Gastric aspiration and its role in airway inflammation

Gastro-Oesophageal Reflux (GOR) has been associated with chronic airway diseases while the passage of foreign matter into airways and lungs through aspiration has the potential to initiate a wide spectrum of pulmonary disorders. The clinical syndrome resulting from such aspiration will depend both on the quantity and nature of the aspirate as well as the individual host response. Aspiration of gastric fluids may cause damage to airway epithelium, not only because acidity is toxic to bronchial epithelial cells but also due to the effect of digestive enzymes such as pepsin and bile salts. Experimental models have shown that direct instillation of these factors to airways epithelia cause damage with a consequential inflammatory response. The pathophysiology of these responses is gradually being dissected, with better understanding of acute gastric aspiration injury, a major cause of acute lung injury, providing opportunities for therapeutic intervention and potentially, ultimately, improved understanding of the chronic airway response to aspiration. Ultimately, clarification of the inflammatory pathways which are related to micro-aspiration via pepsin and bile acid salts may eventually progress to pharmacological intervention and surgical studies to assess the clinical benefits of such therapies in driving symptom improvement or reducing disease progression

Post-tuberculosis mycetoma: bronchoscopic removal

A 76‐year‐old male non‐smoker presented to our institution with cough and haemoptysis. He had been treated for cavitatory pulmonary Mycobacterium tuberculosis of the right upper lobe 10 years previously. Chest radiograph and subsequent computed tomography (CT) of the chest demonstrated a right upper cavity containing a mass suspicious for mycetoma. Flexible bronchoscopy under conscious sedation demonstrated a mass obstructing the anterior segment of the right upper lobe. The abnormality was subsequently removed using a flexible endobronchial cryoprobe. Histopathological analysis demonstrated abundant fungal organisms morphologically consistent with Aspergillus species. Microbiological culture of the bronchoalveolar lavage (BAL) from the cavity isolated both Aspergillus fumigatus and Staphylococcus aureus. The patient was commenced on the anti‐fungal drug posaconazole and received a course of flucloxacillin. Three months later, there was no endobronchial obstruction and lavage of the affected cavity again isolated Staphylococcus aureus without Aspergillus species. Repeat thoracic CT and flexible bronchoscopy demonstrated no further re‐occurrence of the mycetoma at 3 months

A protocol for a randomised clinical trial of the effect of providing feedback on inhaler technique and adherence from an electronic device in patients with poorly controlled severe asthma.

INTRODUCTION: In clinical practice, it is difficult to distinguish between patients with refractory asthma from those with poorly controlled asthma, where symptoms persist due to poor adherence, inadequate inhaler technique or comorbid diseases. We designed an audio recording device which, when attached to an inhaler, objectively identifies the time and technique of inhaler use, thereby assessing both aspects of adherence. This study will test the hypothesis that feedback on these two aspects of adherence when passed on to patients improves adherence and helps clinicians distinguish refractory from difficult-to-control asthma. METHODS: This is a single, blind, prospective, randomised, clinical trial performed at 5 research centres. Patients with partially controlled or uncontrolled severe asthma who have also had at least one severe asthma exacerbation in the prior year are eligible to participate. The effect of two types of nurse-delivered education interventions to promote adherence and inhaler technique will be assessed. The active group will receive feedback on their inhaler technique and adherence from the new device over a 3-month period. The control group will also receive training in inhaler technique and strategies to promote adherence, but no feedback from the device. The primary outcome is the difference in actual adherence, a measure that incorporates time and technique of inhaler use between groups at the end of the third month. Secondary outcomes include the number of patients who remain refractory despite good adherence, and differences in the components of adherence after the intervention. Data will be analysed on an intention-to-treat and a per-protocol basis. The sample size is 220 subjects (110 in each group), and loss to follow-up is estimated at 10% which will allow results to show a 10% difference (0.8 power) in adherence between group means with a type I error probability of 0.05. TRIAL REGISTRATION NUMBER: NCT01529697; Pre-results

In patients with severe uncontrolled asthma, does knowledge of adherence and inhaler technique using electronic monitoring improve clinical decision making? A protocol for a randomised controlled trial

