BACKGROUND AND OBJECTIVE:Aberrant apoptosis is a disease susceptibility mechanism relevant for asthma, whereby fragility of the airway epithelium and enhanced survival of inflammatory cells, contributes to its pathogenesis and prolongation. Cellular Inhibitor of Apoptosis Proteins (cIAP) suppress apoptosis, and participate in the immune response. In this study, single nucleotide polymorphisms (SNP) in the BIRC2 (codes cIAP1) and BIRC3 (cIAP2) genes were evaluated for an association with asthma.METHODS:Caucasian asthmatic (n = 203) and control (n = 198) subjects were selected from participants in the North West Adelaide Health Study. SNPs (n = 9) spanning the consecutively positioned BIRC2 and BIRC3 genes, were selected using a haplotype tagging approach. Alleles and haplotype associations were analysed by logistic regression, assuming an additive genetic model, and adjusted for gender and atopy.RESULTS:The frequency of the minor allele for the BIRC3 SNP rs3460 was significantly lower in asthmatics compared to the control cases (P = 0.046). BIRC3 SNPs rs7928663 and rs7127583 associated with a reduction in eosinophil and neutrophil abundance when assessed across the study population (multivariate P values = 0.002, and 0.005, respectively). Further, the frequency of a haplotype tagged by rs3460, rs7928663 and rs7127583 was reduced in the asthma sub group (P = 0.05), while the presence of the major allele for rs7928663 associated with an increased load of circulating eosinophils and neutrophils (multivariate P value = 0.001).CONCLUSIONS:Polymorphisms in the BIRC3 gene, but not BIRC2, are associated with a protective effect with regards to asthma susceptibility, and a reduced load of inflammatory cells.

Background Pregnancy presents a unique situation for the management of asthma as it can alter the course of asthma severity and its treatment, which in turn can affect pregnancy outcomes. Despite awareness of the substantial adverse effects associated with asthma during pregnancy, little has been done to improve its management and reduce associated perinatal morbidity and mortality. The aim of this randomized controlled trial is to evaluate the clinical and cost effectiveness of an Antenatal Asthma Management Service. Methods/design Design: Multicentre, randomized controlled trial. Inclusion criteria: Women with physician diagnosed asthma, which is not currently in remission, who are less than 20 weeks gestation with a singleton pregnancy and do not have a chronic medical condition. Trial entry and randomization: Eligible women with asthma, stratified by treatment site, disease severity and parity, will be randomized into either the ‘Standard Care Group’ or the ‘Intervention Group’. Study groups: Both groups will be followed prospectively throughout pregnancy. Women in the ‘Standard Care Group’ will receive routine obstetric care reflecting current clinical practice in Australian hospitals. Women in the ‘Intervention Group’ will receive additional care through the nurse-led Antenatal Asthma Management Service, based in the antenatal outpatient clinic. Women will receive asthma education with a full assessment of their asthma at 18, 24, 30 and 36 weeks gestation. Each antenatal visit will include a 60 min session where asthma management skills are assessed including: medication adherence and knowledge, inhaler device technique, recognition of asthma deterioration and possession of a written asthma action plan. Furthermore, subjects will receive education about asthma control and management skills including trigger avoidance and smoking cessation counseling when appropriate. Primary study outcome: Asthma exacerbations during pregnancy. Sample size: A sample size of 378 women will be sufficient to show an absolute reduction in asthma exacerbations during pregnancy of 20% (alpha 0.05 two-tailed, 90% power, 5% loss to follow-up). Discussion The integration of an asthma education program within the antenatal clinic setting has the significant potential to improve the participation of pregnant women in the self-management of their asthma, reduce asthma exacerbations and improve perinatal health outcomes. Trial registration ACTRN12613000244707

Recent data show great benefit from beta adrenergic blocking drug (β‐blocker) use in heart failure and has resulted in increased use of these established agents. Older data caution against their use in patients with reversible airways disease because of risks of bronchoconstriction. Anecdotally, we noted a difference in willingness to prescribe β‐blockers by cardiologists and respiratory physicians, especially for patients with coexisting airways disease. We sought to test this difference.

Background and objective Aberrant apoptosis in asthma contributes to airway inflammation. Early apoptosis and fragility of airway epithelial cells and delayed apoptosis of inflammatory lymphocytes can cooperate to increase airway inflammation. In this study, single nucleotide polymorphisms (SNPs) and copy number variation (CNV) in the Baculoviral inhibitor of apoptosis protein repeat-containing 4 (BIRC4) gene (which encodes X-linked inhibitor of apoptosis protein) were evaluated for associations with asthma. Methods Asthma cases (n=203) were identified from Caucasian cohort participants in the North West Adelaide Health Study and matched with 198 controls. Asthma status was defined using self-report of doctor-diagnosed asthma, in conjunction with spirometry and bronchodilator response. Seven SNPs, which spanned the entire BIRC4 gene, were selected for the study on the basis of a haplotype tagging approach. SNPs genotyping was performed on the SEQUENOM MassARRAY iPLEX Gold platform, and genotyping success rate was >98%. BIRC4 gene CNV was measured using a duplex Taqman qPCR assay, with RNAseP as the reference gene. Alleles and haplotype associations were analysed by logistic regression, assuming an additive genetic model, and adjusted for gender and atopy. Results BIRC4 gene copy number was determined entirely by gender. All SNPs were in HardyWeinberg equilibrium for both case and control females. BIRC4 allele and haplotype frequencies were comparable between asthma cases and controls. Conclusions There is no evidence of CNV in BIRC4, and BIRC4 is not a susceptibility gene for asthma.

