Bronchial thermoplasty (BT) is a bronchoscopic treatment for severe asthma targeting airway smooth muscle (ASM). Observational studies have shown ASM mass reduction after BT, but appropriate control ...groups are lacking. Furthermore, as treatment response is variable, identifying optimal candidates for BT treatment is important.
First, to assess the effect of BT on ASM mass, and second, to identify patient characteristics that correlate with BT response.
Patients with severe asthma (
= 40) were randomized to immediate (
= 20) or delayed (
= 20) BT treatment. Before randomization, clinical, functional, blood, and airway biopsy data were collected. In the delayed control group, reassessment, including biopsies, was performed after 6 months of standard clinical care, followed by BT. In both groups, post-BT data including biopsies were obtained after 6 months. ASM mass (% positive desmin or α-smooth muscle actin area in the total biopsy) was calculated with automated digital analysis software. Associations between baseline characteristics and Asthma Control Questionnaire and Asthma Quality of Life Questionnaire (AQLQ) improvement were explored.
Median ASM mass decreased by >50% in the immediate BT group (
= 17) versus no change in the delayed control group (
= 19) (
= 0.0004). In the immediate group, Asthma Control Questionnaire scores improved with -0.79 (interquartile range IQR, -1.61 to 0.02) compared with 0.09 (IQR, -0.25 to 1.17) in the delayed group (
= 0.006). AQLQ scores improved with 0.83 (IQR, -0.15 to 1.69) versus -0.02 (IQR, -0.77 to 0.75) (
= 0.04). Treatment response in the total group (
= 35) was positively associated with serum IgE and eosinophils but not with baseline ASM mass.
ASM mass significantly decreases after BT when compared with a randomized non-BT-treated control group. Treatment response was associated with serum IgE and eosinophil levels but not with ASM mass.
Background
Coronavirus disease 2019 (COVID‐19) can lead to systemic coagulation activation and thrombotic complications.
Objectives
To investigate the incidence of objectively confirmed venous ...thromboembolism (VTE) in hospitalized patients with COVID‐19.
Methods
Single‐center cohort study of 198 hospitalized patients with COVID‐19.
Results
Seventy‐five patients (38%) were admitted to the intensive care unit (ICU). At time of data collection, 16 (8%) were still hospitalized and 19% had died. During a median follow‐up of 7 days (IQR, 3‐13), 39 patients (20%) were diagnosed with VTE of whom 25 (13%) had symptomatic VTE, despite routine thrombosis prophylaxis. The cumulative incidences of VTE at 7, 14 and 21 days were 16% (95% CI, 10‐22), 33% (95% CI, 23‐43) and 42% (95% CI 30‐54) respectively. For symptomatic VTE, these were 10% (95% CI, 5.8‐16), 21% (95% CI, 14‐30) and 25% (95% CI 16‐36). VTE appeared to be associated with death (adjusted HR, 2.4; 95% CI, 1.02‐5.5). The cumulative incidence of VTE was higher in the ICU (26% (95% CI, 17‐37), 47% (95% CI, 34‐58), and 59% (95% CI, 42‐72) at 7, 14 and 21 days) than on the wards (any VTE and symptomatic VTE 5.8% (95% CI, 1.4‐15), 9.2% (95% CI, 2.6‐21), and 9.2% (2.6‐21) at 7, 14, and 21 days).
Conclusions
The observed risk for VTE in COVID‐19 is high, particularly in ICU patients, which should lead to a high level of clinical suspicion and low threshold for diagnostic imaging for DVT or PE. Future research should focus on optimal diagnostic and prophylactic strategies to prevent VTE and potentially improve survival.
Background
Activated eosinophils cause major pathology in stable and exacerbating asthma; however, they can also display protective properties like an extracellular antiviral activity. Initial murine ...studies led us to further explore a potential intracellular antiviral activity by eosinophils.
Methods
To follow eosinophil‐virus interaction, respiratory syncytial virus (RSV) and influenza virus were labeled with a fluorescent lipophilic dye (DiD). Interactions with eosinophils were visualized by confocal microscopy, electron microscopy, and flow cytometry. Eosinophil activation was assessed by both flow cytometry and ELISA. In a separate study, eosinophils were depleted in asthma patients using anti‐IL‐5 (mepolizumab), followed by a challenge with rhinovirus‐16 (RV16).
Results
DiD‐RSV and DiD‐influenza rapidly adhered to human eosinophils and were internalized and inactivated (95% in ≤ 2 hours) as reflected by a reduced replication in epithelial cells. The capacity of eosinophils to capture virus was reduced up to 75% with increasing severity of asthma. Eosinophils were activated by virus in vitro and in vivo. In vivo this correlated with virus‐induced loss of asthma control.
