Advancing the management of obstructive airways diseases through translational research.

Obstructive airways diseases (OAD) represent a huge burden of illness world-wide, and in spite of the development of effective therapies, significant morbidity and mortality related to asthma and COPD still remains. Over the past decade, our understanding of OAD has improved vastly, and novel treatments have evolved. This evolution is the result of successful translational research, which has connected clinical presentations of OAD and underlying disease mechanisms, thereby enabling the development of targeted treatments. The next challenge of translational research will be to position these novel treatments for OAD for optimal clinical use. At the same time, there is great potential in these treatments providing even better insights into disease mechanisms in OAD by studying the effects of blocking individual immunological pathways. To optimize this potential, there is a need to ensure that translational aspects are added to randomized clinical trials, as well as real-world studies, but also to use other trial designs such as platform studies, which allow for simultaneous assessment of different interventions. Furthermore, demonstrating clinical impact, that is research translation, is an increasingly important component of successful translational research. This review outlines concepts of translational research, exemplifying how translational research has moved management of obstructive airways diseases into the next century, with the introduction of targeted, individualized therapy. Furthermore, the review describes how these therapies may be used as research tools to further our understanding of disease mechanisms in OAD, through translational, mechanistic studies. We underline the current need for implementing basic immunological concepts into clinical care in order to optimize the use of novel targeted treatments and to further the clinical understanding of disease mechanisms. Finally, potential barriers to adoption of novel targeted therapies into routine practice and how these may be overcome are described.

Obese asthmatics are characterized by altered adipose tissue macrophage activation.

BACKGROUND: Adipose tissue-derived inflammation is linked to obesity-related comorbidities. This study aimed to quantify and immuno-phenotype adipose tissue macrophages (ATMs) from obese asthmatics and obese non-asthmatics and to examine associations between adipose tissue, systemic and airway inflammation. METHODS: Visceral (VAT) adipose tissue and subcutaneous (SAT) adipose tissue were collected from obese adults undergoing bariatric surgery and processed to obtain the stromovascular fraction. Pro-inflammatory (M1) and anti-inflammatory (M2) macrophages were quantified by flow cytometry. Cytospins of induced sputum were stained for differential cell counts. Plasma C-reactive protein (CRP) and CD163 were measured by ELISA. RESULTS: VAT contained a higher number of ATMs compared to SAT. A higher percentage of M1 ATMs was observed in VAT of obese asthmatics compared to obese non-asthmatics. The M1:M2 ratio in VAT was negatively associated with FEV1 %. Sputum macrophage count was correlated positively with M1 ATMs and negatively with M2 ATMs in VAT. In obese asthmatics, CRP was positively associated with M1:M2 ratio in VAT. There were no associations with CD163. An elevated ratio of M1:M2 ATMs was observed in VAT of obese asthmatics with increased disease severity. CONCLUSIONS AND CLINICAL RELEVANCE: Visceral inflammation with increased pro-inflammatory macrophages (M1) occurs in obese asthma and may be a determinant of systemic inflammation and asthma severity.

Working while unwell: Workplace impairment in people with severe asthma.

BACKGROUND: Severe asthma affects quality of life; however, its impact on workplace productivity is poorly understood. OBJECTIVE: To compare workplace productivity-absenteeism and presenteeism-and impairment in daily activities in severe and non-severe asthma over time and identify characteristics associated with presenteeism in severe asthma. METHODS: The Severe Asthma Web-based Database is an ongoing observational registry from Australia, New Zealand and Singapore. At April 2017, 434 patients with severe asthma and 102 with non-severe asthma were enrolled (18-88 years; 59% female). Participants provided comprehensive clinical and questionnaire data at baseline and were followed-up every 6 months for 24 months. Absenteeism (percentage of time not at work), presenteeism (self-reported impairment at work) and impairment in daily activities outside work due to health problems in the last week were calculated. RESULTS: At baseline, 61.4% of participants with severe asthma and 66.2% with non-severe asthma under 65 years were employed. At younger ages (30-50 years), fewer severe asthma participants were employed (69% vs 100%). Presenteeism and impairment in daily activity were more frequently reported in severe asthma and in participants with poorer asthma control, poorer lung function and more past-year exacerbations (P < .01). Over time, deteriorating asthma control was associated with increasing presenteeism. Although absenteeism was not different between severe and non-severe asthma, worse asthma control was associated with absenteeism (P < .001). In participants with severe asthma, presenteeism was reported more frequently in those with poorer asthma control, poorer asthma-related quality of life and symptoms of depression or anxiety (P < .01). CONCLUSION AND CLINICAL RELEVANCE: Severe asthma was associated with impairment at work and outside the workplace. Improving asthma control and mental health may be important targets for optimizing workplace productivity in severe asthma. Presenteeism and absenteeism may represent key metrics for assessing intervention efficacy in people with severe asthma of working age.

