Mark Hew

Bronchoscopic evaluation of the mediastinum using endobronchial ultrasound: A description of the first 216 cases carried out at an Australian tertiary hospital

Background: Performance of linear probe endobronchial ultrasound‐guided transbronchial needle aspiration (EBUS‐TBNA) for staging non‐small‐cell lung cancer has been extensively studied. Alternate indications for its use are less well characterised, and performance in other clinical settings may differ.

Expression and activation of TGF-β isoforms in acute allergen-induced remodelling in asthma

Background: Airway wall remodelling and inflammation are features of chronic asthma. Transforming growth factor β (TGF-β) has been implicated in these processes. Aim: To determine the effect of allergen challenge on airway inflammation and remodelling and whether TGF-β isoforms and the Smad signalling pathways are involved. Methods: Thirteen patients with atopic asthma underwent inhalational challenge with 0.9% saline, followed by allergen 3–4 weeks later. After both challenges, fibreoptic bronchoscopy was undertaken to obtain bronchial biopsies and tissue samples were processed for immunohistochemistry and examined by microscopy. Results: Forced expiratory volume in 1 s (FEV1) fell after allergen challenge (mean (SE) −28.1 (0.9)% at 30 min with a late response at 7 hours (−23.0 (1.2)%). Allergen challenge caused an increase in neutrophils and eosinophils in the bronchial mucosa compared with saline. Sub-basement membrane (SBM) thickness did not change after allergen, but tenascin deposition in SBM was increased. Intranuclear (activated) Smad 2/3 and Smad 4 detected by immunohistochemistry were increased after allergen challenge in epithelial and subepithelial cells of bronchial biopsies. No inhibitory Smad (Smad 7) protein was detected. TGF-β isoforms 1, 2 and 3 were expressed predominantly in bronchial epithelium after saline and allergen challenges, but only TGF-β2 expression was increased after allergen. Double immunostaining showed an increase in TGF-β2 positive eosinophils and neutrophils but not in TGF-β1 positive eosinophils and neutrophils after allergen challenge. Conclusions: TGF-β2 may contribute to the remodelling changes in allergic asthma following single allergen exposure.

Effect of p38 MAPK inhibition on corticosteroid suppression of cytokine release in severe asthma

Patients with severe asthma respond less well to corticosteroids than those with non-severe asthma. Increased p38 mitogen-activated protein kinase (MAPK) activation in alveolar macrophages (AMs) from severe asthma patients has been associated with a reduced inhibition of cytokine release by dexamethasone. We determined whether p38 MAPK inhibitors would modulate corticosteroid suppression of cytokine release from AMs and peripheral blood mononuclear cells (PBMCs). PBMCs were isolated from venous blood and AMs by bronchoalveolar lavage in severe and non-severe asthma patients. PBMCs and AMs were exposed to lipopolysaccharide (LPS) with and without the p38 MAPK inhibitor, SD282, or dexamethasone. We determined the concentration-dependent effects of another p38 MAPK inhibitor, GW-A, on dexamethasone-induced inhibition of interleukin (IL)-8 release from PBMCs. Cytokines were assayed using an ELISA-based method. SD282 (10−7 M), with dexamethasone (10−6 M), caused a greater inhibition of release of IL-1β, IL-6, macrophage inflammatory protein-1α and IL-10, than with dexamethasone alone in AMs from severe and non-severe asthma. At 10−9 and 10−10 M, GW-A, that had no direct effects, increased the inhibitory activity of dexamethasone (10−8 and 10−6 M) on LPS-induced IL-8 release in PBMCs from severe asthma. Corticosteroid insensitivity in severe asthma patients may be improved by inhibitors of p38 MAPK.

Inflammatory biomarkers in airways of patients with severe asthma compared with non‐severe asthma

Background About 5–10% of patients with asthma suffer from poorly‐controlled disease despite corticosteroid (CS) therapy.

Corticosteroid suppression of lipoxin A4 and leukotriene B4from alveolar macrophages in severe asthma

BackgroundAn imbalance in the generation of pro-inflammatory leukotrienes, and counter-regulatory lipoxins is present in severe asthma. We measured leukotriene B4 (LTB4), and lipoxin A4 (LXA4) production by alveolar macrophages (AMs) and studied the impact of corticosteroids.MethodsAMs obtained by fiberoptic bronchoscopy from 14 non-asthmatics, 12 non-severe and 11 severe asthmatics were stimulated with lipopolysaccharide (LPS,10 μg/ml) with or without dexamethasone (10-6M). LTB4 and LXA4 were measured by enzyme immunoassay.ResultsLXA4 biosynthesis was decreased from severe asthma AMs compared to non-severe (p < 0.05) and normal subjects (p < 0.001). LXA4 induced by LPS was highest in normal subjects and lowest in severe asthmatics (p < 0.01). Basal levels of LTB4 were decreased in severe asthmatics compared to normal subjects (p < 0.05), but not to non-severe asthma. LPS-induced LTB4 was increased in severe asthma compared to non-severe asthma (p < 0.05). Dexamethasone inhibited LPS-induced LTB4 and LXA4, with lesser suppression of LTB4 in severe asthma patients (p < 0.05). There was a significant correlation between LPS-induced LXA4 and FEV1 (% predicted) (rs = 0.60; p < 0.01).ConclusionsDecreased LXA4 and increased LTB4 generation plus impaired corticosteroid sensitivity of LPS-induced LTB4 but not of LXA4 support a role for AMs in establishing a pro-inflammatory balance in severe asthma.

