Showing papers by "Peter G. Gibson published in 2010"

CICADA: Cough in Children and Adults: Diagnosis and Assessment. Australian cough guidelines summary statement.

Abstract: Cough is a common and distressing symptom that results in significant health care costs from medical consultations and medication use. Cough is a reflex activity with elements of voluntary control that forms part of the somatosensory system involving visceral sensation, a reflex motor response and associated behavioural responses. At the initial assessment for chronic cough, the clinician should elicit any alarm symptoms that might indicate a serious underlying disease and identify whether there is a specific disease present that is associated with chronic cough. If the examination, chest x-ray and spirometry are normal, the most common diagnoses in ADULTS are asthma, rhinitis or gastro-oesophageal reflux disease (GORD). The most common diagnoses in CHILDREN are asthma and protracted bronchitis. Management of chronic cough involves addressing the common issues of environmental exposures and patient or parental concerns, then instituting specific therapy. In ADULTS, conditions that are associated with removable causes or respond well to specific treatment include protracted bacterial bronchitis, angiotensin-converting enzyme inhibitor use, asthma, GORD, obstructive sleep apnoea and eosinophilic bronchitis. In CHILDREN, diagnoses that are associated with removable causes or respond well to treatment are exposure to environmental tobacco smoke, protracted bronchitis, asthma, motor tic, habit and psychogenic cough. In ADULTS, refractory cough that persists after therapy is managed by empirical inhaled corticosteroid therapy and speech pathology techniques.

IL-27/IFN-γ Induce MyD88-Dependent Steroid-Resistant Airway Hyperresponsiveness by Inhibiting Glucocorticoid Signaling in Macrophages

Abstract: Inflammation and airway hyperresponsiveness (AHR) are hallmark features of asthma and often correlate with the severity of clinical disease. Although these features of asthma can be effectively managed with glucocorticoid therapy, a subgroup of patients, typically with severe asthma, remains refractory to therapy. The mechanisms leading to steroid resistance in severe asthmatics are poorly understood but may be related to the activation of innate host defense pathways. Previously, we have shown that IFN-γ-producing cells and LPS, two factors that are associated with severe asthma, induce steroid-resistant AHR in a mouse model. We now demonstrate that cooperative signaling induced by IFN-γ and LPS results in the production of IL-27 by mouse pulmonary macrophages. IL-27 and IFN-γ uniquely cooperate to induce glucocorticoid-resistant AHR through a previously unknown MyD88-dependent mechanism in pulmonary macrophages. Importantly, integrated signaling by IL-27/IFN-γ inhibits glucocorticoid-induced translocation of the glucocorticoid receptor to the nucleus of macrophages. Furthermore, expression of both IL-27 and IFN-γ was increased in the induced sputum of steroid-refractory asthmatics. These results suggest that a potential mechanism for steroid resistance in asthma is the activation of MyD88-dependent pathways in macrophages that are triggered by IL-27 and IFN-γ, and that manipulation of these pathways may be a therapeutic target.

Early-life chlamydial lung infection enhances allergic airways disease through age-dependent differences in immunopathology

Abstract: Background Asthma typically originates in early-life, and the impact of infection during immunologic maturation is a critical factor in disease pathogenesis. The progression of aberrant T H 2 cell responses and disease development has been attributed to a lack of infections. However, exposure to specific pathogens such as Chlamydia may alter immunologic programming and predispose to asthma. Objective To investigate the effects of chlamydial infection at different ages on allergic airways disease in later life. Methods Neonatal, infant, or adult BALB/c mice were infected and 6 weeks later were sensitized and subsequently challenged with ovalbumin. Hallmark features of allergic airways disease were compared with uninfected allergic and nonallergic controls. Results Early-life (neonatal and infant) but not adult chlamydial infection enhanced the development of hallmark features of asthma in ovalbumin-induced allergic airways disease. Notably early-life infection increased mucus-secreting cell numbers, IL-13 expression, and airway hyperresponsiveness. Neonatal infection attenuated eosinophil influx and ovalbumin-specific T H 2 cytokine release and numbers of activated myeloid dendritic cells (DCs) in lymph nodes. By contrast, infant infection augmented features of allergic inflammation with increased airway eosinophils, T H 2 cytokine, and DC responses. Both neonatal and infant infection increased systemic DC-induced IL-13 release from CD4 + T cells. The timing of infection had significant effects on lung structure because neonatal but not infant or adult infection induced increases in alveolar diameter. Conclusion Early-life respiratory chlamydial infections modulate immune responses, alter lung function and structure, and enhance the severity of allergic airways disease in later life.

