Transbronchial lung cryobiopsy under real-time radial EBUS: First report on a novel twist of the classical technique.

Transbronchial lung cryobiopsy (TBLC) is a relatively new technique for obtaining lung biopsies, known for being the least invasive method while offering a high diagnostic yield, a favourable safety profile, and a significant reduction in morbidity, mortality, and hospital stay length compared to surgical lung biopsy. Radial-EBUS (r-EBUS) represent a cornerstone modality for accessing 'invisible' peripheral pulmonary lesions. However, a major drawback of these techniques is the lack of 'real-time' visualization of the biopsy being obtained. In this case report, we present a young woman who was referred to us with a cough, haemoptysis, and a non-resolving lung consolidation. She underwent TBLC under real-time rEBUS guidance. This clinical case demonstrates that, in specific clinical scenarios, TBLC with real-time rEBUS is an excellent diagnostic tool.

Bronchoscopy with and without needle-based confocal laser endomicroscopy for peripheral lung nodule diagnosis: protocol for a multicentre randomised controlled trial (CLEVER trial).

INTRODUCTION: Despite many technological advances, the diagnostic yield of bronchoscopic peripheral lung nodule analysis remains limited due to frequent mispositioning. Needle-based confocal laser endomicroscopy (nCLE) enables real-time microscopic feedback on needle positioning, potentially improving the sampling location and diagnostic yield. Previous studies have defined and validated nCLE criteria for malignancy, airway and lung parenchyma. Larger studies demonstrating the effect of nCLE on diagnostic yield are lacking. We aim to investigate if nCLE-imaging integrated with conventional bronchoscopy results in a higher diagnostic yield compared with conventional bronchoscopy without nCLE. METHODS AND ANALYSIS: This is a parallel-group randomised controlled trial. Recruitment is performed at pulmonology outpatient clinics in universities and general hospitals in six different European countries and one hospital in the USA. Consecutive patients with a for malignancy suspected peripheral lung nodule (10-30 mm) with an indication for diagnostic bronchoscopy will be screened, and 208 patients will be included. Web-based randomisation (1:1) between the two procedures will be performed. The primary outcome is diagnostic yield. Secondary outcomes include diagnostic sensitivity for malignancy, needle repositionings, procedure and fluoroscopy duration, and complications. Pathologists will be blinded to procedure type; patients and endoscopists will not. ETHICS AND DISSEMINATION: Primary approval by the Ethics Committee of the Amsterdam University Medical Center. Dissemination involves publication in a peer-reviewed journal. SUPPORT: Financial and material support from Mauna Kea Technologies. TRIAL REGISTRATION NUMBER: NCT06079970.

Expression of PD-1/PD-L1 axis in mediastinal lymph nodes and lung tissue of human and experimental lung fibrosis indicates a potential therapeutic target for idiopathic pulmonary fibrosis.

BACKGROUND: Mediastinal lymph node enlargement is prevalent in patients with idiopathic pulmonary fibrosis (IPF). Studies investigating whether this phenomenon reflects specific immunologic activation are lacking. METHODS: Programmed cell death-1 (PD-1)/ programmed cell death ligand-1 (PD-L1) expression in mediastinal lymph nodes and lung tissues was analyzed. PD-1, PD-L1 mRNA expression was measured in tracheobronchial lymph nodes of mice following bleomycin-induced injury on day 14. Finally, the effect of the PD-1 inhibitor, pembrolizumab, in bleomycin-induced pulmonary fibrosis was investigated. RESULTS: We analyzed mediastinal lymph nodes of thirty-three patients (n = 33, IPF: n = 14, lung cancer: n = 10, concomitant IPF and lung cancer: n = 9) and lung tissues of two hundred nineteen patients (n = 219, IPF: 123, controls: 96). PD-1 expression was increased, while PD-L1 expression was decreased, in mediastinal lymph nodes of patients with IPF compared to lung cancer and in IPF lungs compared to control lungs. Tracheobronchial lymph nodes isolated on day 14 from bleomycin-treated mice exhibited increased size and higher PD-1, PD-L1 mRNA levels compared to saline-treated animals. Pembrolizumab blunted bleomycin-induced lung fibrosis, as indicated by reduction in Ashcroft score and improvement in respiratory mechanics. CONCLUSIONS: Mediastinal lymph nodes of patients with IPF exhibit differential expression profiles than those of patients with lung cancer indicating distinct immune-mediated pathways regulating fibrogenesis and carcinogenesis. PD-1 expression in mediastinal lymph nodes is in line with lung tissue expression. Lower doses of pembrolizumab might exert antifibrotic effects. Clinical trials aiming to endotype patients based on mediastinal lymph node profiling and accordingly implement targeted therapies such as PD-1 inhibitors are greatly anticipated.

