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.

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.

Can we HALT obesity following lung transplant? A Dietitian- and Physiotherapy-directed pilot intervention.

INTRODUCTION: Unintentional weight gain, overweight and obesity following solid organ transplantation (SOT) are well-established and linked to morbidity and mortality risk factors. No interventional studies aimed at prevention have been undertaken among lung transplant (LTx) recipients. The combination of group education and telephone coaching is effective in the general population but is untested among SOT cohorts. METHODS: A non-randomized, interventional pilot study was conducted among new LTx recipients. The control group received standard care. In addition to standard care, the intervention involved four group education and four individual, telephone coaching sessions over 12-months. Data collection occurred at 2 weeks, 3- and 12 months post-LTx. Measurements included weight, BMI, fat mass (FM), fat mass index (FMI), fat-free mass (FFM), fat-free mass index (FFMI), waist circumference (WC), visceral adipose tissue (VAT), nutrition knowledge, diet, physical activity, lipid profile, HbA1C , FEV1 , six-minute walk distance and patient satisfaction. RESULTS: Fifteen LTx recipients were recruited into each group. One control participant died 120 days post-LTx, unrelated to the study. There were trends towards lower increases in weight (6.7±7.2 kg vs. 9.8±11.3 kg), BMI (9.6% of baseline vs. 13%), FM (19.7% vs. 40%), FMI, VAT (7.1% vs. 30.8%) and WC (5.5% vs. 9.5%), and greater increases in FFM and FFMI (all P > .05), among the intervention group by 12 months. The intervention was well-accepted by participants. CONCLUSION: This feasible intervention demonstrated non-significant, but clinically meaningful, favorable weight and body composition trends among LTx recipients over 12 months compared to standard care.

When immunosuppression and COVID-19 intersect: An exploratory qualitative study of young lung transplant recipient perceptions of daily life during a pandemic.

BACKGROUND: The COVID-19 pandemic poses an increased risk of infection, severe illness, hospitalization and mortality for young people who are immunosuppressed, including lung transplant (LTx) recipients. The aim of this study was to explore the intersection between immunosuppression and COVID-19, through the impacts of the pandemic upon the daily lives of young LTx recipients residing in the Australian state of Victoria. METHODS: An exploratory qualitative research study was undertaken via consumer engagement. A purposive sample of 11 LTx recipients, residing in Victoria, was recruited during the first year of the COVID-19 pandemic. Semi-structured interviews were conducted to gain insights into their daily life and healthcare experiences, including the impacts of the COVID-19 pandemic. Data were interpreted using thematic analysis. RESULTS: Four major themes were identified: (1) occupational deprivation due to the intersection of COVID-19 and lung transplant; (2) resilience and acceptance of restrictions; (3) infection control and vigilance about risk; and (4) care experiences of telehealth. CONCLUSIONS: Occupational deprivation emerged as a common theme, specifically in the context of loss of access to meaningful everyday activities of developmental significance. However, participants also commonly reflected upon their ability to flexibly adjust to changing socially regulated community and healthcare environments. A high degree of acceptance and compliance with public health orders was self-reported, may be indicative of this cohort's long-term experience of chronic illness and their understanding of the importance of minimizing infection risks. Youth-informed healthcare strategies were identified as keystone to engaging them in institutional change and program adaptation during a pandemic.

The Utility of Prophylactic Zoledronic Acid in Patients Undergoing Lung Transplantation.

Osteoporosis is prevalent among lung transplant candidates and is exacerbated post-transplant by immunosuppressive therapy. Low bone mineral density (BMD) is a well-recognized surrogate for fragility fracture risk, which is associated with significant morbidity and mortality. Intravenous zoledronic acid (ZA) effectively reduces BMD loss and prevents fractures in postmenopausal osteoporosis. Many groups, ours included, prophylactically treat lung transplant recipients (LTR) with bisphosphonates, but no documented consensus currently exists. Our protocol comprises ZA every 6-months from transplant wait-listing, with interval reassessment to guide ongoing treatment. We evaluate the impact of a dose of ZA within 6 months of transplantation on BMD and fracture occurrence. A retrospective analysis was performed on all adult LTR from April 2012 to October 2014, of which 60 met our inclusion criteria. LTR who received ZA within 6 months of transplantation (n = 37) were compared to those who did not (n = 23), and followed up for a minimum of three years. Outcome measures were BMD change at the lumbar spine and femur (primary), and fracture occurrence (secondary). LTR treated with ZA within 6 months of transplantation experienced a median BMD change of +8.11% at the lumbar spine and +1.39% at the femur, compared to -1.20% and -3.92%, respectively, in LTR who did not receive a ZA dose within 6 months of transplantation (p = 0.002 & p = 0.008 respectively). Our findings indicate that prophylactic ZA within 6 months of transplantation prevents BMD loss in LTR.