Potentially pathogenic bacteria cultured from the sputum of stable asthmatics are associated with increased 8-isoprostane and airway neutrophilia.

Abstract: Potential bacterial pathogens are found in the airways in several diseases that are associated with neutrophilic inflammation. The aim of this study was to characterize subjects with stable asthma, with no symptoms of respiratory infection, to assess whether key potentially pathogenic bacteria were present in significant quantities in the airways and to correlate this with the pattern of airway inflammation and oxidative stress. Subjects with stable asthma (n = 115) and healthy controls (n = 8) underwent clinical assessment, including hypertonic saline challenge combined with sputum induction. A significant load of potentially pathogenic bacteria (> 10(6) cfu/mL) was cultured from the sputum of 17 (15%) subjects with stable asthma and was associated with higher total cell counts, proportion and number of neutrophils, sputum IL-8 and 8-isoprostane concentrations. The role of bacteria in potentiating neutrophilic asthma warrants further investigation. Therapies such as antibiotic and antioxidant treatment may be most effective in this sub-group of patients.

Cough reflex sensitivity improves with speech language pathology management of refractory chronic cough

Abstract: Speech language pathology is an effective management intervention for chronic cough that persists despite medical treatment. The mechanism behind the improvement has not been determined but may include active cough suppression, reduced cough sensitivity or increased cough threshold from reduced laryngeal irritation. Objective measures such as cough reflex sensitivity and cough frequency could be used to determine whether the treatment response was due to reduced underlying cough sensitivity or to more deliberate control exerted by individual patients. The number of treatments required to effect a response was also assessed. The aim of this study was to investigate subjective and objective measures of cough before, during and after speech language pathology treatment for refractory chronic cough and the mechanism underlying the improvement. Adults with chronic cough (n = 17) were assessed before, during and after speech language pathology intervention for refractory chronic cough. The primary outcome measures were capsaicin cough reflex sensitivity, automated cough frequency detection and cough-related quality of life. Following treatment there was a significant improvement in cough related quality of life (Median (IQR) at baseline: 13.5 (6.3) vs. post treatment: 16.9 (4.9), p = 0.002), objective cough frequency (Mean ± SD at baseline: 72.5 ± 55.8 vs. post treatment: 25 ± 27.9 coughs/hr, p = 0.009), and cough reflex sensitivity (Mean ± SD log C5 at baseline: 0.88 ± 0.48 vs. post treatment: 1.65 ± 0.88, p < 0.0001). This is the first study to show that speech language pathology management is an effective intervention for refractory chronic cough and that the mechanism behind the improvement is due to reduced laryngeal irritation which results in decreased cough sensitivity, decreased urge to cough and an increased cough threshold. Speech language pathology may be a useful and sustained treatment for refractory chronic cough. Australian New Zealand Clinical Trials Register, ACTRN12608000284369.

Differential gene expression and cytokine production from neutrophils in asthma phenotypes

Abstract: Asthma is characterised into eosinophilic and non-eosinophilic phenotypes based on inflammatory cell patterns in airway secretions. Neutrophils are important in innate immunity, and are increased in the airways in non-eosinophilic asthma. The present study investigated the activity of neutrophils in asthma phenotypes. Participants with eosinophilic (n = 8) and non-eosinophilic asthma (n = 9) and healthy controls (n = 11) underwent sputum induction and blood collection. Neutrophils were isolated and cultured with or without lipopolysaccharide. Cytokines were measured by ELISA, and gene expression was analysed using a gene expression microarray and quantitative PCR. In non-eosinophilic asthma, blood neutrophils released significantly higher levels of interleukin-8 at rest. Cytokine gene expression and sputum neutrophil protein production did not differ between asthma subtypes. Microarrays demonstrated closely related expression profiles from participants with non-eosinophilic asthma that were significantly distinct from those in eosinophilic asthma. A total of 317 genes were significantly altered in resting neutrophils from participants with non-eosinophilic asthma versus eosinophilic asthma, including genes related to cell motility and regulation of apoptosis. Non-eosinophilic and eosinophilic asthma are associated with specific gene expression profiles, providing further evidence that these phenotypes of asthma involve different molecular mechanisms of disease pathogenesis at the systemic level. The mechanisms of non-eosinophilic asthma may involve enhancement of blood neutrophil chemotaxis and survival.

