LTx Patients Research Articles

Soluble intercellular adhesion molecule (ICAM)-1 detects invasive fungal infections in patients following liver transplantation

Purpose Despite antifungal prophylaxis, liver transplanted patients are endangered by invasive fungal infections (IFI). Routinely used microbiological procedures are hallmarked by significant weaknesses, which may lead to a delay in antifungal treatment. Methods Culture-based fungal findings, routinely used biomarkers of infection/inflammation (e.g., procalcitonin or C-reactive protein), as well as corresponding plasma concentrations of soluble Intercellular Adhesion Molecule (ICAM)-1 were analysed in 93 patients during a period of 28 days following liver transplantation (LTX). Results Plasmatic sICAM-1 was significantly elevated in patients affected by an IFI within the first 28 days in comparison to fungally colonised or unobtrusive LTX patients. sICAM-1 might therefore be helpful for the identification of IFI patients after LTX (e.g., Receiver Operating Characteristic (ROC)-Area Under the Curve (AUC): 0.714 at 14d after LTX). The diagnostic performance of sICAM-1 was further improved by its combined use with different other IFI biomarkers (e.g., midregional proadrenomedullin). Conclusion The diagnostic deficiencies of routinely used microbiological procedures for IFI detection in patients after LTX may be reduced by plasmatic sICAM-1 measurements. Clinical Trial Notation. German Clinical Trials Register: DRKS00005480

Energy Expenditure and Liver Transplantation: What We Know and Where We Are.

Patients with end-stage liver disease (ESLD) and undergoing liver transplantation (LTx) commonly present with malnutrition attributed to various etiologies. One of the causes is potential hypermetabolism resulting from increased resting energy expenditure (REE). After the surgery, it is hypothesized that these patients show a reduction in REE, which may contribute to the weight gain observed in this population. However, there have been controversial results regarding the metabolic status of ESLD patients and liver recipients, which has led us to critically review the pertinent literature. We enrolled studies with the following goals: assessment of REE of these patients either before or after surgery by using indirect calorimetry (measured REE [mREE]) and comparison of these mREE values with those of healthy controls or with REE values obtained using predictive equations (predicted REE [pREE]). For most patients, mREE and pREE values were comparable. However, ≥5.3% of patients exhibited hypermetabolism when the mREE was compared with the pREE using the Harris-Benedict formula. Three follow-up studies that were conducted postsurgery showed a progressive reduction in the mREE for ≤1 year. However, conflicting data have been published, and cross-sectional studies have not reported hypometabolic patients. In conclusion, there is no consensus regarding the metabolic status of pre-LTx and post-LTx patients, which may be due to differences in the methods used for comparison. Therefore, we highlight this aspect of LTx patient management, which impacts the quality of nutrition therapy required by these patients.

Chronic Obstructive Pulmonary Disease and Lung Transplantation.

Lung transplantation (LTx) has been a viable option for patients with end-stage chronic obstructive pulmonary disease (COPD), with more than 20,000 procedures performed worldwide. Survival after LTx lags behind most other forms of solid-organ transplantation, with median survival for COPD recipients being a sobering 6.0 years. Given the limited supply of suitable donor organs, not all patients with end-stage COPD are candidates for LTx. We discuss appropriate criteria for accepting patients for LTx, as well as contraindications and exclusionary criteria. In the first year post-LTx, infection and graft failure are the leading causes of death. Beyond this chronic graft rejection-currently referred to as chronic lung allograft dysfunction-represents the leading cause of death at all time points, with infection and over time malignancy also limiting survival. Referral of COPD patients to a lung transplant center should be considered in the presence of progressing disease despite maximal medical therapy. As a rule of thumb, a forced expiratory volume in 1 second < 25% predicted in the absence of exacerbation, hypoxia (PaO2 < 60 mm Hg/8 kPa), and/or hypercapnia (PaCO2 > 50 mm Hg/6.6 kPa) and satisfactory general clinical condition should be considered the basic prerequisites for timely referral. We also discuss salient issues post-LTx and factors that impact posttransplant survival and morbidity such as infections, malignancy, renal insufficiency, and complications associated with long-term immunosuppression.

