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Background: Although the demand for allografts continuously surpasses the supply, the majority of lungs offered for transplant are declined based on various factors, including donor age. This in turn sustains the wait-list mortality of patients with end-stage pulmonary disease., Methods: In this single-center, observational cohort study, we investigated the impact of donor age on graft survival. We additionally compared our center's data to data reported to the International Society for Heart and Lung Transplantation (ISHLT) Thoracic Organ Transplant Registry. Kaplan-Meier method was used to describe overall graft survival. Multivariate Cox proportional hazards regression was used to assess clinical features associated with graft loss., Results: Between January 2010 and December 2023, Alfred performed 1,101 single and double lung transplants and the combined ISHLT cohort totaled 32,200 transplants. At Alfred, grafts originating from donors ≥65 years were used in 13.3% of lung transplant cases and univariate analysis showed no impact of donor age ≥65 on graft survival (hazard ratio [HR] 0.86, p = 0.34). In the combined cohort, North America had a lower proportion of donors aged ≥65 years compared to Europe and the Alfred (2.4% vs 9.8% vs 13.3%, p < 0.001). The univariate analysis showed a negative impact of donor age ≥65 on graft survival (HR 1.16, p < 0.001). However, this did not hold in a multivariate model (HR 1.06, p = 0.298) when adjusted for center experience and recipient characteristics., Conclusions: Donor age might impact outcomes to a lesser degree than previously suggested. Therefore, appropriately assessed age-extended lungs should be routinely considered for lung transplantation., Competing Interests: Disclosure statement A.M.D. reports grants from the University Hospital Basel, and Lungitude Foundation, lecture honoraria from AstraZeneca, GSK and Sanofi, travel support from OrPha Swiss, MSD and Janssen, and advisory board participation with Gebro Pharma, Janssen and MSD outside submitted work. M.P. reports the positions as ESHLT Treasurer and board member for Scandiatransplant, roles within ISHLT Thoracic Transplant Registry, and ERS 8.02 Group, an institutional grant from PulmonX, consulting fees from rhyme medical, Takeda, Zambon, and TTF, lecture honoraria from AstraZeneca outside submitted work. B.J.L., H.V.S., M.A.P., K.V., S.L.E., G.P.W., and G.I.S. have nothing to report. We would like to thank Dr Wida Cherikh, principal biostatistician and manager of the United Network of Organ Sharing Research Department, for reviewing our manuscript and Dr Zakary Doherty, research fellow at Monash University, for his support with the data analysis. Andrei Darie would like to thank the University of Basel and Freiwillige Akademische Gesellschaft Basel for the research grants supporting the present work., (Copyright © 2024 International Society for the Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Lung transplantation is a well-established treatment for advanced lung disease, improving survival and quality of life. Over the last 60 years all aspects of lung transplantation have evolved significantly and exponential growth in transplant volume. This has been particularly evident over the last decade with a substantial increase in lung transplant numbers as a result of innovations in donor utilization procurement, including the use donation after circulatory death and ex-vivo lung perfusion organs. Donor lungs have proved to be surprisingly robust, and therefore the donor pool is actually larger than previously thought. Parallel to this, lung transplant outcomes have continued to improve with improved acute management as well as microbiological and immunological insights and innovations. The management of lung transplant recipients continues to be complex and heavily dependent on a tertiary care multidisciplinary paradigm. Whilst long term outcomes continue to be limited by chronic lung allograft dysfunction improvements in diagnostics, mechanistic understanding and evolutions in treatment paradigms have all contributed to a median survival that in some centres approaches 10 years. As ongoing studies build on developing novel approaches to diagnosis and treatment of transplant complications and improvements in donor utilization more individuals will have the opportunity to benefit from lung transplantation. As has always been the case, early referral for transplant consideration is important to achieve best results., (© 2024 The Authors. Respirology published by John Wiley & Sons Australia, Ltd on behalf of Asian Pacific Society of Respirology.)

