Transbronchial cryobiopsy increases diagnostic confidence in interstitial lung disease: a prospective multicentre trial.

INTRODUCTION: The accurate diagnosis of individual interstitial lung diseases (ILD) is often challenging, but is a critical determinant of appropriate management. If a diagnosis cannot be made after multidisciplinary team discussion (MDTD), surgical lung biopsy is the current recommended tissue sampling technique according to the most recent guidelines. Transbronchial lung cryobiopsy (TBLC) has been proposed as an alternative to surgical lung biopsy. METHODS: This prospective, multicentre, international study analysed the impact of TBLC on the diagnostic assessment of 128 patients with suspected idiopathic interstitial pneumonia by a central MDTD board (two clinicians, two radiologists, two pathologists). The level of confidence for the first-choice diagnoses were evaluated in four steps, as follows: 1) clinicoradiological data alone; 2) addition of bronchoalveolar lavage (BAL) findings; 3) addition of TBLC interpretation; and 4) surgical lung biopsy findings (if available). We evaluated the contribution of TBLC to the formulation of a confident first-choice MDTD diagnosis. RESULTS: TBLC led to a significant increase in the percentage of cases with confident diagnoses or provisional diagnoses with high confidence (likelihood ≥70%) from 60.2% to 81.2%. In 32 out of 52 patients nondiagnostic after BAL, TBLC provided a diagnosis with a likelihood ≥70%. The percentage of confident diagnoses (likelihood ≥90%) increased from 22.7% after BAL to 53.9% after TBLC. Pneumothoraces occurred in 16.4% of patients, and moderate or severe bleeding in 15.7% of patients. No deaths were observed within 30 days. INTERPRETATION: TBLC increases diagnostic confidence in the majority of ILD patients with an uncertain noninvasive diagnosis, with manageable side-effects. These data support the integration of TBLC into the diagnostic algorithm for ILD.

Bronchoscopist's perception of the quality of the single-use bronchoscope (Ambu aScope4™) in selected bronchoscopies: a multicenter study in 21 Spanish pulmonology services.

BACKGROUND: The disposable bronchoscope is an excellent alternative to face the problem of SARS-CoV-2 and other cross infections, but the bronchoscopist's perception of its quality has not been evaluated. METHODS: To evaluate the quality of the Ambu-aScope4 disposable bronchoscope, we carried out a cross-sectional study in 21 Spanish pulmonology services. We use a standardized questionnaire completed by the bronchoscopists at the end of each bronchoscopy. The variables were described with absolute and relative frequencies, measures of central tendency and dispersion depending on their nature. The existence of learning curves was evaluated by CUSUM analysis. RESULTS: The most frequent indications in 300 included bronchoscopies was bronchial aspiration in 69.3% and the median duration of these was 9.1 min. The route of entry was nasal in 47.2% and oral in 34.1%. The average score for ease of use, image, and aspiration quality was 80/100. All the planned techniques were performed in 94.9% and the bronchoscopist was satisfied in 96.6% of the bronchoscopies. They highlighted the portability and immediacy of the aScope4TM to start the procedure in 99.3%, the possibility of taking and storing images in 99.3%. The CUSUM analysis showed average scores > 70/100 from the first procedure and from the 9th procedure more than 80% of the scores exceeded the 80/100 score. CONCLUSIONS: The aScope4™ scored well for ease of use, imaging, and aspiration. We found a learning curve with excellent scores from the 9th procedure. Bronchoscopists highlighted its portability, immediacy of use and the possibility of taking and storing images.

Diagnostic yield of transbronchial cryobiopsy in interstitial lung disease: a randomized trial.

BACKGROUND AND OBJECTIVE: Transbronchial lung biopsy (TBLB) is required for evaluation in selected patients with interstitial lung disease (ILD). The diagnostic yield of histopathologic assessment is variable and is influenced by factors such as the size of samples and the presence of crush artefacts left by conventional biopsy forceps. We compared the diagnostic yield and safety of TBLB with cryoprobe sampling versus conventional forceps sampling. METHODS: This randomized clinical trial analysed data for 77 patients undergoing TBLB for evaluation of ILD; patients were assigned to either a conventional-forceps group or a cryoprobe group. Two pathologists assessed the tissue samples and agreed on histopathologic diagnoses. We also compared the duration of procedures, complications and sample-quality variables. RESULTS: The most frequent diagnosis observed in the cryoprobe group was non-specific interstitial pneumonia. Histopathologic diagnoses were identified in more cases in the cryoprobe group (74.4%) than in the conventional-forceps group (34.1%) (P < 0.001), and the diagnostic yield was higher in the cryoprobe group (51.3% vs 29.1% in the conventional forceps group; P = 0.038). A larger mean area of tissue was harvested by cryoprobe (14.7 ± 11 mm(2) ) than by conventional forceps (3.3 ± 4.1 mm(2)) (P < 0.001). More grade 2 bleeding (not statistically significant) occurred in the cryoprobe group (56.4%) than in the conventional-forceps group (34.2%). No differences in other complications were observed. CONCLUSIONS: TBLB by cryoprobe is safe and potentially useful in the diagnosis of ILD. Larger multisite randomized trials are required to confirm the potential benefits of this procedure. Clinical trial registration at ClinicalTrials.gov: NCT01064609.