Sputum basophils are increased in eosinophilic asthma compared with non-eosinophilic asthma phenotypes.

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

Resistin is a predictor of asthma risk and resistin:adiponectin ratio is a negative predictor of lung function in asthma.

BACKGROUND: Adipokines, such as resistin and adiponectin, modify inflammation and may contribute to increased asthma risk and severity in obese people. OBJECTIVE: To examine plasma resistin and resistin:adiponectin ratio (i) in asthmatics compared to healthy controls, (ii) according to asthma severity, obesity and gender (iii) following weight loss in obese asthmatics. METHODS: In a cross-sectional observational study of asthmatic adults (n = 96) and healthy controls (n = 46), plasma resistin and adiponectin were measured. In a separate intervention study, obese asthmatic adults (n = 27) completed a 10-week weight loss intervention and plasma resistin and adiponectin concentrations were analysed. RESULTS: Plasma resistin and resistin:adiponectin ratio were higher in asthma compared to controls and were higher again in subjects with a severe vs. mild-to-moderate asthma pattern. Amongst asthmatic subjects, resistin was not modified by gender or obesity, while adiponectin was lower in males and obese subjects. As a result, resistin:adiponectin ratio was higher in obese males, non-obese males and obese females, compared to non-obese females. In a logistic regression model, plasma resistin concentration was a predictor of asthma risk. In a multiple linear regression model, plasma resistin:adiponectin ratio was a negative predictor of FEV1 in asthma. Following weight loss, neither resistin, adiponectin nor resistin:adiponectin ratio was changed. However, the change (∆) in %body fat was associated with ∆ resistin:adiponectin ratio. Post-intervention ∆ resistin was negatively correlated with both ∆FRC and ∆RV. CONCLUSION AND CLINICAL RELEVANCE: This study demonstrates that resistin and resistin:adiponectin ratio are higher in asthma and are higher again in subjects who have more severe disease. Resistin:adiponectin ratio is highest in obese male asthmatics. As resistin is a predictor of asthma risk and resistin:adiponectin is a predictor of FEV1 in asthma, these adipokines may be contributing to the obese asthma phenotype, thus providing a potential therapeutic target for obese asthma.

Blood cytotoxic/inflammatory mediators in non-eosinophilic asthma.

BACKGROUND: Non-eosinophilic asthma (NEA) is a distinct, often corticosteroid-resistant inflammatory asthma phenotype. NK and NKT-like cells are effector lymphocytes that we have shown, like CD28null T cells, to be relatively resistant to steroids and major sources of pro-inflammatory/cytotoxic mediators. We hypothesized that these cells and mediators would be increased in peripheral blood in NEA. METHODS: Adults with severe asthma and variable airflow obstruction, poorly controlled despite maintenance therapy with inhaled glucocorticosteroids and long-acting bronchodilators, were recruited. Blood was assessed in those with eosinophilic asthma (n = 12), NEA (n = 25) and healthy non-smoking controls (n = 30). We applied flow cytometry to measure T, CD28null, NK and NKT-like cells and their expression of granzyme B, perforin, and killer inhibitory/activating receptors CD94(Kp43), CD158b and CD107A. Intracellular pro-inflammatory cytokine production (IFN-γ and TNF-α) was assessed in 18 controls and 10 patients with asthma/group. RESULTS: In NEA, there was increased expression of granzyme B by CD8+ T cells vs. CONTROLS: There was increased expression of granzyme B and CD158 and decreased CD94 on NK cells, vs. healthy controls and those with eosinophilic asthma. IFN-γ production by NK cells and TNF-α production by NKT-like cells in NEA were significantly increased vs. CONTROLS: In both eosinophilic and NEA phenotypes, there were significant increases in CD4+28null T cells (72% and 81% increases, respectively, vs. controls) and their expression of pro-inflammatory cytokines. Significant correlations were noted between blood CD4+28null T cells and neutrophil numbers in induced sputum, and between corticosteroid dose and blood NKT-like cells, and their production of granzyme B and TNF-α and NK IFN-γ. CONCLUSION AND CLINICAL RELEVANCE: In poorly controlled asthma, altered expression of cytotoxic/pro-inflammatory mediators can be seen on a variety of lymphocyte subsets in the peripheral blood; these changes are most apparent in NEA. Whether this pattern of expression is a marker of treatment responsiveness and future risk of exacerbations remains to be determined.

