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Abstract Introduction In Germany, the estimation of the disease burden of respiratory syncytial virus (RSV) in older adults is limited. This makes it challenging for public health decision-makers to develop evidence-based recommendations for newly available vaccines against RSV for individuals aged 60 years and older (60+). This study investigates publicly available data sources in Germany to address the current gaps in evidence regarding the burden of RSV. Methods Hospitalisation databases from the German Federal Statistical Office and national mortality statistic between 2000 and 2023, as well as regular surveillance reports from the national public health institute since 2014, were utilised to extract, combine and analyse data on RSV-related morbidity and mortality. These data were used to triangulate the age-specific burden of RSV. Results The data indicate that the number of RSV-related outpatient consultations ranges between 1,313,100 and 3,911,800 cases per season from 2014/2015 to 2022/2023 for all age groups, with approximately 13.0% of outpatient consultations occurring in adults 60+. The significant increase in hospitalisations over time suggests that heightened testing due to the coronavirus disease 2019 (COVID-19) pandemic revealed the underdetection of inpatient RSV cases in pre-pandemic seasons. In the most recent season recorded, 2022/2023, the data show 12,800 RSV-related hospitalisations in adults 60+ (24% of all RSV-related hospitalisations) and 1340 in-hospital deaths in adults 60+ (93% of all RSV-related deaths). Conclusion The comparison of pre- to post-pandemic seasons strongly suggest up to a sevenfold underdetection of RSV in individuals 60+, and the analysis of in-hospital mortality reveals higher mortality rates compared with the general German mortality statistics. These findings highlight the urgent need to improve surveillance and implement targeted prevention strategies to mitigate the impact of RSV in older adults.

Background: Many hospitalized patients decline in functional status after discharge, but functional decline in emergency admissions with hypoxemia is unknown. The primary aim of this study was to study functional outcomes as a clinical endpoint in a cohort of patients with acute hypoxemia. Methods: A multicenter prospective observational study was conducted in patients with new-onset hypoxemia emergently admitted to two respiratory departments at a university hospital and an academic teaching hospital. Using the WHO scale, the patients’ functional status 4 weeks before admission and at hospital discharge was assessed. The type and duration of oxygen therapy, hospital length of stay and survival and risk of hypercapnic failure were recorded. Results: A total of 151 patients with a median age of 74 were included. Two-thirds declined in functional status by at least one grade at discharge. A good functional status (OR 4.849 (95% CI 2.209–10.647)) and progressive cancer (OR 6.079 (1.197–30.881)) were more associated with functional decline. Most patients were treated with conventional oxygen therapy (n = 95, 62%). The rates of in-hospital mortality and need for intubation were both 8%. Conclusions: Patients with acute hypoxemia in the emergency room have a poorer functional status after hospital discharge. This decline may be of multifactorial origin.

Background: Chronic lung allograft dysfunction (CLAD) is the leading cause of death after the first postoperative years of lung transplantation (LTx). Objective: To assess the number of disability-adjusted life years (DALYs) per patient with severe CLAD. Methods: The clinical and demographic data of patients who received their lung transplantation between 2010 and 2020 in the Hanover Medical School (Germany) were evaluated. Results: A total of 1025 lung transplant patients were followed for a median of 51 months (4.25 years); the median age at transplantation was 52.8 (interquartile range (IQR) 19) years. More than a quarter of transplant patients (271/1025 or 26.4%) developed CLAD, mostly (60%) of the bronchiolitis obliterans syndrome (BOS) phenotype. Of the CLAD patients, 99, or 36.5%, suffered from significant disability, which on average occurred after 2 years (IQR 2.55). The survival of CLAD patients with disability after transplantation was significantly lower compared to that of patients without CLAD (median 4.04 versus 5.41 years). Adjusted to the DALY estimation approach, CLAD patients lost 1.29 life years (YLL) and lived for 0.8 years with their disability (YLD), adding up to 2.09 DALYs (range 1.99–2.72) per patient. Conclusions: CLAD after lung transplantation is a major public health problem and is associated with substantial disability and costs. Further work is needed to develop therapeutic interventions that reduce its development.