Tracheal resection in patients post-COVID-19 is associated with high reintervention rate and early restenosis.

Objectives: A remarkable increase in the number of patients presenting with tracheal complications after prolonged endotracheal intubation and mechanical ventilation for the management of the severe COVID-19-associated respiratory failure has been observed. In this study, we assessed the postoperative outcomes of tracheal resection in patients with COVID-19. Methods: We conducted a retrospective study in which all patients with a history of prolonged invasive mechanical ventilation due to COVID-19 infection, who were treated with tracheal resection and reconstruction, were included. The primary objective was in-hospital mortality and postoperative reintervention rate. The secondary objective was the time to tracheal restenosis. Results: During the 16-month study period, 11 patients with COVID-19 with tracheal complications underwent tracheal resection with end-to-end anastomosis. Mean patient age was 51.5 ± 9 years, and the majority were male (9 patients). Eight patients were referred for management of postintubation tracheal stenosis, and 3 patients were referred for tracheoesophageal fistula. Eight patients had a history of tracheostomy during the COVID-19 infection hospitalization. There was 1 in-hospital death (9.1%) due to septicemia in the intensive care unit approximately 2 months after the operation. Postoperatively, 32 reinterventions were required for tracheal restenosis due to granulation tissue formation. The risk for reintervention was higher during the first 3 months after the index operation. Four patients developed tracheal restenosis (36.4%), and 2 of them required endotracheal stent placement during the follow-up period. Conclusions: Tracheal resection and reconstruction after COVID-19 infection are associated with a high reintervention rate postoperatively. Such patients require close follow-up in expert interventional pulmonology units, and physicians should be on high alert for the early diagnosis and optimal management of tracheal restenosis.

Statins' still controversial role in pulmonary fibrosis: What does the evidence show?

Pulmonary fibrosis (PF) represents the end stage of a broad range of interstitial lung diseases (ILDs). Statins are among the compounds which have been implicated in drug-induced ILD development. However, recent studies (both in vitro and in vivo) have provided evidence that statins may exert anti-inflammatory and anti-fibrotic effects potentially offering benefits to patients with PF. Several protective molecular mechanisms including the suppression of mevalonic acid pathway, the inhibition of NADPH oxidase activation in macrophages and the inhibition of several profibrotic mediators have been proposed to explain the observed in vivo decrease of the oxidative stress in the lung and the preservation of lung function in patients. Earlier clinical studies relating statins with drug-induced ILD development are contradicted by increasing new data showing the beneficial effects of statins in clinical outcomes in ILD patients who receive statins for concomitant cardiovascular indications. Future research may further elucidate the wide spectrum of pathways of IPF pathogenesis, and genetic heterogeneity, identifying clinically applicable biomarkers and specific endotypes thus recognizing in which patients statins could confer benefit and in which they might cause detrimental effects.

Paucigranulocytic Asthma: Potential Pathogenetic Mechanisms, Clinical Features and Therapeutic Management.

Asthma is a heterogeneous disease usually characterized by chronic airway inflammation, in which several phenotypes have been described, related to the age of onset, symptoms, inflammatory characteristics and treatment response. The identification of the inflammatory phenotype in asthma is very useful, since it allows for both the recognition of the asthmatic triggering factor as well as the optimization of treatment The paucigranulocytic phenotype of asthma (PGA) is characterized by sputum eosinophil levels <1−3% and sputum neutrophil levels < 60%. The precise characteristics and the pathobiology of PGA are not fully understood, and, in some cases, it seems to represent a previous eosinophilic phenotype with a good response to anti-inflammatory treatment. However, many patients with PGA remain uncontrolled and experience asthmatic symptoms and exacerbations, irrespective of the low grade of airway inflammation. This observation leads to the hypothesis that PGA might also be either a special phenotype driven by different kinds of cells, such as macrophages or mast cells, or a non-inflammatory phenotype with a low grade of eosinophilic inflammation. In this review, we aim to describe the special characteristics of PGA and the potential therapeutic interventions that could be offered to these patients.

