Idiopathic Pulmonary Fibrosis Is Associated with Common Genetic Variants and Limited Rare Variants.

Rationale: Idiopathic pulmonary fibrosis (IPF) is a rare, irreversible, and progressive disease of the lungs. Common genetic variants, in addition to nongenetic factors, have been consistently associated with IPF. Rare variants identified by candidate gene, family-based, and exome studies have also been reported to associate with IPF. However, the extent to which rare variants, genome-wide, may contribute to the risk of IPF remains unknown. Objectives: We used whole-genome sequencing to investigate the role of rare variants, genome-wide, on IPF risk. Methods: As part of the Trans-Omics for Precision Medicine Program, we sequenced 2,180 cases of IPF. Association testing focused on the aggregated effect of rare variants (minor allele frequency ⩽0.01) within genes or regions. We also identified individual rare variants that are influential within genes and estimated the heritability of IPF on the basis of rare and common variants. Measurements and Main Results: Rare variants in both TERT and RTEL1 were significantly associated with IPF. A single rare variant in each of the TERT and RTEL1 genes was found to consistently influence the aggregated test statistics. There was no significant evidence of association with other previously reported rare variants. The SNP heritability of IPF was estimated to be 32% (SE = 3%). Conclusions: Rare variants within the TERT and RTEL1 genes and well-established common variants have the largest contribution to IPF risk overall. Efforts in risk profiling or the development of therapies for IPF that focus on TERT, RTEL1, common variants, and environmental risk factors are likely to have the largest impact on this complex disease.

Meta-Analysis on Utility of Bronchoscopy in Addition to Computed Tomography Thorax in the Investigation of Lung Cancer in Patients with Haemoptysis.

BACKGROUND: In patients with haemoptysis, many healthcare systems support bronchoscopy regardless of computed tomography (CT) findings. OBJECTIVE: This meta-analysis aimed to address whether a normal CT alone is sufficient to out-rule lung cancer in patients with haemoptysis. METHODS: A search was performed of the following databases: EBSCO (Medline), PubMed, Academic Search Complete, CINAHL, Cochrane Library, and Embase. Meta-Disc 1.4 and RevMan software were used to test for heterogeneity, risk of bias, and to summarize the test performance characteristics using forest plots and summary receiver operating characteristic (SROC) curves. SPSS was used to compare the diagnostic accuracy of CT and bronchoscopy. RESULTS: A total of 14 studies (2,960 patients) were included. The pooled sensitivities for detection of lung cancer using CT scan and bronchoscopy were 0.99 (95% CI: 0.97-1.00) and 0.84 (95% CI: 0.78-0.88), respectively. The sensitivity of CT was higher than that of bronchoscopy (p < 0.001). The pooled specificities for CT scan and bronchoscopy were 0.99 (95% CI: 0.99-1.00) and 1.00 (95% CI: 0.99-1.00), respectively. Of 2,960 patients, 257 had lung cancer (8.7%) at initial investigation. 254 of these had a CT thorax, and the CT scan was false negative in 4/255 (1.6%), with bronchoscopy only identifying one cancer with a normal CT (0.4%). CONCLUSION: CT scan showed a higher diagnostic accuracy than bronchoscopy. This study indicated that bronchoscopy offers an insignificant additional value in the investigation of lung cancer in patients with haemoptysis and a negative CT scan.

Single-Use or Disposable Flexible Bronchoscopy in Advanced Bronchoscopy Procedures: Experience in a Quaternary Referral Centre.

BACKGROUND: The development of single-use flexible or disposable bronchoscopes (SUFBs) has accelerated in recent years, with the reduced risk of infectious transmission and reduced need for endoscopy staffing particularly advantageous in the COVID-19 pandemic era. OBJECTIVE: The objective of this study was to assess the performance of a novel single-use bronchoscope in an academic quaternary referral centre with on-site interventional pulmonology programme. METHODS: With ethical approval in a quaternary referral centre, we prospectively collected data on sequential bronchoscopy procedures using The Surgical Company Broncoflex© range of SUFBs. Data collected included demographic, procedural, scope performance, user satisfaction, and complication parameters in a tertiary bronchoscopy service. RESULTS: 139 procedures were performed by five pulmonology faculty from January to July 2021. The majority were carried out for infection (45%) and malignancy (32%). Most were performed in the endoscopy suite and 8% were COVID positive or suspected. Most procedures reported the highest score in satisfaction (85%) with technical limitations reported in 15% (predominately related to scope suction or inadequate image quality) reverting to a reusable scope in 2.8 %. CONCLUSION: In our subset of patients in a bronchoscopy unit, SUFBs are safe, and both routine and advanced bronchoscopy procedures can be performed with high satisfaction reported.

