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The Quantiferon-Cytomegalovirus (QF-CMV) assay was introduced to predict CMV infection and inform prophylaxis duration in our lung transplant recipients (LTR) from 2012. The aims of this retrospective cohort study were to review our QF-CMV experience, understand factors associated with positive results and further explore its predictive utility.LTR with QF-CMV testing performed at 5 months post-transplant were included. Patients receiving QF-directed prophylaxis (5 or 11 months) were compared to those receiving our prior standard of care (5 months). Outcomes were CMV infection1,000 IU/mL in blood and/or bronchoalveolar lavage fluid. Factors associated with positive QF-CMV results were identified. Patients were compared based on serostatus, QF-CMV results and prophylaxis duration.Our cohort included 263 LTR (59 D+/R-, 204 R+). QF-directed prophylaxis was used in 195 of 263 (74%) and was associated with reduced CMV infection (84/195, 43% vs 41/68, 60%, p.001). Patients receiving extended prophylaxis experienced less CMV if negative and/or indeterminate (43% vs 70%, p.01) or positive (10% vs 51%, p.01). Only 5 of 59 (8%) D+/R- patients were QF-CMV positive compared to 155 of 204 (76%) R+ patients (adjusted OR 0.03, 0.01-0.07, p.001). After controlling for prophylaxis duration, only D+/R- serostatus remained independently associated with CMV infection (adjusted HR 4.90, 95% CI 2.68-9.00, p.0001).QF-CMV results were strongly correlated with serostatus, with D+/R- patients unlikely to test positive while receiving prophylaxis. Extended prophylaxis was associated with delayed onset, reduced frequency and severity of CMV infection across all subgroups. After accounting for serostatus, the incremental predictive value of QF-CMV in this cohort was limited.

Background Lung transplantation is a recognised treatment for end-stage lung disease due to bronchiectasis. Non-CF bronchiectasis and CF are often combined into one cohort, however outcomes for non-CF bronchiectasis patients varies between centres, and in comparison to those for CF. Aims To compare lung transplantation mortality and morbidity of bronchiectasis (non-CF) patients to those with CF and other indications. Methods Retrospective analysis of patients undergoing lung transplantation between 01 January 2008-31 December 2013. Time to and cause of lung allograft loss was censored on 01 April 2018. A case-note review was conducted on a sub-group of 78 patients, to analyse hospital admissions as a marker of morbidity. Results 341 patients underwent lung transplantation, 22 (6%) had bronchiectasis compared to 69 (20%) with CF. The 5-year survival for the bronchiectasis group was 32%, compared to CF 69%, obstructive lung disease (OLD) 64%, pulmonary hypertension 62% and ILD 55% (p = 0.008). Lung allograft loss due to CLAD with predominant infection was significantly higher in the bronchiectasis group at 2 years. The rate of acute admissions was 2.24 higher in the bronchiectasis group when compared to OLD (p = 0.01). Patients with bronchiectasis spent 45.81 days in hospital per person year after transplantation compared with 18.21 days for CF. Conclusions Bronchiectasis patients in this study had a lower 5-year survival and poorer outcomes in comparison to other indications including CF. Bronchiectasis should be considered a separate entity to CF in survival analysis. This article is protected by copyright. All rights reserved.

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 FEV1 measurements 12-month post-transplant. Normal spirometry was defined as FEV1/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 Spiro12M. Normal Spiro12M was associated improved survival (hazard ratio [HR] 0.60, 95% confidence interval [CI] 0.41-0.88], p = 0.009. Each 10% decrement in FEV1 increased the risk of death in a stepwise fashion. Additionally, CLAD was reduced in those with normal Spiro12M (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 Spiro12M. Conclusions Abnormal Spiro12M 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.

Lung transplantation (LTx) has evolved significantly since its inception and the improvement in LTx outcomes over the last three decades has predominantly been driven by advances in immunosuppression management. Despite the lack of new classes of immunosuppression medications, immunosuppressive strategies have evolved significantly from a universal method to a more targeted approach, reflecting a greater understanding of the need for individualized therapy and careful consideration of all factors that are influenced by immunosuppression choice. This has become increasingly important as the demographics of lung transplant recipients have changed over time, with older and more medically complex candidates being accepted and undergoing LTx. Furthermore, improved survival post lung transplant has translated into more immunosuppression related comorbidities long-term, predominantly chronic kidney disease (CKD) and malignancy, which has required further nuanced management approaches. This review provides an update on current traditional lung transplant immunosuppression strategies, with modifications based on pre-existing recipient factors and comorbidities, peri-operative challenges and long term complications, balanced against the perpetual challenge of chronic lung allograft dysfunction (CLAD). As we continue to explore and understand the complexity of LTx immunology and the interplay of different factors, immunosuppression strategies will require ongoing critical evaluation and personalization in order to continue to improve lung transplant outcomes.

Summary A best evidence topic was written according to a structured protocol. The question addressed was: ‘Does continuation of antifibrotics before lung transplantation (LTx) influence post-transplant outcomes in patients with idiopathic pulmonary fibrosis (IPF) with regard to mortality, bronchial anastomotic dehiscence, reoperation for bleeding and wound complications, primary graft dysfunction or longer-term survival and allograft rejection?’ A total of 261 articles were found using the reported search strategy, of which 7 represented the best evidence to answer the clinical question. Six out of 7 studies demonstrated equivalent post-transplant survival among IPF patients on antifibrotics before LTx compared with controls. Five out of 6 studies showed no increase in the risk of major bleeding, wound or bronchial anastomotic complications. One bi-institutional study found a higher incidence of early bronchial anastomotic dehiscence, but this difference was not statistically significant after longer term follow-up. In a study that only included IPF patients who underwent single LTx, a lower incidence of grade 3 primary graft dysfunction was reported in the antifibrotic group compared with controls. Overall, to date, only small (N, A best evidence topic was constructed according to a structured protocol.

