Showing papers by "Peter G. Gibson published in 2017"

Role for NLRP3 Inflammasome-mediated, IL-1β-Dependent Responses in Severe, Steroid-Resistant Asthma.

Abstract: Rationale: Severe, steroid-resistant asthma is the major unmet need in asthma therapy. Disease heterogeneity and poor understanding of pathogenic mechanisms hampers the identification of therapeutic targets. Excessive nucleotide-binding oligomerization domain–like receptor family, pyrin domain–containing 3 (NLRP3) inflammasome and concomitant IL-1β responses occur in chronic obstructive pulmonary disease, respiratory infections, and neutrophilic asthma. However, the direct contributions to pathogenesis, mechanisms involved, and potential for therapeutic targeting remain poorly understood, and are unknown in severe, steroid-resistant asthma.Objectives: To investigate the roles and therapeutic targeting of the NLRP3 inflammasome and IL-1β in severe, steroid-resistant asthma.Methods: We developed mouse models of Chlamydia and Haemophilus respiratory infection–mediated, ovalbumin-induced severe, steroid-resistant allergic airway disease. These models share the hallmark features of human disease, including ele...

Precision medicine in airway diseases: moving to clinical practice

Abstract: On February 21, 2017, a European Respiratory Society research seminar held in Barcelona discussed how to best apply precision medicine to chronic airway diseases such as asthma and chronic obstructive pulmonary disease. It is now clear that both are complex and heterogeneous diseases, that often overlap and that both require individualised assessment and treatment. This paper summarises the presentations and discussions that took place during the seminar. Specifically, we discussed the need for a new taxonomy of human diseases, the role of different players in this scenario (exposome, genes, endotypes, phenotypes, biomarkers and treatable traits) and a number of unanswered key questions in the field. We also addressed how to deploy airway precision medicine in clinical practice today, both in primary and specialised care. Finally, we debated the type of research needed to move the field forward.

Soluble Fibre Meal Challenge Reduces Airway Inflammation and Expression of GPR43 and GPR41 in Asthma

Abstract: Short chain fatty acids (SCFAs) are produced following the fermentation of soluble fibre by gut bacteria. In animal models, both dietary fibre and SCFAs have demonstrated anti-inflammatory effects via the activation of free fatty acid receptors, such as G protein-coupled receptor 41 and 43 (GPR41 and GPR43). This pilot study examined the acute effect of a single dose of soluble fibre on airway inflammation-including changes in gene expression of free fatty acid receptors-in asthma. Adults with stable asthma consumed a soluble fibre meal (n = 17) containing 3.5 g inulin and probiotics, or a control meal (n = 12) of simple carbohydrates. Exhaled nitric oxide (eNO) was measured and induced sputum was collected at 0 and 4 h for differential cell counts, measurement of interleukin-8 (IL-8) protein concentration, and GPR41 and GPR43 gene expression. At 4 h after meal consumption, airway inflammation biomarkers, including sputum total cell count, neutrophils, macrophages, lymphocytes, sputum IL-8, and eNO significantly decreased compared to baseline in the soluble fibre group only. This corresponded with upregulated GPR41 and GPR43 sputum gene expression and improved lung function in the soluble fibre group alone. Soluble fibre has acute anti-inflammatory effects in asthmatic airways. Long-term effects of soluble fibre as an anti-inflammatory therapy in asthma warrants further investigation.

Macrophage dysfunction in the pathogenesis and treatment of asthma

Abstract: Asthma is a chronic respiratory condition frequently associated with aberrant airway and systemic inflammation. Various inflammatory phenotypes in asthmatic airways have been described that relate to clinical phenotypes and impact on responses to conventional and novel asthma therapies. Macrophages are abundant immunocytes in the lung, capable of mounting diverse responses required for homeostasis and defence against pathogens.Here, we summarise the clinical evidence regarding macrophage dysfunction in asthma. We also describe evidence supporting the role of macrophages as therapeutic targets in asthma. We conclude that macrophage dysfunction in asthma is highly prevalent and heterogeneous, and hypothesise that macrophages may play roles in promoting the discrete inflammatory phenotypes of asthma.These clinical findings, along with recent ground-breaking insights into the ontogeny, behavioural complexity and longevity of pulmonary macrophages, support continued research into the role of macrophages as disease modifiers, biomarkers and therapeutic targets in asthma.

