Obesity affects type 2 biomarker levels in asthma.

OBJECTIVE: Type 2 (T2) inflammation offers a therapeutic target for biologics. Previous trials suggest obesity influences T2-biomarker levels in asthma, though have not accounted for key variables, e.g. inhaled (ICS)/oral corticosteroid (OCS) use. We hypothesized that body mass index (BMI) would affect T2-biomarker levels, after adjusting for covariates. METHODS: A retrospective analysis of data from two recent local trials of 153 participants with asthma (102 difficult-to-treat, 51 mild). Measurements included BMI, fractional exhaled nitric oxide (FeNO) and eosinophils. Correlation and regression analysis were performed for each biomarker to describe their relationship with BMI. Data was analyzed overall, and by asthma severity, T2-status and BMI tertile. RESULTS: Increasing BMI was associated with reduction in FeNO when stratified by BMI tertile (25 ppb lowest tertile, 18 ppb highest tertile; p = 0.014). Spearmans rank showed a negative correlation between BMI and FeNO in difficult-to-treat asthma (ρ= -0.309, p = 0.002). Linear regression adjusting for sex, age, smoking, atopy, allergic/perennial rhinitis, ICS and OCS confirmed BMI as a predictor of FeNO overall (ß= -2.848, p = 0.019). Eosinophils were reduced in the highest BMI tertile versus lowest in difficult-to-treat asthma (0.2x109/L, 0.3x109/L respectively; p = 0.02). CONCLUSIONS: Increasing BMI is associated with lower FeNO in asthma when adjusted for relevant covariates, including steroid use. There also appears to be an effect on eosinophil levels. Obesity, therefore, affects T2 biomarker levels with implications for disease endotyping and determination of eligibility for biologic therapy. Whether this is due to masking of underlying T2-high status or development of a truly T2-low endotype requires further research.

Physical activity levels in asthma: relationship with disease severity, body mass index and novel accelerometer-derived metrics.

OBJECTIVES: Patients with asthma may feel limited in physical activity (PA). Reduced PA has been demonstrated in asthmatics versus healthy controls, and increasing PA associated with improved asthma outcomes. Obesity is commonly found with difficult-to-control asthma and worsens outcomes. We compared PA levels in participants with difficult-to-control asthma and elevated body mass index (BMI) (DOW group) and two mild-moderate asthma groups: one with BMI <25 kg/m2 (MHW) and one with BMI ≥25 (MOW). METHODS: This cross-sectional study used 7-day recordings from wrist-worn accelerometers to compare PA between groups. Inactive time, light (LPA), moderate-vigorous PA (MVPA) were measured, along with two novel metrics: intensity gradient (IG) reflecting PA intensity, and average acceleration (AA) reflecting PA volume. PA parameters were compared using ANOVA or Kruskall-Wallis testing. Correlation and linear regression analyses explored associations between PA parameters and asthma outcomes. As AA was the PA parameter correlated most closely with asthma-related outcomes, an exploratory analysis compared outcomes in highest and lowest AA quartiles. RESULTS: 75 participants were recruited; 57 accelerometer readings were valid and included in analysis. Inactive time was significantly higher (p < 0.001), and LPA (p < 0.007), MVPA (p < 0.001), IG (p < 0.001) and AA (p < 0.001) all significantly lower in DOW versus MHW and MOW groups, even after adjusting for age and BMI. Quartiles based on AA had significantly different asthma profiles. CONCLUSIONS: Overweight/obese participants with difficult-to-control asthma performed less PA, and activity of reduced intensity and volume. Increased AA is associated with improvement in several asthma-related outcomes. Increased PA should be recommended to relevant patients.

Factors affecting adherence with treatment advice in a clinical trial of patients with severe asthma.