Endobronchial Balloon Blockers: A Retrospective Analysis of Their Implementation for Use in Transbronchial Cryobiopsy Under Conscious Sedation.

INTRODUCTION: Transbronchial lung cryobiopsy (TBLC) is a promising technique that is evolving as a standard diagnostic procedure in the diagnosis of interstitial lung disease. However, there are a variety of non-standardised techniques adopted for this procedure. We aim to describe our approach to TBLC with balloon blockade under conscious sedation (CS). METHODS: We performed a retrospective analysis of patients undergoing TBLC using flexible bronchoscopy under CS in our institution over the calendar years 2017-2018; before and after a transition to the use of endobronchial balloon blockers (EBB) in 2017. RESULTS: 25 patients underwent transbronchial cryobiopsy during the study period. Of these; 12 procedures used EBB. EBB subjects had significantly less moderate or severe airway bleeding (8.3% vs 38.5%) despite higher biopsy rates in the EBB group, 2.9 (2-4) vs 2.4 (1-4) in the non-EBB group. No severe airway bleeding occurred in the EBB group. A multidisciplinary meeting (MDM) confirmed diagnosis was achieved in 88% of patients. 10/12 subjects (83%) in the EBB group and 12/13 subjects (92%) in the non-EBB group (p = 0.5). CONCLUSION: Our institution is novel in using EBB as standard during TBLC specifically under CS with flexible bronchoscopy in the bronchoscopy suite. This retrospective analysis demonstrates that EBB enhances the safety profile of performing TBLC under CS and did not appear to impact diagnostic yield or patient safety.

Transbronchial lung cryobiopsy (TBLC) in the diagnosis of interstitial lung disease: experience of first 100 cases performed under conscious sedation with flexible bronchoscope.

BACKGROUND: Diagnosing the aetiology of interstitial lung disease (ILD) may require histology via a surgical lung biopsy (SLB). SLB is associated with significant complications. Transbronchial lung cryobiopsy (TBLC) can provide large, adequate biopsies with fewer complications offering a potential alternative to SLB. AIMS: This study evaluated the safety, diagnostic yield and impact of TBLC on diagnostic certainty in the multidisciplinary diagnosis (MDD) of ILD within routine clinical practice. METHODS: A retrospective study of all TBLC performed in a tertiary institute from March 2014 to December 2016 was performed. Procedures were performed using a flexible bronchoscope and cryoprobe without fluoroscopic guidance. RESULTS: One hundred procedures were performed on 85 patients. A total of 272 cryobiopsies were obtained with a mean biopsy diameter of 5.9 ± 3.2 mm. Ninety-seven percent contained alveolated lung tissue. Diagnosis based against MDD gold standard was confirmed using TBLC in 67.1% of patients and in 72/100 procedures. Three patients proceeded to SLB. The addition of histological information changed the clinic-radiological diagnosis in twelve patients. The most common diagnosis based on clinical-radiologic-pathologic correlation at MDD was idiopathic pulmonary fibrosis (IPF) (51.2%) and hypersensitivity pneumonitis (15.9%). Moderate bleeding occurred in 18% of cases and five patients (5%) developed pneumothorax requiring intervention. Eleven patients required admission, with a mean length of stay of 1.3 ± 0.9 days. CONCLUSION: TBLC aids the diagnosis of ILD in the appropriate patient and may be an acceptable alternative to SLB with fewer complications. Further work on standardizing the procedure is required.

Single-Use (Disposable) Flexible Bronchoscopes: The Future of Bronchoscopy?

The coronavirus disease (COVID-19) pandemic has highlighted the importance of reducing occupational exposure to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The reprocessing procedure for reusable flexible bronchoscopes (RFBs) involves multiple episodes of handling of equipment that has been used during an aerosol-generating procedure and thus is a potential source of transmission. Single-use flexible bronchoscopes (SUFBs) eliminate this source. Additionally, RFBs pose a risk of nosocomial infection transmission between patients with the identification of human proteins, deoxyribonucleic acid (DNA) and pathogenic organisms on fully reprocessed bronchoscopes despite full adherence to the guidelines. Bronchoscopy units have been hugely impacted by the pandemic with restructuring of pre- and post-operative areas, altered patient protocols and the reassessment of air exchange and cleaning procedures. SUFBs can be incorporated into these protocols as a means of improving occupational safety. Most studies on the efficacy of SUFBs have occurred in an anaesthetic setting so it remains to be seen whether they will perform to an acceptable standard in complex respiratory procedures such as transbronchial biopsies and cryotherapy. Here, we outline their potential uses in a respiratory setting, both during and after the current pandemic.

Hyponatremia and hypercalcemia: a study of a large cohort of patients with lung cancer.