Aberrant apoptosis of airway epithelial cells (AECs) is a disease contributing feature in the airways of asthmatics. The proinflammatory cytokines tumor necrosis factor α (TNFα) and interferon γ (IFNγ) are increased in asthma and have been shown to contribute to apoptosis at the airways. In the present study, we investigated the role of the inhibitor of apoptosis protein (IAP) family in primary AECs exposed to TNFα and IFNγ. IAPs are potent regulators of caspase activity elicited by the intrinsic and extrinsic apoptosis pathways. However, while caspase-mediated apoptosis was observed in AECs exposed to doxorubicin, it was not observed after cytokine treatment. Instead, AECs exhibited proapoptotic changes evidenced by an increased Bax:Bcl2 transcript ratio and partial processing of procaspase-3. Examination by quantitative reverse transcription polymerase chain reaction (qRT-PCR) and Western analysis showed that proapoptotic changes were associated with a time- and dose-dependent induction of cellular IAP-2 (cIAP2), potentiated primarily by IFNγ. The abundance of the IAP antagonists X-linked IAP-associated factor 1 (XAF1) and second mitochondria-derived activator of caspases did not change, although a moderate nuclear redistribution was observed for XAF1, which was also observed for cIAP2. Small interfering RNA (siRNA)-mediated depletion of cIAP2 from AECs leads to caspase-3 activation and poly (ADP-ribose) polymerase cleavage, but this required extended cytokine exposure to produce a concomitant decrease in cIAP1 and Bcl2. These results indicate that AECs possess endogenous mechanisms making them highly resistant to apoptosis due to asthma-related inflammatory cytokines, and the activity of cIAP2 plays an important role in this protection.

Little is known about innate immunity and components of inflammasomes in airway epithelium. This study evaluated immunohistological evidence for NLRP3 inflammasomes in normal and inflamed murine (Balb/c) airway epithelium in a model of ovalbumin (OVA) induced allergic airway inflammation. The airway epithelium of control mice exhibited strong cytoplasmic staining for total caspase-1, ASC, and NLRP3, whereas the OVA mice exhibited strong staining for active caspase-1, with redistribution of caspase-1, IL-1β and IL-18, indicating possible activation of the NLRP3 inflammasome. Active caspase-1, NLRP3, and other inflammasome components were also detected in tissue eosinophils from OVA mice, and may potentially contribute to IL-1β and IL-18 production. In whole lung, inRNA expression of NAIP and procaspase-1 was increased in OVA mice, whereas NLRP3, IL-1β and IL-18 decreased. Some OVA-treated mice also had significantly elevated and tightly correlated serum levels of IL-1β and TNFα. In cultured normal human bronchial epithelial cells, LPS priming resulted in a significant increase in NLRP3 and II-lp protein expression. This study is the first to demonstrate NLRP3 inflammasome components in normal airway epithelium and changes with inflammation. We propose activation and/or luminal release of the inflammasome is a feature of allergic airway inflammation which may contribute to disease pathogenesis.

This study examined associations of abdominal adiposity with lung function, asthma symptoms and current doctor-diagnosed asthma and mediation by insulin resistance (IR) and sleep disordered breathing (SDB).

Large surveillance studies or phase IV clinical studies of long-acting β-agonists (LABA) compared with placebo in asthma patients using variable (from nil to regular) doses of inhaled corticosteroids (ICS) have raised the issue of mortality risk in patients with asthma taking regular LABA. There have been a number of meta-analyses and systematic reviews that have examined the risk of LABA in asthma patients, and the general conclusion is that LABA added to ICS reduces asthma-related hospitalizations compared with ICS alone and there is no statistical increase in mortality. However, LABA without ICS do increase mortality risk in asthma. All reviews and analyses show a greater number of LABA deaths, but not all are statistically significant. A recent meta-analysis found LABA with concomitant ICS had a higher mortality rate in asthma than ICS alone. The flaw in the study is the higher doses of ICS in the control arms, but the implicit message remains: the essential need for enough ICS to control airway inflammation. We suggest that the pragmatic solution is to have LABA only available in the same device as ICS for asthma treatment. We do not think that a study comparing the safety of LABA plus ICS versus ICS alone in asthma is necessary. If such a study is conducted, the measurement of morbidity from increased doses of ICS is an essential design consideration. Furthermore, the critical focus in asthma management should not be forgotten — education of health professionals and the community of the critical role of ICS, and the need for good communication between health professionals and the asthma patient to facilitate good asthma control. The same arguments apply to the asthma-with-chronic obstructive pulmonary disease overlap syndrome in older patients. There is an urgent need to provide medical practitioners with the capability to diagnose the overlap syndrome.

ABSTRACT Background and objective: Mouse models of asthma show that zinc deficiency is associated with airway inflammation (AI), which is attenuated by zinc supplements. Whether zinc has a similar role in the human airway remains controversial, with studies demonstrating both high and low plasma zinc concentrations [Zn] in asthmatic patients compared with control subjects. This variability may reflect the inability of plasma measurements to accurately assess airway zinc levels. Examination of induced sputum is an established technique for measuring AI and mediators of inflammation. Recent advances allow measurement of the rapidly exchangeable (labile) and total zinc pools in sputum. The aims of this study were to measure labile and total [Zn] in sputum and plasma of subjects with or without asthma, and second to correlate [Zn] with symptoms, asthma severity, lung function (FEV 1 ) and airway hyper‐responsiveness. Methods: A total of 163 subjects (114 with asthma) completed a single visit for sputum induction and a blood test. Labile and total [Zn] were measured by Zinquin fluorescence and atomic absorption spectrophotometry. Results: The mean (SD) age of subjects with and without asthma was 55 (14) and 57 (14) years, respectively. Baseline FEV 1 was significantly lower in subjects with asthma (94.2 (16)%) than in those without asthma (103 (16.6)%). Sputum total and labile [Zn] were lower in subjects with asthma compared with control subjects, with median (interquartile range) values of 31.8 (117) versus 50 (188.5), P = 0.02 and 0 (48) versus 26 (84.5) µg/L, P = 0.05, respectively. Increased frequency of wheeze, as well as asthma severity and reduced FEV 1 , was associated with significantly lower labile sputum [Zn]. Conclusions: These findings suggest that sputum [Zn] reflect clinical outcomes and underlying AI, suggesting a potential role for zinc as a biomarker in asthma.

