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Purpose Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) is currently the major threat for immunocompromised individuals. The course of COVID-19 in lung transplant recipients in the Omicron era remains unknown. The aim of the study was to assess outcome and associated factors in lung transplant recipients in a German-wide multicenter approach. Methods All affected individuals from January 1st to March 20th, 2022 from 8 German centers during the Omicron wave were collected. Baseline characteristics and antiviral measures were associated with outcome. Results Of 218 patients with PCR-proven SARS-CoV-2 infection 166 patients (76%) received any early (2 were independent risk factors for a severe or critical COVID-19. Conclusion COVID-19 due to Omicron remains an important threat for lung transplant recipients. In particular, elderly patients and patients with impaired kidney function are at risk for worse outcome. Prophylaxis and therapy in highly immunocompromised individuals need further improvement.

BackgroundThe published experience of lung transplantation in acute respiratory distress syndrome (ARDS) is limited. The aim of this study was to investigate the contemporary results of lung transplantation attempts in ARDS in major European centres.MethodsWe conducted a retrospective multicentre cohort study of all patients listed for lung transplantation between 2011 and 2019. We surveyed 68 centres in 22 European countries. All patients admitted to the waitlist for lung transplantation with a diagnosis of “ARDS/pneumonia” were included. Patients without extracorporeal membrane oxygenation (ECMO) or mechanical ventilation were excluded. Patients were followed until 1 October 2020 or death. Multivariable analysis for 1-year survival after listing and lung transplantation was performed.Results55 centres (81%) with a total transplant activity of 12 438 lung transplants during the 9-year period gave feedback. 40 patients with a median age of 35 years were identified. Patients were listed for lung transplantation in 18 different centres in 10 countries. 31 patients underwent lung transplantation (0.25% of all indications) and nine patients died on the waitlist. 90% of transplanted patients were on ECMO in combination with mechanical ventilation before lung transplantation. On multivariable analysis, transplantation during 2015–2019 was independently associated with better 1-year survival after lung transplantation (OR 10.493, 95% CI 1.977–55.705; p=0.006). 16 survivors out of 23 patients with known status (70%) returned to work after lung transplantation.ConclusionsLung transplantation in highly selected ARDS patients is feasible and outcome has improved in the modern era. The selection process remains ethically and technically challenging.

In light of the organ shortage, there is a great responsibility to assess postmortal organs for which procurement has been consented and to increase the life span of transplanted organs. The former responsibility has moved many centers to accept extended criteria organs. The latter responsibility requires an exact diagnosis and, if possible, omission of the harmful influence on the transplant. We report the course of a kidney transplant that showed a steady decline of function over a decade, displaying numerous cysts of different sizes. Clinical workup excluded the most frequent causes of chronic transplant failure. The filed allocation documents mentioned the donor’s disease of oral‐facial‐digital syndrome, a rare ciliopathy, which can also affect the kidney. Molecular diagnosis was performed by culturing donor tubular cells from the recipient´s urine more than 10 years after transplantation. Next‐generation panel sequencing with DNA from tubular urinary cells revealed a novel truncating mutation in OFD1, which sufficiently explains the features of the kidney transplants, also found in the second kidney allograft. Despite this severe donor disease, lifesaving transplantation with good long‐term outcome was enabled for 5 recipients.

