How do we expand the lung donor pool?

PURPOSE OF REVIEW: Lung transplantation activity continues to be limited by the availability of timely quality donor lungs. It is apparent though that progress has been made. The steady evolution of clinical practice, combined with painstaking scientific discovery and innovation are described. RECENT FINDINGS: There have been successful studies reporting innovations in the wider use and broader consideration of donation after circulatory death donor lungs, including an increasing number of transplants from each of the controlled, uncontrolled and medically assisted dying donor descriptive categories. Donors beyond age 70 years are providing better than expected long-term outcomes. Hepatitis C PCR positive donor lungs can be safely used if treated postoperatively with appropriate antivirals. Donor lung perfusion at a constant 10 degrees appears capable of significantly improving donor logistics and ex-vivo lung perfusion offers the potential of an ever-increasing number of novel donor management roles. Bioartificial and xenografts remain distant possibilities only at present. SUMMARY: Donor lungs have proved to be surprisingly robust and combined with clinical, scientific and engineering innovations, the realizable lung donor pool is proving to be larger than previously thought.

Comparison of human leukocyte antigen immunologic risk stratification methods in lung transplantation.

Outcomes after lung transplantation (LTx) remain poor, despite advances in sequencing technology and development of algorithms defining immunologic compatibility. Presently, there is no consensus regarding the best approach to define human leukocyte antigen (HLA) compatibility in LTx. In this study, we compared 5 different HLA compatibility tools in a high-resolution HLA-typed, clinically characterized cohort, to determine which approach predicts outcomes after LTx. In this retrospective single-center study, 277 donor-recipient transplant pairs were HLA-typed using next generation sequencing. HLA compatibility was defined using HLAMatchmaker, HLA epitope mismatch algorithm (HLA-EMMA), predicted indirectly recognizable HLA epitopes (PIRCHE), electrostatic mismatch score (EMS), and amino acid mismatches (AAMMs). Associations with HLA mismatching and survival, chronic lung allograft dysfunction (CLAD), and anti-HLA donor-specific antibody (DSA) were calculated using adjusted Cox proportional modeling. Lower HLA class II mismatching was associated with improved survival as defined by HLAMatchmaker (P < .01), HLA-EMMA (P < .05), PIRCHE (P < .05), EMS (P < .001), and AAMM (P < .01). All approaches demonstrated that HLA-DRB1345 matching was associated with freedom from restrictive allograft syndrome and HLA-DQ matching with reduced DSA development. Reducing the level of HLA mismatching, in T cell or B cell epitopes, electrostatic differences, or amino acid, can improve outcomes after LTx and potentially guide immunosuppression strategies.

Oscillometry in Stable Single and Double Lung Allograft Recipients Transplanted for Interstitial Lung Disease: Results of a Multi-Center Australian Study.

Peak spirometry after single lung transplantation (SLTx) for interstitial lung disease (ILD) is lower than after double lung transplantation (DLTx), however the pathophysiologic mechanisms are unclear. We aim to assess respiratory mechanics in SLTx and DLTx for ILD using oscillometry. Spirometry and oscillometry (tremoflo® C-100) were performed in stable SLTx and DLTx recipients in a multi-center study. Resistance (R5, R5-19) and reactance (X5) were compared between LTx recipient groups, matched by age and gender. A model of respiratory impedance using ILD and DLTx data was performed. In total, 45 stable LTx recipients were recruited (SLTx n = 23, DLTx n = 22; males: 87.0% vs. 77.3%; median age 63.0 vs. 63.0 years). Spirometry was significantly lower after SLTx compared with DLTx: %-predicted mean (SD) FEV1 [70.0 (14.5) vs. 93.5 (26.0)%]; FVC [70.5 (16.8) vs. 90.7 (12.8)%], p < 0.01. R5 and R5-19 were similar between groups (p = 0.94 and p = 0.11, respectively) yet X5 was significantly worse after SLTx: median (IQR) X5 [-1.88 (-2.89 to -1.39) vs. -1.22 (-1.87 to -0.86)] cmH2O.s/L], p < 0.01. R5 and X5 measurements from the model were congruent with measurements in SLTx recipients. The similarities in resistance, yet differences in spirometry and reactance between both transplant groups suggest the important contribution of elastic properties to the pathophysiology. Oscillometry may provide further insight into the physiological changes occurring post-LTx.

