Radial Endobronchial Ultrasound and Electromagnetic Navigation Bronchoscopy with Fluoroscopy for the Diagnosis of Peripheral Lung Lesions.

Diagnosing lung cancer using a flexible bronchoscope is a safe procedure with a very low risk of complications. Bronchoscopy has high diagnostic accuracy for endobronchial lesions, but it falls short when sampling peripheral lesions. Therefore, several modalities have been invented to guide the bronchoscope to the lesion and confirm the location of the tumor before tissue sampling. Fluoroscopy is used during bronchoscopy to provide a 2D X-ray image of the thorax during the procedure. The bronchoscope and tools will be visible, as well as lesions if larger than 2.0-2.5 cm. Radial endobronchial ultrasound (rEBUS) consists of an ultrasound probe, small enough to be inserted into the working channel of the bronchoscope. The ultrasound probe is used to differentiate between consolidated tissue, such as tumor tissue, and normal air-filled lung parenchyma. Electromagnetic navigation bronchoscopy (ENB) creates a 3D model of the bronchial tree from computed tomography (CT) scans of the patient. Prior to the bronchoscopy, a route from the trachea to the lesion is planned, to create real-time guidance of the bronchoscope to the lesion during the procedure, similar to the Global Positioning System. The aim of this article is to describe a stepwise approach to performing bronchoscopy with rEBUS and fluoroscopy, bronchoscopy with ENB, rEBUS, and fluoroscopy. In the discussion section, the pros and cons of each modality will be discussed.

Airway hyperresponsiveness reflects corticosteroid-sensitive mast cell involvement across asthma phenotypes.

BACKGROUND: Airway hyperresponsiveness is a hallmark of asthma across asthma phenotypes. Airway hyperresponsiveness to mannitol specifically relates to mast cell infiltration of the airways, suggesting inhaled corticosteroids to be effective in reducing the response to mannitol, despite low levels of type 2 inflammation. OBJECTIVE: We sought to investigate the relationship between airway hyperresponsiveness and infiltrating mast cells, and the response to inhaled corticosteroid treatment. METHODS: In 50 corticosteroid-free patients with airway hyperresponsiveness to mannitol, mucosal cryobiopsies were obtained before and after 6 weeks of daily treatment with 1600 µg of budesonide. Patients were stratified according to baseline fractional exhaled nitric oxide (Feno) with a cutoff of 25 parts per billion. RESULTS: Airway hyperresponsiveness was comparable at baseline and improved equally with treatment in both patients with Feno-high and Feno-low asthma: doubling dose, 3.98 (95% CI, 2.49-6.38; P < .001) and 3.85 (95% CI, 2.51-5.91; P < .001), respectively. However, phenotypes and distribution of mast cells differed between the 2 groups. In patients with Feno-high asthma, airway hyperresponsiveness correlated with the density of chymase-high mast cells infiltrating the epithelial layer (ρ, -0.42; P = .04), and in those with Feno-low asthma, it correlated with the density in the airway smooth muscle (ρ, -0.51; P = .02). The improvement in airway hyperresponsiveness after inhaled corticosteroid treatment correlated with a reduction in mast cells, as well as in airway thymic stromal lymphopoietin and IL-33. CONCLUSIONS: Airway hyperresponsiveness to mannitol is related to mast cell infiltration across asthma phenotypes, correlating with epithelial mast cells in patients with Feno-high asthma and with airway smooth muscle mast cells in patients with Feno-low asthma. Treatment with inhaled corticosteroids was effective in reducing airway hyperresponsiveness in both groups.

Allergen Immunotherapy Enhances Airway Epithelial Antiviral Immunity in Patients with Allergic Asthma (VITAL Study): A Double-Blind Randomized Controlled Trial.