BACKGROUND: Understanding why patients with severe asthma do not follow healthcare provider (HCP) advice to adjust treatment is critical to achieving personalised disease management. METHODS: We reviewed patient choice to follow HCP advice to adjust asthma treatment in a UK-based randomised, controlled, single-blind (study participant), multicentre, parallel group 48-week clinical study comparing biomarker-directed treatment adjustment with standard care in severe asthma. RESULTS: Of 1572 treatment advisories (291 participants), instructions were followed in 1377 cases (87.6%). Patients were more likely to follow advice to remain on treatment (96.7%) than to either reduce (70.3%) or increase (67.1%) their treatment, with 64% of patients following all treatment advice. Multivariate analysis associated belonging to an ethnic minority group (OR 3.10, 95% CI 1.68-5.73) and prior study medication changes (two or more changes: OR 2.77, 95% CI 1.51-5.10) with failure to follow treatment advice. In contrast, emergency room attendance in the prior year (OR 0.54, 95% CI 0.32-0.92) was associated with following treatment advice. The largest effect was seen with transition onto or off oral corticosteroids (OR 29.28, 95% CI 16.07-53.36) when compared with those requested to maintain treatment. Centre was also an important determinant regarding the likelihood of patients to follow treatment advice. CONCLUSIONS: Belonging to an ethnic minority group and multiple prior treatment adjustments were associated with not following HCP treatment advice. Patients also responded differently to HCP advice across UK specialist centres. These findings have implications for the generalisability of models of care in severe asthma and require further focused studies.

A pragmatic randomised controlled trial of tailored pulmonary rehabilitation in participants with difficult-to-control asthma and elevated body mass index.

BACKGROUND: Difficult-to-control asthma associated with elevated body mass index (BMI) is challenging with limited treatment options. The effects of pulmonary rehabilitation (PR) in this population are uncertain. METHODS: This is a randomised controlled trial of an eight-week asthma-tailored PR programme versus usual care (UC) in participants with difficult-to-control asthma and BMI ≥ 25 kg/m2. PR comprised two hours of education and supervised exercise per week, with encouragement for two individual exercise sessions. Primary outcome was difference in change in Asthma Quality of Life Questionnaire (AQLQ) in PR versus UC groups between visits. Secondary outcomes included difference in change in Asthma Control Questionnaire-6 (ACQ6), and a responder analysis comparing proportion reaching minimum clinically important difference for AQLQ and ACQ6. RESULTS: 95 participants were randomised 1:1 to PR or UC. Median age was 54 years, 60% were female and median BMI was 33.8 kg/m2. Mean  (SD) AQLQ was 3.9 (+/-1.2) and median (IQR) ACQ6 2.8(1.8-3.6). 77 participants attended a second visit and had results analysed. Median (IQR) change in AQLQ was not significantly different: 0.3 (- 0.2 to 0.6) in PR and - 0.1 (- 0.5 to 0.4) in UC, p = 0.139. Mean change in ACQ6 was significantly different: - 0.4 (95% CI - 0.6 to - 0.2) in PR and 0 (- 0.3 to + 0.3) in UC, p = 0.015, but below minimum clinically important difference. In ACQ6 responder analysis, minimum clinically important difference was reached by 18 PR participants (54.5%) versus 10 UC (22.7%), p = 0.009. Dropout rate was 31% between visits in PR group, and time to completion was significantly prolonged in PR group at 94 (70-107) days versus 63 (56-73) in UC, p < 0.001. CONCLUSIONS: PR improved asthma control and reduced perceived breathlessness in participants with difficult-to-control asthma and elevated BMI. However, this format appears to be suboptimal for this population with high drop-out rates and prolonged time to completion. Trial registration Clinicaltrials.gov. ID NCT03630432. Retrospectively registered, submitted May 26th 2017, posted August 14th 2018.

Obesity, Inflammation, and Severe Asthma: an Update.