The current practice in the diagnostic work-up of patients with hemoptysis of unknown etiology: an international survey.

BACKGROUND: Hemoptysis is a challenging and potentially life-threatening medical condition. The most appropriate diagnostic work-up is debated and several diagnostic approaches are implemented worldwide. METHODS: An international, online survey was carried out to investigate the current practice of the diagnostic work-up of patients with hemoptysis of unknown etiology. RESULTS: Overall, 604 physicians responded to the survey. At baseline, chest X-ray was suggested as the first diagnostic investigation by 342 (56.6%) participants. Computed tomography (CT) was suggested in each patient with non- and life-threatening hemoptysis by 310 (51.3%) and 526 (87.1%) respondents, respectively. Contrast-enhanced CT is the currently preferred technique (333, 55.1%). In case of patchy ground glass opacities and negative CT, 287 (47.5%) and 222 (36.8%) participants, respectively, would always offer bronchoscopy. Otorhinolaryngological evaluation was mostly suggested in case of suspected upper airways bleeding before other investigations (212, 35.1%). A follow-up was recommended for idiopathic hemoptysis by the majority of the participants (316, 52.3%). A multidisciplinary assessment is deemed crucial for each patient with life-threatening hemoptysis (437, 72.4%). CONCLUSIONS: Chest X-ray and contrast-enhanced CT are currently preferred as the first diagnostic investigations, regardless of hemoptysis severity. Bronchoscopy is suggested in case of negative radiological examination and when CT shows only ground glass opacities. Otorhinolaryngological evaluation is advised before any other investigations when upper airways bleeding is suspected. Patients with idiopathic hemoptysis are suggested to undergo a clinical follow-up and in case of life-threatening bleeding a multidisciplinary assessment is deemed crucial. Due to the heterogeneous approaches a consensus statement would be needed.

Differentiation using minimally-invasive bioimpedance measurements of healthy and pathological lung tissue through bronchoscopy.

Purpose: To use minimally-invasive transcatheter electrical impedance spectroscopy measurements for tissue differentiation among healthy lung tissue and pathologic lung tissue from patients with different respiratory diseases (neoplasm, fibrosis, pneumonia and emphysema) to complement the diagnosis at real time during bronchoscopic procedures. Methods: Multi-frequency bioimpedance measurements were performed in 102 patients. The two most discriminative frequencies for impedance modulus (|Z|), phase angle (PA), resistance (R) and reactance (Xc) were selected based on the maximum mean pair-wise Euclidean distances between paired groups. One-way ANOVA for parametric variables and Kruskal-Wallis for non-parametric data tests have been performed with post-hoc tests. Discriminant analysis has also been performed to find a linear combination of features to separate among tissue groups. Results: We found statistically significant differences for all the parameters between: neoplasm and pneumonia (p < 0.05); neoplasm and healthy lung tissue (p < 0.001); neoplasm and emphysema (p < 0.001); fibrosis and healthy lung tissue (p ≤ 0.001) and pneumonia and healthy lung tissue (p < 0.01). For fibrosis and emphysema (p < 0.05) only in |Z|, R and Xc; and between pneumonia and emphysema (p < 0.05) only in |Z| and R. No statistically significant differences (p > 0.05) are found between neoplasm and fibrosis; fibrosis and pneumonia; and between healthy lung tissue and emphysema. Conclusion: The application of minimally-invasive electrical impedance spectroscopy measurements in lung tissue have proven to be useful for tissue differentiation between those pathologies that leads increased tissue and inflammatory cells and those ones that contain more air and destruction of alveolar septa, which could help clinicians to improve diagnosis.

Relaxation differences using EIS through bronchoscopy of healthy and pathological lung tissue.

