Multicentre retrospective analysis on pulmonary metastasectomy: an European perspective.

OBJECTIVES: To assess the current practice of pulmonary metastasectomy at 15 European Centres. Short- and long-term outcomes were analysed. METHODS: Retrospective analysis on patients ≥18 years who underwent curative-intent pulmonary metastasectomy (January 2010 to December 2018). Data were collected on a purpose-built database (REDCap). Exclusion criteria were: previous lung/extrapulmonary metastasectomy, pneumonectomy, non-curative intent and evidence of extrapulmonary recurrence at the time of lung surgery. RESULTS: A total of 1647 patients [mean age 59.5 (standard deviation; SD = 13.1) years; 56.8% males] were included. The most common primary tumour was colorectal adenocarcinoma. The mean disease-free interval was 3.4 (SD = 3.9) years. Relevant comorbidities were observed in 53.8% patients, with a higher prevalence of metabolic disorders (32.3%). Video-assisted thoracic surgery was the chosen approach in 54.9% cases. Wedge resections were the most common operation (67.1%). Lymph node dissection was carried out in 41.4% cases. The median number of resected lesions was 1 (interquartile range 25-75% = 1-2), ranging from 1 to 57. The mean size of the metastases was 18.2 (SD = 14.1) mm, with a mean negative resection margin of 8.9 (SD = 9.4) mm. A R0 resection of all lung metastases was achieved in 95.7% cases. Thirty-day postoperative morbidity was 14.5%, with the most frequent complication being respiratory failure (5.6%). Thirty-day mortality was 0.4%. Five-year overall survival and recurrence-free survival were 62.0% and 29.6%, respectively. CONCLUSIONS: Pulmonary metastasectomy is a low-risk procedure that provides satisfactory oncological outcomes and patient survival. Further research should aim at clarifying the many controversial aspects of its daily clinical practice.

Implementation of an enhanced recovery protocol for lung volume reduction surgery: an observational cohort study.

OBJECTIVES: Lung volume reduction surgery (LVRS) is an established therapeutic option for advanced emphysema. To improve patients' safety and reduce complications, an enhanced recovery protocol (ERP) was implemented. This study aims to describe and evaluate the short-term outcome of this ERP. METHODS: This retrospective single-centre study included all consecutive LVRS patients (1 January 2017 until 15 September 2020). An ERP for LVRS was implemented and stepwise optimised from 1 August 2019, it consisted of changes in pre-, peri- and postoperative care pathways. Patients were compared before and after implementation of ERP. Primary outcome was incidence of postoperative complications (Clavien-Dindo), and secondary outcomes included chest tube duration, incidence of prolonged air leak (PAL), length of stay (LOS) and 90-day mortality. Lung function and exercise capacity were evaluated at 3 and 6 months post-LVRS. RESULTS: Seventy-six LVRS patients were included (pre-ERP: n=41, ERP: n=35). The ERP cohort presented with lower incidence of postoperative complications (42% vs 83%, P=0.0002), shorter chest tube duration (4 vs 12 days, P<0.0001) with a lower incidence of PAL (21% vs 61%, P=0.0005) and shorter LOS (6 vs 14 days, P<0.0001). No in-hospital mortality occurred in the ERP cohort versus 4 pre-ERP. Postoperative forced expiratory volume in 1 s was higher in the ERP cohort compared to pre-ERP at 3 months (1.35 vs 1.02 l) and at 6 months (1.31 vs 1.01 l). CONCLUSIONS: Implementation of ERP as part of a comprehensive reconceptualisation towards LVRS, demonstrated fewer postoperative complications, including PAL, resulting in reduced LOS. Improved short-term functional outcomes were observed at 3 and 6 months.

Complications related to extracorporeal life support in lung transplantation: single-center analysis.

