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Lung transplantation is still hindered by a high rate of chronic rejection necessitating profound immunosuppression with its associated complications. Donor-specific blood transfusion is a pre-transplant strategy aimed at improving graft acceptance. In contrast with standard stored blood or donor-specific regulatory T cells transfusions, this approach utilizes fresh whole blood from the donor prior to allograft transplantation, encompassing all cell types and plasma. The precise mechanisms underlying donor-specific blood transfusion-induced tolerance remain incompletely understood. Associations with regulatory/helper T cells, modulation of mononuclear phagocytic cells or microchimerism have been suggested. While numerous (pre-)clinical studies have explored its application in solid organ transplants like liver, kidney, and intestine, limited attention has been given to the setting of lung transplantation. This comprehensive review summarizes existing knowledge on the mechanisms and outcomes of donor-specific blood transfusion in solid organ transplants both in preclinical and clinical settings. We also address the potential benefits and risks associated with donor-specific blood transfusion in the field of lung transplantation, offering insights into future research directions. [ABSTRACT FROM AUTHOR]

Lung transplantation is still hindered by a high rate of chronic rejection necessitating profound immunosuppression with its associated complications. Donor-specific blood transfusion is a pre-transplant strategy aimed at improving graft acceptance. In contrast with standard stored blood or donor-specific regulatory T cells transfusions, this approach utilizes fresh whole blood from the donor prior to allograft transplantation, encompassing all cell types and plasma. The precise mechanisms underlying donor-specific blood transfusion-induced tolerance remain incompletely understood. Associations with regulatory/helper T cells, modulation of mononuclear phagocytic cells or microchimerism have been suggested. While numerous (pre-)clinical studies have explored its application in solid organ transplants like liver, kidney, and intestine, limited attention has been given to the setting of lung transplantation. This comprehensive review summarizes existing knowledge on the mechanisms and outcomes of donor-specific blood transfusion in solid organ transplants both in preclinical and clinical settings. We also address the potential benefits and risks associated with donor-specific blood transfusion in the field of lung transplantation, offering insights into future research directions. [ABSTRACT FROM AUTHOR]

The role of immunosuppressive therapy on SARS-CoV-2 infection risk and COVID-19 severity remains unclear in unvaccinated solid organ transplant recipients. We included 1957 organ transplant recipients between July 2020 and April 2021 to analyze whether baseline immunosuppressive therapy and other risk factors are associated with SARS-CoV-2 infection and severe COVID-19. In total, 247 (12.6%) had SARS-CoV-2 (defined as positive nasopharyngeal swab and/or positive antibody titer). Of these, 57 (23.1%) had severe COVID-19, defined as oxygen supplementation, intensive care unit admission or death. Multivariable analysis identified diabetes (hazard ratio (HR) 1.39 (95% confidence interval (CI) 1.05–1.83)), chronic lung disease (HR 1.71 (95% CI 1.13–2.60)) and contact with a COVID-19 positive individual (HR 3.61 (95% CI 2.61–4.99) as independent risk factors for SARS-CoV-2 infection. There was no association between immunosuppressive therapy and infection risk. Severe COVID-19 was multivariably associated with hypertension (OR 5.45 (95% CI 1.66–17.84)), chronic kidney disease (OR 3.55 (95% CI 1.75–7.19)), corticosteroid use (OR 2.93 (95% CI 1.03–2.55)) and having a COVID-19 positive housemate (OR 6.77 (95% CI 2.65–17.28)). In conclusion, baseline corticosteroid use, but no other immunosuppressive agent, is independently associated with severe COVID-19 in unvaccinated SOT recipients after correction for hypertension, chronic kidney disease, housemates affected by COVID-19 and transplant type. [ABSTRACT FROM AUTHOR]

Introduction: Lung transplantation has become increasingly utilized in patients with COVID‐19. While several single‐center and UNOS database studies have been published on lung transplants (LTs) for end‐stage lung disease (ESLD) from Coronavirus disease 2019 (COVID‐19), there is a lack of multi‐center and international data. Methods: This is a multicenter analysis from 11 high‐volume lung transplant centers in the United States and Europe. Data were collected through the Multi‐Institutional ECLS Registry and stratified by ESLD due to COVID‐19 versus other etiologies. Demographics and clinical variables were compared using Chi‐square test and Fisher's exact test. Survival was assessed by Kaplan‐Meier curves and compared by log‐rank test with propensity score matching. Results: Of 1606 lung transplant recipients, 46 (2.9%) were transplanted for ESLD from COVID‐19 compared to 1560 (97.1%) without a history of COVID‐19. Among COVID‐19 patients, 30 (65.2%) had COVID‐19‐associated ARDS and 16 (34.8%) had post‐COVID‐19 fibrosis. COVID‐19 patients had higher lung allocation scores (78.0 vs. 44.4, p < 0.0001), had severely limited functional status (37.0% vs. 2.9%, p < 0.0001), had higher preoperative ECMO usage (65.2% vs. 5.4%, p < 0.0001), and spent less time on the waitlist (32 vs. 137 days, p < 0.0001). A 30‐day survival was comparable between COVID‐19 and non‐COVID‐19 patients before (100% vs. 98.7%, p = 0.39) and after propensity matching (p = 0.15). Conclusions: Patients who received LTs due to COVID‐19 had short‐term survival comparable to that of patients without COVID‐19. Our findings support the idea that lung transplantation should be considered for select patients with ESLD due to COVID‐19. [ABSTRACT FROM AUTHOR]