The use of electrical impedance spectroscopy for lung tissue differentiation is an opportunity for the improvement of clinical diagnosis. The aim of this work is to distinguish among different lung tissue states by evaluating the differences among impedance spectrum parameters between two separate frequencies (15 kHz and 307 kHz) in the beta dispersion region. In previous studies we have used single frequency measurements for tissue differentiation. Differences (P < 0.05) are found between those tissues that undergo an increase in tissue density (neoplasm and fibrosis) and those tissues that lead to tissue destruction (emphysema). Electrical impedance spectroscopy shows its utility for lung tissue differentiation for diagnosis improvement among pathologies with different tissue structure. Further studies are necessary for the differentiation among those tissue states that are more similar to each other.Clinical Relevance- Expand the diagnostic tools currently available in bronchoscopy by using minimally-invasive bioimpedance measurements to differentiate between lung patterns.

Sarcoidosis following SARS-CoV-2 infection: Cause or consequence?

The COVID-19 pandemic has been a worldwide medical challenge. Despite rapid advancements, many questions regarding SARS-CoV-2 interaction with other pathologies and long-term consequences remained unanswered. Sarcoidosis is a multi-systemic granulomatous disease that develops in genetically predisposed individuals following their exposure to an environmental trigger. We present the case of a patient who was diagnosed with sarcoidosis following a SARS-CoV-2 infection.

Bronchoalveolar Lavage Complements Transbronchial Cryobiopsy Diagnosis in Diffuse Interstitial Lung Diseases.

BACKGROUND: Bronchoalveolar lavage (BAL) is a technique classically used for the study of diffuse interstitial lung diseases (DILDs). Given the recent advances in the diagnosis of DILD by transbronchial cryobiopsy (TBCB), it is relevant to assess what BAL can contribute to TBCB. PATIENTS AND METHODS: This is a retrospective descriptive study that included patients with DILD who, between 2013 and 2017, underwent BAL and TBCB in the same bronchoscopy intervention. We evaluated the complementary information provided by BAL to TBCB that facilitated the diagnosis by a multidisciplinary committee. Epidemiological, clinical, and functional variables and high-resolution chest tomography findings were recorded, along with complications associated with the procedures. RESULTS: A total of 60 patients were included. TBCB, conditioned by the underlying radiologic pattern, provided diagnostic information in 75% of cases. BAL provided complementary information that supported the diagnosis and treatment in 22% of cases. Differential BAL findings were related to microbiology, cell count, and immunology. Regarding the safety of the procedure, 47% of the patients experienced complications, although none were serious. CONCLUSION: BAL findings contribute to TBCB findings in the diagnosis of DILDs, with no serious complications associated with their combined use.

Influence of Malignant Pleural Fluid from Lung Adenocarcinoma Patients on Neutrophil Response.

Malignant pleural effusion (MPE) is a common severe complication of advanced lung adenocarcinoma (LAC). Neutrophils, an essential component of tumor infiltrates, contribute to tumor progression and their counts in MPE have been associated with worse outcome in LAC. This study aimed to evaluate phenotypical and functional changes of neutrophils induced by MPE to determine the influence of MPE immunomodulatory factors in neutrophil response and to find a possible association between neutrophil functions and clinical outcomes. Pleural fluid samples were collected from 47 LAC and 25 heart failure (HF) patients. We measured neutrophil degranulation products by ELISA, oxidative burst capacity and apoptosis by flow cytometry, and NETosis by fluorescence. The concentration of degranulation products was higher in MPE-LAC than in PE-HF. Functionally, neutrophils cultured with MPE-LAC had enhanced survival and neutrophil extracellular trap (NET) formation but had reduced oxidative burst capacity. In MPE, NETosis was positively associated with MMP-9, P-selectin, and sPD-L1 and clinically related to a worse outcome. This is the first study associating NETs with a worse outcome in MPE. Neutrophils likely contribute to tumor progression through the release of NETs, suggesting that they are a potential therapeutic target in LAC.

Minimally Invasive Real-Time Electrical Impedance Spectroscopy Diagnostic Tool for Lung Parenchyma Pathologies.

Electrical Impedance Spectroscopy has already demonstrated the ability to distinguish different tissues types, or tumors from normal tissue, or tissues displaying diverse degrees of pathology. When applying the technique, however, the necessity to make contact with the tissue often constitutes a practical limitation. Electrical Impedance Imaging (EIT), or in a broader sense, regional impedance assessment, struggle to assess different tissue conditions out of measurements from the surface of the body. But sensitivity is very small even for tissue a few centimeters under the skin, and in-vivo measurements are often not viable.The lung offer a third approximation by introducing a catheter though a bronchoscope, which is a routine clinical procedure. Measurements have been obtained by using 3 or 4-electrode techniques and allow us to distinguish, at least, fibrotic, emphysema or neoplastic regions from normal parenchyma. New instrumental developments, clinical measurements and preliminary results are presented and discussed.

