HLA Matching at the Eplet Level Protects Against Chronic Lung Allograft Dysfunction.

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

Donation After Circulatory Determination of Death Lung Transplantation for Pulmonary Arterial Hypertension: Passing the Toughest Test.

Lung transplantation (LTx) is a therapeutic option for severe pulmonary arterial hypertension (PAH) patients failing optimal medical therapy. The use of donation after circulatory determination of death (DCDD) donor lungs for PAH LTx has rarely been reported, primarily reflecting concerns that DCDD lungs represent extended criteria donors, at risk of morbidity and mortality. A retrospective study of all Alfred Hospital DCDD and DNDD (donation after neurologic determination of death) PAH LTx was undertaken. Protocolized fluid/inotrope/ventilator and extracorporeal membrane oxygenation (ECMO) strategies were utilized. Since our first DCDD LTx in 2006, 512 LTx have been performed. Of 31 PAH recipients, 11 received DCDD lungs (11% of DCDD LTx) and 20 received DNDD lungs (5% of DNDD LTx) (p = 0.04). Only one PAH patient died on the LTx waiting list. Peri-LTx ECMO was utilized in 3/11 (27%) DCDD and 6/20 (30%) DNDD PAH LTx (p = 0.68). Primary graft dysfunction, intensive care, and overall stay were the same in both groups. Survival at 1 and 8 years was 100% and 80% for DCDD versus 100% and 70% for DNDD LTx (p = 0.88), respectively. In conclusion, excellent results can be achieved for PAH LTx. DCDD donor lungs are not extended lungs per se having passed the toughest test.

Evolving practice: X-linked agammaglobulinemia and lung transplantation.

X-linked agammaglobulinemia (XLA) is a rare primary humoral immunodeficiency syndrome characterized by agammaglobulinemia, recurrent infections and bronchiectasis. Despite the association with end-stage bronchiectasis, the literature on XLA and lung transplantation is extremely limited. We report a series of 6 XLA patients with bronchiectasis who underwent lung transplantation. Short-term outcomes were excellent however long-term outcomes were disappointing with a high incidence of pulmonary sepsis and chronic lung allograft dysfunction (CLAD).

Outcomes of simultaneous heart-kidney and lung-kidney transplantations: the Australian and New Zealand experience.

BACKGROUND: Heart or lung transplantation alone in individuals with significant pre-existing renal impairment results in high mortality and morbidity. Simultaneous heart-kidney (SHK) or simultaneous lung-kidney (SLK) transplantation may be considered in patients with dual organ failure not suitable for single organ transplantation. AIM: We aimed to outline the Australian and New Zealand experience of SHK and SLK transplantations, focussing on patient characteristics and survival. METHODS: We analysed all SHK and SLK transplants performed in four centres across Australia and New Zealand between 1990 and 2014. RESULTS: Over the study period, 35 SHK and 3 SLK transplants were performed across 4 transplant centres. Mean age at transplantation for SHK transplants was 45 years, and for SLK transplant was 27 years. The most common aetiology of renal failure was glomerulonephritis. Most SHK transplant patients (77%) required renal replacement therapy prior to transplantation, with only one of the three patients undergoing SLK transplant, dialysis dependent. One-year survival for the cohort was 79%, which is lower than reported for single organ transplantation. However, 5- and 10-year survivals of 76% and 68%, respectively, were comparable. Isolated renal graft loss was seen in five patients, with only one patient successfully re-transplanted and the rest commencing dialysis. CONCLUSION: The Australian and New Zealand experience of SHK and SLK includes 38 patients with a high 1-year mortality, but excellent 5- and 10-year survivals. Based on this, it seems reasonable to continue to offer combined organ transplantation to select patients with dual organ failure.

Diabetes is a major risk factor for mortality after lung transplantation.

Survival following lung transplant (LTx) remains significantly lower than after other solid organ transplants. Diabetes mellitus (DM) is a mortality risk factor not comprehensively studied in LTx recipients. Notably, neither the relation of time of DM onset to survival nor the actual causes of DM-associated excess mortality have been described. We determined DM status, DM diagnosis date and all-cause mortality in 386 consecutive adults who underwent LTx at our institution from January 1, 2001 to July 31, 2010. The relationship of DM to survival both as a categorical and time-dependent variable was studied. Fifty-three percent of patients had DM. Overall median survival was 5.2 (95% CI 3.8-6.6) years. At study end, 52% of patients had died, of whom 64% had DM. Estimated median survival was 10 years in patients without DM, 5.0 (3.3-6.8) years in patients with DM pre- and post-LTx and 4.3 (3.1-5.5) years in patients with new onset DM. As a time-dependent covariate, DM was the strongest risk factor for mortality, hazard ratio 3.96 (2.85-5.51). Bronchiolitis obliterans syndrome was the main cause of death in all patients surviving >90 days, but its incidence was not increased in patients with DM. Further studies are warranted to determine whether improved glycemic control could improve outcomes in LTx recipients.