Background: The role of the number of involved structures (NIS) in thymic epithelial tumors (TETs) has been investigated for inclusion in future staging systems, but large cohort results still are missing. This study aimed to analyze the prognostic role of NIS for patients included in the European Society of Thoracic Surgeons (ESTS) thymic database who underwent surgical resection. Methods: Clinical and pathologic data of patients from the ESTS thymic database who underwent surgery for TET from January 2000 to July 2019 with infiltration of surrounding structures were reviewed and analyzed. Patients' clinical data, tumor characteristics, and NIS were collected and correlated with CSS using Kaplan–Meier curves. The log-rank test was used to assess differences between subgroups. A multivariable model was built using logistic regression analysis. Results: The final analysis was performed on 303 patients. Histology showed thymoma for 216 patients (71.3%) and NET/thymic carcinoma [TC]) for 87 patients (28.7%). The most frequently infiltrated structures were the pleura (198 cases, 65.3%) and the pericardium in (185 cases, 61.1%), whereas lung was involved in 96 cases (31.7%), great vessels in 74 cases (24.4%), and the phrenic nerve in 31 cases (10.2%). Multiple structures (range, 2–7) were involved in 183 cases (60.4%). Recurrence resulted in the death of 46 patients. The CSS mortality rate was 89% at 5 years and 82% at 10 years. In the univariable analysis, the favorable prognostic factors were neoadjuvant therapy, Masaoka stage 3, absence of metastases, absence of myasthenia gravis, complete resection, thymoma histology, and no more than two NIS. Patients with more than two NIS presented with a significantly worse CSS than patients with no more than two NIS (CSS 5- and 10-year rates: 9.5% and 83.5% vs 93.2% and 91.2%, respectively; p = 0.04). The negative independent prognostic factors confirmed by the multivariable analysis were incomplete resection (hazard ratio [HR] 2.543; 95% confidence interval [CI] 1.010–6.407; p = 0.048) and more than two NIS (HR 1.395; 95% CI 1.021–1.905; p = 0.036). Conclusions: The study showed that more than two involved structures are a negative independent prognostic factor in infiltrative thymic epithelial tumors that could be used for prognostic stratification. [ABSTRACT FROM AUTHOR]

Controlled hypothermic storage (CHS) is a recent advance in lung transplantation (LTx) allowing preservation at temperatures higher than those achieved with traditional ice storage. The mechanisms explaining the benefits of CHS compared to conventional static ice storage (SIS) remain unclear and clinical data on safety and feasibility of lung CHS are limited. Therefore, we aimed to provide a focus review on animal experiments, molecular mechanisms, CHS devices, current clinical experience, and potential future benefits of CHS. Rabbit, canine and porcine experiments showed superior lung physiology after prolonged storage at 10°C vs. =4°C. In recent molecular analyses of lung CHS, better protection of mitochondrial health and higher levels of antioxidative metabolites were observed. The acquired insights into the underlying mechanisms and development of CHS devices allowed clinical application and research using CHS for lung preservation. The initial findings are promising; however, further data collection and analysis are required to draw more robust conclusions. Extended lung preservation with CHS may provide benefits to both recipients and healthcare personnel. Reduced time pressure between procurement and transplantation introduces flexibility allowing better decision-making and overnight bridging by delaying transplantation to daytime without compromising outcome. [ABSTRACT FROM AUTHOR]

To improve outcomes following lung transplantation, it is essential to understand the immunological mechanisms that result in chronic graft failure. The associated clinical syndrome is termed chronic lung allograft dysfunction (CLAD), which is known to be induced by alloimmune-dependent (i.e., rejection) and alloimmune-independent factors (e.g., infections, reflux and environmental factors). We aimed to explore the alloimmune-related mechanism, i.e., pulmonary rejection. In this study, we use a murine orthotopic left lung transplant model using isografts and allografts (C57BL/6 or BALB/c as donors to C57BL/6 recipients), with daily immunosuppression (10 mg/kg cyclosporin A and 1.6 mg/kg methylprednisolone). Serial sacrifice was performed at days 1, 7 and 35 post-transplantation (n = 6 at each time point for each group). Left transplanted lungs were harvested, a single-cell suspension was made and absolute numbers of immune cells were quantified using multicolor flow cytometry. The rejection process followed the principles of a classic immune response, including innate but mainly adaptive immune cells. At day 7 following transplantation, the numbers of interstitial macrophages, monocytes, dendritic cells, NK cells, NKT cells, CD4+ T cells and CD8+ T and B cells were increased in allografts compared with isografts. Only dendritic cells and CD4+ T cells remained elevated at day 35 in allografts. Our study provides insights into the immunological mechanisms of true pulmonary rejection after murine lung transplantation. These results might be important in further research on diagnostic evaluation and treatment for CLAD. [ABSTRACT FROM AUTHOR]

Lung transplantation (LTx) is a challenging procedure. Following the process of ischemia-reperfusion injury, the transplanted pulmonary graft might become severely damaged, resulting in primary graft dysfunction. In addition, during the intraoperative window, the right ventricle (RV) is at risk of acute failure. The interaction of right ventricular function with lung injury is, however, poorly understood. We aimed to address this interaction in a translational porcine model of pulmonary ischemia-reperfusion injury. Advanced pulmonary and hemodynamic assessment was used, including right ventricular pressure-volume loop analysis. The acute model was based on clamping and unclamping of the left lung hilus, respecting the different hemodynamic phases of a clinical lung transplantation. We found that forcing entire right ventricular cardiac output through a lung suffering from ischemia-reperfusion injury increased afterload (pulmonary vascular resistance from baseline to end experiment P < 0.0001) and induced right ventricular failure (RVF) in 5/9 animals. Notably, we identified different compensation patterns in failing versus nonfailing ventricles (arterial elastance P = 0.0008; stroke volume P < 0.0001). Furthermore, increased vascular pressure and flow produced by the right ventricle resulted in higher pulmonary injury, as measured by ex vivo CT density (correlation: pressure r = 0.8; flow r = 0.85). Finally, RV ischemia as measured by troponin-T was negatively correlated with pulmonary injury (r = -0.76); however, troponin-T values did not determine RVF in all animals. In conclusion, we demonstrate a delicate balance between development of pulmonary ischemia-reperfusion injury and right ventricular function during lung transplantation. Furthermore, we provide a physiological basis for potential benefit of extracorporeal life support technology. NEW & NOTEWORTHY: In contrast to the abundant literature of mechanical pulmonary artery clamping to increase right ventricular afterload, we developed a model adding a biological factor of pulmonary ischemia-reperfusion injury. We did not only focus on the right ventricular behavior, but also on the interaction with the injured lung. We are the first to describe this interaction while addressing the hemodynamic intraoperative phases of clinical lung transplantation. [ABSTRACT FROM AUTHOR]

