Long-term outcome and bridging success of patients evaluated and bridged to lung transplantation on the ICU.

BACKGROUND: Evaluating and bridging patients to lung transplantation (LTx) on the intensive care unit (ICU) remains controversial, especially without a previous waitlist status. Long term outcome data after LTx from ICU remains scarce. We compared long-term survival and development of chronic lung allograft dysfunction (CLAD) in elective and LTx from ICU, with or without previous waitlist status. METHODS: Patients transplanted between 2004 and 2018 in 2 large academic Dutch institutes were included. Long-term survival and development of CLAD was compared in patients who received an elective LTx (ELTx), those bridged and transplanted from the ICU with a previous listing status (BTT), and in patients urgently evaluated and bridged on ICU (EBTT). RESULTS: A total of 582 patients underwent a LTx, 70 (12%) from ICU, 39 BTT and 31 EBTT. Patients transplanted from ICU were younger than ELTx (46 vs 51 years) and were bridged with mechanical ventilation (n = 42 (60%)), extra corporeal membrane oxygenation (n = 28 (40%)), or both (n = 21/28). Bridging success was 48% in the BTT group and 72% in the EBTT group. Patients bridged to LTx on ICU had similar 1 and 5 year survival (86.8% and 78.4%) compared to elective LTx (86.8% and 71.9%). This was not different between the BTT and EBTT group. 5 year CLAD free survival was not different in patients transplanted from ICU vs ELTx. CONCLUSION: Patients bridged to LTx on the ICU with and without prior listing status had excellent short and long-term patient and graft outcomes, and was similar to patients electively transplanted.

Using a novel concept to measure outcomes in solid organ recipients provided promising results.

OBJECTIVES: Efforts to evaluate the health of solid organ transplant recipients are hampered by the lack of adequate patient-reported outcome measures (PROMs) targeting this group. We developed the Transplant ePROM (TXP), which is based on a novel measurement model and administered through a mobile application to fill this gap. The main objective of this article is to elucidate how we derived the weights for different items, and to report initial empirical results. STUDY DESIGN AND SETTING: The nine health items in the TXP were fatigue, skin, worry, self-reliance, activities, weight, sexuality, stooling, and memory. Via an online survey solid organ recipient participating in the TransplantLines Biobank and Cohort study (NCT03272841) were asked to describe and then compare their own health state with six other health states. Coefficients for item levels were obtained using a conditional logit model. RESULTS: A total of 232 solid organ transplant recipients (mean age: 54 years) participated. The majority (106) were kidney recipients, followed by lung, liver, and heart recipients. Fatigue was the most frequent complaint (54%). The strongest negative coefficients were found for activities and worry, followed by self-reliance and memory. CONCLUSION: A set of coefficients and values were developed for TXP. The TXP score approximated an optimal health state for the majority of respondents and recipients of different organs reported comparable health states.

Health items with a novel patient-centered approach provided information for preference-based transplant outcome measure.

OBJECTIVES: Patient-reported outcome measures (PROMs) are widely applied to assess perceived health status. To date, no transplant-specific PROM is available for generating a single, standardized score regarding the health status of transplant recipients. The objective of this study is to generate health items for a new patient-centered PROM for organ recipients: the Transplant PROM (TXP). STUDY DESIGN AND SETTING: A five-phase, mixed-method approach was applied to identify and select the health items: scoping literature review, expert meetings, focus-group meetings with organ recipients, a special judgmental task within an online survey, and expert meetings for final selection of health items. RESULTS: Based on a previously published scoping literature review, a first round of expert meetings, and a total of four focus-group meetings with kidney, lung, and liver transplant recipients (N = 18), a list of 83 relevant health items relating to post-transplant life was selected. In an online survey, 183 transplant recipients selected the 10 most important health items from this list. After evaluating the frequency of selected health items and combining items that assess closely related or similar concepts in the second round of expert meetings, nine health items were chosen to be included in TXP: fatigue, skin, worry/anxiety, self-reliance, activities, weight, sexuality, stooling, and memory/concentration. CONCLUSION: The nine TXP health items reflect the most prominent issues transplant recipients experience. The TXP can be administered by means of a mobile phone app.