A randomized, double-blind, placebo-controlled, multicenter study of rabbit ATG in the prophylaxis of acute rejection in lung transplantation.

ATG-Fresenius S (ATG-F) is a polyclonal anti-human-T-lymphocyte immunoglobulin preparation that has been clinically developed to prevent episodes of acute cellular rejection. This study evaluated the efficacy and safety of ATG-F at doses of 5 and 9 mg/kg versus placebo in adult recipients of a primary lung allograft. The primary efficacy composite end point was defined as death, graft loss, acute rejection and/or loss to follow-up within 12 months of transplantation. The interim analysis showed the ATG-F 5 mg/kg treatment to be inefficacious, and it would be impossible to enroll enough patients to power the study to show a difference between the 9 mg/kg arm and the placebo arm. Therefore, the main focus of the study shifted to the safety end points and a descriptive analysis of the primary end point. At 12 months posttransplant, the efficacy failure rate was not significantly different between the ATG-F 9 mg/kg group and the placebo group (40.2% vs. 36.7%, respectively). This large study did not demonstrate a significant reduction in acute cellular rejection, graft loss or death with single-dose induction therapy with ATG-F within the first year after lung transplantation.

Patients' expectations and experiences of rehabilitation following lung transplantation.

INTRODUCTION: Exercise rehabilitation is a key element of care following lung transplantation; however, little is known about the patients' experience of rehabilitation, or whether it meets the needs of this complex patient group. This qualitative study explored patients' expectations of a supervised exercise rehabilitation program following lung transplantation. METHODS: Participants undertook two semi-structured interviews, one before and one after the rehabilitation program. Interviews were digitally recorded, and themes were developed using line-by-line iterative thematic analysis and grounded theory. RESULTS: Eighteen adults (11 females) with mean age of 52 participated in a mean of 26 sessions of exercise training. Themes were (i) desire for normalcy including resuming family roles and performing everyday activities; (ii) the importance of rehabilitation as the mechanism for how this transformation occurred; (iii) the benefits of exercising in a group setting; and (iv) the limitations on rehabilitation that were imposed by comorbidities, either existing pre-transplant or occurring as a postoperative sequelae. CONCLUSION: Post-transplant exercise rehabilitation was perceived as a highly valuable tool that assisted recipients to return to "normal life." Group exercise was motivational, offered peer support, and therefore was advantageous to assist patients to achieve their desired physical performance level following transplantation.

Lessons and insights from ABO-incompatible lung transplantation.

With ABO blood group incompatibility (ABOi) between donor and recipient becoming a part of mainstream living-donor renal transplantation, the applicability of ABOi to other areas of transplantation is being reconsidered. Here we present a case of inadvertent ABOi lung retransplantation managed successfully with initial plasmapheresis, antithymocyte globulin and intravenous immunoglobulin; and subsequently with oral cyclophosphamide and sirolimus in addition to tacrolimus and prednisolone. Interestingly, in the setting of solid levels of tacrolimus and sirolimus, the patient developed a fatal thrombotic microangiopathy of uncertain origin subsequent to the cessation of cyclophosphamide at 9 years posttransplant. It is apparent that ABOi lung transplantation can result in surprisingly successful long-term outcomes. Low pretransplant antibody titers likely aid this and, in pediatric neonatal or infant cases, this may not be uncommon. We must proceed cautiously as there are significant risks. Understanding the monitoring, prevention and treatment of lung transplant antibody-mediated rejection, while avoiding the long-term complications of overimmunosuppression, will be the keys to the success of future cases.

Preemptive treatment with voriconazole in lung transplant recipients.