Major technological advances will enhance Australian donor-recipient matching and improve transplant outcomes.

In recent times, numerous and significant technological and supportive changes have taken place in Australian transplantation. These changes are often deployed without the wider clinical community having a full understanding of what has brought about these changes and the impacts they have. Here, we aim to clarify the reasoning behind these changes and shed light on potential future endeavours to improve patient outcomes.

An Audit of Lung Donor Pool: Optimal Current Donation Strategies and the Potential of Novel Time-Extended Donation After Circulatory Death Donation.

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.

Mitral Valve Regurgitation After Lung Transplantation: Aetiology, Management and Outcome.

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 extracorporeal 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.

Improving the predictability of time to death in controlled donation after circulatory death lung donors.

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.

Evaluation of Quantiferon®-Monitor as a biomarker of immunosuppression and predictor of infection in lung transplant recipients.

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 < .001). Patients with QFM values <10 and <60 IU/mL were more likely to develop a serious opportunistic infection between 3 and 6 months (HR 6.38, 95% CI 1.37-29.66, P = .02) and 6-12 months (HR 3.25, 95% CI 1.11-9.49, P = .03) post-transplant, respectively. CONCLUSIONS: QFM values declined significantly post-transplant, with patients recovering at different rates. Prednisolone dose significantly impacted QFM results. Low levels were associated with infection beyond 3 months post-transplant, suggesting that QFM may be able to identify overly immunosuppressed patients who could be targeted for dose reduction. Larger prospective studies are needed to further evaluate this promising assay.

Donor Lung Referrals for Lung Transplantation: A 'Behind The Scenes' View.

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 and 30% >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.

Single-centre study of therapeutic drug monitoring of posaconazole in lung transplant recipients: factors affecting trough plasma concentrations.

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 < 0.01]. Variability in posaconazole Cmin was apparent regardless of the formulations prescribed and dose adjustments were routinely undertaken to maintain therapeutic Cmin. A clear dose-response relationship was observed in patients receiving posaconazole MR tablets. Non-specific adverse events (fatigue, tremor, lethargy, sweating, nausea/vomiting and weight loss) were reported in 3/78 (4%) patients receiving posaconazole MR tablets. Posaconazole Cmin in these three patients was determined to be 9.6, 6.2 and 2.3 mg/L. Conclusions: The current study has provided clinically important insights into the TDM of posaconazole in LTx recipients. Routine TDM should be undertaken in LTx recipients receiving posaconazole suspension and/or MR tablets.

Donation after Brain Death versus Donation after Circulatory Death: Lung Donor Management Issues.

Lung transplantation (LTx) has traditionally been limited by a lack of suitable donor lungs. With the recognition that lungs are more robust than initially thought, the size of the donor pool of available lungs has increased dramatically in the past decade. Donation after brain death (DBD) and donation after circulatory death (DCD) lungs, both ideal and extended are now routinely utilized. DBD lungs can be damaged. There are important differences in the public's understanding, legal and consent processes, intensive care unit strategies, lung pathophysiology, logistics, and potential-to-actual donor conversion rates between DBD and DCD. Notwithstanding, the short- and long-term outcomes of LTx from any of these DBD versus DCD donor scenarios are now similar, robust, and continue to improve. Large audits suggest there remains a large untapped pool of DCD (but not DBD) lungs that may yet further dramatically increase lung transplant numbers. Donor scoring systems that might predict the donor conversion rates and lung quality, the role of ex vivo lung perfusion as an assessment and lung resuscitation tool, as well as the potential of donor lung quality biomarkers all have immense promise for the clinical field.

Clinical effectiveness of early posaconazole suspension pre-emptive therapy in lung transplant recipients: The Alfred's experience.

