Monogenic gene variants in lung transplant recipients with usual interstitial pneumonia

Question addressed by the studyThe prevalence of monogenic disease-causing gene variants in lung-transplant recipients with idiopathic pulmonary fibrosis is not fully known. Their impact on clinical outcomes before and after transplantation requires more evidence.Patients and MethodsWe retrospectively performed sequence analysis of genes associated with pulmonary fibrosis in a cohort of 23 patients with histologically confirmed usual interstitial pneumonia that had previously undergone double lung transplantation. We evaluated the impact of confirmed molecular diagnoses on disease progression, clinical outcomes and incidence of acute rejection or chronic lung allograft dysfunction after transplantation.ResultsFifteen patients out of 23 (65%) had a variant in a gene associated with interstitial lung disease. Eleven patients (48%) received a molecular diagnosis, of which nine involved genes for telomerase function. Five diagnostic variants were found in the gene for Telomerase reverse transcriptase. Two of these variants, p.(Asp684Gly) and p.(Arg774*), seemed to be enriched in Finnish lung-transplant recipients. Disease progression and the incidence of acute rejection and chronic lung allograft dysfunction was similar between patients with telomere-related disease and the rest of the study population. The incidence of renal or bone marrow insufficiency or skin malignancies did not differ between the groups.Answer to the questionGenetic variants are common in lung transplant recipients with pulmonary fibrosis and are most often related to telomerase function. A molecular diagnosis for telomeropathy does not seem to impact disease progression or the risk of complications or allograft dysfunction after transplantation.

MiR-21 in Lung Transplant Recipients With Chronic Lung Allograft Dysfunction

Background: Micro-RNA-21 (miR-21) is a post-translational regulator involved in epithelial-to-mesenchymal transition (EMT). Since EMT is thought to contribute to chronic lung allograft dysfunction (CLAD), we aimed to characterize miR-21 expression and distinct EMT markers in CLAD.Methods: Expression of miR-21, vimentin, Notch intracellular domain (NICD) and SMAD 2/3 was investigated in explanted CLAD lungs of patients who underwent retransplantation. Circulating miR-21 was determined in collected serum samples of CLAD and matched stable recipients.Results: The frequency of miR-21 expression was higher in restrictive allograft syndrome (RAS) than in bronchiolitis obliterans syndrome (BOS) specimens (86 vs 30%, p = 0.01); Vimentin, NICD and p-SMAD 2/3 were positive in 17 (100%), 12 (71%), and 7 (42%) BOS patients and in 7 (100%), 4 (57%) and 4 (57%) RAS cases, respectively. All four markers were negative in control tissue from donor lungs. RAS patients showed a significant increase in serum concentration of miR-21 over time as compared to stable recipients (p = 0.040).Conclusion: To the best of our knowledge this is the first study highlighting the role miR-21 in CLAD. Further studies are necessary to investigate the involvement of miR-21 in the pathogenesis of CLAD and its potential as a therapeutic target.

A Systematized Review of Professional Employment Following Thoracic Transplantation

Introduction Acknowledging the evolved landscape in thoracic transplantation, professional employment becomes an important outcome measure to quantify the success of this costly procedure. Objective We aimed to assess rates of and characterize factors associated with professional employment in patients following thoracic transplantation, and create an evidence-base on the relationship between professional employment and relevant outcome parameters. Methods We systematically searched Medline, Cinahl, and GoogleScholar to identify studies published between 1998 and 2021 reporting on professional employment following heart and lung transplantation. Results Twenty-two studies from 11 countries with varying sample sizes (N = 27; 10 066) were included. Employment rates ranged from 19.7% to 69.4% for heart, and from 7.4% to 50.8% for lung transplant recipients. Most frequently reported positively associated factors with employment after transplant were younger age, higher education, and history of pretransplant employment. Longer duration of unemployment prior to transplantation and Medicaid coverage were the most frequently reported negatively associated factors. Relationships between professional employment and clinical outcomes included lower rates of acute and chronic rejection, less infection episodes, and better quality of life among working patients; one study reported a lower 5-year-mortality rate. Reasons not to work were “physical or mental health-related,” “employment-related,” “financial reasons,” and “lifestyle choices.” Discussion Substantial proportions of patients following thoracic transplantation are not professionally employed, potentially diminishing the success of transplantation on individual and societal levels. Considering adverse clinical outcomes in employed transplant recipients were low, more efforts are needed to identify modifiable factors for employment in these populations.

Postoperative Management of Lung Transplant Recipients in the Intensive Care Unit

The number of lung transplantations is progressively increasing worldwide, providing new challenges to interprofessional teams and the intensive care units. The outcome of lung transplantation recipients is critically affected by a complex interplay of particular pathophysiologic conditions and risk factors, knowledge of which is fundamental to appropriately manage these patients during the early postoperative course. As high-grade evidence-based guidelines are not available, the authors aimed to provide an updated review of the postoperative management of lung transplantation recipients in the intensive care unit, which addresses six main areas: (1) management of mechanical ventilation, (2) fluid and hemodynamic management, (3) immunosuppressive therapies, (4) prevention and management of neurologic complications, (5) antimicrobial therapy, and (6) management of nutritional support and abdominal complications. The integrated care provided by a dedicated multidisciplinary team is key to optimize the complex postoperative management of lung transplantation recipients in the intensive care unit.

Donor NK and T Cells in the Periphery of Lung Transplant Recipients Contain High Frequencies of Killer Cell Immunoglobulin-Like Receptor-Positive Subsets

IntroductionFor end-stage lung diseases, double lung transplantation (DLTx) is the ultimate curative treatment option. However, acute and chronic rejection and chronic dysfunction are major limitations in thoracic transplantation medicine. Thus, a better understanding of the contribution of immune responses early after DLTx is urgently needed. Passenger cells, derived from donor lungs and migrating into the recipient periphery, are comprised primarily by NK and T cells. Here, we aimed at characterizing the expression of killer cell immunoglobulin-like receptors (KIR) on donor and recipient NK and T cells in recipient blood after DLTx. Furthermore, we investigated the functional status and capacity of donor vs. recipient NK cells.MethodsPeripheral blood samples of 51 DLTx recipients were analyzed pre Tx and at T0, T24 and 3wk post Tx for the presence of HLA-mismatched donor NK and T cells, their KIR repertoire as well as activation status using flow cytometry.ResultsWithin the first 3 weeks after DLTx, donor NK and T cells were detected in all patients with a peak at T0. An increase of the KIR2DL/S1-positive subset was found within the donor NK cell repertoire. Moreover, donor NK cells showed significantly higher frequencies of KIR2DL/S1-positive cells (p<0.01) 3wk post DLTx compared to recipient NK cells. This effect was also observed in donor KIR+ T cells 3wk after DLTx with higher proportions of KIR2DL/S1 (p<0.05) and KIR3DL/S1 (p<0.01) positive T cells. Higher activation levels of donor NK and T cells (p<0.001) were detected compared to recipient cells via CD25 expression as well as a higher degranulation capacity upon activation by K562 target cells.ConclusionHigher frequencies of donor NK and T cells expressing KIR compared to recipient NK and T cells argue for their origin in the lung as a part of a highly specialized immunocompetent compartment. Despite KIR expression, higher activation levels of donor NK and T cells in the periphery of recipients suggest their pre-activation during the ex situ phase. Taken together, donor NK and T cells are likely to have a regulatory effect in the balance between tolerance and rejection and, hence, graft survival after DLTx.