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Bronchial thermoplasty decreases airway remodelling by blocking epithelium-derived heat shock protein-60 secretion and protein arginine methyltransferase-1 in fibroblasts

期刊: EUROPEAN RESPIRATORY JOURNAL, 2019; 54 (6)

Bronchial thermoplasty (BT) is to date the only therapy that provides a lasting reduction in airway wall remodelling. However, the mechanism of action of BT is not well understood. This study aimed to characterise the changes of remodelling regulating signalling pathways by BT in asthma. Bronchoalveolar lavage fluid (BALF) was obtained from eight patients with severe asthma before and after BT. Primary bronchial epithelial cells were isolated from 23 patients before (n=66) and after (n=62) BT. Epithelial cell culture supernatant (Epi.S) was collected and applied to primary fibroblasts. Epithelial cells obtained from asthma patients after BT proliferated significantly faster compared with epithelial cells obtained before BT. In airway fibroblasts, BALF or Epi.S obtained before BT increased CCAAT enhancer-binding protein-beta (C/EBP beta) expression, thereby downregulating microRNA-19a. This upregulated extracellular signal-regulated kinase-1/2 (ERK1/2) expression, protein arginine methyltransferase-1 (PRMT1) expression, cell proliferation and mitochondrial mass. BALF or Epi.S obtained after BT reduced the expression of C/EBP beta, ERK1/2, peroxisome proliferator-activated receptor-gamma coactivator-1 alpha (PGC1 alpha), PRMT1 and mitochondrial mass in airway fibroblasts. Proteome and transcriptome analyses indicated that epithelial cell-derived heat shock protein-60 (HSP60) is the main mediator of BT effects on fibroblasts. Further analysis suggested that HSP60 regulated PRMT1 expression, which was responsible for the increased mitochondria( mass and a-smooth muscle actin expression by asthmatic fibroblasts. These effects were ablated after BT. These results imply that BT reduces fibroblast remodelling through modifying the function of epithelial cells, especially by reducing HSP60 secretion and subsequent signalling pathways that regulate PRMT1 expression. We therefore hypothesise that BT decreases airway remodelling by blocking epithelium-derived HSP60 secretion and PRMT1 in fibroblasts.

IF:11.81

Cloud algorithm-driven oximetry-based diagnosis of obstructive sleep apnoea in symptomatic habitually snoring children

期刊: EUROPEAN RESPIRATORY JOURNAL, 2019; 53 (2)

The ability of a cloud-driven Bluetooth oximetry-based algorithm to diagnose obstructive sleep apnoea syndrome (OSAS) was examined in habitually snoring children concurrently undergoing overnight polysomnography. Children clinically referred for overnight in-laboratory polysomnographic evaluation for suspected OSAS were simultaneously hooked to a Bluetooth oximeter linked to a smartphone. Polysomnography findings were scored and the apnoea/hypopnoea index (AHIPSG) was tabulated, while oximetry data yielded an estimated AHIOXI using a validated algorithm. The accuracy of the oximeter in identifying correctly patients with OSAS in general, or with mild (AHI 1-5 events.h(-1)), moderate (5-10 events.h(-1)) or severe (>10 events.h(-1)) OSAS was examined in 432 subjects (6.5 +/- 3.2 years), with 343 having AHIPSG >1 event.h(-1). The accuracies of AHIOXI were consistently >79% for all levels of OSAS severity, and specificity was particularly favourable for AHI >10 events.h(-1) (92.7%). Using the criterion of AHIPSG >1 event.h(-1), only 4.7% of false-negative cases emerged, from which only 0.6% of cases showed moderate or severe OSAS. Overnight oximetry processed via Bluetooth technology by a cloud-based machine learning-derived algorithm can reliably diagnose OSAS in children with clinical symptoms suggestive of the disease. This approach provides virtually limitless scalability and should alleviate the substantial difficulties in accessing paediatric sleep laboratories while markedly reducing the costs of OSAS diagnosis.