Extracorporeal photopheresis (ECP) is used by few lung transplant centers to treat chronic lung allograft dysfunction (CLAD). Although reported results suggest a beneficial effect on CLAD progression, evidence is limited to single center experiences. The aim of this study is to analyze outcomes of ECP in a large multicenter European cohort. The primary endpoint was patient survival after initiation of ECP. This study included 631 patients, 87% suffered from bronchiolitis obliterans syndrome (BOS), and 13% had restrictive allograft syndrome (RAS). Long-term stabilization was achieved in 42%, improvement in 9%, and no response in 26%. Within the first 12 months of therapy, 23% of patients died. Patients’ survival after initiation of ECP at 5 years was 56% in stable, 70% in responders, and 35% in non-responders (p = 0.001). In multivariable Cox regression, both stabilization (HR: 0.48, CI: 0.27–0.86, p = 0.013) and response (HR: 0.11, CI: 0.04–0.35, p < 0.001) to ECP were associated with survival. Absolute FEV1 at baseline was also protective (HR: 0.09, CI: 0.01–0.94, p = 0.046). RAS phenotype was the only risk factor for mortality (HR: 2.11, 1.16–3.83, p = 0.006). This study provides long-term outcomes of ECP use in CLAD patients in the largest published cohort to date. Two-thirds of the cohort had a sustained response to ECP with excellent long-term results.

Background: Obstructive airway complications (OACs) represent a significant problem after lung transplantation (LTx). Bilateral OACs after double lung transplantation are infrequently reported. Objectives: The aim of this study was to investigate management and outcome of OAC. Design: Retrospective single-center cohort study Methods: Adult patients with bilateral LTx performed between 2010 and 2021 were included. Patients with follow-ups of less than 3 months and after heart–lung transplantation were excluded. OAC was defined either as the need for stenting, surgical revision, or balloon dilatation. Outcome parameters included graft survival, graft function, quality of life, and management. Results: During the study period, 1,170 patients were included. Hundred thirty-five (11.5%) patients developed OAC. Forty-six (4.4%) patients had significant bilateral OAC. Thirty-seven (80%) bilateral OAC patients were treated by stent insertion; in 34 patients, biodegradable stents were used. The median number of bronchoscopies in bilateral OAC was 26 during the first postoperative year compared with nine in controls ( p

BackgroundData on calcineurin-inhibitor (CNI) free immunosuppression after lung transplantation (LTx) are limited. Aim of this study was to investigate CNI-free immunosuppression using mechanistic target of rapamycin (mTOR) inhibitors.MethodsThis retrospective analysis was performed at a single center. Adult patients after LTx without CNI during the follow-up period were included. Outcome was compared to those LTx patients with malignancy who continued CNI.ResultsAmong 2,099 patients in follow-up, fifty-one (2.4%) were converted median 6.2 years after LTx to a CNI-free regimen combining mTOR inhibitors with prednisolone and an antimetabolite, two patients were switched to mTOR inhibitors with prednisolone only. In 25 patients, malignancies without curative treatment options were the reason of the conversion, with a 1-year survival of 36%. The remaining patients had a 1-year survival of 100%. Most common non-malignant indication was neurological complications (n = 9). Fifteen patients were re-converted to a CNI-based regimen. The median duration of CNI-free immunosuppression was 338 days. No acute rejections were detected in 7 patients with follow-up biopsies. In multivariate analysis, CNI-free immunosuppression were not associated with improved survival after malignancy. The majority of patients with neurological diseases improved 12 months after conversion. Glomerular filtration rate increased by median 5 (25 and 75% percentiles -6; +18) ml/min/1.73 m2.ConclusionsmTOR inhibitor based CNI-free immunosuppression may be safely performed in selected patients after LTx. This approach was not associated with improved survival in patients with malignancy. Significant functional improvements were observed in patients with neurological diseases.

Bronchiolitis obliterans syndrome (BOS) may develop after either lung or haematopoietic stem cell transplantation (HSCT), with similarities in histopathological features and clinical manifestations. However, there are differences in the contributory factors and clinical trajectories between the two conditions. BOS after HSCT occurs due to systemic graft-versus-host disease (GVHD), whereas BOS after lung transplantation is limited to the lung allograft. BOS diagnosis after HSCT is more challenging, as the lung function decline may occur due to extrapulmonary GVHD, causing sclerosis or inflammation in the fascia or muscles of the respiratory girdle. Treatment is generally empirical with no established effective therapies. This review provides rare insights and commonalities of both conditions, which are not well elaborated elsewhere in contemporary literature, and highlights the importance of cross disciplinary learning from experts in other transplant modalities. Treatment algorithms for each condition are presented, based on the published literature and consensus clinical opinion. Immunosuppression should be optimised, and other conditions or contributory factors treated where possible. When initial treatment fails, the ultimate therapeutic option is lung transplantation (or re-transplantation in the case of BOS after lung transplantation) in carefully selected candidates. Novel therapies under investigation include aerosolised liposomal cyclosporine, Janus kinase inhibitors, antifibrotic therapies and (in patients with BOS after lung transplantation) B-cell-directed therapies. Effective novel treatments that have a tangible impact on survival and thereby avoid the need for lung transplantation or re-transplantation are urgently required.