Risk Factors for Cytomegalovirus Reactivation in Lung Transplant Recipients.

We examined risk factors that may have contributed to Cytomegalovirus (CMV) reactivation among patients who underwent lung transplantation (LTx). We reviewed medical records of patients who underwent LTx at a tertiary healthcare hospital in South Korea between January 2013 and May 2017. We excluded patients who died within the first year after LTx and those lost to follow-up. CMV reactivation was defined as the detection of CMV titers above 3000 copies/ml regardless of specific symptoms after prophylaxis cessation. Of 89 patients included, 39 (43.8%) developed CMV reactivation. Of those 39 patients, 16 (41.0%) experienced additional CMV reactivation. Multivariate analysis identified lymphocyte counts below 1.0 × 103/μl (hazard ratio [HR] 49.33, p < 0.001) and use of steroids at more than twice the standard dose (HR 8.07, p < 0.001) as risk factors for CMV reactivation. The multivariate model also identified chronic kidney disease (CKD; HR 5.19, p = 0.016) and pneumonia (HR 17.22, p = 0.013) as risk factors for repetitive CMV reactivation. This study suggests that lymphopenia and high doses of steroids may be important risk factors for CMV reactivation in LTx patients. Our results also suggest that repetitive CMV reactivation may be associated with CKD and pneumonia.

Sleep-disordered breathing after lung transplantation: An observational cohort study.

Data concerning sleep-disordered breathing (SDB) after lung transplantation (LTX) are scarce. This study aims to analyze prevalence, associated factors, and impact on survival of moderate to severe SDB in a large cohort of consecutive LTX patients (n=219). Patients underwent a diagnostic polysomnography 1year after LTX. Moderate to severe SDB was present in 57.5% of patients, with the highest prevalence in chronic obstructive pulmonary disease/emphysema (71.1%) and pulmonary fibrosis (65.1%). SDB patients were older, mostly male, and had higher body mass index and neck circumference. Nocturnal diastolic and 24-hour blood pressures were higher in SDB patients. In 45 patients, polysomnography was also performed pre-LTX. Compared to pre-LTX, mean apnea/hypopnea index (AHI) increased significantly after LTX. A significant correlation was seen between lung function parameters and AHI, suggesting a role of decreased caudal traction on the pharynx. Presence of SDB had no impact on mortality or prevalence of chronic lung allograft dysfunction. However, survival was better in continuous positive airway pressure (CPAP) compliant SDB patients compared to SDB patients without CPAP treatment. These findings may be pertinent for systematic screening of SDB after LTX.

Mucosal associated invariant T cells are differentially impaired in tolerant and immunosuppressed liver transplant recipients.

Mucosal associated invariant T (MAIT-) cells represent a semi-invariant T cell population responsive to microbial vitamin B metabolite and innate cytokine stimulation, executing border tissue protection and particularly contributing to human liver immunity. The impact of immunosuppressants on MAIT cell biology alone and in context with solid organ transplantation has not been thoroughly examined. Here, we demonstrate that in vitro cytokine activation of peripheral MAIT cells from healthy individuals was impaired by glucocorticoids, whereas antigen-specific stimulation was additionally sensitive to calcineurin inhibitors. In liver transplant (LTx) recipients, significant depletion of peripheral MAIT cells was observed that was largely independent of the type and dosage of immunosuppression, equally applied to tolerant patients, and was reproducible in kidney transplant recipients. However, MAIT cells from tolerant LTx patients exhibited a markedly diminished ex vivo activation signature, associated with individual regain of functional competence toward antigenic and cytokine stimulation. Still, MAIT cells from tolerant and treated liver recipients exhibited high levels of PD1, accompanied by functional impairment particularly toward bacterial stimulation that also affected polyfunctionality. Our data suggest interlinked effects of primary liver pathology and immunosuppressive treatment on overall MAIT cell fitness after transplantation and propose their monitoring in context with tolerance induction protocols.