The apical cytoplasm of airway epithelium (AE) contains abundant labile zinc (Zn) ions that are involved in the protection of AE from oxidants and inhaled noxious substances. A major question is how dietary Zn traffics to this compartment. In rat airways, in vivo selenite autometallographic (Se-AMG)-electron microscopy revealed labile Zn-selenium nanocrystals in structures resembling secretory vesicles in the apical cytoplasm. This observation was consistent with the starry-sky Zinquin fluorescence staining of labile Zn ions confined to the same region. The vesicular Zn transporter ZnT4 was likewise prominent in both the apical and basal parts of the epithelium both in rodent and human AE, although the apical pools were more obvious. Expression of ZnT4 mRNA was unaffected by changes in the extracellular Zn concentration. However, levels increased 3-fold during growth of cells in air liquid interface cultures and decreased sharply in the presence of retinoic acid. When comparing nasal versus bronchial human AE cells, there were significant positive correlations between levels of ZnT4 from the same subject, suggesting that nasal brushings may allow monitoring of airway Zn transporter expression. Finally, there were marked losses of both basally-located ZnT4 protein and labile Zn in the bronchial epithelium of mice with allergic airway inflammation. This study is the first to describe co-localization of zinc vesicles with the specific zinc transporter ZnT4 in airway epithelium and loss of ZnT4 protein in inflamed airways. Direct evidence that ZnT4 regulates Zn levels in the epithelium still needs to be provided. We speculate that ZnT4 is an important regulator of zinc ion accumulation in secretory apical vesicles and that the loss of labile Zn and ZnT4 in airway inflammation contributes to AE vulnerability in diseases such as asthma.

In mouse asthma models, inflammation can be modulated by zinc (Zn). Given that appetite loss, muscle wasting and poor nutrition are features of chronic obstructive pulmonary disease (COPD) and that poor dietary Zn intake is in itself accompanied by growth retardation and appetite loss, we hypothesised that dietary Zn limitation would not only worsen airway inflammation but also exaggerate metabolic effects of cigarette smoke (CS) exposure in mice. Conversely, Zn supplementation would lessen inflammation. Mice were exposed to CS [2× 2RF, 3×/day; 15 min/cigarette] and fed diets containing 2, 20 or 140 mg/kg Zn ad libitum. Airway cells were collected by bronchoalveolar lavage (BAL). Plasma Zn was measured by fluorometric assay. Inflammatory, metabolic and Zn transport markers were measured by real-time RT-PCR. Mice fed low Zn diets had less plasma labile zinc (0–0.18 μM) than mice fed moderate (0.61–0.98 μM) or high (0.77–1.1 μM) Zn diets (SDs 0.1–0.4, n = 8–10). Smoke exposure increased plasma and BAL labile Zn (1.5–2.5 fold, P < 0.001), bronchoalveolar macrophages (2.0 fold, P < 0.0001) and MT-1 (1.5 fold), MIP-2 (2.3 fold) and MMP-12 (3.5 fold) mRNA. Zn supplementation reduced alveolar macrophage numbers by 62 and 52% in sham and smoke-exposed mice, respectively (Zn effect: P = 0.011). Gastrocnemius, soleus and tibialis anterior muscle mass were affected by both smoke and dietary Zn in the order of 3–7%. The 50–60% reduction in alveolar macrophages in Zn-supplemented mice supports our evolving hypothesis that Zn is an important anti-inflammatory mediator of airway inflammation. Restoring airway Zn levels through dietary supplementation may lessen the severity of lung inflammation when Zn intake is low.

BACKGROUNDThe Global Initiative for Chronic Obstructive Lung Disease (GOLD) guideline removed stage 0 (chronic cough and sputum without airflow obstruction, GOLD-0) because of poor prognostic value. Preventative intervention may be relevant for those with chronic symptoms; therefore, we assessed the stability, morbidity, and FEV(1) decline associated with GOLD stage 0 in a representative adult population cohort.METHODSBaseline (n = 4,060) and follow-up (n = 3,206, mean 3.5 years) clinic assessment of the North West Adelaide Health Study included postbronchodilator spirometry, anthropometry, and measures of doctor-diagnosed asthma, respiratory symptoms, smoking status, quality of life, and depression.RESULTSBaseline GOLD-0 prevalence was 17.0% (n = 584). At follow-up (n = 420), 39.8% remained stable, 1.4% progressed to GOLD stages 1 to 2, and 58.8% resolved to no symptoms. Persistent GOLD-0 at follow-up was associated with persistent smoking (men: odds ratio [OR] = 11.9, 95% CI, 6.4-22.1; women: OR = 4.0, 95% CI, 2.1-7.4), and depressive symptoms (men: OR = 3.8, 95% CI, 1.9-7.6; women: OR = 3.2, 95% CI, 1.7-5.9), with highest quartile of FEV(1) decline (mL) per year (OR = 2.1, 95% CI, 1.2-3.7) and the metabolic syndrome (OR = 1.7, 95% CI, 1.01-3.0) in men, and with older age in women. These associations generally held in smokers and never-smokers. Resolving GOLD-0 was associated with smoking cessation (OR = 13.7; 95% CI, 4.6-40.1), FEV(1) decline (mL) per year below the median (OR = 2.0; 95% CI, 1.1-3.5), normal BMI, and younger age groups. Sensitivity analyses based on the presence of sputum did not change the observed associations.CONCLUSIONPersistent GOLD-0 identified people with physical and psychologic morbidity in both smokers and nonsmokers. Identification of those with persistent respiratory symptoms is therefore important. Excess FEV(1) decline in men suggests GOLD-0 may identify a group at risk to progress to COPD over time.