Summary Background & aims The Global Leadership Initiative on Malnutrition (GLIM) is a novel framework for diagnosing malnutrition and requires evaluation in wide-ranging clinical settings. This study aimed to assess the prevalence of malnutrition and its phenotypic characteristics among lung transplantation (LTx) candidates comparing GLIM to International Classification of Diseases, 10th Revision (ICD-10) criteria. Methods A retrospective analysis was conducted of all adult patients assessed for LTx in a one-year period. Phenotypic criteria included body mass index (BMI), unintentional loss of weight (LOW) over a 12-month period and fat-free mass index (FFMI) using bioelectrical impedance analysis (BIA). Systemic inflammation associated with severe end-stage lung disease met GLIM's etiological criterion. Diagnosis of malnutrition, and its severity, were classified according to each of GLIM and ICD-10. Results Of 130 patients, 112 (86%) had all data to classify malnutrition. Malnutrition prevalence according to GLIM was 59%, which was markedly greater than using ICD-10 criteria (26%). Half of the LTx patients were moderately malnourished using GLIM, compared to 19% using ICD-10. A similar proportion were severely malnourished using GLIM (9%) and ICD-10 (7%). Fat-free mass (FFM) depletion (47% of all patients) was a major contributor to GLIM-malnutrition. Over 60% of LTx patients with GLIM-malnutrition were not detected as malnourished using ICD-10 criteria. Conclusion Malnutrition diagnosis using GLIM was higher than using ICD-10 in LTx patients, primarily attributable to the incorporation of quantitative evaluation of FFM depletion. This highlights the utility of the GLIM framework and the importance of including body composition in malnutrition assessment.

Lung transplantation is limited by a lack of suitable lung donors. In Australia, the national donation organisation (DonateLife) has taken a major role in optimising organ donor identification. However, the potential outside the DonateLife network hospitals remains uncertain. We aimed to create a prediction model for lung donation within the DonateLife network and estimate the untapped lung donors outside of the DonateLife network. We reviewed all deaths in the state of Victoria’s intensive care units using a prospectively collected population-based intensive care unit database linked to organ donation records. A logistic regression model derived using patient-level data was developed to characterise the lung donors within DonateLife network hospitals. Consequently, we estimated the expected number of lung donors in Victorian hospitals outside the DonateLife network and compared the actual number. Between 2014 and 2018, 291 lung donations occurred from 8043 intensive care unit deaths in DonateLife hospitals, while only three lung donations occurred from 1373 ICU deaths in non-DonateLife hospitals. Age, sex, postoperative admission, sepsis, neurological disease, trauma, chronic respiratory disease, lung oxygenation and serum creatinine were factors independently associated with lung donation. A highly discriminatory prediction model with area under the receiver operator characteristic curve of 0.91 was developed and accurately estimated the number of lung donors. Applying the model to non-DonateLife hospital data predicted only an additional five lung donors. This prediction model revealed few additional lung donor opportunities outside the DonateLife network, and the necessity of alternative and novel strategies for lung donation. A donor prediction model could provide a useful benchmarking tool to explore organ donation potential across different jurisdictions, hospitals and transplanting centres.

The continuing shortage of pulmonary grafts from donors after brain death has led to a resurgence of interest in lung transplantation from donors after circulatory death (DCD). Most lungs from donors after withdrawal from life-sustaining therapy can be recovered rapidly and transplanted directly without ex-vivo assessment in case functional warm ischemic time is limited to 30 to 60 min. The potential of the DCD lung pool is still underutilized and should be maximized in countries with existing legislation. Countries lacking a DCD pathway should be encouraged to develop national ethical, professional, and legal frameworks to address public and professional concerns.

Although the use of donation after circulatory death (DCD) donors has increased lung transplant activity, 25-40% of intended DCD donors do not convert to actual donation because of no progression to asystole in the required time frame after withdrawal of cardiorespiratory support (WCRS). No studies have specifically focussed on DCD lung donor progression. This retrospective study reviewed intended DCD lung donors to make a prediction model of the likelihood of progression to death using logistic regression and classification and regression tree (CART). Between 2014 and 2018, 159 of 334 referred DCD donors were accepted, with 100 progressing to transplant, while 59 (37%) did not progress. In logistic regression, a length of ICU stay ≤ 5 days, severe infra-tentorial brain damage on imaging and use of vasopressin were related with the progression to actual donation. CART modelling of the likelihood of death within 90-minute post-WCRS provided prediction with a sensitivity of 1.00 and positive predictive value of 0.56 in the validation data set. In the nonprogressed DCD group, 26 died within 6 h post-WCRS. Referral received early after ICU admission, with nonspontaneous ventilatory mode, deep coma and severe infra-tentorial damage were relevant predictors. The CART model is useful to exclude DCD donor candidates with low probability of progression.

BACKGROUND We previously developed molecular assessment systems for lung transplant transbronchial biopsies (TBBs) with high surfactant and bronchial mucosal biopsies, identifying T-cell‒mediated rejection (TCMR) on the basis of the expression of rejection-associated transcripts, but the relationship of rejection to graft loss is unknown. This study aimed to develop molecular assessments for TBBs and mucosal biopsies and to establish the impact of molecular TCMR on graft survival. METHODS We used microarrays and machine learning to assign TCMR scores to an expanded cohort of 457 TBBs (367 high surfactant plus 90 low surfactant) and 314 mucosal biopsies. We tested the score agreement between TBB–TBB, mucosal–mucosal, and TBB–mucosal biopsy pairs in the same patient. We also assessed the association of molecular TCMR scores with graft loss (death or retransplantation) and compared it with the prognostic associations for histology and donor-specific antibodies. RESULTS The molecular TCMR scores assigned in all the TBBs performed similarly to those in high-surfactant TBBs, indicating that variation in alveolation in TBBs does not prevent the detection of TCMR. Mucosal biopsy pieces showed less piece-to-piece variation than TBBs. TCMR scores in TBBs agreed with those in mucosal biopsies. In both TBBs and mucosal biopsies, molecular TCMR was associated with graft loss, whereas histologic rejection and donor-specific antibodies were not. CONCLUSIONS Molecular TCMR can be detected in TBBs regardless of surfactant and in mucosal biopsies, which show less variability in the sampled tissue than TBBs. On the basis of these findings, molecular TCMR appears to be an important predictor of the risk of future graft failure. Trial registration ClinicalTrials.gov NCT02812290.