Assessment and reproducibility of non-eosinophilic asthma using induced sputum.

Abstract: Background: The assessment of eosinophilic airway inflammation using induced sputum identifies a corticosteroid-responsive subtype that can be used to guide anti-inflammatory therap

Chlamydial Respiratory Infection during Allergen Sensitization Drives Neutrophilic Allergic Airways Disease

Abstract: Neutrophilic asthma is a prevalent, yet recently described phenotype of asthma. It is characterized by neutrophilic rather than eosinophilic airway inflammation and airways hyperresponsiveness (AHR) and may have an infectious origin. Chlamydial respiratory infections are associated with asthma, but how these Th1-inducing bacteria influence Th2-mediated asthma remains unknown. The effects of chlamydial infection on the development of asthma were investigated using a BALB/c mouse model of OVA-induced allergic airways disease (AAD). The effects of current and resolved Chlamydia muridarum infection during OVA sensitization on AAD were assessed and compared with uninfected and nonsensitized controls. Current, but not resolved, infection attenuated hallmark features of AAD: pulmonary eosinophil influx, T cell production of IL-5, mucus-secreting cell hyperplasia, and AHR. Current infection also induced robust OVA-driven neutrophilic inflammation and IFN-γ release from T cells. The phenotype of suppressed but persistent Th2 responses in association with enhanced neutrophilia is reminiscent of neutrophilic asthma. This phenotype was also characterized by increased pulmonary IL-12 and IL-17 expression and activation of APCs, as well as by reduced thymus- and activation-regulated chemokine. Inhibition of pulmonary neutrophil influx during infection blocked OVA-induced neutrophilic inflammation and T cell IFN-γ production and reversed the suppressive effects on mucus-secreting cell hyperplasia and AHR during AAD. These changes correlated with decreased IL-12 and IL-17 expression, increased thymus- and activation-regulated chemokine and altered APC activation. Blocking IFN-γ and IL-17 during OVA challenge had no effect. Thus, active chlamydial respiratory infection during sensitization enhances subsequent neutrophilic inflammation and Th1/Th17 responses during allergen exposure and may have a role in the pathogenesis of neutrophilic asthma.

The effect of cigarette smoking on asthma control during exacerbations in pregnant women

Abstract: Background Smoking and severe asthma exacerbations in pregnancy are risk factors for low birth weight babies. No studies have assessed the clinical implications of smoking on asthma exacerbations in pregnancy. Methods Pregnant women with current asthma (n=80) were prospectively assessed at clinic visits (18, 30, 36 weeks), during exacerbations and with fortnightly phone calls. The asthma control questionnaire was administered at each contact and exacerbations classified as severe (requiring medical intervention) or mild (self-managed). Medications, self-management skills, smoking history, fractional exhaled nitric oxide (FENO), exhaled carbon monoxide (ECO) and lung function were assessed. Pregnant women without asthma (controls, n=46) were assessed prospectively at clinic visits. Results Women with asthma were more likely to smoke (34% current smokers) than women without asthma (15% current smokers). In women with asthma, the median (IQR) exacerbation rate during pregnancy was 2.0 (1.0–3.0) in current smokers, 2.0 (1.0–3.0) in ex-smokers and 1.5 (1.0–2.0) in never smokers. The asthma control score during exacerbations was higher in current smokers (median (IQR) 2.17 (1.17–2.7)) compared with never smokers (1.17 (0.8–2.17), p=0.056). An adjusted linear regression model found that smoking was significantly associated with higher asthma control score during exacerbation (p=0.04). Birth weights were lower among children of smokers than non-smokers (p=0.023 control group, p=0.086 asthma group). Conclusions During pregnancy, asthma exacerbations are more common and more severe in current smokers than never smokers. The risk of effects of maternal asthma on the fetus may be greater among smokers.