Rates and modulators of SARS‐CoV‐2 vaccine nonresponse and breakthrough infections remain unclear in serially vaccinated transplant recipients. In a prospective, mono‐centric, observational study, 1878 adult solid organ and hematopoietic cell transplant recipients, with prior SARS‐CoV‐2 vaccination, were included between March 2021 and February 2022. SARS‐CoV‐2 anti‐spike IgG antibodies were measured at inclusion and details on SARS‐CoV‐2 vaccine doses and infection were collected. No life‐threatening adverse events were reported after a total of 4039 vaccine doses. In transplant recipients without prior SARS‐CoV‐2 infection (n = 1636), antibody response rates ranged widely, from 47% in lung transplant to 90% in liver transplant and 91% in hematopoietic cell transplant recipients after third vaccine dose. Antibody positivity rate and levels increased after each vaccine dose in all types of transplant recipients. In multivariable analysis, older age, chronic kidney disease and daily dose of mycophenolate and corticosteroids were negatively associated with antibody response rate. Overall rate of breakthrough infections was 25.2% and mainly (90.2%) occurred after third and fourth vaccine dose. Lung transplant recipients had the highest rates of severe breakthrough infection (10.5%) and death (2.5%). In multivariable analysis, older age, daily dose of mycophenolate and corticosteroids were associated with severe breakthrough infection. Transplant recipients with infection before first vaccine dose (n = 160) had higher antibody response rates and levels after each vaccine dose, and a significantly lower overall rate of breakthrough infections compared to those without prior infection. Antibody response after SARS‐CoV‐2 vaccination and rate of severe breakthrough infections vary largely between different transplant types and are modulated by specific risk factors. The observed heterogeneity supports a tailored approach against COVID‐19 in transplant recipients. [ABSTRACT FROM AUTHOR]

Fungal exposure and sensitization negatively affect outcomes in various respiratory diseases, however, the effect of fungal sensitization in lung transplant (LTx) recipients is still unknown. We performed a retrospective cohort study of prospectively collected data on circulating fungal specific IgG/IgE antibodies, and their correlation with fungal isolation, chronic lung allograft dysfunction (CLAD) and overall survival after LTx. 311 patients transplanted between 2014 and 2019 were included. Patients with elevated Aspergillus fumigatus or Aspergillus flavus IgG (10%) had more mold and Aspergillus species isolation (p = 0.0068 and p = 0.0047). Aspergillus fumigatus IgG was specifically associated with Aspergillus fumigatus isolation in the previous or consecutive year (AUC 0.60, p = 0.004 and AUC 0.63, p = 0.022, respectively). Elevated Aspergillus fumigatus or Aspergillus flavus IgG was associated with CLAD (p = 0.0355), but not with death. Aspergillus fumigatus, Aspergillus flavus or Aspergillus niger IgE was elevated in 19.3% of patients, but not associated with fungal isolation, CLAD or death. Mold isolation and Aspergillus species isolation from respiratory cultures were associated with CLAD occurrence (p = 0.0011 and p = 0.0005, respectively), and Aspergillus species isolation was also associated with impaired survival (p = 0.0424). Fungus-specific IgG could be useful in long-term follow-up post-LTx, as a non-invasive marker for fungal exposure, and thus a diagnostic tool for identifying patients at risk for fungal-related complications and CLAD. [ABSTRACT FROM AUTHOR]

Primary ciliary dyskinesia, with or without situs abnormalities, is a rare lung disease that can lead to an irreversible lung damage that may progress to respiratory failure. Lung transplant can be considered in end-stage disease. This study describes the outcomes of the largest lung transplant population for PCD and for PCD with situs abnormalities, also identified as Kartagener’s syndrome. Retrospectively collected data of 36 patients who underwent lung transplantation for PCD from 1995 to 2020 with or without SA as part of the European Society of Thoracic Surgeons Lung Transplantation Working Group on rare diseases. Primary outcomes of interest included survival and freedom from chronic lung allograft dysfunction. Secondary outcomes included primary graft dysfunction within 72 h and the rate of rejection ≥A2 within the first year. Among PCD recipients with and without SA, the mean overall and CLAD-free survival were 5.9 and 5.2 years with no significant differences between groups in terms of time to CLAD (HR: 0.92, 95% CI: 0.27–3.14, p = 0.894) or mortality (HR: 0.45, 95% CI: 0.14–1.43, p = 0.178). Postoperative rates of PGD were comparable between groups; rejection grades ≥A2 on first biopsy or within the first year was more common in patients with SA. This study provides a valuable insight on international practices of lung transplantation in patients with PCD. Lung transplantation is an acceptable treatment option in this population. [ABSTRACT FROM AUTHOR]

Background: Optimal treatment for thymoma with pleural dissemination (TPD) remains unclear. Extended radical resection is the cornerstone for local treatment but the need for pleuro-pneumonectomy is debatable. Cytoreductive surgery with intraoperative hyperthermic intrathoracic chemotherapy (HITHOC) provides an alternative strategy to reduce tumor load and prevent pleural recurrence. Objective: The aim of this review was to provide an overview of current literature regarding HITHOC for TPD. Methods: A systematic literature review (PRISMA) was performed in the EMBASE, MEDLINE, Cochrane and Web of Science databases, resulting in 154 papers selected for screening (PROSPERO: CRD42020208242). Title, abstract, and full-text screening resulted in 13 papers subjected to structured data extraction and methodological quality assessment. One additional case from our department was included. Inclusion criteria were original research reporting on patients diagnosed with TPD; oncological outcome reporting; intraoperative HITHOC; and papers written in English, Dutch or German. Methodological quality was assessed using the Risk-of-Bias (RoB)-2 Tool and the Newcastle–Ottawa scale. Results: HITHOC for TPD was reported in 171 cases. HITHOC-related mortality was absent and morbidity was reported in three cases. Intrathoracic perfusion of a platinum-derivative, often combined with other chemotherapeutic drugs at >40°C for 60 min or longer was always used. Post-HITHOC recurrence was reported in 37/120 cases (31%). In patients with a minimal 1-year follow-up, average time to recurrence was 68.5 months. Conclusion: Combining cytoreductive surgery and HITHOC is feasible and safe for TPD. The strong heterogeneity in the literature impedes proper outcome analysis. More research is needed to better understand the additional benefit of HITHOC in the TPD setting. [ABSTRACT FROM AUTHOR]