Evaluation of 10 years of parainfluenza virus, human metapneumovirus, and respiratory syncytial virus infections in lung transplant recipients.

Respiratory tract infection with pneumoviruses (PVs) and paramyxoviruses (PMVs) are increasingly associated with chronic lung allograft dysfunction (CLAD) in lung transplant recipients (LTRs). Ribavirin may be a treatment option but its effectiveness is unclear, especially with respect to infection severity. We retrospectively analyzed 10 years of PV/PMV infections in LTRs. The main end points were forced expiratory volume in 1 second (FEV1 ) at 3 and 6 months postinfection, expressed as a percentage of pre-infection FEV1 and incidence of new or progressed CLAD 6 months postinfection. A total of 139 infections were included: 88 severe infections (63%) (defined as >10% FEV1 loss at infection) and 51 mild infections (37%) (≤10% FEV1 loss). Overall postinfection CLAD incidence was 20%. Associations were estimated on postinfection FEV1 for ribavirin vs no ribavirin (+13.2% [95% CI: 7.79; 18.67]) and severe vs mild infection (-11.1% [95% CI: -14.76; -7.37]). Factors associated with CLAD incidence at 6 months were ribavirin treatment (odds ratio (OR [95% CI]) 0.24 [0.10; 0.59]), severe infection (OR [95% CI] 4.63 [1.66; 12.88]), and mycophenolate mofetil use (OR [95% CI] 0.38 [0.14; 0.97]). These data provide valuable information about the outcomes of lung transplant recipients with these infections and suggests possible associations of ribavirin use and infection severity with long-term outcomes. Well-designed prospective trials are needed to confirm these findings.

Incidence of Massive Transfusion and Overall Transfusion Requirements During Lung Transplantation Over a 25-Year Period.

OBJECTIVE: To establish the incidence of massive transfusion and overall transfusion requirements during lung transplantation, changes over time, and association with outcome in relation to patient complexity. DESIGN: Retrospective cohort study. SETTING: University hospital. PARTICIPANTS: All 514 adult patients who underwent transplantation from 1990 until 2015. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Patient records and transfusion data, divided into 5-year intervals, were analyzed. The incidence of massive transfusion (>10 units of red blood cells [RBCs] in 24 h) was 27% and did not change over time, whereas the median (interquartile range) transfusion requirement in the whole cohort decreased from 8 (5-12) to 3 (0-10) RBCs (p < 0.001). In patients transplanted from the intensive care unit, the incidence of massive transfusion increased over time from 25% to 54% (p = 0.04) and median transfusion requirements from 4.5 (3-8.5) units to 14.5 (5-26) units of RBCs (p = 0.03). Multivariable analysis showed that circulatory support, pulmonary hypertension, re-transplantation, cystic fibrosis, Eisenmenger syndrome, bilateral transplantation, and low body mass index were associated with massive transfusion. Patients with massive transfusion had more primary graft dysfunction grade III at 0, 24, 48, and 72 hours (p < 0.001), higher 30-day mortality (13% v 4%; p < 0.001), and lower 5-year survival (hazard ratio 3.67 [95% confidence interval 1.72-7.85]; p < 0.001). CONCLUSION: The incidence of massive transfusion did not change over time, whereas transfusion requirements in the whole cohort decreased. In patients transplanted from the intensive care unit, massive transfusion and transfusion requirements increased. Massive transfusion was associated with poor outcome.

99mTc-HYNIC-IL-2 scintigraphy to detect acute rejection in lung transplantation patients: a proof-of-concept study.

