Lung function trajectory and biomarkers in the Tasmanian Longitudinal Health Study.

BACKGROUND AND OBJECTIVE: Different lung function trajectories through life can lead to COPD in adulthood. This study investigated whether circulating levels of biomarkers can differentiate those with accelerated (AD) from normal decline (ND) trajectories. METHODS: The Tasmanian Longitudinal Health Study (TAHS) is a general population study that measured spirometry and followed up participants from ages 7 to 53 years. Based on their forced expiratory volume in 1 s (FEV1) trajectories from age 7 to 53 years, this analysis included those with COPD at age 53 years (60 with AD and 94 with ND) and controls (n=720) defined as never-smokers with an average FEV1 trajectory. Circulating levels of selected biomarkers determined at 53 and 45 years of age were compared between trajectories. RESULTS: Results showed that CC16 levels (an anti-inflammatory protein) were lower and C-reactive protein (CRP) (a pro-inflammatory marker) higher in the AD than in the ND trajectory. Higher CC16 levels were associated with a decreased risk of belonging to the AD trajectory (OR=0.79 (0.63-0.98) per unit increase) relative to ND trajectory. Higher CRP levels were associated with an increased risk of belonging to the AD trajectory (OR=1.07, 95% CI: 1.00-1.13, per unit increase). Levels of CC16 (area under the curve (AUC)=0.69, 95% CI: 0.56-0.81, p=0.002), CRP (AUC=0.63, 95% CI: 0.53-0.72, p=0.01) and the combination of both (AUC=0.72, 95% CI: 0.60-0.83, p<0.001) were able to discriminate between the AD and ND trajectories. Other quantified biomarkers (interleukin (IL)-4, IL-5, IL-6, IL-10 and tumour necrosis factor-α (TNF-α)) were not significantly different between AD, ND and controls. CONCLUSIONS: Circulating levels of CRP and CC16 measured in late adulthood identify different lung function trajectories (AD versus ND) leading to COPD at age 53 years.

Childhood Respiratory Risk Factor Profiles and Middle-Age Lung Function: A Prospective Cohort Study from the First to Sixth 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.

Initial diagnosis and management of chronic obstructive pulmonary disease in Australia: views from the coal face.

BACKGROUND: Early diagnosis and management can mitigate the long-term morbidity and mortality of chronic obstructive pulmonary disease (COPD). AIMS: To gain insights into the initial diagnostic process and early management of COPD by Australian general practitioners (GP). METHODS: A random sample of Australian GP was invited to complete a postal survey, which assessed familiarity with and use of contemporary practice guidelines, diagnostic criteria and management preferences for COPD. RESULTS: A total of 233 GP completed the survey. While most GP based a COPD diagnosis on smoking history (94.4%), symptoms (91.0%) and spirometry (88.8%), only 39.9% of respondents recorded a formal diagnosis of COPD after the patient's first symptomatic presentation. Tiotropium was the preferred treatment in 77.3% of GP for the initial management of COPD, while only 27.5% routinely recommended pulmonary rehabilitation. GP routinely recorded patients' smoking status and offered smoking cessation advice, but the timing of this advice varied. Less than half of the respondents routinely used COPD management guidelines or tools and resources provided by the Australian Lung Foundation. CONCLUSION: There is scope for major improvement in GP familiarity with and use of COPD management guidelines and readily available tools and resources. Some systematic issues were highlighted in the Australian primary care setting, such as a reactive and relatively passive and delayed approach to diagnosis, potentially delayed smoking cessation advice and underutilisation of pulmonary rehabilitation. There is an urgent need to devise strategies for improving patient outcomes in COPD using resources that are readily available.

Traffic-related air pollution exposure is associated with allergic sensitization, asthma, and poor lung function in middle age.