Pneumococcal conjugate vaccine-induced regulatory T cells suppress the development of allergic airways disease

Abstract: Background Infections with some bacteria, including Streptococcus pneumoniae , have been associated with a reduced incidence of asthma. Components of S pneumoniae may have the potential to modulate allergic inflammatory responses and suppress the development of asthma. Objectives To determine if human S pneumoniae vaccines have the potential to suppress asthma by elucidating their effect on allergic airways disease (AAD) in mouse models. Methods AAD was induced in BALB/c mice by intraperitoneal sensitisation and intranasal challenge with ovalbumin. Pneumococcal conjugate or polysaccharide vaccines were administered at the time of sensitisation or during established AAD. Hallmark features of AAD were assessed. Levels of regulatory T cells (Tregs) were quantified by fluorescence-activated cell sorting, and their immunoregulatory capacity was assessed using proliferation assays and anti-CD25 antibody treatment. Results Intranasal administration of the conjugate vaccine, but not the polysaccharide vaccine, suppressed the hallmark features of AAD, including: eosinophilic and T helper 2-mediated inflammation; airway hyper-responsiveness; circulating immunoglobulin E (IgE) levels; and mucus hypersecretion. Intramuscular administration of the conjugate vaccine had limited protective effects. The conjugate vaccine increased Tregs in the lung-draining lymph nodes, lung and spleen. Furthermore, conjugate vaccine-induced Tregs had an enhanced capacity to suppress T effector responses. Anti-CD25 administration reversed the suppressive effects of the conjugate vaccine. Conclusions A currently available human conjugate vaccine suppresses the hallmark features of AAD through the induction of Tregs. Thus targeted administration may provide a novel immunoregulatory treatment for asthma.

Mannitol challenge for assessment of airway responsiveness, airway inflammation and inflammatory phenotype in asthma

Abstract: Summary Background Assessment of airway inflammation in asthma is becoming increasingly important, as the inflammatory phenotype underpins the treatment response. Objective This study aimed to evaluate mannitol as a tool for assessing airway responsiveness and airway inflammation in asthma, compared with hypertonic saline. Methods Fifty-five subjects with stable asthma completed a hypertonic (4.5%) saline challenge and a mannitol challenge at two separate visits, performed 48–72 h apart, in random order. Results Induced sputum was obtained from 49 (89%) subjects during the saline challenge and 42 (76%) subjects during the mannitol challenge (P>0.05). There was a significant correlation between the greatest percentage fall in forced expiratory volume in 1 s (FEV1) (r=0.6, P<0.0001), the dose–response slope (r=0.73), cumulative dose (r=0.55) and PD15 (r=0.46) for mannitol and hypertonic saline. The greatest percentage fall in FEV1 to mannitol was less in non-eosinophilic asthma. There was a lower total cell count in mannitol vs. hypertonic-saline-induced sputum. However, sputum eosinophils and neutrophils were not significantly different. Using mannitol, a higher proportion of subjects were classified as having eosinophilic asthma. There were no differences in IL-8, neutrophil elastase or matrix-metalloproteinase 9 concentrations in sputum samples induced with mannitol or hypertonic saline. Conclusion We conclude that mannitol can be used to induce good-quality sputum, useful for analysis of inflammatory mediators and for predicting the inflammatory phenotype in asthma. Cite this as: L. G. Wood, H. Powell and P. G. Gibson, Clinical & Experimental Allergy, 2010 (40) 232–241.

Sex-specific associations between cortisol and birth weight in pregnancies complicated by asthma are not due to differential glucocorticoid receptor expression