Pregnancy after thoracic organ transplantation is feasible for select individuals but requires multidisciplinary subspecialty care. Key components for a successful pregnancy after lung or heart transplantation include preconception and contraceptive planning, thorough risk stratification, optimization of maternal comorbidities and fetal health through careful monitoring, and open communication with shared decision-making. The goal of this consensus statement is to summarize the current evidence and provide guidance surrounding preconception counseling, patient risk assessment, medical management, maternal and fetal outcomes, obstetric management, and pharmacologic considerations., Competing Interests: Disclosure statement The authors have no conflicts of interest to disclose., (Copyright © 2022 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Currently, the assessment of immunological risk in lung transplantation (LTx) does not completely consider HLA compatibility at the molecular level. We have previously demonstrated the association of HLA eplets in predicting chronic lung allograft dysfunction following LTx; however, the associations between HLA eplet mismatch (epMM) loads and overall survival are unknown., Methods: In this retrospective, single-center study, 277 LTx donor-recipient pairs were high resolution HLA typed and analyzed for HLA epMMs using HLAMatchmaker (version 3.1). LTx pairs were also assessed for the presence of the previously described risk epitope mismatches DQ2-DQA1*05 and DQ7-DQA1*05., Results: HLA class I epMMs were not associated with deleterious outcomes; however, lower HLA class II (≤19), DQA1 (≤2), and combined HLA class I and II (≤29) epMM demonstrated an association with increased time to chronic lung allograft dysfunction and improved overall survival. The presence of a risk epitope mismatch was not associated with worse clinical outcomes., Conclusions: HLA epMM can risk-stratify LTx recipients and potentially guide donor-recipient matching and immunosuppression strategies., Competing Interests: The authors declare no funding or conflicts of interest., (Copyright © 2022 The Author(s). Transplantation Direct. Published by Wolters Kluwer Health, Inc.)

Background: The prognostic value of evaluating spirometry at a fixed time point using standardized population reference has not previously been evaluated. Our aim was to assess the association between spirometric phenotype at 12 months (Spiro 12M ), survival and incidence of chronic lung allograft dysfunction (CLAD) in bilateral lung transplant recipients., Methods: We conducted a retrospective cohort study of bilateral lung transplant recipients transplanted between January 2003 and September 2012. We defined Spiro 12M as the mean of the 2 prebronchodilator FEV 1 measurements 12-month post-transplant. Normal spirometry was defined as FEV 1 /FVC ≥0.7 and FEV1≥80% and FVC≥80% predicted population-based values for that recipient. Abnormal spirometry was defined as failure to attain normal function by 12-months. We used a Cox regression model to assess the association between Spiro 12M , survival, and CLAD. We used logistic regression to assess potential pretransplant donor and recipient factors associated with abnormal Spiro 12M RESULTS: One hundred and eleven (51%) lung transplant recipients normalized their Spiro 12M . Normal Spiro 12M was associated improved survival (hazard ratio [HR] 0.60, 95% confidence interval [CI] 0.41-0.88], p = 0.009. Each 10% decrement in FEV 1 increased the risk of death in a stepwise fashion. Additionally, CLAD was reduced in those with normal Spiro 12M (HR:0.65, 95%CI:0.46-0.92, p = 0.016). Donor smoking history (OR:2.93, 95% CI:1.21-7.09; p = 0.018) and mechanical ventilation time in hours (OR:1.03, 95% CI:1.004-1.05; p = 0.02) were identified as independent predictors of abnormal Spiro 12M ., Conclusions: Abnormal Spiro 12M is associated with increased mortality and the development of CLAD. The effect is dose dependent with increased dysfunction corresponding to increased risk. This assessment of phenotype at 12-months can easily be incorporated into standard of care., (Copyright © 2021 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Chronic lung allograft dysfunction (CLAD) remains a significant challenge and the major determinant of morbidity and mortality post lung transplantation (LTx). The definition of CLAD has evolved significantly over the last ten years, reflecting better understanding of pathophysiology and different phenotypes. While there is an agreed consensus approach to CLAD, questions remain regarding the limitations of lung function parameters as well as the role of imaging and histopathology. Here we present a current snapshot of the definition of CLAD, its evolution and future directions., Competing Interests: Conflicts of Interest: The series “Strategies to Achieve Long-Term Success of Lung Transplantation” was commissioned by the editorial office without any funding or sponsorship. The authors have no other conflicts of interest to declare., (2020 Annals of Translational Medicine. All rights reserved.)

Background: A donor arterial PO 2 /FiO 2 (P/F ratio) of less than the 300 threshold would frequently result in either exclusion of the donor or placement of the lungs on ex vivo lung perfusion (EVLP). The aim was to investigate the veracity of the P/F ratio threshold of 300 for donor lung acceptability., Methods: In 93 brain dead lung donors, arterial blood gases were drawn in the intensive care unit (ICU) just before procurement and each of the 4 donor pulmonary veins in the operating room (OR). No donor lungs were rejected for transplantation based on the last ICU or OR P/F ratio, and EVLP was not used. The recipients were followed up 6 and 12 months following transplantation., Results: There were 93 recipients of bilateral lung transplantation. An arterial P/F ratio of < 300 was largely driven by a low P/F ratio in the lower lobes. There were no differences between the recipients receiving donor lungs where the ICU P/F ratio was < 300 compared with ≥ 300 in the time to extubation, grade of primary graft dysfunction, pulmonary function at 6 and 12 months, and 12-month survival., Conclusions: From this study:(1) If a donor P/F threshold of 300 was adhered to, 36% would have been rejected, and (2) The donor P/F ratio threshold of 300 is excessively conservative and results in the wastage of donor lungs and the application of unnecessary EVLP., (Copyright © 2019. Published by Elsevier Inc.)