Characteristics of lung cancer in idiopathic pulmonary fibrosis with single lung transplant versus non-transplanted patients: a retrospective observational study

BackgroundPatients with idiopathic pulmonary fibrosis (IPF) have significantly higher incidence of lung cancer (LC) relative to the general population. There is a further increase in LC incidence in patients with...

P0569ACUTE KIDNEY INJURY AFTER LUNG TRANSPLANTATION: INCIDENCE, RISK FACTORS AND OUTCOMES IN A MONOCENTRIC RETROSPECTIVE COHORT STUDY

Abstract Background and Aims Acute kidney Injury (AKI) occurs in more than 50% of patients after lung transplantation (LTx). Our aim was to describe the incidence, risk factors and outcomes associated with AKI after LTx in a retrospective monocentric cohort study. Method We studied all recipients of LTx (&amp;gt; 16 years of age) occurring at Ospedale Maggiore Policlinico Milano between Jan 1st 2015 and Dec 31st 2017. AKI was defined according to KDIGO classification, eGFR was calculated according to CKD (Chronic Kidney Disease) Epidemiology Collaboration formula and CKD was defined by an eGFR&amp;lt; 60 ml/min per 1.73 m2. Chi square, Fisher exact test, t.-test and logistic regression were used to define risk factors for AKI in the early post-surgical period and for CKD at 1 and 2 years after LTx. AKI-related survival was estimated using Kaplan Meyer model. Results Of 78 LTx patients enrolled in our Center, 50% of patients was affected by cystic fibrosis. Median age at transplant was 43 years (27-55); median follow- up was 31 months (20-40). Survival rate was 80.77% at 1 year, 69.23% at 2 years and 66.67% on Dec 31st 2019 (last follow-up). AKI occurred in 42 (53.85%) patients within the first week after LTx, respectively grade I and II in 12 each (15.38%) and grade III in 18 (23.08%) patients. Pre-transplant low albumin levels and hypertension were independently associated with AKI at univariate and multivariate (p= 0.0018 and 0.0004 respectively) analysis. Pre-transplant low albumin levels, pre-transplant ECMO-use, hypertension, ECMO-use during transplant surgery were associated with severe AKI in univariate analysis but only pre-transplant hypertension and ECMO-use during transplant surgery were independently associated in the multivariate one (p=0.0266 and 0.0463 respectively). Survival was significantly reduced in patients affected by AKI (p=0.035); this observation became strongly significant when only mild and moderate (grade I and II) AKI was considered (p=0.0071). CKD was diagnosed in 38.09% of patients at 1 year and 35.18% at 2 years. While numerous risk factors were related to the occurrence of CKD at 1 and 2 years after LTx at univariate analysis, only grade III AKI remained independently associated with CKD at multivariate analysis (p= 0.0081 for 1 year-CKD, p=0.0154 for 2 year-CKD). Conclusions In our population, AKI after LTx occurred in about half of the patients and was predicted by history of hypertension, low albumin levels and hemodynamic instability during the surgery. Mild-moderate AKI, often clinically underestimated, was strongly associated with reduced survival. Severe forms of AKI were predictive of occurrence of CKD.

Bronchoalveolar Lavage-microRNAs Are Potential Novel Biomarkers of Outcome After Lung Transplantation.

BAL-microRNAs (miRNAs) from 16 patients were collected 7 days (T0), 15 days (T1), and 3 months (T2) after bilateral LTx and profiled on low-density array. Unsupervised and supervised analyses were used to identify miRNAs associated with clinical features, pneumonia, or AR. Prognostic markers were identified using the Cox model. Targeted signaling pathways were predicted in silico. A second series of 11 patients were used to validate AR-associated miRNAs. Variation in BAL-miRNAs was associated with acute lung allograft dysfunction. Increased levels of miR-23b-3p at T2 were detected in patients with pneumonia, whereas let-7f-5p, miR-146b-3p, miR-22-5p, miR-29c-5p, miR-362-5p, and miR-452-5p were upregulated at T2 in patients with AR. miR-148b-5p and miR-744-3p distinguished LTx patients with AR in both cohorts. Low miR-148b-5p and high miR-744-3p expression levels were significantly associated with a shorter time to AR either within the first year after LTx or during follow-up. Combination of the 2 miRNAs identified LTx patients with higher AR risk independently of clinical variables. Our data provide new insights into the roles of BAL-miRNAs in regulating the pulmonary environment after transplantation and suggest that these miRNAs could serve as biomarkers of early- or mid-stage events. If validated, these findings could pave the way to a personalized clinical approach in LTx patients.