IF:11.81

Long-term prognosis of patients with systemic lupus erythematosus-associated pulmonary arterial hypertension: CSTAR-PAH cohort study

期刊: EUROPEAN RESPIRATORY JOURNAL, 2019; 53 (2)

This study aimed to identify the long-term clinical outcomes and prognostic factors of patients with systemic lupus erythematosus (SLE)-associated pulmonary arterial hypertension (PAH) confirmed by right heart catheterisation. A multicentre prospective cohort of SLE-associated PAH was established. Baseline and follow-up records were collected. The primary end-point was death. The secondary exploratory end-point was treatment goal achievement (TGA), defined as an integrated outcome. In total, 310 patients were enrolled from 14 PAH centres. The 1-, 3- and 5-year survival rates were 92.1%, 84.8% and 72.9%, respectively. The 1-, 3- and 5-year TGA rates were 31.5%, 53.6% and 62.7%, respectively. Baseline serositis, 6-min walking distance >380 m and cardiac index >= 2.5 L.min(-1).m(-2) were identified as independent prognostic factors of TGA. Patients with baseline serositis were more likely to reach TGA after intensive immunosuppressive therapy. TGA was identified as a positive predictor of survival in patients with SLE-associated PAH. TGA was associated with long-term survival, which supports the treat-to-target strategy in SLE-associated PAH. Baseline heart function predicted both survival and treatment goal achievement in patients with SLE-associated PAH. Patients with serositis at baseline tended to benefit from intensive immunosuppressive therapy and have a better clinical outcome.

IF:11.81

Introducing molecular testing of pyrazinamide susceptibility improves multidrug-resistant tuberculosis treatment outcomes: a prospective cohort study

期刊: EUROPEAN RESPIRATORY JOURNAL, 2019; 53 (3)

The current treatment for multidrug-resistant tuberculosis (MDR-TB) takes a lengthy period of 18-24 months and has a poor cure rate of 50-60%. A multicenter, prospective cohort study was conducted to assess the role of testing for molecular susceptibility to pyrazinamide (PZA) in optimising treatment for MDR-TB. We assigned 76 patients to an optimised molecular susceptibility group and 159 patients to a regular treatment group where PZA susceptibility was not determined. Of these patients, 152 were matched after propensity score matching (76 in the optimised group and 76 in the regular group). Treatment success rate was measured in the propensity-matched cohort as the primary outcome. Patients in the optimised group achieved a higher treatment success rate than those in the regular group (76.3% versus 55.3%, p=0.006). Of 51 patients with isolates that were susceptible to PZA and who were receiving a 12-month regimen, 42 (82.4%) were treated successfully. The optimised group showed faster culture conversion than the regular group (p=0.024). After exclusion of pre-extensively drug-resistant TB (pre-XDR-TB), the treatment outcome in the optimised group was still better than the regular group (83.1% versus 62.1%, p=0.009). Introducing molecular susceptibility testing for PZA improved the treatment outcomes for MDR-TB without the use of new drugs. Introducing PZA for patients with PZA-susceptible (PZA-S) MDR-TB allows the current regimen to be shortened to 12 months with comparable success rates to the World Health Organization (WHO) recommended shorter regimen.

IF:11.81

Role of anlotinib-induced CCL2 decrease in anti-angiogenesis and response prediction for nonsmall cell lung cancer therapy

期刊: EUROPEAN RESPIRATORY JOURNAL, 2019; 53 (3)

Background: Anlotinib has been demonstrated in clinical trials to be effective in prolonging the progression-free survival (PFS) and overall survival (OS) of refractory advanced nonsmall cell lung cancer (NSCLC) patients. However, the underlying molecular mechanisms and predictive biomarkers of anlotinib are still unclear. Methods: A retrospective analysis of anlotinib administered to 294 NSCLC patients was performed to screen for underlying biomarkers of anlotinib-responsive patients. Transcriptome and functional assays were performed to understand the antitumour molecular mechanisms of anlotinib. Changes in serum CCL2 levels were analysed to examine the correlation of the anlotinib response between responders and nonresponders. Results: Anlotinib therapy was beneficial for prolonging OS in NSCLC patients harbouring positive driver gene mutations, especially patients harbouring the epithelial growth factor receptor (EGFR) T790M mutation. Moreover, anlotinib inhibited angiogenesis in an NCI-H1975-derived xenograft model via inhibiting CCL2. Finally, anlotinib-induced serum CCL2 level decreases were associated with the benefits of PFS and OS in refractory advanced NSCLC patients. Conclusions: Our study reports a novel anti-angiogenesis mechanism of anlotinib via inhibiting CCL2 in an NCI-H1975-derived xenograft model and suggests that changes in serum CCL2 levels may be used to monitor and predict clinical outcomes in anlotinib-administered refractory advanced NSCLC patients using third-line therapy or beyond.