Serology is an important way to monitor SARS-CoV-2 infection in the population and support vaccine development. Here the authors develop a multiplex immunoassay including spike and nucleocapsid proteins of SARS-CoV-2 and the endemic human coronaviruses with high specificity and sensitivity.

Abstract Background Immunosuppression including high-dose calcineurin inhibitors (CNI) is essential after lung transplantation. Dosing is usually guided by therapeutic drug monitoring adjusted to target trough levels of CNIs to keep the balance between over-dose causing severe toxicity and increased risk of infections or under-dose with a risk of graft injury. Adaptation of CNI-based immunosuppression by monitoring of torque teno virus (TTV), a latent nonpathogenic DNA virus, measured in the whole blood in addition to conventional therapeutic drug monitoring may reduce the toxicity of immunosuppression with similar efficacy. Methods/design An open-label, randomized, controlled, parallel-group, multicenter trial in lung transplant recipients will be conducted to investigate the safety and efficacy of immunosuppression guided by TTV monitoring as an add-on to conventional therapeutic drug monitoring. Adult lung transplant recipients 21 to 42 days after transplantation are eligible to participate. Patients (N = 144) will be randomized 1:1 to the experimental intervention (arm 1: immunosuppression guided by TTV monitoring in addition to conventional therapeutic drug monitoring of tacrolimus trough levels) and control intervention (arm 2: conventional therapeutic drug monitoring). Outcomes will be assessed 12 months after randomization with the change in glomerular filtration rate as the primary endpoint. Secondary endpoints will be additional measurements of renal function, allograft function, incidence of acute rejections, incidence of chronic lung allograft dysfunction, graft loss, and infections. Discussion The results of this randomized controlled trial may reduce the toxicity of immunosuppression after lung transplantation while maintaining the efficacy of immunosuppression. Study results are transferable to all other solid organ transplantations. Trial registration ClinicalTrials.gov NCT04198506 . Registered on 12 December 2019

BackgroundAcute kidney injury (AKI) after lung transplantation (LuTx) is associated with increased long-term mortality. In this prospective observational study, commonly used AKI-definitions were examined regarding prediction of long-term mortality and compared to simple use of the serum creatinine value at day 7 for patients who did not receive hemodialysis, and serum creatinine value immediately before initiation of hemodialysis (d7/preHD-sCr).Methods185 patients with LuTx were prospectively enrolled from 2013-2014 at our center. Kidney injury was assessed within 7 days by: (1) the Kidney Disease Improving Global Outcomes criteria (KDIGO-AKI), (2) the Acute Disease Quality Initiative 16 Workgroup classification (ADQI-AKI) and (3) d7/preHD-sCr. Prediction of all-cause mortality was examined by Cox regression analysis, and clinical as well as laboratory factors for impaired kidney function post-LuTx were analyzed.ResultsAKI according to KDIGO and ADQI-AKI occurred in 115 patients (62.2%) within 7 days after LuTx. Persistent ADQI-AKI, KDIGO-AKI stage 3 and higher d7/preHD-sCr were associated with higher mortality in the univariable analysis. In the multivariable analysis, d7/preHD-sCr in combination with body weight and intra- and postoperative platelet transfusions predicted mortality after LuTx with similar performance as models using KDIGO-AKI and ADQI-AKI (concordance index of 0.75 for d7/preHD-sCr vs., 0.74 and 0.73, respectively). Pre-transplant reduced renal function, diabetes, higher BMI, and intraoperative ECMO predicted higher d7/preHD-sCr (r2 = 0.354, p < 0.001).ConclusionOur results confirm the importance of AKI in lung transplant patients; however, a simple and pragmatic indicator of renal function, d7/preHD-sCr, predicts long-term mortality equally reliable as more complex AKI-definitions like KDIGO and ADQI.