Multidimensional assessment of severe asthma: A systematic review and meta-analysis

Abstract: The management of severe asthma is complex. Multidimensional assessment (MDA) of specific traits has been proposed as an effective strategy to manage severe asthma, although it is supported by few prospective studies. We aimed to systematically review the literature published on MDA in severe asthma, to identify the traits included in MDA and to determine the effect of MDA on asthma-related outcomes. We identified 26 studies and classified these based on study type (cohort/cross-sectional studies; experimental/outcome studies; and severe asthma disease registries). Study type determined the comprehensiveness of the assessment. Assessed traits were classified into three domains (airways, co-morbidities and risk factors). The airway domain had the largest number of traits assessed (mean ± SD = 4.2 ± 1.7) compared with co-morbidities (3.6 ± 2.2) and risk factors (3.9 ± 2.1). Bronchodilator reversibility and airflow limitation were assessed in 92% of studies, whereas airway inflammation was only assessed in 50%. Commonly assessed co-morbidities were psychological dysfunction, sinusitis (both 73%) and gastro-oesophageal reflux disease (GORD; 69%). Atopic and smoking statuses were the most commonly assessed risk factors (85% and 86%, respectively). There were six outcome studies, of which five concluded that MDA is effective at improving asthma-related outcomes. Among these studies, significantly more traits were assessed than treated. MDA studies have assessed a variety of different traits and have shown evidence of improved outcomes. This promising model of care requires more research to inform which traits should be assessed, which traits should be treated and what effect MDA has on patient outcomes.

A sputum gene expression signature predicts oral corticosteroid response in asthma.

Abstract: Biomarkers that predict responses to oral corticosteroids (OCS) facilitate patient selection for asthma treatment. We hypothesised that asthma patients would respond differently to OCS therapy, with biomarkers and inflammometry predicting response. Adults with stable asthma underwent a randomised controlled cross-over trial of 50 mg prednisolone daily for 10 days (n=55). A six-gene expression biomarker signature ( CLC , CPA3 , DNASE1L3 , IL1B , ALPL and CXCR2 ) in induced sputum, and eosinophils in blood and sputum were assessed and predictors of response were investigated (changes in forced expiratory volume in 1 s (ΔFEV 1 ), six-item Asthma Control Questionnaire score (ΔACQ6) or exhaled nitric oxide fraction (Δ F eNO )). At baseline, responders to OCS (n=25) had upregulated mast cell CPA3 gene expression, poorer lung function, and higher sputum and blood eosinophils. Following treatment, CLC and CPA3 gene expression was reduced, whereas DNASE1L3, IL1B, ALPL and CXCR2 expression remained unchanged. Receiver operating characteristic (ROC) analysis showed the six-gene expression biomarker signature as a better predictor of clinically significant responses to OCS than blood and sputum eosinophils. The six-gene expression signature including eosinophil and Th2 related mast cell biomarkers showed greater precision in predicting OCS response in stable asthma. Thus, a novel sputum gene expression signature highlights an additional role of mast cells in asthma, and could be a useful measurement to guide OCS therapy in asthma.