BACKGROUND: Hyponatremia and hypercalcemia are reported to be associated with poorer prognosis in lung cancer. Our study assessed the incidence of hyponatremia and hypercalcemia in a recent large cohort of patients diagnosed with lung cancer in an academic institution and correlated incidence with patient and tumour parameters. METHODS: All patients presented at our regional lung cancer multidisciplinary team meeting between January 2011 and December 2016 were included. The incidence of hyponatremia (serum sodium ≤135 mEq/L) and hypercalcemia (serum calcium >2.62 mmol/L), including severity (mild, moderate or severe) was evaluated and stratified by tumour subtype and stage, and correlated with patient parameters. RESULTS: A total of 624 patients (mean age, 67.4 years; 59.3% male) diagnosed with tissue-proven lung cancer were included. Hyponatremia and hypercalcemia were present in 31.6% (n=197) and 7.1% (n=44) at time of diagnosis. Hyponatremia occurred most commonly in patients with small cell lung carcinoma (SCLC) (n=42; 41.2%; P=0.001). Hypercalcemia occurred most commonly in patients with non-small cell lung carcinoma (NSCLC) squamous subtype (n=27; 12.2%; P=0.003). The incidence of hyponatremia and hypercalcemia were significantly higher in the advanced stages (P<0.041), except in SCLC where no difference in hypercalcemia incidence across the stages was observed (P=0.573). The Eastern Cooperative Oncology Group Performance Status (ECOG-PS) score was positively correlated with severity of hyponatremia at the early stage of NSCLC (Spearman correlation coefficient =0.325; P=0.003). CONCLUSIONS: Hyponatremia is a common association in lung cancer, especially in SCLC. Hypercalcemia is an uncommon but significant association in the NSCLC squamous subtype. Hyponatremia might contribute to poorer ECOG-PS scores at the early stage of NSCLC.

Lung cancer in young patients: tumour characteristics and treatment in an Irish population.

BACKGROUND: Lung cancer is the leading cause of cancer death in both sexes in Ireland. Studies suggest that lung cancer in younger patients has distinct characteristics. The aim of this study is to define the characteristics of lung cancer in patients 55-year-old or younger in an Irish population. METHODS: Data was collected retrospectively from local medical records and the hospital electronic database regarding all patients diagnosed with lung cancer aged 55-year-old and younger, from 2010-2016. Information regarding patient demographics, smoking status, tumour histology, molecular analysis, stage and location, diagnostic modality and initial treatment choice was collected. In all cases the diagnosis of lung cancer was confirmed at the regional lung cancer multidisciplinary team (MDT) meeting. RESULTS: In total, 8% (n=130) of all cases of lung cancer diagnosed from 2010 to 2016 in our center occurred in patients aged 55 years old or younger; 83% (n=108) were 45 to 55-year-old, 15% (n=19) were 35 to 44-year-old and 2% (n=3) were younger than 35-year-old; 88% (n=115) of patients reported a smoking history. There was a female preponderance (58%, n=76), higher rates of NSCLC non-squamous subtype (53%, n=69) and an upper lobe predominance (42%, n=54); 53% (n=68) of patients had IV or extensive disease at presentation. Epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK) and Kirsten rat sarcoma oncogene (KRAS) mutation rates were 9% (n=4) and 3% (n=1) and 80% (n=4) respectively. CONCLUSIONS: Lung cancer in younger patients has distinct characteristics. This study suggests a female preponderance, high smoking rates and a predilection for the upper lobes. Further large-scale multicenter studies are required to verify these results and to clarify the responsible mechanisms.

Peripheral tumour targeting using open-source virtual bronchoscopy with electromagnetic tracking: a multi-user pre-clinical study.

Objectives: The goal was to demonstrate the utility of open-source tracking and visualisation tools in the targeting of lung cancer.Material and methods: The study demonstrates the first deployment of the Anser electromagnetic (EM) tracking system with the CustusX image-guided interventional research platform to navigate using an endobronchial catheter to injected tumour targets. Live animal investigations validated the deployment and targeting of peripheral tumour models using an innovative tumour marking routine.Results: Novel tumour model deployment was successfully achieved at all eight target sites across two live animal investigations without pneumothorax. Virtual bronchoscopy with tracking successfully guided the tracked catheter to 2-12 mm from the target tumour site. Deployment of a novel marker was achieved at all eight sites providing a reliable measure of targeting accuracy. Targeting accuracy within 10 mm was achieved in 7/8 sites and in all cases, the virtual target distance at marker deployment was within the range subsequently measured with x-ray.Conclusions: Endobronchial targeting of peripheral airway targets is feasible using existing open-source technology. Notwithstanding the shortcomings of current commercial platforms, technological improvements in EM tracking and registration accuracy fostered by open-source technology may provide the impetus for widespread clinical uptake of electromagnetic navigation in bronchoscopy.