The relevance of gastrointestinal manifestations of cystic fibrosis (CF) is increasing due to an improved life expectancy. We report on 2 adult patients with prior lung transplantation who presented with a severe inflammatory disorder of the ileocecal region. One patient underwent ileocecal resection; the second patient died after emergency surgery for intestinal perforation. Both cases did not show typical signs of CF-related distal intestinal obstruction syndrome or extensive fibrosing colonopathy. However, the clinical and histopathological findings revealed CF-induced inflammatory alterations of the intestinal mucosa. Thus, these cases illustrate a further CF-related bowel disorder, which can be especially relevant in long-term CF survivors.Aufgrund der gestiegenen Lebenserwartung von Patienten mit Zystischer Fibrose (CF) nimmt die Bedeutung gastrointestinaler Manifestationen der Erkrankung zu. In zwei Fallberichten stellen wir erwachsene, lungentransplantierte CF-Patienten mit ausgeprägten inflammatorischen Veränderungen der Ileozökalregion vor, welche letztlich einer operativen Versorgung zugeführt werden mussten. In beiden Fällen konnten keine eindeutigen Zeichen eines distalen intestinalen Obstruktionssyndroms oder einer zugrundeliegenden fibrosierenden Kolonopathie festgestellt werden. Dennoch sprechen sowohl das klinische Erscheinungsbild als auch die histopathologischen Befunde für das Vorliegen einer CF-induzierten entzündlichen intestinalen Erkrankung. Daher muss von einer bisher nicht ausreichend charakterisierten CF-Manifestation des Intestinums ausgegangen werden, welche besonders für erwachsene CF-Patienten von klinischer Relevanz ist.