Does lobar or size-reduced lung transplantation offer satisfactory early and late outcomes?

A best evidence topic was constructed according to a structured protocol. The question addressed was whether size-reduced or lobar lung transplantation (LLTx) offers the same benefit as classic lung transplantation (LTx). Of the 147 papers found using the reported search, 9 were selected to provide the best evidence. Details of the studies regarding authors, date, journal, country of publication, study type, group studied, relevant outcomes and results are given. All studies reported survival rates of LLTx and most compared it with classical LTx. No statistical differences were reported in medium term and long term. Two of the studies reported a higher incidence of postoperative complications, such as the need for cardiopulmonary bypass, reperfusion oedema or primary graft dysfunction, and longer intubation or intensive care unit stay times. Although the largest study showed a significantly worse 1-year survival in LLTx, a sub-analysis considering patients successfully discharged showed similar outcomes at 1, 3 and 5 years when compared with classic LTx patients. We conclude that LLTx is a valid therapeutic option for recipients with significant donor size mismatch, offering similar outcomes as classical LTx in the medium term and long term.

Sympatho-Vagal Dysfunction in Patients with End-Stage Lung Disease Awaiting Lung Transplantation.

Although the literature demonstrates that cardiac autonomic control (CAC) might be impaired in patients with chronic pulmonary diseases, the interplay between CAC and disease severity in end-stage lung disease has not been studied yet. We investigated the effects of end-stage lung disease on CAC through the analysis of heart rate variability (HRV) among patients awaiting lung transplantation. Forty-nine patients on the waiting list for lung transplantation (LTx; 19 men, age 38 ± 15 years) and 49 healthy non-smoking controls (HC; 22 men, age 40 ± 16 years) were enrolled in a case–control study at Policlinico Hospital in Milan, Italy. LTx patients were divided into two groups, according to disease severity evaluated by the Lung Allocation Score (LAS). To assess CAC, electrocardiogram (ECG) and respiration were recorded at rest for 10 min in supine position and for 10 min during active standing. Spectral analysis identified low and high frequencies (LF, sympathetic, and HF, vagal). Symbolic analysis identified three patterns, i.e., 0V% (sympathetic) and 2UV% and 2LV% (vagal). Compared to HCs, LTx patients showed higher markers of sympathetic modulation and lower markers of vagal modulation. However, more severely affected LTx patients, compared to less severely affected ones, showed an autonomic profile characterized by loss of sympathetic modulation and predominant vagal modulation. This pattern can be due to a loss of sympathetic rhythmic oscillation and a subsequent prevalent respiratory modulation of heart rate in severely affected patients.

Lack of Relationship Between Renal Function and Genetic Variants of CYP3A4, CYP3A5, MDR1, MRP2, UGT1A9, UGT1A8, and UGT2B7 in Patients After Liver Transplantation in a 2-Year Follow-up

BackgroundThe prolonged survival time after liver transplantation (LTX) creates the possibility of the occurrence and development of complications in the late post-transplantation period. Deterioration of renal function is 1 of these complications. The nephrotoxicity of calcineurin inhibitors (CNIs) and their metabolites produced during pharmacokinetic processes in the body is also postulated. The study was aimed at assessment of the relationship between selected single gene polymorphisms (SNPs) for enzymes and transport proteins and change of estimated glomerular filtration rate (ΔeGFR) during 2-year follow-up in LTX patients. MethodsThe study involved 244 patients after LTX (105 women [43.0%] and 139 men [57.0%]) receiving tacrolimus (191; 78.3%) or cyclosporine A (53; 21.7%). The study protocol conforms with the Declaration of Helsinki. ResultsWe have not observed significant differences of ΔeGFR between groups distinguished based on analyzed genotypes in patients treated with cyclosporine or tacrolimus. ConclusionGenetic variations of CYP3A4, CYP3A5, MDR1, MRP2, UGT1A9, UGT2B7, and UGT2B7 tested in LTX recipients are not associated with kidney function during the 24-month follow-up.