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.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.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.HLA epMM can risk-stratify LTx recipients and potentially guide donor-recipient matching and immunosuppression strategies.

Rationale: Chronic bronchitis (CB) is characterized by productive cough with excessive mucus production, resulting in quality-of-life impairment and increased exacerbation risk. Bronchial rheoplast...

Background Australia’s increasing organ donor rate has translated to increased lung donor referrals and subsequent lung transplantation (LTx). The LTx sector attempts to utilise as many organs as possible—but in reality, not all are used. This analysis aims to assess the utility and efficiency of donor lung referrals to the Alfred Hospital. Methods All Donatelife Australia donor lung referrals for the year 2017 were analysed retrospectively. Results From a total of 440 lung referrals, 220 were local from the state of Victoria (population 6.4 million) and 220 from the Rest-of-Australia (ROA). Sixty-eight per cent (68%) of Victorian and 48% of the ROA were via the donation after circulatory death (DCD) pathway. One hundred and two (102) LTx were performed: 32 represent 21% of 149 Victorian and 8% of 106 ROA DCD donors, 70 represent 54% of the Victorian and 24% of the ROA donation after brain death (DBD) donors. Eighty per cent (80%) of all donors aged 35 years were used or potentially useable. Thirteen per cent (13%) of DCD and 44% of DBD donors aged >65 years were used. Logistical and resource considerations, around the retrieval of older DCD lungs, are a significant issue. At 11.1 LTx per-million-population the Alfred has one of the highest lung donor conversion and LTx activity rates in the world. Conclusion The Australian donor lung pool could still be further extended by focussing effort and logistics on optimising DBD referrals. Additional resources (staff and transport), tighter referral criteria, and the use of extended warm ischaemic time donors could increase particularly DCD recovery rates.

Diagnosing lung transplant rejection currently depends on histologic assessment of transbronchial biopsies (TBB) with limited reproducibility and considerable risk of complications. Mucosal biopsies are safer but not histologically interpretable. Microarray-based diagnostic systems for TBBs and other transplants suggest such systems could assess mucosal biopsies as well. We studied 243 mucosal biopsies from the third bronchial bifurcation (3BMBs) collected from seven centers and classified them using unsupervised machine learning algorithms. Using the expression of a set of rejection-associated transcripts annotated in kidneys and validated in hearts and lung transplant TBBs, the algorithms identified and scored major rejection and injury-related phenotypes in 3BMBs without need for labeled training data. No rejection or injury, rejection, late inflammation, and recent injury phenotypes were thus scored in new 3BMBs. The rejection phenotype correlated with IFNG-inducible transcripts, the hallmarks of rejection. Progressive atrophy-related changes reflected by the late inflammation phenotype in 3BMBs suggest widespread time-dependent airway deterioration, which was especially pronounced after two years posttransplant. Thus molecular assessment of 3BMBs can detect rejection in a previously unusable biopsy format with potential utility in patients with severe lung dysfunction where TBB is not possible and provide unique insights into airway deterioration. ClinicalTrials.gov NCT02812290.

Refereed/Peer-reviewed Immune sensitization, defined as the presence of alloreactive donor-specific antibodies (DSA), is associated with increased wait-times and inferior transplant outcomes. Identifying pretransplant DSA with a physical cell-based assay is critical in defining immunological risk. However, improved solid phase antibody detection has provided the potential to forgo this physical assay. Here, we evaluated the association between DSA mean fluorescence intensity (MFI) and the recently introduced Halifaster Flow cytometry crossmatch (FXM) to determine if MFI could predict the outcome of FXM and whether a virtual crossmatch (VXM) would provide an accurate risk assessment. Sera from 134 waitlisted lung patients was retrospectively assessed by Halifaster FXM against lymphocytes preparations from 32 donors, resulting in 265 FXMs. HLA typing was performed to 2-field allelic level and Luminex single antigen beads (SAB) used to identify DSA. The association between FXM and Luminex MFI was calculated using ROC analysis. MFI threshold accuracy was confirmed using a separate validation cohort (174 recipient sera and 34 donors), whereby both VXM and FXMs were compared. From the 265 FXM performed, 48 (18%) T-cell (TFXM) and 56 (21%) B-cell (BFXM) were positive. In the evaluation cohort, MFI thresholds of 2000 for HLA-A, B, DRB1, and > 4000 for DQB1, were predictive of a positive FXM. The validation cohort of 233 paired FXM and VXM confirmed these MFI thresholds for both TFXM and BFXM with an accuracy of 91.4% and 89.3%, respectively. A positive VXM, defined with HLA-specific MFI thresholds predicts Halifaster FXM reactivity, and can potentially expedite organ allocation, by minimizing the need for the more time-consuming FXM.

Cystic fibrosis (CF) is an inherited multisystem disease characterised by bronchiectasis and chronic respiratory infections which eventually cause end stage lung disease. Lung transplantation (LTx) is a well-established treatment option for patients with CF-associated lung disease, improving survival and quality of life. Navigating recurrent infections in the setting of LTx is often difficult, where immune suppression must be balanced against the constant threat of infection. Sepsis/infections are one of the major contributors to post-LTx mortality and multiresistant organisms (eg, Burkholderia cepacia complex, Mycobacterium abscessus complex, Scedosporium spp. and Lomentospora spp.) pose a significant threat to survival. This review will summarize current and novel therapies to assist with the management of multiresistant bacterial, mycobacterial, viral and fungal infections which threaten the CF LTx cohort.