Background: Extracorporeal life support (ECLS) is not routinely used at our center during sequential single-lung transplantation (LTx), but is restricted to anticipate and overcome hemodynamic and respiratory problems occurring peri-operatively. In this retrospective descriptive cohort study, we aim to describe our single-center experience with ECLS in LTx, analyzing ECLS-related complications. Methods: All transplantations with peri-operative ECLS use [2010-2020] were retrospectively analyzed. Multi-organ and heart-lung transplantation were excluded. Demographics, support type and indications are described. Complications are categorized according to the underlying nature and type. Data are presented as median [interquartile range (IQR)]. Kaplan-Meier was used for survival analysis. Results: The overall use of ECLS was 22% (156/703 patients) with a mean age of 52 years (IQR, 36-59 years). Transplant indications in ECLS cohort were interstitial lung disease (38%; n=60), chronic obstructive pulmonary disease (COPD) (19%; n=29), cystic fibrosis (17%; n=26) and others (26%; n=41). Per indication, 94% (15/16) of pulmonary arterial hypertension patients required ECLS, whereas only 8% (29/382) of COPD patients did. In 16% (25/156) of supported patients, veno-venous extracorporeal membrane oxygenation was initiated, while 77% (120/156) required veno-arterial support, and 7% (11/156) cardiopulmonary bypass. Thirty-day mortality was 6% (9/156). Sixteen percent (25/156) of patients were bridged to transplantation on ECLS and 24% (37/156) required post-operative support. Main reasons to use ECLS were intra-operative hemodynamic instability (53%; n=82), ventilation/oxygenation problems (22%; n=34) and reperfusion edema (17%; n=26). Overall incidence of patients with at least one ECLS-related complication was 67% (n=104). Most common complications were hemothorax (25%; n=39), need for continuous renal replacement therapy (19%; n=30), and thromboembolism (14%; n=22). Conclusions: ECLS was required in 22% of LTxs, with a reported ECLS-related complication rate of 67%, of which the most common was hemothorax. Larger databases are needed to further analyze complications and develop tailored deployment strategies for ECLS-use in LTx.

The hemodynamic interplay between pulmonary ischemia-reperfusion injury and right ventricular function in lung transplantation: a translational porcine model.

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.

Radiologic and Histologic Correlates of Early Interstitial Lung Changes in Explanted Lungs.

Background Interstitial lung abnormalities (ILAs) reflect imaging features on lung CT scans that are compatible with (early) interstitial lung disease. Despite accumulating evidence regarding the incidence, risk factors, and prognosis of ILAs, the histopathologic correlates of ILAs remain elusive. Purpose To determine the correlation between radiologic and histopathologic findings in CT-defined ILAs in human lung explants. Materials and Methods Explanted lungs or lobes from participants with radiologically documented ILAs were prospectively collected from 2010 to 2021. These specimens were air-inflated, frozen, and scanned with CT and micro-CT (spatial resolution of 0.7 mm and 90 µm, respectively). Subsequently, the lungs were cut and sampled with core biopsies. At least five samples per lung underwent micro-CT and subsequent histopathologic assessment with semiquantitative remodeling scorings. Based on area-specific radiologic scoring, the association between radiologic and histopathologic findings was assessed. Results Eight lung explants from six donors (median age at explantation, 71 years [range, 60-83 years]; four men) were included (unused donor lungs, n = 4; pre-emptive lobectomy for oncologic indications, n = 2). Ex vivo CT demonstrated ground-glass opacification, reticulation, and bronchiectasis. Micro-CT and histopathologic examination demonstrated that lung abnormalities were frequently paraseptal and associated with fibrosis and lymphocytic inflammation. The histopathologic results showed varying degrees of fibrosis in areas that appeared normal on CT scans. Regions of reticulation on CT scans generally had greater fibrosis at histopathologic analysis. Vasculopathy and bronchiectasis were also often present at histopathologic examination of lungs with ILAs. Fully developed fibroblastic foci were rarely observed. Conclusion This study demonstrated direct histologic correlates of CT-defined interstitial lung abnormalities. © RSNA, 2022 Supplemental material is available for this article. See also the editorial by Jeudy in this issue.

Can we attenuate ischaemia-reperfusion injury of allografts in a porcine left lung transplant models by adsorption of cytokines?