Long-Term Follow-up of Liver Transplant Recipients Treated With Direct-Acting Antiviral Agents for Hepatitis C Recurrence After Transplantation

BackgroundTreatment of hepatitis C virus (HCV) recurrence after liver transplantation (LTX) with direct-acting antiviral agents (DAA) is effective and leads to sustained viral response (SVR) in most cases. Long-term effect of HCV elimination on LTX function is not clear. The aim of the study was to evaluate the long-term influence of DAA with HCV on the liver function in LTX recipients. MethodsThe study included 120 LTX patients with HCV recurrence. Before starting DAA therapy, all patients underwent liver biopsy and elastography. Biochemical tests and HCV viremia were assessed at baseline, 4, 12, and 24 weeks and 24 months after the end of treatment (EOT). The study protocol conformed with the Declaration of Helsinki. ResultsIn the HCV genotype 1 (G1) group, 106 patients were treated with ledipasvir/sofosbuvir with ribavirin (RBV), and 3 patients received paritaprevir/ritonavir/ombitasvir/dasabuvir/RBV. All HCV genotype 3 (G3) patients were treated with sofosbuvir/RBV; all HCV genotype 4 (G4) patients were treated with paritaprevir/ombitasvir/RBV. The efficacy of the treatment defined as SVR at week 12 after EOT (SVR12) was 97.3% in G1 group, 75% in G3, and 100% in G4 group. Median alanine (ALT) and aspartate (AST) transaminase before therapy were 44.0 IU/mL and 42.5 IU/mL, respectively. Median ALT and AST at 24 months after EOT were 17 IU/mL and 22 IU/mL, respectively. The lack of transaminases normalization was observed in 10 patients 24 months after EOT. ConclusionThe efficacy of DAA therapy of HCV recurrence after LTX is as high as that reported in randomized clinical trials. It is also associated with the improvement of liver function tests during long-term follow-up.

Transcutaneous Electrical Stimulation Rescues Gastric Emptying in Lung Transplant Patients with Moderate to Severe Gastroparesis

Gastroparesis (GP) is prevalent after lung transplant (Ltx) (50-68%). GP has been associated with symptoms and delayed absorption of medications. Of particular concern after Ltx, GP can predispose to gastroesophageal reflux disease considered the main culprit for chronic allograft dysfunction. Therefore, early diagnosis and treatment is recommended in Ltx patients. Pharmacologic intervention for GP is not efficacious to improve gastric emptying and can induce potential serious side effects. Transcutaneous electric stimulation (TES) has been proposed to improve motility in various gastrointestinal motility disorders METHODS: We tested the hypothesis that TES may improve gastric emptying in Ltx patients. A 4-hour solid-phase gastric emptying study was done for worsening lung function before and after TES. Surveillance gastric emptying study (GEE) was done 2-12 weeks after TES. Five patients (4 female, age 48 ± 8), interval post-transplant (1-10 years), underwent TES as rescue therapy for moderate to severe GP (gastric retention >25% at 4 hours) that failed standard pharmacologic and dietary interventions. TES was delivered in continuous square wave, pulse rate 120 Hz, pulse width 220 µs, and pulse intensity to the maximum tolerated level without pain or muscle twitching. Two cutaneous electrodes were placed between T6 and T10 spinal levels (gastric autonomic segment) over the spine. Patients were instructed to use TES for 30 min after meals and for 30 min at bedtime RESULTS: Following TES, the percentage of gastric retention at 4 hours improved in the majority of patients (42 median, 25-73 min-max before TES; 20 median 7-43 min-max) after TES, p=0.01; figure 1). Three patients reported GP symptoms. Only one patient reported no significant improvement in the severity of symptoms CONCLUSION: TES appears to modulate symptom perception and significantly improves gastric emptying in Ltx patients with moderate to severe gastroparesis.