Pulmonary alveolar proteinosis (PAP) is a rare, diffuse lung disorder characterized by surfactant accumulation in the small airways due to defective clearance by alveolar macrophages, resulting in impaired gas exchange. Whole lung lavage is the current standard of care treatment for PAP. Lung transplantation is an accepted treatment option when whole lung lavage or other experimental treatment options are ineffective, or in case of extensive pulmonary fibrosis secondary to PAP. A disadvantage of lung transplantation is recurrence of PAP in the transplanted lungs, especially in hereditary PAP. The hereditary form of PAP is an ultra-rare condition caused by genetic mutations in genes encoding for the granulocyte macrophage-colony stimulating factor (GM-CSF) receptor, and intrinsically affects bone marrow derived-monocytes, which differentiate into macrophages in the lung. Consequently, these macrophages typically display disrupted GM-CSF receptor-signaling, causing defective surfactant clearance. Bone marrow/hematopoietic stem cell transplantation may potentially reverse the lung disease in hereditary PAP. In patients with hereditary PAP undergoing lung transplantation, postlung transplant recurrence of PAP may theoretically be averted by subsequent hematopoietic stem cell transplantation, which results in a graft-versus-disease (PAP) effect, and thus could improve long-term outcome. We describe the successful long-term post-transplant outcome of a unique case of end-stage respiratory failure due to hereditary PAP-induced pulmonary fibrosis, successfully treated by bilateral lung transplantation and subsequent allogeneic hematopoietic stem cell transplantation. Our report supports treatment with serial lung and hematopoietic stem cell transplantation to improve quality of life and prolong survival, without PAP recurrence, in selected patients with end-stage hereditary PAP. [ABSTRACT FROM AUTHOR]

The MUC5B promoter polymorphism (rs35705950) has been associated with interstitial lung disease (ILD) and with prolonged pre-transplant survival in idiopathic pulmonary fibrosis (IPF), but no information is available regarding its prevalence in other respiratory diseases and its influence on post-transplant outcome. We included the Leuven lung transplantation cohort between 1991 and 2015 (n = 801). We assessed the minor allele frequency (MAF) of the MUC5B variant in the entire study cohort and investigated the influence of recipient MUC5B promoter polymorphism on post-transplant outcome in patients who were transplanted after 2004. MUC5B was successfully genotyped in 746 patients. The MAF was significantly higher in ILD (17.6%) compared to chronic obstructive pulmonary disease (COPD)/emphysema (9.3%), cystic fibrosis (CF)/bronchiectasis (BRECT) (7.5%) and pulmonary hypertension (PHT) (7.4%) (p < 0.001). No association was observed between rs35705950 and chronic lung allograft dysfunction (CLAD)/graft loss in the ILD population [CLAD: HR 1.37 95% CI (0.70-2.68); graft loss: HR 1.02 95% CI (0.55-1.89)], nor the entire study cohort [CLAD: HR 0.96 95%CI (0.69-1.34); graft loss: HR 0.97 95% CI (0.70-1.35)]. The MUC5B promoter polymorphism is a very specific predictive factor for the presence of pulmonary fibrosis as it is only associated with pulmonary fibrosis and not with other chronic respiratory diseases. While the MUC5B promoter variant is associated with better pre-transplant survival among IPF patients, recipient MUC5B promoter variant does not play a role in post-transplant outcome. [ABSTRACT FROM AUTHOR]

Objective: The impact of previous lung volume reduction surgery (LVRS) or endoscopic lung volume reduction (ELVR) on lung transplantation (LuTX) remains unclear. This study assesses the risk of previous lung volume reduction on the outcome of a later LuTX. Methods: Patients suffering from emphysema who underwent bilateral LuTX were included in this multicenter analysis. Study groups were defined as: previous LVRS, previous ELVR, controls. Imbalances were corrected by coarsened exact matching for center, gender, age, diagnosis, and BMI. A comparative analysis of intraoperative characteristics, perioperative outcome and long-term survival was performed. Results: 615 patients were included (LVRS = 26; ELVR = 60). Compared to controls, LVRS patients had a higher rate of postoperative ECMO (15.4 vs. 3.9%; p = 0.006), whereas ELVR patients suffered more often from wound infections (8.9% vs. 2.5%; p = 0.018). Perioperative outcome, duration of ventilation, ICU stay, and hospital stay were comparable between groups. Bacterial colonization of the airway differed significantly between both LVR groups and controls in pre- and post-LuTX cultures. Survival was not impacted (1-/3-/5-year survival for LVRS: 92.3%/85.7%/77.1%; controls: 91.3%/82.4%/76.3%; p = 0.58| ELVR: 93.1%/91%/91%; controls 91.2%/81.7%/75.3%; p = 0.17). Conclusion: Lung volume reduction does not impact short and long-time survival after bilateral LuTX. Due to differences in airway colonization after LVR, caution to prevent infectious complications is warranted. [ABSTRACT FROM AUTHOR]

RT-PCR on a biopsy of the donor lung before LTx revealed a low viral load with a Ct value of 35, reflecting persistence of viral RNA. Keywords: lung transplantation; NAAT; point-of-care test; rapid antigen test; SARS-CoV-2 EN lung transplantation NAAT point-of-care test rapid antigen test SARS-CoV-2 1 5 5 03/31/22 20220401 NES 220401 Point-of-care tests may play a valuable role in reducing the risk of donor-derived SARS-CoV-2 transmission in lung transplantation. We anticipate that the COVID-19 pandemic will pave the way for a more regular use of POCTs to reduce the risk of donor-derived transmission of other pathogens that reside in the donor lungs. Donor to recipient transmission of SARS-CoV-2 by lung transplantation despite negative donor upper respiratory tract testing. [Extracted from the article]

Lung transplant recipients experience a high rate of invasive pulmonary aspergillosis infections, for which voriconazole is the treatment of choice. We report a patient who developed voriconazole-induced myositis that relapsed after one dose of isavuconazole. Our patient was a 38-year-old man who received a single sequential lung transplantation and liver transplantation because of end-stage cystic fibrosis. He presented to our emergency room with acute pain in both forearms at 3 weeks after voriconazole was initiated for invasive pulmonary aspergillosis infection. Levels of voriconazole were normal during the course of therapy. After stopping voriconazole, the symptoms decreased but relapsed after one dose of isavuconazole. Other causes of muscle pain and inflammation were excluded. Magnetic resonance imaging of both arms showed muscle edema in both arms, including involvement of the fascia, consistent with myositis. There were no signs of necrosis. Isavuconazole was discontinued, and the corticosteroid dose was temporarily increased, with rapid resolution of all complaints. Our patient is the fourth reported case of voriconazole-induced myositis, and the first whose symptoms relapsed after initiating isavuconazole. [ABSTRACT FROM AUTHOR]