Objective: To evaluate whether systematic asthma care involving a register-recall system, postcard prompts for review, and education for general practitioners and staff in Australian general practice improves the quality of care and health outcomes for adult patients with moderate to severe asthma . Design and setting: Cluster randomised controlled trial in 40 general practices in urban and rural South Australia and New South Wales over the 2 years 2004 and 2005, practices were randomly allocated to the intervention or control groupParticipants: 565 adult patients of these randomly allocated practices who had doctor-diagnosed moderate to severe asthma and were taking inhaled corticosteroidsMain outcome measures: Clinical asthma indicators, quality of care, acceptability of the intervention to patients, quality of life, and asthma self-management skills at baseline, 6 months and 12 monthsResults: Although 46% of patients in the intervention group practices responded to the postcard prompts, only 32% actually attended for their asthma review At 12 months, there was a statistically significant difference in provision of written asthma action plans (rate ratio, 1 9, 95% CI, 1 0-3 5, P = 0 04) for intervention group patients compared with control group patients, there was no significant difference in other indicatorsConclusion: We found little objective evidence of improvement in patient management and outcomes resulting from a systematic model of asthma care

Objective: To examine the comparative prevalence and distribution of obesity and psychological disturbance in the asthma and non-asthma populations, and to determine how these comorbidities are associated with physical functioning.Design, setting and participants: A South Australian population-representative study of 3175 adults who provided data on asthma, psychological morbidity, physical functioning, and body mass index. Bivariate and multivariate analyses identified how these comorbidities were distributed in asthma and non-asthma subpopulations, and the variance in physical functioning that they explained.Main outcome measures: Rates of obesity and psychological morbidity, and physical functioning scores in asthma and non-asthma populations.Results: Men and women in the asthma population had similar prevalences of obesity (35.3% v 33.6%) and psychological morbidity (29.5% v 29.4%). When compared with non-asthma controls, both comorbidities were significantly higher only in men with asthma. The prevalence of psychological morbidity within different weight categories in the asthma population compared with non-asthma weight-category controls varied by sex. Physical functioning was lower in the asthma population than the non-asthma population (46.6 [95% CI, 45.9-47.3] v 48.8 [95% CI, 47.8-50.0]; P < 0.001), ad psychological morbidity explained 22% of this variance.Conclusions: Psychological morbidity and obesity are common in people with asthma. The sex-specific variation in psychological morbidity across weight categories suggests that future studies of psychological morbidity in groups with asthma should adopt designs that consider sex-specific controls rather than comparisons between the sexes. MJA 2010; 192: 381-383