Background: We provide the results of the first interventional study of cytomegalovirus (CMV)-specific immune monitoring to direct the length of antiviral prophylaxis in lung transplantation (LTx)., Methods: Patients (n = 118) at risk of CMV infection were randomized 1:2 to either 5 months or variable length valganciclovir prophylaxis (5-11 mo post-LTx), as determined by the QuantiFERON (QFN)-CMV assay. Patients with a negative QFN-CMV assay (< 0.2 IU/mL) received prolonged valganciclovir prophylaxis., Results: The primary endpoint that was the incidence of CMV infection in the lung allograft within 18 months of LTx was significantly reduced in the QFN-CMV directed arm (37% versus 58%, P = 0.03). Secondary endpoints that included blood viremia, acute rejection, and chronic lung allograft dysfunction did not differ between the 2 arms. Of the 80/118 patients who ceased antiviral prophylaxis at 5 months, the incidence of viremia (> 600 copies/mL) within the blood was significantly reduced in patients with a positive QFN-CMV assay compared with those without protective immunity (13% versus 67%, P = 0.0003), as was the incidence of severe viremia (> 10 000 copies/mL) (3% versus 50%, P < 0.001). Ceasing antiviral prophylaxis at 11 months in patients with a negative assay was associated with a 25% incidence of late CMV viremia., Conclusions: Cytomegalovirus immune monitoring allows an individualized approach to CMV prophylaxis and reduces late CMV infection within the lung allograft.

Lung transplantation can offer life-prolonging therapy to children with otherwise terminal end-stage lung disease. However, infectious complications, like those experienced by their adult counterparts, are a significant cause of morbidity and mortality. These include bacteria, viruses, and fungi that infect the patient pretransplant and those that may be acquired from the donor or by the recipient in the months to years posttransplant. An understanding of the approach to the management of each potential infecting organism is required to ensure optimal outcomes. In particular, emphasis on aggressive preoperative management of infections in pediatric patients with cystic fibrosis is important. These include multidrug-resistant Gram-negative bacteria, fungi, and Mycobacterium abscessus, the posttransplant outcome of which depends on optimal pretransplant management, including vaccination and other preventive, antibiotic-sparing strategies. Similarly, increasing the transplant donor pool to meet rising transplant demands is an issue of critical importance. Expanded-criteria donors-those at increased risk of blood-borne viruses in particular-are increasingly being considered and transplants undertaken to meet the rising demand. There is growing evidence in the adult pool that these transplants are safe and associated with comparable outcomes. Pediatric transplanters are therefore likely to be presented with increased-risk donors for their patients. Finally, numerous novel antibiotic-sparing therapeutic approaches are on the horizon to help combat infections that currently compromise transplant outcomes.

A 27-year-old female with Eisenmenger's syndrome underwent closure of a patent ductus arteriosus, closure of a perimembranous ventricular septal defect and mid muscular defect and bilateral lung transplantation. Her immediate postoperative course was complicated by severe right ventricular outflow tract (RVOT) obstruction resulting in hemodynamic collapse, a condition described as suicide right ventricle. The patient was placed on central Veno-Arterial Extra-Corporeal Membrane Oxygenation as a bridge to the relief of RVOT obstruction which included a right ventricular outflow muscle resection and a right ventricle outflow tract patch. The patient made an uneventful recovery., (© 2018 Wiley Periodicals, Inc.)

Lung transplantation in Australia is 32 years old in 2018. From its early infancy in 1986, it continues to evolve and is internationally recognised as demonstrating world's best practices in organ donation, utilisation and transplantation procedures. Over the past decade, transplant numbers have increased substantially due to innovations in donor procurement, such as donation after circulatory death, the use of ex vivo lung perfusion, extended criteria and organ utilisation, with more than 200 lung transplants undertaken in Australia annually. Parallel to this, lung transplant outcomes have continued to improve. While the management of lung transplant recipients is heavily dependent on a tertiary care paradigm, this model is well developed and has been extremely successful, with Australian outcomes exceeding those of the International Society for Heart and Lung Transplantation Registry at all time points.