Atrial Flutter and Fibrillation Following Lung Transplantation: Incidence, Associations and a Suggested Therapeutic Algorithm.

BACKGROUND: Atrial arrhythmias are relatively common following lung transplantation and confer considerable perioperative risk, specifically haemodynamic instability, pulmonary congestion, dyspnoea, and can mask other post-transplant complications such as infection or acute rejection. However, for most patients, arrhythmias are limited to the short-term perioperative period. METHODS: We present a retrospective case-control analysis of 200 lung transplant recipients and using multivariate regression analysis, document the present incidence, risk factors, and outcomes between the two groups. RESULTS: Twenty-five per cent (25%) of lung transplantation patients developed atrial flutter or fibrillation, most frequently at day 5-7 post lung transplantation, and more commonly present in older recipients and those with underlying chronic obstructive pulmonary disease (COPD), but not in those with previously noted structural heart disease, or in those undergoing single rather than double lung transplants. Atrial arrhythmias were associated with increased intensive care unit and overall length of stay, but were not associated with increased risk of in-hospital stroke, or mortality. Based on our experience, we propose a suggested management algorithm for pharmacological and mechanical rate/rhythm control strategies, for anticoagulation, and discuss the appropriate duration of treatment. CONCLUSIONS: Atrial arrhythmias are relatively common post lung transplantation. Carefully managed, the associated risk of perioperative morbidity and mortality can be mitigated. Further prospective studies are required to validate these strategies.

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.

Cryptococcal infection in lung transplant recipients: A 5-year retrospective review at an Australian transplant center.

Cryptococcosis is a common invasive fungal infection (IFI) in solid organ transplant (SOT) recipients. Little is known about cryptococcosis in lung transplant (LTx) recipients despite having one of the highest risks of infection. The aim of this study was to describe demographic and clinical features of cryptococcal infection in LTx recipients. We performed a retrospective, observational study of cryptococcal infection in LTx recipients at The Alfred Hospital in Melbourne, Australia, from 2012 to 2017. A total of 11 cases were identified. Seven patients (64%) were male and the median age was 54.7 years (range 34-69 years). Diagnosis occurred at a median of 233 days (range 1-3650 days) post-transplant. Nine patients (82%) had isolated pulmonary infection of whom 7 (78%) were asymptomatic. All were treated with oral antifungal therapy and 1 required surgical resection of infected lung. Two patients (18%) had disseminated infection; 1 with pulmonary and central nervous system (CNS) infection and 1 with isolated CNS infection. Both patients presented with headache and brain imaging demonstrated cerebral edema, myelinosis, and leptomeningeal enhancement. One of these patients died. This study highlights the fact that cryptococcal infection should remain a consideration in asymptomatic LTx recipients, especially in the presence of non-specific nodules on chest imaging, and that the presence of headache in these patients requires urgent investigation for CNS infection.

A successful aggressive surgical and medical approach to pulmonary artery obstruction due to Mycobacterium abscessus infection post lung transplantation.

Mycobacterium abscessus infection following lung transplantation has historically been associated with poor outcomes. We report a case of bilateral lung retransplantation complicated by obstruction of the right pulmonary artery secondary to M. abscessus mycotic aneurysm. Aggressive surgical management, including reconstruction of the right pulmonary artery, was undertaken with prolonged antimicrobial therapy. Thirty-six months later, antibiotics have been discontinued and the patient has stable soft tissue chest wall disease with good graft function. Mortality and morbidity associated with M. abscessus infection is considerable but this case illustrates that with aggressive early management, outcomes may be favorable.

Lung transplantation in Australia, 1986-2018: more than 30 years in the making.

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

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.

Suicide right ventricle after lung transplantation for pulmonary vascular disease.

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

Donor-Derived Mycoplasma hominis and an Apparent Cluster of M. hominis Cases in Solid Organ Transplant Recipients.

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

Herpes simplex virus-2 transmission following solid organ transplantation: Donor-derived infection and transplantation from prior organ recipients.