Real-life effectiveness of omalizumab in severe allergic asthma above the recommended dosing range criteria.

BACKGROUND: Omalizumab (Xolair) dosing in severe allergic asthma is based on serum IgE and bodyweight. In Australia, patients eligible for omalizumab but exceeding recommended ranges for IgE (30-1500 IU/mL) and bodyweight (30-150 kg) may still receive a ceiling dose of 750 mg/4 weeks. About 62% of patients receiving government-subsidized omalizumab are enrolled in the Australian Xolair Registry (AXR). OBJECTIVES: To determine whether AXR participants above the recommended dosing ranges benefit from omalizumab and to compare their response to within-range participants. METHODS: Data were stratified according to dose range status (above-range or within-range). Further sub-analyses were conducted according to the reason for being above the dosing range (IgE only vs. IgE and weight). RESULTS: Data for 179 participants were analysed. About 55 (31%) were above recommended dosing criteria; other characteristics were similar to within-range participants. Above-range participants had higher baseline IgE [812 (IQR 632, 1747) IU/mL vs. 209 (IQR 134, 306) IU/mL] and received higher doses of omalizumab [750 (IQR 650, 750) mg] compared to within-range participants [450 (IQR, 300, 600) mg]. At 6 months, improvements in Juniper 5-item Asthma Control Questionnaire (ACQ-5, 3.61 down to 2.01 for above-range, 3.47 down to 1.93 for within-range, P < 0.0001 for both) and Asthma Quality of Life Questionnaire (AQLQ mean score (3.22 up to 4.41 for above-range, 3.71 up to 4.88 for within-range, P < 0.0001) were observed in both groups. Forced expiratory volume in one second (FEV1 ) improved among above-range participants. There was no difference in response between above-range and within-range participants. Above-range participants due to either IgE alone or IgE and weight had similar improvements in ACQ-5, AQLQ and FEV1 . CONCLUSIONS AND CLINICAL RELEVANCE: Patients with severe allergic asthma above recommended dosing criteria for omalizumab have significantly improved symptom control, quality of life and lung function to a similar degree to within-range participants, achieved without dose escalation above 750 mg.

Sex hormones and systemic inflammation are modulators of the obese-asthma phenotype.

BACKGROUND: Both systemic inflammation and sex hormones have been proposed as potential mediators of the obese-asthma phenotype. The aim of this study was to examine the associations between sex hormones, oral contraceptive pill (OCP) use, systemic inflammation and airway inflammation in adults with asthma. METHODS: Obese (n = 39) and nonobese (n = 42) females and obese (n = 24) and nonobese (n = 25) males with asthma were recruited. Females were further categorized as reproductive-aged (<50 years old; n = 36) or older (>50 years old; n = 45). Thirteen (36.1%) reproductive-aged females were using the OCP. Participants had induced sputum cell counts measured and blood analysed for sex hormones and inflammatory markers. RESULTS: Obese reproductive-aged females had higher sputum %neutrophils than nonobese reproductive-aged females (45.4 ± 24.3% vs 27.5 ± 17.5%, P = 0.016); however, there was no difference in sputum neutrophils in obese compared with nonobese males (P = 0.620) or older females (P = 0.087). Multiple linear regression analysis found testosterone and OCP use to be negative predictors of sputum %neutrophils, while C-reactive protein and IL-6 were positive predictors of sputum %neutrophils. BMI and age were not significant predictors in the multivariate model. Reproductive-aged females using the OCP had significantly lower sputum %neutrophils than those not using the OCP (23.2 ± 12.6% vs 42.1 ± 23.8%, P = 0.015). CONCLUSIONS: This study suggests that sex hormones and systemic inflammation may be mediating the obese-asthma phenotype. The observation that OCP use was associated with lower sputum %neutrophils in reproductive-aged females warrants further investigation.

Effectiveness and response predictors of omalizumab in a severe allergic asthma population with a high prevalence of comorbidities: the Australian Xolair Registry.

