Lymphocyte Depleting and Modulating Therapies for Chronic Lung Allograft Dysfunction.

Chronic lung rejection, also called chronic lung allograft dysfunction (CLAD), remains the major hurdle limiting long-term survival after lung transplantation, and limited therapeutic options are available to slow the progressive decline in lung function. Most interventions are only temporarily effective in stabilizing the loss of or modestly improving lung function, with disease progression resuming over time in the majority of patients. Therefore, identification of effective treatments that prevent the onset or halt progression of CLAD is urgently needed. As a key effector cell in its pathophysiology, lymphocytes have been considered a therapeutic target in CLAD. The aim of this review is to evaluate the use and efficacy of lymphocyte depleting and immunomodulating therapies in progressive CLAD beyond usual maintenance immunosuppressive strategies. Modalities used include anti-thymocyte globulin, alemtuzumab, methotrexate, cyclophosphamide, total lymphoid irradiation, and extracorporeal photopheresis, and to explore possible future strategies. When considering both efficacy and risk of side effects, extracorporeal photopheresis, anti-thymocyte globulin and total lymphoid irradiation appear to offer the best treatment options currently available for progressive CLAD patients. SIGNIFICANCE STATEMENT: Effective treatments to prevent the onset and progression of chronic lung rejection after lung transplantation are still a major shortcoming. Based on existing data to date, considering both efficacy and risk of side effects, extracorporeal photopheresis, anti-thymocyte globulin, and total lymphoid irradiation are currently the most viable second-line treatment options. However, it is important to note that interpretation of most results is hampered by the lack of randomized controlled trials.

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.

Demonstration of the Rationale for Therapeutic Drug Monitoring of Isavuconazole: A Case Report with a Lung Transplant Recipient.

Mucormycosis is a rare invasive fungal disease diagnosed in immunocompromised patients, including those with diabetes or iron overload, and in patients treated for hematological malignancies or after transplantation. Isavuconazole is a triazole antifungal effective against Mucorales with good tolerability, but with potential for relatively high interindividual variability in pharmacokinetics. This report demonstrates the case of a lung transplant recipient treated with isavuconasole that exhibits a very long elimination half-life of 159 hours, and discusses the practical implications of this finding for dosage adjustment and need for therapeutic drug monitoring.

Transcripts associated with chronic lung allograft dysfunction in transbronchial biopsies of lung transplants.

Transplanted lungs suffer worse outcomes than other organ transplants with many developing chronic lung allograft dysfunction (CLAD), diagnosed by physiologic changes. Histology of transbronchial biopsies (TBB) yields little insight, and the molecular basis of CLAD is not defined. We hypothesized that gene expression in TBBs would reveal the nature of CLAD and distinguish CLAD from changes due simply to time posttransplant. Whole-genome mRNA profiling was performed with microarrays in 498 prospectively collected TBBs from the INTERLUNG study, 90 diagnosed as CLAD. Time was associated with increased expression of inflammation genes, for example, CD1E and immunoglobulins. After correcting for time, CLAD manifested not as inflammation but as parenchymal response-to-wounding, with increased expression of genes such as HIF1A, SERPINE2, and IGF1 that are increased in many injury and disease states and cancers, associated with development, angiogenesis, and epithelial response-to-wounding in pathway analysis. Fibrillar collagen genes were increased in CLAD, indicating matrix changes, and normal transcripts were decreased-dedifferentiation. Gene-based classifiers predicted CLAD with AUC 0.70 (no time-correction) and 0.87 (time-corrected). CLAD related gene sets and classifiers were strongly prognostic for graft failure and correlated with CLAD stage. Thus, in TBBs, molecular changes indicate that CLAD primarily reflects severe parenchymal injury-induced changes and dedifferentiation.

ERS International Congress 2023: highlights from the Thoracic Surgery and Lung Transplantation Assembly.

Five sessions presented at the European Respiratory Society Congress 2023 were selected by Assembly 8, consisting of thoracic surgeons and lung transplant professionals. Highlights covering management of adult spontaneous pneumothorax, malignant pleural effusion, infectious and immune-mediated complications after lung transplantation, as well as the pro and con debate on age limit in lung transplantation and results of the ScanCLAD study were summarised by early career members, supervised by the assembly faculty.

Molecular monitoring of lung allograft health: is it ready for routine clinical use?