Diagnosis and invasive staging: Non-surgical invasive mediastinal staging. Endobronchial ultrasound.

The diagnosis and staging of lung cancer are an important process that identifies treatment options and guides disease prognosis. Therefore, an accurate mediastinal lymph node (LN) staging is required not only to offer the appropriate treatment but also to avoid unnecessary invasive procedures. At present, endobronchial ultrasound (EBUS)-transbronchial needle aspiration is the preferred modality for sampling mediastinal lymph nodes because of its minimally invasive nature and high diagnostic yield. In this review, we discuss the utility of EBUS in mediastinal LN staging of non-small cell lung cancer (NSCLC). RELEVANCE FOR PATIENTS: The use of EBUS-TBNA in the diagnosis of mediastinal and hilar LN pathology has become in an essential endoscopic technique and the first step for staging of lung cancer.

Experimental supporting data on the influence of platelet-derived factors of malignant pleural effusions on T cell effector functions and their relevance in predicting prognosis of lung adenocarcinoma patients with pleural metastasis.

The data described in this article are supplementary to our primary article "Platelet factor 4 regulates T cell effector functions in malignant pleural effusions". Malignant pleural effusion (MPE) is a common complication of advanced lung adenocarcinoma (LAC) associated with a poor life expectancy [1]. Several challenges need to be addressed to identify non-invasive molecular biomarkers that help to predict the prognosis of LAC patients with MPE [2]. In the primary publication, we proposed that platelet-derived factors, especially platelet factor 4 (PF4), can negatively regulate T lymphocyte activation and granzyme B expression in pleural metastasis and its levels were associated with a worse prognosis. Here, we provide data on the influence of other platelet-derived factors, including transforming growth factor ß (TGF-ß), vascular endothelial factor (VEGF), and P-selectin on T lymphocyte response in MPE and their relevance as prognostic factors in lung cancer patients with pleural metastasis. Pleural fluids from 35 lung adenocarcinoma (LAC) and 20 heart failure (HF) patients were collected by thoracentesis and its platelet-derived factors' content was measured by specific enzyme-linked immunosorbent assay (ELISAs). Correlations between pleural levels of platelet-derived factors and T cell functions were analyzed by Pearson coefficients. Kaplan-Meier curves were used to estimate the effect of pleural concentrations of platelet-derived factors on overall survival of LAC patients with pleural metastasis. These analyses showed that the concentration of platelet-derived factors was not associated with T cell proliferation and cytotoxicity. Furthermore, their levels do not predict the survival of LAC with MPE.

Transbronchial biopsy results according to diffuse interstitial lung disease classification. Cryobiopsy versus forceps: MULTICRIO study.

BACKGROUND: In recent years, transbronchial cryobiopsy (TBCB) has come to be increasingly used in interventional pulmonology units as it obtains larger and better-quality samples than conventional transbronchial lung biopsy (TBLB) with forceps. No multicenter studies have been performed, however, that analyse and compare TBCB and TBLB safety and yield according to the interstitial lung disease (ILD) classification. OBJECTIVES: We compared the diagnostic yield and safety of TBCB with cryoprobe sampling versus conventional TBLB forceps sampling in the same patient. METHOD: Prospective multicenter clinical study of patients with ILD indicated for lung biopsy. Airway management with orotracheal tube, laryngeal mask and rigid bronchoscope was according to the protocol of each centre. All procedures were performed using fluoroscopy and an occlusion balloon. TBLB was followed by TBCB. Complications were recorded after both TBLB and TBCB. RESULTS: Included were 124 patients from 10 hospitals. Airway management was orotracheal intubation in 74% of cases. Diagnostic yield according to multidisciplinary committee results for TBCB was 47.6% and for TBLB was 19.4% (p<0.0001). Diagnostic yield was higher for TBCB compared to TBLB for two groups: idiopathic interstitial pneumonias (IIPs) and ILD of known cause or association (OR 2.5; 95% CI: 1.4-4.2 and OR 5.8; 95% CI: 2.3-14.3, respectively). Grade 3 (moderate) bleeding after TBCB occurred in 6.5% of patients compared to 0.8% after conventional TBLB. CONCLUSIONS: Diagnostic yield for TBCB was higher than for TBLB, especially for two disease groups: IIPs and ILD of known cause or association. The increased risk of bleeding associated with TBCB confirms the need for safe airway management and prophylactic occlusion-balloon use. TRIAL REGISTRATION: clinicaltrials.gov identifier: NCT02464592.