BACKGROUND: Invasive fungal infection (IFI) is associated with high mortality in lung transplant (LTx) recipients. Data for voriconazole use in preemptive treatment remain scant. METHOD: A single-center, retrospective cohort study was conducted to investigate the efficacy and safety of voriconazole preemptive treatment for post-LTx colonization. RESULTS: We reviewed 62 adult LTx patients, who received their first course of voriconazole prophylaxis (i.e., as preemptive treatment) between July 2003 and June 2010. Outcomes were determined at 6 and 12 months after commencing therapy. Aspergillus fumigatus (75.8%) was the most common colonizing isolate. Median duration of voriconazole prophylaxis was 85 days. At 6 months, 1 LTx patient (1.6%) had IFI, 47 (75.8%) cleared their colonizing isolate, 3 (4.8%) had persistent colonization, 7 (11.3%) had recurrent colonization, 1 (1.6%) had new colonization, 2 (3.2%) had aspergilloma, and 1 (1.6%) was clinically unstable with no culture results. Sixteen (25.8%) had died by 12 months. Ten (16.1%) had likely drug-related hepatotoxicity. LTx patients with diabetes mellitus within 30 days before commencing prophylaxis were at higher risk of recurrent Aspergillus colonization at 6 months (P = 0.030). Chronic rejection within 30 days before prophylaxis was associated with 12-month mortality (P = 0.007). CONCLUSIONS: Voriconazole preemptive treatment resulted in low incidence of IFI and IFI-related mortality.

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.

Excellent clinical outcomes from a national donation-after-determination-of-cardiac-death lung transplant collaborative.

Donation-after-Determination-of-Cardiac-Death (DDCD) donor lungs can potentially increase the pool of lungs available for Lung Transplantation (LTx). This paper presents the 5-year results for Maastricht category III DDCD LTx undertaken by the multicenter Australian National DDCD LTx Collaborative. The Collaborative was developed to facilitate interaction with the Australian Organ Donation Authority, standardization of definitions, guidelines, education and audit processes. Between 2006 and 2011 there were 174 actual DDCD category III donors (with an additional 37 potentially suitable donors who did not arrest in the mandated 90 min postwithdrawal window), of whom 71 donated lungs for 70 bilateral LTx and two single LTx. In 2010 this equated to an "extra" 28% of donors utilized for LTx. Withdrawal to pulmonary arterial flush was a mean of 35.2 ± 4.0 min (range 18-89). At 24 h, the incidence of grade 3 primary graft dysfunction was 8.5%[median PaO(2)/FiO(2) ratio 315 (range 50-507)]. Overall the incidence of grade 3 chronic rejections was 5%. One- and 5-year actuarial survival was 97% and 90%, versus 90% and 61%, respectively, for 503 contemporaneous brain-dead donor lung transplants. Category III DDCD LTx therefore provides a significant, practical, additional quality source of transplantable lungs.

The impact of pandemic influenza A H1N1 2009 on Australian lung transplant recipients.

Influenza A H1N1 2009 led to 189 deaths during the Australian pandemic. Community-acquired respiratory viruses not only can cause prolonged allograft dysfunction in lung transplant recipients but have also been linked to bronchiolitis obliterans syndrome (BOS). We report the impact of the 2009 H1N1 pandemic on Australian lung transplant recipients. An observational study of confirmed H1N1 cases was conducted across five Australian lung transplant programs during the pandemic. An electronic database collected patient demographics, clinical presentation, management and outcomes up to a year follow-up. Twenty-four H1N1 cases (mean age 43 ± 14 years, eight females) were identified, incidence of 3%. Illness severity varied from upper respiratory tract symptoms only in 29% to lung allograft dysfunction (≥10% decline FEV1) in 75% to death in 5 (21%) cases (pre-existing BOS grade 3, n = 4). Treatment with oseltamivir occurred in all but one case confirmed after death, reduced immunosuppression, n = 1, augmented corticosteroid therapy, n = 16, and mechanical/noninvasive ventilation, n = 4. There was BOS grade decline within a year in six cases (32%). In conclusion, Australian lung transplant recipients were variably affected by the H1N1 pandemic mirroring the broader community with significant morbidity and mortality. After initial recovery, a considerable proportion of survivors have demonstrated BOS progression.

Antifungal prophylaxis in lung transplantation--a world-wide survey.