Maintenance of long-term lung allograft health in lung transplant recipients (LTRs) requires a fine balancing act between providing sufficient immunosuppression to reduce the risk of rejection whilst at the same time not over-immunosuppressing individuals and exposing them to the myriad of immunosuppressant drug side-effects that can cause morbidity and mortality. At present, lung transplant physicians only have limited and rather blunt tools available to assist them with this task. Although therapeutic drug monitoring provides clinically useful information about single time point and longitudinal exposure of LTRs to immunosuppressants, it lacks precision in determining the functional level of immunosuppression that an individual is experiencing. There is a significant gap in our ability to monitor lung allograft health and therefore tailor optimal personalised immunosuppression regimens. Molecular diagnostics performed on blood, bronchoalveolar lavage or lung tissue that can detect early signs of subclinical allograft injury, differentiate rejection from infection or distinguish cellular from humoral rejection could offer clinicians powerful tools in protecting lung allograft health. In this review, we look at the current evidence behind molecular monitoring in lung transplantation and ask if it is ready for routine clinical use. Although donor-derived cell-free DNA and tissue transcriptomics appear to be the techniques with the most immediate clinical potential, more robust data are required on their performance and additional clinical value beyond standard of care.

Dosing Optimization of Posaconazole in Lung-Transplant Recipients Based on Population Pharmacokinetic Model.

Although posaconazole tablets show relatively low variability in pharmacokinetics (PK), the proportion of patients achieving the PK/PD target at the approved uniform dose for both prophylaxis and therapy is not satisfactory. The aim of this study was to develop a posaconazole population PK model in lung-transplant recipients and to propose a covariate-based dosing optimization for both prophylaxis and therapy. In this prospective study, 80 posaconazole concentrations obtained from 32 lung-transplant patients during therapeutic drug monitoring were analyzed using nonlinear mixed-effects modelling, and a Monte Carlo simulation was used to describe the theoretical distribution of posaconazole PK profiles at various dosing regimens. A one-compartment model with both linear absorption and elimination best fit the concentration-time data. The population apparent volume of distribution was 386.4 L, while an apparent clearance of 8.8 L/h decreased by 0.009 L/h with each year of the patient's age. Based on the covariate model, a dosing regimen of 200 mg/day for prophylaxis in patients ˃60 years, 300 mg/day for prophylaxis in patients ˂60 years and for therapy in patients ˃60 years, and 400 mg/day for therapy in patients ˂60 years has been proposed. At this dosing regimen, the PK/PD target for prophylaxis and therapy is reached in 95% and 90% of population, respectively, representing significantly improved outcomes in comparison with the uniform dose.

Effect of SARS-CoV-2 infection on anti-HLA antibodies and de novo donor specific antibodies incidence in lung transplant recipients.

PURPOSE: There are no clear guidelines on how to handle immunosuppression in lung transplant recipients (LTRs) infected by SARS-CoV-2. Antimetabolite reduction with corticosteroid escalation is the most frequent strategy. The aim of this study was to determine the effect of this therapeutic approach on the incidence of de novo donor specific-antibodies (dnDSA). METHODS: We retrospectively analysed a cohort of 27 LTRs diagnosed with SARS-CoV-2 infection between September 2020 and April 2021 with available anti-HLA antibodies screening before and after infection. Managed as per the centre's SARS-CoV-2 protocol, the treatment modalities included specific virostatic treatment, convalescent plasma administration, reduction or discontinuation of mycophenolate and transient corticosteroid escalation initiated in the second week post-infection. RESULTS: All 27 patients received virostatics: 15 (55.6%) remdesivir and 12 (44.4%) favipiravir. In addition, 18 patients (66.7%) underwent convalescent plasma therapy. Of the 27 patients, 25 (92.6%) received mycophenolate as a part of their maintenance immunosuppressive regimen, which was temporarily reduced in 10 (37%) and discontinued in 15 LTRs (55.6%), the median resumption times for mycophenolate daily doses of at least 1000 mg being 13 days (IQR 11.0-63.5) and 59 days (IQR 26.0-130.0), respectively. Corticosteroids were escalated in 25 patients (92.6%), of whom 9 (33.3%) received IV methylprednisolone (median 80 mg/day; IQR 80-187.5) and 16 (59.3%) had oral prednisone adjusted (median 20 mg/day; IQR 16.3-38.8). The median time to revert to the corticosteroid dosage of ≤20 mg/day was 42 days (IQR 36.0-87.0). Notably, no dnDSA were detected in any LTR between 1 and 9 months from the onset of the SARS-CoV-2 infection. CONCLUSION: Our findings suggest that antimetabolite cessation with a transient corticosteroid escalation is a safe therapeutic strategy regarding anti-HLA dynamics in SARS-CoV-2 infected LTRs.

COVID-19 progression in hospitalized patients using follow-up in vivo CT and ex vivo microCT.