Severe Asthma: Current Management, Targeted Therapies and Future directions-A Roundtable Report

Abstract: Asthma is a chronic respiratory disease characterized by respiratory symptoms, airway inflammation, airway obstruction and airway hyper-responsiveness. Asthma is common and directly affects 10% of Australians, 1-5% of adults in Asia and 300 million people worldwide. It is a heterogeneous disorder with many clinical, molecular, biological and pathophysiological phenotypes. Current management strategies successfully treat the majority of patients with asthma who have access to them. However, there is a subset of an estimated 5-10% of patients with asthma who have severe disease and are disproportionately impacted by symptoms, exacerbations and overall illness burden. The care required for this relatively small proportion of patients is also significant and has a major impact on the healthcare system. A number of new therapies that hold promise for severe asthma are currently in clinical trials or are entering the Australian and international market. However, recognition of severe asthma in clinical practice is variable, and there is little consensus on the best models of care or how to integrate emerging and often costly therapies into current practice. In this article, we report on roundtable discussions held with severe asthma experts from around Australia, and make recommendations about approaches for better patient diagnosis and assessment. We assess current models of care for patient management and discuss how approaches may be optimized to improve patient outcomes. Finally, we propose mechanisms to assess new therapies and how to best integrate these approaches into future treatment.

The Expression of IL-6, TNF-α, and MCP-1 in Respiratory Viral Infection in Acute Exacerbations of Chronic Obstructive Pulmonary Disease

Abstract: Viral infection is a common trigger for acute exacerbations of chronic obstructive pulmonary disease (AECOPD). The aim of this study is to investigate the expression of cytokines in AECOPD. Patients with AECOPD requiring hospitalization were recruited. Meanwhile healthy volunteers of similar age that accepted routine check-ups and showed no clinical symptoms of inflammatory diseases were also recruited. Induced sputum and serum were collected. Induced sputum of participants was processed and tested for thirteen viruses and bacteria. Forty cytokines were assayed in serum using the Quantibody Human Inflammation Array 3 (Ray Biotech, Inc.). The most common virus detected in virus positive AECOPD (VP) was influenza A (16%). No virus was found in controls. Circulating levels of IL-6, TNF-α, and MCP-1 were elevated in VP and coinfection subjects (p 0.05). Additionally, VP patients were less likely to have received influenza vaccination. VP patients had a systemic inflammation response involving IL-6, TNF-α, and MCP-1 which may be due to virus-induced activation of macrophages. There are important opportunities for further investigating AECOPD mechanisms and for the development of better strategies in the management and prevention of virus-related AECOPD.

Role of Obesity in Asthma: Mechanisms and Management Strategies.

Abstract: Obesity is a commonly reported comorbidity in asthma, particularly in severe asthma. Obese asthmatics are highly symptomatic with a poor quality of life, despite using high-dose inhaled corticosteroids. While the clinical manifestations have been documented, the aetiologies of obese-asthma remain unclear. Several potential mechanisms have been proposed, including poor diet quality, physical inactivity and consequent accrual of excess adipose tissue. Each of these factors independently activates inflammatory pathways, potentially exerting effects in the airways. Because the origins of obesity are multifactorial, it is now believed there are multiple obese-asthma phenotypes, with varied aetiologies and clinical consequences. In this review, we will describe the clinical implications of obesity in people with asthma, our current understanding of the mechanisms driving this association and describe recently proposed obese-asthma phenotypes. We will then discuss how asthma management is complicated by obesity, and provide graded recommendations for the management of obesity in this population.

Sputum basophils are increased in eosinophilic asthma compared with non‐eosinophilic asthma phenotypes

Abstract: Sputum basophil numbers are increased in allergic asthmatics, but it is unclear what role airway basophils play in "TH2-low" asthma phenotypes. Using flow cytometry, we found that basophils were significantly increased in all asthmatics (n=26) compared with healthy controls (n=8) (P=0.007) with highest levels observed in eosinophilic asthma (EA); median 0.22%, IQR 0.11%-0.47%; n=14) compared with non-EA (NEA) (0.06%, 0.00%-0.20%; n=12; P<0.05). In asthmatics, basophils were positively correlated with sputum eosinophils (r=0.54; P<0.005) and inversely with sputum neutrophils (r=-0.46: P<0.05), but not with FEV1 (% predicted), FEV1 /FVC or bronchodilator reversibility. In a subgroup initially identified as inadequately controlled asthma (n=7), there was a trend (P=0.08) towards a reduction in sputum basophils following increased inhaled corticosteroid (ICS) treatment. Our findings suggest that basophils may be particularly important in eosinophilic asthma and that sputum basophil assessment could be a useful additional indicator of "TH2-high" asthma.