IF:11.81

Predicting EGFR mutation status in lung adenocarcinoma on computed tomography image using deep learning

期刊: EUROPEAN RESPIRATORY JOURNAL, 2019; 53 (3)

Epidermal growth factor receptor (EGFR) genotyping is critical for treatment guidelines such as the use of tyrosine kinase inhibitors in lung adenocarcinoma. Conventional identification of EGFR genotype requires biopsy and sequence testing which is invasive and may suffer from the difficulty of accessing tissue samples. Here, we propose a deep learning model to predict EGFR mutation status in lung adenocarcinoma using non-invasive computed tomography (CT). We retrospectively collected data from 844 lung adenocarcinoma patients with pre-operative CT images, EGFR mutation and clinical information from two hospitals. An end-to-end deep learning model was proposed to predict the EGFR mutation status by CT scanning. By training in 14926 CT images, the deep learning model achieved encouraging predictive performance in both the primary cohort (n=603; AUC 0.85, 95% CI 0.83-0.88) and the independent validation cohort (n=241; AUC 0.81, 95% CI 0.79-0.83), which showed significant improvement over previous studies using hand-crafted CT features or clinical characteristics (p<0.001). The deep learning score demonstrated significant differences in EGFR-mutant and EGFR-wild type tumours (p<0.001). Since CT is routinely used in lung cancer diagnosis, the deep learning model provides a non-invasive and easy-to-use method for EGFR mutation status prediction.

IF:11.81

Exhaled air dispersion during high-flow nasal cannula therapy versus CPAP via different masks

期刊: EUROPEAN RESPIRATORY JOURNAL, 2019; 53 (4)

Background: High-flow nasal cannula (HFNC) is an emerging therapy for respiratory failure but the extent of exhaled air dispersion during treatment is unknown. We examined exhaled air dispersion during HFNC therapy versus continuous positive airway pressure (CPAP) on a human patient simulator (HPS) in an isolation room with 16 air changes.h(-1). Methods: The HPS was programmed to represent different severity of lung injury. CPAP was delivered at 5-20 cm H2O via nasal pillows (Respironics Nuance Pro Gel or ResMed Swift FX) or an oronasal mask (ResMed Quattro Air). HFNC, humidified to 37 degrees C, was delivered at 10-60 L.min(-1) to the HPS. Exhaled airflow was marked with intrapulmonary smoke for visualisation and revealed by laser light-sheet. Normalised exhaled air concentration was estimated from the light scattered by the smoke particles. Significant exposure was defined when there was. 20% normalised smoke concentration. Results: In the normal lung condition, mean +/- SD exhaled air dispersion, along the sagittal plane, increased from 186 +/- 34 to 264 +/- 27 mm and from 207 +/- 11 to 332 +/- 34 mm when CPAP was increased from 5 to 20 cmH2O via Respironics and ResMed nasal pillows, respectively. Leakage from the oronasal mask was negligible. Mean +/- SD exhaled air distances increased from 65 +/- 15 to 172 +/- 33 mm when HFNC was increased from 10 to 60 L.min(-1). Air leakage to 620 mm occurred laterally when HFNC and the interface tube became loose. Conclusion: Exhaled air dispersion during HFNC and CPAP via different interfaces is limited provided there is good mask interface fitting.