Conclusions
This previously unrecognized and in asthma attenuated antiviral property provides a new perspective to eosinophils in asthma. This is indicative of an imbalance between protective and cytotoxic properties by eosinophils that may underlie asthma exacerbations.
1,19 – dioctadecyl ‐ 3, 3, 39, 39 – tetramethylindocarbocyanine (DiD)‐respiratory syncytial virus and DiD‐influenza adhered to human eosinophils. Both viruses were internalized and inactivated by eosinophils. The capacity of eosinophils to capture virus was reduced with increasing severity of asthma. IL‐5 Tg: IL‐5 transgenic; RSV: Respiratory syncytial virus; WT: Wild‐type
Bronchial thermoplasty (BT) is a bronchoscopic treatment for patients with severe asthma who remain symptomatic despite optimal medical therapy. In this “expert best practice” paper, the background ...and practical aspects of BT are highlighted. Randomized, controlled clinical trials have shown BT to be safe and effective in reducing severe exacerbations, improving quality of life, and decreasing emergency department visits. Five-year follow-up studies have provided evidence of the functional stability of BT-treated patients with persistence of a clinical benefit. The Global Initiative for Asthma (GINA) guidelines state that BT can be considered as a treatment option for adult asthma patients at step 5. Patient selection for BT requires close collaboration between interventional pulmonologists and severe asthma specialists. Key patient selection criteria for BT will be reviewed. BT therapy is delivered in 3 separate bronchoscopy sessions at least 3 weeks apart, covering different regions of the lung separately. Patients are treated with 50 mg/day of prednisolone or equivalent for 5 days, starting treatment 3 days prior to the procedure. The procedure is performed under moderate-to-deep sedation or general anesthesia. At bronchoscopy a single-use catheter with a basket design is inserted through the instrument channel and the energy is delivered by a radiofrequency (RF) generator (Alair TM Bronchial Thermoplasty System). BT uses temperature-controlled RF energy to impact airway remodeling, including a reduction of excessive airway smooth muscle within the airway wall, which has been recognized as a predominant feature of asthma. The treatment should be performed in a systemic manner, starting at the most distal part of the (sub)segmental airway, then moving proximally to the main bronchi, ensuring that the majority of the airways are treated. In general, 40–70 RF activations are provided in the lower lobes, and between 50 and 100 activations in the upper lobes combined. The main periprocedural adverse events are exacerbation of asthma symptoms and increased cough and sputum production. Occasionally, atelectasis has been observed following the procedure. The long-term safety of BT is excellent. An optimized BT responder profile – i.e., which specific asthma phenotype benefits most – is a topic of current research.
Eosinophils drive pathophysiology in stable and exacerbating eosinophilic asthma, and therefore treatment is focused on the reduction of eosinophil numbers. Mepolizumab, a humanized monoclonal ...antibody that neutralizes IL-5 and efficiently attenuates eosinophils, proved clinically effective in severe eosinophilic asthma but not in mild asthma.
To study the effect of mepolizumab on virus-induced immune responses in mild asthma.
Patients with mild asthma, steroid-naive and randomized for eosinophil numbers, received 750 mg mepolizumab intravenously in a placebo-controlled double-blind trial, 2 weeks after which patients were challenged with rhinovirus (RV) 16. FEV
, FVC, fractional exhaled nitric oxide, symptom scores (asthma control score), viral load (PCR), eosinophil numbers, humoral (luminex, ELISA), and cellular (flow cytometry) immune parameters in blood, BAL fluid, and sputum, before and after mepolizumab and RV16, were assessed.
Mepolizumab attenuated baseline blood eosinophils and their activation, attenuated trendwise sputum eosinophils, and enhanced circulating natural killer cells. Mepolizumab did not affect FEV
, FVC, and fractional exhaled nitric oxide, neither at baseline nor after RV16. On RV16 challenge mepolizumab did not prevent eosinophil activation but did enhance local B lymphocytes and macrophages and reduce neutrophils and their activation. Mepolizumab also enhanced secretory IgA and reduced tryptase in BAL fluid. Finally, mepolizumab affected particularly RV16-induced macrophage inflammatory protein-3a, vascular endothelial growth factor-A, and IL-1RA production in BAL fluid.
Mepolizumab failed to prevent activation of remaining eosinophils and changed RV16-induced immune responses in mild asthma. Although these latter effects likely are caused by attenuated eosinophil numbers, we cannot exclude a role for basophils. Clinical trial registered with www.clinicaltrials.gov (NCT 01520051).