Asthma during Pregnancy: Exacerbations, Management, and Health Outcomes for Mother and Infant.

Abstract: One in 10 pregnant women worldwide has asthma and of these, 10% will have a severe exacerbation requiring oral corticosteroids (OCSs) in pregnancy This review of recent publications in the field will describe the effects of exacerbation on maternal and neonatal health, the use of asthma medications during pregnancy, and will suggest novel management approaches for asthma in pregnancy Pregnancy results in unpredictable changes in the disease; therefore, regular monitoring of symptoms is recommended Uncontrolled asthma is frequently described in cohorts of pregnant women with asthma, and some recent studies show associations with adverse perinatal outcomes, as previously demonstrated with exacerbations Guidelines for the management of asthma recommend the continued use of inhaled corticosteroids (ICSs) in pregnancy, with budesonide having a particularly good safety profile Recent data suggest small effects of asthma and/or asthma medication use on congenital malformations; however, there is less data available on the safety of ICS/long-acting β agonist combinations, which are increasingly used for maintenance treatment Novel management strategies are needed to address the complex needs of pregnant women with asthma These include medication nonadherence and the presence of numerous comorbidities which can affect asthma, such as rhinitis, cigarette smoking, obesity, and mental health issues Inflammation-based management has been shown to be effective in reducing exacerbations in pregnancy and may also improve perinatal outcomes The involvement of a multidisciplinary team and the assessment of comorbidities have potential to improve the health of mothers and their offspring

Management of severe asthma: targeting the airways, comorbidities and risk factors.

Abstract: Severe asthma is a complex heterogeneous disease that is refractory to standard treatment and is complicated by multiple comorbidities and risk factors. In mild to moderate asthma, the burden of disease can be minimised by inhaled corticosteroids, bronchodilators and self-management education. In severe asthma, however, management is more complex. When patients with asthma continue to experience symptoms and exacerbations despite optimal management, severe refractory asthma (SRA) should be suspected and confirmed, and other aetiologies ruled out. Once a diagnosis of SRA is established, patients should undergo a systematic and multidimensional assessment to identify inflammatory endotypes, risk factors and comorbidities, with targeted and individualised management initiated. We describe a practical approach to assessment and management of patients with SRA.

Treatment burden, clinical outcomes, and comorbidities in COPD: an examination of the utility of medication regimen complexity index in COPD

Abstract: BACKGROUND COPD patients are often prescribed multiple medications for their respiratory disease and comorbidities. This can lead to complex medication regimens resulting in poor adherence, medication errors, and drug-drug interactions. The relationship between clinical outcomes and medication burden beyond medication count in COPD is largely unknown. OBJECTIVES The aim of this study was to explore the relationships of medication burden in COPD with clinical outcomes, comorbidities, and multidimensional indices. METHODS In a cross-sectional study, COPD patients (n=222) were assessed for demographic information, comorbidities, medication use, and clinical outcomes. Complexity of medication regimens was quantified using the validated medication regimen complexity index (MRCI). RESULTS Participants (58.6% males) had a mean (SD) age of 69.1 (8.3) years with a postbronchodilator forced expiratory volume in 1 second % predicted of 56.5 (20.4) and a median of five comorbidities. The median (q1, q3) total MRCI score was 24 (18.5, 31). COPD-specific medication regimens were more complex than those of non-COPD medications (median MRCI: 14.5 versus 9, respectively; P<0.0001). Complex dosage formulations contributed the most to higher MRCI scores of COPD-specific medications while dosing frequency primarily drove the complexity associated with non-COPD medications. Participants in Global Initiative for Chronic Obstructive Lung Disease quadrant D had the highest median MRCI score for COPD medications (15.5) compared to those in quadrants A (13.5; P=0.0001) and B (12.5; P<0.0001). Increased complexity of COPD-specific treatments showed significant but weak correlations with lower lung function and 6-minute walk distance, higher St George's Respiratory Questionnaire and COPD assessment test scores, and higher number of prior year COPD exacerbations and hospitalizations. Comorbid cardiovascular, gastrointestinal, or metabolic diseases individually contributed to higher total MRCI scores and/or medication counts for all medications. Charlson Comorbidity Index and COPD-specific comorbidity test showed the highest degree of correlation with total MRCI score (ρ=0.289 and ρ=0.326; P<0.0001, respectively). CONCLUSION In COPD patients, complex medication regimens are associated with disease severity and specific class of comorbidities.