Respirology has continued to function as a ‘voice’ for clinical respiratory science in the Asia–Pacific region. The journal reports the research activities of clinicians and scientists from a vast geographical area and Respirology has been receiving growing numbers of manuscripts from our traditional support base in the Asia–Pacific region including countries such as Australia, China, Japan, India and Korea. However, submissions have also increased from researchers in Europe and North America who now frequently submit high impact scientific papers for review and publication. In 2008 a considerable amount of asthma research reported in Respirology again emphasized its importance as a disease in the region and contrasted with trends in many respiratory journals where it is often being overshadowed by COPD. This is likely to be because asthma remains a significant clinical and public health problem and priority in developing countries and hence many researchers have taken the opportunity to research key local clinical, management and therapeutic questions in this field. The overall themes and impact of asthma research studies are summarized in this review. However, during 2008 new information about numerous other lung diseases and conditions has also been published in Respirology and the highlights will be summarized in this paper. In developed countries asthma is often perceived at present as being no longer a significant public health problem. Improvements in asthma management have delivered marked reductions in hospital admissions and in mortality, particularly over the last 20 years. However, it still represents challenges in developing countries where preventer medications often remain to be fully implemented.1 Moreover, severe asthma represents a significant hard core of patients who are inadequately controlled in spite of optimal management.2 Much still needs to be understood of the basic pathophysiological mechanisms (such as airway hyper-responsiveness) and simple non-invasive methods to monitor airway inflammation are currently being sought. One of the highlights of 2008 was the outstanding review examining mechanisms of airway hyper-responsiveness by Berend et al.3 Increased responsiveness to various challenges is a fundamental abnormality in asthma. Potential factors contributing to this excessive response are reviewed as well as practical aspects related to measurements of hyper responsiveness and the value of gauging responses to anti-inflammatory treatments. Finally, associations with ventilation distribution and airway closure are discussed and the possibility is raised that the link could be exploited to enhance clinical assessments of airway hyper-responsiveness. Overall, this review provides a superb explanation and summary of the complex components determining dose response curves in asthma. Much remains to be understood of the broad epidemiology of asthma, particularly in developing countries. One aspect was examined by Raimondi et al., who studied Argentinean hospital admissions cross-sectionally 5 years after an initial survey.4 Rather disappointingly they found no evidence of significant improvements in parameters of asthma control, severity and treatment, suggesting a need for ongoing optimization of all aspects of asthma management. The prevalence of asthma symptoms was also studied in the Torres Strait region of Northern Australia, and the findings were compared with two previous studies. The investigators found a stable prevalence of various indices that included self-reported wheeze (12.5%), exercise induced wheezing (5.9%) and having asthma (12.2%).5 The findings were broadly similar to the results of surveys done in mainland Australia, and the increase in asthma prevalence noted in recent years appears to have reached a plateau. Jang et al.6 examined associations between BMI and aspirin intolerant asthma to gauge the influence of body weight on putative leucotriene metabolism. Overall, there did not appear to be strong links between asthmatic responses and the nutritional parameters examined in this study but more patients with genuine obesity need to be included in future studies. Asthma is often worsened by external factors as well as by comorbidities present in the individual patient. A fascinating study from Sydney, Australia assessed links between anxiety or depression and symptom perception and quality of life measures.7 The study was conducted cross-sectionally in an Emergency Department and found that the presence of anxiety and depression accounted for more than a quarter of the variance in asthma quality of life. This important study suggests a possible role for interventions treating this key comorbidity that, if successful, may have profound impacts on patient's quality of life. An elegant study by Hallani et al.8 examined the effects of mouth breathing on lung function. Enforced oral breathing caused a small reduction in lung function of mild asthmatics and precipitated asthma symptoms in some patients. The results raise interesting questions including whether asthmatics should be trained to use the nasal route, whether warm humidified gas should be used to treat acute asthma and if nasal and sinus disease in asthmatics should be managed more aggressively. Further studies are needed to examine these practical clinical questions. Asthma is an inflammatory condition that responds often dramatically to corticosteroid therapy. However, it has been difficult to judge the extent of airway inflammation in patients and to correlate this with treatment responses. Non-invasive measures of inflammation are being urgently sought and three recent papers in Respirology have contributed new information to this quest. Qian et al. examined high-sensitivity CRP (h5-CRP) with emphasis on severe asthma.9 They found that odds ratios for severe asthma increased with every quartile increase in CRP. The highest (fourth) quartile had adjusted odds ratios > 6, indicating that h5-CRP may be a good marker of asthma severity and possibly also airway inflammation. Exhaled breath condensate (EBC) is a minimally invasive technique that was evaluated by Ueno et al. in a broad ranging study.10 Overall, they found differences in various EBC measurements between asthmatics and controls, but failed to correlate EBC with asthma severity. The effects of corticosteroids could also not be excluded. Exhaled nitric oxide may reflect eosinophil-mediated airway inflammation and was used to try to differentiate atopic cough from cough-variant asthma.11 The investigators found that exhaled nitric oxide could provide such a distinction, most likely due to lower degrees of eosinophil-associated inflammation in atopic cough. Several interesting studies investigating aspects of asthma pharmacological treatments were published in 2008. A preliminary study of CD4+CD25+ T cells and their expression of a cytotoxic antigen (CTLA-4) found upregulation by of a commonly used inhaled glucocorticosteroid, fluticasone.12 This was accompanied by increases in IL-10 and reduced sputum eosinophils, suggesting modulated regulation of T-cell tolerance. Larger studies are needed to clarify clinical benefits. Other research investigated corticosteroid dose reduction strategies in childhood asthma13 and evaluated the effect of dietary antioxidants by meta-analysis.14 In the latter study the authors used a comprehensive search strategy and identified ten acceptable quality studies for inclusion in the analysis. Disappointingly, a higher intake of dietary antioxidants was not associated with a lower risk of asthma and no effects on lung function were noted. Sarcoidosis remains an important granulomatous disease, often suspected initially to be tuberculosis (TB), which continues to baffle and challenge clinicians. Judson et al. assessed the utility of chest radiography to identify exacerbations of sarcoidosis.15 The investigators used the radiological International Labour Organisation profusion score and could not identify a cut-point to diagnose exacerbations reliably, again emphasizing the importance of taking all aspects of the patient's disease profile into account when deciding about changes in