RATIONALE: Acute allograft rejection is one of the major complications after lung transplantation, and adequate and early recognition is important. Till now, the reference standard to detect acute rejection is the histopathological grading of transbronchial biopsies (TBBs). Acute rejection is characterised by high levels of activated T lymphocytes. Interleukin-2 (IL-2) binds specifically to high-affinity IL-2 receptors expressed on the cell membrane of activated T lymphocytes. The aim of this proof-of-concept study was to evaluate if non-invasive imaging with 99mTc-HYNIC-IL-2 is able to detect acute rejection after lung transplantation. METHODS: 99mTc-HYNIC-IL-2 scintigraphy (static, SPECT/CT of the lungs) was performed shortly before routine transbronchial biopsy (pathology as reference standard). Scans were scored as likely or unlikely for rejection, and semiquantitative analysis (target-to-background ratio) was performed. RESULTS: Thirteen patients were included of which 3 showed acute rejection at transbronchial biopsy; in 2 of these patients (scored as graded 2-3 at pathology), the scan was scored likely for rejection, and in 1 patient (scored grade 1 at pathology), the scan was scored unlikely. No correlation was found between biopsy results and semiquantitative analysis. CONCLUSION: 99mTc-HYNIC-IL-2 scintigraphy proved to be a good technique to detect grade 2 and 3 acute rejection in a small sample population of patients after lung transplantation. Larger studies are necessary to really show the added value of this non-invasive specific imaging technique over transbronchial biopsy. Alternatively, imaging with the PET tracer 18F-IL-2 may be useful for this purpose.

First experience with ex vivo lung perfusion for initially discarded donor lungs in the Netherlands: a single-centre study.

OBJECTIVES: Despite progress in lung transplantation (LTx) techniques, a shortage of donor lungs persists worldwide. Ex vivo lung perfusion (EVLP) is a technique that evaluates, optimizes and enables transplantation of the lungs that would otherwise have been discarded. Herein, we present our centre's first EVLP experiences between July 2012 and June 2016, when we performed 149 LTxs. METHODS: It was a single-centre, retrospective analysis of a prospectively collected database. The EVLP group (n = 9) consisted of recipients who initially received discarded donor lungs that were reconditioned using EVLP. The non-EVLP (N-EVLP) group (n = 18) consisted of data-matched patients receiving conventional quality lungs in the conventional way. Both groups were compared on primary graft dysfunction (PGD) grades 0-3, pulmonary function, chronic lung allograft dysfunction and survival. RESULTS: In the EVLP group, 33% (3/9) developed PGD1 at 72 h post-LTx. In the N-EVLP group, 11% (2/18) developed PGD1, 6% (1/18) PGD2 and 11% (2/18) PGD3 at 72 h post-LTx. At 3 and 24 months post-LTx, forced expiratory volume in 1 s as percentage of predicted was similar in the EVLP (78% and 92%) and N-EVLP groups (69% and 89%). Forced vital capacity as a percentage of predicted was comparable in the EVLP (77% and 93%) and N-EVLP groups (68% and 101%). Chronic lung allograft dysfunction was diagnosed in 1 N-EVLP patient at 2 years post-LTx. Three-year survival was 78% (7/9) (the EVLP group) vs 83% (15/18) (the N-EVLP group). CONCLUSIONS: These results are in line with the existing literature suggesting that transplantation of the previously discarded lungs recovered by EVLP leads to equal outcomes compared to conventional LTx methods.

Donor Hypernatremia is Not Related with the Duration of Postoperative Mechanical Ventilation, Primary Graft Dysfunction, or Long-Term Outcome Following Lung Transplantation.

BACKGROUND Donor hypernatremia has been associated with reduced graft and recipient survival after heart, liver, kidney, and pancreas transplantation. However, it is unknown what effect donor hypernatremia has on graft and recipient outcomes after lung transplantation. The aim of this study was to investigate the relation of donor hypernatremia with the duration of postoperative mechanical ventilation, the incidence of severe primary graft dysfunction, and survival following lung transplantation. MATERIAL AND METHODS We analyzed all consecutive lung transplantations performed in adult patients at our center between 1995 and 2016. During the study period, donor hypernatremia was not considered a reason to reject lungs for transplantation. Donors were classified into 3 groups: normonatremia (sodium <145 mmol/L), moderate hypernatremia (sodium 145-154 mmol/L), or severe hypernatremia (sodium ≥155 mmol/L). Short-term outcome was defined by the duration of mechanical ventilation and incidence of primary graft dysfunction; long-term outcome was defined by 10-year mortality. RESULTS Donor hypernatremia was recorded in 275 (58%) of the 474 donors. There were no differences in baseline characteristics between the 3 study groups. The duration of mechanical ventilation was similar for all groups (8±25, 7±17, and 9±15 days respectively, P=0.204). Severe primary graft dysfunction was not different between the 3 groups (29%, 26%, 28%, P=0.724). Donor hypernatremia was not associated with (graft) survival, or after correction for potential confounders. CONCLUSIONS Donor hypernatremia was not associated with a worse outcome in lung transplant recipients. Thus, in contrast to solid organ transplantation, donor hypernatremia is not a contraindication for lung transplantation.