PURPOSE OF REVIEW: Obesity-associated difficult asthma continues to be a substantial problem and, despite a move to address treatable traits affecting asthma morbidity and mortality, it remains poorly understood with limited phenotype-specific treatments. The complex association between asthma, obesity, and inflammation is highlighted and recent advances in treatment options explored. RECENT FINDINGS: Obesity negatively impacts asthma outcomes and has a causal link in the pathogenesis of adult-onset asthma. Imbalance in the adipose organ found in obesity favours a pro-inflammatory state both systemically and in airways. Obesity may impact currently available asthma biomarkers, and obesity-associated asthma specific biomarkers are needed. Whilst surgical weight loss interventions are associated with improvements in asthma control and quality of life, evidence for pragmatic conservative options are sparse. Innovative approaches tackling obesity-mediated airway inflammation may provide novel therapies. The immunopathological mechanisms underlying obesity-associated asthma require further research that may lead to novel therapeutic options for this disease. However, weight loss appears to be effective in improving asthma in this cohort and focus is also needed on non-surgical treatments applicable in the real-world setting.

Sputum mast cell subtypes relate to eosinophilia and corticosteroid response in asthma.

Mast cells are a resident inflammatory cell of the airways, involved in both the innate and adaptive immune response. The relationship between mast cells and inflammatory phenotypes and treatment response of asthma is not clear.Clinical characteristics of subjects with stable asthma (n=55), inflammatory cell counts and gene expression microarrays in induced sputum were analysed. Sputum mast cell subtypes were determined by molecular phenotyping based on expression of mast cell biomarkers (tryptase (TPSAB1), chymase (CMA1) and carboxypeptidase A3 (CPA3)). Effects of mast cell subtypes on steroid response were observed in a prospective cohort study (n=50).MCT(n=18) and MCT/CPA3(mRNA expression of TPSAB1 and CPA3; n=29) subtypes were identified, as well as a group without mast cell gene expression (n=8). The MCT/CPA3 subtype had elevated exhaled nitric oxide fraction, sputum eosinophils, bronchial sensitivity and reactivity, and poorer asthma control. This was accompanied by upregulation of 13 genes. Multivariable logistic regression identified CPA3(OR 1.21, p=0.004) rather than TPSAB1(OR 0.92, p=0.502) as a determinant of eosinophilic asthma. The MCT/CPA3 subtype had a better clinical response and reduced signature gene expression with corticosteroid treatment.Sputum mast cell subtypes of asthma can be defined by a molecular phenotyping approach. The MCT/CPA3 subtype demonstrated increased bronchial sensitivity and reactivity, and signature gene expression, which was associated with airway eosinophilia and greater corticosteroid responsiveness.

Biomarker-based asthma phenotypes of corticosteroid response.

BACKGROUND: Asthma is a heterogeneous disease with different phenotypes. Inhaled corticosteroid (ICS) therapy is a mainstay of treatment for asthma, but the clinical response to ICSs is variable. OBJECTIVE: We hypothesized that a panel of inflammatory biomarkers (ie, fraction of exhaled nitric oxide [Feno], sputum eosinophil count, and urinary bromotyrosine [BrTyr] level) might predict steroid responsiveness. METHODS: The original study from which this analysis originates comprised 2 phases: a steroid-naive phase 1 and a 28-day trial of ICSs (phase 2) during which Feno values, sputum eosinophil counts, and urinary BrTyr levels were measured. The response to ICSs was based on clinical improvements, including a 12% or greater increase in FEV1, a 0.5-point or greater decrease in Asthma Control Questionnaire score, and 2 doubling dose or greater increase in provocative concentration of adenosine 5'-monophosphate causing a 20% decrease in FEV1 (PC20AMP). Healthy control subjects were also evaluated in this study for comparison of biomarkers with those seen in asthmatic patients. RESULTS: Asthmatic patients had higher than normal Feno values, sputum eosinophil counts, and urinary BrTyr levels during the steroid-naive phase and after ICS therapy. After 28-day trial of ICSs, Feno values decreased in 82% of asthmatic patients, sputum eosinophil counts decreased in 60%, and urinary BrTyr levels decreased in 58%. Each of the biomarkers at the steroid-naive phase had utility for predicting steroid responsiveness, but the combination of high Feno values and high urinary BrTyr levels had the best power (13.3-fold, P < .01) to predict a favorable response to ICS therapy. However, the magnitude of the decrease in biomarker levels was unrelated to the magnitude of clinical response to ICS therapy. CONCLUSION: A noninvasive panel of biomarkers in steroid-naive asthmatic patients predicts clinical responsiveness to ICS therapy.