treatment. Sarcoidosis was found to impair spermatogenesis in a patient with disseminated disease16 and the authors showed that oral corticosteroid treatment restored the defect. A broad-ranging review by Heffner17 provided up-to-date information on diagnosis and management of pleural effusion caused by malignancy. Only 50% of patients with cancer developing a pleural effusion during their clinical course have pleural malignancy. It is incumbent on the clinician to establish the exact aetiology as therapy may be radically different depending on the exact cause. Valuable diagnostic and management guidance is also provided in this review. Yap et al.18 analysed associations of pleural effusion with pulmonary embolism. They demonstrated that effusions are common (approximately 50% of cases) and found that most effusions were small and occurred on the side of the emboli. It was inferred that large and contralateral effusions should elicit a search for other possible diagnoses. Rare causes of pleural effusion are often perplexing and one such aetiology, Sjogren's syndrome without associated autoimmune disease, was detailed in a case report from Japan.19 There remains considerable interest in new diagnostic modalities applied to pleural effusion. Liao et al. used assays of pro-brain natriuretic peptide (pro-BNP) to distinguish between pulmonary embolism, coronary artery bypass grafting and congestive heart failure as causes of pleural effusion.20 They demonstrated a dramatic benefit for pro-BNP to differentiate congestive heart failure with levels above 2220 pg/mL being essentially diagnostic. Porcel et al. assessed the value of IL-8 and CRP as markers of high risk complicated effusions ultimately requiring chest tube drainage.21 IL-8 provided the most benefit (sensitivity 84%, specificity 82%), but overall IL-8 and CRP were not superior and provided similar diagnostic accuracy as had been reported for other classic parameters such as pleural fluid pH. An interesting study postulated that neoplastic cells may increase pleural fluid viscosity22 and found that it was a significant determinant with an odds ratio of > 6 (95% CI: 1.32–29.8). Further investigations in other disease conditions associated with exudates are clearly merited. Use of small bore chest drains inserted using Seldinger techniques has become popular to drain pleural fluid. Davies et al. audited complications in 100 consecutive insertions and found few serious complications except for drains becoming dislodged.23 Approximately, 9% of drains became blocked, a problem reduced by saline drain flushes. Malignant pleural effusion remains problematic and chronic indwelling pleural catheters with expensive single-use vacuum containers are often required. An innovative study used a reusable surgivac pump as an affordable alternative and found it to be safe and reliable.24 This may be of considerable usefulness, particularly in developing countries. Survival from lung cancer remains very low (10–15%) although this may fluctuate between regions and countries. Sutherland and Aitken25 reviewed 3-year data on ethnicity, socioeconomic status and cancer stage in a New Zealand population. They found disproportionate involvement of indigenous populations and socially disadvantaged groups coupled to low survival. Poor survival was associated with late presentation, a factor that could be reflective of the situation overall in the Asia–Pacific region; it merits strategies to achieve risk reduction (smoking cessation) and prompt recognition of symptoms in at-risk groups. The at times extraordinary clinical manifestations of lung cancer were detailed in a number of reports.26-29 An interesting study examined an association of Torque teno virus with the development of lung cancer in IPF.30 The virus has not been associated with specific pathologies and this study found that it was detectable in > 90% of cases of IPF with or without lung cancer. However, if > 103 copies/mL was used as cut-off, the patients with IPF and lung cancer were 100% positive versus 77.1% (IPF) and 85.9% (cancer). Further studies in selected populations are indicated. A comprehensive meta-analysis of carcinoembryonic antigen as a diagnostic method in malignant pleural effusion was presented by Shi et al.31 It appeared to be a useful but not fully diagnostic parameter in this context. Treatment of lung cancer remains a research priority. Lee et al. describe a case of spontaneous regression of small cell lung cancer and detail possible mechanisms.32 Surgery may provide reasonable palliation, and extended resection of lung cancer invading the liver is described in a report from Japan.33 Outcome was generally favourable with 11 months' survival at the time of the report. Finally, a multi-centre study reported by Takayama et al. provided valuable information on the use of uracil-tegafur with cisplatin in advanced non-small cell lung cancer.34 Relatively modest toxicity was noted and a response to therapy was observed in approximately one-third of patients. The review by Yew and Leung35 contained useful information about the epidemiology of multi-drug-resistant TB (MDR-TB) and described the situation in high prevalence countries. There is an emphasis on the importance of directly observed therapy short course (DOTS) to provide prevention against TB generally, with additional strategies in people with MDR-TB. DOTS is less effective for MDR-TB with cure rates being relatively low (< 60%) and with high recurrence rates (> 28%). There needs to be ongoing development of appropriate strategies for the treatment of MDR-TB with individualized treatment after appropriate identification. The review also highlights the emergence of extensively drug-resistant TB (XDR-TB), often in HIV co-infected patients, which has poor prognosis with high treatment failure and high mortality rate. The emerging XDR-TB infection emphasize the need for rapid diagnostic test to determine the potential of infections being treatment resistant, access to appropriate second-line drugs and the initiation of broad strategies to promote infection control. The review contains useful tables outlining side-effects of anti-TB drugs. Tabarsi et al.36 describes a series of patients who were referred to the Iran National TB Centre with possible MDR-TB over a 3 years' period. While there is no true estimate of prevalence of MDR-TB, approximately 20% of referrals did not have TB infection emphasizing the need for accurate diagnosis. A retrospective review by Kim et al.37 found a higher level of active TB occurring in patients with solid organ malignancy (3.07/1000 person-year vs 0.77 in controls). There is a need for awareness that the risk of reactivation of TB may be higher in those people who are having treatment with chemotherapy for malignancy or from the malignancy alone. The background level of TB in the population is relevant, and in this Korean study 17% of patients had old-healed TB on CXR. Higuchi et al.38 treated 34 presumed latent pulmonary TB patients (a positive QuantiFERON-TB Gold test) with isoniazid. Twenty-eight of the 34 patients were re-tested at 6 months and seven had a negative test and the others showed declines in test values. At 18 months there were no further declines. The question to be answered is whether the lack of conversion to a negative test indicates a problem with the test or the adequacy of treatment. Lee et al.39 describe the purifications of antigens including MTB12 and a 38-kDa antigen. They used ELISA techniques to measure IgG levels in the sera of TB patients and healthy controls. The data suggest that the use of the MTB-12 and 38-kDa antigen and a measurement of anti-IgG's to these antigens have good sensitivity and specificity for diagnosing TB. This paper is an example of continuing work to supplement or supplant smear testing as the usual test for TB. Skinner et al.40 undertook a prospective randomized study comparing the ‘tennis ball technique’ to avoid supine sleep versus nasal CPAP in 20 adults with mild to moderately severe position-dependent OSA. Treatment success was achieved in 13 of 18 subjects with the tennis ball and 16 of 18 of subjects with nasal CPAP, but nasal CPAP