BACKGROUND: Traffic-related air pollution (TRAP) exposure is associated with allergic airway diseases and reduced lung function in children, but evidence concerning adults, especially in low-pollution settings, is scarce and inconsistent. OBJECTIVES: We sought to determine whether exposure to TRAP in middle age is associated with allergic sensitization, current asthma, and reduced lung function in adults, and whether these associations are modified by variants in Glutathione S-Transferase genes. METHODS: The study sample comprised the proband 2002 laboratory study of the Tasmanian Longitudinal Health Study. Mean annual residential nitrogen dioxide (NO2) exposure was estimated for current residential addresses using a validated land-use regression model. Associations between TRAP exposure and allergic sensitization, lung function, current wheeze, and asthma (n = 1405) were investigated using regression models. RESULTS: Increased mean annual NO2 exposure was associated with increased risk of atopy (adjusted odds ratio [aOR], 1.14; 95% CI, 1.02-1.28 per 1 interquartile range increase in NO2 [2.2 ppb]) and current wheeze (aOR, 1.14; 1.02-1.28). Similarly, living less than 200 m from a major road was associated with current wheeze (aOR, 1.38; 95% CI, 1.06-1.80) and atopy (aOR, 1.26; 95% CI, 0.99-1.62), and was also associated with having significantly lower prebronchodilator and postbronchodilator FEV1 and prebronchodilator forced expiratory flow at 25% to 75% of forced vital capacity. We found evidence of interactions between living less than 200 m from a major road and GSTT1 polymorphism for atopy, asthma, and atopic asthma. Overall, carriers of the GSTT1 null genotype had an increased risk of asthma and allergic outcomes if exposed to TRAP. CONCLUSIONS: Even relatively low TRAP exposures confer an increased risk of adverse respiratory and allergic outcomes in genetically susceptible individuals.

Target oxygen saturation range: 92-96% Versus 94-98.

This scientific letter considers the rationale for the target oxygen saturation measured by pulse oximetry (SpO2 ) range of 92-96% for oxygen therapy in adult patients without COPD or other conditions associated with chronic respiratory failure, recommended by the Thoracic Society of Australia and New Zealand, in contrast to the 94-98% target range recommended by the British Thoracic Society. We conclude from the available evidence that the SpO2 target of 92-96% may be preferable to 94-98%.

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.

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

BACKGROUND AND OBJECTIVE: 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. METHODS: The fifth-decade follow-up of the Tasmanian Longitudinal Health Study cohort, which was first studied in 1968 (n = 8583), included a 2004 postal survey (n = 5729 responses) and subsequent laboratory attendance (n = 1389) for comprehensive lung function testing between 2006 and 2008. Multivariable linear and logistic regression models included sampling weights. RESULTS: Post-bronchodilator airflow obstruction (less than fifth percentile) was detected for 9.3% (n = 123) of middle-aged offspring. Its association with heavy maternal smoking (>20 cigarettes/day) during childhood was 2.7-fold higher than for those without exposure (95% confidence interval [1.3, 5.7] P = 0.009). Maternal smoking per se approximately doubled the adverse effect of personal smoking on gas transfer factor (z-score -0.46 [-0.6 to -0.3] vs -0.25 [-0.4 to -0.1], P[interaction] = 0.048) and was paradoxically associated with reduced residual volumes for non-smokers. CONCLUSIONS: Heavy maternal smoking during childhood appears to predispose to spirometrically defined COPD. The interplay between maternal and personal smoking on gas transfer factor suggests that early life exposure increases an individual's susceptibility to adult smoking exposure. These findings provide further evidence to suggest that maternal smoking might be a risk factor for COPD and reinforce the public health message advocating smoking abstinence.

Thoracic Society of Australia and New Zealand oxygen guidelines for acute oxygen use in adults: 'Swimming between the flags'.

The purpose of the Thoracic Society of Australia and New Zealand guidelines is to provide simple, practical evidence-based recommendations for the acute use of oxygen in adults in clinical practice. The intended users are all health professionals responsible for the administration and/or monitoring of oxygen therapy in the management of acute medical patients in the community and hospital settings (excluding perioperative and intensive care patients), those responsible for the training of such health professionals, and both public and private health care organizations that deliver oxygen therapy.

Describing drivers of and barriers to persistence with tiotropium in patients with chronic obstructive pulmonary disease: a mixed-methods approach.

OBJECTIVE: To understand the factors influencing persistence with tiotropium in patients with chronic obstructive pulmonary disease (COPD). METHODS: Patients classified as 'persistent' or 'non-persistent' with tiotropium were identified from pharmacy dispensing records. Patients were compared for health status, beliefs and behaviours using data from questionnaires and interviews. KEY FINDINGS: Perceptions of the risks and benefits of medication, fear of worsening illness, and the GP's emphasis on the importance of the medication were key determinants of tiotropium persistence. CONCLUSIONS: Perceptions, attitudes and beliefs of patients and doctors influence persistence with tiotropium. These complex interactions need to be targeted to improve persistence with medicines in COPD.