Sputum gene expression signature of 6 biomarkers discriminates asthma inflammatory phenotypes.

BACKGROUND: Airway inflammation is associated with asthma exacerbation risk, treatment response, and disease mechanisms. OBJECTIVE: This study aimed to identify and validate a sputum gene expression signature that discriminates asthma inflammatory phenotypes. METHODS: An asthma phenotype biomarker discovery study generated gene expression profiles from induced sputum of 47 asthmatic patients. A clinical validation study (n = 59 asthmatic patients) confirmed differential expression of key genes. A 6-gene signature was identified and evaluated for reproducibility (n = 30 asthmatic patients and n = 20 control subjects) and prediction of inhaled corticosteroid (ICS) response (n = 71 asthmatic patients). Receiver operating characteristic curves were calculated, and area under the curve (AUC) values were reported. RESULTS: From 277 differentially expressed genes between asthma inflammatory phenotypes, we identified 23 genes that showed highly significant differential expression in both the discovery and validation populations. A signature of 6 genes, including Charcot-Leydon crystal protein (CLC); carboxypeptidase A3 (CPA3); deoxyribonuclease I-like 3 (DNASE1L3); IL-1ß (IL1B); alkaline phosphatase, tissue-nonspecific isozyme (ALPL); and chemokine (C-X-C motif) receptor 2 (CXCR2), was reproducible and could significantly (P < .0001) discriminate eosinophilic asthma from other phenotypes, including patients with noneosinophilic asthma (AUC, 89.6%), paucigranulocytic asthma (AUC, 92.6%), or neutrophilic asthma (AUC, 91.4%) and healthy control subjects (AUC, 97.6%), as well as discriminating patients with neutrophilic asthma from those with paucigranulocytic asthma (AUC, 85.7%) and healthy control subjects (AUC, 90.8). The 6-gene signature predicted ICS response (>12% change in FEV1; AUC, 91.5%). ICS treatment reduced the expression of CLC, CPA3, and DNASE1L3 in patients with eosinophilic asthma. CONCLUSIONS: A sputum gene expression signature of 6 biomarkers reproducibly and significantly discriminates inflammatory phenotypes of asthma and predicts ICS treatment response. This signature has the potential to become a useful diagnostic tool to assist in the clinical diagnosis and management of asthma.

Accelerometer-derived sleep metrics in mild and difficult-to-treat asthma.

INTRODUCTION: Poor sleep health is associated with increased asthma morbidity and mortality. Accelerometers have been validated to assess sleep parameters though studies using this method in patients with asthma are sparse and none have compared mild to difficult-to-treat asthma populations. METHODS: We performed a retrospective analysis from two recent in-house trials comparing sleep metrics between patients with mild and difficult-to-treat asthma. Participants wore accelerometers for 24-hours/day for seven days. RESULTS: Of 124 participants (44 mild, 80 difficult-to-treat), no between-group differences were observed in sleep-window, sleep-time, sleep efficiency or wake time. Sleep-onset time was ~ 40 min later in the difficult-to-treat group (p = 0.019). DISCUSSION: Broadly, we observed no difference in accelerometer-derived sleep-metrics between mild and difficult-to-treat asthma. This is the largest analysis of accelerometer-derived sleep parameters in asthma and the first comparing groups by asthma severity. Sleep-onset initiation may be delayed in difficult-to-treat asthma but a dedicated study is needed to confirm.

A Total Diet Replacement Weight Management Program for Difficult-to-Treat Asthma Associated With Obesity: A Randomized Controlled Feasibility Trial.