COVID-19 Patients Presenting with Post-Intubation Upper Airway Complications: A Parallel Epidemic?

During the current pandemic, we witnessed a rise of post-intubation tracheal stenosis (PITS) in patients intubated due to COVID-19. We prospectively analyzed data from patients referred to our institution during the last 18 months for severe symptomatic post-intubation upper airway complications. Interdisciplinary bronchoscopic and/or surgical management was offered. Twenty-three patients with PITS and/or tracheoesophageal fistulae were included. They had undergone 31.85 (±22.7) days of ICU hospitalization and 17.35 (±7.4) days of intubation. Tracheal stenoses were mostly complex, located in the subglottic or mid-tracheal area. A total of 83% of patients had fracture and distortion of the tracheal wall. Fifteen patients were initially treated with rigid bronchoscopic modalities and/or stent placement and eight patients with tracheal resection-anastomosis. Post-treatment relapse in two of the bronchoscopically treated patients required surgery, while two of the surgically treated patients required rigid bronchoscopy and stent placement. Transient, non-life-threatening post-treatment complications developed in 60% of patients and were all managed successfully. The histopathology of the resected tracheal specimens didn't reveal specific alterations in comparison to pre-COVID-era PITS cases. Prolonged intubation, pronation maneuvers, oversized tubes or cuffs, and patient- or disease-specific factors may be pathogenically implicated. An increase of post-COVID PITS is anticipated. Careful prevention, early detection and effective management of these iatrogenic complications are warranted.

The Value of Dyspnea and Spirometry in Detecting Relapse of Benign Tracheal Stenosis.

BACKGROUND: Benign tracheal stenosis may relapse after management. OBJECTIVES: This study aimed to assess the value of dyspnea and spirometry in detecting relapse of benign tracheal stenosis. METHODS: Patients with benign tracheal stenosis were evaluated post-management, at regular follow-up and emergency visits, with the Medical Research Council (MRC) dyspnea scale, spirometry, and flexible bronchoscopy. Patient visits were categorized and compared, in terms of change in clinical and functional parameters, in 2 groups: visits with relapse (case group) and visits with no relapse (control group). The ability of the MRC dyspnea scale and spirometry to predict relapse was evaluated. RESULTS: Thirty-five patients with benign tracheal stenosis were included. Mean follow-up duration was 3.2 years (standard deviation = 3.3). Spirometry data were analyzed from 43 relapse visits (23 patients) versus 90 nonrelapse visits. The MRC dyspnea score and most spirometric indices were associated with relapse. In the receiver operating characteristic analysis, forced expiratory volume in 1 s, forced expiratory flow when 25% of forced vital capacity has been expired, peak expiratory flow (PEF), and total peak flow were superior to the MRC dyspnea score in predicting relapse. Among spirometric indices, >10.8% of PEF reduction has been very sensitive and specific. CONCLUSIONS: This study supports the role of dyspnea and spirometry in monitoring benign tracheal stenosis, with spirometry predicting relapse even in clinically stable patients. PEF being a very sensitive index has the additional advantage of being assessed by peak flow meter and could potentially be used for remote monitoring.

Epidemiological characteristics and outcomes from 187 patients with COVID-19 admitted to 6 reference centers in Greece: an observational study during the first wave of the COVID-19 pandemic.

