Lung allocation score: the Eurotransplant model versus the revised US model - a cross-sectional study.

Both Eurotransplant (ET) and the US use the lung allocation score (LAS) to allocate donor lungs. In 2015, the US implemented a new algorithm for calculating the score while ET has fine-tuned the original model using business rules. A comparison of both models in a contemporary patient cohort was performed. The rank positions and the correlation between both scores were calculated for all patients on the active waiting list in ET. On February 6th 2017, 581 patients were actively listed on the lung transplant waiting list. The median LAS values were 32.56 and 32.70 in ET and the US, respectively. The overall correlation coefficient between both scores was 0.71. Forty-three per cent of the patients had a < 2 point change in their LAS. US LAS was more than two points lower for 41% and more than two points higher for 16% of the patients. Median ranks and the 90th percentiles for all diagnosis groups did not differ between both scores. Implementing the 2015 US LAS model would not significantly alter the current waiting list in ET.

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.

Unbound Plasma, Total Plasma, and Whole-Blood Tacrolimus Pharmacokinetics Early After Thoracic Organ Transplantation.

BACKGROUND AND OBJECTIVE: Therapeutic drug monitoring of tacrolimus whole-blood concentrations is standard care in thoracic organ transplantation. Nevertheless, toxicity may appear with alleged therapeutic concentrations possibly related to variability in unbound concentrations. However, pharmacokinetic data on unbound concentrations are not available. The objective of this study was to quantify the pharmacokinetics of whole-blood, total, and unbound plasma tacrolimus in patients early after heart and lung transplantation. METHODS: Twelve-hour tacrolimus whole-blood, total, and unbound plasma concentrations of 30 thoracic organ recipients were analyzed with high-performance liquid chromatography-tandem mass spectrometry directly after transplantation. Pharmacokinetic modeling was performed using non-linear mixed-effects modeling. RESULTS: Plasma concentration was < 1% of the whole-blood concentration. Maximum binding capacity of erythrocytes was directly proportional to hematocrit and estimated at 2700 pg/mL (95% confidence interval 1750-3835) with a dissociation constant of 0.142 pg/mL (95% confidence interval 0.087-0.195). The inter-individual variability in the binding constants was considerable (27% maximum binding capacity, and 29% for the linear binding constant of plasma). CONCLUSIONS: Tacrolimus association with erythrocytes was high and suggested a non-linear distribution at high concentrations. Monitoring hematocrit-corrected whole-blood tacrolimus concentrations might improve clinical outcomes in clinically unstable thoracic organ transplants. CLINICAL TRIAL REGISTRATION: NTR 3912/EudraCT 2012-001909-24.

High Variability of Whole-Blood Tacrolimus Pharmacokinetics Early After Thoracic Organ Transplantation.

BACKGROUND AND OBJECTIVE: Oral tacrolimus is initiated perioperatively in heart and lung transplantation patients. There have been few studies on oral tacrolimus pharmacokinetics early post-transplantation, even though tacrolimus-related toxicity may occur early, potentially leading to morbidity and mortality. Therefore, we aimed to study the pharmacokinetics of oral tacrolimus in thoracic organ recipients during the first days after transplantation. METHODS: We conducted a pharmacokinetic study in 30 thoracic organ transplants at intensive care at the University Medical Center Utrecht in the first week post-transplantation. Twelve-hour whole-blood tacrolimus profiles were examined using high-performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS) and analysed via population pharmacokinetic modelling. RESULTS: The concentration-time profiles showed high variability. Concentrations at 12 h were outside the target range in 69% of the cases. A two-compartment model with mixed first-order and zero-order absorption adequately described tacrolimus concentrations. The typical value of the apparent clearance was 19.6 L/h (95% CI 16.2-22.9), and the apparent distribution volumes of central and peripheral compartments, V1 and V2, were 231 L (95% CI 199-267) and 521 L (95% CI 441-634), respectively. Inter-occasion (dose-to-dose) variability far exceeded the interindividual variability (IIV), with an estimated variability in relative bioavailability of 55% (95% CI 48.5-64.4). CONCLUSIONS: The high variability of tacrolimus pharmacokinetics early after thoracic organ transplantation is largely due to excessive variability in bioavailability, making individualised dosing based on measured concentrations futile. To bypass this bioavailability issue, we suggest administering tacrolimus intravenously and aiming below the upper therapeutic range early post-transplantation. Clinical Trial Registraion: NTR 3912/EudraCT 2012-001909-24.