While variations in antifungal prophylaxis have been previously reported in lung transplant (LTx) recipients, recent clinical practice is unknown. Our aim was to determine current antifungal prophylactic practice in LTx centers world-wide. One nominated LTx clinician from each active center was invited by e-mail to participate in a web-based survey between September 2009 and January 2010. Fifty-seven percent (58/102) responded. The majority of responses were from medical directors of LTx centers (72.4%), and from the United States (44.8%). Within the first 6 months post-LTx, most centers (58.6%) employed universal prophylaxis, with 97.1% targeting Aspergillus species. Voriconazole alone, and in combination with inhaled amphotericin B (AmB), were the preferred first-line agents. Intolerance to side effects of voriconazole (69.2%) was the main reason for switching to alternatives. Beyond 6 months post-LTx, most (51.8%) did not employ antifungal prophylaxis. Fifteen centers (26.0%) conducted routine antifungal therapeutic drug monitoring during prophylactic period. There are differences in strategies employed between U.S. and European centers. Most respondents indicated a need for antifungal prophylactic guidelines. In comparison to earlier findings, there was a major shift toward prophylaxis with voriconazole and an increased use of echinocandins, posaconazole and inhaled lipid formulation AmB.

Cytomegalovirus replication within the lung allograft is associated with bronchiolitis obliterans syndrome.

Early studies reported cytomegalovirus (CMV) pneumonitis as a risk factor for development of bronchiolitis obliterans syndrome (BOS) following lung transplantation. While improvements in antiviral prophylaxis have resulted in a decreased incidence of CMV pneumonitis, molecular diagnostic techniques allow diagnosis of subclinical CMV replication in the allograft. We hypothesized that this subclinical CMV replication was associated with development of BOS. We retrospectively evaluated 192 lung transplant recipients (LTR) from a single center between 2001 and 2009. Quantitative (PCR) analysis of CMV viral load and histological evidence of CMV pneumonitis and acute cellular rejection was determined on 1749 bronchoalveolar lavage (BAL) specimens and 1536 transbronchial biopsies. CMV was detected in the BAL of 41% of LTR and was significantly associated with the development of BOS (HR 1.8 [1.1-2.8], p = 0.02). This association persisted when CMV was considered more accurately as a time-dependent variable (HR 2.1 [1.3-3.3], p = 0.003) and after adjustment for significant covariates in a multivariate model. CMV replication in the lung allograft is common following lung transplantation and is associated with increased risk of BOS. As antiviral prophylaxis adequately suppresses CMV longer prophylactic strategies may improve long-term outcome in lung transplantation.

Comparative immunogenicity and enhanceability of individual H-2K and H-2D specificities of the murine histocompatibility-2 complex.

The immunogenicity of single, private H-2 specificities has been tested. In most cases, the specificity was known to be confined either to H-2K or to H-2D. This was accomplished by the appropriate choice, as donor and recipient, or parent of the F(1) hybrid recipient, of congenic strains differing at H-2 only, and of recombinant haplotypes in donor and/or recipient. By nearly all tests, the H-2K antigen appeared to be a stronger immunogen than the H-2D antigen. Skin grafts with an H-2K difference showed median survival times (MST) of 9.3-14.5 days; for H-2D the values were 13.8-18.6. The difference was also present, though narrowed, for second-set grafts. H-2K grafts regularly engendered a demonstrable cytotoxic antibody response; with H-2D differences the response was absent or very weak. K end cytotoxic titers after multiple immunizations with lymphoid tissues ranged from 1/32 to 1/2,048, D end titers from 0 to 1/128. Hemagglutination titers showed no clear difference. The results of passive enhancement of skin grafts with H-2 alloantibody produced in donor recipient combinations, identical to those used for the skin grafts showed a different pattern. H-2K, despite its greater immunogenic strength was more easily enhanced than H-2D. Prolongation of MST's for H-2K was 2.4-6.7 days, for H-2D grafts, 0.2-1.5 days.

Genetic control of the immune response. Mapping of the Ir-1 locus.

