring PLEX; 16 patients (29%) had repeat episodes of AMR within 6 weeks to 47 months of the first episode. Most patients showed improvement in AMR on biopsy (69%) and a decline in DSA (68%). Our data suggest that treatment with combined PLEX and IVIG protocol appears effective for treating lung AMR.

Time to Rethink Bronchiolitis Obliterans Syndrome Following Lung or Hematopoietic Cell Transplantation in Pediatric Patients.

Background: Similar in histological characteristics and clinical manifestations, bronchiolitis obliterans syndrome (BOS) can develop following lung transplantation (LTx) or hematopoietic cell transplantation (HCT). In contrast to lung transplantation, where BOS is restricted to the lung allograft, HCT-related systemic graft-versus-host disease (GVHD) is the root cause of BOS. Because lung function declines following HCT, diagnosis becomes more difficult. Given the lack of proven effective medicines, treatment is based on empirical evidence. Methods: Cross-disciplinary learning is crucial, and novel therapies are under investigation to improve survival and avoid LTx. Recent advances have focused on updating the understanding of the etiology, clinical features, and pathobiology of BOS. It emphasizes the significance of learning from experts in other transplant modalities, promoting cross-disciplinary knowledge. Results: Our treatment algorithms are derived from extensive research and expert clinical input. It is important to ensure that immunosuppression is optimized and that any other conditions or contributing factors are addressed, if possible. Clear treatment algorithms are provided for each condition, drawing from the published literature and consensus clinical opinion. There are several novel therapies currently being investigated, such as aerosolized liposomal cyclosporine, Janus kinase inhibitors, antifibrotic therapies, and B-cell-directed therapies. Conclusions: We urgently need innovative treatments that can greatly increase survival rates and eliminate the need for LTx or re-transplantation.

Utilization of the Liver-First Approach in Combined Lung-Liver Transplant Provides Comparable Outcomes to the Traditional Lung-First Approach: A UNOS Study.

Multiorgan transplantation is offered to a selected group of patients every year. The sequence in which organs are transplanted depends on ischemic time graft tolerance and thesickest organ first strategy. In the case of Lung-Liver transplantation, lung allografts are usually implanted before the liver. There are some theoretical advantages to a liver-first strategy and a few centers have reported aseries of cases that spark a growing interest in the feasibility and potential benefits of this approach. In this contemporary study of the United Network for Organ Sharing (UNOS) database, we evaluate and report outcomes using either strategy.

Lung Allograft Dysbiosis Associates with Immune Response and Primary Graft Dysfunction.

Lung Allograft Dysbiosis Associates with Immune Response and Primary Graft Dysfunction.

Postoperative conditions of rehabilitative interest in lung transplantation: a systematic review.

Lung transplantation is an elective treatment option for end-stage respiratory diseases in which all medical therapy options have been exhausted. The current study aimed to identify updated information on the postoperative conditions that may impair rehabilitation after lung transplantation and to provide specific considerations of their clinical relevance during the recovery process. The present study is a systematic review conducted by searching three primary databases: the United States National Library of Medicine PubMed system, Scopus, and the Cochrane Library. The databases were searched for articles published from database inception until May 2024; at the end of the selection process, 27 documents were included in the final analysis. The retrieved material identified 19 conditions of rehabilitative interest that potentially affect the postoperative course: graft dysfunction, dysphagia, postsurgical pain, cognitive impairment, chronic lung allograft dysfunction-bronchiolitis obliterans syndrome, phrenic nerve injury, delayed extracorporeal membrane oxygenation weaning, airway clearance, refractory hypoxemia, mediastinitis, reduced oxidative capacity, sternal dehiscence, coronavirus disease 2019 (COVID-19), gastroparesis, ossification of the elbow, Takotsubo cardiomyopathy, airway dehiscence, recurrent pleural effusion, and scapular prolapse. Although some patients are not amenable to rehabilitation techniques, others can significantly improve with rehabilitation.

Prognosis and Risks for Probable Chronic Lung Allograft Dysfunction: A Prospective Multicenter Study.

