What Happens to Frailty in the First Year After Lung Transplantation?

BACKGROUND: Frailty is prevalent in lung transplant (LTx) candidates, but the impact and subsequent frailty trajectory is unclear. This study aimed to investigate frailty over the first year after LTx. METHOD: Post-LTx recipients completed a thrice weekly 12-week directly supervised exercise rehabilitation program. Edmonton Frail Scale (EFS) was used to assess frailty. Primary outcome was 6-Minute Walk Distance (6MWD) measured at pre-LTx, prerehabilitation, postrehabilitation, and 1 year post-LTx. RESULTS: 106 of 139 recruited participants underwent LTx: mean age 58 years, 48% male, 52% with chronic obstructive pulmonary disease. Mean (± SD) frailty scores pre-LTx and 1 year post-LTx were 5.54 ± 2.4 and 3.28 ±1.5. Mean 6MWD improved significantly for all: prerehabilitation 326 m (SD 116), versus postrehabilitation 523 m (SD 101) (p < 0.001) versus 1 year 512 m (SD 120) (p < 0.001). There were significant differences between an EFS > 7 (frail) and EFS ≤ 7 (not frail) for 6MWD, grip strength (GS), anxiety, and depression. Postrehabilitation, there were no significant differences in 6MWD, GS, anxiety, or depression while comparing EFS > 7 versus ≤ 7. At 1 year, there was a significant difference in depression but not 6MWD, GS, or anxiety between those EFS ≤ 7 and > 7 (p = 0.017). CONCLUSION: Participants in a structured post-LTx rehabilitation program improved in functional exercise capacity (6MWD), GS, depression, and anxiety. For frail participants exercise capacity, depression, anxiety, and GS were well managed in rehabilitation with no significant differences between those who were not frail. Pre-LTx frailty may be reversible post-LTx and should not be an absolute contraindication to LTx.

Defining a natural killer cell-enriched molecular rejection-like state in lung transplant transbronchial biopsies.

In lung transplantation, antibody-mediated rejection (AMR) diagnosed using the International Society for Heart and Lung Transplantation criteria is uncommon compared with other organs, and previous studies failed to find molecular AMR (ABMR) in lung biopsies. However, understanding of ABMR has changed with the recognition that ABMR in kidney transplants is often donor-specific antibody (DSA)-negative and associated with natural killer (NK) cell transcripts. We therefore searched for a similar molecular ABMR-like state in transbronchial biopsies using gene expression microarray results from the INTERLUNG study (#NCT02812290). After optimizing rejection-selective transcript sets in a training set (N = 488), the resulting algorithms separated an NK cell-enriched molecular rejection-like state (NKRL) from T cell-mediated rejection (TCMR)/Mixed in a test set (N = 488). Applying this approach to all 896 transbronchial biopsies distinguished 3 groups: no rejection, TCMR/Mixed, and NKRL. Like TCMR/Mixed, NKRL had increased expression of all-rejection transcripts, but NKRL had increased expression of NK cell transcripts, whereas TCMR/Mixed had increased effector T cell and activated macrophage transcripts. NKRL was usually DSA-negative and not recognized as AMR clinically. TCMR/Mixed was associated with chronic lung allograft dysfunction, reduced one-second forced expiratory volume at the time of biopsy, and short-term graft failure, but NKRL was not. Thus, some lung transplants manifest a molecular state similar to DSA-negative ABMR in kidney and heart transplants, but its clinical significance must be established.

Everolimus Based Immunosuppression Strategies in Adult Lung Transplant Recipients: Calcineurin Inhibitor Minimization Versus Calcineurin Inhibitor Elimination.

Everolimus (EVE) provides an alternative to maintenance immunosuppression when conventional immunosuppression cannot be tolerated. EVE can be utilized with a calcineurin inhibitor (CNI) minimization or elimination strategy. To date, clinical studies investigating EVE after lung transplant (LTx) have primarily focused on the minimization strategy to preserve renal function. The primary aim was to determine the preferred method of EVE utilization for lung transplant recipients (LTR). To undertake this aim, we compared the safety and efficacy outcomes of EVE as part of minimization and elimination immunosuppressant regimens. Single center retrospective study of 217 LTR initiated on EVE (120 CNI minimization and 97 CNI elimination). Survival outcomes were calculated from the date of EVE commencement. On multivariate analysis, LTR who received EVE as part of the CNI elimination strategy had poorer survival outcomes compared to the CNI minimization strategy [HR 1.61, 95% CI: 1.11-2.32, p=0.010]. Utilization of EVE for renal preservation was associated with improved survival compared to other indications [HR 0.64, 95% CI: 0.42-0.97, p=0.032]. EVE can be successfully utilized for maintenance immunosuppression post LTx, particularly for renal preservation. However, immunosuppressive regimens containing low dose CNI had superior survival outcomes, highlighting the importance of retaining a CNI wherever possible.

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.

Transcripts associated with chronic lung allograft dysfunction in transbronchial biopsies of lung transplants.