BACKGROUND: Severe asthma is a high impact disease. Omalizumab targets the allergic inflammatory pathway; however, effectiveness data in a population with significant comorbidities are limited. AIMS: To describe severe allergic asthma, omalizumab treatment outcomes and predictors of response among the Australian Xolair Registry participants. METHODS: A web-based post-marketing surveillance registry was established to characterise the use, effectiveness and adverse effects of omalizumab (Xolair) for severe allergic asthma. RESULTS: Participants (n = 192) (mean age 51 years, 118 female) with severe allergic asthma from 21 clinics in Australia were assessed, and 180 received omalizumab therapy. They had poor asthma control (Asthma Control Questionnaire, ACQ-5, mean score 3.56) and significant quality of life impairment (Asthma-related Quality of Life Questionnaire score 3.57), and 52% were using daily oral corticosteroid (OCS). Overall, 95% had one or more comorbidities (rhinitis 48%, obesity 45%, cardiovascular disease 23%). The omalizumab responder rate, assessed by an improvement of at least 0.5 in ACQ-5, was high at 83%. OCS use was significantly reduced. The response in participants with comorbid obesity and cardiovascular disease was similar to those without these conditions. Baseline ACQ-5 ≥ 2.0 (P = 0.002) and older age (P = 0.05) predicted the magnitude of change in ACQ-5 in response to omalizumab. Drug-related adverse events included anaphylactoid reactions (n = 4), headache (n = 2) and chest pains (n = 1). CONCLUSION: Australian patients with severe allergic asthma report a high disease burden and have extensive comorbidity. Symptomatic response to omalizumab was high despite significant comorbid disease. Omalizumab is an effective targeted therapy for severe allergic asthma with comorbidity in a real-life setting.

Effects of short-term oral corticosteroid intake on dietary intake, body weight and body composition in adults with asthma - a randomized controlled trial.

BACKGROUND: Oral corticosteroids (OCS) are an efficacious treatment for asthma exacerbations, yet risk of adverse effects may decrease patient adherence to therapy. In particular, changes in appetite and dietary intake, which lead to weight gain and changes in body composition, are considered undesirable. OBJECTIVE: To determine whether 10-day OCS therapy in adults with asthma causes changes in leptin, appetite, dietary intake, body weight and body composition. METHODS: Double-blinded, placebo-controlled randomized cross-over trial of 10 days prednisolone (50 mg) in adults with stable asthma (n = 55) (ACTRN12611000562976). Pre- and post-assessment included spirometry, body weight, body composition measured by dual-energy X-ray absorptiometry and bioelectrical impedance analysis, appetite measured using a validated visual analogue scale (VAS) and dietary intake assessed using 4-day food records. Leptin was measured as a biomarker of appetite and eosinophils as an adherence biomarker. Outcomes were analysed by generalized linear mixed models. RESULTS: Subject adherence was confirmed by a significant decrease in blood eosinophils (× 10(9) /L) following prednisolone compared to placebo [Coef. -0.29, 95% CI: (-0.39, -0.19) P < 0.001]. There was no difference in serum leptin (ng/mL) [Coef. 0.13, 95% CI: (-3.47, 3.72) P = 0.945] or appetite measured by VAS (mm) [Coef. -4.93, 95% CI: (-13.64, 3.79) P = 0.267] following prednisolone vs. placebo. There was no difference in dietary intake (kJ/day) [Coef. 255, 95% CI: (-380, 891) P = 0.431], body weight (kg) [Coef. -0.38, 95% CI: (-0.81, 0.05) P = 0.083] or body fat (%) [Coef. -0.31, 95% CI: (-0.81, 0.20) P = 0.230]. Symptoms including sleep and gastrointestinal disturbance were reported significantly more often during prednisolone vs. placebo. CONCLUSIONS AND CLINICAL RELEVANCE: Short-term OCS in stable asthma did not induce significant changes in appetite, dietary intake, body weight or composition, although other adverse effects may require medical management. This evidence may assist in increasing medication adherence of asthmatics prescribed OCS for exacerbations.

Dietary inflammatory index is related to asthma risk, lung function and systemic inflammation in asthma.