Chronic lung allograft dysfunction (CLAD) hinders lung transplant success. A 2019 consensus refined CLAD diagnosis, introducing probable or definite CLAD based on persistence of lung function decline. Outcomes and risks for probable CLAD remain uncertain. Determine the prognosis and clinical risks for probable CLAD in a prospective multicenter cohort. Clinical Trials in Organ Transplantation-20 included 745 CLAD-eligible adult lung recipients at 5 centers and applied rigorous methods to prospectively adjudicate probable CLAD. The impact of probable CLAD on graft loss was determined using a Cox model that considered CLAD as a time-dependent covariate. Regularized Cox modeling with LASSO penalty was used to evaluate donor or recipient characteristics and the occurrence and timing of posttransplant events as probable CLAD risks. Similar analyses were performed for definite CLAD. Probable CLAD occurred in 29.7% of patients at 3 years posttransplant and conferred a marked increase in risk for graft loss (unadjusted HR 4.38, p<0.001). Most patients (80%) with probable CLAD progressed to definite CLAD. Cytomegalovirus infection and specifically late presence (>90 days posttransplant) of donor-specific alloantibodies, acute rejection, acute lung injury, or organizing pneumonia contributed the greatest independent information about probable CLAD risk. Definite CLAD risks were similar. Probable CLAD identifies patients at high risk for graft loss, supporting prospective identification of this condition for early initiation of CLAD-directed interventions. More effective strategies to prevent posttransplant cytomegalovirus, inhibit allospecific immunity, and reduce tissue injury are needed to reduce probable CLAD and improve lung recipient survival.

Impact of Long-Term Atorvastatin Therapy on the Development of Chronic Lung Allograft Dysfunction in Patients with Azithromycin Prophylaxis after Lung Transplantation

ObjectiveTo assess the impact of long-term atorvastatin (ATO) therapy on reducing recipient inflammation and immune response, thus lowering the risk of chronic lung allograft dysfunction (CLAD) in lung transplant recipients. This study aimed to investigate the effects of ATO on overall survival, lung function recovery, and its influence on inflammatory factors alongside azithromycin (AZI) prophylaxis. MethodsThis retrospective single-center study included lung transplant recipients from January 2017 to December 2022. Patients who survival >1 year after lung transplantation and who were receiving AZI prophylaxis for >6 months were selected. Outcome measures involved pulmonary function assessments at various time points after AZI treatment, complete blood cell analysis, and inflammatory factor evaluations. ResultsThe incidence of CLAD was significantly lower in the long-term ATO group compared with those not on ATO (P = .011). Long-term ATO treatment significantly delayed CLAD onset after lung transplantation (850 days vs. 630 days; P = .041), with patients showing notably enhanced lung function recovery within 6 months of AZI therapy compared with the non-ATO group. Neutrophil levels decreased in patients with CLAD, and interleukin-6 concentrations significantly decreased in the AZI + ATO group compared with the AZI group. Overall patient survival was significantly better in the AZI+ATO group than in the AZI group (P = .02). ConclusionIn cases where CLAD develops despite AZI prophylaxis, long-term ATO treatment may lead to short-term improvements in lung function. It could also decrease inflammation levels in lung transplant recipients and enhance overall survival. The combination of AZI and long-term ATO therapy may be beneficial for CLAD prevention.

Remote kidney and liver injury after transplantation of lung allografts in an allogeneic mouse model

Background: Remote organ dysfunction is common after lung transplantation and might negatively affect outcome. The local anesthetic ropivacaine was previously demonstrated to attenuate acute rejection after allogeneic lung transplantation in mice. We hypothesized that lung transplantation might result in detectable molecular signs of injury in kidneys and liver and that ropivacaine might attenuate this damage. Methods: Organs from C57BL/6 mice undergoing allogeneic orthotopic single-lung transplantation were procured at postoperative day five and analyzed using western blot and real-time quantitative polymerase chain reaction probing for Src protein tyrosine kinase, STAT3 and bax/bcl-2. During cold ischemia, the allograft had either been flushed with normal saline only or in combination with ropivacaine (1 µM). A non-transplanted group of animals served as baseline controls. Results: The allogeneic stimulus induced by transplantation lead to an increase in Src-phosphorylation and STAT3-expression in kidneys and livers of lung-transplanted mice compared to non-transplanted animals. Bax/bcl-2 as a marker of cellular apoptosis was not affected by the transplantation. In contrast to the findings in the transplanted lungs, the addition of ropivacaine did not have an effect on the examined markers of inflammation in the remote organs. Conclusions: The observed increase in the inflammatory signaling provides first insight into a possible mechanism, by which remote organ dysfunction after lung transplantation might occur.