Corticosteroid insensitivity in severe asthma: significance, mechanisms and aetiology

Chronic severe asthma remains a challenging clinical problem despite the availability of modern treatments. Relative corticosteroid insensitivity is present in severe asthma and may contribute to continuing disease severity. Advances in the understanding of molecular mechanisms underlying corticosteroid insensitivity may yield new therapeutic targets. Furthermore, aetiological factors for corticosteroid insensitivity have been identified and these may be amenable to modification.

Comorbidities in difficult asthma are independent risk factors for frequent exacerbations, poor control and diminished quality of life

Little is known about how comorbidities affect difficult asthma patients across different domains of asthma outcomes. We hypothesized that comorbidities in difficult asthma significantly influence asthma outcomes.

Capsaicin cough sensitivity in bronchiectasis

Background: Bronchiectasis is a suppurative airway disease characterised by persistent cough and sputum production associated with bronchial dilatation. A study was undertaken to determine whether cough sensitivity is increased in bronchiectatic patients. Methods: Twenty two patients with bronchiectasis and 20 healthy non-smoking controls matched for age and sex were recruited into the study. Quality of life (Leicester Cough Questionnaire score), total cough symptom score, and extent of bronchiectasis on HRCT scans were recorded. Cough sensitivity was assessed using incremental inhalation of capsaicin concentrations; the concentration at which 5 or more coughs occurred (C5) was recorded. Results: Patients with bronchiectasis had increased sensitivity to capsaicin compared with controls (mean (SE) log10 C5 1.22 (0.20) v 1.89 (0.21); p<0.03). Capsaicin sensitivity correlated positively with the Leicester Cough Questionnaire score (r = 0.64; p = 0.005) and inversely with the total cough symptom score (r = −0.58; p = 0.004), but not with the extent of the disease. It also correlated with forced expiratory volume in 1 second (FEV1) in litres (r = 0.58; p = 0.005) but not with FEV1 % predicted. Capsaicin sensitivity was not related to the presence of infected sputum or to corticosteroid or bronchodilator use. Conclusions:: Patients with bronchiectasis have a sensitive cough reflex which reflects the severity of cough symptoms. A measure of cough severity could be part of health assessment for patients with bronchiectasis.

Safety of investigative bronchoscopy in the Severe Asthma Research Program.

BACKGROUND Investigative bronchoscopy was performed in a subset of participants in the Severe Asthma Research Program to gain insights into the pathobiology of severe disease. We evaluated the safety aspects of this procedure in this cohort with specific focus on patients with severe asthma. OBJECTIVE To evaluate prospectively changes in lung function and the frequency of adverse events related to investigative bronchoscopy. METHODS Bronchoscopy was performed by using a common manual of procedures. A subset of very severe asthma was defined by severe airflow obstruction, chronic oral corticosteroid use, and recent asthma exacerbations. Subjects were monitored for changes in lung function and contacted by telephone for 3 days after the procedure. RESULTS A total of 436 subjects underwent bronchoscopy (97 normal, 196 not severe, 102 severe, and 41 very severe asthma). Nine subjects were evaluated in hospital settings after bronchoscopy; 7 of these were respiratory-related events. Recent emergency department visits, chronic oral corticosteroid use, and a history of pneumonia were more frequent in subjects who had asthma exacerbations after bronchoscopy. The fall in FEV₁ after bronchoscopy was similar in the severe and milder asthma groups. Prebronchodilator FEV₁ was the strongest predictor of change in FEV₁ after bronchoscopy with larger decreases observed in subjects with better lung function. CONCLUSION Bronchoscopy in subjects with severe asthma was well tolerated. Asthma exacerbations were rare, and reduction in pulmonary function after the procedure was similar to that in subjects with less severe asthma. With proper precautions, investigative bronchoscopy can be performed safely in severe asthma.

Expression of transforming growth factor-β (TGF-β) in chronic idiopathic cough

In patients with chronic idiopathic cough, there is a chronic inflammatory response together with evidence of airway wall remodelling and an increase in airway epithelial nerves expressing TRPV-1. We hypothesised that these changes could result from an increase in growth factors such as TGFβ and neurotrophins.We recruited 13 patients with persistent non-asthmatic cough despite specific treatment of associated primary cause(s), or without associated primary cause, and 19 normal non-coughing volunteers without cough as controls, who underwent fiberoptic bronchoscopy with bronchoalveolar lavage (BAL) and bronchial biopsies.There was a significant increase in the levels of TGFβ in BAL fluid, but not of nerve growth factor(NGF) and brain-derived nerve growth factor(BDNF) compared to normal volunteers. Levels of TFGβ gene and protein expression were assessed in bronchial biopsies. mRNA expression for TGFβ was observed in laser-captured airway smooth muscle and epithelial cells, and protein expression by immunohistochemistry was increased in ASM cells in chronic cough patients, associated with an increase in nuclear expression of the transcription factor, smad 2/3. Subbasement membrane thickness was significantly higher in cough patients compared to normal subjects and there was a positive correlation between TGF-β levels in BAL and basement membrane thickening.TGFβ in the airways may be important in the airway remodelling changes observed in chronic idiopathic cough patients, that could in turn lead to activation of the cough reflex.