IF:11.81

IL-17F, rather than IL-17A, underlies airway inflammation in a steroid-insensitive toluene diisocyanate-induced asthma model

期刊: EUROPEAN RESPIRATORY JOURNAL, 2019; 53 (4)

Steroid insensitivity constitutes a major problem for asthma management. Toluene diisocyanate (TDI) is one of the leading allergens of asthma that induces both T-helper Th2 and Th17 responses, and is often associated with poor responsiveness to steroid treatment in the clinic. We sought to evaluate the effects of inhaled and systemic steroids on a TDI-induced asthma model and to find how interleukin (IL)-17A and IL-17F function in this model. BALB/c mice were exposed to TDI for generating an asthma model and were treated with inhaled fluticasone propionate, systemic prednisone, anti-IL-17A, anti-IL-17F, recombinant IL-17A or IL-17F. Both fluticasone propionate and prednisone showed no effects on TDI-induced airway hyperresponsiveness (AHR), bronchial neutrophilia and eosinophilia, and epithelial goblet cell metaplasia. TDI-induced Th2 and Th17 signatures were not suppressed by fluticasone propionate or prednisone. Treatment with anti-IL-17A after TDI exposure led to increased AHR, aggravated mucus production and airway eosinophil recruitment, accompanied by amplified Th2 responses, whereas anti-IL-17F ameliorated TDI-induced AHR and airway neutrophilia, with decreased Th17 responses. Recombinant IL-17A and IL-17F showed opposite effects to the monoclonal antibodies. IL-17A and IL-17F exert distinct biological effects during airway inflammation of a TDI-induced asthma model, which is unresponsive to both inhaled and systemic steroids.

IF:11.81

Transcriptomics of atopy and atopic asthma in white blood cells from children and adolescents

期刊: EUROPEAN RESPIRATORY JOURNAL, 2019; 53 (5)

Early allergic sensitisation (atopy) is the first step in the development of allergic diseases such as atopic asthma later in life. Genes and pathways associated with atopy and atopic asthma in children and adolescents have not been well characterised. A transcriptome wide association study (TWAS) of atopy and atopic asthma in white blood cells (WBCs) or whole blood was conducted in a cohort of 460 Puerto Ricans aged 9 20 years (EVA PR study) and in a cohort of 250 Swedish adolescents (BAMSE study). Pathway enrichment and network analyses were conducted to further assess top findings, and classification models of atopy and atopic asthma were built using expression levels for the top differentially expressed genes (DEGs). In a meta analysis of the study cohorts, both previously implicated genes (e. g. IL5RA and IL1RL1) and genes not previously reported in TWASs (novel) were significantly associated with atopy and/or atopic asthma. Top novel genes for atopy included SIGLEC8 (p=8.07x10 13), SLC29A1 (p=7.07x10 12) and SMPD3 (p=1.48x10 11). Expression quantitative trait locus analyses identified multiple asthma relevant genotype expression pairs, such as rs2255888/ALOX15. Pathway enrichment analysis uncovered 16 significantly enriched pathways at adjusted p< 0.01, including those relevant to T helper cell type 1 (Th1) and Th2 immune responses. Classification models built using the top DEGs and a few demographic/parental history variables accurately differentiated subjects with atopic asthma from nonatopic control subjects (area under the curve 0.84). We have identified genes and pathways for atopy and atopic asthma in children and adolescents, using transcriptome wide data from WBCs and whole blood samples.

IF:11.81

Disease severity and clinical outcomes of community-acquired pneumonia caused by non-influenza respiratory viruses in adults: a multicentre prospective registry study from the CAP-China Network

期刊: EUROPEAN RESPIRATORY JOURNAL, 2019; 54 (2)