Objectives: This study describes the clinical outcomes and therapeutic drug monitoring (TDM) following posaconazole suspension pre-emptive therapy in lung transplant (LTx) recipients. Methods: This was a single-centre, retrospective cohort study evaluating posaconazole suspension pre-emptive therapy in LTx recipients between January 2009 and December 2015. Results: Forty-two LTx recipients were prescribed posaconazole suspension pre-emptively. Aspergillus fumigatus was the most commonly isolated fungal organism. Of the patients receiving posaconazole suspension as the initial antifungal post-LTx, 93% had eradication of colonization at 6 months after commencing therapy. In contrast, only 61% had eradication of fungal colonization when posaconazole suspension was administered following initial therapy with voriconazole. Posaconazole suspension appeared to be well tolerated, although one case was curtailed following concern about abnormal liver function and another due to nausea/vomiting. TDM was performed in 37 patients. The initial median (IQR) trough plasma concentration ( C min ) following 400 mg twice-daily posaconazole suspension was 0.78 (0.46-1.19) mg/L. Doses beyond 800 mg daily did not appear to result in a higher median C min. Conclusions: Early initiation of posaconazole suspension pre-emptive therapy in LTx recipients appears to be well tolerated and may potentially afford favourable clinical outcomes.

Procurement of lungs for transplantation following donation after circulatory death: the Alfred technique.

INTRODUCTION: Donation after circulatory death (DCD) is an evolving method for lung transplantation (LTx) with results comparable to donation after brain death (DBD). MATERIALS AND METHODS: DCD lung transplant program requires a systematic approach for an efficient utilization of hospital resources. The surgical techniques have been developed to minimize the ischemic time during lung procurement. We have presented our management protocol and the surgical techniques as used at the Alfred Hospital in Melbourne, Australia. RESULTS: We have transplanted 92 recipients with lungs procured from 91 donors over an 8 year period from May 2006 to July 2014. This accounted for an extra 19% lung transplant operations performed during this time period. Operative mortality was 1% and 8 year survival was 71% in DCD lung recipients. CONCLUSIONS: DCD lung transplantation provides an additional significant pool of lung donors with satisfactory short and long term outcomes.

Acute fibrinoid organizing pneumonia after lung transplantation.

RATIONALE: The barrier to long-term success after lung transplantation is the development of chronic lung allograft dysfunction. As the experience with lung transplantation accrues, it has become increasingly apparent that not all chronic allograft dysfunction is consistent with the traditionally recognized small-airway histological process of obliterative bronchiolitis (OB). OBJECTIVES: To identify and describe chronic allograft dysfunction that is not consistent with the well-described bronchiolitis obliterans syndrome and to further characterize a novel histopathological process, acute fibrinoid organizing pneumonia (AFOP), that has led invariably to respiratory decline and death after lung transplantation. METHODS: We evaluated 194 bilateral lung transplant recipients, identifying 87 individuals who developed chronic allograft dysfunction. They were then classified according to features on spirometry, chest imaging, and histopathological specimens. MEASUREMENTS AND MAIN RESULTS: Two main phenotypes of chronic allograft dysfunction were identified; 39 (45%) recipients were categorized as having developed OB and 22 (25%) as having AFOP. Survival in those who developed AFOP was significantly worse than in those who developed OB (median time to death 101 vs. 294 d; P = 0.02), with all exhibiting a rapid decline in respiratory function leading to death. CONCLUSIONS: AFOP is a novel form of chronic allograft dysfunction exhibiting spirometric, radiological, and histopathological characteristics that differentiate it from OB. The further characterization of chronic allograft dysfunction and its heterogeneous manifestations will allow the targeting of clinical and experimental efforts to prevent and treat chronic allograft dysfunction.

Utility of the Stanford Integrated Psychosocial Assessment for Transplant in predicting outcomes before and after lung transplantation.

BACKGROUND: Optimizing donor use and achieving maximal survival following lung transplantation (LTx) require a pretransplant assessment that identifies clinical, physiological, and psychosocial patient factors associated with both poor and optimal post-LTx survival. We examined the utility of a psychosocial tool, the Stanford Integrated Psychosocial Assessment for Transplant (SIPAT), to identify patient suitability for LTx, as well as its association with clinical outcomes before and after LTx. METHODS: This was a retrospective single-center study analyzing LTx assessment clinical variables (age, gender, diagnosis, functional capacity, nutrition, renal function), with a particular focus on the utility of the SIPAT score, to predict patient suitability for LTx. The same variables were analyzed against LTx waitlist mortality, as well as post-LTx survival. RESULTS: Over an 8-year period dating from December 2012, 914 patients (male 54.4%, mean age 55.2 years) underwent LTx assessment. Patients declined for LTx (n = 152, 16.6%) were older and had reduced functional capacity, nutritional markers, and renal function but had a higher SIPAT score. Once listed for LTx, a higher SIPAT score was not associated with waitlist mortality or reduced post-LTx survival. CONCLUSIONS: The SIPAT tool measures psychosocial suitability for transplantation that can be incorporated into a standardized assessment of LTx suitability. While patients with higher SIPAT score were more likely to be declined for LTx, the SIPAT score did not predict outcome in transplanted patients. A subgroup of patients with high SIPAT scores were successfully transplanted, suggesting that unfavorable psychosocial variables are potentially modifiable with a well-resourced multidisciplinary LTx team.