Objectives: It has been recommended that all candidates for lung transplantation undergo pre-transplant psychosocial evaluation for risk assessment. However, psychosocial issues are only important if they correlate with outcomes after transplantation.Methods: In this prospective study patients who were referred for lung transplantation from 2016 to 2018 (n = 352) at Hannover Medical School were evaluated using the Transplant Evaluation Rating Scale (TERS). Clinical outcomes included listing, and post-transplant outcomes including mortality, medical aspects such as lung allograft dysfunction, hospitalizations, and renal function, behavioral aspects such as BMI and adherence, and mental issues such as levels of depression, anxiety, and quality of life. TERS scores were divided into tertiles and, in addition, the impact of the two subscale scores—“defiance” and “emotional sensitivity”—was investigated.Results: Of the patients who were transplanted (n = 271) and were still alive (n = 251), 240 had already reached their 1-year assessment at the end of 2020 and were evaluated 1 year after the operation. A subgroup of 143 received an extended mental assessment. BMI, adherence scores, levels of anxiety, depression, and quality of life 1 year post-transplantation differed significantly between TERS tertiles with higher TERS scores predicting less favorable outcomes. The TERS subscale “defiance” was predictive of BMI and adherence whereas the TERS subscale “emotional sensitivity” was predictive of symptoms of anxiety and depression, and quality of life 1 year after transplantation. Patients in the lowest TERS tertile were more likely to having been listed and—as a trend—to having survived the first year after transplantationConclusions: Our findings show that psychosocial factors as measured by TERS score are predictors of behavioral and mental outcomes 1 year after lung transplantation. The TERS allows us to focus on psychosocial risk factors that can be treated or minimized before or after transplantation.

Abstract Background Despite modern intensive care with standardized strategies against acute respiratory distress syndrome (ARDS), Pneumocystis pneumonia (PcP) remains a life-threatening disease with a high mortality rate. Here, we analyzed a large mixed cohort of immunocompromised patients with PcP, with regard to clinical course and treatment, and aimed at identifying predictors of outcome. Methods This was a single-center retrospective analysis in a tertiary care institution across 17 years. Diagnosis of PcP required typical clinical features and microbiological confirmation of Pneumocystis jirovecii. Epidemiological, clinical, laboratory and outcome data were collected from patient records. Results A total of 52,364 specimens from 7504 patients were sent for microbiological assessment (3653 with clinical suspicion of Pneumocystis pneumonia). PcP was confirmed in 240 patients, about half of them HIV positive (52%). The remaining subjects were either solid organ transplant recipients (16.3%) or suffered from malignancy (15.8%) or autoimmune diseases (11.7%). Of note, 95% of patients with PcP were not receiving chemoprophylaxis. Overall in-hospital mortality was 25.4%, increasing to 58% if ICU admission was required. Multivariable regression identified lactate dehydrogenase (LDH) as predictor of in-hospital mortality (adjusted OR 1.17 (95% CI 1.09–1.27), p

Patients after lung transplantation are at risk for life-threatening infections. Recently, several publications on COVID-19 outcomes in this patient population appeared, but knowledge on optimal treatment, mortality, outcomes, and appropriate risk predictors is limited. A retrospective analysis was performed in a German high-volume lung transplant center between 19th March 2020 and 18th May 2021. Impact of COVID-19 on physical and psychological health, clinical outcomes, and mortality were analyzed including follow-up visits up to 12 weeks after infection in survivors. Predictive parameters on survival were assessed using univariate and multivariate proportional hazards regression models. Out of 1,046 patients in follow-up, 31 acquired COVID-19 during the pandemic. 12 of 31 (39%) died and 26 (84%) were hospitalized. In survivors a significant decline in exercise capacity (p = 0.034), TLC (p = 0.02), and DLCO (p = 0.007) was observed at follow-up after 3 months. Anxiety, depression, and self-assessed quality of life remained stable. Charlson comorbidity index predicted mortality (HR 1.5, 1.1-2.2; p = 0.023). In recipients with pre-existing CLAD, mortality and clinical outcomes were inferior. However, pre-existing CLAD did not predict mortality. COVID-19 remains a life-threatening disease for lung transplant recipients, particularly in case comorbidities. Further studies on long term outcomes and impact on pre-existing CLAD are needed.