Rationale: Allergic asthma is linked to impaired bronchial epithelial secretion of IFNs, which may be causally linked to the increased risk of viral exacerbations. We have previously shown that allergen immunotherapy (AIT) effectively reduces asthma exacerbations and prevents respiratory infections requiring antibiotics; however, whether AIT alters antiviral immunity is still unknown. Objectives: To investigate the effect of house dust mite sublingual AIT (HDM-SLIT) on bronchial epithelial antiviral and inflammatory responses in patients with allergic asthma. Methods: In this double-blind, randomized controlled trial (VITAL [The Effect of Allergen Immunotherapy on Anti-viral Immunity in Patients with Allergic Asthma]), adult patients with HDM allergic asthma received HDM-SLIT 12-SQ or placebo for 24 weeks. Bronchoscopy was performed at baseline and at Week 24, which included sampling for human bronchial epithelial cells. Human bronchial epithelial cells were cultured at baseline and at Week 24 and stimulated with the viral mimic polyinosinic:polycytidylic acid (poly(I:C)). mRNA expression was quantified using qRT-PCR, and protein concentrations were measured using multiplex ELISA. Measurements and Main Results: Thirty-nine patients were randomized to HDM-SLIT (n = 20) or placebo (n = 19). HDM-SLIT resulted in increased polyinosinic:polycytidylic acid-induced expression of IFN-ß at both the gene (P = 0.009) and protein (P = 0.02) levels. IFN-λ gene expression was also increased (P = 0.03), whereas IL-33 tended to be decreased (P = 0.09). On the other hand, proinflammatory cytokines IL-6 (P = 0.009) and TNF-α (tumor necrosis factor-α) (P = 0.08) increased compared with baseline in the HDM-SLIT group. There were no significant changes in TSLP (thymic stromal lymphopoietin), IL-4, IL-13, and IL-10. Conclusions: HDM-SLIT improves bronchial epithelial antiviral resistance to viral infection. These results potentially explain the efficacy of HDM-SLIT in reducing exacerbations in allergic asthma. Clinical trial registered with www.clinicaltrials.gov (NCT04100902).

When Pulmonologists Are Novice to Navigational Bronchoscopy, What Predicts Diagnostic Yield?

Predicting factors of diagnostic yield in electromagnetic navigation bronchoscopy (ENB) have been explored in a number of previous studies based on data from experienced operators. However, little is known about predicting factors when the procedure is carried out by operators in the beginning of their learning curve. We here aim to identify the role of operators' experience as well as lesion- and procedure characteristics on diagnostic yield of ENB procedures in the hands of novice ENB operators. Four operators from three centers without prior ENB experience were enrolled. The outcome of consecutive ENB procedures was assessed and classified as either diagnostic or non-diagnostic and predicting factors of diagnostic yield were assessed. A total of 215 procedures were assessed. A total of 122 (57%) of the ENB procedures resulted in diagnostic biopsies. Diagnostic ENB procedures were associated with a minor yet significant difference in tumor size compared to non-diagnostic/inconclusive ENB procedures (28 mm vs. 24 mm; p = 0.03). Diagnostic ENB procedures were associated with visible lesions at either fluoroscopy (p = 0.003) or radial endobronchial ultrasound (rEBUS), (p = 0.001). In the logistic regression model, lesion visibility on fluoroscopy, but none of operator experience, the presence of a bronchus sign, lesion size, or location nor visibility on rEBUS significantly impacted the diagnostic yield. In novice ENB operators, lesion visibility on fluoroscopy was the only factor found to increase the chance of obtaining a diagnostic sample.

Mucosal cryobiopsies: a new method for studying airway pathology in asthma.