A Bumpy Road: Work Integration of People with Cystic Fibrosis after Lung Transplantation

Lung transplantation (LTX) is an established therapy in selected patients with advanced cystic fibrosis (CF) lung disease. Resumption of employment after LTX is generally supported. In Switzerland, there is no data on long-term LTX employment in patients with CF. In a single center cross-sectional study at our institution, data from LTX patients with CF from 01/1996 to 12/2016 were retrospectively analyzed. Influence of potential pre-LTX factors (i.e., age, sex, lung function, body mass index, 6-min walk distance, education, relationship status, housing situation, LTX wait list time, gainful employment on the wait list) and post-LTX factors on gainful employment after LTX [chronic allograft dysfunction (CLAD), dialysis, cancer diagnosis (except skin cancer)] were investigated using mixed logistic regression models with random effects. Descriptive analyses of gainful employment were performed for various periods after LTX (i.e., >1, 1-3, 3-5, 5-10, >10 years). 99 patients (35±10 years; 49.5% female) were enrolled. Mean wait time for LTX was 42±39 weeks. Employment for <1 (n=93), 1-3 (n=90), 3-5 (n=68), 5-10 (n=53) and >10 (n=32) years post-LTX was 35%, 68%, 79%, 72% and 78%, respectively. Pre-LTX gainful employment (OR 32.16, 95% CI 9.48 - 177.09, p<0.0001), vocational training (academic vs. non-academic, OR 4.40, 95% CI 1.07 - 20.55, p=0.04) and time to LTX (log scale) OR 4.94, 95% CI 2.95 - 9.38, p<0.0001) were main factors influencing post-LTX earning capacity. Clinical factors, such as CLAD, had no influence on LTX employment. Pre-LTX employment is the dominant factor influencing LTX employment in people with CF. Patients should be encouraged to work for as long as possible, where health permits. Professional reintegration after successful LTX should be supported interdisciplinary by the LTX team.

Regulation of Cysteine-Protease Activity Prevents Graft Dysfunction during Ischemia-Lung Reperfusion

Lung transplantation (LTx) is the final treatment option in end-stage lung diseases. Despite significant improvements, the long-term outcome remains uncertain with a 6 year survival of 53% LTx patients. Among risk factors, primary graft dysfunction (PGD) is the leading cause of early morbidity and mortality after LTx. PGD is a form of acute lung injury that results from ischemia, defined as a deficiency of oxygen, caused by the restriction of the blood flow, and blood reperfusion of the ischemic tissue, which may induces tissue injury reperfusion injury (IRI). This process is associated with increased permeability of capillaries, hypoxemia, cell death, and cytokine release. Our aim is to investigate the pathway involved in PGD and develop a therapeutic approach. An orthotopic left lung murine model was used to simulate PGD. Lung grafts were stored at 4°C for 18h in Perfadex® solution, supplemented with and without cysteine-protease inhibitor, and perfused for 2h via ex vivo lung perfusion (EVLP) with and without inhibitor. The left lung was implanted for 4 hours in a recipient mouse, in order to simulate IRI. Gas exchange function, Apoptosis, bronchoalveolar lavage fluid (BALF), and perfusate were determined RESULTS: Lungs stored and perfused with cysteine-protease-inhibitor showed a better oxygen-exchange (93,9 % vs 74,47 % pO2) in the alveolar compartment, less total cell (30,4 vs 65,26 per field of view) and AT2 cell apoptosis after 4h of warm reperfusion compared with the control group. These findings correlate with reduced TNF-α release in perfusate after cold storage and EVLP, which promotes a better preservation of the organ. In-vitro experiments well simulated IRI injury features that further confirmed in-vivo findings. Cysteine-protease inhibitor, added to the cell medium prevents cysteine-protease activity and TNFα release after cold storage CONCLUSION: Here, we showed that ischemia-reperfusion damage is associated with an increase of cysteine-proteases´s activity, in particular after warm-reperfusion of the graft, which results in enhanced maturation of TNF-α, and enhanced cell apoptosis of alveolar AT2 cells, that affect oxygen exchange of the implanted lung. These results provide a new therapeutic strategy for a safer organ preservation and reperfusion after LTx.