produced lower mean AHI. The ‘tennis ball technique’ reduced the mean per cent supine sleep time as compared with nasal CPAP. Forty-three subjects with newly diagnosed severe OSA (AHI > 30 events/h) participated in a comparison of auto versus fixed CPAP.41 Effectiveness outcomes were similar between the two treatment arms but the objective compliance was higher in the auto-CPAP arm than the fixed-CPAP arm. Despite more side-effects in the fixed-CPAP arm it was reported that patient preference favoured the fixed-CPAP rather than auto-CPAP, suggesting that device cost is important in patient choice. OSA and gastroesophageal reflux were common in 14 lung transplant patients (6 of whom had various stages of bronchiolitis obliterans syndrome (BOS)).42 No casual association with BOS was found. Izumizaki et al.43 presented data on changing properties in inspiratory skeletal muscle muscles and how positive pressure by CPAP contributes to this in normal subjects. They measured the passive stiffness of a muscle, which is influenced by whether the inspiratory muscles were contracted at long length or short length. It appeared that the conditioning of the inspiratory muscles at low lung volumes (i.e. short length) provided a greater effect on reducing operating chest wall volume, but there was significant variation between subjects. More development of these findings may lead to alterations in treatment and programmes for patients with COPD. In the President's review series Rosen44 described the pulmonary complications of HIV infection. This article provides an excellent overview and describes the variation in opportunistic infections between geographic regions. The review contains useful tables of the association between CXR pattern in HIV infection and the common pathogens and complicating illnesses. Additionally, it describes the increased prevalence of pulmonary hypertension and lung cancer along with airways disease and the immune reconstitution inflammatory syndrome, which is a diagnosis of exclusion in HIV-infected patients, particularly those on antiretroviral therapy. The use of surveillance cultures taken by low-volume blind BAL specimens in 412 patients requiring 48 h or more of ventilation is described by Boots et al.45 The study shows that the procedure is relatively safe and that surveillance cultures were useful in predicting up to 90% of the organism causing ventilator-associated pneumonia and had a high negative predictive value for the development ventilator-associated pneumonia. The surveillance process does not obviate the need to obtain specimens at the time of diagnosis of ventilator-associated pneumonia. Generalization of this data will be difficult given that regular surveillance has not been found to be universally useful. A prospective study comparing surveillance methods and looking at patient outcomes is required for definitive evidence. The antibiotic sensitivities of Streptoccus pneumoniae isolated from adult patients with community-acquired pneumonia across 10 institutions in Japan are described by Ishida et al.46 Penicillin resistance to S. pneumoniae was less than that of cephem and macrolide. This study argues for local or regional knowledge of antibiotic sensitivity patterns to be incorporated into treatment guidelines. Hung et al.47 report 31 patients presenting with pulmonary cryptococcosis at a Taiwan tertiary hospital over a 7-year period and describe the features of disseminated infections seen in seven patients. Associated risk factors for disseminated infection were impaired immunity, interstitial abnormalities on CXR and pleural effusion. The mortality from disseminated infection was high. Coccidioidomycosis is rare in Japan. Kishi et al.48 report on four cases diagnosed after return from south-western USA where coccidioidomycosis is endemic. Knowledge of recent travel and change of location is important in all countries when patients present with infective symptoms. The association of evidence of past respiratory tract infections and lung function in indigenous Australians is reported by Musk et al.49 They found that previous respiratory tract infections (viruses and atypical infections) were associated with reduced FEV1 and lower FEV1/FVC ratios indicating airflow obstruction, and this was independent of smoking status. Serology for common bacterial infections such as H. influenzae and S. pneumoniae was not performed, and therefore the relationship between these infections and the loss of lung function is uncertain. An ELISA for Chlamydophila pneumoniae-specific IgM was measured in 100 patients with an acute respiratory tract infection.50 A high rate of false positives was found in patients with acute respiratory tract infections, indicating the need for additional work examining the cut-off levels and the reasons for the false positives. Miyashita et al.51 followed on to compare the value of an enzyme immunoassay for detecting anti-C. pneumoniae-specific IgM antibody with existing ELISA assay and microimmunofluorescence tests. The assays examined eight serum samples from a patient with acute C. pneumoniae, 34 serum samples from ELISA false positive results, and 137 samples from patients with community-acquired pneumonia. The enzyme immunoassay was more sensitive and specific than the other tests and may become a more rapid and accurate test for C. pneumoniae infection. We were reminded by case reports that infections such as pulmonary aspergillosis can resemble tumours radiologically.52 Pulmonary mucormycosis diagnosis by ultrathin fibre optic bronchoscopy53 and treated with amphotericin and steroids54 are interesting case reports. Patients with community-acquired pneumonia associated with influenza in Turkey had a higher mortality, lower serum calcium and lymphocyte count, and higher creatinine kinase levels than those with pneumonia and no influenza.55 At this stage these findings are associations rather than distinct cut-points that can contribute to detection and perhaps influence the introduction of antiviral treatment. A Taiwanese study of community-acquired pneumonia found that procalcitonin levels were lower in the 17 survivors compared with the 5 patients who died.56 Although this is a small study, there may be prognostic indicators identified, which may indicate the need for additional interventions above standard care in community-acquired pneumonia. A multi-centre Japanese study of hospital acquired pneumonia looked at modifying severity guidelines on the basis of mortality, with a view to try to predict prognosis.57 They developed a simplified risk factor strategy for classifying severity incorporating clinical features, CRP and extent of infiltrate on the CXR with five classification criteria similar to the A-DROP criteria. Shindo et al.58 have compared two severity scoring systems for community-acquired pneumonia—A-DROP and CURB-65 in a retrospective Japanese study and found that the scoring systems provided very similar results. For pneumonia severity scores to be clinically relevant they need to be applied at the time of admission to influence treatment and outcome. Continuing audit may improve the uptake. In 518 Finland military conscripts Juvonen et al.59 found that BMI > 25 kg/m2 and previous respiratory tract infections were the two independent risk factors for respiratory infections in the 6 months service period as a conscript. The levels of clarithromycin were higher in bronchial epithelial lining fluid, alveolar epithelial lining fluid and alveolar macrophages than in serum in a study by Kikuchi et al.60 There is a potential efficacy advantage for clarithromycin given these fluid and cell concentrations, but these subjects were non-smokers and without any recent history of respiratory infection. Independent lung ventilation may provide therapeutic gain in the situation of a patient having a severely affected lung by pneumonia, but with the other lung less affected.61 The topics published on COPD range from genetics through diagnosis to treatments and outcome. An interesting study of Japanese patients with COPD compared with smoking and non-smoking controls found higher levels of prostaglandin E2 metalloproteinase-2 