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease-19 (COVID-19) which can lead to acute respiratory distress syndrome (ARDS) and evolve to pulmonary fibrosis. Computed tomography (CT) is used to study disease progression and describe radiological patterns in COVID-19 patients. This study aimed to assess disease progression regarding lung volume and density over time on follow-up in vivo chest CT and give a unique look at parenchymal and morphological airway changes in "end-stage" COVID-19 lungs using ex vivo microCT. Methods: Volumes and densities of the lung/lobes of three COVID-19 patients were assessed using follow-up in vivo CT and ex vivo whole lung microCT scans. Airways were quantified by airway segmentations on whole lung microCT and small-partition microCT. As controls, three discarded healthy donor lungs were used. Histology was performed in differently affected regions in the COVID-19 lungs. Results: In vivo, COVID-19 lung volumes decreased while density increased over time, mainly in lower lobes as previously shown. Ex vivo COVID-19 lung volumes decreased by 60% and all lobes were smaller compared to controls. Airways were more visible on ex vivo microCT in COVID-19, probably due to fibrosis and increased airway diameter. In addition, small-partition microCT showed more deformation of (small) airway morphology and fibrotic organization in severely affected regions with heterogeneous distributions within the same lung which was confirmed by histology. Conclusions: COVID-19-ARDS and subsequent pulmonary fibrosis alters lung architecture and airway morphology which is described using in vivo CT, ex vivo microCT, and histology.

Mapping of the lung megakaryocytes: A role in pathogenesis of idiopathic pulmonary arterial hypertension?

It has been postulated that platelets are produced by fragmentation of the megakaryocytes within the pulmonary circulation rather than budding of their cytoplasm within the bone marrow. Although literature is scarce depicting the levels of the megakaryocytes within the lungs from previously healthy individuals, there are several studies describing the presence of these cells in human necropsy specimens, and it has been hypothesized that their rearrangements could contribute to the pathogenesis of chronic pulmonary vascular disorders. The objective of this study was to describe the characteristics, distribution and total count of megakaryocytes in explants from lung transplant (LTx) recipients based on the final clinicopathological diagnosis, as well as in samples from LTx donors without previously known pulmonary disease. Using the immunohistochemical marker CD61 we quantified and characterized such cells in 20 biopsy samples from LTx donors and in 30 biopsy samples from LTx recipients with different pathologic conditions: vascular disorders of the lungs, obstructive pulmonary disorders and fibrotic lung diseases. Patients suffering from idiopathic pulmonary arterial hypertension (IPAH) showed morphological differences and strikingly higher numbers of the lungs megakaryocytes (264.5 cells/cm2) compared to all the other groups (the average count among donors was 33.55 megakaryocytes/cm2). Such finding could contribute to the understanding of the origin of vasoconstriction, thrombosis and vascular remodeling of the pulmonary circulation - all the basic mechanisms leading to the development of IPAH, as for there is an increasing evidence of several products of platelets and megakaryocytes to be capable of triggering such processes.

The molecular features of chronic lung allograft dysfunction in lung transplant airway mucosa.

BACKGROUND: Many lung transplants fail due to chronic lung allograft dysfunction (CLAD). We recently showed that transbronchial biopsies (TBBs) from CLAD patients manifest severe parenchymal injury and dedifferentiation, distinct from time-dependent changes. The present study explored time-selective and CLAD-selective transcripts in mucosal biopsies from the third bronchial bifurcation (3BMBs), compared to those in TBBs. METHODS: We used genome-wide microarray measurements in 324 3BMBs to identify CLAD-selective changes as well as time-dependent changes and develop a CLAD classifier. CLAD-selective transcripts were identified with linear models for microarray data (limma) and were used to build an ensemble of 12 classifiers to predict CLAD. Hazard models and random forests were then used to predict the risk of graft loss using the CLAD classifier, transcript sets associated with rejection, injury, and time. RESULTS: T cell-mediated rejection and donor-specific antibody were increased in CLAD 3BMBs but most had no rejection. Like TBBs, 3BMBs showed a time-dependent increase in transcripts expressed in inflammatory cells that was not associated with CLAD or survival. Also like TBBs, the CLAD-selective transcripts in 3BMBs reflected severe parenchymal injury and dedifferentiation, not inflammation or rejection. While 3BMBs and TBBs did not overlap in their top 20 CLAD-selective transcripts, many CLAD-selective transcripts were significantly increased in both for example LOXL1, an enzyme controlling matrix remodeling. In Cox models for one-year survival, the 3BMB CLAD-selective transcripts and CLAD classifier predicted graft loss and correlated with CLAD stage. Many 3BMB CLAD-selective transcripts were also increased by injury in kidney transplants and correlated with decreased kidney survival, including LOXL1. CONCLUSIONS: Mucosal and transbronchial biopsies from CLAD patients reveal a diffuse molecular injury and dedifferentiation state that impacts prognosis and correlates with the physiologic disturbances. CLAD state in lung transplants shares features with failing kidney transplants, indicating elements shared by the injury responses of distressed organs.