Lung Transplantation after Allogeneic Stem Cell Transplantation: A Single-Centre Experience

Pulmonary chronic graft versus host disease (GVHD) is one of the thoracic manifestations that can complicate allogeneic hematopoietic stem cell transplantation (HSCT) causing respiratory failure and death. Lung transplantation (LTx) often remains the only therapeutic option for progressive forms although it has been reported in a small number of patients worldwide. This retrospective study focused on patients who underwent LTx for pulmonary GVHD in our Centre and consisted in a careful review of all crucial post-transplantation clinical (primary graft dysfunction, CLAD-free survival, overall survival) and pathological data [acute rejection and infection indices in all follow-up scheduled bronchoscopies (total number of biopsies: 35, total number of bronchoalveolar lavages: 33), signs of chronic rejection]. 467 patients underwent LTx in the 1995-2019 period: in 5 cases the referral diagnosis was pulmonary chronic GVHD (1%) [all males, mean age: 27±13 yrs, two patients aged ≤16, developed 23±14 months following HSCT for neoplastic conditions (mean±SD)]. At census date, 2 were alive (40%) with a median (Q1-Q3) follow-up of 59 (17-64) months. At 5 years post-LTx the overall survival was 60%. One patient died for multiorgan failure early after LTx. Two deaths occurred after 17 and 64 months due to infectious complications (cytomegalovirus, CMV) and, interestingly, only these cases developed CLAD with features of obliterans bronchiolitis during follow-up (at 8 and 13 months, respectively). At the last follow-up, no patients had a recurrence of haematological malignancy and the two patients who are still alive (at 80 and 59 months) have had viral infections but never CMV. Acute rejection index was 18% (12%-23%), if we consider only the first year post-LTx it was 10% (0%-32%) while in age-matched patients transplanted for cystic fibrosis (CF) at our centre it was 29% (12.5%-50%). Finally, the infection index was 50% (32%-66%). All indices are expressed as median (Q1-Q3). LTx is a feasible option for patients with severe GVHD. Survival is in line with data reported in the literature, as well as with the general LTx population; deaths were mainly related to CMV infections. Concerning acute rejection indexes, they were lower than those detected at our Centre when considering all LTx patients or only those with CF.

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

Calcinuerin inhibitor (CNI) based immunosuppression (IS) regimens remain the cornerstone of IS protocols post lung transplantation (LTx). Everolimus (EVE) has been used to augment IS in LTx patients or as a CNI minimization/ elimination agent in those with renal impairment or recurrent CMV infection. There is limited evidence to support EVE based IS regimens and the impact on progression to chronic lung allograft dysfunction (CLAD). The primary aim was to compare patients who remained on CNI-based IS to those who switched to EVE-based IS and assess the impact of EVE-based IS on time to CLAD and ultimately survival. Single centre retrospective study of 91 patients who were initiated on EVE from 1550 consecutive LTx recipients between 1993 and 2018. Each EVE patient was matched with a patient who remained on CNI-based IS. Criteria for matching included indication for LTx, gender, LTx procedure and age at LTx. A survival analysis was performed in the EVE cohort. 182 LTx recipients [91 EVE & 91 CNI-based IS, mean age 51 ±15 years, 70% male, 82% BSLTx, LTx diagnosis: COPD 35%, ILD 22%, CF 22%, PAH 8%]. The incidence of CLAD was similar across the groups (51% EVE-based vs 48% CNI-based). Patients with CLAD at initiation of EVE had a 3.6 times higher risk of death than those without CLAD [HR 3.60, 95% CI: 2.16 - 6.01, p = 0.0001]. However there was no significant difference in the risk of developing CLAD between EVE-based IS and CNI-based IS [HR 1.05, 95% CI: 0.65 - 1.71]. The incidence of the RAS phenotype of CLAD was higher in the EVE-based group (56% EVE-based vs 39%- CNI-based) but not significant. The risk of death is not significant between EVE-based IS and CNI-based IS from time of switch [HR 1.22, 95% CI: 0.77 - 1.88]. The median days from CLAD to death was significantly higher (p = 0.01) in the EVE-based IS group (1127, IQR: 504 - 2210) compared to the CNI-based group (427, IQR: 236 - 1229). The survival analysis noted a higher mortality with 1) Earlier initiation post LTx (2% / month closer to LTx, 95% CI 1.0 - 3.0%, p = 0.001), 2) Increasing age at initiation (3% /year of age, 95% CI, 0 - 5%, p = 0.029). 3) Diabetes at the time of initiating EVE (HR 2.74 [1.48 - 5.09], p = 0.001). EVE-based IS can be successfully utilized for second-line IS for CNI minimization / elimination and was not associated with an increase in CLAD incidence or CLAD related mortality.