INTRODUCTION: Epidemiological data from patients with COVID-19 has been recently published in several countries. Nationwide data of hospitalized patients with COVID-19 in Greece remain scarce. MATERIAL AND METHODS: This was an observational, retrospective study from 6 reference centers between February 26 and May 15, 2020. RESULTS: The patients were mostly males (65.7%) and never smokers (57.2%) of median age 60 (95% CI: 57.6-64) years. The majority of the subjects (98%) were treated with the standard-of-care therapeutic regimen at that time, including hydroxychlo-roquine and azithromycin. Median time of hospitalization was 10 days (95% CI: 10-12). Twenty-five (13.3%) individuals were intubated and 8 died (4.2%). The patients with high neutrophil-to-lymphocyte ratio (NLR) ( > 3.58) exhibited more severe disease as indicated by significantly increased World Health Organization (WHO) R&D ordinal scale (4; 95% CI: 4-4 vs 3; 95% CI: 3-4, p = 0.0001) and MaxFiO2% (50; 95% CI: 38.2-50 vs 29.5; 95% CI: 21-31, p < 0.0001). The patients with increased lactate dehydrogenase (LDH) levels ( > 270 IU/ml) also exhibited more advanced disease compared to the low LDH group ( < 270 IU/ml) as indicated by both WHO R&D ordinal scale (4; 95% CI: 4-4 vs 4; 95% CI: 3-4, p = 0.0001) and MaxFiO2% (50; 95% CI: 35-60 vs 28; 95% CI: 21-31, p < 0.0001). CONCLUSION: We present the first epidemiological report from a low-incidence and mortality COVID-19 country. NLR and LDH may represent reliable disease prognosticators leading to timely treatment decisions.

A 68-year-old man with haemoptysis and extensive ipsilateral lung infiltrates.

Can you diagnose this 68-year-old male with 24-h history of haemoptysis, 5-year history of productive cough and ipsilateral lung infiltrates? https://bit.ly/3tyhANB.

Bronchoscopic management as an alternative treatment in non-operable benign tracheal stenosis.

BACKGROUND: Endoluminal therapy either by dilatation, scar tissue resection or stent insertion is an established treatment for non-malignant airway stenosis although the surgical approach is still considered the "gold standard." No clear consensus exists on the structured role of each modality. AIMS: We aimed to investigate the role of bronchoscopic management in non-operable tracheal stenosis cases, evaluating the effectiveness and safety of each procedure based on a structured algorithmic approach. PATIENTS AND METHODS: This prospective study was carried out on (40) consecutive patients diagnosed between March 2017 and March 2020 with tracheal stenosis not amenable to surgery. All strictures were first evaluated by flexible bronchoscopy and classified as simple or complex. Patients were treated following a standardised therapeutic algorithm approach based on published evidence and our own expertise. RESULTS: The mean age of the study population was 45.25 ± 18.79; lesions were classified as simple (14) and complex (24), while two patients had mixed type stenosis. Long term success rate was 100% in simple stenosis and 87.5% in the complex ones. Stents were deployed in 24 cases, most of which were of the complex type and only two of the simple type. Post-procedural mild to moderate complications were detected overall in 70% of the patients. All complications were non-life threatening, mostly stent-related and were effectively managed. CONCLUSION: We conclude that after accurate classification and a structured algorithmic approach, interventional bronchoscopic management may play a crucial role in the effective treatment of benign tracheal stenosis.

Therapeutic bronchoscopy for central airway diseases.

Over the past century rigid bronchoscopy has been established as the main therapeutic means for central airway diseases of both benign and malignant aetiology. Its use requires general anaesthesia and mechanical ventilation usually in the form of manual or high-frequency jet ventilation. Techniques applied to regain patency of the central airways include mechanical debulking, thermal ablation (laser, electrocautery and argon plasma coagulation) and cryo-surgery. Each of these techniques have their advantages and limitations and best results can be attained by combining different modalities according to the type, location and extent of the airway blockage. If needed, deployment of airway endoprostheses (stents), as either fixed-diameter silicone or self-expandable metal stents, may preserve the airways patency often at the cost of several complications. Newer generation of customised stents either three-dimensional printed or drug-eluting stents constitute a promise for improved safety and efficacy results in the near future. Treating central disease of benign or malignant aetiology, foreign body aspiration or massive bleeding in the airways requires a structured approach with combined techniques, a dedicated team of professionals and experience to treat eventual complications. Specific training and fellowships in interventional pulmonology should therefore be offered to those who wish to specialise in this field.

An International Survey of Mediastinal Staging Practices amongst Interventional Bronchoscopists.