Prediction Equations Underestimate Resting Energy Expenditure in Patients With End-Stage Cystic Fibrosis.

BACKGROUND: Resting energy expenditure (REE) is increased in patients with cystic fibrosis (CF) with end-stage lung disease due to chronic inflammation and pulmonary infections. After lung transplantation (LTx), energy expenditure is expected to be lower because inflammation will decrease. We assessed the agreement between measured and predicted REE in pre-LTx CF and post-LTx patients with CF and differences in REE in pre-LTx CF and post-LTx patients with CF in a cross-sectional study. METHODS: Included were 12 pre-LTx patients with CF (9 women; median age 31.6 years; interquartile range [IQR], 23.3-40.0) and 12 patients with CF within 2 years after LTx (6 women; median age 33.5 years; IQR, 22.3-40.3). REE was measured in a fasted state using indirect calorimetry. Values were compared with predicted REE calculated by formulas of Harris-Benedict (1919 and 1984), Schofield, and the World Health Organization (1985). A calculated REE between 90% and 110% of REE measured was considered adequate. RESULTS: Prediction equations underestimate REE in at least 75% of pre-LTx and 33% of post-LTx patients with CF. Mean (SD) REE measured by indirect calorimetry was 1735 (251) kcal pre-LTx and 1650 (235) kcal post-LTx ( P = .40). REE expressed per kilogram of fat-free mass (FFM) was 40.5 kcal/kg in pre-LTx patients with CF, which was higher than the 34.3 kcal/kg in post-LTx patients with CF ( P = .01). CONCLUSIONS: Prediction equations underestimate REE in patients with end-stage CF. REE per kg of FFM is lower post-LTx than pre-LTx in patients with CF. Measurement of REE is recommended for patients with CF, especially pre-LTx, to optimize energy requirements for improving nutrition status.

Body Weight and Body Mass Index in Patients with End-Stage Cystic Fibrosis Stabilize After the Start of Enteral Tube Feeding.

BACKGROUND: Enteral tube feeding (ETF) is widely used in patients with cystic fibrosis (CF) and end-stage lung disease, but previous studies have been limited to investigating whether ETF improves outcomes in patients with moderately or mildly impaired pulmonary function. OBJECTIVE: This study investigated body weight, body mass index (BMI; calculated as kg/m2), pulmonary function, and the presence of CF-related diabetes before and after the start of ETF. DESIGN: This was a retrospective observational study. PARTICIPANTS/SETTING: Data from 26 adult patients in an outpatient setting who had end-stage CF (19 women) and had been using ETF for at least 6 months between 2000 and 2014 were analyzed. MAIN OUTCOME MEASURES: Body weight, BMI, pulmonary function (forced expiratory volume in 1 second as percent of predicted) and incidence of CF-related diabetes from 6 months before to 6 months after starting ETF. STATISTICAL ANALYSES PERFORMED: Time effects were tested with one-way analysis of variance for data that were normally distributed and the Friedman test for non-parametric data. Correlations were tested with Pearson's r or Spearman's ρ, depending on the distribution of the data. RESULTS: Mean body weight increased by 3.5 kg (95% CI 2.2 to 4.8 kg) after patients started ETF. In women, mean BMI decreased by 0.7 in the 6 months before the start of ETF (P<0.05) and increased by 1.4 in the 6 months thereafter (P<0.05). In men, BMI changes were similar (-0.8 and +1.1), but not statistically significant. Forced expiratory volume in 1 second as percent of predicted significantly decreased in time from a median of 28% to 26% at the start of ETF to 25% after 6 months (P=0.0013), with similar trends in women and men. There was no correlation between changes in weight and lung function. CF-related diabetes was already present in 12 patients and developed in 1 more patient after the start of ETF. CONCLUSIONS: ETF improved body weight and BMI but not pulmonary function in 26 patients with end-stage CF. Clinical outcomes were similar in women and men, but the sample size of men was too small to determine statistical significance.