OBJECTIVES: Primary graft dysfunction resulting from ischaemia-reperfusion injury remains a major obstacle after lung transplantation (LTx) and is associated with morbidity and mortality. Continuous release of inflammatory cytokines, due to the process of ischaemia and reperfusion, triggers a complex cascade of apoptosis and necrosis resulting in graft dysfunction. Previous studies demonstrated successful graft improvement by cytokine filtration during ex vivo lung perfusion. We hypothesize that plasma cytokine filtration with CytoSorb® during in vivo graft perfusion immediately after implantation may attenuate ischaemia-reperfusion injury after left LTx in a porcine model. METHODS: Left porcine LTx was performed with allografts preserved for 24 h at 4°C. In the treatment group [T] (n = 7), a veno-venous shunt was created to insert the cytokine filter (CytoSorbents, Berlin, Germany). In the sham group [S] (n = 4), the shunt was created without the filter. Haemodynamic parameters, lung mechanics, blood gases and plasma cytokines were assessed during 6 h in vivo reperfusion. RESULTS: During 6 h of reperfusion, significant differences in plasma pro-inflammatory cytokine [interferon (IFN)-α, IFN-γ and interleukin (IL)-6] concentrations were observed between [T] and [S], but surprisingly with higher plasma levels in the [T] group. Plasma concentrations of other pro-inflammatory cytokines (IL-1ß, IL-12p40, IL-4, IL-6, IL-8, IFN-α, IFN-γ and tumour necrosis factor-α) and anti-inflammatory cytokines (IL-10) did not find any evidence for a difference. Furthermore, our study failed to show meaningful difference in haemodynamics and blood gases. Also, no statistically significant differences were found between [T] and [S] in biopsies and wet-to-dry ratio at the end of the experiment. CONCLUSIONS: In our porcine left LTx model cytokine filtration did not achieve the intended effect. This is in contrast to previous studies with CytoSorb use during ex vivo lung perfusion as a surrogate LTx model. Our findings might highlight the fact that the theoretical benefit of inserting an additional cytokine adsorber to improve graft function in clinical practice should be critically evaluated with further studies.

Impact of the extent of lung resection on postoperative outcomes of pulmonary metastasectomy for colorectal cancer metastases: an exploratory systematic review.

Background: Pulmonary metastasectomy (PM) with curative intent has become a widely accepted treatment for lung metastases from solid tumours in selected patients, with low perioperative morbidity and mortality. In particular, PM is strongly recommended in selected patients with secondary lesions from colorectal cancer (CRC), due to its excellent postoperative prognosis. Nevertheless, the impact of the extent of PM on recurrence and survival remains controversial. This review aimed at assessing differences in short- and long-term postoperative outcomes depending on the extent of lung resection for lung metastases. Methods: A systematic literature review of studies comparing anatomical and non-anatomical resections of lung metastases was performed (Prospective Register of Systematic Reviews Registration: 254931). A literature search for articles published in English between the date of database inception and January 31, 2021 was performed in EMBASE (via Ovid), MEDLINE (via PubMed) and Cochrane CENTRAL. Retrospective studies, randomised and non-randomised controlled trials were included. The Cochrane Collaboration tool was used to determine the risk of bias for the primary outcome for included studies. Results: Out of 432 papers, three retrospective non-randomised studies (1,342 patients) were selected for systematic reviewing. Although our search design did not exclude any primary tumour histology, all selected studies investigated surgical resection of lung metastases from CRC. Because of variations in the compared surgical approaches to pulmonary metastases, a meta-analysis proved unfeasible. There was a tendency to perform anatomical resections for larger metastases. Multivariate analyses revealed that anatomical resections were protective for recurrence-free survival (RFS), while the impact of such procedures on overall survival (OS) remained uncertain. A significantly higher incidence of resection-margin recurrences was observed in patients who underwent non-anatomical resections. Discussion: Anatomical resections of lung metastases from CRC seem to be associated with improved RFS. However, well-constructed comparative clinical trials focusing on the extent of PM are needed.

Allogeneic Hematopoietic Stem Cell Transplantation After Prior Lung Transplantation for Hereditary Pulmonary Alveolar Proteinosis: A Case Report.

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, post-lung 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.

The MUC5B Promoter Polymorphism is Not Associated With Non-ILD Chronic Respiratory Diseases or Post-transplant Outcome.

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.

Once daily tacrolimus conversion in lung transplantation: A prospective study on safety and medication adherence.

