Haydn Walters

Identification of IL6R and chromosome 11q13.5 as risk loci for asthma

BACKGROUND We aimed to identify novel genetic variants affecting asthma risk, since these might provide novel insights into molecular mechanisms underlying the disease. METHODS We did a genome-wide association study (GWAS) in 2669 physician-diagnosed asthmatics and 4528 controls from Australia. Seven loci were prioritised for replication after combining our results with those from the GABRIEL consortium (n=26,475), and these were tested in an additional 25,358 independent samples from four in-silico cohorts. Quantitative multi-marker scores of genetic load were constructed on the basis of results from the GABRIEL study and tested for association with asthma in our Australian GWAS dataset. FINDINGS Two loci were confirmed to associate with asthma risk in the replication cohorts and reached genome-wide significance in the combined analysis of all available studies (n=57,800): rs4129267 (OR 1·09, combined p=2·4×10(-8)) in the interleukin-6 receptor (IL6R) gene and rs7130588 (OR 1·09, p=1·8×10(-8)) on chromosome 11q13.5 near the leucine-rich repeat containing 32 gene (LRRC32, also known as GARP). The 11q13.5 locus was significantly associated with atopic status among asthmatics (OR 1·33, p=7×10(-4)), suggesting that it is a risk factor for allergic but not non-allergic asthma. Multi-marker association results are consistent with a highly polygenic contribution to asthma risk, including loci with weak effects that might be shared with other immune-related diseases, such as NDFIP1, HLA-B, LPP, and BACH2. INTERPRETATION The IL6R association further supports the hypothesis that cytokine signalling dysregulation affects asthma risk, and raises the possibility that an IL6R antagonist (tocilizumab) may be effective to treat the disease, perhaps in a genotype-dependent manner. Results for the 11q13.5 locus suggest that it directly increases the risk of allergic sensitisation which, in turn, increases the risk of subsequent development of asthma. Larger or more functionally focused studies are needed to characterise the many loci with modest effects that remain to be identified for asthma. FUNDING National Health and Medical Research Council of Australia. A full list of funding sources is provided in the webappendix.

Airway wall remodelling: the influence of corticosteroids

Purpose of the reviewWe have attempted to bring together recent findings, mainly from airway endobronchial biopsies, on the structural changes that constitute ’remodelling’ in airway disease, with a particular focus on asthma. We have tried to put this into the context of classic studies on the asthma pathological phenotype. Having described these basic changes, we have then given an update on recent studies investigating the effects of corticosteroid medication on the different manifestations of remodelled airways. Recent findingsThe effects of corticosteroid on airway remodelling seem to vary a great deal; some aspects are steroid responsive while others are not, or less so. It is likely that different manifestations of remodelling require different doses and timescales for treatment to be effective. SummaryFurther longitudinal interventional studies are required, with multiple airway sampling times, to fully elucidate the full potential for corticosteroids to benefit remodelling of the airways in chronic inflammatory diseases. There needs to be more attention to pathophysiological and clinical correlations in such studies. It is likely that even when used optimally corticosteroids will have limited efficacy overall in this aspect of asthma pathogenesis. The search is on for newer and better treatments. Abbreviations ASM: airway smooth muscle; BAL: bronchoalveolar lavage; BHR: bronchial hyperresponsiveness; BOS: bronchiolitis obliterans syndrome; EGF: epidermal growth factor; ICS: inhaled corticosteroid; RBM: reticular basement membrane; VEGF: vascular endothelial growth factor.

Cigarette smoke and platelet-activating factor receptor dependent adhesion of Streptococcus pneumoniae to lower airway cells