BACKGROUND: Owing to limited availability of donor organs, previous solid organ transplant (SOT) recipients are increasingly considered as potential organ donors. We report donor-derived transmission of herpes simplex virus type-2 (HSV-2) to two clusters of SOT recipients with transmission from the original donor and an HSV-2-infected recipient who subsequently became a donor. METHODS: We reviewed medical records of the donors and recipients in both clusters. Pre-transplant serology and virological features of HSV-2 were characterized. Genotyping of HSV-2 isolates to determine potential for donor transmission of HSV-2 through transplantation of organs from prior organ recipients was performed. RESULTS: A kidney-pancreas recipient died day 9 post transplant. Following confirmation of brain death, the lungs and recently transplanted kidney were donated to two further recipients. The liver was not retrieved, but biopsy confirmed HSV-2 infection. Testing on the original donor showed negative HSV-2 polymerase chain reaction and HSV immunoglobulin (Ig)M, but positive HSV-2 IgG. The liver recipient from the original donor developed HSV-2 hepatitis and cutaneous infection that responded to treatment with intravenous acyclovir. In the second cluster, lung and kidney recipients both developed HSV-2 viremia that was successfully treated with antiviral therapy. Genotyping of all HSV-2-positive samples showed 100% sequence homology for three recipients. CONCLUSIONS: Donor-derived HSV infection affected two clusters of recipients because of transplantation of organs from a prior organ recipient. HSV should be considered as a possible cause of illness in febrile SOT recipients in the immediate post-transplant period and may cause disseminated disease and re-infection in HSV-2-seropositive recipients. Testing of HSV serology and prophylaxis may be considered in SOT recipients not receiving cytomegalovirus prophylaxis.

Antibody-mediated rejection.

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

Lung transplantation in adults and children: putting lung function into perspective.

The number of lung transplants performed globally continues to increase year after year. Despite this growing experience, long-term outcomes following lung transplantation continue to fall far short of that described in other solid-organ transplant settings. Chronic lung allograft dysfunction (CLAD) remains common and is the end result of exposure to a multitude of potentially injurious insults that include alloreactivity and infection among others. Central to any description of the clinical performance of the transplanted lung is an assessment of its physiology by pulmonary function testing. Spirometry and the evaluation of forced expiratory volume in 1 s and forced vital capacity, remain core indices that are measured as part of routine clinical follow-up. Spirometry, while reproducible in detecting lung allograft dysfunction, lacks specificity in differentiating the different complications of lung transplantation such as rejection, infection and bronchiolitis obliterans. However, interpretation of spirometry is central to defining the different 'chronic rejection' phenotypes. It is becoming apparent that the maximal lung function achieved following transplantation, as measured by spirometry, is influenced by a number of donor and recipient factors as well as the type of surgery performed (single vs double vs lobar lung transplant). In this review, we discuss the wide range of variables that need to be considered when interpreting lung function testing in lung transplant recipients. Finally, we review a number of novel measurements of pulmonary function that may in the future serve as better biomarkers to detect and diagnose the cause of the failing lung allograft.

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.

Donor selection and management.

This article reviews recent developments in the selection, assessment, and management of the potential lung donor, which aim to increase donor organ use. The scarcity of suitable donor organs continues to limit lung transplantation, but the situation is changing. An expanded donor pool, including the now widespread use of donation after cardiac death (DCD) lungs; the use of extended donor lungs; and the ability of ex vivo lung perfusion (EVLP) to evaluate and improve donor lungs are key initiatives. These strategies have substantially lifted donor lung utilization rates from historically low levels of less than 15% to rates greater than 50%. Indeed, since 2004 there has been an accelerated year-on-year increase in the number of lungs transplanted globally. Intermediate-term studies are now confirming that long-term outcomes are not being significantly compromised and that more individuals with terminal, symptomatic lung disease are being transplanted. It is now quite clear that many of the historical factors used to define a lung as "extended" do not actually produce significantly inferior outcomes. There has been a dramatic increase in research and clinical interest in donor lung assessment, management, and novel therapeutic strategies. The lessons learned are now being applied widely beyond the lung as researchers aim to increase availability and optimize other solid organs for transplantation.

Reproductive health after thoracic transplantation: An ISHLT expert consensus statement.

Pregnancy after thoracic organ transplantation is feasible for select individuals but requires multidisciplinary subspecialty care. Key components for a successful pregnancy after lung or heart transplantation include preconception and contraceptive planning, thorough risk stratification, optimization of maternal comorbidities and fetal health through careful monitoring, and open communication with shared decision-making. The goal of this consensus statement is to summarize the current evidence and provide guidance surrounding preconception counseling, patient risk assessment, medical management, maternal and fetal outcomes, obstetric management, and pharmacologic considerations.

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.