BACKGROUND: Lung transplantation (LTx) requires a calcineurin inhibitor-based immunosuppressive regimen. A once daily (QD) tacrolimus regimen was developed to increase medication adherence. However, data concerning its safety and efficacy in LTx are lacking. METHODS: In this prospective study, stable LTx patients were consecutively converted from twice daily (BID) tacrolimus to QD tacrolimus on a 1 mg:1 mg basis. Trough level (Cmin), renal function, cholesterol, fasting glucose, potassium and lung function were monitored six months before and up to one year after conversion. Adherence and its barriers were assessed by self-reported questionnaires (Basel Assessment of Adherence to Immunosuppressive Medications Scale (BAASIS) and Identification of Medication Adherence Barriers questionnaire (IMAB)) and blood-based assays (mean Cmin and coefficient of variation (CV)). RESULTS: We included 372 patients, in whom we observed a decrease in tacrolimus Cmin of 18.5% (p < 0.0001) post-conversion, requiring subsequent daily dose adaptations in both cystic fibrosis (CF) (n = 72) and non-CF patients (n = 300). We observed a small decrease in eGFR one year post-conversion (p = 0.024). No significant changes in blood creatinine, potassium, fasting glucose, cholesterol or rate of lung function decline were observed. In a subgroup of 166 patients, significantly fewer patients missed doses (8.4% vs. 19.3%, p = 0.016) or had irregular intake post-conversion (19.3% vs. 32.5%, p = 0.019). Mean Cmin and CV, as well as the total number of barriers, also decreased significantly post-conversion. CONCLUSIONS: In LTx, conversion from BID to QD tacrolimus (1 mg:1 mg) requires close monitoring of tacrolimus Cmin. QD tacrolimus after transplantation is safe with respect to renal function, metabolic parameters and allograft function and improves LTx recipient adherence.

Distinct Airway Involvement in Subtypes of End-Stage Fibrotic Pulmonary Sarcoidosis.

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.

Diagnostic Yield of 18F-FDG PET After Lung Transplantation: A Single-center, Retrospective Cohort Study.

BACKGROUND: To investigate the diagnostic yield of 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET) in lung transplant recipients. METHODS: A single-center, retrospective cohort study including 234 18F-FDG PET examinations in 199 lung transplant recipients. Indication for PET referral, 18F-FDG PET diagnosis/findings and final clinical diagnosis were classified into 3 groups: malignancy, infection/inflammation not otherwise specified, and chronic lung allograft dysfunction with restrictive allograft syndrome phenotype. Sensitivity/specificity analysis was performed to determine accuracy of 18F-FDG PET in each group. RESULTS: Sensitivity of 18F-FDG PET for malignancy was 91.4% (95% confidence interval, 82.5%-96.0%) and specificity was 82.3% (95% confidence interval, 74.5%-88.1%). Infection/inflammation not otherwise specified and restrictive allograft syndrome as indication for 18F-FDG PET comprised relatively small groups (14 and 31 cases, respectively). In addition, 18F-FDG PET revealed clinically relevant incidental findings in 15% of cases. CONCLUSIONS: Referral for 18F-FDG PET after lung transplantation mainly occurred to confirm or rule out malignancy. In this specific setting, 18F-FDG PET has a high diagnostic yield. Accuracy of 18F-FDG PET for other indications is less clear, given small sample sizes. Clinically relevant diagnoses, unrelated to the primary indication for 18F-FDG PET, are found relatively often in this immunocompromised cohort.

Case Report: An Unusual Course of Angiosarcoma After Lung Transplantation.

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. Donor-transmitted 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.

Small airway loss in the physiologically ageing lung: a cross-sectional study in unused donor lungs.

BACKGROUND: Physiological lung ageing is associated with a gradual decline in dynamic lung volumes and a progressive increase in residual volume due to diminished elastic recoil of the lung, loss of alveolar tissue, and lower chest wall compliance. However, the effects of ageing on the small airways (ie, airways <2·0 mm in diameter) remain largely unknown. By using a combination of ex-vivo conventional CT (resolution 1 mm), whole lung micro-CT (resolution 150 µm), and micro-CT of extracted cores (resolution 10 µm), we aimed to provide a multiresolution assessment of the small airways in lung ageing in a large cohort of never smokers. METHODS: For this cross-sectional study, we included donor lungs collected from 32 deceased never-smoking donors (age range 16-83 years). Ex-vivo CT and whole lung high-resolution CT (micro-CT) were used to determine total airway numbers, stratified by airway diameter. Micro-CT was used to assess the number, length, and diameter of terminal bronchioles (ie, the last generation of conducting airways); mean linear intercept; and surface density in four lung tissue cores from each lung, extracted using a uniform sampling approach. Regression ß coefficients are calculated using linear regression and polynomial models. FINDINGS: Ex-vivo CT analysis showed an age-dependent decrease in the number of airways of diameter 2·0 mm to less than 2·5 mm (ß coefficient per decade -0·119, 95% CI -0·193 to -0·045; R2=0·29) and especially in airways smaller than 2·0 mm in diameter (-0·158, -0·233 to -0·084; R2=0·47), between 30 and 80 years of age, but not of the larger (≥2·5 mm) diameter airways (-0·00781, -0·04409 to 0·02848; R2=0·0007). In micro-CT analysis of small airways, the total number of terminal bronchioles per lung increased until the age of 30 years, after which an almost linear decline in the number of terminal bronchioles was observed (ß coefficient per decade -2035, 95% CI -2818 to -1252; R2=0·55), accompanied by a non-significant increase in alveolar airspace size (6·44, -0·57 to 13·45, R2=0·10). Moreover, this decrease in terminal bronchioles was associated with the age-related decline of pulmonary function predicted by healthy reference values. INTERPRETATION: Loss of terminal bronchioles is an important structural component of age-related decline in pulmonary function of healthy, non-smoking individuals. FUNDING: Research Foundation-Flanders, KU Leuven, Parker B Francis Foundation, UGent, Canadian Institutes for Health.