Introduction: Many patients with asthma remain poorly controlled despite the use of inhaled corticosteroids and long-acting beta agonists. Poor control may arise from inadequate adherence, incorrect inhaler technique or because the condition is refractory. Without having an objective assessment of adherence, clinicians may inadvertently add extra medication instead of addressing adherence. This study aims to assess if incorporating objectively recorded adherence from the Inhaler Compliance Assessment (INCA) device and lung function into clinical decision making provides more cost-effective prescribing and improves outcomes. Methods and analysis: This prospective, randomised, multicentre study will compare the impact of using information on adherence to influence asthma treatment. Patients with severe uncontrolled asthma will be included. Data on adherence, inhaler technique and electronically recorded peak expiratory flow rate will be used to promote adherence and guide a clinical decision protocol to guide management in the active group. The control group will receive standard inhaler and adherence education. Medications will be adjusted using a protocol based on Global Initiativefor Asthma (GINA) recommendations. The primary outcome is the between-group difference in the proportion of patients who have refractory disease and are prescribed appropriate medications at the end of 32 weeks. A co-primary outcome is the difference between groups in the rate of adherence to salmeterol/fluticasone inhaler over the last 12 weeks. Secondary outcomes include changes in symptoms, lung function, type-2 cytokine biomarkers and clinical outcomes between both groups. Cost-effectiveness and cost-utility analyses of the INCA device intervention will be performed. The economic impact of a national implementation of the INCA-SUN programme will be evaluated. Ethics and dissemination:The results of the study will be published as a manuscript in peer-reviewed journals. The study has been approved by the ethics committees in the five participating hospitals. Trial registration NCT02307669; Pre-results

The presence of Aspergillus fumigatus in asthmatic airways is not clearly related to clinical disease severity

Background: It is suggested that airway fungi, in particular Aspergillus may impinge on clinical phenotype in asthma. Indeed, the term severe asthma with fungal sensitization (SAFS) has been coined. We aimed to ascertain whether the presence of fungi, in particular Aspergillus fumigatus, in the airway correlated with asthma severity and control. Furthermore, we aimed to determine whether traditional markers of Aspergillus sensitization related to the presence of Aspergillus within the airway. Methods: Sixty‐nine patients characterized by asthma severity (GINA) and level of control (ACQ‐7) underwent bronchoscopy and bronchoalveolar lavage (BAL). Serum was assessed for A fumigatus‐specific IgE and total IgE. Galactomannan and relevant cytokine levels were assessed in serum, plasma and BAL. BAL was analyzed for the presence of A fumigatus. Results: In BAL, fungi were visible by microscopy in 70% and present by qPCR in 86% of patients, while A fumigatus was detectable by qPCR in 46%. Plasma and BAL IL‐4, IL‐6, IL‐10, IL‐13 and TNF‐α correlated with BAL fungal presence, while plasma IL‐17 correlated with BAL fungal presence. Aspergillus positive BAL correlated with increased plasma and BAL IL‐6 and BAL IL‐13. There was no relationship between fungal airway presence and steroid dose, asthma severity or control. The presence of Aspergillus within the airway did not relate to serum IgE positivity for Aspergillus. Conclusions: Fungi were present in a large proportion of our asthmatic patients’ airways, but their presence was not predicted by traditional markers of sensitization, nor did it appear to be related to measures of disease severity or control

Pharmacogenetic meta-analysis of genome-wide association studies of LDL cholesterol response to statins

Statins effectively lower LDL cholesterol levels in large studies and the observed interindividual response variability may be partially explained by genetic variation. Here we perform a pharmacogenetic meta-analysis of genome-wide association studies (GWAS) in studies addressing the LDL cholesterol response to statins, including up to 18,596 statin-treated subjects. We validate the most promising signals in a further 22,318 statin recipients and identify two loci, SORT1/CELSR2/PSRC1 and SLCO1B1, not previously identified in GWAS. Moreover, we confirm the previously described associations with APOE and LPA. Our findings advance the understanding of the pharmacogenetic architecture of statin response

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

Post-tuberculosis mycetoma: bronchoscopic removal

A 76‐year‐old male non‐smoker presented to our institution with cough and haemoptysis. He had been treated for cavitatory pulmonary Mycobacterium tuberculosis of the right upper lobe 10 years previously. Chest radiograph and subsequent computed tomography (CT) of the chest demonstrated a right upper cavity containing a mass suspicious for mycetoma. Flexible bronchoscopy under conscious sedation demonstrated a mass obstructing the anterior segment of the right upper lobe. The abnormality was subsequently removed using a flexible endobronchial cryoprobe. Histopathological analysis demonstrated abundant fungal organisms morphologically consistent with Aspergillus species. Microbiological culture of the bronchoalveolar lavage (BAL) from the cavity isolated both Aspergillus fumigatus and Staphylococcus aureus. The patient was commenced on the anti‐fungal drug posaconazole and received a course of flucloxacillin. Three months later, there was no endobronchial obstruction and lavage of the affected cavity again isolated Staphylococcus aureus without Aspergillus species. Repeat thoracic CT and flexible bronchoscopy demonstrated no further re‐occurrence of the mycetoma at 3 months