Transplanted lungs suffer worse outcomes than other organ transplants with many developing chronic lung allograft dysfunction (CLAD), diagnosed by physiologic changes. Histology of transbronchial biopsies (TBB) yields little insight, and the molecular basis of CLAD is not defined. We hypothesized that gene expression in TBBs would reveal the nature of CLAD and distinguish CLAD from changes due simply to time posttransplant. Whole-genome mRNA profiling was performed with microarrays in 498 prospectively collected TBBs from the INTERLUNG study, 90 diagnosed as CLAD. Time was associated with increased expression of inflammation genes, for example, CD1E and immunoglobulins. After correcting for time, CLAD manifested not as inflammation but as parenchymal response-to-wounding, with increased expression of genes such as HIF1A, SERPINE2, and IGF1 that are increased in many injury and disease states and cancers, associated with development, angiogenesis, and epithelial response-to-wounding in pathway analysis. Fibrillar collagen genes were increased in CLAD, indicating matrix changes, and normal transcripts were decreased-dedifferentiation. Gene-based classifiers predicted CLAD with AUC 0.70 (no time-correction) and 0.87 (time-corrected). CLAD related gene sets and classifiers were strongly prognostic for graft failure and correlated with CLAD stage. Thus, in TBBs, molecular changes indicate that CLAD primarily reflects severe parenchymal injury-induced changes and dedifferentiation.

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.

Surgical management of giant pulmonary artery aneurysms in patients with severe pulmonary arterial hypertension.

BACKGROUND AND AIM: Giant aneurysm of the pulmonary artery (PAA) is an extremely rare condition that may develop in patients with pulmonary arterial hypertension (PAH) which may be complicated by rupture, dissection or intravascular thrombus formation. The aim of this study was to examine available literature with regard to surgical strategies in patients undergoing transplantation for PAH with PAA. RESULTS: These patients were traditionally considered for heart-lung transplantation but more recently, there have been reports of successful lung transplantation with reconstruction of the pulmonary artery. CONCLUSIONS: Unless there is a mandatory indication for heart-lung transplantation, patients with PAH and PAA can undergo lung transplantation and reconstruction of the pulmonary artery without compromising the outcome.

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.

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.

Effect of Upper Limb Rehabilitation Compared to No Upper Limb Rehabilitation in Lung Transplant Recipients: A Randomized Controlled Trial.

OBJECTIVE: To investigate the effect of a supervised upper limb (UL) program (SULP) compared to no supervised UL program (NULP) after lung transplantation (LTx). DESIGN: Randomized controlled trial. SETTING: Physiotherapy gym. PARTICIPANTS: Participants (N=80; mean age, 56±11y; 37 [46%] men) were recruited after LTx. INTERVENTIONS: All participants underwent lower limb strength thrice weekly and endurance training. Participants randomized to SULP completed progressive UL strength training program using handheld weights and adjustable pulley equipment. MAIN OUTCOME MEASURES: Overall bodily pain was rated on the visual analog scale. Shoulder flexion and abduction muscle strength were measured on a hand held dynamometer. Health related quality of life was measured with Medical Outcomes Study 36-item Short Form health Survey and the Quick Dash. Measurements were made at baseline, 6 weeks, 12 weeks, and 6 months by blinded assessors. RESULTS: After 6 weeks of training, participants in the SULP (n=41) had less overall bodily pain on the visual analog scale than did participants in the NULP (n=36) (mean VAS bodily pain score, 2.1±1.3cm vs 3.8±1.7cm; P<.001) as well as greater UL strength than did participants in the NULP (mean peak force, 8.4±4.0Nm vs 6.7±2.8Nm; P=.037). At 12 weeks, participants in the SULP better quality of life related to bodily pain (76±17 vs 66±26; P=.05), but at 6 months there were no differences between the groups in any outcome measures. No serious adverse events were reported. CONCLUSIONS: UL rehabilitation results in short-term improvements in pain and muscle strength after LTx, but no longer-term effects were evident.

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.

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.

Longer Versus Shorter Duration of Supervised Rehabilitation After Lung Transplantation: A Randomized Trial.

OBJECTIVE: To investigate the effects of a supervised longer- (14wk) versus shorter-duration (7wk) rehabilitation program after lung transplantation (LTX). DESIGN: Randomized controlled trial. SETTING: Outpatient rehabilitation gym setting. PARTICIPANTS: Post-LTX patients aged ≥18 years (N=66; 33 women; mean age, 51±13y) who had undergone either single LTX or bilateral LTX. INTERVENTION: Outpatient rehabilitation program consisting of thrice-weekly sessions with cardiovascular training on bike ergometer and treadmill plus upper and lower limb strength training. MAIN OUTCOME MEASURES: Measures were taken at baseline, 7 weeks, 14 weeks, and 6 months by assessors who were blinded to group allocation. Functional exercise capacity was measured by the 6-minute walk test (6MWT). Strength of quadriceps and hamstrings was measured on an isokinetic dynamometer and recorded as average peak torque of 6 repetitions for both muscles. Quality of life (QOL) was assessed with the Medical Outcomes Study 36-Item Short-Form Health Survey. RESULTS: Of the participants, 86% had bilateral LTX and 41% had primary diagnosis of chronic obstructive pulmonary disease. The 6MWT increased in both groups with no significant difference between groups at any time point (mean 6mo 6MWD: short, 590±85m vs long, 568±127m; P=0.5). Similarly, at 6 months, there was no difference between groups in quadriceps average peak torque (mean, 115±38Nm vs 114±40Nm, respectively; P=.59), hamstring average peak torque (57±18Nm vs 52±19Nm, respectively; P=.36), or mental or physical health domains of quality of life. CONCLUSIONS: Shorter duration (7wk) of rehabilitation achieves comparable outcomes with 14 weeks of supervised rehabilitation for functional exercise capacity, lower limb strength, and quality of life at 6 months after LTX.