INTRODUCTION: In potentially curable non-small-cell lung cancer, different practice guidelines recommend invasive me-diastinal staging in tumors larger than 3 cm, central, or hy-permetabolic N1 lymph nodes. There is no consensus concerning the use of an endosonographic procedure or a mediastinoscopy in the first line in patients with a radiologically normal mediastinum, while in case of a mediastinal involvement, the latest European guidelines recommend the combination of endobronchial ultrasound (EBUS) and endoscopic ultrasound/endoscopic ultrasound with EBUS endoscope (EUS/EUS-B), using a systematic endosonographic procedure. This international survey was conducted to describe current medical practices in endoscopic mediastinal staging amongst interventional bronchoscopists. METHODS: A survey was developed and sent to all members of different interventional pulmonology societies, with the purpose to describe who, when and how an endoscopic mediastinal staging was performed. RESULTS: One hundred and fifty-three bronchoscopists responded to the survey. Most of them practiced in Europe (n = 84, 55%) and North America (n = 52, 34%). In the first line, EBUS alone was the most widely used endoscopic procedure for mediastinal staging. Half of the responders performed a systematic endoscopic staging procedure, including a systematic examination of all accessible nodal stations and a sampling of all lymph nodes >5 mm in the short axis at each station. A higher proportion of bronchoscopists who have completed a dedicated fellowship program performed systematic endoscopic mediastinal staging. Few endoscopists routinely perform combined EBUS/EUS(-B) for mediastinal staging and use the combination only in selected cases. CONCLUSION: There are several areas of divergence between published guidelines and current practices reported by interventional bronchoscopists. EBUS alone is the most widely used endoscopic procedure for mediastinal staging in lung cancer, and a combined endoscopic approach is frequently omitted by the responders. A fellowship program appears to be associated with a higher rate of systematic endoscopic staging procedures.

Localized Bronchial Hyperemia in Cases of Iatrogenic Hemoptysis: Clinical Presentations and Pathophysiological Mechanisms.

Hemoptysis is a frequently encountered symptom in many clinical settings, and etiologic diagnosis can sometimes prove challenging. Bronchoscopy may not promptly reveal the source or the cause of bleeding and few reports have focused so far on the abnormalities of bronchial mucosa vasculature that may unveil the underlying pathophysiology. In this special feature article, we present a series of cases presenting with hemoptysis after angiographic interventions in the thoracic vessels. Localized hyperemia and vascular dilatations in the bronchial mucosa observed during bronchoscopy as unique findings became clues enabling the correct diagnosis and management. We suggest the relevant pathophysiological mechanisms and discuss the available published experience on similar clinical entities.

Postpneumonectomy-like syndrome due to bronchial carcinoid: a unique case report.

BACKGROUND: Postpneumonectomy-like syndrome is a rare condition resulting from unilateral lung disease with severe lung volume loss leading to excessive mediastinal shift and herniation of the healthy lung into the contralateral hemithorax, mimicking the mediastinal shift observed in postpneumonectomy syndrome after pneumonectomy. We report a unique case of postpneumonectomy-like syndrome caused by an atypical bronchial carcinoid completely occluding the left main bronchus. CASE PRESENTATION: A 25-year-old woman presented with symptoms of chronic exertional dyspnea and productive cough. Imaging studies showed complete left lung atelectasis due to a mass occluding the left main bronchus, as well as extreme mediastinal deviation and substantial herniation of the right lung into the left hemithorax. Bronchoscopic biopsy of the tumor and subsequent left pneumonectomy with concurrent lymph node dissection revealed an atypical carcinoid. Sixteen months after surgery the patient has been asymptomatic with repeat imaging studies showing no change in mediastinal shifting. CONCLUSION: Bronchial carcinoids are notorious for causing bronchial obstruction. The present case represents an extreme complication of centrally located bronchial carcinoid, resulting in postpneumonectomy-like syndrome with severe mediastinal shift and herniation of the healthy lung into the diseased hemithorax.

Lobectomy due to Pulmonary Vein Occlusion after Radiofrequency Ablation for Atrial Fibrillation.