To date, investigations of the microbiota in the lungs of people with Cystic Fibrosis (PWCF) have primarily focused on microbial community composition in luminal mucus, with fewer studies observing the microbiota in tissue samples from explanted lung tissue. Here, we analysed both tissue and airway luminal mucus samples extracted from whole explanted lungs of PWCF and unused donor lungs. We determined if the lung microbiota in end-stage CF varied within and between patients, was spatially heterogeneous and related to localized structural damage. Microbial community composition was determined by Illumina MiSeq sequencing and related to the CF-Computed Tomography (CT) score and features of end-stage lung disease on micro-CT. Ninety-eight CF tissue (n=11 patients), 20 CF luminal mucus (n=8 patients) and 33 donor tissue (n=4 patients) samples were analysed. Additionally, we compared 20 paired CF tissue and luminal mucus samples that enabled a direct "geographical" comparison of the microbiota in these two niches. Significant differences in microbial communities were apparent between the 3 groups. However, overlap between the three groups, particularly between CF and donor tissue and CF tissue and CF luminal mucus was also observed. Microbial diversity was lower in CF luminal mucus compared to CF tissue, with dominance higher in luminal mucus. For both CF and donor tissue, intra- and inter-patient variability in ecological parameters was observed. No relationships were observed between ecological parameters and CF-CT score, or features of end-stage lung disease. The end-stage CF lung is characterised by a low diversity microbiota, differing within and between individuals. No clear relationship was observed between regional microbiota variation and structural lung damage. [ABSTRACT FROM AUTHOR]

Repeated exposure to antigens via inhalation is the primary cause of hypersensitivity pneumonitis, a form of interstitial pneumonia. The chronic form of hypersensitivity pneumonitis leads to progressive loss of respiratory function; lung transplantation is the only therapeutic option for chronically ill patients. The ESTS Lung Transplantation Working Group conducted a retrospective multicentred cohort study to increase the body of knowledge available on this rare indication for lung transplantation. Data were collected for every patient who underwent lung transplant for hypersensitivity pneumonitis in participating centres between December 1996 and October 2019. Primary outcome was overall survival; secondary outcome was freedom from chronic lung allograft dysfunction. A total of 114 patients were enrolled from 9 centres. Almost 90% of patients were diagnosed with hypersensitivity pneumonitis before transplantation, yet the antigen responsible for the infection was identified in only 25% of cases. Eighty per cent of the recipients received induction therapy. Survival at 1, 3, and 5 years was 85%, 75%, and 70%, respectively. 85% of the patients who survived 90 days after transplantation were free from chronic lung allograft dysfunction after 3 years. The given study presents a large cohort of HP patients who underwent lung transplants. Overall survival rate is higher in transplanted hypersensitivity pneumonitis patients than in those suffering from any other interstitial lung diseases. Hypersensitivity pneumonitis patients are good candidates for lung transplantation. [ABSTRACT FROM AUTHOR]

A 35-year-old woman underwent bilateral lung transplantation for primary ciliary dyskinesia and developed vascular tumors over a slow time course. Initial presentation of non-specific vascular tumors in the lungs and liver for up to 6 years after transplantation evolved toward bilateral ovarian angiosarcoma. Tumor analysis by haplotyping and human leukocyte antigen typing showed mixed donor chimerism, proving donor origin of the tumoral lesions. In retrospect, the donor became brain dead following neurosurgical complications for a previously biopsy-proven cerebral hemangioma, which is believed to have been a precursor lesion of the vascular malignancy in the recipient. Donortransmitted tumors should always be suspected in solid organ transplant recipients in case of uncommon disease course or histology, and proper tissue-based diagnosis using sensitive techniques should be pursued. [ABSTRACT FROM AUTHOR]

Aim: Pleural dissemination of pseudomyxoma peritonei (PMP) is an extremely rare diagnosis, for which no standard therapy is available. Methods: We describe the successful treatment of a 67-year-old male diagnosed with left-sided intrapleural dissemination of PMP (low-grade appendiceal mucinous neoplasm), 2 years after treatment of abdominal PMP with cytoreductive surgery (CRS) and hyperthermic intra-peritoneal chemotherapy. Treatment consisted of extended pleural decortication (ePD) and oxaliplatin-based hyperthermic intrathoracic chemotherapy (HITHOC). The patient is doing well without complications or signs of recurrence, 26 months after thoracic surgery. Conclusion: ePD in combination with HITHOC is a valuable treatment for thoracic PMP. [ABSTRACT FROM AUTHOR]

Background: Sarcoidosis is a systemic granulomatous disease that in most patients affects the lung. Pulmonary fibrotic sarcoidosis is clinically, radiologically, and pathologically a heterogeneous condition. Although substantial indirect evidence suggests small airways involvement, direct evidence currently is lacking.Research Question: What is the role of the (small) airways in fibrotic sarcoidosis?Study Design and Methods: Airway morphologic features were investigated in seven explant lungs with end-stage fibrotic sarcoidosis using a combination of CT scanning (large airways), micro-CT scanning (small airways), and histologic examination and compared with seven unused donor lungs as controls with specific attention focused on different radiologically defined sarcoidosis subtypes.Results: Patients with central bronchial distortion (n = 3), diffuse bronchiectasis (n = 3), and usual interstitial pneumonia pattern (n = 1) were identified based on CT scan, showing a decrease and narrowing of large airways, a similar airway number and increased airway diameter of more distal airways, or an increase in airway number and airway diameter, respectively, compared with control participants. The number of terminal bronchioles per milliliter and the total number of terminal bronchioles were decreased in all forms of fibrotic sarcoidosis. Interestingly, the number of terminal bronchioles was inversely correlated with the degree of fibrosis. Furthermore, we identified granulomatous remodeling as a cause of small airways loss using serial micro-CT scanning and histologic examination.Interpretation: The large airways are involved differentially in subtypes of sarcoidosis, but the terminal bronchioles universally are lost. This suggests that small airways loss forms an important aspect in the pathophysiologic features of fibrotic pulmonary sarcoidosis. [ABSTRACT FROM AUTHOR]