Background: Recipient adolescent age for non-lung solid-organ transplantation is associated with higher rates of rejection, graft loss and mortality. Although there have been no studies specifically examining adolescent outcomes after lung transplantation (LTx), limited data from the International Society of Heart and Lung Transplantation (ISHLT) Registry suggest that a similar association may exist. Recently, adolescence has been defined as 10 to 24 years of age, taking into account the biologic and sociologic transitions that occur during this age interval., Methods: The ISHLT Registry was used to examine the survival outcomes of LTx recipients 10 to 24 years of age between 2005 and 2013. Given the developmental changes that occur in adolescence, survival outcomes for the tertiles of adolescence (10 to 14, 15 to 19 and 20 to 24 years old) were also examined., Results: Adolescents made up 9% (n = 2,319) of the 24,730 LTxs undertaken during the study period. Kaplan-Meier survival estimates at 3 years showed lower adolescent survival (65%) when compared with younger children (73%, p = 0.006) and adults 25 to 34 (75%, p < 0.00001) and 35 to 49 (71%, p < 0.00001) years of age, without a significant survival difference compared with those 50 to 65 years old. Critically, 15- to 19-year-old recipients had the poorest outcomes, with reduced 1-year survival (82%) compared with those 10 to 14 years old (88%, p = 0.02), and reduced 3-year survival (59%) compared with those 10 to 14 (73%, p < 0.00001) and 20 to 24 (66%, p < 0.0001) years old., Conclusions: Adolescent LTx recipients have poorer overall survival when compared with younger children and adults, with those 15 to 19 years old having the highest risk of death. This survival disparity among age groups likely reflects the difficult period of adolescence and its biologic and social transitions, which may influence both immunologic function and adherence., (Copyright © 2018 International Society for the Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Background: Invasive and disseminated Mycoplasma hominis infections are well recognized but uncommon complications in solid organ transplant recipients. In a single center, a cluster of M. hominis infections were identified in lung transplant recipients from the same thoracic intensive care unit (ICU). We sought to determine the source(s) of these infections., Methods: Medical records of the donor and infected transplant recipients were reviewed for clinical characteristics. Clinical specimens underwent routine processing with subculture on Mycoplasma-specific Hayflick agar. Mycoplasma hominis identification was confirmed using sequencing of the 16S ribosomal RNA gene. Mycoplasma hominis isolates were subjected to whole-genome sequencing on the Illumina NextSeq platform., Results: Three lung transplant recipients presented with invasive M. hominis infections at multiple sites characterized by purulent infections without organisms detected by Gram staining. Each patient had a separate donor; however, pretransplant bronchoalveolar lavage fluid was only available from the donor for patient 1, which subsequently grew M. hominis. Phylo- and pangenomic analyses indicated that the isolates from the donor and the corresponding recipient (patient 1) were closely related and formed a distinct single clade. In contrast, isolates from patients 2 and 3 were unrelated and divergent from one another., Conclusions: Mycoplasma hominis should be considered a cause of donor-derived infection. Genomic data suggest donor-to-recipient transmission of M. hominis. Additional patients co-located in the ICU were found to have genetically unrelated M. hominis isolates, excluding patient-to-patient transmission., (© The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