Methods We did a multicentre, double-blind, randomised, placebo-controlled, parallel phase 2b trial (RELIEF) in 17 centres with expertise in ILD in Germany. Eligible participants were patients aged 18?80 years with progressive fibrotic ILD due to four diagnoses: collagen or vascular diseases (ie, connective tissue disease-associated ILDs), fibrotic non-specific interstitial pneumonia, chronic hypersensitivity pneumonitis, or asbestos-induced lung fibrosis. Other eligibility criteria included a forced vital capacity (FVC) of 40?90% predicted, a diffusing capacity of the lung for carbon monoxide of 10?90% predicted, and an annual decline of FVC of at least 5% predicted despite conventional therapy, based on at least three measurements within 6?24 months before enrolment. Patients who had received any previous antifibrotic therapy were excluded. We randomly assigned patients (1:1) to either oral pirfenidone (267 mg three times per day in week 1, 534 mg three times per day in week 2, and 801 mg three times per day thereafter) or matched placebo, added to their ongoing medication. Randomisation was done centrally using permuted block randomisation with varying block sizes stratified by the four diagnostic groups. Patients, investigators, statisticians, monitors, and the study coordinator were masked to treatment assignment until database closure. The placebocontrolled study period was 48 weeks (including up-titration). The primary endpoint was absolute change in percentage of predicted FVC (FVC % predicted) from baseline to week 48 in the intention-to-treat population, with imputation of missing data by the smallest sum of squared differences and attribution of deceased patients to the lowest rank in a rank ANCOVA model. Additionally, we did linear mixed-model repeated measures slope analyses of FVC % predicted longitudinal data over the course of the study as a prespecified sensitivity analysis and post-hoc sensitivity analyses of the primary endpoint in the intention-to-treat population using imputation methods of last observation carried forward [LOCF] and a regression-based multiple imputation procedure. Safety was assessed in all patients who received at least one dose of study medication. This trial is registered with EudraCT 2014-000861-32;Background Pirfenidone has been shown to slow disease progression in patients with idiopathic pulmonary fibrosis (IPF). However, there are few treatment options for progressive fibrotic interstitial lung diseases (ILDs)) other than IPF. In view of the pathomechanistic and clinical similarities between IPF and other progressive fibrotic ILDs, we aimed to assess the efficacy and safety of pirfenidone in patients with four non-IPF progressive fibrotic ILDs. Methods We did a multicentre, double-blind, randomised, placebo-controlled, parallel phase 2b trial (RELIEF) in 17 centres with expertise in ILD in Germany. Eligible participants were patients aged 18-80 years with progressive fibrotic ILD due to four diagnoses: collagen or vascular diseases (ie, connective tissue disease-associated ILDs), fibrotic non-specific interstitial pneumonia, chronic hypersensitivity pneumonitis, or asbestos-induced lung fibrosis. Other eligibility criteria included a forced vital capacity (FVC) of 40-90% predicted, a diffusing capacity of the lung for carbon monoxide of 10-90% predicted, and an annual decline of FVC of at least 5% predicted despite conventional therapy, based on at least three measurements within 6-24 months before enrolment. Patients who had received any previous antifibrotic therapy were excluded. We randomly assigned patients (1:1) to either oral pirfenidone (267 mg three times per day in week 1, 534 mg three times per day in week 2, and 801 mg three times per day thereafter) or matched placebo, added to their ongoing medication. Randomisation was done centrally using permuted block randomisation with varying block sizes stratified by the four diagnostic groups. Patients, investigators, statisticians, monitors, and the study coordinator were masked to treatment assignment until database closure. The placebo controlled study period was 48 weeks (including up-titration). The primary endpoint was absolute change in percentage of predicted FVC (FVC % predicted) from baseline to week 48 in the intention-to-treat population, with imputation of missing data by the smallest sum of squared differences and attribution of deceased patients to the lowest rank in a rank ANCOVA model. Additionally, we did linear mixed-model repeated measures slope analyses of FVC % predicted longitudinal data over the course of the study as a prespecified sensitivity analysis and post-hoc sensitivity analyses of the primary endpoint in the intention-to-treat population using imputation methods of last observation carried forward [LOCF] and a regression-based multiple imputation procedure. Safety was assessed in all patients who received at least one dose of study medication. This trial is registered with EudraCT 2014-000861-32; DRKS00009822 and is no longer recruiting. Findings Between April 5, 2016, and Oct 4, 2018, we randomly assigned 127 patients to treatment: 64 to pirfenidone, 63 to placebo. After 127 patients had been randomised, the study was prematurely terminated on the basis of an interim analysis for futility triggered by slow recruitment. After 48 weeks and in the overall population of 127 patients, rank ANCOVA with diagnostic group included as a factor showed a significantly lower decline in FVC % predicted in the pirfenidone group compared with placebo (p=0.043); the result was similar when the model was stratified by diagnostic group (p=0.042). A significant treatment effect was also observed when applying the LOCF and multiple imputation methods to analyses of the primary endpoint.The median difference (Hodges-Lehmann estimate) between pirfenidone and placebo groups for the primary endpoint was 1.69 FVC % predicted (95% CI -0.65 to 4.03). In the linear mixed-model repeated measures slope analysis of FVC % predicted, the estimated difference between treatment and placebo groups from baseline to week 48 was 3.53 FVC % predicted (95% CI 0.21 to 6.86) with imputation of deaths as prespecified, or 2.79 FVC % predicted (95% CI 0.03 to 5.54) without imputation. One death (non-respiratory) occurred in the pirfenidone group (2%) and five deaths (three of which were respiratory) occurred in the placebo group (8%). The most frequent serious adverse events in both groups were infections and infestations (five [8%] in the pirfenidone group, ten [16%] in the placebo group); general disorders including disease worsening (two [3%] in the pirfenidone group, seven [11%] in the placebo group); and cardiac disorders (one ([2%] in the pirfenidone group, 5 [8%] in the placebo group). Adverse events (grade 3-4) of nausea (two patients on pirfenidone, two on placebo), dyspnoea (one patient on pirfenidone, one on placebo), and diarrhoea (one patient on pirfenidone) were also observed. Interpretation In view of the premature study termination, results should be interpreted with care. Nevertheless, our data suggest that in patients with fibrotic ILDs other than IPF who deteriorate despite conventional therapy, adding pirfenidone to existing treatment might attenuate disease progression as measured by decline in FVC. Funding German Center for Lung Research, Roche Pharma.