Azathioprine to mycophenolate mofetil transition and risk of squamous cell carcinoma after lung transplantation.

BACKGROUND: Chronic immunosuppression after solid-organ transplantation is a risk factor for cutaneous squamous cell carcinoma (cSCC) development. Certain immunosuppressant drugs, namely azathioprine and calcineurin inhibitors, increase this risk more than others. We investigated incidence of cSCC in a Dutch lung transplant recipient (LTR) cohort and analyzed associated risk factors. METHODS: All LTRs with post-transplant survival of >30 days were included. Data included indication for lung transplantation and duration of medication use. Skin cancer data were extracted from the Dutch nationwide registry of histopathology (PALGA). Uni- and multivariable hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazards regression analyses. RESULTS: Five hundred forty-four patients were included with a median survival of 11.05 years. Fifty-two (9.6%) LTRs developed at least one cSCC, with a cumulative incidence of 3.9% and 15.3% after 5 and 10 years, respectively. Multivariate analyses showed that the sequential use of azathioprine and mycophenolate mofetil (MMF), both at for least 1 year, was associated with a lower risk of developing cSCC (hazard ratio [HR] 0.24; 95% confidence interval [CI] 0.10 to 0.56) compared with azathioprine use only. Furthermore, age at transplantation (HR 3.42; 95% CI 1.33 to 8.79), male gender (HR 1.75; 95% CI 1.00 to 3.05), previous skin cancer (HR 4.75; 95% CI 1.14 to 19.76), and history of smoking (HR 3.30; 95% CI 1.69 to 6.44) were associated with increased risk of developing cSCC in univariate analyses. CONCLUSIONS: Apart from known risk factors, we found that switching from azathioprine to MMF is associated with reduced incidence of cSCC in LTR, prompting a discussion of whether switching azathioprine to MMF should be considered in high-risk patients.

Extracorporeal Life Support as a Bridge to Lung Transplantation: A Single-Center Experience With an Emphasis on Health-Related Quality of Life.

BACKGROUND: Extracorporeal life support (ECLS) as a bridge to lung transplantation is increasingly used, but information on long-term outcome is scarce. We aim to summarize our experience with an emphasis on health-related quality of life. Secondary outcomes include ICU and hospital stay and pre- and post-transplant mortality. METHODS: A retrospective cohort study of all adult subjects receiving ECLS as a bridge to lung transplantation from 2010 to 2014 was reviewed and compared with all adult subjects who underwent bilateral lung transplantation in the same period. For the ECLS group, the general health status was assessed with the use of the EuroQol Group 5-Dimension Self-Report Questionnaire. RESULTS: A total of 130 bilateral transplants were performed, 9 transplants were performed after ECLS therapy. Another 11 subjects died on the waiting list while receiving ECLS. Quality of life, at 12 months after surgery, from a subject's perspective was comparable in both groups with a median score of 80 on the visual analog scale. The median (interquartile range [IQR]) EuroQol Group 5-Dimension Self-Report Questionnaire 3L score from the societal perspective in the ECLS group was 0.73 (0.5-0.9). Median (IQR) ICU stay was 25 d (9-68 d) for the ECLS group versus 7 d (4-18 d) for the control group (P = .001), and in-hospital stay was 66 d (40-114 d) versus 42 d (29-62 d) (P = .004). CONCLUSIONS: ECLS can be used as a bridge to lung transplantation. A significant number of subjects were not bridged successfully due to different reasons. Outcomes after successful transplantation after ECLS might be comparable with the general population undergoing lung transplantation in terms of quality of life, lung function, performance tests, and mortality, although ICU and hospital stay are longer.

An association of particulate air pollution and traffic exposure with mortality after lung transplantation in Europe.