Severe and uncontrolled asthma in China: a cross-sectional survey from the Australasian Severe Asthma Network

Abstract: Background: Severe asthma is largely unexplored in the Chinese population. Patients with asthma underwent systematic evaluation, by investigating the characteristics of uncontrolled asthma and of asthma treated with three different controller therapies. Methods: This multi-centre, real-world study was conducted from March 2014 to September 2015. Adults with stable asthma underwent assessment of medication use, asthma control, quality of life, psychological symptoms, work productivity and activity impairment, bronchodilator response and sputum induction. Results: Participants (n=379) had a mean (SD) age of 47.4 (14.0) years, and 57.0% were female. There were 14.8% (n=56) of patients receiving treatment with Step 4/5 as severe asthma, but only 13 (3.4%) met ERS/ATS severe refractory asthma criteria. The patients with severe asthma usually used triple controller therapy: ICS/LABA, additional leukotriene modifier or theophylline, and reported better asthma control. Two fifths of patients (n=147) had uncontrolled asthma, with worse symptoms, psychological symptoms (both P vs. 0.2% (0.0, 1.3%), P Conclusions: Although there is a relatively low proportion of severe refractory asthma based on ERS/ATS criteria, two of five patients with asthma in China are uncontrolled, displaying more psychological symptoms and reduced work productivity. Substantial gain in asthma control is obtained by triple controller therapy and this may be a promising therapeutic option for persistent asthma.

Airway gene expression of IL-1 pathway mediators predicts exacerbation risk in obstructive airway disease

Abstract: BACKGROUND Exacerbations of asthma and COPD are a major cause of morbidity and mortality and are responsible for significant health care costs. This study further investigates interleukin (IL)-1 pathway activation and its relationship with exacerbations of asthma and COPD. METHODS In this prospective cohort study, 95 participants with stable asthma (n=35) or COPD (n=60) were recruited and exacerbations recorded over the following 12 months. Gene expressions of IL-1 pathway biomarkers, including the IL-1 receptors (IL1R1, IL1R2, and IL1RN), and signaling molecules (IRAK2, IRAK3, and PELI1), were measured in sputum using real-time quantitative polymerase chain reaction. Mediators were compared between the frequent (≥2 exacerbations in the 12 months) and infrequent exacerbators, and the predictive relationships investigated using receiver operating characteristic curves and area under the curve (AUC) values. RESULTS Of the 95 participants, 89 completed the exacerbation follow-up, where 30 participants (n=22 COPD, n=8 asthma) had two or more exacerbations. At the baseline visit, expressions of IRAK2, IRAK3, PELI1, and IL1R1 were elevated in participants with frequent exacerbations of both asthma and COPD combined and separately. In the combined population, sputum gene expression of IRAK3 (AUC=75.4%; P<0.001) was the best predictor of future frequent exacerbations, followed by IL1R1 (AUC=72.8%; P<0.001), PELI1 (AUC=71.2%; P<0.001), and IRAK2 (AUC=68.6; P=0.004). High IL-1 pathway gene expression was associated with frequent prior year exacerbations and correlated with the number and severity of exacerbations. CONCLUSION The upregulation of IL-1 pathway mediators is associated with frequent exacerbations of obstructive airway disease. Further studies should investigate these mediators as both potential diagnostic biomarkers predicting at-risk patients and novel treatment targets.