BackgroundChronic Lung Allograft Dysfunction (CLAD) is a major obstacle for long term survival after lung transplantation (LTx). Besides Bronchiolitis Obliterans Syndrome, two other phenotypes of CLAD, restrictive allograft syndrome (RAS) and mixed phenotype, have been described. Trials to test in these conditions are desperately needed and analyzing natural outcome to plan such trials is essential.MethodsWe performed a retrospective analysis of functional outcome in bilateral LTx recipients with RAS and mixed phenotype, transplanted between 2009 and 2018 in five large European centers with follow- up spirometry up to 12 months after diagnosis. Based on these data, sample size and power calculations for randomized therapeutic trial was estimated using two imputation methods for missing values.ResultsSeventy patients were included (39 RAS and 31 mixed phenotype), median 3.1 years after LTx when CLAD was diagnosed. Eight, 13 and 25 patients died within 6, 9 and 12 months after diagnosis and a two patients underwent re-transplantation within 12 months leading to a graft survival of 89, 79 and 61% six, nine and 12 months after diagnosis, respectively. Observed FEV1 decline was 451 ml at 6 months and stabilized at 9 and 12 months, while FVC showed continuous decline. Using two methods of imputation, a progressive further decline after 6 months for FEV1 was noted.ConclusionThe poor outcome of these two specific CLAD phenotypes suggests the urgent need for future therapeutic randomized trials. The number of missing values in a potential trial seems to be high and most frequently attributed to death. Survival may be used as an endpoint in clinical trials in these distinct phenotypes and imputation techniques are relevant if graft function is used as a surrogate of disease progression in future trials.

Background: Fibroblastic foci (FF) are characteristic features of usual interstitial pneumonia (UIP)/idiopathic pulmonary fibrosis (IPF) and one cardinal feature thought to represent a key mechanism of pathogenesis. Hence, FF have a high impact on UIP/IPF diagnosis in current guidelines. However, although less frequent, these histomorphological hallmarks also occur in other fibrotic pulmonary diseases. Currently, there is therefore a gap in knowledge regarding the underlying molecular similarities and differences of FF in different disease entities. Methods: In this work, we analyzed the compartment-specific gene expression profiles of FF in IPF and sarcoidosis in order to elucidate similarities and differences as well as shared pathomechanisms. For this purpose, we used laser capture microdissection, mRNA and protein expression analysis. Biological pathway analysis was performed using two different gene expression databases. As control samples, we used healthy lung tissue that was donated but not used for lung transplantation. Results: Based on Holm Bonferroni corrected expression data, mRNA expression analysis revealed a significantly altered expression signature for 136 out of 760 genes compared to healthy controls while half of these showed a similar regulation in both groups. Immunostaining of selected markers from each group corroborated these results. However, when comparing all differentially expressed genes with the fdr-based expression data, only 2 of these genes were differentially expressed between sarcoidosis and IPF compared to controls, i.e., calcium transport protein 1 (CAT1) and SMAD specific E3 ubiquitin protein ligase 1 (SMURF1), both in the sarcoidosis group. Direct comparison of sarcoidosis and IPF did not show any differentially regulated genes independent from the statistical methodology. Biological pathway analysis revealed a number of fibrosis-related pathways pronounced in IPF without differences in the regulatory direction. Conclusions: These results demonstrate that FF of end-stage IPF and sarcoidosis lungs, although different in initiation, are similar in gene and protein expression, encouraging further studies on the use of antifibrotic agents in sarcoidosis.

Pulmonary fibroelastotic remodelling occurs within a broad spectrum of diseases with vastly divergent outcomes. So far, no comprehensive terminology has been established to adequately address and distinguish histomorphological and clinical entities. We aimed to describe the range of fibroelastotic changes and define stringent histological criteria. Furthermore, we wanted to clarify the corresponding terminology in order to distinguish clinically relevant variants of pulmonary fibroelastotic remodelling. We revisited pulmonary specimens with fibroelastotic remodelling sampled during the last ten years at a large European lung transplant centre. Consensus-based definitions of specific variants of fibroelastotic changes were developed on the basis of well-defined cases and applied. Systematic evaluation was performed in a steps-wise algorithm, first identifying the fulcrum of the respective lesions, and then assessing the morphological changes, their distribution and the features of the adjacent parenchyma. We defined typical alveolar fibro-elastosis as collagenous effacement of the alveolar spaces with accompanying hyper-elastosis of the remodelled and paucicellular alveolar walls, independent of the underlying disease in 45 cases. Clinically, this pattern could be seen in (idiopathic) pleuroparenchymal fibro-elastosis, interstitial lung disease with concomitant alveolar fibro-elastosis, following hematopoietic stem cell and lung transplantation, autoimmune disease, radio-/chemotherapy, and pulmonary apical caps. Novel in-transit and activity stages of fibroelastotic remodelling were identified. For the first time, we present a comprehensive definition of fibroelastotic remodelling, its anatomic distribution, and clinical associations, thereby providing a basis for stringent patient stratification and prediction of outcome.

