Outcomes of oncological intended thoracic surgery after lung transplantation.

Background: Lung cancer following lung transplantation (LT) may require thoracic surgery (TS). There is an urgent need for data on surgical feasibility, clinical and surgical characteristics, as well as outcome data. Methods: We reviewed the medical records of LT patients who had undergone TS at the University Hospital Leipzig between the years 2000 and 2022. Data on medical and surgical history, pulmonary function test, arterial blood gas analysis, six-minute walking distance test, and surgical approach, perioperative management, anesthesiologic, and surgical procedures were analyzed. Results: Among 248 LT patients, 13 patients (5.2%) developed lung cancer after 4.2 years on average and on 6 of them (46.2%), major TS procedure was performed for the resection of lung cancer. In one patient who underwent TS for a suspicious pulmonary nodule, it turned out to be a parenchymal scar. TS was carried out in 57.1% on the native lung and 42.9% on the transplant lung. Pneumonia and acute renal failure were predominantly observed postoperative complications. We found that the capacity of gas exchange either before or after TS was related to the degree of postoperative complications. The in-hospital survival was 71.4%. Conclusions: Incidence of lung cancer is increased after LT. Follow-up care allows early diagnosis with a comparably high share of operable tumor stage. Cancer as well as postoperative complications were more likely after single lung transplantation (SLT). Postoperative morbidity and mortality are higher in this scarce group of patients and hence, warrants a centered and experienced interdisciplinary approach.

Outcome of lung transplant recipients infected with SARS-CoV-2/Omicron/B.1.1.529: a Nationwide German study.

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 (< 7 days) antiviral therapy median 2 (interquartile range 1-4) days after symptom onset. Most patients received sotrovimab (57%), followed by remdesivir (21%) and molnupiravir (21%). An early combination therapy was applied in 45 patients (21%). Thirty-four patients (16%) developed a severe or critical disease severity according to the WHO scale. In total, 14 patients (6.4%) died subsequently associated with COVID-19. Neither vaccination and antibody status, nor applied treatments were associated with outcome. Only age and glomerular filtration rate < 30 ml/min/1.73m2 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.

SARS-CoV-2 T Cell Response in Severe and Fatal COVID-19 in Primary Antibody Deficiency Patients Without Specific Humoral Immunity.

Morbidity and mortality of COVID-19 is increased in patients with inborn errors of immunity (IEI). Age and comorbidities and also impaired type I interferon immunity were identified as relevant risk factors. In patients with primary antibody deficiency (PAD) and lack of specific humoral immune response to SARS-CoV-2, clinical disease outcome is very heterogeneous. Despite extensive clinical reports, underlying immunological mechanisms are poorly characterized and levels of T cellular and innate immunity in severe cases remain to be determined. In the present study, we report clinical and immunological findings of 5 PAD patients with severe and fatal COVID-19 and undetectable specific humoral immune response to SARS-CoV-2. Reactive T cells to SARS-CoV-2 spike (S) and nucleocapsid (NCAP) peptide pools were analyzed comparatively by flow cytometry in PAD patients, convalescents and naïve healthy individuals. All examined PAD patients developed a robust T cell response. The presence of polyfunctional cytokine producing activated CD4+ T cells indicates a memory-like phenotype. An analysis of innate immune response revealed elevated CD169 (SIGLEC1) expression on monocytes, a surrogate marker for type I interferon response, and presence of type I interferon autoantibodies was excluded. SARS-CoV-2 RNA was detectable in peripheral blood in three severe COVID-19 patients with PAD. Viral clearance in blood was observed after treatment with COVID-19 convalescent plasma/monoclonal antibody administration. However, prolonged mucosal viral shedding was observed in all patients (median 67 days) with maximum duration of 127 days. PAD patients without specific humoral SARS-CoV-2 immunity may suffer from severe or fatal COVID-19 despite robust T cell and normal innate immune response. Intensified monitoring for long persistence of SARS-CoV-2 viral shedding and (prophylactic) convalescent plasma/specific IgG as beneficial treatment option in severe cases with RNAemia should be considered in seronegative PAD patients.

Five-year Outcome of an Early Everolimus-based Quadruple Immunosuppression in Lung Transplant Recipients: Follow-up of the 4EVERLUNG Study.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Lung transplantation for acute respiratory distress syndrome: a retrospective European cohort study.

BACKGROUND: The 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. METHODS: We 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. RESULTS: 55 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. CONCLUSIONS: Lung transplantation in highly selected ARDS patients is feasible and outcome has improved in the modern era. The selection process remains ethically and technically challenging.

Molecular diagnosis of kidney transplant failure based on urine.

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.

Severe ileocecal inflammatory syndrome in adult patients with cystic fibrosis.

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.

Factors Associated with Worse Lung Function in Cystic Fibrosis Patients with Persistent Staphylococcus aureus.

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<0.001). Patients with exacerbations (n = 60), S. aureus small-colony variants (SCVs, n = 84) and co-infection with Stenotrophomonas maltophilia (n = 44) had worse lung function (p = 0.0068; p = 0.0011; p = 0.0103). Patients with SCVs were older (p = 0.0066) and more often treated with trimethoprim/sulfamethoxazole (p = 0.0078). IL-6 levels positively correlated with decreased lung function (p<0.001), S. aureus density in sputa (p = 0.0016), SCVs (p = 0.0209), exacerbations (p = 0.0041) and co-infections with S. maltophilia (p = 0.0195) or A. fumigatus (p = 0.0496). CONCLUSIONS: In CF-patients with chronic S. aureus cultures, independent risk factors for worse lung function are high bacterial density in throat cultures, exacerbations, elevated IL-6 levels, presence of S. aureus SCVs and co-infection with S. maltophilia. TRIAL REGISTRATION: ClinicalTrials.gov NCT00669760.

Thoracic [18F]fluorodeoxyglucose uptake measured by positron emission tomography/computed tomography in pulmonary hypertension.

Positron emission tomography (PET) visualizes increased cellular [F]fluorodeoxyglucose ([F]FDG) uptake. Pulmonary hypertension (PH) is conceived of a proliferative disease of the lung vessels. Increased glucose uptake can be quantified as pulmonary [F]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 [F]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 [F]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/cm (P < 0.001, P = 0.045, P < 0.001, P < 0.001, P = 0.26, respectively). The [F]FDG uptake in these regions positively correlated also with mPAP, PVR, and N-terminal pro-brain natriuretic peptide. The SUVR of PA positively correlated with the SUVR of LP and RV (r = 0.55, r = 0.42, respectively).Pulmonary and cardiac [F]FDG uptake in PET imaging positively correlated with the presence and severity of PH in patients with end-stage pulmonary disease. Increased glucose metabolism in the central PAs seems to play a certain role in terms of severity of PH. These results suggest that [F]FDG-PET imaging can help understand the pathophysiology of PH as a proliferative pulmonary disease.

Hepatitis B Vaccination in End-Stage Pulmonary Disease Patients Evaluated for Lung Transplantation: A Retrospective Single-Center Evaluation.

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 titers >100 IU/L, 10-100 IU/L, and <10 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 titer >10 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.