Intracerebral abscess due to Cutibacterium acnes after lung transplantation.

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.

Survival in adult lung transplantation: where are we in 2020?

PURPOSE OF REVIEW: In this article, an overview of the survival after lung transplantation will be given, with a focus on factors affecting outcome and differences in survival determined by underlying disease. RECENT FINDINGS: Lung transplantation is an established treatment modality for patients with various end-stage lung diseases. The most recent International Society for Heart and Lung Transplantation Registry reports a 1 and 5-year survival of 85 and 59%, respectively, for adult lung transplant recipients transplanted since 2010. Over the past decades, significant improvements in patient outcomes have been achieved related to changes in donor selection, organ preservation, perioperative management and better treatment of postoperative complications. However, long-term graft and patient outcomes still lag behind that of other solid organ transplantations. Chronic lung allograft dysfunction (CLAD) a condition which develops in about 50% of recipients 5 year after lung transplantation, remains the major barrier for long-term survival, although development of solid organ cancer is nowadays also an increasing cause of late mortality. SUMMARY: Lung transplantation offers a survival benefit in well chosen patients with end-stage lung diseases. However, CLAD, side effects of immunosuppressive therapy and solid organ cancer remain important challenges impairing long-term survival. Advances in prevention and treatment of chronic rejection are critical to further improve outcome.

Early protein expression profile in bronchoalveolar lavage fluid and clinical outcomes in primary graft dysfunction after lung transplantation.

OBJECTIVES: Primary graft dysfunction (PGD) remains a major post-transplant complication and is associated with increased morbidity and mortality. Mechanisms evoking PGD are not completely clear, but inflammation plays a central role. We investigated the association between PGD and inflammatory proteins present in immediate postoperative bronchoalveolar lavage. METHODS: All double-lung recipients transplanted at our institution from 2002 to 2018 were included in our study. We retrospectively selected 80 consecutive lung transplant recipients with different PGD grades (n = 20 for each PGD grades 0-1 to 2-3). In bronchoalveolar lavage performed within the first 24 h after donor aortic cross-clamping following lung transplantation, concentrations of 30 cytokines, chemokines and growth factors were assessed by enzyme-linked immunosorbent assay (ELISA) and correlated with donor and recipient demographics and outcomes. For analysis, 2 groups were defined: 'mild' PGD (grade 0-1) and 'severe' PGD (grades 2-3). RESULTS: Significant differences between mild and severe PGD were found in 8 biomarkers [interleukin (IL)-6, IL-10, IL-13, eotaxin, granulocyte colony-stimulating factor, interferon γ, macrophage inflammatory protein 1α, surfactant protein D (SP-D); P < 0.05]. Increased IL-10 and IL-13, but none of the other proteins, were associated with short-term outcome (longer time to extubation; P = 0.005 and P < 0.0001; increased intensive care unit stay; P = 0.012 and P < 0.0001; and hospital stay; P = 0.041 and P = 0.002). There were no significant differences in donor and recipient characteristics between the groups. CONCLUSIONS: Expression profiles of key inflammatory mediators in bronchoalveolar lavage fluid differed significantly between lung transplant recipients with severe versus mild PGD and correlated with clinical outcome variables. Further research should focus on the early mechanisms leading to PGD.

Small airways pathology in idiopathic pulmonary fibrosis: a retrospective cohort study.