BACKGROUND: Asthma prevalence has increased in recent years, and evidence suggests that diet may be a contributing factor. Increased use of processed foods has led to a decrease in diet quality, which may be creating a pro-inflammatory environment, thereby leading to the development and/or progression of various chronic inflammatory diseases and conditions. Recently, the dietary inflammatory index (DII) has been developed and validated to assess the inflammatory potential of individual diets. OBJECTIVE: This study aimed to examine the DII in subjects with asthma compared to healthy controls and to relate the DII to asthma risk, lung function and systemic inflammation. METHODS: Subjects with asthma (n = 99) and healthy controls (n = 61) were recruited. Blood was collected and spirometry was performed. The DII was calculated from food frequency questionnaires administered to study subjects. RESULTS: The mean DII score for the asthmatics was higher than the mean DII score for healthy controls (- 1.40 vs. - 1.86, P = 0.04), indicating that their diets were more pro-inflammatory. For every 1 unit increase in DII score, the odds of having asthma increased by 70% (OR: 1.70, 95% CI: 1.03, 2.14; P = 0.040). FEV1 was significantly associated with DII score (ß = - 3.44, 95% CI: - 6.50, - 0.39; P = 0.020), indicating that for every 1 unit increase in DII score, FEV1 decreased by 3.44 times. Furthermore, plasma IL-6 concentrations were positively associated with DII score (ß = 0.13, 95% CI: 0.05, 0.21; P = 0.002). CONCLUSION AND CLINICAL RELEVANCE: As assessed using the DII score, the usual diet consumed by asthmatics in this study was pro-inflammatory relative to the diet consumed by the healthy controls. The DII score was associated with increased systemic inflammation and lower lung function. Hence, consumption of pro-inflammatory foods may contribute to worse asthma status, and targeting an improvement in DII in asthmatics, as an indicator of suitable dietary intake, might be a useful strategy for improving clinical outcomes in the disease.

Activity and expression of histone acetylases and deacetylases in inflammatory phenotypes of asthma.

BACKGROUND: Histone acetyltransferases (HATs) and histone deacetylases (HDACs) regulate gene expression, yet differences in the activity of these enzymes in the inflammatory phenotypes of asthma are unknown. We hypothesized that neutrophilic asthma (NA) would be associated with increased HAT and decreased HDAC activity. OBJECTIVE: To investigate total HAT/HDAC activity and gene expression in isolated blood monocytes and sputum macrophages from healthy and patients with asthma. METHODS: Peripheral blood and induced sputum were collected from adults with asthma (n = 52) and healthy controls (n = 9). Sputum inflammatory cell counts were performed and asthma inflammatory phenotypes were classified according to sputum eosinophil and neutrophil cut-off's of > 3% and > 61% respectively. Peripheral blood monocytes were isolated (n = 61) and sputum macrophages were isolated from a subgroup of patients with asthma (n = 14), using immunomagnetic cell separation. RNA and nuclear proteins were extracted and quantified. Enzyme activity was assessed using fluorescent assays and gene expression of EP300, KAT2B, CREBBP, and HDACs 1, 2 and 3 were measured by qPCR. RESULTS: There was a significant inverse association between blood monocyte HAT and HDAC activity (r = -0.58, P < 0.001). NA was associated with increased blood monocyte HAT enzyme activity (P = 0.02), decreased HDAC activity (P = 0.03), and increased HAT: HDAC ratio (P < 0.01) compared with eosinophilic asthma. There were no differences in gene expression of EP300, KAT2B, CREBBP, or HDACs 1, 2 and 3 in blood monocytes from subjects with asthma or inflammatory phenotypes of asthma. There was no effect of inhaled corticosteroid use, poor asthma control, or asthma severity on HAT/HDAC activities. Sputum macrophages had increased expression of KAT2B in eosinophilic compared with paucigranulocytic asthma. CONCLUSIONS AND CLINICAL RELEVANCE: Neutrophilic airway inflammation is associated with increased HAT and reduced HDAC activity in blood monocytes, demonstrating further systemic manifestations relating to the altered inflammatory gene transcription profile of neutrophilic asthma.

Sputum ADAM8 expression is increased in severe asthma and COPD.

BACKGROUND: Severe asthma and chronic obstructive pulmonary disease (COPD) are chronic inflammatory airway diseases in which the mechanisms are not fully understood. A disintegrin and metalloproteinase domain 8 (ADAM8) is an enzyme expressed on most leucocytes and may be important for facilitating leucocyte migration in respiratory disease. OBJECTIVE: To investigate ADAM8 mRNA and protein expression in asthma and COPD and its relationship between asthma severity and inflammatory phenotypes. METHODS: Induced sputum was collected from 113 subjects with asthma (severe n = 31, uncontrolled n = 39 and controlled n = 35), 20 subjects with COPD and 21 healthy controls. Sputum ADAM8 mRNA expression was measured by qPCR, and soluble ADAM8 (sADAM8) protein was measured in the sputum supernatant by validated ELISA. RESULTS: ADAM8 mRNA correlated with ADAM8 protein levels (r = 0.27, P < 0.01). ADAM8 mRNA (P = 0.004) and sADAM8 protein (P = 0.014) levels were significantly higher in both asthma and COPD compared with healthy controls. ADAM8 mRNA (P = 0.035) and sADAM8 protein (P = 0.002) levels were significantly higher in severe asthma compared with controlled asthma. Total inflammatory cell count (P < 0.01) and neutrophils (P < 0.01) were also elevated in severe asthmatic sputum. Although ADAM8 mRNA was significantly higher in eosinophilic and neutrophilic asthma (P < 0.001), sADAM8 did not differ between asthma inflammatory phenotypes. ADAM8 expression positively correlated with sputum total cell count and sputum neutrophils. CONCLUSIONS AND CLINICAL RELEVANCE: ADAM8 expression is increased in both severe asthma and COPD and associated with sputum total cell count and neutrophils. ADAM8 may facilitate neutrophil migration to the airways in severe asthma and COPD.