Background: Connective tissue growth factor (CTGF) is an important mediator in several fibrotic diseases, including lung fibrosis. We investigated CTGF-expression in chronic lung allograft dysfunction (CLAD) and pulmonary graft-versus-host disease (GVHD). Materials and Methods: CTGF expression was assessed by quantitative real-time polymerase chain reaction (qPCR) and immunohistochemistry in end-stage CLAD explant lung tissue (bronchiolitis obliterans syndrome (BOS), n=20; restrictive allograft syndrome (RAS), n=20), pulmonary GHVD (n=9). Unused donor lungs served as control group (n=20). Next, 60 matched lung transplant recipients (BOS, n=20; RAS, n=20; stable lung transplant recipients, n=20) were included for analysis of CTGF protein levels in plasma and broncho-alveolar lavage (BAL) fluid at 3 months post-transplant, 1 year post-transplant, at CLAD diagnosis or 2 years post-transplant in stable patients. Results: qPCR revealed an overall significant difference in the relative content of CTGF mRNA in BOS, RAS and pulmonary GVHD vs. controls (p=0.014). Immunohistochemistry showed a significant higher percentage and intensity of CTGF-positive respiratory epithelial cells in BOS, RAS and pulmonary GVHD patients vs. controls (p<0.0001). BAL CTGF protein levels were significantly higher at 3 months post-transplant in future RAS vs. stable or BOS (p=0.028). At CLAD diagnosis, BAL protein content was significantly increased in RAS patients vs. stable (p=0.0007) and BOS patients (p=0.042). CTGF plasma values were similar in BOS, RAS, and stable patients (p=0.74). Conclusions: Lung CTGF-expression is increased in end-stage CLAD and pulmonary GVHD; and higher CTGF-levels are present in BAL of RAS patients at CLAD diagnosis. Our results suggest a potential role for CTGF in CLAD, especially RAS, and pulmonary GVHD. [ABSTRACT FROM AUTHOR]

Background: Synovial sarcomas (SS) are malignant mesenchymal neoplasms that account for about 10% of all sarcomas. Complete surgical excision is the mainstay of primary treatment for localized disease, but SS have a high tendency for local relapse and metastases. Metastatic disease is commonly treated with systemic chemotherapy. Methods: We designed a retrospective analysis to describe the clinical presentation, course of treatment, outcome, and prognosis of patients with SS. Univariate and multivariate analyses were performed for potential prognostic factors. Results: We identified 134 patients treated between 1987 and 2018, with a cutoff date of December 2018. Demographics, disease characteristics, treatment, and survival rates were collected and analyzed. The median overall survival (mOS) from the date of diagnosis was 96.7 months. The median progression-free survival was 6.37 months. Disease-free survival was 26 months. Age over 65 years was found to be a prognostic factor with statistically significant value in the univariate analysis regarding mOS (p = 0.015) and mOS after local relapse (p = 0.0228). Conclusions: Even though our study is limited by the retrospective nature of the analysis, it adds an important amount of clinical data regarding the treatment and outcome of SS. [ABSTRACT FROM AUTHOR]

A decision to withdraw life-sustaining treatment (WLST) is derived by a conclusion that further treatment will not enable a patient to survive or will not produce a functional outcome with acceptable quality of life that the patient and the treating team regard as beneficial. Although many hospitalized patients die under such circumstances, controlled donation after the circulatory determination of death (cDCDD) programs have been developed only in a reduced number of countries. This International Collaborative Statement aims at expanding cDCDD in the world to help countries progress towards self-sufficiency in transplantation and offer more patients the opportunity of organ donation. The Statement addresses three fundamental aspects of the cDCDD pathway. First, it describes the process of determining a prognosis that justifies the WLST, a decision that should be prior to and independent of any consideration of organ donation and in which transplant professionals must not participate. Second, the Statement establishes the permanent cessation of circulation to the brain as the standard to determine death by circulatory criteria. Death may be declared after an elapsed observation period of 5 min without circulation to the brain, which confirms that the absence of circulation to the brain is permanent. Finally, the Statement highlights the value of perfusion repair for increasing the success of cDCDD organ transplantation. cDCDD protocols may utilize either in situ or ex situ perfusion consistent with the practice of each country. Methods to accomplish the in situ normothermic reperfusion of organs must preclude the restoration of brain perfusion to not invalidate the determination of death. [ABSTRACT FROM AUTHOR]

Background: Primary graft dysfunction (PGD) remains a major obstacle after lung transplantation. Ischemia–reperfusion injury is a known contributor to the development of PGD following lung transplantation. We developed a novel approach to assess the impact of increased pulmonary blood flow in a large porcine single-left lung transplantation model. Materials: Twelve porcine left lung transplants were divided in two groups (n = 6, in low- (LF) and high-flow (HF) group). Donor lungs were stored for 24 h on ice, followed by left lung transplantation. In the HF group, recipient animals were observed for 6 h after reperfusion with partially clamping right pulmonary artery to achieve a higher flow (target flow 40–60% of total cardiac output) to the transplanted lung compared to the LF group, where the right pulmonary artery was not clamped. Results: Survival at 6 h was 100% in both groups. Histological, functional and biological assessment did not significantly differ between both groups during the first 6 h of reperfusion. injury was also present in the right native lung and showed signs compatible with the pathophysiological hallmarks of ischemia–reperfusion injury. Conclusions: Partial clamping native pulmonary artery in large animal lung transplantation setting to study the impact of low versus high pulmonary flow on the development of ischemia reperfusion is feasible. In our study, differential blood flow had no effect on IRI. However, our findings might impact future studies with extracorporeal devices and represent a specific intra-operative problem during bilateral sequential single-lung transplantation. [ABSTRACT FROM AUTHOR]

Cutibacterium (C) acnes, a Gram‐positive bacterium that is part of the commensal flora, is increasingly noticed as an opportunistic pathogen in serious infections in both immunocompromised and immunocompetent patients. The indolent character and often difficult identification because of its slow growth contribute to delayed diagnosis or underdiagnosis. This report highlights a unique case of a lung transplant recipient with a C acnes intracerebral abscess, and we recommend including this organism in such differential diagnosis. A 66‐year‐old woman, 2 years after bilateral lung transplantation for chronic obstructive pulmonary disease, presented with frontal headache, without other complaints, and with normal neurological examination. Magnetic resonance imaging showed an extensive lesion in the right frontal lobe with extensive perilesional edema. Given the broad differential diagnosis, stereotactic brain biopsy was performed and culture became positive for C acnes. She was treated with intravenous ceftriaxone for 8 weeks and per oral clindamycin for 6 months, as well as corticosteroids in tapered dose. There was a rapid favorable clinical and radiographic evolution. [ABSTRACT FROM AUTHOR]