Background Exposure to cigarette smoke (CS) is associated with increased risk of pneumococcal infection. The mechanism for this association is unknown. We recently reported that the particulate matter from urban air simulates platelet-activating factor receptor (PAFR)-dependent adhesion of pneumococci to airway cells. We therefore sought to determine whether CS stimulates pneumococcal adhesion to airway cells. Methods Human alveolar (A549), bronchial (BEAS2-B), and primary bronchial epithelial cells (HBEpC) were exposed to CS extract (CSE), and adhesion of Streptococcus pneumoniae determined. The role of PAFR in mediating adhesion was determined using a blocker (CV-3988). PAFR transcript level was assessed by quantitative real-time PCR, and PAFR expression by flow cytometry. Lung PAFR transcript level was assessed in mice exposed to CS, and bronchial epithelial PAFR expression assessed in active-smokers by immunostaining. Results In A549 cells, CSE 1% increased pneumococcal adhesion (p<0.05 vs control), PAFR transcript level (p<0.01), and PAFR expression (p<0.01). Pneumococcal adhesion to A549 cells was attenuated by CV-3988 (p<0.001). CSE 1% stimulated pneumococcal adhesion to BEAS2-B cells and HBEpC (p<0.01 vs control). CSE 1% increased PAFR expression in BEAS2-B (p<0.01), and in HBEpC (p<0.05). Lung PAFR transcript level was increased in mice exposed to CS in vivo (p<0.05 vs room air). Active smokers (n=16) had an increased percentage of bronchial epithelium with PAFR-positive cells (p<0.05 vs never smokers, n=11). Conclusion CSE stimulates PAFR-dependent pneumococcal adhesion to lower airway epithelial cells. We found evidence that CS increases bronchial PAFR in vivo.

Definition of a COPD self-management intervention: International Expert Group consensus

There is an urgent need for consensus on what defines a chronic obstructive pulmonary disease (COPD) self-management intervention. We aimed to obtain consensus regarding the conceptual definition of a COPD self-management intervention by engaging an international panel of COPD self-management experts using Delphi technique features and an additional group meeting. In each consensus round the experts were asked to provide feedback on the proposed definition and to score their level of agreement (1=totally disagree; 5=totally agree). The information provided was used to modify the definition for the next consensus round. Thematic analysis was used for free text responses and descriptive statistics were used for agreement scores. In total, 28 experts participated. The consensus round response rate varied randomly over the five rounds (ranging from 48% (n=13) to 85% (n=23)), and mean definition agreement scores increased from 3.8 (round 1) to 4.8 (round 5) with an increasing percentage of experts allocating the highest score of 5 (round 1: 14% (n=3); round 5: 83% (n=19)). In this study we reached consensus regarding a conceptual definition of what should be a COPD self-management intervention, clarifying the requisites for such an intervention. Operationalisation of this conceptual definition in the near future will be an essential next step. Consensus of a conceptual definition of what should be a COPD self-management intervention with its requisites http://ow.ly/Zfr0F

Management and treatment perceptions among young adults with asthma in Melbourne: The Australian experience from the European Community Respiratory Health Survey

As part of the European Community Respiratory Health Survey (ECRHS) in 1992–1993 we assessed management practices and treatment perceptions among young asthmatic adults in Melbourne, Australia.

Iron overload and nitric oxide-derived oxidative stress following lung transplantation

BACKGROUND Reactive oxygen species (ROS) may contribute to airway injury and the development of the bronchiolitis obliterans syndrome (BOS) following lung transplantation (LT). Chemically active iron released from ferritin stores and nitric oxide (NO)-derived radicals may add to the oxidative burden. METHODS We determined the concentrations of ferritin and the aqueous NO derivative nitrite (NO2(-)) within bronchoalveolar lavage fluid (BALF) of 14 stable LT recipients (ST) and 7 subjects with BOS and 21 normal controls. We also assessed the relationship between BALF ferritin and hemosiderin-laden macrophages (HLMs) using a hemosiderin score (HS) and determined BALF albumin concentration as a marker of microvascular leakage. RESULTS BALF ferritin concentrations and HSs were significantly elevated in LT recipients overall compared with normal controls (p < 0.05). BALF NO2(-) levels were elevated in BOS subjects and STs compared with normal controls (p = 0.002 and p = 0.09, respectively), but there was no difference between transplant groups. BALF albumin concentrations were elevated in BOS patients compared with normal controls (p = 0.02) and ST (p = 0.05), but there was no difference between STs and controls. There was a significant relationship between BALF ferritin concentration and HS in LT recipients overall (r(s) = 0.7, p < 0.001). In BOS subjects, but not ST, BALF ferritin was significantly related to BALF albumin (r(s) = 0.8, p = 0.05) and there was a weak relationship with NO2(-) concentration (r(s) = 0.6, p = 0.1). BALF NO2(-) was strongly related to BALF % neutrophils in BOS subjects (r(s) = 0.9, p < 0.01), but there was no such relationship in STs. CONCLUSIONS Our findings suggest that the allograft could be subject to significant iron-generated oxidative stress, which may be exacerbated by NO and neutrophil-derived ROS, particularly in BOS. Microvascular leakage may be a feature of established chronic rejection, which potentiates the iron overload and contributes to further airway damage and remodeling.