Full blood count parameters for the detection of asthma inflammatory phenotypes.

BACKGROUND: In asthma, the airway inflammatory phenotype influences clinical characteristics and treatment response. Although induced sputum is the gold standard test for phenotyping asthma, a more accessible method is needed for clinical practice. OBJECTIVE: To investigate whether white blood cell counts and/or their derived ratios can predict sputum eosinophils or neutrophils in uncontrolled asthma. METHODS: This cross-sectional study evaluated 164 treated but uncontrolled asthmatic patients with sputum induction and blood collection. Receiver-operating characteristic (ROC) curves were used to assess the relationship between blood and sputum parameters. RESULTS: There was a significant positive relationship between blood eosinophil parameters and the percentage of sputum eosinophil count. A weak but significant correlation was found between sputum neutrophil percentage and blood neutrophil percentage (r = 0.219, P = 0.005). ROC curve analysis identified that blood eosinophil percentage count was the best predictor for eosinophilic asthma, with an area under the curve (AUC) of 0.907 (P < 0.001). The optimum cut-point for blood eosinophil percentage was 2.7%, and this yielded a sensitivity of 92.2% and a specificity of 75.8%. The absolute blood eosinophil count was also highly predictive with an AUC of 0.898 (P < 0.0001) at a blood eosinophil cut-off of 0.26 × 10(9) /L. The blood eosinophil/lymphocyte ratio (ELR) and eosinophil/neutrophil ratio (ENR) were increased in eosinophilic asthma, and the neutrophil/lymphocyte ratio (NLR) was increased in neutrophilic asthma. Neutrophilic asthma could also be detected by blood neutrophil percentages and NLR, but with less accuracy. CONCLUSIONS AND CLINICAL RELEVANCE: Blood eosinophil counts and derived ratios (ELR and ENR) can accurately predict eosinophilic asthma in patients with persistent uncontrolled asthma despite treatment. Blood neutrophil parameters are poor surrogates for the proportion of sputum neutrophils. Blood counts may be a useful aid in the monitoring of uncontrolled asthma.

Diet-induced weight loss in obese children with asthma: a randomized controlled trial.

BACKGROUND: Obesity is highly prevalent in asthmatic children and associated with worse clinical outcomes. Energy restriction to induce weight loss in asthmatic children has not been investigated in a randomized controlled trial (RCT). OBJECTIVE: To assess if (1) weight loss can be achieved in obese asthmatic children using a dietary intervention; and (2) changes in asthma outcomes occur following diet-induced weight loss. METHODS: In a 10-week pilot RCT, obese asthmatic children, aged 8-17 years, were randomized to a wait-list control (WLC) (n = 15) or dietary-intervention group (DIG) (n = 13). Lung function, Asthma Control Questionnaire (ACQ) score, and sputum and systemic inflammation were assessed at baseline and post-intervention. (Australian New Zealand Clinical Trials Registry: ACTRN12610000955011). RESULTS: Body mass index (BMI) z-score reduced significantly in the DIG vs. the WLC (-0.2 [-0.4, -0.1] vs. 0.0 [-0.1, 0.0], P = 0.014). Expiratory reserve volume (ERV) increased significantly within the DIG, but not compared to the WLC (0.7 [0.0, 1.0] L vs. 0.3 [0.0, 0.8] L, P = 0.355). ACQ improved significantly in the DIG, compared to the WLC (-0.4 [-0.7, 0.0] vs. 0.1 [0.0, 0.6], P = 0.004). Airway and systemic inflammation did not change within the DIG. In comparison, C-Reactive Protein (CRP) increased significantly in the WLC (-0.4 [-0.5, 0.4] vs. 0.7 [-0.1, 1.9], P = 0.037). Change (∆) in BMI z-score correlated with ∆CRP (r = 0.47, P = 0.012) and ∆exhaled nitric oxide (eNO) (r = 0.46, P = 0.034), and ∆ACQ was associated with ∆CRP (r = 0.43, P = 0.029). CONCLUSION AND CLINICAL RELEVANCE: Dietary intervention can induce acute weight loss in obese asthmatic children with subsequent improvements in static lung function and asthma control. Systemic and airway inflammation did not change following weight loss. However, changes in BMI z-score were associated with changes in airway and systemic inflammation and this requires further investigation in a larger RCT. This is the first weight loss RCT conducted in obese asthmatic children. Diet-induced weight loss can achieve significant improvements in clinical outcomes for obese children with asthma.