Platelet factor 4 regulates T cell effector functions in malignant pleural effusions.

Malignant pleural effusion (MPE) is defined as the presence of tumor cells in pleural fluid and it is a fatal complication of advanced lung adenocarcinoma (LAC). To understand the immune response to the tumor in MPE, we compared the concentration of immunomodulatory factors in MPE of LAC and pleural effusion of heart failure (HF) patients by ELISA, and the proliferation and cytotoxic phenotype of T cells stimulated in the presence of LAC and HF pleural fluids by cytometry. Platelet factor 4 (PF4), vascular endothelial growth factor (VEGF), transforming growth factor beta (TGF-ß) and P-selectin levels were higher in LAC than in HF pleural fluids. However, plasmatic PF4 and P-selectin levels were similar in LAC and HF. VEGF positively correlated with TGF-ß and sPD-L1 in LAC but not in HF pleural fluids. LAC pleural fluids also inhibited T lymphocyte proliferation and cytotoxicity and reduced IL-17 production. PF4 levels inversely correlated with T cell function. The high content of PF4 in MPE was associated with poor prognosis. Our findings suggest that an impaired response of T lymphocytes induced by PF4 provides a significant advantage for tumor progression.

A Multidisciplinary Proposal for a Diagnostic Algorithm in Idiopathic Pulmonary Fibrosis: The Role of Transbronchial Cryobiopsy. / Propuesta multidisciplinar respecto al algoritmo diagnóstico de la fibrosis pulmonar idiopática: papel de la criobiopsia transbronquial.

The diagnosis of idiopathic pulmonary fibrosis (IPF) is a complex process that requires the multidisciplinary integration of clinical, radiological, and histological variables. Due to its diagnostic yield, surgical lung biopsy has been the recommended procedure for obtaining samples of lung parenchyma, when required. However, given the morbidity and mortality of this technique, alternative techniques which carry a lower risk have been explored. The most important of these is transbronchial cryobiopsy -transbronchial biopsy with a cryoprobe- which is useful for obtaining lung tissue with less comorbidity. Yield may be lower than surgical biopsy, but it is higher than with transbronchial biopsy with standard forceps. This option has been discussed in the recent clinical guidelines for the diagnosis of IPF, but the authors do not go so far as recommend it. The aim of this article, the result of a multidisciplinary discussion forum, is to review current evidence and make proposals for the use of transbronchial cryobiopsy in the diagnosis of IPF.

Migrated T lymphocytes into malignant pleural effusions: an indicator of good prognosis in lung adenocarcinoma patients.

The presence of leukocyte subpopulations in malignant pleural effusions (MPEs) can have a different impact on tumor cell proliferation and vascular leakiness, their analysis can help to understand the metastatic microenvironment. We analyzed the relationship between the leukocyte subpopulation counts per ml of pleural fluid and the tumor cell count, molecular phenotype of lung adenocarcinoma (LAC), time from cancer diagnosis and previous oncologic therapy. We also evaluated the leukocyte composition of MPEs as a biomarker of prognosis. We determined CD4+ T, CD8+ T and CD20+ B cells, monocytes and neutrophils per ml in pleural effusions of 22 LAC and 10 heart failure (HF) patients by flow cytometry. Tumor cells were identified by morphology and CD326 expression. IFNγ, IL-10 and IL-17, and chemokines were determined by ELISAs and migratory response to pleural fluids by transwell assays. MPEs from LAC patients had more CD8+ T lymphocytes and a tendency to more CD4+ T and CD20+ B lymphocytes than HF-related fluids. However, no correlation was found between lymphocytes and tumor cells. In those MPEs which were detected >1 month from LAC diagnosis, there was a negative correlation between pleural tumor cells and CD8+ T lymphocytes. CXCL10 was responsible for the attraction of CD20+ B, CD4+ T and CD8+ T lymphocytes in malignant fluids. Concentrations of IL-17 were higher in MPEs than in HF-related effusions. Survival after MPE diagnosis correlated positively with CD4+ T and CD8+ T lymphocytes, but negatively with neutrophils and IL-17 levels. In conclusion, lymphocyte enrichment in MPEs from LAC patients is mostly due to local migration and increases patient survival.