Eleven strains of mice bearing recombinant H-2 chromosomes derived from known crossover events between known H-2 types were immunized with a series of branched, multichain, synthetic polypeptide antigens [(T,G)-A--L, (H,G)-A--L, and (Phe,G)-A--L]. Results with nine of the eleven H-2 recombinants indicated that the gene(s) controlling immune response to these synthetic polypeptides (Ir-1) is on the centromeric or H-2K part of the recombinant H-2 chromosome. Results with two of the eleven recombinant H-2 chromosomes indicated that Ir-1 was on the telomeric or H-2D part of the recombinant H-2 chromosome. Both of these recombinants were derived from crossovers between the H-2K locus and the Ss-Slp locus near the center of the H-2 region. One of these recombinants, H-2(y), was derived from a known single crossover event. These results indicate that Ir-1 lies near the center of the H-2 region between the H-2K locus and the Ss-Slp locus. The results of a four-point linkage test were consistent with these results. In 484 offspring of a cross designed to detect recombinants between H-2 and Ir-1, only two putative recombinants were detected. Both of these recombinants were confirmed by progeny testing. Extensive analysis of one of them has shown that the crossover event occurred within the H-2 region. (Testing of the second recombinant is currently under way.) Thus, in the linkage test, recombinants between H-2 and Ir-1 are in fact intra-H-2 crossovers. These results permit assignment of Ir-1 to a position between the H-2K locus and the Ss-Slp locus.

Does anaesthetic management affect early outcomes after lung transplant? An exploratory analysis.

BACKGROUND: Primary graft dysfunction (PGD) is a predominant cause of early morbidity and mortality after lung transplantation. Although substantial work has been done to understand risk factors for PGD in terms of donor, recipient, and surgical factors, little is understood regarding the potential role of anaesthetic management variables in its development. METHODS: We conducted a retrospective exploratory analysis of 107 consecutive lung transplants to determine if anaesthesia factors were associated with early graft function quantified by Pa(O(2))/Fi(O(2)). Multivariate regression techniques were used to explore the association between anaesthetic management variables and Pa(O(2))/Fi(O(2)) ratio 12 h after operation. The relationship between these variables and both time to tracheal extubation and intensive care unit (ICU) length of stay was further examined using the Cox proportional hazards. RESULTS: On multivariate analysis, increasing volume of intraoperative colloid, comprising predominantly Gelofusine (succinylated gelatin), was independently associated with a lower Pa(O(2))/Fi(O(2)) 12 h post-transplantation [beta coefficient -42 mm Hg, 95% confidence interval (CI) -7 to -77 mm Hg, P=0.02] and reduced rate of extubation [hazard ratio (HR) 0.65, 95% CI 0.49-0.84, P=0.001]. There was a trend for intraoperative colloid to be associated with a reduced rate of ICU discharge (HR 0.79, 95% CI 0.31-1.02, P=0.07). CONCLUSIONS: We observed an inverse relationship between volume of intraoperative colloid and early lung allograft function. The association persists, despite detailed sensitivity analyses and adjustment for potential confounding variables. Further studies are required to confirm these findings and explore potential mechanisms through which these associations may act.

Medium-term outcome of fundoplication after lung transplantation.

Gastroesophageal reflux disease (GERD) in lung transplant recipients has gained increasing attention as a factor in allograft failure. There are few data on the impact of fundoplication on survival or lung function, and less on its effect on symptoms or quality of life. Patients undergoing fundoplication following lung transplantation from 1999 to 2005 were included in the study. Patient satisfaction, changes in GERD symptoms, and the presence of known side effects were assessed. The effect on lung function, body mass index, and rate of progression to the bronchiolitis obliterans syndrome (BOS) were recorded. Twenty-one patients (13 males), in whom reflux was confirmed on objective criteria, were included, with a mean age of 43 years (range 20-68). Time between transplantation and fundoplication was 768 days (range 145-1524). The indication for fundoplication was suspected microaspiration in 13 and symptoms of GERD in 8. There was one perioperative death, at day 17. There were three other late deaths. Fundoplication did not appear to affect progression to BOS stage 1, although it may have slowed progression to stage 2 and 3. Forced expiratory volume-1% predicted was 72.9 (20.9), 6 months prior to fundoplication and 70.4 (26.8), six months post-fundoplication, P= 0.33. Body mass index decreased significantly in the 6 months following fundoplication (23 kg/m(2) vs. 21 kg/m(2), P= 0.05). Patients were satisfied with the outcome of the fundoplication (mean satisfaction score 8.8 out of 10). Prevalence of GERD symptoms decreased significantly following surgery (11 of 14 vs. 4 of 17, P= 0.002). Fundoplication does not reverse any decline in lung function when performed at a late stage post-lung transplantation in patients with objectively confirmed GERD. It may, however, slow progression to the more advanced stages of BOS. Reflux symptoms are well controlled and patients are highly satisfied. Whether performing fundoplication early post-lung transplant in selected patients can prevent BOS and improve long-term outcomes requires formal evaluation.