The application of stereology to lung casts and two-dimensional microscopy images is the gold standard for quantification of the human lung anatomy. However, these techniques are labor intensive, involving fixation, embedding, and histological sectioning of samples and thus have prevented comprehensive studies. Our objective was to demonstrate the application of stereology to volumetric multiresolution computed tomography (CT) to efficiently and extensively quantify the human lung anatomy. Nontransplantable donor lungs from individuals with no evidence of respiratory disease (n 13) were air inflated, frozen at 10 cmH2O, and scanned using CT. Systematic uniform random samples were taken, scanned using micro-CT, and assessed using stereology. The application of stereology to volumetric CT imaging enabled comprehensive quantification of total lung volume, volume fractions of alveolar, alveolar duct, and tissue, mean linear intercept, alveolar surface area, alveolar surface area density, septal wall thickness, alveolar number, number-weighted mean alveolar volume, and the number and morphometry of terminal and transitional bronchioles. With the use of this data set, we found that women and men have the same number of terminal bronchioles (last generation of conducting airways), but men have longer terminal bronchioles, a smaller wall area percentage, and larger lungs due to a greater number of alveoli per acinus. The application of stereology to multiresolution CT imaging enables comprehensive analysis of the human lung parenchyma that identifies differences between men and women. The reported data set of normal donor lungs aged 25-77 yr provides reference data for future studies of chronic lung disease to determine exact changes in tissue pathology. NEW & NOTEWORTHY Stereology has been the gold standard to quantify the three-dimensional lung anatomy using two-dimensional microscopy images. However, such techniques are labor intensive. This study provides a method that applies stereology to volumetric computed tomography images of frozen whole human lungs and systematic uniform random samples. The method yielded a comprehensive data set on the small airways and parenchymal lung structures, highlighting morphometric sex differences and providing a reference data set for future pathological studies. [ABSTRACT FROM AUTHOR]

The excellent review on 'Optimal strategies for referral and patient selection for lung transplantation' by Mitchell and Glanville in the latest issue of I Therapeutic Advances in Respiratory Diseases i [1] accurately describes the important historic changes in referral and listing strategies, driven by experience and increasingly also by scientific evidence, aiming to achieve the "best" results after lung transplantation. The international thoracic organ transplant registry of the international society for heart and lung transplantation: thirty-fifth adult lung and heart-lung transplant report-2018; focus theme: multiorgan transplantation. [Extracted from the article]

Summary: Limited results about treatment with total lymphoid irradiation (TLI) in lung transplant (LTx) recipients suffering from progressive bronchiolitis obliterans syndrome (BOS) have been reported. We performed a retrospective analysis of all LTx recipients undergoing TLI for progressive BOS in our center, focusing on long‐term outcomes regarding overall survival and lung allograft function. Treatment with TLI (2004–2017, n = 20, 1 BOS stage 1, 6 BOS stage 2, and 13 BOS stage 3) resulted in significant attenuation of the FEV1‐decline in the majority of patients, mainly in those with a rapid decline (P = 0.0005). This allowed bridging to redo‐transplantation in five patients. However, three patients progressed from BOS to RAS following prior TLI. Overall patient survival was 44% at 2 years post‐TLI and 38% after 17 years. Generally, TLI was well tolerated, with limited side effects and no serious adverse events. TLI may attenuate the decline in FEV1 of LTx recipients with rapid progressive BOS and could thus help to bridge selected patients to redo‐transplantation. [ABSTRACT FROM AUTHOR]

Summary: Detailed data on postoperative death in lung transplant (LTx) recipients are lacking. Therefore, we investigated all deaths after LTx in a large, single‐centre, 25‐year follow‐up cohort. Prevalence, time, place and cause of death (COD) were retrospectively analysed for all patients undergoing primary LTx between July 1991 and December 2015 in our centre. Over subsequent years, postoperative survival significantly improved, with proportionally more patients surviving to 1‐year post‐LTx (P < 0.0001). A total of 347 (38.9%) LTx recipients died, of which 53.6% expired within 3 years post‐LTx [median time to death 910 (236–2447) days]. Autopsy was performed in 34.8% of deaths. COD included CLAD in 27.1% (BOS 63.8% vs. RAS 36.2%); infection (26.5%); malignancy (15.6%); postoperative complication (11.2%); cardiovascular disease (4.6%) or other causes (6.9%). In 8.1%, no clear COD could be determined. COD significantly differed between the various LTx indications (P = 0.047). With longer follow‐up, infection becomes a less prevalent COD, but CLAD and malignancies a more important COD. The majority of patients died on the intensive care unit (40.6%) or hospital ward (29.1%), but place of death varied depending on the underlying COD. The current study provides insights into the postoperative deaths of LTx recipients. [ABSTRACT FROM AUTHOR]

The excellent review on 'Optimal strategies for referral and patient selection for lung transplantation' by Mitchell and Glanville in the latest issue of I Therapeutic Advances in Respiratory Diseases i [1] accurately describes the important historic changes in referral and listing strategies, driven by experience and increasingly also by scientific evidence, aiming to achieve the "best" results after lung transplantation. The international thoracic organ transplant registry of the international society for heart and lung transplantation: thirty-fifth adult lung and heart-lung transplant report-2018; focus theme: multiorgan transplantation. [Extracted from the article]

The United States is widely characterized as having liberal (limited state) ideology and institutions, while Belgium is relatively statist. Yet the United States relies primarily on local public monopolies to provide elementary and secondary education, while Belgium provides schooling through robust education free markets including and in some locales dominated by publicly funded faith-based schools. We present comparative case studies of the evolution of each educational system, in search of explanations. Our American case summarizes prior accounts, while the Belgian case uses archival research. The evolution of each system reflects similar late 19th and early 20th Century conflicts between the Catholic Church and the state, though American “public” schools were essentially Protestant, and Protestant majorities eventually imposed state-funded quasimonopolies. In contrast, in Belgium the contending parties (traditionalist Catholics opposing Liberals) had relatively equal political power over the long term, giving each incentives for market-based compromises which still endure Belgian school wars, Blaine Amendments, Catholic education, school choice and religion, school vouchers. [ABSTRACT FROM AUTHOR]