Aim: Single (SLTx) and double lung transplantation (DLTx) are therapeutic options for end-stage interstitial lung disease (ILD). The aim of this study is to describe oscillometry indices in stable SLTx compared to DLTx recipients. Methods: Oscillometry & spirometry were performed on all stable LTx recipients at 2 Australian centres from 2020-2021 using TremoFlo C-100 to obtain resistance (R5, R5-19), reactance (X5) and reactance area (Ax). Subjects with baseline, acute or chronic lung allograft dysfunction were excluded. SLTx for ILD (SLTx-ILD) recipients were compared with DLTx for ILD (DLTx-ILD) and were matched by age and gender. Results: 17 SLTx-ILD were included and compared with 10 matched stable DLTx-ILD. Baseline demographics of SLTx-ILD [88% males; mean age 64 (SD 5)] and DLTx-ILD [90% males; mean age 63 (SD 6)] were similar. Median X5 (-1.86 vs -1.14, p=0.02) and Ax (12.60 vs 5.57, p=0.04) differed significantly between SLTx-ILD and DLTx-ILD recipients, but resistance (R5, R5-19) measurements did not. Conclusion: SLTx for ILD is characterised by significantly worse X5 and Ax (increased elastance) as compared to DLTx for ILD. The abnormal reactance, in addition to insignificant differences in resistance measurements between SLTx and DLTx, may be due to the fibrotic contralateral native lung. However, contribution from other factors such as differences in lung size matching needs to be assessed. Longitudinal oscillometry studies are required to ascertain whether abnormal reactance – when assessed against patients9 baseline measurements – can be indicative of earlier progressive lung graft dysfunction and a worse prognosis in SLTx, as compared to using traditional methods.

It is recognized that donor factors contribute to lung transplant outcomes. Recent observations and studies have started to elucidate potential mechanisms behind explaining these observations. This perspective piece summarizes evolving lung transplant literature on the subject, focusing on donor "passenger" organisms, cells, hormones, and proteins transferred to the recipient. Many extrinsic and intrinsic donor features or properties have important consequences for subsequent allograft function in the recipient. Potentially, a better understanding of these features may provide useful novel therapeutic targets to enhance allograft outcomes.

The burden of comorbidities post-lung transplant is well documented; however, there remains a paucity of studies on insomnia in this population. Sleep disturbance has been well documented in other organ transplants. We evaluated the prevalence and potential associations of insomnia in a lung transplant cohort. A cross-sectional study of lung transplant patients attending routine follow-up at a lung transplant clinic was conducted. Participants completed the Insomnia Severity Index (ISI) and Hospital Anxiety and Depression Scale (HADS). Insomnia was defined as ISI score ≥ 15. Logistic regression analysis was used to study the relationship with variables including demographics, transplant and immunosuppression characteristics, and HADS scores for anxiety (HADS-A) and depression (HADS-D). Eighty-one patients were recruited (age 57 ± 13 years; 35 women). Median time since transplantation was 350 days (128–1228). The prevalence of insomnia was 32% (26 of 81). Insomnia was more common amongst women [odds ratio (OR) 5.0, p = 0.002], and associated with HADS-A (OR 1.24, p = 0.004) and HADS-D scores (OR 1.23, p = 0.01). These associations remained significant on multivariable analysis. There was no association with age, lung function, time since transplant, prednisolone dose or Tacrolimus level. We found a high prevalence of insomnia in lung transplant recipients at our institution. This is similar to the results of previous studies on insomnia and sleep quality in lung transplant recipients. Insomnia is potentially associated with female sex, anxiety and depression. Future studies should elucidate the incidence and predictors of insomnia to guide screening and diagnosis.

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).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.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.Cytomegalovirus immune monitoring allows an individualized approach to CMV prophylaxis and reduces late CMV infection within the lung allograft.

BACKGROUND Improved understanding of lung transplant disease states is essential because failure rates are high, often due to chronic lung allograft dysfunction. However, histologic assessment of lung transplant transbronchial biopsies (TBBs) is difficult and often uninterpretable even with 10 pieces. METHODS We prospectively studied whether microarray assessment of single TBB pieces could identify disease states and reduce the amount of tissue required for diagnosis. By following strategies successful for heart transplants , we used expression of rejection-associated transcripts (annotated in kidney transplant biopsies) in unsupervised machine learning to identify disease states. RESULTS All 242 single-piece TBBs produced reliable transcript measurements. Paired TBB pieces available from 12 patients showed significant similarity but also showed some sampling variance. Alveolar content, as estimated by surfactant transcript expression, was a source of sampling variance. To offset sampling variation, for analysis, we selected 152 single-piece TBBs with high surfactant transcripts. Unsupervised archetypal analysis identified 4 idealized phenotypes (archetypes) and scored biopsies for their similarity to each: normal; T-cell‒mediated rejection (TCMR; T-cell transcripts); antibody-mediated rejection (ABMR)-like (endothelial transcripts); and injury (macrophage transcripts). Molecular TCMR correlated with histologic TCMR. The relationship of molecular scores to histologic ABMR could not be assessed because of the paucity of ABMR in this population. CONCLUSIONS Molecular assessment of single-piece TBBs can be used to classify lung transplant biopsies and correlated with rejection histology. Two or 3 pieces for each TBB will probably be needed to offset sampling variance.