Impaired macrophage phagocytosis in non-eosinophilic asthma.

BACKGROUND: Many patients with non-eosinophilic asthma have increased numbers of neutrophils in the airways. The explanation for this chronic inflammation remains unclear, but may result from an impaired ability of alveolar macrophages to phagocytose apoptotic cells (a process termed 'efferocytosis'), as we have shown in chronic obstructive pulmonary disease (COPD). OBJECTIVES: To examine induced sputum as a non-invasive technique to characterize efferocytosis in chronic lung diseases and to compare efferocytosis in patients with non-eosinophilic asthma, eosinophilic asthma and COPD. METHODS: Participants with stable asthma (20 with eosinophilic and 30 with non-eosinophilic) and COPD (n = 11) underwent clinical assessment including allergy skin tests, saline challenge and sputum induction. Sputum cells were dispersed using dithiothreitol and resuspended in culture medium. Efferocytosis of apoptotic bronchial epithelial cells by sputum-derived macrophages was determined using flow cytometry. RESULTS: There were no significant differences in efferocytosis between paired sputum and bronchoalveolar lavage macrophages from three subjects. Efferocytosis was significantly impaired in patients with non-eosinophilic asthma [mean (SD) 0.95 (0.24)] compared with eosinophilic asthma [1.17 (0.19)] and to a similar degree as patients with COPD [1.04 (0.16)]. Sputum neutrophils were significantly higher in patients with COPD and non-eosinophilic asthma compared with eosinophilic asthma. CONCLUSION AND CLINICAL RELEVANCE: Induced sputum provides a reliable and non-invasive method for studying macrophage efferocytosis in chronic lung disease. Macrophage efferocytosis is impaired in non-eosinophilic asthma to a similar degree as that in COPD and may explain the persistent airway neutrophilia and chronic inflammation that characterizes this asthma subtype.

Dietary restriction and exercise improve airway inflammation and clinical outcomes in overweight and obese asthma: a randomized trial.

BACKGROUND: Obesity and asthma are associated conditions; however, the mechanisms linking the two remain unclear. Few studies have examined the effects of weight loss on inflammation and clinical outcomes in obese-asthma. OBJECTIVE: To compare the effects of weight loss achieved by dietary restriction, exercise or combined dietary restriction and exercise on airway inflammation and clinical outcomes in overweight and obese adults with asthma. METHODS: Participants (n = 46; 54.3% female, body mass index (mean ± SD) 33.7 ± 3.5 kg/m(2) ) were randomized to complete a 10-week dietary, exercise or combined dietary and exercise intervention. Dual-energy x-ray absorptiometry was performed, the Juniper Asthma Control Questionnaire and Juniper Asthma Quality of Life Questionnaire completed and inflammatory markers, dietary intake and physical activity measured. The trial was registered with the Australian Clinical Trials Registry: ACTRN12611000235909. RESULTS: Retention was 82.6%. Mean ± SD weight loss was 8.5 ± 4.2%, 1.8 ± 2.6% and 8.3 ± 4.9% after the dietary, exercise and combined interventions respectively. Asthma control improved after the dietary (mean ± SD; -0.6 ± 0.5, P ≤ 0.001) and combined interventions (-0.5 ± 0.7, P = 0.040), whereas quality of life improved after the dietary [median (IQR); 0.9 (0.4, 1.3), P = 0.002], exercise [0.49 (0.03, 0.78), P = 0.037] and combined [0.5 (0.1, 1.0), P = 0.007] interventions. A 5-10% weight loss resulted in clinically important improvements to asthma control in 58%, and quality of life in 83%, of subjects. Gynoid adipose tissue reduction was associated with reduced neutrophilic airway inflammation in women [ß-coefficient (95% CI); 1.75 (0.02, 3.48), P = 0.047], whereas a reduction in dietary saturated fat was associated with reduced neutrophilic airway inflammation in males (r = 0.775, P = 0.041). The exercise intervention resulted in a significant reduction to sputum eosinophils [median (IQR); -1.3 (-2.0, -1.0)%, P = 0.028]. CONCLUSION AND CLINICAL RELEVANCE: This study suggests a weight-loss goal of 5-10% be recommended to assist in the clinical management of overweight and obese adults with asthma. The obese-asthma phenotype may involve both innate and allergic inflammatory pathways.