OBJECTIVES: Current guidelines recommend preoperative invasive mediastinal staging in centrally located tumours with negative mediastinum on positron emission tomography-computed tomography, based on a 20-30% prevalence of occult mediastinal disease (pN2-3). However, a uniform definition of central tumour location is lacking. Our objective was to determine the best definition in predicting occult pN2-3. METHODS: A single-institution database was queried for patients with (suspected) non-small-cell lung cancer staged cN0 after positron emission tomography-computed tomography and referred to invasive staging and/or primary surgery. We evaluated 5 definitions: inner 1/3, inner 2/3, contact with bronchovascular structures, <_2 cm from bronchus or endobronchial visualization. RESULTS: Between 2005 and 2015, 813 patients were eligible (cT1: 42%, cT2: 28%, cT3: 17% and cT4: 11%). Invasive mediastinal staging and resection were performed in 30% and 97% of patients, respectively. Any nodal upstaging (pN+) was found in 21% of patients, of whom pN2-3 was found in 8%. Central tumour location demonstrated 4 times higher odds for any pN+ [for inner 1/3 vs outer 2/3, odds ratio 3.90 (95% confidence interval 2.24-6.77), P < 0.001], whereas no significantly different odds was observed for pN2-3. The discriminative ability for pN+ was not significantly different between the several definitions. CONCLUSIONS: The prevalence of occult pN2-3 was only 8% when modern fusion positron emission tomography-computed tomography imaging pointed at clinical N0 non-small-cell lung cancer. None of the 5 verified definitions of centrality was predictive for occult pN2-3. However, each definition of centrality was related to any pN+ at a prevalence of 21%, without significant differences in discriminative ability between definitions. These data question whether indication for preoperative invasive mediastinal staging should be based on centrality alone. [ABSTRACT FROM AUTHOR]

Background: The advice of a dynamic multidisciplinary discussion (MDD) is believed to be important in the diagnosis of interstitial lung diseases (ILDs). However, to what extent MDD diagnoses differ from the preliminary diagnoses before formal workup and MDD (preMDD diagnoses) is still insufficiently studied.Methods: We compared preMDD and MDD diagnoses in patients discussed at the Leuven University Hospitals MDDs between January 2005 and December 2015.Results: Of 938 consecutive patients discussed in an MDD, 755 (80.5%) received a specific diagnosis. From the 183 patients with unclassifiable ILD, 150 patients (16.0%) received suggestions concerning further investigations to establish a definite diagnosis. In 191 patients (41.9% of patients with a preMDD diagnosis), the MDD changed the diagnosis. In 384 patients (79.5% of patients without preMDD diagnosis), MDD provided a diagnosis when the referring physician did not. MDD diagnosis showed a trend toward better prognostic discrimination between idiopathic pulmonary fibrosis and other ILDs compared with preMDD diagnosis (Harrell C-index, 0.666 vs 0.631; P = .08), which was particularly clear in patients with discordant MDD and preMDD diagnoses (hazard ratio, 2.68 vs 0.84; P = .012 vs .768).Conclusions: The MDD provided a definite diagnosis in 80.5% of presented cases, suggesting further investigations in almost all others. Given the high number of patients without preMDD diagnosis, the rate of change in preMDD diagnoses (41.9% of patients with a preMDD diagnosis) probably is an underestimation. The better prognostic discrimination among ILDs by using MDD indicates the added value of MDD in ILD. [ABSTRACT FROM AUTHOR]

Bronchiolitis obliterans syndrome (BOS) remains the major problem which precludes long-term survival after lung transplantation. Previously, an open label pilot study from our group demonstrated a possible beneficial effect of montelukast in progressive BOS patients with low airway neutrophilia (<15%), and already on azithromycin treatment, in whom the further decline in pulmonary function was attenuated. This was, however, a non-randomized and non-placebo controlled trial. The study design is a single center, prospective, interventional, randomized, double blind, placebo-controlled trial, with a two arm parallel group design and an allocation ratio of 1:1. Randomization to additional montelukast (10 mg/day, n = 15) or placebo (n = 15) was performed from 2010 to 2014 at the University Hospitals Leuven (Leuven, Belgium) in all consecutive patients with late-onset (>2years posttransplant) BOS ≥1. Primary end-point was freedom from graft loss 1 year after randomization; secondary end-points were acute rejection, lymphocytic bronchiolitis, respiratory infection rate; and change in FEV1, airway and systemic inflammation during the study period. Graft loss at 1 y and 2y was similar in both groups (respectively p = 0. 981 and p = 0.230). Montelukast had no effect on lung function decline in the overall cohort. However, in a post-hoc subanalysis of BOS stage 1 patients, montelukast attenuated further decline of FEV1 during the study period, both in absolute (L) (p = 0.008) and % predicted value (p = 0.0180). A linear mixed model confirmed this association. Acute rejection, lymphocytic bronchiolitis, respiratory infections, systemic and airway inflammation were comparable between groups over the study period. This randomized controlled trial showed no additional survival benefit with montelukast compared to placebo, although the study was underpowered. The administration of montelukast was associated with an attenuation of the rate of FEV1 decline, however, only in recipients with late-onset BOS stage 1. [ABSTRACT FROM AUTHOR]

Abstract: Introduction: Previous studies demonstrated that increased cytokine and chemokine levels, either shortly before or after lung transplantation, were associated with post‐transplant outcome. However, small patient cohorts were mostly used, focusing on 1 molecule and 1 outcome. In a large single‐center cohort, we investigated the predictive value of immediate post‐operative broncho‐alveolar lavage (BAL) expression of IL‐6 and IL‐8 on multiple key outcomes, including PGD, CLAD, graft survival, as well as several secondary outcomes. Material and methods: All patients undergoing a first lung transplant in whom routine bronchoscopy with BAL was performed during the first 48 hours post‐transplantation were included. IL‐6 and IL‐8 protein levels were measured in BAL via ELISA. Results: A total of 336 patients were included. High IL‐6 levels measured within 24 hours of transplantation were associated with longer time on ICU and time to hospital discharge; and increased prevalence of PGD grade 3. Increased IL‐8 levels, measured within 24 hours, were associated with PGD3, more ECMO use, higher donor paO2, younger donor age, but not with other short‐or long‐term outcome. IL‐6 and IL‐8 measured between 24 and 48 hours of transplantation were not associated with any outcome parameters. Conclusion: Recipient BAL IL‐6 and IL‐8 within 24 hours post‐transplant were associated with an increased incidence of PGD3. [ABSTRACT FROM AUTHOR]