BACKGROUND Optimizing immunosuppression in lung transplant recipients (LTR) is crucially important in minimizing the risk of infection and rejection. Quantiferon®-Monitor (QFM) is a candidate immune function biomarker which has not yet been rigorously evaluated in the lung transplant setting. The aim of this prospective cohort study was to explore relationships between QFM results, immunosuppression, and infection/rejection in LTR. METHODS QFM, which measures interferon-γ after stimulation with innate and adaptive immune antigens, was tested before and at 2, 6, 12, 24 and 52 weeks post-transplant. Immunosuppression relationships were assessed with linear mixed effects models. Clinical outcomes were analyzed based on the preceding QFM result. RESULTS Eighty LTR were included. Median pre-transplant QFM levels were 171 IU/mL (IQR 45-461), decreasing to 3 IU/mL (IQR 1-8) at 2 weeks post-transplant then progressively recovering toward baseline with time from transplant. Prednisolone was strongly inversely associated with QFM level (0.1 mg/kg dose increase correlating with 88 IU/mL QFM decrease, 95% CI 61-114, P

Introduction Scedosporium apiospermum and Lomentospora prolificans (Scedosporium/Lomentospora) species are emerging, multi-resistant pathogens that cause life-threatening illnesses among lung transplant (LTx) recipients. The current epidemiology and management in LTx are unknown. Methods We performed a retrospective single center audit of all sputum/bronchoscopy samples for Scedosporium/Lomentospora species in LTx patients over a 24-year period (1995-2019). Patients were diagnosed as colonized or with invasive fungal disease. Results From a cohort of 962 LTx recipients, 30 patients (3.1%) cultured Scedosporium/Lomentospora (1.2%, 1.9%, respectively). There were no isolates from 1995 to 2013, with multiple yearly isolates thereafter. Nineteen (63%) cases were classified as IFD, and 11 (37%) as colonization. The median time to first culture from transplantation was 929 days (Interquartile-range [IQR] 263-2960). Most patients (63%) had received antifungals prior to the first positive culture of Scedosporium/Lomentospora for other fungal infection. The most common antifungal used for treatment of Scedosporium/Lomentospora was posaconazole (n = 16; 53%). Median duration of therapy was 364 days (IQR 164-616). Treatment was associated with improved lung function over 6 months (median FEV1 increased from 1.3L[IQR 0.9-1.8L] to 1.8L[IQR 1.1-2.3] P = .05). Six patients cultured Scedosporium/Lomentospora prior to transplantation, and no survival disadvantage was seen as compared to our whole LTx cohort (P = .8). Conclusion Our single center 24-year experience suggests that the incidence of Scedosporium/Lomentospora is increasing. Scedosporium/Lomentospora is typically isolated several years after LTx, and requires prolonged anti-fungal treatment that is usually associated with improved in lung function. Culture of Scedosporium/Lomentospora prior to LTx did not pose a survival disadvantage. Further surveillance is required to fully characterize implications of these organisms for LTx recipients.

Background In Australia, increased organ donation and subsequent lung transplantation (LTx) rates have followed enhanced donor identification, referral and management, as well as the introduction of a donation after circulatory death (DCD) pathway. However, the number of patients waiting for LTx still continues to exceed the number of lung donors and the search for further suitable donors is critical. Methods All 2014–2018 Victorian DonateLife hospital deaths after intensive care unit (ICU) admission were analysed retrospectively to quantify unrecognised lung donors using current criteria, as well as novel time-extended (90 mins–24 hrs post-withdrawal) DCD lung donors. Results Using standard lung donor eligibility criteria, we identified 473 potential lung donors and a further 122 time-extended DCD potential lung donors among 3,538 patients meeting general eligibility criteria. Detailed review of end-of-life discussions with patient families and the reasons why they were not offered donation revealed several categories of additional lung donors–traditional lung donors missed in current practice (n=2); hepatitis C infected lung donors potentially treatable with direct-acting antivirals (n=14), time-extended DCD lung donors (n=60); donor lungs potentially suitable for transplant with use of ex-vivo lung perfusion (EVLP) (n=7). Conclusion While the number of lung donor opportunities missed under existing DonateLife donor identification and management processes was limited, a time-extended DCD lung donation pathway could substantially expand the lung donor pool. The use of hepatitis C infected donors, and the possibility of EVLP to solve donor graft assessment or logistic issues, could also provide small additional lung donor opportunities.

BACKGROUND Anti-viral treatments to control cytomegalovirus (CMV) after lung transplantation (LTx) are associated with toxicity and anti-viral resistance. Cellular immunotherapy with virus-specific cytotoxic T cells has yielded promising results but requires donor/recipient matching. γδ T cells are involved in anti-viral immunity and can recognize antigens independently of major histocompatibility complex molecules and may not require the same level of matching. We assessed the phenotype of circulating γδ T cells after LTx to identify the candidate populations for CMV immunotherapy. METHODS Peripheral blood mononuclear cells were isolated from lung transplant recipients before transplantation and at routine bronchoscopies after LTx. Patients were stratified by risk of CMV disease into moderate risk (recipient CMV seropositive, n = 15) or high risk (HR) (recipient CMV seronegative/donor CMV seropositive, n = 10). CMV replication was classified as polymerase chain reaction positive (>150 copies/ml) in blood and/or bronchoalveolar lavage within the first 18 months. The phenotype of γδ T cells was assessed by multicolor flow cytometry, and T-cell receptor (TCR) sequences were determined by deep sequencing. RESULTS In HR lung transplant recipients with CMV replication, we observed striking phenotypic changes in γδ T cells, marked by an increase in the proportion of effector Vδ1+ γδ T cells expressing the activating natural killer cell receptor NKG2C. Moreover, we observed a remarkable increase in TCR diversity. CONCLUSIONS NKG2C+ Vδ1+ γδ T cells were associated with CMV replication and may indicate their potential to control infection. As such, we propose that they could be a potential target for cellular therapy against CMV.