Identification and validation of asthma phenotypes in Chinese population using cluster analysis

Abstract: Background Asthma is a heterogeneous airway disease, so it is crucial to clearly identify clinical phenotypes to achieve better asthma management. Objective To identify and prospectively validate asthma clusters in a Chinese population. Methods Two hundred eighty-four patients were consecutively recruited and 18 sociodemographic and clinical variables were collected. Hierarchical cluster analysis was performed by the Ward method followed by k -means cluster analysis. Then, a prospective 12-month cohort study was used to validate the identified clusters. Results Five clusters were successfully identified. Clusters 1 (n = 71) and 3 (n = 81) were mild asthma phenotypes with slight airway obstruction and low exacerbation risk, but with a sex differential. Cluster 2 (n = 65) described an "allergic" phenotype, cluster 4 (n = 33) featured a "fixed airflow limitation" phenotype with smoking, and cluster 5 (n = 34) was a "low socioeconomic status" phenotype. Patients in clusters 2, 4, and 5 had distinctly lower socioeconomic status and more psychological symptoms. Cluster 2 had a significantly increased risk of exacerbations (risk ratio [RR] 1.13, 95% confidence interval [CI] 1.03–1.25), unplanned visits for asthma (RR 1.98, 95% CI 1.07–3.66), and emergency visits for asthma (RR 7.17, 95% CI 1.26–40.80). Cluster 4 had an increased risk of unplanned visits (RR 2.22, 95% CI 1.02–4.81), and cluster 5 had increased emergency visits (RR 12.72, 95% CI 1.95–69.78). Kaplan-Meier analysis confirmed that cluster grouping was predictive of time to the first asthma exacerbation, unplanned visit, emergency visit, and hospital admission ( P Conclusion We identified 3 clinical clusters as "allergic asthma," "fixed airflow limitation," and "low socioeconomic status" phenotypes that are at high risk of severe asthma exacerbations and that have management implications for clinical practice in developing countries.

Sputum colour can identify patients with neutrophilic inflammation in asthma.

Abstract: Introduction Sputum colour is associated with neutrophilic inflammation in chronic bronchitis and chronic obstructive pulmonary disease (COPD). Neutrophilia and sputum expectoration is notable in asthma, but whether sputum colour is associated with and predicts the presence of neutrophilic inflammation in asthma is unknown. The objective of the study is to assess the ability of sputum colour in distinguishing asthma inflammatory phenotypes. Methods Induced sputum samples collected from 271 adults with stable asthma were retrospectively assessed. Sputum colour was determined using the BronkoTest sputum colour chart and correlated to differential cell counts and CXCL-8 concentration. Neutrophilic inflammation was defined as an age-corrected sputum neutrophil proportion (≥61.6% for age 20–40 years; ≥63.2% for age 40–60 and ≥67.2% for age >60 years), whereas neutrophilic bronchitis (NB) was defined as high total cell count (≥5.1×106 cells/mL) plus an increased age-corrected neutrophil proportion. The optimal cut-off for sputum colour to predict neutrophilic inflammation and NB was determined using receiver operator characteristic curve analysis. Results A sputum colour score of ≥3 represented and predicted neutrophilic inflammation with modest accuracy (area under the curve (AUC)=0.64; p Conclusions Visual gradation of sputum colour in asthma relates to high total cell count and neutrophilic inflammation. Assessment of sputum colour can identify adults with asthma who are likely to have NB without the need for sputum processing and differential cell count, which may facilitate asthma management.

Obesity in COPD: to treat or not to treat?

Abstract: Chronic obstructive pulmonary disease (COPD) is a significant chronic disease, particularly in aging populations. Both the prevalence and mortality of COPD are increasing throughout the world [1], ...