Non-adherence to therapy is associated with impaired outcome in solid organ allograft recipients. Outcome data are limited after lung transplantation. In a single-center cohort study, adherence was assessed in 427 patients undergoing lung transplantation from 2010 to 2013. Objective criteria of adherence were judged by health care workers on every visit on a five item Likert scale including trough level monitoring, home spirometry and contact with an overall rating of adherence between 0 and 100%. Cut-off values for good vs. suboptimal adherence were defined retrospectively. Primary outcome was allograft survival, secondary outcomes were patient survival, prevalence of chronic lung allograft dysfunction, hospitalizations, renal function and quality of life. Follow-up ended on 31st December 2018. Median adherence was 86% on 6,623 visits, this cut-off was used as a discriminator between good and suboptimal adherers. Patients with good adherence within the first three years showed better 5-year allograft (74% vs. 60%, p = 0.003) and patient survival (79% vs. 64%, p

Background. Nonmelanoma skin cancer (NSMC) is the most common malignancy after organ transplantation. Lung transplant recipients (LTRs) are particularly prone to develop NMSC as compared to renal or hepatic transplant recipients due to higher dosages of immunosuppression needed. Everolimus, an immunosuppressant used in organ transplant recipients, is thought to inherit a lower risk for NMSC than calcineurin inhibitors, especially in renal transplant recipients. It is currently unknown whether this also applies to LTRs. Objectives. To determine risk factors for NMSC and precancerous lesions after lung transplantation (LTx) and to characterize the effect of everolimus-based regimens regarding this risk. Materials and Methods. 90 LTRs and former participants of the interventional trial “Immunosuppressive Therapy with Everolimus after Lung Transplantation”, who were randomized to receive either an everolimus- or mycophenolate mofetil- (MMF-) based regimen, were enrolled and screened in this retrospective, single-center cohort study. Results. After a median follow-up of 101 months, we observed a prevalence of 38% for NMSC or precancerous lesions. 33% of the patients continuously receiving everolimus from LTx to dermatologic examination compared to 39% of all other patients, predominantly receiving an MMF-based regimen, were diagnosed with at least one NMSC or precancerous lesion (P=.66). Independent risk factors for NMSC or precancerous lesions after LTx were male sex and duration of voriconazole therapy. Conclusion. NMSC or precancerous lesions were very common after LTx, and risk factors were similar to previous reports on LTRs. Everolimus did not decrease this risk under the given circumstances of this study. Patients should be counseled regarding their risk, perform vigorous sunscreen, and undergo regular dermatological controls, regardless of their immunosuppressive regimen.

Background. Preoperative low-dose whole-body irradiation (IRR) with 1.5 and 7 Gy thymic IRR of the recipient, combined with a perioperative donor splenocyte infusion lead to reliable donor specific peripheral tolerance in our allogeneic porcine lung transplantation model. To reduce the toxicity of this preconditioning regime, modifications of the IRR protocol and their impact on allograft survival were assessed. Methods. Left-sided single lung transplantation from major histocompatibility complex and sex mismatched donors was performed in 14 adult female minipigs. Recipient animals were exposed to 3 different protocols of nonmyeloablative IRR within 12 hours before transplantation. All animals were administered a donor splenocyte infusion on the day of lung transplantation. Intravenous pharmacologic immunosuppression was withdrawn after 28 postoperative days. Allograft survival was monitored by chest radiographs and bronchoscopy. Results. IRR prolonged transplant survival in a dose- and field-dependent manner. Shielding of the bone marrow from IRR (total lymphoid IRR at 1.5 and 7 Gy thymic IRR) significantly reduced protocol toxicity defined as thrombocytopenia and consecutive increased bleeding propensity, but had a less effective impact on graft survival. Whole-body IRR at 0.5 and 7 Gy thymic IRR proved to be ineffective for reliable tolerance induction. Eventually, high levels of circulating CD4+CD25high regulatory T cells were present in long-term survivors. Conclusions. These data show that the infusion of donor-specific alloantigen in combination with IRR is efficient once a threshold dose is exceeded.