Background Even in the extended-criteria era, the reasons for declining lung donors are not always clear. Furthermore, it has not been determined how many actual declined lungs would be retrieved by ex vivo lung perfusion (EVLP) beyond that already achieved in centers with an existing high utilization rate. Methods This retrospective study reviewed all lung donor referrals between 2014 and 2018, including detailed formal referrals and preliminary notifications. This study categorized reasons for lung donor non-acceptance and estimated how many declined grafts could have been theoretically retrievable by using EVLP. Results In total, 966 lung donor candidates were referred, including 313 transplanted donors, 336 declined donors after detailed referrals (group A) and 258 preliminary declined. In group A, the primary reasons for refusal were lung quality issues (49%), general medical issues (25%), and organization issues (26%), combined with secondary reasons in many cases. Main lung quality issues were an extensive smoking history, abnormal chest radiography, and underlying lung disease. Although 73 declined lung donors had indications for EVLP, the retrievable lungs decreased to only 30 cases after considering the details of all clinical contraindications and organizational issues. Nevertheless, 59 intended donation after circulatory death donors did not progress to death after withdrawal of cardiorespiratory support in the required timeframe, and EVLP may have an emerging additional role here. Conclusions Based on commonly cited criteria for EVLP indication, the number of EVLP retrievable lung donors represented only a small portion of declined donor lungs referred to our center from the state donation network.

BACKGROUND Problematic mitral regurgitation (MR) may develop following lung transplantation (LTx). There is limited information on the management of MR in LTx patients, as such we sought to evaluate our centre's experience. METHODS From 2000 to 2019, 1,054 patients underwent LTx at our centre (896 bilateral, 158 single). We identified patients in whom significant MR developed at any point post-LTx. The aetiology of MR, management and outcome were retrospectively analysed. RESULTS Eight (8) patients developed severe MR post-LTx, six following bilateral LTx and two following single LTx. Lung transplantation indications included interstitial lung disease (n=5), chronic obstructive pulmonary disease (n=2) and pulmonary arterial hypertension (n=1). Severe MR occurred intraoperatively (n=1), postoperative day 1 (n=1) with the remaining six cases between 80 and 263 days post-LTx. The aetiology was noted to be due to severe left ventricular dysfunction following unmasking of a chronically pulmonary hypertension-related under-preloaded left ventricle in one case, and in the remaining seven patients causes included myxomatous degeneration, ischaemic MR, and functional MR due to annular dilatation. In the patient with intraoperative severe MR, the MR became mild with veno-arterial extra corporeal membrane oxygenation (VA-ECMO) and in the remaining seven patients a variety of procedures were used, including mitral valve repair, valve replacement and transcatheter edge-to-edge mitral valve repair. All patients survived the mitral procedure. Two (2) deaths occurred at 12.9 years (stroke) and 5 years (cancer) from mitral valve surgery. CONCLUSIONS Development of significant mitral valve regurgitation is a rare but morbid complication after lung transplantation. This may represent the progressive natural history of pre-existing degenerative mitral valve disease and rarely, early after transplantation may be related to changes in ventricular geometry. Management of severe MR can follow the same management approach as in the non-transplant community, with the expectation of similarly good results.

BACKGROUND Donor smoking histories are common in the lung donor pool, which are known to adversely affect post–lung transplant (LTx) outcomes. However, no evidence is available about smoking status (current/former), cumulative dose effect, or the combined effect of tobacco with marijuana. METHODS We retrospectively reviewed our local state-based donation organization records and subsequent LTx recipient outcomes. The primary outcome was 3-year graft survival, with cause of death as secondary outcomes. Univariate and multivariate Cox regression analyses were used to explore smoking status or cumulative dose effect. RESULTS Between 2014 and 2018, 304 LTxs were performed: 133 (44%) LTxs were from never-smoker donors, 68 (22%) from former-smoker donors, and 103 (34%) from current-smoker donors. Of the current-smoker donors, 48% had a marijuana use history. There was no significant difference in early mortality, although recipients who received transplants from current-smoker donors had a lower 3-year graft survival than those who received transplants from never smokers. Multivariate modeling showed that current tobacco smoking (hazard ratio: 2.13, 95% CI: 1.13–3.99) and a more than 5-year weekly marijuana use (hazard ratio: 2.97, 95% CI: 1.29–6.87) were independent donor factors affecting graft survival. Chronic lung allograft dysfunction accounted for a higher proportion of the causes of death within 3 years after LTx where lungs from current/former smokers were utilized compared with those from never smokers (chronic lung allograft dysfunction-cause mortality: 11%, 7%, 0%, respectively). CONCLUSIONS More than 50% of LTx donors had smoking histories. Current tobacco use or more than 5-year weekly marijuana smoking history adversely affected 3-year graft survival. Our findings support the importance of obtaining a detailed donor tobacco and marijuana smoking history.

BACKGROUND General practitioners are increasingly likely to encounter elderly patients who are receiving immunosuppressants for the management of autoimmune diseases or solid organ transplants. OBJECTIVE The aim of this article is to provide an overview of the long-term management of the elderly patient treated with immunosuppressants. Recommendations for monitoring, preventing and managing adverse effects of immunosuppressants are summarised. DISCUSSION Elderly patients prescribed immunosuppressants may present a number of unique challenges. Immunosenescence, altered pharmacokinetics and the presence of multiple comorbidities can all affect response to immunosuppressants. Through close collaboration with tertiary care providers and regular screening, the general physician is well placed to recognise medication-related complications.

Background Although it is intense in health care resources, by facilitating assessment and reconditioning, ex vivo lung perfusion (EVLP) has the potential to expand the donor pool and improve lung transplant outcomes. However, inclusion criteria used in EVLP trials have not been validated. Methods This retrospective study from 2014 to 2018 reviewed our local state-based donation organization donor records as well as subsequent recipient outcomes to explore the relation between EVLP indications used in clinical trials and recipient outcomes. The primary outcome was primary graft dysfunction grade 3 at 24 hours, with 30-day mortality and posttransplant survival time as secondary outcomes, compared with univariate and multivariate analysis. Results From 705 lung donor referrals, 304 lung transplantations were performed (use rate of 42%); 212 of recipients (70%) met at least 1 of the commonly cited EVLP initiation criteria. There was no significant difference in primary graft dysfunction grade 3 or 30-day mortality between recipients with or without an EVLP indication (10.2% versus 7.8%, P = .51; and 2.4% versus 0%, P = .14, respectively). Multivariate analyses showed no significant relationship between commonly cited EVLP criteria and primary graft dysfunction grade 3 or survival time. Recipient outcomes were significantly associated with recipient diagnosis. Conclusions At least 1 commonly cited criterion for EVLP initiation was present in 70% of the transplanted donors, and yet it did not predict clinical results; acceptable outcomes were seen in both subgroups. To discover the true utility of EVLP beyond good clinical management and focus EVLP on otherwise unacceptable lungs, a reconsideration of EVLP inclusion criteria is required.