COVID-19 infection is mild and has minimal impact on lung function in well vaccinated and widely treated lung transplant recipients.

BACKGROUND: COVID-19 has become a common infection affecting lung transplant recipients (LTR), who are at high risk for poor outcomes. Outcomes early in the pandemic were poor, but since the rollout of vaccination and novel COVID-19 treatments, outcomes of LTR have not been well described. Our aim was to evaluate the effect of COVID-19 on the clinical course and lung function trajectory in an Australian cohort of LTR. METHODS: Data were retrospectively collected from LTR with confirmed COVID-19 managed at Alfred Health, between August 2020 and December 2022. Baseline demographics, COVID-19 disease details (including severity) and spirometry pre- and postinfection have been analyzed. RESULTS: A total of 279 LTR were included. The cohort was comorbid, but well vaccinated, with 275/279 (98.6%) having ≥2 COVID-19 vaccines at symptom onset. Severe disease occurred in only 17 cases (6%) and overall mortality was very low (4%). Prompt treatment with antivirals, particularly remdesevir (OR 0.18, 95% CI 0.04-0.81, p = 0.02) and vaccination (OR 0.24, CI 0.08-0.81, p = 0.01), was protective. There was not a clinically significant drop in lung function post-COVID-19 with the median absolute decline in forced expiratory volume (FEV1) being 40 ml (IQR 5-120 ml, p < 0.001), with a decline of >10% occurring in only 42 patients (17%). After multivariate adjustment, only rejection before COVID-19 was significantly associated with FEV1 decline afterward (OR 3.74, 1.12-11.86, p = 0.03). CONCLUSIONS: In our highly COVID-19 vaccinated, promptly treated LTR, the majority of COVID-19 infections were mild and did not result in a clinically significant decline in lung function.

HLA-C mismatching improves outcomes following lung transplantation.

HLA (HLA) are a major barrier to transplant success, as HLA-A and -B molecules are principal ligands for T-cells, and HLA-C for Killer cell Immunoglobulin-like Receptors (KIR), directing Natural Killer (NK) cell function. HLA-C molecules are designated "C1" or "C2" ligands based on residues 77 and 80, which determine the NK cell responses. Here, we investigated donor/recipient HLA-C mismatch associations with the development of chronic lung allograft dysfunction (CLAD) following lung transplantation (LTx). 310 LTx donor/recipient pairs were Next Generation Sequenced and assessed for C1 and C2 allotypes. PIRCHE scores were used to quantify HLA mismatching between donor/recipients at amino acid level and stratify recipients into low, moderate or highly mismatched groups (n = 103-104). Associations between C ligands and freedom from CLAD was assessed with Cox regression models and survival curves. C2/C2 recipients (n = 42) had less CLAD than those with C1/C1 (n = 138) or C1/C2 genotypes (n = 130) (p < 0.05). Incidence of CLAD was lower in C2/C2 recipients receiving a mismatched C1/C1 allograft (n = 14), compared to matched (n = 8) or heterozygous (n = 20) allografts. Furthermore, ~80% of these recipients (C2/C2 recipients receiving C1/C1 transplants) remained CLAD-free for 10 years post-LTx. Recipients with higher HLA-C mismatching had less CLAD (p < 0.05) an observation not explained by linkage disequilibrium with other HLA loci. Our data implicates a role for HLA-C in CLAD development. HLA-C mismatching was not detrimental to LTx outcome, but potentially beneficial, representing a paradigm shift in assessing donor/recipient matching. This may inform better selection of donor/recipient pairs and potentially more targeted approaches to treating CLAD.

Chronic lung allograft dysfunction is associated with an increased number of non-HLA antibodies.