After lung transplantation, pulmonary vein thrombosis is a rare, potentially life-threatening adverse event arising at the pulmonary venous anastomosis that typically occurs early and presents as graft failure and hemodynamic compromise with an associated mortality of up to 40%. The incidence, presentation, outcomes, and treatment of late pulmonary vein thrombosis remain poorly defined. Management options include anticoagulant agents for asymptomatic clots, and thrombolytic agents or surgical thrombectomy for hemodynamically significant clots. We present a rare case highlighting a delayed presentation of pulmonary vein thrombosis occurring longer than 2 weeks after lung transplantation and manifesting clinically as graft failure secondary to refractory pulmonary edema. The patient was treated successfully with surgical thrombectomy and remains well. We recommend a high index of suspicion of pulmonary vein thrombosis when graft failure after lung transplantation occurs and is not responsive to conventional therapy, and consideration of investigation with transesophageal echocardiography or computed tomography with venous phase contrast in such patients even more than 2 weeks after lung transplantation., (Copyright © 2016 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Donor selection in lung transplantation (LTx) is historically based upon clinical urgency, ABO compatibility, and donor size. HLA matching is not routinely considered; however, the presence or later development of anti-HLA antibodies is associated with poorer outcomes, particularly chronic lung allograft dysfunction (CLAD). Using eplet mismatches, we aimed to determine whether donor/recipient HLA incompatibility was a significant predictor of CLAD. One hundred seventy-five LTx undertaken at the Alfred Hospital between 2008 and 2012 met criteria. Post-LTx monitoring was continued for at least 12 months, or until patient death. HLA typing was performed by sequence-based typing and Luminex sequence-specific oligonucleotide. Using HLAMatchmaker, eplet mismatches between each donor/recipient pairing were analyzed and correlated against incidences of CLAD. HLA-DRB1/3/4/5+DQA/B eplet mismatch was a significant predictor of CLAD (hazard ratio [HR] 3.77, 95% confidence interval [CI]: 1.71-8.29 p < 0.001). When bronchiolitis obliterans syndrome (BOS) and restrictive allograft syndrome (RAS) were analyzed independently, HLA-DRB1/3/4/5 + DQA/B eplet mismatch was shown to significantly predict RAS (HR 8.3, 95% CI: 2.46-27.97 p < 0.001) but not BOS (HR 1.92, 95% CI: 0.64-5.72, p = 0.237). HLA-A/B eplet mismatch was shown not to be a significant predictor when analyzed independently but did provide additional stratification of results. This study illustrates the importance of epitope immunogenicity in defining donor-recipient immune compatibility in LTx., (© Copyright 2016 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Purpose of Review: Pulmonary antibody-mediated rejection (AMR) while contributing to acute and chronic allograft dysfunction remains a diagnostic and therapeutic challenge. The diagnostic tenets upon which AMR is defined will be reviewed in the light of recent studies., Recent Findings: The introduction of solid phase assays such as the Luminex platform has provided a wealth of quantitative data on the presence of anti-human leukocyte antigen (HLA) donor-specific antibodies (DSA). Further studies are required to better define the relationship of circulating DSA and activation of proinflammatory immune pathways that result in allograft dysfunction. The limitations of C4d staining in defining AMR are highlighted from recent studies in lung transplantation and from the 2013 Banff meeting on renal transplantation., Summary: The current challenge to the lung transplant community is to agree on a working definition of pulmonary AMR. Only then can we better appreciate the epidemiology, clinical phenotypes, and treatment of AMR.

Background: The importance of antibody-mediated rejection (AMR) following lung transplantation remains contentious. In particular, the diagnostic criteria suggested to define AMR, namely the presence of donor-specific antibodies (DSA), C4d immunoreactivity, histological features and allograft dysfunction are not always readily applicable or confirmatory in lung transplantation., Methods: In a retrospective single-center study of 255 lung transplant recipients (LTR), we identified 9 patients in whom a clinical diagnosis of AMR was made within 12months of transplant, and define the immunological, histological, clinical features, as well as the therapeutic response of this cohort., Results: Nine LTR with AMR underwent combination therapy with high-dose intravenous corticosteroid, intravenous immunoglobulin, plasmapheresis and rituximab. Following therapy, while the total number of the original DSA dropped by 17%, and the median value of the mean fluorescence intensity (mfi) of the originally observed DSA decreased from 5292 (IQR 1319-12,754) to 2409 (IQR 920-6825) (p<0.001), clinical outcomes were variable with a number of patients progressing to either chronic lung allograft dysfunction or death within 12month., Conclusion: AMR in lung transplantation remains both a diagnostic and therapeutic challenge, but when clinically suspected is associated with a variable response to therapy and poor long-term outcomes., (Copyright © 2014 Elsevier B.V. All rights reserved.)

The management of patients undergoing lung transplantation has continued to evolve, leading to improvements in 90-day and 1-year survival. The significant advancements in donor management and utilization at our center have led to significant increases in lung transplant activity without any compromise in recipient outcomes. Through the use of a patient-centered multidisciplinary model of care involved in all aspects of recipient management, from assessment and waitlisting to pre-, peri- and post-operative care, our lung transplant outcomes represent 2015 world's best lung transplant practice.

The enduring success of lung transplantation is built on the use of immunosuppressive drugs to stop the immune system from rejecting the newly transplanted lung allograft. Most patients receive a triple-drug maintenance immunosuppressive regimen consisting of a calcineurin inhibitor, an antiproliferative and corticosteroids. Induction therapy with either an antilymphocyte monoclonal or an interleukin-2 receptor antagonist are prescribed by many centres aiming to achieve rapid inhibition of recently activated and potentially alloreactive T lymphocytes. Despite this generic approach acute rejection episodes remain common, mandating further fine-tuning and augmentation of the immunosuppressive regimen. While there has been a trend away from cyclosporine and azathioprine towards a preference for tacrolimus and mycophenolate mofetil, this has not translated into significant protection from the development of chronic lung allograft dysfunction, the main barrier to the long-term success of lung transplantation. This article reviews the problem of lung allograft rejection and the evidence for immunosuppressive regimens used both in the short- and long-term in patients undergoing lung transplantation.