Everolimus-based quadruple low calcineurin inhibitor (CNI) maintenance immunosuppression has been shown to be effective in preserving short-term renal function without compromising efficacy or safety after lung transplantation; however, long-term benefit remains unknown.An investigator-initiated 5-y follow-up analysis of the 4EVERLUNG study (NCT01404325), comparing everolimus-based quadruple low CNI with standard triple regimen, was performed. Patients who remained on the randomized drug regimen until the end of the 5-y observation were analyzed as the per protocol (PP) population. Patients in whom the assigned regimen was switched were analyzed as the intention-to-treat (ITT) population.In total, 123 patients (95%) from the core study were analyzed. During the observation period in 11 patients (19%) of the standard triple regimen and in 30 patients (46%) of the quadruple low CNI regimen, the assigned immunosuppressive regimen was switched ( P = 0.002). Estimated glomerular filtration rate at 5-y follow-up did not differ between the groups in both the ITT (56 [48-73] versus 58 [48-69] mL/min; P =0.951) and PP (59 [50-73] versus 59 [48-69] mL/min; P = 0.946) populations. Thromboembolic events occurred more frequently in the quadruple low CNI regimen (ITT: 11% versus 24%, P = 0.048; PP: 11% versus 22%, P = 0.162). There was a trend for a higher chronic lung allograft dysfunction-free survival for the quadruple low CNI regimen in the PP population ( P = 0.082). No difference in the graft survival was found.Initiation of an early everolimus-based quadruple low CNI regimen may have no long-term benefit on renal function. The immunosuppressive efficacy and safety profile seems comparable with the standard triple regimen.

Background Staphylococcus aureus is one of the most isolated pathogens from the airways of cystic fibrosis (CF) patients. There is a lack of information about the clonal nature of S. aureus cultured from CF patients and their impact on disease. We hypothesized that patients would differ in their clinical status depending on S. aureus clonal carriage profiles during persistence. Methods During a 21-months prospective observational multicenter study (Junge et al., 2016), 3893 S. aureus isolates (nose, oropharynx, and sputa) were cultured from 183 CF patients (16 German centers, 1 Austrian center) and subjected to spa-sequence typing to assess clonality. Data were associated to lung function, age, gender, and antibiotic treatment by multivariate regression analysis. Results Two hundred and sixty-five different spa-types were determined with eight prevalent spa-types (isolated from more than 10 patients): t084, t091, t008, t015, t002 t012, t364, and t056. We observed different carriage profiles of spa-types during the study period: patients being positive with a prevalent spa-type, only one, a dominant or related spa-type/s. Patients with more antibiotic cycles were more likely to be positive for only one spa-type (p = 0.005), while older patients were more likely to have related (p = 0.006), or dominant spa-types (p = 0.026). Two percent of isolates were identified as methicillin-resistant S. aureus (MRSA) and evidence of transmission of clones within centers was low. Conclusion There was a significant association of antibiotic therapy and age on S. aureus carriage profiles in CF patients indicating that antibiotic therapy prevents acquisition of new clones, while during aging of patients with persisting S. aureus, dominant clones were selected and mutations in the spa-repeat region accumulated.

Background: Immunosuppression after lung transplantation (LuTx) in patients with end-stage pulmonary disease consists of a fine line between organ tolerance and prevention of infections. Cancer immunosurveillance is considered to comprise crucial immune responses to arising tumour cells and is potentially restricted by immunosuppressive therapy. Objectives: We intended to find out whether there was a predominating tumour entity in LuTx patients including its localisation and time to tumour diagnosis. Methods: We analysed 238 patients after LuTx, regarding occurrence of malignant diseases between 2000 and 2016. We collected data on surgical procedure for Tx, smoking status, immunosuppressive therapy, infections, interval from LuTx to tumour diagnosis, tumour histology, and TNM stage. Results: We identified 13 patients (5.5%, eight men, five women) harbouring 15 tumours diagnosed after LuTx. Of these, pulmonary end-stage diseases consisted of chronic obstructive pulmonary disease, interstitial lung disease, and pulmonary arterial hypertension, in six, six, and one patient, respectively. Lung cancer was found in five transplant lungs (62.5%) and in three native lungs after single LuTx (37.5%). Smoking history was positive in 11 patients (84.6%) including all lung cancer patients. One patient developed three different tumours comprising cancer of the lung, the prostate and the skin. The median interval LuTx to tumour was 4.5 years (range 1.46 – 5.56) and was the shortest for pulmonary tumours compared with extrapulmonary (2.1 vs. 4.0 years, respectively). Conclusion: Lung cancer was the most frequent malignant tumour with the shortest interval LuTx to tumour following LuTx. Its early diagnosis requires thorough post-Tx follow-up.