in smoking subjects and patients with COPD.62 These findings did not delineate specific groups as there was considerable overlap in the levels measured. However, these may be pointers towards the targeting of interventions against these substances as a useful future strategy. A study of the polymorphisms of the cathepsin S promoter in Japanese subjects showed that there were some novel genetic polymorphisms detected but there was no association with clinical COPD phenotypes.63 The hypothesis that angiotensin-converting enzyme polymorphisms may be related to the inflammatory reaction in COPD and might influence function has been tested by Zhang et al.64 They found no difference in lung function or exercise response in three genotypes. A study examining β-2 adrenoreceptor genotypes and the bronchodilator effect of tiotropium in COPD65 found that patients with the arg/arg homozygous state had greater bronchodilator response than heterozygous arg/gly and gly/gly homozygous states. This is of significant interest but the study is limited by the large overlap in bronchodilator responses and the fact that there were some very large acute bronchodilator responses exceeding 300 mL. These patients may have a component of asthma and may require more detailed description of phenotype with tests such as sputum eosinophils and exhaled NO. The use of a COPD symptom-based questionnaire to help in the diagnosis of COPD in a Japanese population is described by Kawayama et al.66 There is a difference in the performance of the questionnaire from that in Western COPD patients and the utility of questionnaires will not replace spirometry in the definition of COPD. A small population of Australian COPD patients showed the usefulness of the BODE score in predicting frequency of hospital admissions and reduced quality of life.67 Tanaka68 found that a cut-point of lactate increase of 0.5 mmol/L from baseline to post-exercise indicated a significant difference in activities of daily living between small numbers of COPD patients and hence may be useful to predict the timing of the introduction of rehabilitation. Treatment studies with CPAP and oxygen were also published. A study of CPAP in stable COPD patients to reduce hyperinflation has been conducted in a small population.69 The findings suggest that patients with predominantly emphysema would generally benefit from CPAP improving inspiratory capacity and about half of the small group of bronchitic patients showed benefit as well. The study results need to be confirmed with plethysmography measurements of RV and TLC. A study of the effect of supplemental oxygen in hypoxemic patients with COPD found that oxygen therapy did not improve driving performance acutely.70 In six patients with severe COPD during an exacerbation and in remission, Hanaoka et al.71 found that supplemental oxygen reduced pulmonary artery pressure increases during exacerbations and exercise. A study from Taiwan reports the cost of COPD and has found as expected that the direct medical costs were increased with increase in severity of disease and that hospital costs were the major contributor.72 Respirology in 2008 detailed a series of novel technical investigations, studies focussed on prediction equations and reports updating international standardization of lung function measurement. The use of endo-bronchial ultrasound to delineate causes of central airway expiratory collapse is described in an article by Murgu et al.73 The next component arising from this study will need to determine whether distinguishing between cartilaginous problems versus posterior membrane problems can lead to a change in management for patients suffering central airway collapse. The ability to import hyperpolarized helium from Europe and undertake functional MRI in patients may aid pulmonary research programmes in Australia.74 The continuing development of CT scanning documenting airway dimensions in patients with COPD is described in a longitudinal study by Ohara et al.75 The best test for COPD management is likely to remain spirometric measurements, but the use of CT scanning will enable examination of pharmacological interventions in localized regions of the lungs. The acceptance of bronchoscopy has been studied in a Japanese group of patients by Hirose et al.76 In this study men seem to be more accepting of the procedure, but there are significant symptoms bothering the patients, which need to be considered in the consent procedure as well as highlighting the need for appropriate sedation for the procedure. Davoudi et al.77 have developed a web-based curriculum relating to bronchoscopic knowledge in a number of languages, which will be useful in aiding the development of competency-based training for bronchoscopy. There are several studies detailing aspect of lung function measurement. Leung et al.78 describe the effect of the changes in the recent standardization of diffusing capacity measurement. Perhaps most notable was the increase in valid DLCO measurements in a Chinese population because of the reduction in the stringency of the inspiratory volume criteria and breath hold time. Newbury et al.79 describe an initial study which is going to aid in the development of Australian predictive equations for impulse oscillometry. A Korean population has been used to derive predictive equations for spirometry.80 When comparing the derived equations to that of Caucasian predictive equations, the investigators found that there was a change in the number of people being diagnosed as having a restrictive abnormality or a particular severity classification of COPD. These data emphasize that local normative data are essential as a foundation for an understanding of local disease prevalence. Yu et al.81 described the use of an empirical treatment programme for subjects attending a respiratory clinic with a cough lasting more than 8 weeks. They achieved relief in 88% of patients using sequential simple diagnostic tests and the introduction of drugs aimed at reducing allergy, and minimizing the empirical approach may be useful in areas where there is limited access to investigation facilities. Bosentan improved quality of life and 6MWD in a retrospective review of pulmonary artery hypertension patients.82 However, as with other studies there was a poor relationship between the two outcome measures. In 15 patients with tuberous sclerosis complex, it was found that 11/15 had multifocal pneumocyte hyperplasia diagnosed by VAT.83 Lymphangioleiomyomatosis was found in over half the patients. Finally, recent guidelines have described disease profiles in which oxygen may be relatively contraindicated. However, Oku and Okada84 described benefits of oxygen therapy in a patient with lateral medullary infarction of the brain. Respirology continues to publish clinical science that tests hypotheses, detects associations and determines the effectiveness of algorithms, guidelines and treatment strategies for respiratory disease. The sharing of this information in Respirology stimulates thinking around causation and therapy of lung disease in the Asia–Pacific region and generates ideas internationally for advancing the care of lung diseases.

From around the world we have had evidence that the “guideline-driven” attainment of good asthma control is not being achieved.1 2 3 Surveys over the past decade have provided the evidence and concluded that “physicians and patients should raise their expectations of the level of asthma control that can be achieved”,2 and “the critical need for improved asthma care, including a more global evaluation of asthma control, implementation of asthma treatment plans and addressing co-morbid conditions”.3 In this issue of Thorax the article by Kandane-Rathnayake et al 4 describes the loss of lung function in middle-aged patients not using inhaled corticosteroids for their asthma ( see page 1025 ). This study adds to the survey evidence1 2 3 by providing lung function data in a population that has been part of an asthma cohort study for several decades. It is a timely wake-up call that, in spite of having doctor-agreed guidelines for asthma management available for two decades,5 predominantly in …