Lung Transplantation for Acute Respiratory Distress Syndrome Patients: A Single Center Experience

Acute respiratory distress syndrome (ARDS) is a rapidly progressive lung disease with a high mortality rate. Although lung transplantation (LTx) remains the only lifesaving option for certain end-stage pulmonary diseases, ARDS as indication for LTx is discussed controversially and only limited data are available. For example, in the Eurotransplant region, only 17 patients transplanted for ARDS are documented. Since we have followed a liberal approach of accepting ARDS patients for LTx, we reviewed retrospectively the outcome of this particular patient cohort in our center. From 08/98 to 03/19 a total of 10 patients transplanted for ARDS were identified in our center. Demographic and clinical data of these patients were collected and analyzed. Eight/10 patients were listed and transplanted while on extracorporeal membrane oxygenation (ECMO). The remaining 2 patients could be initially weaned from ECMO but were respirator dependent at the time of referral for LTx. The median mechanical ventilation time and median length of ECMO was 33.5 (IQR: 3.5-62.3) and 29.5 (28-38) days before LTx. Length of ICU and length of hospital stay was 38 (24.5-52) and 57 (43.5-94) days. The 30-day mortality was 10% and 1-year survival rate was calculated as 55.5% (Figure 1). One patient developed chronic lung allograft dysfunction (CLAD) and received re-transplantation 12 years after the primary procedure. The median follow up time was 82 (49.9-1065) days. Lung transplantation is feasible in carefully selected ARDS patients. Given the lack of alternative treatment options it provides acceptable long-term results.

Economic Burden of Bronchiolitis Obliterans Syndrome (BOS) in Lung Transplant Patients

BOS, a common complication after lung tansplantation (LTx), is a rapidly progressive obstructive airway disease characterized by T-cell mediated inflammation and fibrosis that leads to respiratory failure and death. Lung failure can occur 9-24 months after diagnosis and up to half of LTx patients experience BOS within 5 years of transplantation. Currently there are no approved treatments and there is no general consensus regarding drug treatment. Additionally, information on the economic burden of BOS is lacking. The data source for this longitudinal retrospective study was the IQVIA Pharmetrics Plus database, with enrollment, demographic, medical and prescription drug claim data for commercially insured individuals in the U.S. The study period was 01/01/2006 to 09/30/2018. Eligible patients were <65y old, with a diagnosis for BOS after lung transplantation, identified using ICD diagnosis and procedure codes, and CPT codes. Patients were observable for at least 12 months before index BOS diagnosis. Study outcomes were healthcare resource use (HRU) and costs in the post-BOS diagnosis year. Costs were defined as those paid by the insurer. Among 492 patients, mean age was 47.5 years; 49% were female. In the year after BOS diagnosis, mean per patient costs totaled $173,672. The majority of these costs were for inpatient services ($109,593; SD: 340,235), reflecting lengthy hospital stays (mean: 53.2 days [SD: 386.8] per admission) and 2 admissions per patient [SD:3.0] The remaining costs were for prescription medications ($16,290 [SD:19,976]) and outpatient visits and tests ($47,128 [SD:57,919]). Outpatient hospital visits underlay most outpatient costs ($36,970 [SD:53,801]) (Figure). The economic burden of BOS after lung transplant is high, with mean per patient costs in the year after diagnosis of $174,000. These costs reflect lengthy hospitalizations and limited treatment options for preventing or delaying the devastating effects of BOS.