Introduction: Obtaining a tissue diagnosis of centrally located lung tumors in patients presenting without endobronchial abnormalities is challenging, and therefore a considerable diagnostic problem. ...Objective: The objective of this study was to evaluate the performance of linear endobronchial ultrasound guided-transbronchial-needle aspiration (EBUS-TBNA) for the diagnosis of centrally located lung tumors. Methods: We performed a systematic review (PROSPERO, CRD42017080968) and searched MEDLINE, Embase, BIOSIS Previews, and Web of Science till November 18, 2018 for studies that evaluated the yield and/or sensitivity of EBUS-TBNA for diagnosing centrally located lung tumors. We assessed the study quality using QUADAS-2 and performed random-effects meta-analysis. Results: A total of 5,657 manuscripts were identified; of these 14 were considered for the study, including 1,175 patients who underwent EBUS-TBNA for diagnosing an intrapulmonary tumor. All studies had a high risk of bias or applicability concerns, predominately regarding patient selection. The average yield of EBUS-TBNA for diagnosing centrally located lung tumors was 0.89 (95% CI 0.84–0.92) and average sensitivity for diagnosing malignant tumors was 0.91 (95% CI 0.88–0.94). Among studies reporting this information, EBUS-related complications occurred in 5.4% of patients (42/721). Conclusion: EBUS-TBNA has a high yield and sensitivity for diagnosing centrally located lung tumors and is safe in selected patients. Prospective studies are recommended to evaluate the routine use of this procedure for diagnosing intrapulmonary tumors.
In diseases such as interstitial lung diseases (ILDs), patient diagnosis relies on diagnostic analysis of bronchoalveolar lavage fluid (BALF) and biopsies. Immunological BALF analysis includes ...differentiation of leukocytes by standard cytological techniques that are labor-intensive and time-consuming. Studies have shown promising leukocyte identification performance on blood fractions, using third harmonic generation (THG) and multiphoton excited autofluorescence (MPEF) microscopy.
To extend leukocyte differentiation to BALF samples using THG/MPEF microscopy, and to show the potential of a trained deep learning algorithm for automated leukocyte identification and quantification.
Leukocytes from blood obtained from three healthy individuals and one asthma patient, and BALF samples from six ILD patients were isolated and imaged using label-free microscopy. The cytological characteristics of leukocytes, including neutrophils, eosinophils, lymphocytes, and macrophages, in terms of cellular and nuclear morphology, and THG and MPEF signal intensity, were determined. A deep learning model was trained on 2D images and used to estimate the leukocyte ratios at the image-level using the differential cell counts obtained using standard cytological techniques as reference.
Different leukocyte populations were identified in BALF samples using label-free microscopy, showing distinctive cytological characteristics. Based on the THG/MPEF images, the deep learning network has learned to identify individual cells and was able to provide a reasonable estimate of the leukocyte percentage, reaching >90% accuracy on BALF samples in the hold-out testing set.
Label-free THG/MPEF microscopy in combination with deep learning is a promising technique for instant differentiation and quantification of leukocytes. Immediate feedback on leukocyte ratios has potential to speed-up the diagnostic process and to reduce costs, workload and inter-observer variations.
Background and Objective
Robotic bronchoscopy has demonstrated high navigational success in small peripheral lung nodules but the diagnostic yield is discrepantly lower. Needle based confocal laser ...endomicroscopy (nCLE) enables real‐time microscopic imaging at the needle tip. We aim to assess feasibility, safety and needle repositioning based on real‐time nCLE‐guidance during robotic bronchoscopy in small peripheral lung nodules.
Methods
Patients with suspected peripheral lung cancer underwent fluoroscopy and radial EBUS assisted robotic bronchoscopy. After radial EBUS nodule identification, nCLE‐imaging of the target area was performed. nCLE‐malignancy and airway/lung parenchyma criteria were used to identify the optimal sampling location. In case airway was visualized, repositioning of the biopsy needle was performed. After nCLE tool‐in‐nodule confirmation, needle passes and biopsies were performed at the same location.
Measurements and Main Results
Twenty patients were included (final diagnosis n = 17 (lung) cancer) with a median lung nodule size of 14.5 mm (range 8–28 mm). No complications occurred. In 19/20 patients, good quality nCLE‐videos were obtained. In 9 patients (45%), real‐time nCLE‐imaging revealed inadequate positioning of the needle and repositioning was performed. After repositioning, nCLE‐imaging provided tool‐in‐nodule‐confirmation in 19/20 patients. Subsequent ROSE demonstrated representative material in 9/20 patients (45%) and overall diagnostic yield was 80% (16/20). Of the three patients with malignant nCLE‐imaging but inadequate pathology, two were diagnosed with malignancy during follow‐up.
Conclusion
Robotic bronchoscopic nCLE‐imaging is feasible and safe. nCLE‐imaging in small, difficult‐to‐access lung nodules provided additional real‐time feedback on the correct needle positioning with the potential to optimize the sampling location and diagnostic yield.