The risk of congenital malformations, perinatal mortality and neonatal hospitalisation among pregnant women with asthma: a systematic review and meta-analysis.

BACKGROUND: There is conflicting literature on the effect of maternal asthma on congenital malformations and neonatal outcomes. OBJECTIVES: This review and meta-analysis sought to determine if maternal asthma is associated with an increased risk of adverse neonatal outcomes. SEARCH STRATEGY: We searched electronic databases for: (asthma or wheeze) and (pregnan* or perinat* or obstet*). SELECTION CRITERIA: Cohort studies published between 1975 and March 2012 reporting at least one perinatal outcome of interest (congenital malformations, neonatal complications, perinatal mortality). DATA COLLECTION AND ANALYSIS: In all, 21 studies met inclusion criteria in pregnant women with and without asthma. Further analysis was conducted on 16 studies where asthmatic women were stratified by exacerbation history, corticosteroid use, bronchodilator use or asthma severity. MAIN RESULTS: Maternal asthma was associated with a significantly increased risk of congenital malformations (relative risk [RR] 1.11, 95% confidence interval [95% CI] 1.02-1.21, I(2)  = 59.5%), cleft lip with or without cleft palate (RR 1.30, 95% CI 1.01-1.68, I(2)  = 65.6%), neonatal death (RR 1.49, 95% CI 1.11-2.00, I(2)  = 0%), and neonatal hospitalisation (RR 1.50, 95% CI 1.03-2.20, I(2)  = 64.5%). There was no significant effect of asthma on major malformations (RR 1.31, 95% CI 0.57-3.02, I(2)  = 70.9%) or stillbirth (RR 1.06, 95% CI 0.9-1.25, I(2)  = 35%). Exacerbations and use of bronchodilators and inhaled corticosteroids were not associated with congenital malformation risk. AUTHORS' CONCLUSIONS: Despite limitations related to the observational nature of the primary studies, this review demonstrates a small increased risk of neonatal complications among pregnant women with asthma. Further investigations into mechanisms and potential preventive interventions to improve infant outcomes are required.

Soluble RAGE is deficient in neutrophilic asthma and COPD.

The receptor for advanced glycation end-products (RAGE) is a pattern-recognition receptor involved in the host response to injury, infection and inflammation. It is a membrane receptor, but also has soluble forms (sRAGE). Deficiencies in sRAGE are linked to heightened inflammation in various chronic conditions. We determined whether airway and systemic levels of sRAGE and the RAGE ligands HMGB1 (high-mobility group box-1) and serum amyloid A (SAA) are related to neutrophilic inflammation in asthma and chronic obstructive pulmonary disease (COPD). Bronchial lavage fluid from subjects with moderate-to-severe persistent asthma (n = 16) or COPD (n = 37), or from healthy controls (n = 18), was analysed for neutrophils, total sRAGE, endogenous secretory RAGE (esRAGE), HMGB1 and SAA. We also determined systemic levels of sRAGE in a separate group of asthmatic (n = 101) and COPD (n = 34) subjects. Subjects with neutrophilic asthma or COPD had undetectable levels of lung sRAGE, while levels of sRAGE in asthma/COPD without neutrophilia were similar to those in controls. Systemic sRAGE was significantly decreased in subjects with neutrophilic asthma or COPD compared with those without airway neutrophilia. There was significant positive correlation between total sRAGE and esRAGE in the lung and systemically. HMGB1 levels were similar in all subject groups, while SAA was below detectable levels. Neutrophilic airway inflammation in asthma and COPD is associated with reduced sRAGE.

Exacerbations of severe asthma.

Exacerbations occur frequently in severe asthma. They result in significant morbidity and can lead to hospitalization and death. Severe exacerbations can also lead to an accelerated decline in lung function. Phenotyping severe asthma can aid with both prognostication of exacerbation risk and maintenance treatment selection to minimize future risks of exacerbations in severe asthma. The rate of exacerbations differs by phenotype, and is most frequent in refractory eosinophilic asthma and early onset allergic asthma. Phenotype specific therapy can reduce exacerbations in both these forms of severe asthma. Exacerbations are multi-component events. Each exacerbation represents an opportunity to assess and target treatment to the domains of airway pharmacotherapy, self-management behaviour, risk factors, and relevant co-morbidities.