Australian Idiopathic Pulmonary Fibrosis Registry : vital lessons from a national prospective collaborative project

There is little Australian epidemiologic data on idiopathic pulmonary fibrosis (IPF), a relatively uncommon but devastating disease. The vast geographic distances in Australia have been a major impediment for collaborative research into IPF. A collaborative national effort, the Australian IPF Registry, has been formed, launched and is recruiting successfully (n = 359, January 2014). Our experience provides unique insights for others wishing to set up IPF registries and in time for a global IPF registry.

A reliable and valid asthma general knowledge questionnaire useful in the training of asthma educators.

Using the responses of 115 adults attending an asthma educator training course, the Asthma General Knowledge Questionnaire for Adults (AGKQA) was found to be an acceptably valid and reliable measure for assessing knowledge related to the management of asthma by adults. Content and face validity: expert assessors considered the AGKQA to be a relevant and plausible test of the asthma general knowledge content of the programme. Criterion-related validity: the pretraining scores of educators were significantly higher (P < 0.001) than those of adults with no experience of asthma; total scores for the AGKQA and an asthma knowledge questionnaire developed for parents of children with asthma correlated strongly, 0.72. Test-retest reproducibility: the Spearman rank correlation for the test-retest score was 0.72 (P < 0.02), kappas for concordance of item responses were moderate to very good for two thirds of the items. Internal consistency for the total scale was also acceptable, KR20 0.66.

Mother's smoking and complex lung function of offspring in middle age: A cohort study from childhood

Existing evidence that supports maternal smoking to be a potential risk factor for chronic obstructive pulmonary disease (COPD) for adult offspring has barely been mentioned in major guideline documents, suggesting a need for more robust and consistent data. We aimed to examine whether such early life exposure can predispose to COPD in middle age, possibly through its interaction with personal smoking.

Childhood Respiratory Risk Factor Profiles, Their Interactions and Mediators, and Middle-age Lung Function: A Prospective Cohort Study from the 1st to 6th Decade

Rationale: Childhood risk factors for long‐term lung health often coexist and their specific patterns may affect subsequent lung function differently. Objectives: To identify childhood risk factor profiles and their influence on lung function and chronic obstructive pulmonary disease (COPD) in middle age, and potential pathways. Methods: Profiles of 11 childhood respiratory risk factors, documented at age 7, were identified in 8,352 participants from the Tasmanian Longitudinal Health Study using latent class analysis. We investigated associations between risk profiles and post‐bronchodilator lung function and COPD at age 53, mediation by childhood lung function and adult asthma, and interaction with personal smoking. Results: Six risk profiles were identified: 1) unexposed or least exposed (49%); 2) parental smoking (21.5%); 3) allergy (10%); 4) frequent asthma, bronchitis (8.7%); 5) infrequent asthma, bronchitis (8.3%); and 6) frequent asthma, bronchitis, allergy (2.6%). Profile 6 was most strongly associated with lower forced expiratory volume in 1 second (FEV1) (−261; 95% confidence interval, −373 to −148 ml); lower FEV1/forced vital capacity (FVC) (−3.4; −4.8 to −1.9%) and increased COPD risk (odds ratio, 4.9; 2.1 to 11.0) at age 53. The effect of profile 6 on COPD was largely mediated by adult active asthma (62.5%) and reduced childhood lung function (26.5%). Profiles 2 and 4 had smaller adverse effects than profile 6. Notably, the effects of profiles 2 and 6 were synergistically stronger for smokers. Conclusions: Profiles of childhood respiratory risk factors predict middle‐age lung function levels and COPD risk. Specifically, children with frequent asthma attacks and allergies, especially if they also become adult smokers, are the most vulnerable group. Targeting active asthma in adulthood (i.e., a dominant mediator) and smoking (i.e., an effect modifier) may block causal pathways and lessen the effect of such established early‐life exposures.