INTRODUCTION:Topical airway anesthesia is known to improve tolerance and patient satisfaction during flexible bronchoscopy (FB). Lidocaine is commonly used, delivered as an atomized spray. The current study assesses safety and patient satisfaction for nasal anesthesia of a new atomization device during outpatient bronchoscopy in lung transplant recipients. METHODS:Using a prospective, non-blinded, cross-over design, patients enrolled between 01-10-2014 and 24-11-2014 received 2% lidocaine using the standard reusable nasal atomizer (CRNA). Those enrolled between 25-11-2014 and 30-01-2015, received a disposable intranasal mucosal atomization device (DIMAD). After each procedure, the treating physician, their assistant and the patient independently rated side-effects and satisfaction, basing their responses on visual analogue scales (VAS). At their next scheduled bronchoscopy during the study period, patients then received the alternative atomizer. Written consent was obtained prior to the first bronchoscopy, and the study approved by the institutional ethics committee. RESULTS:Of the 252 patients enrolled between 01-10-2014 and 30-01-2015, 80 (32%) received both atomizers. Physicians reported better efficacy (p = 0.001) and fewer side effects (p< = 0.001) for DIMAD in patients exposed to both procedures. Among patients with one visit, physicians and their assistants reported improved efficacy (p = 0.018, p = 0.002) and fewer side effects (p< = 0.001, p = 0.029) for the disposable atomizer, whereas patients reported no difference in efficacy or side effects (p = 0.72 and p = 0.20). No severe adverse events were noted. The cost of the reusable device was 4.08€ per procedure, compared to 3.70€ for the disposable device. DISCUSSION:Topical nasal anesthesia via a disposable intranasal mucosal atomization device (DIMAD) offers comparable safety and patient comfort, compared to conventional reusable nasal atomizers (CRNA) in lung transplant recipients. Procedural costs were reduced by 0.34€ per procedure. TRIAL REGISTRATION:clinicaltrials.gov NCT02237651.

A 62-year-old male, who received immune suppressive therapy due to a lung transplantation several years ago, developed multiple painful abscesses in the right forearm. First misdiagnosed as staphylococcal abscesses, Mycobacterium tuberculosis was eventually cultured from the abscesses. In addition, the patient also suffered from pulmonary tuberculosis and respiratory specimens were also culture-positive for Mycobacterium tuberculosis . Cutaneous tuberculosis must be kept as a differential diagnosis in the case of abscess-like lesions on the skin, especially in immunocompromised patients. Mycobacteria specific tests (polymerase chain reaction in respiratory samples and wound smears) and antituberculotic combination therapy are necessary to treat Mycobacterium tuberculosis infection/reactivation adequately.

OBJECTIVES: To prospectively evaluate quantitative airway wall measurements of thin-section CT for the diagnosis of Bronchiolitis Obliterans Syndrome (BOS) following lung transplantation. MATERIALS AND METHODS: In 141 CT examinations, bronchial wall thickness (WT), the wall area percentage (WA%) calculated as the ratio of the bronchial wall area and the total area (sum of bronchial wall area and bronchial lumen area) and the difference of the WT on inspiration and expiration (WTdiff) were automatically measured in different bronchial generations. The measurements were correlated with the lung function parameters. WT and WA% in CT examinations of patients with (n = 25) and without (n = 116) BOS, were compared using the unpaired t-test and univariate analysis of variance, while also considering the differing lung volumes. RESULTS: Measurements could be performed in 2,978 bronchial generations. WT, WA%, and WTdiff did not correlate with the lung function parameters (r

RATIONALE:There is a need to expand knowledge on cardio-pulmonary pathophysiology of bronchiolitis obliterans syndrome (BOS) following lung transplantation (LTx). OBJECTIVES:The purpose of this study was to assess MRI-derived biventricular cardiac mass and function parameters as well as flow hemodynamics in patients with and without BOS after LTx. METHODS:Using 1.5T cardiac MRI, measurements of myocardial structure and function as well as measurements of flow in the main pulmonary artery and ascending aorta were performed in 56 lung transplant patients. The patients were dichotomized into two gender matched groups of comparable age range: one with BOS (BOS stages 1-3) and one without BOS (BOS 0/0p). MEASUREMENTS AND MAIN RESULTS:Significantly lower biventricular cardiac mass, right and left ventricular end-diastolic volume, biventricular stroke volume, flow hemodynamics and significant higher heart rate but preserved cardiac output were observed in patients with BOS 1-3 compared to the BOS 0/0p group (p < 0.05). In a stepwise logistic regression analysis global cardiac mass (p = 0.046) and days after LTx (p = 0.0001) remained independent parameters to predict BOS. In a second model an indicator for the physical fitness level - walking number of stairs - was added to the logistic regression model. In this second model, time after LTx (p = 0.005) and physical fitness (p = 0.01) remained independent predictors for BOS. CONCLUSION:The observed changes in biventricular cardiac mass and function as well as changes in hemodynamic flow parameters in the pulmonary trunk and ascending aorta are likely attributed to the physical fitness level of patients after lung transplantation, which in turn is strongly related to lung function.