Supporting cystic fibrosis with ICT.

ICT use in cystic fibrosis management provides an alternative means of information supply to individuals, families, health care professionals and other stakeholders. The purpose of this paper is to present the evolution of a series of projects culminating in a project that translates the previous research into practice. In this paper the sequential nature of the projects will be detailed. The three projects explored are the Pathways Home for Respiratory Illness Project (Pathways Home), Enhancing Self-Efficacy for Self-Management in People with Cystic Fibrosis and the Tasmanian Community Fund Project (myCF pilot).

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.

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.

Pharmacist-initiated general practitioner referral of patients with suboptimal asthma management.

OBJECTIVE: To assess the impact of an intervention initiated by community pharmacists, involving the provision of educational material and general practitioner (GP) referral, on asthma knowledge and self-reported asthma control and asthma-related quality of life (QOL) in patients who may have suboptimal management of their asthma, as evidenced by pharmacy dispensing records. Setting Community pharmacies throughout Tasmania, Australia. METHODS: Forty-two pharmacies installed a software application that data mined dispensing records and generated a list of patients with suboptimal asthma management, as indicated by having three or more canisters of inhaled short-acting beta-2-agonists dispensed in the preceding 6 months. Identified patients were randomised to an intervention or control group. At baseline, intervention patients were mailed intervention packs consisting of a letter encouraging them to see their GP for a review, educational material, asthma knowledge, asthma control and asthma-related QOL questionnaires, and a letter with a dispensing history to give to their GP. Pharmacists were blinded to the control patients' identities for 6 months, after which time intervention patients were sent repeat questionnaires, and control patients were sent intervention packs. MAIN OUTCOME MEASURES: Asthma knowledge, asthma control and asthma-related QOL scores. RESULTS: Thirty-five pharmacies completed the study, providing 706 intervention and 427 control patients who were eligible to receive intervention packs. Intervention patients' asthma control and asthma-related QOL scores at 6 months were significantly higher compared to the control patients (P < 0.01 and P < 0.05, respectively) and to the intervention patients' baseline scores (P < 0.001 and P < 0.05, respectively). Symptom-related QOL was significantly higher compared to the control patients (P < 0.01) and activities-related QOL significantly improved compared to baseline (P < 0.05). No significant change was observed in asthma knowledge. CONCLUSION: The results suggest that community pharmacists are ideally placed to identify patients with suboptimal asthma management and refer such patients for a review by their GP. This type of collaborative intervention can significantly improve self-reported asthma control and asthma-related QOL in patients identified as having suboptimal management of their asthma. A larger trial is needed to confirm the effects are real and sustained.

The effect of season on cytokine expression in multiple sclerosis and healthy subjects.

We measured the levels of IFNgamma, TNFalpha, Il-4 and Il-10 produced by mitogen-stimulated peripheral blood mononuclear cells (PBMC) from healthy people, and those with the relapse/remitting form of multiple sclerosis. Blood was taken in summer and winter. Healthy people had a summer excess of Il-4, Il-10 and TNFalpha, and a winter excess of IFNgamma. Untreated MS cases had a summer excess of Il-10, whereas those treated with Interferon-beta had lower levels of all cytokines, and displayed no seasonal effect.

Policy challenges from the "White" Senate inquiry into workplace-related health impacts of toxic dusts and nanoparticles.

On 22 June 2005 the Senate of the Commonwealth of Australia voted to establish an inquiry into workplace harm related to toxic dust and emerging technologies (including nanoparticles). The inquiry became known as the "White" Inquiry after Mr Richard White, a financially uncompensated sufferer of industrial sandblasting-induced lung disease who was instrumental in its establishment. The "White" Inquiry delivered its final report and recommendations on 31 May 2006. This paper examines whether these recommendations and their implementation may provide a unique opportunity not only to modernize relevant monitoring standards and processes, but related compensation systems for disease associated with workplace-related exposure to toxic dusts. It critically analyzes the likely role of the new Australian Safety and Compensation Council (ASCC) in this area. It also considers whether recommendations related to potential workplace related harm from exposure to nanoparticles could commence a major shift in Australian healthcare regulation.

Airway wall remodelling: the influence of corticosteroids.

PURPOSE OF THE REVIEW: We 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 FINDINGS: The 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. SUMMARY: Further 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.