Robotic bronchoscopic nCLE‐imaging is feasible, safe and enables real‐time visualization of tumour cells at the needle tip. Based on nCLE‐guidance, the robotic bronchoscope was repositioned in almost half of patients. Our data show the potential of robotic bronchoscopic nCLE‐imaging as a safe, improved strategy to diagnose small difficult‐to‐access lung nodules.
Patients with chronic thromboembolic disease (CTED) may suffer from exercise intolerance without pulmonary hypertension at rest. Pulmonary endarterectomy (PEA) for symptomatic CTED results in ...improvement of symptoms and quality of life. Neither the pathophysiology of the exercise limitation nor the underlying mechanisms of the PEA-induced improvement have been studied previously.
We studied hemodynamic and ventilatory responses upon exercise in 14 patients with CTED. After 1 year, we studied the underlying physiologic mechanisms of the PEA-induced symptomatic improvement.
Cardiopulmonary exercise testing (CPET) was performed during right heart catheterization, and noninvasive CPET was performed 1 year postoperatively.
During exercise, we observed abnormal pulmonary vascular responses, that is, a steep mean pulmonary artery pressure/cardiac output (2.7 ± 1.2 mm Hg·min·L−1), and low pulmonary vascular compliance (2.8 ± 1.1 mL·mm Hg−1); mean pulmonary artery pressure/cardiac output slope correlated with dead-space ventilation (r = 0.586; P = .028) and ventilatory equivalents for carbon dioxide slope (r = .580; P = .030). Postoperatively, the improvement observed in exercise capacity was related to improvements in CPET-derived parameters pointing to restoration of right ventricle stroke volume response (oxygen pulse: 11.7 ± 3.1 to 13.3 ± 3.3; P = .027; heart rate response: 80.9 ± 12.4 to 72.0 ± 5.7; P = .003); and, indicating improved ventilatory efficiency, the ventilatory equivalents for carbon dioxide slope decreased from 38.2 ± 3.6 to 32.8 ± 7.0 (P = .014).
Patients with CTED showed an abnormal pulmonary vascular response to exercise and a decreased ventilatory efficiency. Responses after PEA point to restoration of right ventricle stroke volume response and ventilatory efficiency.
Background and objective
Endosonography with intrathoracic nodal sampling is proposed as the single test with the highest granuloma detection rate in suspected sarcoidosis stage I/II. However, most ...studies have been performed in limited geographical regions. Studies suggest that oesophageal endosonographic nodal sampling has higher diagnostic yield than endobronchial endosonographic nodal sampling, but a head‐to‐head comparison of both routes has never been performed.
Methods
Global (14 hospitals, nine countries, four continents) randomized clinical trial was conducted in consecutive patients with suspected sarcoidosis stage I/II presenting between May 2015 and August 2017. Using an endobronchial ultrasound (EBUS) scope, patients were randomized to EBUS or endoscopic ultrasound (EUS)‐B‐guided nodal sampling, and to 22‐ or 25‐G ProCore needle aspiration (2 × 2 factorial design). Granuloma detection rate was the primary study endpoint. Final diagnosis was based on cytology/pathology outcomes and clinical/radiological follow‐up at 6 months.
Results
A total of 358 patients were randomized: 185 patients to EBUS‐transbronchial needle aspiration (EBUS‐TBNA) and 173 to EUS‐B‐fine‐needle aspiration (FNA). Final diagnosis was sarcoidosis in 306 patients (86%). Granuloma detection rate was 70% (130/185; 95% CI, 63–76) for EBUS‐TBNA and 68% (118/173; 95% CI, 61–75) for EUS‐B‐FNA (p = 0.67). Sensitivity for diagnosing sarcoidosis was 78% (129/165; 95% CI, 71–84) for EBUS‐TBNA and 82% (115/141; 95% CI, 74–87) for EUS‐B‐FNA (p = 0.46). There was no significant difference between the two needle types in granuloma detection rate or sensitivity.
Conclusion
Granuloma detection rate of mediastinal/hilar nodes by endosonography in patients with suspected sarcoidosis stage I/II is high and similar for EBUS and EUS‐B. These findings imply that both diagnostic tests can be safely and universally used in suspected sarcoidosis patients.
This global RCT in patients with suspected sarcoidosis stage I/II with an indication for endosonographic nodal sampling showed a similarly high granuloma detection rate and sensitivity for diagnosing sarcoidosis with endobronchial ultrasound versus endoscopic ultrasound‐B. The findings imply that both diagnostic tests (endobronchial/oesophageal) can be used safely and universally in suspected sarcoidosis patients.
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