Resolution of Acute Lung Allograft Rejection Detected by Probe-based Confocal Laser Endomicroscopy.

Resolution of Acute Lung Allograft Rejection Detected by Probe-based Confocal Laser Endomicroscopy.

Deep learning-based approach for acquisition time reduction in ventilation SPECT in patients after lung transplantation.

We aimed to evaluate the image quality and diagnostic performance of chronic lung allograft dysfunction (CLAD) with lung ventilation single-photon emission computed tomography (SPECT) images acquired briefly using a convolutional neural network (CNN) in patients after lung transplantation and to explore the feasibility of short acquisition times. We retrospectively identified 93 consecutive lung-transplant recipients who underwent ventilation SPECT/computed tomography (CT). We employed a CNN to distinguish the images acquired in full time from those acquired in a short time. The image quality was evaluated using the structural similarity index (SSIM) loss and normalized mean square error (NMSE). The correlation between functional volume/morphological volume (F/M) ratios of full-time SPECT images and predicted SPECT images was evaluated. Differences in the F/M ratio were evaluated using Bland-Altman plots, and the diagnostic performance was compared using the area under the curve (AUC). The learning curve, obtained using MSE, converged within 100 epochs. The NMSE was significantly lower (P < 0.001) and the SSIM was significantly higher (P < 0.001) for the CNN-predicted SPECT images compared to the short-time SPECT images. The F/M ratio of full-time SPECT images and predicted SPECT images showed a significant correlation (r = 0.955, P < 0.0001). The Bland-Altman plot revealed a bias of -7.90% in the F/M ratio. The AUC values were 0.942 for full-time SPECT images, 0.934 for predicted SPECT images and 0.872 for short-time SPECT images. Our findings suggest that a deep-learning-based approach can significantly curtail the acquisition time of ventilation SPECT, while preserving the image quality and diagnostic accuracy for CLAD.

Successful prevention of BK-polyomavirus nephropathy using extracorporeal photopheresis for immunosuppression minimisation following severe BK polyomavirus replication after kidney transplantation in a double lung transplant recipient, a case report

BackgroundBK-polyomavirus (BKpyV) nephropathy (BKVN) is associated with end-stage kidney disease in kidney and non-kidney solid organ transplantation, with no curative treatment.Case presentationA 45-year-old woman with a past medical history of double lung transplantation subsequently developed end-stage kidney disease, of undetermined origin. One month after receiving a kidney transplant, a diagnosis of early BKVN was suspected, and in retrospect was a reasonable cause for the loss of her native kidneys. Minimisation of immunosuppression, achieved through extracorporeal photopheresis, allowed clearance of BKpyV and so prevented nephropathy. Both lung and kidney grafts had a satisfactory and stable function after one year of follow-up, with no rejection.ConclusionsExtracorporeal photopheresis may have facilitated minimisation of immunosuppression and BKpyV clearance without lung allograft rejection.

The Role of GERD Diagnosis and Treatment in Preventing Lung Function Decline After Pediatric Lung Transplantation.