BACKGROUND: Chronic lung allograft dysfunction (CLAD) is the major cause of adverse outcomes in lung transplant recipients. Multiple factors, such as infection, alloimmunity, and autoimmunity, may lead to CLAD. Here, we aim to examine the role of non-human leukocytes antigen (HLA) antibodies in CLAD in a large retrospective cohort. METHODS: We analyzed non-HLA antibodies in the pre- and post-transplant sera of 226 (100 CLAD, 126 stable) lung transplant recipients from 5 centers, and we used a separate cohort to confirm our findings. RESULTS: A panel of 18 non-HLA antibodies was selected for analysis based on their significantly higher positive rates in CLAD vs stable groups. The panel-18 non-HLA antibodies (n > 3) may be positive pre- or post-transplant; the risk for CLAD is higher in the latter. The presence of both non-HLA antibody and HLA donor-specific antibody (DSA) was associated with an augmented risk of CLAD (HR=25.09 [5.52-14.04], p < 0.001), which was higher than that for single-positive patients. In the independent confirmatory cohort of 61 (20 CLAD, 41 stable) lung transplant recipients, the risk for CLAD remained elevated in double-positive patients (HR=10.67 [0.98-115.68], p = 0.052). After adjusting for nonstandard immunosuppression, patients with double-positive DSA/Non-HLA antibodies had an elevated risk for graft loss (HR=2.53 [1.29-4.96], p = 0.007). CONCLUSIONS: Circulating non-HLA antibodies (n > 3) were independently associated with a higher risk for CLAD. Furthermore, when non-HLA antibodies and DSA were detected concomitantly, the risk for CLAD and graft loss was significantly increased. These results show that humoral immunity to HLA and non-HLA antigens may contribute to CLAD development.

Relationship between trough plasma and epithelial lining fluid concentrations of voriconazole in lung transplant recipients.

Trough (predose) voriconazole concentrations in plasma and pulmonary epithelial lining fluid (ELF) of lung transplant recipients receiving oral voriconazole preemptive treatment were determined. The mean (± standard deviation [SD]) ELF/plasma ratio was 12.5 ± 6.3. A strong positive linear relationship was noted between trough plasma and ELF voriconazole concentrations (r(2) = 0.87), suggesting the feasibility of using trough plasma voriconazole concentration as a surrogate to estimate the corresponding concentration in ELF of lung transplant recipients.

Airway oscillometry parameters in baseline lung allograft dysfunction: Associations from a multicenter study.

BACKGROUND: Baseline lung allograft dysfunction (BLAD), the failure to achieve ≥80%-predicted spirometry after lung transplant (LTx), is associated with impaired survival. Physiologic abnormalities in BLAD are poorly understood. Airway oscillometry measures respiratory system mechanics and may provide insight into understanding the mechanisms of BLAD. OBJECTIVES: This study aims to describe and measure the association between airway oscillometry parameters [Reactance (Xrs5, Ax), Resistance (Rrs5, Rrs5-19)] (1) stable LTx recipients, comparing those with normal spirometry and those with BLAD; and (2) in recipients with chronic lung allograft dysfunction (CLAD), comparing those with normal baseline spirometry and those with BLAD. METHODS: A multi-center cross-sectional study was performed including bilateral LTx between January 2020 and June 2021. Participants performed concurrent airway oscillometry and spirometry. Multivariable logistic regression was performed to measure the association between oscillometry parameters and BLAD. RESULTS: A total of 404 LTx recipients performed oscillometry and 253 were included for analysis. Stable allograft function was confirmed in 149 (50.2%) recipients (92 (61.7%) achieving normal spirometry and 57 (38.3%) with BLAD). Among stable LTx recipients, lower Xrs5 Z-Score (aOR 0.50 95% CI 0.37-0.76, p = 0.001) was independently associated with BLAD. CLAD was present in 104 (35.0%) recipients. Among recipients with CLAD, lower Xrs5 Z-Score (aOR 0.73 95% CI 0.56-0.95, p = 0.02) was associated with BLAD. CONCLUSIONS: Oscillometry provides novel physiologic insights into mechanisms of BLAD. The independent association between Xrs5 and BLAD, in both stable recipients and those with CLAD suggests that respiratory mechanics, in particular abnormal elastance, is an important physiologic feature. Further longitudinal studies are needed to understand the trajectory of oscillometry parameters in relation to allograft outcomes.