Accurate immunosuppression is of critical importance in preventing rejection, while avoiding toxicity following lung transplantation. The mainstay immunosuppressants are calcineurin inhibitors, which require regular monitoring due to interactions with other medications and diet. Adherence to immunosuppression and patient knowledge is vital and can be improved through patient education. Education using tablet-computers was investigated.To compare tablet-PC education and conventional education in improving immunosuppression trough levels in target range 6 months after a single education. Secondary parameters were ratio of immunosuppression level measurements divided by per protocol recommended measurements, time and patient satisfaction regarding education.Single-centre, open labelled randomised controlled trial.Patients >6 months after lung-transplantation with

BACKGROUND: Myostatin is a muscle derived factor that functions as a negative regulator of skeletal muscle growth. Induction of myostatin expression was observed in rodent models of muscle wasting and in cachectic patients with cancer or pulmonary disease. Therefore, there is an increasing interest to use serum myostatin as a biomarker. METHODS: We established an immunoradiometric sandwich assay (IRMA), which uses a commercially available chicken polyclonal, affinity purified antibody directed against human myostatin prodomain. We determined the serum concentrations of myostatin prodomain in 249 healthy individuals as well as 169 patients with heart failure, 53 patients with cancer and 44 patients with chronic pulmonary disease. RESULTS: The IRMA had a detection limit of 0.7ng/ml, an intraassay imprecision of ≤14.1% and an interassay imprecision of ≤ 18.9%. The specificity of our assay was demonstrated by size exclusion chromatography, detection of myostatin by Western-blotting and a SMAD-dependent transcriptional-reporter assay in the signal-rich serum fractions, as well as lack of interference by unspecific substances like albumin, hemoglobin or lipids. Myostatin prodomain was stable at room temperature and resistant to freeze-thaw cycles. Apparently healthy individuals over the age of 55 had a median myostatin prodomain serum concentration of 3.9ng/ml (25(th)-75(th) percentiles, 2-7ng/ml) and we could not detect increased levels in patients with stable chronic heart failure or cancer related weight loss. In contrast, we found strongly elevated concentrations of myostatin prodomain (median 26.9ng/ml, 25(th)-75(th) percentiles, 7-100ng/ml) in the serum of underweight patients with chronic pulmonary disease. CONCLUSIONS: We established a highly specific IRMA for the quantification of myostatin prodomain concentration in human serum. Our assay could be useful to study myostatin as a biomarker for example in patients with chronic pulmonary disease, as we detected highly elevated myostatin prodomain serum levels in underweight individuals of this group.

Background: In the first 6 months following lung transplantation, the most frequently occurring complications are infection, acute rejection and anastomotic dysfunction. The utility of vibration response imaging (VRI) lung images in assisting with the detection of these complications was evaluated. Objectives: The study aimed to evaluate if VRI is a good, non-invasive method of detecting clinical problems in lung transplant (LTx) recipients during early follow-up. Methods: Between 06/2006 and 03/2007 all LTx patients who received transplants during the preceding 6 months at the Hannover Medical School received baseline VRI at enrolment with subsequent reassessment in combination with standard follow-up at 1, 3 and 6 months thereafter. The resulting images were analysed by two blinded reviewers. Results: Fifty-five lung transplant recipients were enrolled in the study, with 49 patients successfully completing follow-up. Device operability and patient participation occurred without significant problems. High numbers of abnormal scans were detected. According to the clinical diagnosis, 29 patients (59.2 %) were stable at all four visits. Twenty clinical problems occurred (e.g., infections, rejections, obstructions, unknown deterioration). Agreement with clinical interpretation of rejections and infections was poor. Central airway obstruction (CAO) was detected in 80% by both reviewers. Accuracy in detecting obstructions was 89%; positive predicted value and negative predicted value were 80% and 90%, respectively. Conclusion: The VRI system is a non-invasive easy-to-use method with technical success and good image quality. The high number of abnormal scans makes interpretation following LTx difficult. VRI was unable to detect deterioration in graft function with the exception of ventilation disorders like central airway complications.

Lung transplantation is a suitable treatment to improve the quality of life and the prognosis of patients with various end-stage pulmonary diseases. There is a shortage of organs and the number of patients on waiting list is exceeding the number of transplants per year approximately two-fold in most countries. Strategies to increase the donor pool are therefore crucial. The long-term prognosis after lung transplantation is not yet as good as for other transplantation procedures and special complications should be taken into account. Aside from infections chronic organ dysfunction is the main cause of death and the most important prognosis limiting factor. Other typical problems are rejection, bronchus complications, and primary transplant dysfunction. However, the results of large centers show promising improvements in recent years.