Gastroesophageal reflux disease (GERD) after lung transplantation (LuTx) can lead to chronic lung allograft dysfunction. Our aim was to assess the prevalence of GERD in pediatric LuTx recipients and to investigate the impact of medical and surgical GERD treatment on lung function. Ethical approval was obtained. Data of all consecutive patients who underwent LuTx from 2013 to 2023 and aged < 18 years at the time of the study were prospectively collected. A GERD diagnostic algorithm was established, including assessment of symptoms (vomiting, heartburn, regurgitation, cough, recurrent airway infections), bronchoscopy, forced expiratory volume in 1 second, and pH impedance. Further investigations included upper gastrointestinal series and esophagogastroduodenoscopy. Patients with GERD underwent medical treatment or fundoplication. Lung function was monitored. Thirty-six patients (2 months-18 years, 50% male) were included. Twenty-nine (80%) underwent spirometry, 16 (45%) pH impedance study, and 14 (39%) esophagogastroduodenoscopy. Twenty-two (61%) had no GERD symptoms and 12 (33%) showed normal pH impedance study or esophagogastroduodenoscopy. Fourteen (39%) patients had GERD symptoms, all 9 tested symptomatic patients (25%) had pathological GERD-specific diagnostics. Three (8%) patients underwent fundoplication after a median of 1.6 years (range 1.1-5.7 years) post-LuTx without surgical complications. After a median follow-up of 2.3 years (range 1.3-2.8 years) post-fundoplication, all (n = 3) had complete remission of GERD symptoms and lung function improvement. Lung function decline was observed in 6 (67%) of the tested symptomatic patients on proton-pump inhibitors (PPIs) treatment. Over one-third of our patients presented with GERD symptoms after LuTx. Symptoms and lung function may be reliable GERD indicators. Given the high prevalence of GERD, we suggest a routine posttransplant diagnostic algorithm including pH impedance study. Eighty percent of all symptomatic patients had a lung function decline despite PPI. Fundoplication is safe and may improve long-term outcome in pediatric LuTx recipients.

Cardiac Comorbidity and Exercise Intolerance in Bilateral Lung Transplant Recipients Followed at a Pediatric Center.

Reduced exercise capacity is common in young bilateral lung transplantation (Bi-LTx) recipients, but longer-term data on cardiac comorbidities are limited. We evaluate potential cardiac contributions to long-term exercise intolerance in this population. All Bi-LTx recipients at a single pediatric center, who completed routine clinical post-transplant cardiac assessment, including echocardiogram, cardiac exam, and cardiopulmonary exercise testing (CPET), were included. Cardiac risk factors (CRFs) were assessed by history and laboratory tests. CPET-derived peak and percent-predicted peak myocardial oxygen consumption (VO2 peak, ppVO2 peak) were used to quantitate exercise capacity. Percent-predicted peak oxygen pulse (pp peak O2 pulse) assessed stroke volume. 15 patients (67% M; median age 21.6years, median follow-up from Bi-LTx 7.0years) were included. Almost all patients (14, 93%) had multiple CRFs; hypertension and hyperlipidemia/dyslipidemia were the most common. On CPET, 93% (n = 14) had abnormal (≤ 85%) ppVO2 peak (median 59%). 73% (n = 11) had abnormal pp peak O2 pulse (median 74%). Ten had blunted heart rate response to exercise. Nine had left ventricular diastolic dysfunction (LV-DD) on echocardiogram. Median percent-predicted forced expiratory volume in one second was 70%. One had severe chronic lung allograft dysfunction. Cardiac risk factors and exercise intolerance are common among young Bi-LTx recipients years post-transplant, even among those without significant pulmonary dysfunction. High prevalence of multiple CRFs, LV-DD, chronotropic dysfunction, and abnormal stroke volume suggest cardiac comorbidities may contribute to intolerance. Medical management of CRFs and tailored exercise may decrease cardiac risk and improve functional capacity for Bi-LTx survivors.

Update on the immunological mechanisms of primary graft dysfunction and chronic lung allograft dysfunction.

Primary graft dysfunction (PGD) and chronic lung allograft dysfunction (CLAD) are the leading causes of graft loss in lung transplant recipients. The development of mouse lung transplant models has allowed for the genetic dissection of cellular and molecular pathways that prevent graft survival. This review provides an overview into recent mechanistic insights into PGD and CLAD. Mouse orthotopic lung transplant models and investigations of human lung transplant recipeints have revealed new molecular and cellular targets that promote PGD and CLAD. Donor and recipient-derived innate immune cells promote PGD and CLAD. PGD is driven by communication between classical monocytes and tissue-resident nonclassical monocytes activating alveolar macrophages to release chemokines that recruit neutrophils. Products of cell damage trigger neutrophil NET release, which together with NK cells, antibodies and complement, that further promote PGD. The development of CLAD involves circuits that activate B cells, CD8+ T cells, classical monocytes, and eosinophils. Effective targeted management of PGD and CLAD in lung transplant recipient to improve their long-term outcome remains a critical unmet need. Current mechanistic studies and therapeutic studies in mouse models and humans identify new possibilities for prevention and treatment.