Reduced Expression of Membrane Complement Regulatory Protein CD59 on Leukocytes following Lung Transplantation.

Cellular protection against undesired effects of complement activation is provided by expression of membrane-bound complement regulatory proteins including CD59. This protein prevents membrane attack complex formation and is considered to be involved in graft accommodation. Also, CD59 downregulates CD4+ and CD8+ T-cell activation and proliferation. It is unknown whether CD59 expression is affected by transplantation. The aim of this study was to evaluate the quantitative CD59 antigen expression on distinct leukocyte subsets following lung transplantation (n = 26) and to investigate whether this differs from pretransplantation (n = 9). The results show that CD59 expression on leukocytes is significantly lower posttransplantation compared with healthy controls (p = 0.002) and pretransplantation (p < 0.0001). Moreover, the CD59 expression diminishes posttransplantation on all distinct lymphocyte subsets (p < 0.02). This effect appeared to be specific for CD59 since the expression of other surface markers remained stable or inclined following transplantation. The highest antigen expression posttransplantation was observed on CD4+ T cells and monocytes (p ≤ 0.002). These findings show that CD59 expression on leukocytes diminishes posttransplantation, which could result in decreased resistance against complement and enhanced T-cell activation. If such reduction in CD59 expression also occurs on endothelial cells from the transplanted organ, this could lead to a change into a prothrombotic and proinflammatory phenotype.

Immune status assessment in adult lung transplant candidates.

BACKGROUND: Lung transplant recipients have an increased susceptibility to a variety of infections due to immunosuppressive therapy. Current guidelines recommend pneumococcal and other vaccinations, prior to lung transplantation to protect against post-transplant infections, but measurement of the antibody response to vaccination is not advised. Immune status investigation in lung transplant candidates, including the response to pneumococcal polysaccharide vaccination, has not been described. METHODS: Immune status investigation, including measurement of immunoglobulins, complement and the response to 23-valent pneumococcal polysaccharide vaccination (23vPPV) was performed in 81 adult lung transplant candidates. RESULTS: Eighteen patients had low IgG levels and 32 patients had low IgG1 and/or IgG2 levels. After vaccination with 23vPPV the median antibody concentration of all serotypes increased significantly. Fifty-two patients had protective IgG-post-vaccination antibody levels to at least 10 serotypes. Twenty-nine patients had an impaired response to 23vPPV. CONCLUSIONS: In conclusion, a significant proportion of our cohort of lung transplant candidates had one or more abnormalities in the immune status. It is likely that these patients have an increased risk for infections after transplantation. Revaccination, including measurement of antibody response, and possibly antibody replacement therapy should be considered to minimize infection risk.

Emphysema Is Common in Lungs of Cystic Fibrosis Lung Transplantation Patients: A Histopathological and Computed Tomography Study.

BACKGROUND: Lung disease in cystic fibrosis (CF) involves excessive inflammation, repetitive infections and development of bronchiectasis. Recently, literature on emphysema in CF has emerged, which might become an increasingly important disease component due to the increased life expectancy. The purpose of this study was to assess the presence and extent of emphysema in endstage CF lungs. METHODS: In explanted lungs of 20 CF patients emphysema was semi-quantitatively assessed on histology specimens. Also, emphysema was automatically quantified on pre-transplantation computed tomography (CT) using the percentage of voxels below -950 Houndfield Units and was visually scored on CT. The relation between emphysema extent, pre-transplantation lung function and age was determined. RESULTS: All CF patients showed emphysema on histological examination: 3/20 (15%) showed mild, 15/20 (75%) moderate and 2/20 (10%) severe emphysema, defined as 0-20% emphysema, 20-50% emphysema and >50% emphysema in residual lung tissue, respectively. Visually upper lobe bullous emphysema was identified in 13/20 and more diffuse non-bullous emphysema in 18/20. Histology showed a significant correlation to quantified CT emphysema (p = 0.03) and visual emphysema score (p = 0.001). CT and visual emphysema extent were positively correlated with age (p = 0.045 and p = 0.04, respectively). CONCLUSIONS: In conclusion, this study both pathologically and radiologically confirms that emphysema is common in end-stage CF lungs, and is age related. Emphysema might become an increasingly important disease component in the aging CF population.