There is an ever increasing demand for donor lungs in patients waiting for transplantation. Lungs of many potential donors will be rejected if the standard criteria for donor assessment are followed. We have expanded our donor lung pool by accepting marginal donors and establishing a donation after circulatory death program. We have achieved comparable results using marginal donors and accepting donor lungs following donation after circulatory death. We present our assessment and technical guidelines on lung procurement taking into consideration an increasingly complex cohort of lung donors. These guidelines form the basis of the lung procurement training program involving surgical Fellows at the Alfred Hospital in Melbourne, Australia.

Advances in immunosuppression have been a key component to the ongoing success of lung transplantation. The demographics of patients receiving a lung transplant have evolved with older, more critically ill patients and those with previously contraindicated indications, now becoming recipients. Despite the lack of new classes of maintenance immunosuppression drugs becoming available, advances have been made in the prescribing of traditional immunosuppressive therapies. Developments in immunosuppressive regimens have seen changes in the route of administration, approaches to monitoring and combinations used. Long-term complications of immunosuppression, such as nephrotoxicity and malignancy can limit the success of lung transplantation, and strategies have evolved in recent years to minimise their long-term impact. Although survival outcomes have been steadily improving, chronic lung allograft dysfunction remains a barrier to long-term success. However, treatments for antibody-mediated rejection are emerging as a potential new therapeutic target to decrease the incidence of chronic lung allograft dysfunction. This article provides an update on the current status of immunosuppression after lung transplantation and reviews the evidence for immunosuppressive regimens and the implications for practice.

Objectives: This study describes therapeutic drug monitoring (TDM) of posaconazole suspension and modified release (MR) tablets in lung transplant (LTx) recipients and evaluates factors that may affect posaconazole trough plasma concentration (Cmin). Methods: A single-centre, retrospective study evaluating posaconazole Cmin in LTx recipients receiving posaconazole suspension or MR tablets between January 2014 and December 2016. Results: Forty-seven LTx patients received posaconazole suspension, and 78 received the MR tablet formulation; a total of 421 and 617 Cmin measurements were made, respectively. Posaconazole was concurrently administered with proton pump inhibitor in ≥ 90% of patients. The median (IQR) of initial posaconazole Cmin following 300 mg daily of posaconazole tablet was significantly higher than that of 800 mg daily of posaconazole suspension [1.65 (0.97-2.13) mg/L versus 0.81 (0.48-1.15) mg/L, P

Background In an era of increasing ex vivo lung perfusion (EVLP) use, it remains important to describe what outcomes can be achieved without EVLP, by taking an aggressive approach to donor use to maximize lung transplantation. Methods Data for all lung transplant donor referrals to the Alfred Hospital in Melbourne, Australia were collected for 2012 to 2013. Donor variables were analyzed and calculated into a previously validated lung donor score. Lung transplant recipient outcome data included the following: primary graft dysfunction; duration of mechanical ventilation; need for cardiopulmonary bypass extracorporeal membrane oxygenation; intensive care and hospital length of stay; 30-day, 1-year, and 3- to 4-year survival rates; rates of acute rejection and chronic lung allograft dysfunction; and peak and 12-month lung function (forced expiratory volume in 1 second). Results Of the 318 lung donor offers, 129 resulted in successful lung transplantation, with an overall donor use rate of 41%. There was no correlation between donor score and any of the recipient outcomes, and excellent short-term and longer-term survival was achieved. Conclusions Future studies examining lung transplantation outcomes with EVLP must consider the excellent results that can be achieved by using marginal lungs and conventional donor management. It is important to consider that adopting a strategy of perioperative lung donor evaluation and intervention allows use of what are considered marginal lungs to achieve promising results.

Lung transplantation (LTx) is a successful treatment option for end-stage lung disease, and immunosuppressant regimens, utilized to prevent rejection of the transplanted graft, are paramount to maintaining long-term graft survival. Immunosuppression can be classified as induction, maintenance, and antirejection therapy. This article focuses on maintenance immunosuppression that includes a combination of a calcineurin inhibitor (CNI), cell cycle inhibitor, and corticosteroid. CNIs remain the cornerstone of immunosuppression following LTx, and tacrolimus is now the preferred CNI, based on a better adverse effect profile and some limited evidence for enhanced efficacy. Tacrolimus is associated with a number of unique challenges post-LTx, with erratic and highly variable absorption making it difficult to achieve and maintain therapeutic levels. Current methods of therapeutic drug monitoring are extrapolated from models in liver and kidney transplants and are not validated in the LTx population. Alternative methods of delivering tacrolimus can address some of the issues associated with their use and can be utilized in particular clinical scenarios. Long-term toxicities attributed to tacrolimus, such as nephrotoxicity and neurotoxicity, can limit the long-term success of tacrolimus in preventing allograft rejection. This article emphasizes the current clinical challenges faced when managing LTx recipients with tacrolimus, offers strategies to manage these issues, and highlights the areas that need further research.