Impact of Neutropenia on Clinical Outcomes after Lung Transplantation.

Neutropenia is a frequent complication among solid organ transplant (SOT) recipients receiving immunosuppressive therapy and antimicrobial prophylaxis. However, there are limited studies analysing the frequency and impact of neutropenia in lung transplant recipients (LTRs). Our aim was to analyse the frequency of neutropenia, the need for granulocyte colony-stimulating factor (GCSF) treatment within the first 18 months post-transplant and its association with acute rejection, chronic lung allograft dysfunction (CLAD), overall survival and the development of infections. This observational and retrospective study recruited 305 patients who underwent lung transplantation between 2009 and 2019, with outpatient quarterly follow-up during the first 18 months post-surgery. During this period, 51.8% of patients experienced at least one episode of neutropenia. Neutropenia was classified as mild in 50.57% of cases, moderate in 36.88% and severe in 12.54%. GCSF treatment was indicated in 23.28% of patients, with a mean dose of 3.53 units. No statistically significant association was observed between neutropenia or its severity and the development of acute rejection, CLAD or overall survival. However, the patients who received GCSF treatment had a higher mortality rate compared to those who did not. Sixteen patients (5.25%) developed infections during neutropenia, with bacterial infections being the most common. Neutropenia is common in the first 18 months after lung transplantation and most episodes are mild. We did not find an association between neutropenia and acute rejection, CLAD, or mortality. However, the use of GCSF were associated with worse post-transplant survival.

Systemic Sweet Syndrome Recurrence in Lung Allograft: Autopsy Findings from First Reported Case

Abstract Introduction/Objective Sweet syndrome is a non-vasculitic neutrophilic dermatosis characterized by acute, neutrophilic inflammation, most classically in the skin. Sweet syndrome can, however, manifest with systemic organ involvement including the lungs. Pulmonary involvement by Sweet syndrome is exceedingly rare, and its recurrence in a pulmonary allograft is understudied. Methods/Case Report A 43-year-old female with a history of Sweet syndrome with pulmonary involvement developed chronic bronchiolitis obliterans requiring bilateral lung transplantation. Seven years after transplantation, the patient began exhibiting shortness of breath requiring hospitalization. During the patient’s hospital stay, cytomegalovirus viremia and SARS-CoV-2 positivity were detected, and new oral lesions were concerning for a Sweet syndrome flare. Her respiratory status continued to decline requiring escalating ventilatory support. An autopsy limited to the chest and abdomen was performed after she expired. The pleural cavities had extensive adhesions, and both lungs were heavy. Microscopically, the lungs showed extensive, intralumenal acute inflammation of the bronchi and bronchioles with marked chronic inflammation of the submucosa, histologically similar to the patient’s explanted lung specimen. There was also focal endogenous lipoid pneumonia due to bronchiolar obstruction. In addition to the inflammatory findings, multiple infectious agents were identified in the patient’s respiratory tract including SARS-CoV-2, cytomegalovirus, Epstein-Barr virus, Candida glabrata, Klebsiella pneumoniae, and Stenotrophomonas maltophilia. No underlying malignancy was identified. (This patient’s earlier course was reported previously: PMC8411443) Results (if a Case Study enter NA) NA Conclusion Pulmonary involvement in Sweet syndrome can cause significant morbidity, and prior to this case, allograft recurrence of Sweet syndrome had not previously been reported. For transplant patients with a history of pulmonary Sweet syndrome, recurrence should be considered in cases of allograft dysfunction. This case also highlights the importance of thorough microbiological studies in autopsies of patients with systemic inflammatory diseases being treated with extensive immunosuppressive therapies.