Radiofrequency ablation is an effective treatment for atrial fibrillation. Pulmonary vein stenosis/occlusion is one of its rare complications. Herein, the case of a 50-year-old man with hemoptysis and migratory pulmonary infiltrations after transcatheter radiofrequency ablation for atrial fibrillation is presented. Initially, pneumonia, interstitial pulmonary disease, or lung cancer was suspected, but wedge resection revealed hemorrhagic infiltrations. Chest computed tomography pulmonary angiography detected no left superior pulmonary vein due to its total occlusion, and left upper lobectomy was performed. Post-ablation pulmonary vein occlusion must be strongly suspected in cases of migratory pulmonary infiltrations and/or hemoptysis.

Current Practice of Airway Stenting in the Adult Population in Europe: A Survey of the European Association of Bronchology and Interventional Pulmonology (EABIP).

BACKGROUND: Airway stenting (AS) commenced in Europe circa 1987 with the first placement of a dedicated silicone airway stent. Subsequently, over the last 3 decades, AS was spread throughout Europe, using different insertion techniques and different types of stents. OBJECTIVES: This study is an international survey conducted by the European Association of Bronchology and Interventional Pulmonology (EABIP) focusing on AS practice within 26 European countries. METHODS: A questionnaire was sent to all EABIP National Delegates in February 2015. National delegates were responsible for obtaining precise and objective data regarding the current AS practice in their country. The deadline for data collection was February 2016. RESULTS: France, Germany, and the UK are the 3 leading countries in terms of number of centres performing AS. These 3 nations represent the highest ranked nations within Europe in terms of gross national income. Overall, pulmonologists perform AS exclusively in 5 countries and predominately in 12. AS is performed almost exclusively in public hospitals. AS performed under general anaesthesia is the rule for the majority of institutions, and local anaesthesia is an alternative in 9 countries. Rigid bronchoscopy techniques are predominant in 20 countries. Amongst commercially available stents, both Dumon and Ultraflex are by far the most commonly deployed. Finally, 11 countries reported that AS is an economically viable activity, while 10 claimed that it is not. CONCLUSION: This EABIP survey demonstrates that there is significant heterogeneity in AS practice within Europe. Therapeutic bronchoscopy training and economic issues/reimbursement for procedures are likely to be the primary reasons explaining these findings.

Safety and efficacy of pirfenidone in severe Idiopathic Pulmonary Fibrosis: A real-world observational study.

BACKGROUND: Pirfenidone is a novel anti-fibrotic drug that has shown efficacy in five randomized multicenter clinical trials enrolling patients with Idiopathic Pulmonary Fibrosis of mild-to-moderate disease severity. Scarce data supports the use of pirfenidone in IPF patients with more advanced disease. OBJECTIVE: To investigate the safety and efficacy profile of pirfenidone in IPF patients with severe lung function impairment. PATIENTS AND METHODS: This was a retrospective study enrolling patients with advanced IPF (FVC%predicted < 50% and/or (DLco%predicted <35%) receiving pirfenidone for at least 6 months. RESULTS: Between September 2011 and March 2013, we identified 43 patients with severe IPF (baseline meanFVC%predicted±SD: 63.8 ± 20.3, meanDLCO%predicted: 27.3 ± 8.2), of mean age±SD: 66.3 + 9.7, 34 males (81%) that received pirfenidone (2.403 mg/daily) for one year. Pirfenidone treatment was associated with a trend towards decrease in functional decline compared to 6-months before treatment initiation but failed to show any benefit after one year of treatment (ΔFVC: -3.3 ± 4.6 vs 0.49 ± 11.4 and vs. -5.8 ± 11.8, p = 0.06 and p = 0.04, respectively and ΔDLCO: -13.3 ± 15.2 vs. -10.1 ± 16.6 and vs. 28.3 ± 19.2, p = 0.39 and p = 0.002, respectively). Gastrointestinal disorders (34.9%), fatigue (23.2%) and photosensitivity (18.6%) were the most common adverse events. Adverse events led to treatment discontinuation in 9 patients (20.9%) and dose reduction in 14 (32.5%). CONCLUSION: Pirfenidone appears to be safe when administered in patients with advanced IPF. Pirfenidone efficacy in IPF patients with severe lung function impairment may diminish after 6 months of treatment.