Air pollution from road traffic is a serious health risk, especially for susceptible individuals. Single-centre studies showed an association with chronic lung allograft dysfunction (CLAD) and survival after lung transplantation, but there are no large studies.13 lung transplant centres in 10 European countries created a cohort of 5707 patients. For each patient, we quantified residential particulate matter with aerodynamic diameter ≤10 µm (PM10) by land use regression models, and the traffic exposure by quantifying total road length within buffer zones around the home addresses of patients and distance to a major road or freeway.After correction for macrolide use, we found associations between air pollution variables and CLAD/mortality. Given the important interaction with macrolides, we stratified according to macrolide use. No associations were observed in 2151 patients taking macrolides. However, in 3556 patients not taking macrolides, mortality was associated with PM10 (hazard ratio 1.081, 95% CI 1.000-1.167); similarly, CLAD and mortality were associated with road lengths in buffers of 200-1000 and 100-500 m, respectively (hazard ratio 1.085- 1.130). Sensitivity analyses for various possible confounders confirmed the robustness of these associations.Long-term residential air pollution and traffic exposure were associated with CLAD and survival after lung transplantation, but only in patients not taking macrolides.

Hospital Costs Of Extracorporeal Life Support Therapy.

OBJECTIVES: To conduct an exploration of the hospital costs of extracorporeal life support therapy. Extracorporeal life support seems an efficient therapy for acute, potentially reversible cardiac or respiratory failure, when conventional therapy has been inadequate, or as bridge to transplant, but unfortunately, no evidence in randomized controlled trials is delivered yet. DESIGN: Single-center retrospective exploratory cohort cost study. The study is performed from a hospital perspective with a time horizon of patients' complete hospital admission in which they received extracorporeal life support. SETTING: ICU of a university teaching hospital in The Netherlands. PATIENTS: All 67 consecutive adult patients who were admitted to the ICU of the University Medical Center Groningen in the period 2010-2013 and received extracorporeal life support treatment. INTERVENTION: None. MEASUREMENTS AND MAIN RESULTS: The bottom-up microcosting method was used except when stated otherwise. Medical costs were estimated by multiplying every registered healthcare consumption with unit prices. Unit prices were largely based on Dutch reference prices. For each patient, the personnel costs and material costs were assessed in detail. The costs of extracorporeal life support were differentiated in costs of procedures and costs of daily surcharge of therapy. Procedure-related costs were subdivided in costs of devices and disposables, costs of additional human resources, and surgery hours. The mean total hospital costs were € 106.263 (€ 83.841 to € 126.266) per patient ($145,580). On average, 52% of the total costs arose from hospital nursing days and 11% of direct procedure-related extracorporeal life support costs. Surgery and diagnostics represented a vast amount of the remaining costs. CONCLUSIONS: This large and detailed economic evaluation of hospital costs of extracorporeal life support therapy in the Netherlands showed that mean total hospital cost of extracorporeal life support treatment is € 106.263 per patient. The majority of the costs are composed of nursing days.

Ten-Year Survival in Patients with Idiopathic Pulmonary Fibrosis After Lung Transplantation.

INTRODUCTION: Idiopathic pulmonary fibrosis (IPF) is a progressive and lethal fibrosing lung disease with a median survival of approximately 3 years after diagnosis. The only medical option to improve survival in IPF is lung transplantation (LTX). The purpose of this study was to evaluate trajectory data of IPF patients listed for LTX and to investigate the survival after LTX. METHODS AND RESULTS: Data were retrospectively collected from September 1989 until July 2011 of all IPF patients registered for LTX in the Netherlands. Patients were included after revision of the diagnosis based on the criteria set by the ATS/ERS/JRS/ALAT. Trajectory data, clinical data at time of screening, and donor data were collected. In total, 98 IPF patients were listed for LTX. During the waiting list period, 30 % of the patients died. Mean pulmonary artery pressure, 6-min walking distance, and the use of supplemental oxygen were significant predictors of mortality on the waiting list. Fifty-two patients received LTX with a median overall survival after transplantation of 10 years. CONCLUSIONS: This study demonstrated a 10-year survival time after LTX in IPF. Furthermore, our study demonstrated a significantly better survival after bilateral LTX in IPF compared to single LTX although bilateral LTX patients were significantly younger.

Metalloproteinase Profiling in Lung Transplant Recipients With Good Outcome and Bronchiolitis Obliterans Syndrome.

