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.

Advances in lung transplantation: 60 years on.

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.

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.

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.

Multi-Locus Microsatellite Typing of Colonising and Invasive Aspergillus fumigatus Isolates from Patients Post Lung Transplantation and with Chronic Lung Disease.

Aspergillus fumigatus can cause different clinical manifestations/phenotypes in lung transplant (LTx) recipients and patients with chronic respiratory diseases. It can also precipitate chronic lung allograft dysfunction (CLAD) in LTx recipients. Many host factors have been linked with the severity of A. fumigatus infection, but little is known about the contribution of different A. fumigatus strains to the development of different phenotypes and CLAD. We used multi-locus microsatellite typing (MLMT) to determine if there is a relationship between strain (i.e., genotype) and phenotype in 60 patients post LTx or with chronic respiratory disease across two time periods (1 November 2006-31 March 2009 and 1 November 2015-30 June 2017). The MLMT (STRAf) assay was highly discriminatory (Simpson's diversity index of 0.9819-0.9942) with no dominant strain detected. No specific genotype-phenotype link was detected, but several clusters and related strains were associated with invasive aspergillosis (IA) and colonisation in the absence of CLAD. Host factors were linked to clinical phenotypes, with prior lymphopenia significantly more common in IA cases as compared with A. fumigatus-colonised patients (12/16 [75%] vs. 13/36 [36.1%]; p = 0.01), and prior Staphylococcus aureus infection was a significant risk factor for the development of IA (odds ratio 13.8; 95% confidence interval [2.01-279.23]). A trend toward a greater incidence of CMV reactivation post-A. fumigatus isolation was observed (0 vs. 5; p = 0.06) in LTx recipients. Further research is required to determine the pathogenicity and immunogenicity of specific A. fumigatus strains.

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.

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.

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.

Cytomegalovirus Immunity Assays Predict Viremia but not Replication Within the Lung Allograft.

Cytomegalovirus (CMV) infection causes significant morbidity and mortality in lung transplant recipients. Current guidelines use pretransplant donor and recipient CMV serostatus to predict the risk of subsequent CMV replication and length of antiviral prophylaxis. Immunological monitoring may better inform the risk of CMV infection in patients, thereby allowing for improved tailoring of antiviral prophylaxis. In this study, we compared 2 commercially available assays, the QuantiFERON-CMV (QFN-CMV) and T-Track-CMV (enzyme-linked immunosorbent spot assay), to predict the risk of CMV disease in lung transplant recipients. Methods: We performed CMV immunity assays on 32 lung transplant recipients at risk of CMV disease as defined by serostatus (CMV-seropositive recipients, n = 26; or CMV-seronegative lung transplant recipient receiving a CMV-seropositive donor organ, n = 6). QFN-CMV and T-Track were performed on peripheral blood mononuclear cells, and episodes of CMV replication in both serum and bronchoalveolar lavage were found to be correlated to the CMV immune assays. The predictive ability of the assays was determined using Kaplan-Meier curves. Results: There was a degree of concordance between tests, with 44% of recipients positive for both tests and 28% negative for both tests; however, test results were discordant in 28% of cases. A negative result in either the QFN-CMV (P < 0.01) or T-Track (P < 0.05) assays was obtained in a significantly higher number of recipients who experienced CMV replication in the blood. Using these assays together gave higher predictability of CMV replication, with only 1 recipient experiencing CMV replication in the blood who obtained a positive test result for both assays. Neither assay was able to predict recipients who experienced CMV replication in the lung allograft. Conclusions: Our study demonstrates that CMV immunity assays can predict viremia; however, the lack of association with allograft infection suggests that CMV-specific T-cell immunity in the circulation is not associated with the control of CMV replication within the transplanted lung allograft.

Management of nontuberculous mycobacteria in lung transplant cases: an international Delphi study.

Rationale: Nontuberculous mycobacterial (NTM) diseases are difficult-to-treat infections, especially in lung transplant (LTx) candidates. Currently, there is a paucity of recommendations on the management of NTM infections in LTx, focusing on Mycobacterium avium complex (MAC), M. abscessus and M. kansasii. Methods: Pulmonologists, infectious disease specialists, LTx surgeons and Delphi experts with expertise in NTM were recruited. A patient representative was also invited. Three questionnaires comprising questions with multiple response statements were distributed to panellists. Delphi methodology with a Likert scale of 11 points (5 to -5) was applied to define the agreement between experts. Responses from the first two questionnaires were collated to develop a final questionnaire. The consensus was described as a median rating >4 or <-4 indicating for or against the given statement. After the last round of questionnaires, a cumulative report was generated. Results: Panellists recommend performing sputum cultures and a chest computed tomography scan for NTM screening in LTx candidates. Panellists recommend against absolute contraindication to LTx even with multiple positive sputum cultures for MAC, M. abscessus or M. kansasii. Panellists recommend MAC patients on antimicrobial treatment and culture negative can be listed for LTx without further delay. Panellists recommend 6 months of culture-negative for M. kansasii, but 12 months of further treatment from the time of culture-negative for M. abscessus before listing for LTx. Conclusion: This NTM LTx study consensus statement provides essential recommendations for NTM management in LTx and can be utilised as an expert opinion while awaiting evidence-based contributions.