Bronchoscopy in the investigation of outpatients with hemoptysis at a lung cancer clinic.

BACKGROUND: In the investigation of lung cancer, current practice in many healthcare systems would support bronchoscopy regardless of CT findings in patients with hemoptysis. We sought to identify the cause, the diagnostic yield of CT and bronchoscopy and the requirement for bronchoscopy in at risk patients with hemoptysis with a normal CT scan through our rapid access lung cancer clinic (RALC). METHODS: Initially, a chart review was performed on all patients with hemoptysis (2011-2012) and thereafter a prospective analysis was performed (2013-2016). RESULTS: Our analysis represents the largest study to date in outpatients with hemoptysis. In our retrospective study, 155 patients reported hemoptysis. Causes were lower respiratory tract infections (RTIs) (47%) and lung cancer (16%). Our prospective study included 182 patients. The causes of hemoptysis were RTIs (50%) and lung cancer (18%). There were no false negative CT-scans for lung cancer. 47/57 present with lung cancer underwent bronchoscopy and 43/47 were positive for lung cancer (92%). Patients with hemoptysis and lung cancer have a higher stage of malignancy with a predominance of squamous cell lung carcinoma. Smoking status, the duration of hemoptysis or description of hemoptysis were not predictive of lung cancer however lung cancer was not identified in patients age <50. CONCLUSIONS: One sixth of patients presenting with hemoptysis to our lung cancer clinic had lung cancer. No patient identified with cancer related haemoptysis had a CT negative for lung cancer and a combination of bronchoscopy plus endobronchial ultrasound trans-bronchial needle aspiration (EBUS-TBNA) in those patients with a CT suspicious of lung cancer is 92% sensitive for lung cancer causing hemoptysis.

Automated Catheter Navigation With Electromagnetic Image Guidance.

This paper describes a novel method of controlling an endoscopic catheter by using an automated catheter tensioning system with the objective of providing clinicians with improved manipulation capabilities within the patient. Catheters are used in many clinical procedures to provide access to the cardiopulmonary system. Control of such catheters is performed manually by the clinicians using a handle, typically actuating a single or opposing set of pull wires. Such catheters are generally actuated in a single plane, requiring the clinician to rotate the catheter handle to navigate the system. The automation system described here allows closed-loop control of a custom bronchial catheter in tandem with an electromagnetic tracking of the catheter tip and image guidance by using a 3D Slicer. An electromechanical drive train applies tension to four pull wires to steer the catheter tip, with the applied force constantly monitored through force sensing load cells. The applied tension is controlled through a PC connected joystick. An electromagnetic sensor embedded in the catheter tip enables constant real-time position tracking, whereas a working channel provides a route for endoscopic instruments. The system is demonstrated and tested in both a breathing lung model and a preclinical animal study. Navigation to predefined targets in the subject's airways by using the joystick while using virtual image guidance and electromagnetic tracking was demonstrated. Average targeting times were 29 and 10 s, respectively, for the breathing lung and live animal studies. This paper presents the first reported remote controlled bronchial working channel catheter utilizing electromagnetic tracking and has many implications for future development in endoscopic and catheter-based procedures.

Pre-clinical validation of virtual bronchoscopy using 3D Slicer.

PURPOSE: Lung cancer still represents the leading cause of cancer-related death, and the long-term survival rate remains low. Computed tomography (CT) is currently the most common imaging modality for lung diseases recognition. The purpose of this work was to develop a simple and easily accessible virtual bronchoscopy system to be coupled with a customized electromagnetic (EM) tracking system for navigation in the lung and which requires as little user interaction as possible, while maintaining high usability. METHODS: The proposed method has been implemented as an extension to the open-source platform, 3D Slicer. It creates a virtual reconstruction of the airways starting from CT images for virtual navigation. It provides tools for pre-procedural planning and virtual navigation, and it has been optimized for use in combination with a [Formula: see text] of freedom EM tracking sensor. Performance of the algorithm has been evaluated in ex vivo and in vivo testing. RESULTS: During ex vivo testing, nine volunteer physicians tested the implemented algorithm to navigate three separate targets placed inside a breathing pig lung model. In general, the system proved easy to use and accurate in replicating the clinical setting and seemed to help choose the correct path without any previous experience or image analysis. Two separate animal studies confirmed technical feasibility and usability of the system. CONCLUSIONS: This work describes an easily accessible virtual bronchoscopy system for navigation in the lung. The system provides the user with a complete set of tools that facilitate navigation towards user-selected regions of interest. Results from ex vivo and in vivo studies showed that the system opens the way for potential future work with virtual navigation for safe and reliable airway disease diagnosis.