The Impact of a Weight Loss Intervention on Diet Quality and Eating Behaviours in People with Obesity and COPD

Abstract: There is a paucity of evidence to guide clinicians about appropriate management strategies for people with obesity and Chronic Obstructive Pulmonary Disease (COPD). We have recently published results from the first weight loss intervention in adults (>18 years) with obesity (body mass index; BMI ≥ 30 kg/m²) and COPD, using a low-calorie diet coupled with a partial meal replacement plan and resistance exercise training, which resulted in a 6.4% reduction in weight while maintaining skeletal muscle mass and improving health status. This sub-study aims to evaluate the intervention by (a) examining changes in dietary intake and nutritional biomarkers and (b) examining predictors of weight loss. Dietary intake was evaluated using four-day food diaries, and analysis of plasma fatty acids and plasma carotenoids as biomarkers of dietary fat intake and fruit and vegetable intake, respectively. Twenty-eight obese COPD subjects (n = 17 males, n = 11 females) with a mean (standard deviation; SD) age of 67.6 (6.3) years completed the 12-week weight loss intervention. Pre-intervention, mean (SD) BMI was 36.3 (4.6) kg/m². Micronutrient intake improved from pre- to post-intervention, with the percentage of subjects meeting the Nutrient Reference Values increased for all micronutrients. Post-intervention, significant decreases in total (p = 0.009) and saturated fat intake (p = 0.037), and corresponding decreases in total (p = 0.007) and saturated plasma fatty acids (p = 0.003) were observed. There was a trend towards higher total carotenoids post-intervention (p = 0.078). Older age (p = 0.025), higher pre-intervention uncontrolled eating (p < 0.001) and plasma carotenoids (p = 0.009) predicted weight loss. This demonstrates the efficacy of a weight loss intervention in improving diet quality of obese COPD adults.

"To define is to limit": perspectives on asthma-COPD overlap syndrome and personalised medicine.

Abstract: A precise definition of asthma–COPD overlap syndrome is lacking; personalised medicine is recommended http://ow.ly/sobH30aroWK

Cytokine responses to two common respiratory pathogens in children are dependent on interleukin-1β.

Abstract: Protracted bacterial bronchitis (PBB) in young children is a common cause of prolonged wet cough and may be a precursor to bronchiectasis in some children. Although PBB and bronchiectasis are both characterised by neutrophilic airway inflammation and a prominent interleukin (IL)-1β signature, the contribution of the IL-1β pathway to host defence is not clear. This study aimed to compare systemic immune responses against common pathogens in children with PBB, bronchiectasis and control children and to determine the importance of the IL-1β pathway. Non-typeable Haemophilus influenzae (NTHi) stimulation of peripheral blood mononuclear cells (PBMCs) from control subjects (n=20), those with recurrent PBB (n=20) and bronchiectasis (n=20) induced high concentrations of IL-1β, IL-6, interferon (IFN)-γ and IL-10. Blocking with an IL-1 receptor antagonist (IL-1Ra) modified the cellular response to pathogens, inhibiting cytokine synthesis by NTHi-stimulated PBMCs and rhinovirus-stimulated PBMCs (in a separate PBB cohort). Inhibition of IFN-γ production by IL-1Ra was observed across multiple cell types, including CD3+ T cells and CD56+ NK cells. Our findings highlight the extent to which IL-1β regulates the cellular immune response against two common respiratory pathogens. While blocking the IL-1β pathway has the potential to reduce inflammation, this may come at the cost of protective immunity against NTHi and rhinovirus.

Targeted therapy for chronic respiratory disease: a new paradigm.

Abstract: Targeted therapy has emerged as a highly effective treatment approach for chronic respiratory diseases. Many of these conditions have dismal outcomes; however, targeted therapy shows great results for the subgroup who respond. This represents a new way to approach these conditions and offers great promise as a future treatment direction. In severe eosinophilic asthma, therapy that targets the interleukin-5 pathway with monoclonal antibodies leads to a 50% reduction in asthma exacerbations in previously refractory disease. In cystic fibrosis, lung function improves with therapy that targets specific molecular abnormalities in the cystic fibrosis transmembrane conductance regulator to increase the probability that this chloride channel is open. In lung cancer, specifically adenocarcinoma with epidermal growth factor receptor (EGFR) mutation and overexpression of EGFR tyrosine kinase, therapy that inhibits EGFR tyrosine kinase gives better outcomes than conventional chemotherapy.