Microbiome and metabolome patterns after lung transplantation reflect underlying disease and chronic lung allograft dysfunction

BackgroundProgression of chronic lung disease may lead to the requirement for lung transplant (LTx). Despite improvements in short-term survival after LTx, chronic lung allograft dysfunction (CLAD) remains a critical challenge for long-term survival. This study investigates the molecular and microbial relationships between underlying lung disease and the development of CLAD in bronchoalveolar lavage fluid (BALF) from subjects post-LTx, which is crucial for tailoring treatment strategies specific to allograft dysfunctions.MethodsPaired 16S rRNA gene amplicon sequencing and untargeted LC–MS/MS metabolomics were performed on 856 BALF samples collected over 10 years from LTx recipients (n = 195) with alpha-1-antitrypsin disease (AATD, n = 23), cystic fibrosis (CF, n = 47), chronic obstructive pulmonary disease (COPD, n = 78), or pulmonary fibrosis (PF, n = 47). Data were analyzed using random forest (RF) machine learning and multivariate statistics for associations with underlying disease and CLAD development.ResultsThe BALF microbiome and metabolome after LTx differed significantly according to the underlying disease state (PERMANOVA, p = 0.001), with CF and AATD demonstrating distinct microbiome and metabolome profiles, respectively. Uniqueness in CF was mainly driven by Pseudomonas abundance and its metabolites, whereas AATD had elevated levels of phenylalanine and a lack of shared metabolites with the other underlying diseases. BALF microbiome and metabolome composition were also distinct between those who did or did not develop CLAD during the sample collection period (PERMANOVA, p = 0.001). An increase in the average abundance of Veillonella (AATD, COPD) and Streptococcus (CF, PF) was associated with CLAD development, and decreases in the abundance of phenylalanine-derivative alkaloids (CF, COPD) and glycerophosphorylcholines (CF, COPD, PF) were signatures of the CLAD metabolome. Although the relative abundance of Pseudomonas was not associated with CLAD, the abundance of its virulence metabolites, including siderophores, quorum-sensing quinolones, and phenazines, were elevated in those with CF who developed CLAD. There was a positive correlation between the abundance of these molecules and the abundance of Pseudomonas in the microbiome, but there was no correlation between their abundance and the time in which BALF samples were collected post-LTx.ConclusionsThe BALF microbiome and metabolome after LTx are particularly distinct in those with underlying CF and AATD. These data reflect those who developed CLAD, with increased virulence metabolite production from Pseudomonas, an aspect of CF CLAD cases. These findings shed light on disease-specific microbial and metabolic signatures in LTx recipients, offering valuable insights into the underlying causes of allograft rejection.9jCt4jk1gKgtvTcVFjuR9mVideo

Association between Respiratory Virus Infection and Development of De Novo Donor-Specific Antibody in Lung Transplant Recipients.

Chronic lung allograft dysfunction (CLAD) is the most common cause of long-term lung allograft failure. Several factors, including respiratory virus infection (RVI), have been associated with CLAD development, but the underlying mechanisms of these associations are not well understood. We hypothesize that RVI in lung transplant recipients elicits the development of donor-specific antibodies (DSAs), thus providing a mechanistic link between RVI and CLAD development. To test this hypothesis, we retrospectively evaluated for the presence of HLA antibodies in a cohort of lung transplant recipients with symptomatic RVI within the first four months post-transplant using sera at two time points (at/directly after the transplant and following RVI) and time-matched controls without RVI (post-transplant). We found a trend toward the development of de novo DSAs in those with symptomatic RVI versus controls [6/21 (29%) vs. 1/21 (5%), respectively, p = 0.09]. No cases or controls had DSA at baseline. We also found increased rates of CLAD and death among those who developed class II DSA versus those who did not (CLAD: 5/7 (71.4%) vs. 19/34 (54.3%), death: 5/7 (71.4%) vs. 17/35 (48.6%)). Prospective studies evaluating the temporal development of DSA after RVI in lung transplant patients and the subsequent outcomes are warranted.