Pretransplant HRCT Characteristics Are Associated with Worse Outcome of Lung Transplantation for Cystic Fibrosis Patients.

OBJECTIVES: Peri- and postoperative complications diminish the outcome of lung transplantation (LTx) in patients with cystic fibrosis (CF). We hypothesized that the degree of pathological findings on pre-LTx high resolution computed tomography (HRCT) is associated with higher morbidity and mortality in CF. METHODS: All our CF patients undergoing LTx between 2001 and 2011 were included. HRCT examinations were evaluated according to a scoring system for pulmonary disease in CF patients, the Severe Advanced Lung Disease (SALD) score and for pleural involvement. RESULTS: Fifty-three patients were included. Dominant infectious/inflammatory disease according to the SALD score was observed in 10 patients (19%). Five (50%) of those patients died within one week after LTx, compared to 2 (5%) patients without dominant infectious/inflammatory disease (p<0.001). This difference in survival percentage remained also significant in multivariate analysis. Patients with infectious/inflammatory disease received more packed red blood cells; 26 versus 8 in the first week (p<0.001). Pleural thickening was associated with higher requirement (10 units) for blood transfusion during LTx, compared to patients with normal pleura (4 units). CONCLUSIONS: The analysis of HRCT in CF patients according to the SALD score showed that dominant infectious/inflammatory disease is associated with a higher mortality after LTx. If confirmed in other studies, HRCT might aid estimation of surgical risk in some adult CF patients.

Pulmonary hypertension is a mild comorbidity in end-stage cystic fibrosis patients.

BACKGROUND: This study investigated the prevalence of pulmonary hypertension (PH) in cystic fibrosis (CF) patients awaiting lung transplantation (LTx) and its influence on survival. We also explored the feasibility of using echocardiography as a first assessment for diagnosing PH. METHODS: The study included 93 CF patients (46 women [50%]) evaluated for LTx between 2001 and 2010. Median age was 29 years. PH was defined as a mean pulmonary artery pressure (mPAP) measured by right heart catheterization (mPAP(cath)) of ≥ 25 mm Hg with a wedge pressure of ≤ 15 mm Hg. Echocardiographic results were divided into 3 categories based on current guidelines as "unlikely," "possible," or "likely" to have PH. RESULTS: In 23 patients (25%) the mPAP(cath) was between 25 and 35 mm Hg, and 1 (1%) had severe PH (mPAP(cath) of ≥ 35 mm Hg). PH did not influence survival after enlistment (p = 0.7) and after LTx (p = 0.8). For 62 patients (67%), the sPAP(echo) could be measured, and PH was unlikely in 24 (39%). In another 19 patients (20%), PH was unlikely based on the absence of tricuspid regurgitation. The negative-predictive value (NPV) of measuring PH by echocardiography was 88% in whom PH was estimated to be unlikely (n = 43); whereas in 24 patients with a measurable low sPAP(echo), the NPV was 96%. CONCLUSIONS: PH exists in 26% of end-stage CF patients and has no effect on survival on the waiting list for LTx or after LTx. Echocardiography might be used as the first tool to rule out PH, showing a NPV of 88%.

Crossed wiring closure technique for bilateral transverse thoracosternotomy is associated with less sternal dehiscence after bilateral sequential lung transplantation.