Supplemental Digital Content is available in the text, Positron emission tomography (PET) visualizes increased cellular [18F]fluorodeoxyglucose ([18F]FDG) uptake. Pulmonary hypertension (PH) is conceived of a proliferative disease of the lung vessels. Increased glucose uptake can be quantified as pulmonary [18F]FDG uptake via PET imaging. Because the angioproliferative mechanisms in PH are still in need of further description, the aim of the present study was to investigate whether [18F]FDG PET/CT imaging can elucidate these pathophysiologic mechanisms in different etiologies of PH. Patients (n = 109) with end-stage pulmonary disease being evaluated for lung transplant were included in this observational study. Mean standardized uptake value (SUVmean) of predefined regions of interest in lung parenchyma (LP), left (LV), and right ventricle (RV) of the heart, and SUVmax in pulmonary artery (PA) were determined and normalized to liver uptake. These SUV ratios (SUVRs) were compared with results from right heart catheterization (mean pulmonary artery pressure [mPAP], pulmonary vascular resistance [PVR]), and serum N-terminal pro-brain natriuretic peptide. Group comparisons were performed and Pearson correlation coefficients (r) were calculated. The [18F]FDG uptake ratios in LP, RV, RV/LV, and PA, but not in LV, were found to be significantly higher in both patients with mPAP ≥25 mm Hg (P = 0.013, P = 0.006, P = 0.049, P = 0.002, P = 0.68, respectively) and with PVR ≥480 dyn·s/cm5 (P

BACKGROUND In times of limited organs for transplantation, anti-HBc-positive organs can be accepted for lung transplantation to increase the number of donors. Transplant recipients should be vaccinated against hepatitis B to prevent HBV infection. However, response after HBV vaccination has only been poorly evaluated in patients with end-stage pulmonary disease. MATERIAL AND METHODS Anti-HBs titers of 40 anti-HBc negative patients with end-stage pulmonary disease evaluated for lung transplantation were analyzed with the Architect® system (Abbott, Germany). Responders, partial responders, or non-responders after HBV vaccination were defined by anti-HBs titers100 IU/L, 10-100 IU/L, and10 IU/L, respectively. RESULTS There were 34/40 individuals (85%) vaccinated against hepatitis B, and 6 were not vaccinated. Response, partial response, and non-response after vaccination were observed in 10/34 (29.4%), 11/34 (32.4%), and 13/34 (38.2%) of patients, respectively. Response to vaccination did not correlate with sex, pulmonary disease, comorbidities, immunosuppressive therapy, or smoking status. CONCLUSIONS Although 85% of patients evaluated for lung transplantation were vaccinated against hepatitis B, 38.2% did not show an anti-HBs titer10 IU/L. Thus, anti-HBs titers should be regularly monitored. Nonresponders should be considered for booster vaccinations, alternative vaccination schedules, or prophylactic treatment with a nucleos(t)ide analogue in case of transplantation of an anti-HBc-positive organ.

Background Staphylococcus aureus is an important pathogen in cystic fibrosis (CF). However, it is not clear which factors are associated with worse lung function in patients with persistent S. aureus airway cultures. Our main hypothesis was that patients with high S. aureus density in their respiratory specimens would more likely experience worsening of their lung disease than patients with low bacterial loads. Methods Therefore, we conducted an observational prospective longitudinal multi-center study and assessed the association between lung function and S. aureus bacterial density in respiratory samples, co-infection with other CF-pathogens, nasal S. aureus carriage, clinical status, antibiotic therapy, IL-6- and IgG-levels against S. aureus virulence factors. Results 195 patients from 17 centers were followed; each patient had an average of 7 visits. Data were analyzed using descriptive statistics and generalized linear mixed models. Our main hypothesis was only supported for patients providing throat specimens indicating that patients with higher density experienced a steeper lung function decline (p