BACKGROUND: Bronchiolitis obliterans syndrome (BOS), the major cause of death on lung transplantation, is characterized by bronchiolar inflammation and tissue remodeling. Matrix metalloproteinases (MMPs) have been implicated in these processes, although it is still unclear whether MMP activity and binding to their endogenous inhibitors, tissue inhibitors of metalloproteinases (TIMPs), is abnormal in BOS. METHODS: We studied total MMP-1,-2,-3,-7,-8,-9,-12,-13 levels, their activity state using activity-based extraction and their binding to TIMP-1, -2, -3, and -4 in bronchoalveolar lavage (BAL) of lung transplant recipients with good outcome and BOS using a multiplex immunoassay. RESULTS: The BAL levels of TIMP-1 and -2 and MMP-2, -3, -7, -8, and -9 were significantly increased in BOS compared to good outcome recipients. Interestingly, activity of MMP-7, but none of the other MMPs, was detected in good outcome recipients, whereas no active MMPs were observed in BOS recipients. However, BAL levels of TIMP-bound MMP-8 and -9 were higher in BOS than in good outcome recipients, suggesting activity of these MMPs in an earlier stage. CONCLUSIONS: We demonstrate that development of BOS is associated with increased levels of TIMP-1 and -2 and total MMP-2, -3, -7, -8, and -9. Although active MMP-7 was only observed in good outcome recipients, levels of TIMP-bound MMP-8 and -9 were higher in BOS. By enabling profiling of active and TIMP-bound MMPs, our novel method may open opportunities for the screening of early predictors for BOS.

A staged approach for a lung-liver transplant patient using ex vivo reconditioned lungs first followed by an urgent liver transplantation.

Combined lung-liver transplantation is a logistically challenging procedure hampered by shortage of organ donors. We describe the case of a young patient with end-stage lung disease due to of cystic fibrosis and liver cirrhosis who needed combined lung-liver transplantation. The long waiting for this caused an interesting clinical dilemma. We decided to change our policy in this situation by listing him only for the lung transplantation and to apply for a high urgent liver transplantation if the liver failed after the lung transplantation. This strategy enabled us to use lungs treated with ex vivo lung perfusion (EVLP) from an unsuitable donor after circulatory death. After conditioning for 4 h via EVLP, the pO2 was 59.7 kPa. The lungs were transplanted successfully. He developed an acute-on-chronic liver failure for which he received a successful liver transplantation 19 days after the lung transplantation.

Predicting 6-minute walking distance in recipients of lung transplantation: longitudinal study of 108 patients.

BACKGROUND: Exercise capacity, muscle function, and physical activity levels remain reduced in recipients of lung transplantation. Factors associated with this deficiency in functional exercise capacity have not been studied longitudinally. OBJECTIVE: The study aims were to analyze the longitudinal change in 6-minute walking distance and to identify factors contributing to this change. DESIGN: This was a longitudinal historical cohort study. METHODS: Data from patients who received a lung transplantation between March 2003 and March 2013 were analyzed for the change in 6-minute walking distance and contributing factors at screening, discharge, and 6 and 12 months after transplantation. Linear mixed-model and logistic regression analyses were performed with data on characteristics of patients, diagnosis, waiting list time, length of hospital stay, rejection, lung function, and peripheral muscle strength. RESULTS: Data from 108 recipients were included. Factors predicting 6-minute walking distance were measurement moment, diagnosis, sex, quadriceps muscle and grip strength, forced expiratory volume in 1 second (percentage of predicted), and length of hospital stay. After transplantation, 6-minute walking distance increased considerably. This initial increase was not continued between 6 and 12 months. At 12 months after lung transplantation, 58.3% of recipients did not reach the cutoff point of 82% of the predicted 6-minute walking distance. Logistic regression demonstrated that discharge values for forced expiratory volume in 1 second and quadriceps or grip strength were predictive for reaching this criterion. LIMITATIONS: Study limitations included lack of knowledge on the course of disease during the waiting list period, type and frequency of physical therapy after transplantation, and number of missing data points. CONCLUSIONS: Peripheral muscle strength predicted 6-minute walking distance; this finding suggests that quadriceps strength training should be included in physical training to increase functional exercise capacity. Attention should be paid to further increasing 6-minute walking distance between 6 and 12 months after transplantation.