Case Report: Bilateral Lung Transplantation for Rapidly Progressive Undifferentiated Interstitial Lung Disease-A Cautionary Tale.

Interstitial lung disease is fast becoming one of the most common indications for lung transplantation (LTx); however, LTx for Goodpasture's syndrome with pulmonary involvement has not been previously described in the literature. In this report, we outline the case of a young male with undifferentiated rapidly progressive interstitial lung disease who ultimately received a bilateral sequential LTx after deterioration requiring extracorporeal membrane oxygenation. The original disease soon recurred in the graft, and unfortunately, the patient did not survive. The diagnosis of Goodpasture's syndrome was made postmortem and was not clearly evident on examination of the native explanted tissue, nor was there an elevated titer of antiglomerular basement membrane antibodies during his initial work-up. We hypothesize that the donor and recipient's HLA profile made him more susceptible to aggressive disease. In hindsight, active Goodpasture's disease would have been a contraindication to proceed to transplantation. This case is a cautionary reminder of the high stakes of performing LTx without a certain diagnosis.

Survival after lipiodol escape at embolization for lung transplant chylothorax.

We present imaging of lipiodil escape after thoracic duct embolization for transplant associated chylothorax leading to transient impairment, then resolution.

Rescue Everolimus Post Lung Transplantation is Not Associated With an Increased Incidence of CLAD or CLAD-Related Mortality.

Everolimus (EVE) has been used as a calcineurin inhibitor (CNI) minimization/ elimination agent or to augment immunosuppression in lung transplant recipients (LTR) with CNI-induced nephrotoxicity or neurotoxicity. The long-term evidence for survival and progression to chronic lung allograft dysfunction (CLAD) is lacking. The primary aim was to compare survival outcomes of LTR starting EVE-based immunosuppression with those remaining on CNI-based regimens. The secondary outcomes being time to CLAD, incidence of CLAD and the emergence of obstructive (BOS) or restrictive (RAS) phenotypes. Single center retrospective study of 91 LTR starting EVE-based immunosuppression matched 1:1 with LTR remaining on CNI-based immunosuppression. On multivariate analysis, compared to those remaining on CNI-based immunosuppression, starting EVE was not associated with poorer survival [HR 1.04, 95% CI: 0.67-1.61, p = 0.853], or a statistically significant faster time to CLAD [HR 1.34, 95% CI: 0.87-2.04, p = 0.182]. There was no difference in the emergence of CLAD (EVE, [n = 57, 62.6%] vs. CNI-based [n = 52, 57.1%], p = 0.41), or the incidence of BOS (p = 0.60) or RAS (p = 0.16) between the two groups. Introduction of EVE-based immunosuppression does not increase the risk of death or accelerate the progression to CLAD compared to CNI-based immunosuppression.

Determining Clinical Thresholds for Donor HLA Eplet Compatibility to Predict Best Outcomes Following Lung Transplantation.

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.

Survival and left ventricular dysfunction post lung transplantation for pulmonary arterial hypertension.

PURPOSE: Bilateral lung transplantation for end-stage pulmonary arterial hypertension (PAH) is traditionally associated with higher early post-transplant mortality when compared with other indications. Changes in perioperative management, including the growing use of perioperative extracorporeal membrane oxygenation (ECMO) and an increased awareness of postoperative left ventricular dysfunction (LVD), have resulted in outcomes that are uncertain. MATERIALS AND METHODS: We conducted a single-center, retrospective observational study at a lung transplantation center in Melbourne, Australia, from 2006 to 2019. ECMO use was categorized as preoperative, prophylactic, or rescue. Postoperative LVD was defined as a reduction in left ventricular function on echocardiography or using strict clinical criteria. RESULTS: 50 patients underwent lung transplantation for PAH. 12-month survival was 48/50 (96%). ECMO was used in 26 (52%) patients, and the use of prophylactic VA-ECMO increased over the study period. Postoperative LVD was diagnosed in 21 (42%) patients. 12-month survival and left ventricular function was no different between LVD and non-LVD groups. CONCLUSIONS: This study showed that high survival rates can be achieved following lung transplantation for PAH. We found that ECMO utilization was common, and indications have changed over time. LVD was common but did not impact 12-month survival.

Controlled DCD lung transplantation: Circumventing imagined and real barriers-time for an international taskforce?

Controlled donation after circulatory death (DCD) has the potential to substantially increase the number of lung transplants thus offsetting some of the imbalance between need and organ availability. We examine the potential benefits associated with increased DCD utilization as well as the perceived barriers to the expansion of DCD. Solutions are offered as a means to expand DCD utilization across centers and nations.

Real-world experience of Quantiferon-CMV directed prophylaxis in lung transplant recipients.

BACKGROUND: 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. METHODS: 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 infection >1,000 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. RESULTS: 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). CONCLUSIONS: 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.