Abstract: Background Fetal growth inhibition is a known sequelae of in utero glucocorticoid exposure and has long-term consequences for adult health. Sex-specific fetal growth patterns are observed in pregnancies with maternal asthma and may be due to differential sensitivity of the placenta to glucocorticoids. It is currently unknown whether expression of the placental glucocorticoid receptor (GR) becomes altered with asthma or the use of inhaled corticosteroids. Methods Pregnant women with mild asthma (n¼52), moderateesevere asthma (n¼71) and without asthma (n¼51) were recruited at John Hunter Hospital, Newcastle, Australia. At delivery, placentae and cord blood were collected, and fetal sex and birth weight were recorded. Placental GR heterogeneous nuclear RNA (hnRNA), mRNA and protein were measured and cord blood cortisol concentrations were assessed. Results Placental GR gene activity increased with cortisol exposure but decreased with inhaled corticosteroid treatment (p¼0.05). With maternal asthma, female birth weight centiles were inversely associated with cortisol (r¼� 0.286, p¼0.017) and, despite a decrease in placental GR mRNA (p¼0.003), placental GRa protein levels were unchanged. In males, no change to cortisol, birth weight or placental GR were evident in pregnancies with asthma. Together, these results indicate that in pregnancies complicated by asthma, placental GR gene activity, but not mRNA expression or protein levels, is dependent on cortisol and inhaled corticosteroid treatment. Conclusions The sex-specific associations between cortisol and birth weight observed in pregnancies with asthma are not due to altered GR expression; however, they may be due to differential glucocorticoid sensitivity via preferential transcription of GR isoforms or posttranslational modifications.

Assessment of dietary fat intake and innate immune activation as risk factors for impaired lung function.

Abstract: Preservation of lung health with aging is an important health issue in the general population, as loss of lung function with aging can lead to the development of obstructive lung disease and is a predictor of all-cause and cardiovascular mortality. Inflammation is increasingly linked to loss of lung function and evidence suggests that consumption of dietary fat exacerbates inflammation. We aimed to determine the association between dietary fat intake and lung function in older people. Participants from the Hunter community study, a population-based cohort, were recruited during 2004 and 2005. Participants received a clinical assessment, including spirometry, and provided a blood sample. Diets were analyzed using food-frequency questionnaires. Plasma interleukin (IL)-6 and C-reactive protein was measured by Enzyme-Linked immunosorbent assay. Using backward stepwise linear regression, %energy from dietary fat, age and plasma IL-6 were considered as negative predictors of forced expiratory volume in one second (FEV1) in men. Also in men, %energy intake from dietary fat, age, body mass index and IL-6 were negative predictors of %predicted forced vital capacity (FVC). Smoking and age were negative predictors of FEV1/FVC. In women, plasma IL-6 and age were negative predictors of %FVC, whereas obesity was positively associated with FEV1/FVC. An increased proportion of fat in the diet is associated with the reduced lung function in older men. Dietary-fat induced innate immune activation and IL-6 release may contribute to this effect. Dietary interventions involving fat restriction should be further investigated as means of preserving lung function with aging.

Reduced circulating antioxidant defences are associated with airway hyper-responsiveness, poor control and severe disease pattern in asthma

Abstract: Dietary antioxidants are important in protecting against oxidative stress. We have previously demonstrated that circulating dietary antioxidant levels are reduced in asthma. The present study examined the variation in dietary antioxidant levels in asthma, according to airway responsiveness, asthma control and clinical asthma pattern. Peripheral blood was collected from forty-one subjects with stable, persistent asthma. Airway responsiveness was assessed by hypertonic saline challenge. Asthma control was assessed using the Asthma Control Questionnaire. Clinical asthma pattern was determined using Global Initiative for Asthma (GINA) criteria. Whole-blood carotenoids (beta-carotene, lycopene, alpha-carotene, beta-cryptoxanthin, lutein/zeaxanthin) and tocopherols (alpha-, delta-, gamma-tocopherol) were measured by HPLC. Plasma antioxidant potential (AOP) was determined by colorimetric assay (OxisResearch, Portland, OR, USA). Asthmatic subjects with airway hyper-responsiveness (AHR) had reduced levels of beta-carotene and alpha-tocopherol compared with those without AHR. Subjects with uncontrolled asthma had low levels of AOP compared with those with controlled or partly controlled asthma. Subjects with a severe persistent clinical asthma pattern had reduced levels of alpha-tocopherol compared with those with a mild to moderate asthma pattern. We conclude that asthmatic subjects with AHR, uncontrolled asthma and a severe asthma pattern have impaired antioxidant defences and are thus most susceptible to the damaging effects of oxidative stress. This highlights the potential role for antioxidant supplementation in these subjects.