BACKGROUND: Obesity is often associated with uncontrolled, difficult-to-treat asthma and increased morbidity and mortality. Previous studies suggest that weight loss may improve asthma outcomes, but with heterogenous asthma populations studied and unclear consensus on the optimal method of weight management. The Counterweight-Plus Programme (CWP) for weight management is an evidence-based, dietitian-led total diet replacement (TDR) program. RESEARCH QUESTION: Can use of the CWP compared with usual care (UC) improve asthma control and quality of life in patients with difficult-to-treat asthma and obesity? STUDY DESIGN AND METHODS: We conducted a 1:1 (CWP to UC) randomized, controlled single-center trial in adults with difficult-to-treat asthma and BMI of ≥ 30 kg/m2. The CWP was a 12-week TDR phase (800 kcal/d low-energy formula) followed by stepwise food reintroduction and weight loss maintenance for up to 1 year. The primary outcome was the change in Asthma Control Questionnaire 6 (ACQ6) score over 16 weeks. The secondary outcome was change in Asthma Quality of Life Questionnaire (AQLQ) score. RESULTS: Thirty-five participants were randomized (36 screened) and 33 attended the 16-week follow-up (n = 17 in the CWP group, n = 16 in the UC group). Overall, mean ACQ6 score at baseline was 2.8 (95% CI, 2.4-3.1). Weight loss was greater in the CWP than UC group (mean difference, -12.1 kg; 95% CI, -16.9 to -7.4; P < .001). ACQ6 score improved more in the CWP than UC group (mean difference, -0.69; 95% CI, -1.37 to -0.01; P = .048). A larger proportion of participants achieved the minimal clinically important difference in ACQ6 score with CWP than with UC (53% vs 19%; P = .041; Number needed to treat, 3 [95% CI, 1.5-26.9]). AQLQ score improvement was greater in the CWP than UC group (mean difference, 0.76; 95% CI, 0.18-1.34; P = .013). INTERPRETATION: Using a structured weight management program results in clinically important improvements in asthma control and quality of life over 16 weeks compared with UC in adults with difficult-to-treat asthma and obesity. This generalizable program is easy to deliver for this challenging phenotype. Longer-term outcomes continue to be studied. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT03858608; URL: www. CLINICALTRIALS: gov.

Asthma phenotypes: consistency of classification using induced sputum.

BACKGROUND AND OBJECTIVE: Asthma can be classified as eosinophilic or non-eosinophilic based on the cell profile of induced sputum. This classification can help determine whether corticosteroid treatment is indicated. We assessed the stability of these phenotypes over time and with different treatment regimens. METHODS: Clinically stable, non-smoking, asthmatic adults were enrolled in one of two studies. In study one, induced sputum cell counts from 28 subjects were analysed after 4 weeks without corticosteroid treatment and after 6 week treatments with placebo, regular inhaled beta-agonist, inhaled corticosteroid, and combined beta-agonist and corticosteroid. In study two, sputum from 26 subjects with non-eosinophilic asthma was analysed after 12 weeks of placebo and after four 2-week corticosteroid washouts. Sputum with <2% eosinophils was classified as non-eosinophilic. RESULTS: Sputum classification changed frequently in both studies. In study one, only one of eight participants with non-eosinophilic sputum after placebo treatment remained non-eosinophilic throughout. In study two, all of participants had at least one eosinophilic sputum sample, despite the fact that all had been non-eosinophilic at recruitment. Neutrophilic asthma was uncommon in both studies and was also inconsistent. CONCLUSIONS: The phenotypic classification of asthma changes frequently. A diagnosis of non-eosinophilic asthma should not be based on a single sputum sample.

Composite type-2 biomarker strategy versus a symptom-risk-based algorithm to adjust corticosteroid dose in patients with severe asthma: a multicentre, single-blind, parallel group, randomised controlled trial.