Background: In vivo studies of airway pathology in obstructive lung disease are limited by poor quality of specimens obtained with forceps. Obtainment of cryobiopsies has increased diagnostic yield in cancer and interstitial lung disease but has not been used in patients with asthma. In a recent pilot study, we found mucosal cryobiopsies to be larger and more intact than conventional forceps biopsies. The aim of the present study was to compare quality and safety of mucosal cryobiopsies versus conventional forceps biopsies in patients with asthma. Methods: Endobronchial biopsies were obtained with forceps and cryoprobe from patients with asthma not currently treated with inhaled steroids and evaluated histologically. Results: A total of 240 cryobiopsies and 288 forceps biopsies were obtained from 48 patients. Bleeding from the biopsy site was common but self-limiting. No major complications related to the procedure were seen. Cryobiopsy cross areas were four times larger compared with forceps. Stretches of intact epithelium were detected in all cryobiopsies compared to 33% in forceps biopsies. Further, the length of intact epithelium was on average four times longer in the cryobiopsies. Importantly, there was a good preservation of both antigens and mRNA in the cryobiopsies ensuring a suitability and robustness for immunohistochemistry and in situ hybridisation. Conclusion: Obtainment of mucosal cryobiopsies in patients with asthma is safe and yields biopsies that are significantly larger and morphologically better preserved compared with traditional forceps biopsies. The cryotechnique thus seems to be a promising tool for future in vivo studies of airway pathology.

Learning Curves for Electromagnetic Navigation Bronchoscopy Using CUSUM Analysis.

BACKGROUND: Electromagnetic navigation bronchoscopy (ENB) is a relatively new and technically demanding procedure for the guidance of bronchoscopic biopsy to help locate small lung lesions. The results in experienced hands are well described. However, we do not know the results in unexperienced hands-in other words, we have no knowledge about how fast you can learn the procedure. AIM: The aim of this study was to draw learning curves for beginners in ENB using Cumulated Sum (CUSUM) analysis, a method for quantitative evaluation of the learning curves for clinical procedures. METHODS: Four operators from 3 centers without prior ENB experience were enrolled. The outcome of consecutive ENB procedures was assessed and classified as either diagnostic or nondiagnostic based on sample adequacy. Learning curves were drawn based on diagnostic yield. RESULTS: A total of 215 procedures were assessed. For 2 of the operators (operators 1 and 4), at least 25 to 30 procedures were necessary to obtain competency whereas operators 2 and 3 showed more horizontal learning curves indicating an overweight of diagnostic procedures from the beginning. CONCLUSION: Operators achieve competences in ENB at different paces. This must be taken in account when beginners start to learn the procedure. There is a huge need for a structured educational program and a validated test to determine competences.

Bronchoscopic mucosal cryobiopsies as a method for studying airway disease.

BACKGROUND: Investigating disease mechanisms and treatment responses in obstructive airway diseases with invasive sampling are hampered by the small size and mechanical artefacts that conventional forceps biopsies suffer from. Endoscopic cryobiopsies are larger and more intact and are being increasingly used. However, the technique has not yet been explored for obtaining mucosa biopsies. OBJECTIVE: To investigate differences in size and quality of endobronchial mucosal biopsies obtained with cryotechnique and forceps. Further, to check for eligibility of cryobiopsies to be evaluated with immunohistochemistry and in situ hybridization and to investigate tolerability and safety of the technique. METHODS: Endobronchial mucosal biopsies were obtained with cryotechnique and forceps from patients with haemoptysis undergoing bronchoscopy and evaluated by quantitative morphometry, automated immunohistochemistry and in situ hybridization. RESULTS: A total of 40 biopsies were obtained from 10 patients. Cross-sectional areas were threefold larger in cryobiopsies (median: 3.08 mm2 (IQR: 1.79) vs 1.03 mm2 (IQR: 1.10), P < 0.001). Stretches of intact epithelium were 8-fold longer (median: 4.61 mm (IQR: 4.50) vs 0.55 mm (IQR: 1.23), P = 0.001). Content of glands (median: 0.095 mm2 (IQR: 0.30) vs 0.00 mm2 (IQR: 0.01), P = 0.002) and airway smooth muscle (median: 0.25 mm2 (IQR: 0.30) vs 0.060 mm2 (IQR: 0.11), P = 0.02) was higher in the cryobiopsies compared with forceps biopsies. Further, the cryobiopsies had well-preserved protein antigens and mRNA. Mild to moderate bleeding was the only complication observed. CONCLUSION AND CLINICAL RELEVANCE: By yielding significantly larger and more intact biopsies, the cryotechnique represents a valuable new research tool to explore the bronchi in airway disease. Ultimately with the potential to create better understanding of underlying disease mechanisms and improvement of treatments.