Purpose Baseline and chronic lung allograft dysfunction (BLAD & CLAD) are leading causes of reduced patient survival. Airway oscillometry characterises the lung's mechanical properties with greater sensitivity than spirometry. This study aims to characterise BLAD and CLAD with airway oscillometry. Methods Oscillometry was performed on all bilateral lung transplant (LTx) recipients at 2 Australian centres between Jan-Oct 2020 with the TremoFlo C-100 device to obtain resistance (R5, R19-5), reactance (X5), and reactance area (Ax). Patients with acute lung allograft dysfunction were excluded. CLAD was diagnosed/staged using spirometry as per ISHLT 2019 Consensus Criteria. BLAD was defined as failure to ever achieve >80%-pred FEV1 and FVC. Multivariate logistic regression measured the association between oscillometry risk of CLAD. Results A total of 179 LTx recipients [47% males; median age 54 (IQR 25); duration post-LTx 5 years (IQR 7)] were recruited. 112/179 (63%) patients had no CLAD and of these 27 (24%) patients had BLAD. There was a significant difference in median X5 (-1.64 vs -1.20, p Conclusion BLAD is characterised by abnormal reactance (X5 & Ax), yet resistive airway properties (R5 & R5-19) are similar to patients without BLAD. The association between oscillometry parameters and CLAD demonstrates that oscillometry provides complimentary information about lung dysfunction after transplant. Longitudinal studies are required to determine whether oscillometry has a role in earlier detection of CLAD.

Purpose Although use of donation-after-circulatory-death (DCD) donors has significantly increased lung transplant (LTx) rates, 25-40% of intended DCD do not convert to actual donors due to non-progression to asystole in the required 90 minute time frame from withdrawal of cardio-respiratory support (WCRS). Predicting which intended DCD patient will progress remains problematic & impacts resourcing. Methods This retrospective study reviewed intended DCD lung donors referred between 2014-2018 to our program, to determine specific factors that may predict the likelihood of progression to death in ≤90mins. Donor demographics, relevant medical history, reason for WCRS, ICU hemodynamic/ventilation/admission data were compared between non-progresses and LTx DCD donor cohorts. Significant variables were included in multivariable logistic regression analysis and construction of a classification and regression tree (CART) prediction model. Results 159 of 334 referred DCD donors were accepted for LTx: 100 (63%) progressed to donation, 59 (37%) did not progress. Comparing non-progressed & LTx DCD donors, significant factors associated with death ≤90mins were: length of ICU stay ≤4 days, Glascow Coma Score=3, ventilation mode and severe infra-tentorial brain damage on imaging by CT/MRI . These factors were used to develop a CART predictive model for progression ≤90mins post-WCRS, which had a sensitivity of 0.95 and predictive value of 0.69 (Figure 1). Of the 59 who did not progress, 26 patients (44%) died within the subsequent 6 hours. Conclusion Intended DCD lung donors referred early after ICU admission, in a deep coma with severe infra-tentorial damage suggesting a significant neurological injury, are to most likely to progress within 90-minute post-WCRS. This CART prediction model is now being utilized prospectively to assist LTx team re decisions on potential DCD lung donor retrievals & resource allocation. Use of a time-extended DCD lung protocol up to 6 hours post WCRS, further expands the lung donor pool.

BACKGROUND: Extracorporeal membrane oxygenation (ECMO) is used as a rescue therapy before and after lung transplantation, but little is known about functional recovery or complications after ECMO in this cohort. This study aimed to describe early physical function and leg complications in subjects who received ECMO before or after lung transplantation, and to compare functional outcomes to a matched cohort of subjects who did not require ECMO. METHODS: A retrospective study was conducted over 2 years. Highest mobility level was assessed, in both the ECMO and non-ECMO groups, prior to ICU admission, at ICU discharge, and at hospital discharge, while 6-min walk distance was measured at hospital discharge and at 3 months. Strength was assessed at ICU discharge and at hospital discharge in the ECMO subjects only, and leg complications were recorded up until hospital discharge. RESULTS: 17 subjects (mean age 43 ± 13 y; 65% (11 of 17 subjects) female) required ECMO before or after lung transplant. Survival to hospital discharge was 82% (14 of 17 subjects). At ICU discharge, strength and mobility levels were poor, but both improved by hospital discharge ( P P P = .002) and had worse physical function (ie, lower mobility level at ICU discharge, mean difference −1, P = .02; 6-min walk distance at hospital discharge: mean difference −99 m, P = .004) than lung transplant recipients not requiring ECMO ( n = 28). CONCLUSIONS: In subjects requiring ECMO before or after lung transplantation, 82% survived to hospital discharge, but leg complications were common and physical function was poor at ICU discharge. Physical function improved over time, however subjects who required ECMO had a longer period of hospitalization and worse physical function at ICU and hospital discharge than those who did not require ECMO.

Objective To determine the potential for organ donation after circulatory death (DCD) in Australia by applying ideal and expanded organ suitability criteria, and to compare this potential with actual DCD rates. Design Retrospective cohort study. Setting, methods: We analysed DonateLife audit data for patients aged 28 days to 80 years who died between July 2012 and December 2014 in an intensive care unit or emergency department, or who died within 24 hours of discharge from either, in the 75 Australian hospitals contributing data to DonateLife. Ideal and expanded organ donation criteria were derived from international and national guidelines, and from expert opinion. Potential DCD organ donors were identified by applying these criteria to patients who had been intubated and were neither confirmed as being brain-dead nor likely to have met brain death criteria at the official time of death. Results 8780 eligible patients were identified, of whom 202 were actual DCD donors. For 193 potential ideal (61%) and 313 potential expanded criteria DCD donors (72%), organ donation had not been discussed with their families; most were potential donors of kidneys (416 potential donors) or lungs (117 potential donors). Potential donors were typically older, dying of non-neurological causes, and more frequently had chronic organ disease than actual donors. Identifying all these potential donors, assuming a consent rate of 60%, would have increased Australia's donation rate from 16.1 to 21.3 per million population in 2014. Conclusions The untapped potential for DCD in Australia, particularly of kidneys and lungs, is significant. Systematic review of all patients undergoing end-of-life care in critical care environments for donor suitability could result in significant increases in organ donation rates.