Although broad knowledge of influenza viral pneumonia has been established, the significance of non-influenza respiratory viruses in community-acquired pneumonia (CAP) and their impact on clinical outcomes remains unclear, especially in the non-immunocompromised adult population. Hospitalised immunocompetent patients with CAP were prospectively recruited from 34 hospitals in mainland China. Respiratory viruses were detected by molecular methods. Comparisons were conducted between influenza and non-influenza viral infection groups. In total, 915 out of 2336 adult patients with viral infection were enrolled in the analysis, with influenza virus (28.4%) the most frequently detected virus, followed by respiratory syncytial virus (3.6%), adenovirus (3.3%), human coronavirus (3.0%), parainfluenza virus (2.2%), human rhinovirus (1.8%) and human metapneumovirus (1.5%). Non-influenza viral infections accounted for 27.4% of viral pneumonia. Consolidation was more frequently observed in patients with adenovirus infection. The occurrence of complications such as sepsis (40.1% versus 39.6%; p=0.890) and hypoxaemia (40.1% versus 37.2%; p=0.449) during hospitalisation in the influenza viral infection group did not differ from that of the non-influenza viral infection group. Compared with influenza virus infection, the multivariable adjusted odds ratios of CURB-65 (confusion, urea > 7 mmol.L-1, respiratory rate >= 30 breaths.min(-1), blood pressure < 90 mmHg (systolic) or <= 60 mmHg (diastolic), age >= 65 years) >= 3, arterial oxygen tension/inspiratory oxygen fraction < 200 mmHg, and occurrence of sepsis and hypoxaemia for non-influenza respiratory virus infection were 0.87 (95% CI 0.26-2.84), 0.72 (95% CI 0.26-1.98), 1.00 (95% CI 0.63-1.58) and 1.05 (95% CI 0.66-1.65), respectively. The hazard ratio of 90-day mortality was 0.51 (95% CI 0.13-1.91). The high incidence of complications in non-influenza viral pneumonia and similar impact of non-influenza respiratory viruses relative to influenza virus on disease severity and outcomes suggest more attention should be given to CAP caused by non-influenza respiratory viruses.

IF:11.81

Ultrasound elastography: a novel tool for the differential diagnosis of pleural effusion

期刊: EUROPEAN RESPIRATORY JOURNAL, 2019; 54 (2)

Introduction: Traditional thoracic ultrasound (TUS) is often the initial tool used to help diagnose malignant pleural effusion (MPE). Ultrasound elastography, a relatively new technique, has been used to differentiate malignant disease from benign disease by evaluating tissue "stiffness". However, no studies evaluating the efficacy of ultrasound elastography for diagnosing MPE are available. We assessed the value of ultrasound elsatography for diagnosing MPE prospectively. Methods: All 244 enrolled patients were divided into a development set and a validation set in chronological order. The cut-off elasticity index was established using a receiver operating characteristic curve constructed from the continuous data of the patients in the development set. The diagnostic performance of ultrasound elastography was compared with that of TUS in the validation set. Results: In the development set, the mean elasticity index (47.25 kPa) was the optimal cut-off. In the validation set, pleural ultrasound elastography had a sensitivity of 83.64%, a specificity of 90.67%, a positive predictive value of 86.79%, a negative predictive value of 88.31%, a positive likelihood ratio of 8.96 and a negative likelihood ratio of 0.18 for diagnosing MPE. The sensitivity of ultrasound elastography was significantly higher (p=0.006) than that of TUS (60%). Conclusion: Pleural ultrasound elastography is a better technique than TUS for differentiating MPE from benign pleural disease.

IF:11.81

Tropism of influenza B viruses in human respiratory tract explants and airway organoids

期刊: EUROPEAN RESPIRATORY JOURNAL, 2019; 54 (2)

Despite causing regular seasonal epidemics with substantial morbidity, mortality and socioeconomic burden, there is still a lack of research into influenza B viruses (IBVs). In this study, we provide for the first time a systematic investigation on the tropism, replication kinetics and pathogenesis of IBVs in the human respiratory tract. Physiologically relevant ex vivo explant cultures of human bronchus and lung, human airway organoids, and in vitro cultures of differentiated primary human bronchial epithelial cells and type-I-like alveolar epithelial cells were used to study the cellular and tissue tropism, replication competence and induced innate immune response of 16 IBV strains isolated from 1940 to 2012 in comparison with human seasonal influenza A viruses (IAVs), H1N1 and H3N2. IBVs from the diverged Yamagata-and Victoria-like lineages and the earlier undiverged period were included. The majority of IBVs replicated productively in human bronchus and lung with similar competence to seasonal IAVs. IBVs infected a variety of cell types, including ciliated cells, club cells, goblet cells and basal cells, in human airway organoids. Like seasonal IAVs, IBVs are low inducers of pro-inflammatory cytokines and chemokines. Most results suggested a higher preference for the conducting airway than the lower lung and strain-specific rather than lineage-specific pathogenicity of IBVs. Our results highlighted the non-negligible virulence of IBVs which require more attention and further investigation to alleviate the disease burden, especially when treatment options are limited.

IF:11.81

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