OBJECTIVE: Bilateral transverse thoracosternotomy (clamshell incision) is a widely used approach in bilateral sequential lung transplantation, but the closure technique is associated with sternal dehiscence. This study compares the incidence of sternal dehiscence between the crossed and uncrossed closure techniques. METHODS: In 129 patients who underwent transplantation through a clamshell incision, the sternum was closed using either the crossed or the uncrossed method based on the surgeon's preference. The position of the sternal parts was evaluated on lateral chest radiographs and scored as normal, override, or separation. RESULTS: We observed sternal override in 38 patients and separations in 18 patients. The sternum was closed using the uncrossed method in 79 patients and the crossed method in 50 patients. There were significantly fewer overrides (n = 6, 12.0%) and separations (n = 6, 12.0%) of the sternal parts using the crossed closure technique compared with the uncrossed technique (32 overrides, 41.0%; and 12 separations, 15.1%; P < .001). Reconstructive surgery was only performed in patients with separation of the sternal parts (n = 10). CONCLUSIONS: Using the crossed closure technique for the sternum after bilateral sequential lung transplantation reduces the incidence of sternal dehiscence compared with the uncrossed closure technique and, therefore, reduces the necessity of reconstructive surgery.

[High mortality in patients with idiopathic pulmonary fibrosis on Dutch lung transplant waiting list]. / Hoge sterfte van patiënten met idiopathische pulmonale fibrose op Nederlandse longtransplantatiewachtlijst.

OBJECTIVE: To describe patients diagnosed with idiopathic pulmonary fibrosis (IPF) registered for lung transplantation and to evaluate the current referral guidelines for lung transplantation in the Netherlands. DESIGN: Retrospective study. METHOD: All patients diagnosed with interstitial lung disease and registered for lung transplantation from September 1989-June 2010 were included in this study. Patients who had been diagnosed with IPF according to the American Thoracic Society-European Respiratory Society criteria were included. Clinical data of these patients at the time of screening for lung transplantation and survival data were collected. RESULTS: In total, 289 patients with IPF were registered for lung transplantation. After a first waiting list. During the waiting period, 30 patients (33%) died, 7 were taken off the list due to newly developed comorbidity and excessive physical deterioration, 51 underwent transplantation and 2 were still on the waiting list at the time of study closure. At the time of screening, the mean FVC% predicted of these patients was 51% (SD: 19.0) and the mean diffusing capacity was 27% of predicted (SD: 9.3). CONCLUSION: One-third of the IPF patients on the waiting list died before donor lungs became available. The mean diffusing capacity of 27% of predicted at the time of screening was considerably lower than advised in the international guidelines for placement on the waiting list. This study, therefore, shows that the timing of screening IPF patients for lung transplantation can be improved in the Netherlands.

Pulmonary embolism and pulmonary infarction after lung transplantation.

Venous thromboembolism (VTE), which includes pulmonary embolism (PE) and deep vein thrombosis (DVT), is a common occurrence in patients undergoing surgery and is a potentially fatal complication. Especially after lung transplantation, vascular complications can compromise the function of the allograft and limit survival. Typically, the risk of pulmonary infarction after PE in lung transplant recipients is high because the absence or poor development of the collateral bronchial circulation may predispose lung transplant recipients to pulmonary infarction. This article reports 2 cases of PE with associated pulmonary infarction after lung transplantation with significant morbidity.

Chimerism of dendritic cell subsets in peripheral blood after lung transplantation.

BACKGROUND: Passenger leukocytes of donor origin are transferred to the patient resulting in circulatory microchimerism after lung transplantation (LTx). This chimeric state has been shown to occur in the total leukocyte fraction as well as unseparated peripheral blood mononuclear cells (PBMCs). In this study we determined the microchimerism levels of B cells, monocytes, natural killer (NK) and T cells and dendritic cell (DC) subsets (mDC1, mDC2 and pDC) during the first year after lung transplantation. METHODS: To identify circulating donor cells, 11 donor-patient combinations were selected, which were mismatched for HLA-B8. Analysis consisted of flow cytometry on a minimum of 1 million PBMCs taken monthly up to 1 year after LTx. RESULTS: Levels of microchimerism were found to be stable after LTx for all cell types investigated, although for NK+T cells an above-baseline chimerism of donor cells from the donor lung was observed in the first month after transplantation. Circulating PBMCs consisted of, on average, 0.002%, 1.7%, 0.03% and 0.001% of B cells, monocytes, NK+T cells and DCs, respectively, indicating that overall levels of microchimerism differed between the cell types investigated. In 2 patients no B-cell chimerism and in 1 patient no DC chimerism could be detected. Cell types and DC subsets of recipient origin were normally distributed. Conversely, monocytes, B cells and DCs of donor origin were increased and donor NK+T cells were decreased in number, compared with the recipient ratios. Analysis of circulating recipient DCs showed a normal distribution of mDC1s (70%), mDC2s (5%) and pDCs (25%). However, circulating donor DCs consisted of 80%, 20% and <1% of DC subsets mDC1, MDC2 and pDC, indicating that donor plasmacytoid dendritic cells were not detectable in the circulation. CONCLUSIONS: In the first year after lung transplantation a stable microchimerism was detected for all cell types investigated. However, donor pDCs were consistently absent in all samples investigated, which may be linked with graft rejection often observed after LTx.