Segmental approach to lung volume reduction therapy for emphysema patients.

Emphysema is often distributed heterogeneously throughout the lungs, even at the segmental level. It is important for interventional lung volume reduction therapies to target and treat the most diseased regions of the lung while preserving the less diseased functional regions. Identification and determination of the severity of emphysema can be done using the various quantification measures reviewed in this article. However, all of these measures are similar in what they quantify and are equally good indicators of emphysema. The tissue/air ratio was chosen for our purposes. Software capable of quantifying emphysema severity at the segmental level exists, and can be utilized to identify the most diseased segments while following anatomical boundaries. The segmental heterogeneity index is a new measure being introduced to help quantify differences in emphysema severity at the segmental level. The goal of segmental targeting is to improve efficacy and safety outcomes of vapor ablation patients. The Sequential Staged Treatment of Emphysema with Upper Lobe Predominance (STEP-UP, NCT01719263) trial is currently enrolling patients with upper lobe heterogeneous emphysema using these techniques.

Patterns of Emphysema Heterogeneity.

BACKGROUND: Although lobar patterns of emphysema heterogeneity are indicative of optimal target sites for lung volume reduction (LVR) strategies, the presence of segmental, or sublobar, heterogeneity is often underappreciated. OBJECTIVE: The aim of this study was to understand lobar and segmental patterns of emphysema heterogeneity, which may more precisely indicate optimal target sites for LVR procedures. METHODS: Patterns of emphysema heterogeneity were evaluated in a representative cohort of 150 severe (GOLD stage III/IV) chronic obstructive pulmonary disease (COPD) patients from the COPDGene study. High-resolution computerized tomography analysis software was used to measure tissue destruction throughout the lungs to compute heterogeneity (≥15% difference in tissue destruction) between (inter-) and within (intra-) lobes for each patient. Emphysema tissue destruction was characterized segmentally to define patterns of heterogeneity. RESULTS: Segmental tissue destruction revealed interlobar heterogeneity in the left lung (57%) and right lung (52%). Intralobar heterogeneity was observed in at least one lobe of all patients. No patient presented true homogeneity at a segmental level. There was true homogeneity across both lungs in 3% of the cohort when defining heterogeneity as ≥30% difference in tissue destruction. CONCLUSION: Many LVR technologies for treatment of emphysema have focused on interlobar heterogeneity and target an entire lobe per procedure. Our observations suggest that a high proportion of patients with emphysema are affected by interlobar as well as intralobar heterogeneity. These findings prompt the need for a segmental approach to LVR in the majority of patients to treat only the most diseased segments and preserve healthier ones.

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.

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.

Design of the randomized, controlled sequential staged treatment of emphysema with upper lobe predominance (STEP-UP) study.

BACKGROUND: An innovative approach to lung volume reduction (LVR) for emphysema is introduced in the design of the Sequential Segmental Treatment of Emphysema with Upper Lobe Predominance (STEP-UP) trial where vapour ablation is administered bilaterally over the course of two sessions and is used to target only the most diseased upper lobe segments. By dividing the procedure into two sessions, there is potential to increase the total volume treated per patient but reduce volume treated and energy delivered per session. This is expected to correlate with improvements in vapour ablation's safety and efficacy profiles. METHODS: The STEP-UP trial is a randomized, controlled, open-label, 12 month study of patients with upper lobe predominant emphysema (ULPE). The trial compares patients receiving standard medical management alone against patients receiving bilateral vapour ablation in addition to standard medical management. An intended sixty nine subjects will be randomized at a 2:1 (treatment arm:control arm) ratio. Inclusion criteria include a forced expiratory volume in 1 second (FEV1) between 20% and 45% predicted, total lung capacity > 100% predicted, residual volume > 150% predicted, marked dyspnea scoring ≥ 2 on the modified Medical Research Council (mMRC) scale, and PaCO2 ≤ 50 mm Hg. The primary endpoints are the change in FEV1 %predicted and St. George Respiratory Questionnaire (SGRQ) score between the treatment and control arm at 12 months. Adverse events will be monitored as secondary endpoints along with other efficacy outcomes at 6 and 12 months. DISCUSSION: Vapour ablation can reduce lung volume in the presence of collateral ventilation (CV). Due to this ability, it can be used to target specifically the more diseased segments of each upper lobe. Safety and efficacy outcomes are expected to improve by considering which segments to treat along with the volume treated per session and per patient. TRIAL REGISTRATION: ClinicalTrials.gov NCT01719263.