BACKGROUND: The observation that patients with idiopathic pulmonary fibrosis (IPF) can have higher than normal expiratory flow rates at low lung volumes led to the conclusion that the airways are spared in IPF. This study aimed to re-examine the hypothesis that airways are spared in IPF using a multiresolution imaging protocol that combines multidetector CT (MDCT), with micro-CT and histology. METHODS: This was a retrospective cohort study comparing explanted lungs from patients with severe IPF treated by lung transplantation with a cohort of unused donor (control) lungs. The donor control lungs had no known lung disease, comorbidities, or structural lung injury, and were deemed appropriate for transplantation on review of the clinical files. The diagnosis of IPF in the lungs from patients was established by a multidisciplinary consensus committee according to existing guidelines, and was confirmed by video-assisted thoracic surgical biopsy or by pathological examination of the contralateral lung. The control and IPF groups were matched for age, sex, height, and bodyweight. Samples of lung tissue were compared using the multiresolution imaging approach: a cascade of clinical MDCT, micro-CT, and histological imaging. We did two experiments: in experiment 1, all the lungs were randomly sampled; in experiment 2, samples were selected from regions of minimal and established fibrosis. The patients and donors were recruited from the Katholieke Universiteit Leuven (Leuven, Belgium) and the University of Pennsylvania Hospital (Philadelphia, PA, USA). The study took place at the Katholieke Universiteit Leuven, and the University of British Columbia (Vancouver, BC, Canada). FINDINGS: Between Oct 5, 2009, and July 22, 2016, explanted lungs from patients with severe IPF (n=11), were compared with a cohort of unused donor (control) lungs (n=10), providing 240 samples of lung tissue for comparison using the multiresolution imaging approach. The MDCT specimen scans show that the number of visible airways located between the ninth generation (control 69 [SD 22] versus patients with IPF 105 [33], p=0·0023) and 14th generation (control 9 [6] versus patients with IPF 49 [28], p<0·0001) of airway branching are increased in patients with IPF, which we show by micro-CT is due to thickening of their walls and distortion of their lumens. The micro-CT analysis showed that compared with healthy (control) lung anatomy (mean 5·6 terminal bronchioles per mL [SD 1·6]), minimal fibrosis in IPF tissue was associated with a 57% loss of the terminal bronchioles (mean 2·4 terminal bronchioles per mL [SD 1·0]; p<0·0001), the appearance of fibroblastic foci, and infiltration of the tissue by inflammatory immune cells capable of forming lymphoid follicles. Established fibrosis in IPF tissue had a similar reduction (66%) in the number of terminal bronchioles (mean 1·9 terminal bronchioles per mL [SD 1·4]; p<0·0001) and was dominated by increased airspace size, Ashcroft fibrosis score, and volume fractions of tissue and collagen. INTERPRETATION: Small airways disease is a feature of IPF, with significant loss of terminal bronchioles occuring within regions of minimal fibrosis. On the basis of these findings, we postulate that the small airways could become a potential therapeutic target in IPF. FUNDING: Katholieke Universiteit Leuven, US National Institutes of Health, BC Lung Association, and Genentech.

Histopathologic and radiologic assessment of nontransplanted donor lungs.

Donor organ shortage results in significant waiting list mortality. Donor lung assessment is currently based on donors' history, gas exchange, chest X-ray, bronchoscopy findings, and ultimately in situ inspection but remains subjective. We correlated histopathology and radiology in nontransplanted donor lungs with the clinical indications to decline the offered organ. Sixty-two donor lungs, not used for transplantation (2010-2019), were procured, air-inflated, frozen, scanned with computed tomography, systematically sampled, and histologically and radiologically assessed. Thirty-nine (63%) lungs were declined for allograft-related reasons. In 13/39 (33%) lungs, histology could not confirm the reason for decline, in an additional 8/39 (21%) lungs, histologic abnormalities were only considered mild. In 16/39 (41%) lungs, radiology could not confirm the reason for decline. Twenty-three (37%) donor lungs were not transplanted due to extrapulmonary causes, of which three (13%) lungs displayed severe histologic abnormalities (pneumonia, n = 2; emphysema, n = 1), in addition to mild emphysema in 9 (39%) lungs and minor bronchopneumonia in 1 (4%). Radiology revealed ground-glass opacities in 8/23 (35%) and emphysema in 4/23 (17%) lungs. Histopathologic and radiologic assessment of nontransplanted donor lungs revealed substantial discrepancy with the clinical reason for decline. Optimization of donor lung assessment is necessary to improve current organ acceptance rates.