The Induction of IgM and IgG Antibodies against HLA or MICA after Lung Transplantation.

The production of IgG HLA antibodies after lung transplantation (LTx) is considered to be a major risk factor for the development of chronic rejection, represented by the bronchiolitis obliterans syndrome (BOS). It has recently been observed that elevated levels of IgM HLA antibodies also correlates with the development of chronic rejection in heart and kidney transplantation. This study investigates the relationship between IgM and IgG antibodies against HLA and MICA after lung transplantation. Serum was collected from 49 patients once prior to transplantation and monthly for up to 1 year after lung transplantation was analyzed by Luminex to detect IgM and IgG antibodies against HLA and MICA. The presence of either IgM or IgG HLA and/or MICA antibodies prior to or after transplantation was not related to survival, gender, primary disease, or the development of BOS. Additionally, the production of IgG alloantibodies was not preceded by an increase in levels of IgM, and IgM levels were not followed by an increase in IgG. Under current immune suppressive regimen, although the presence of IgM antibodies does not correlate with BOS after LTx, IgM( high) IgG( low) HLA class I antibody titers were observed more in patients with BOS compared to patients without BOS.

A genetic polymorphism in the CAV1 gene associates with the development of bronchiolitis obliterans syndrome after lung transplantation.

BACKGROUND: Caveolin 1 (Cav-1) is the primary structural component of cell membrane invaginations called 'caveolae'. Expression of Cav-1 is implicated in the pathogenesis of pulmonary fibrosis. Genetic polymorphisms in the CAV1 gene influence the function of Cav-1 in malignancies and associate with renal allograft fibrosis. Chronic allograft rejection after lung transplantation, called 'bronchiolitis obliterans syndrome' (BOS), is also characterised by the development of fibrosis.In this study, we investigated whether CAV1 genotypes associate with BOS and whether Cav-1 serum levels are influenced by the CAV1 genotype and can be used as a biomarker to predict the development of BOS. METHODS: Twenty lung transplant recipients with BOS (BOSpos), ninety without BOS (BOSneg) and four hundred twenty-two healthy individuals donated DNA samples. Four SNPs in CAV1 were genotyped. Serial Cav-1 serum levels were measured in a matched cohort of 10 BOSpos patients and 10 BOSneg patients. Furthermore, single-time point Cav-1 serum levels were measured in 33 unmatched BOSneg patients and 60 healthy controls. RESULTS: Homozygosity of the minor allele of rs3807989 was associated with an increased risk for BOS (odds ratio: 6.13; P = 0.0013). The median Cav-1 serum level was significantly higher in the BOSpos patients than in the matched BOSneg patients (P = 0.026). Longitudinal analysis did not show changes in Cav-1 serum levels over time in both groups. The median Cav-1 serum level in the group of 43 BOSneg patients was lower than that in the healthy control group (P = 0.046).In lung transplant recipients, homozygosity of the minor allele of rs3807989 and rs3807994 was associated with increased Cav-1 serum levels. CONCLUSION: In lung transplant recipients, the CAV1 SNP rs3807989 was associated with the development of BOS and Cav-1 serum levels were influenced by the CAV1 genotype.