BACKGROUND: Asthma treatment guidelines recommend increasing corticosteroid dose to control symptoms and reduce exacerbations. This approach is potentially flawed because symptomatic asthma can occur without corticosteroid responsive type-2 (T2)-driven eosinophilic inflammation, and inappropriately high-dose corticosteroid treatment might have little therapeutic benefit with increased risk of side-effects. We compared a biomarker strategy to adjust corticosteroid dose using a composite score of T2 biomarkers (fractional exhaled nitric oxide [FENO], blood eosinophils, and serum periostin) with a standardised symptom-risk-based algorithm (control). METHODS: We did a single-blind, parallel group, randomised controlled trial in adults (18-80 years of age) with severe asthma (at treatment steps 4 and 5 of the Global Initiative for Asthma) and FENO of less than 45 parts per billion at 12 specialist severe asthma centres across England, Scotland, and Northern Ireland. Patients were randomly assigned (4:1) to either the biomarker strategy group or the control group by an online electronic case-report form, in blocks of ten, stratified by asthma control and use of rescue systemic steroids in the previous year. Patients were masked to study group allocation throughout the entirety of the study. Patients attended clinic every 8 weeks, with treatment adjustment following automated treatment-group-specific algorithms: those in the biomarker strategy group received a default advisory to maintain treatment and those in the control group had their treatment adjusted according to the steps indicated by the trial algorithm. The primary outcome was the proportion of patients with corticosteroid dose reduction at week 48, in the intention-to-treat (ITT) population. Secondary outcomes were inhaled corticosteroid (ICS) dose at the end of the study; cumulative dose of ICS during the study; proportion of patients on maintenance oral corticosteroids (OCS) at study end; rate of protocol-defined severe exacerbations per patient year; time to first severe exacerbation; number of hospital admissions for asthma; changes in lung function, Asthma Control Questionnaire-7 score, Asthma Quality of Life Questionnaire score, and T2 biomarkers from baseline to week 48; and whether patients declined to progress to OCS. A secondary aim of our study was to establish the proportion of patients with severe asthma in whom T2 biomarkers remained low when corticosteroid therapy was decreased to a minimum ICS dose. This study is registered with ClinicalTrials.gov, NCT02717689 and has been completed. FINDINGS: Patients were recruited from Jan 8, 2016, to July 12, 2018. Of 549 patients assessed, 301 patients were included in the ITT population and were randomly assigned to the biomarker strategy group (n=240) or to the control group (n=61). 28·4% of patients in the biomarker strategy group were on a lower corticosteroid dose at week 48 compared with 18·5% of patients in the control group (adjusted odds ratio [aOR] 1·71 [95% CI 0·80-3·63]; p=0·17). In the per-protocol (PP) population (n=121), a significantly greater proportion of patients were on a lower corticosteroid dose at week 48 in the biomarker strategy group (30·7% of patients) compared with the control group (5·0% of patients; aOR 11·48 [95% CI 1·35-97·83]; p=0·026). Patient choice to not follow treatment advice was the principle reason for loss to PP analysis. There was no difference in secondary outcomes between study groups and no loss of asthma control among patients in the biomarker strategy group who reduced their corticosteroid dose. INTERPRETATION: Biomarker-based corticosteroid adjustment did not result in a greater proportion of patients reducing corticosteroid dose versus control. Understanding the reasons for patients not following treatment advice in both treatment strategies is an important area for future research. The prevalence of T2 biomarker-low severe asthma was low. FUNDING: This study was funded, in part, by the Medical Research Council UK.

Simvastatin in the treatment of asthma: lack of steroid-sparing effect.

BACKGROUND: Statins have anti-inflammatory actions which in theory are potentially beneficial in asthma. Small trials have failed to show a significant benefit, but a systematic study to evaluate the steroid-sparing effect of statin treatment has not been carried out. METHODS: A randomised, placebo-controlled, crossover trial was conducted of simvastatin 40 mg at night with simultaneous stepwise reduction of fluticasone propionate dose until loss of control occurred, followed by an increase until regain of control ('minimum' dose required) in 51 patients with asthma and sputum eosinophils (steroid-free) ≥ 2%. RESULTS: 43 patients completed the study. There was no significant difference in 'minimum' inhaled corticosteroid (ICS) dose requirement between simvastatin and placebo: (median (IQR) 50 µg daily (0-250) vs 100 µg daily (0-250), p=0.931). 'Minimum' dose distribution was similar (p=0.269). The fluticasone dose at which loss of control occurred did not differ significantly between simvastatin and placebo (p=0.404). In patients with loss of control in both treatment arms, fluticasone dose at loss of control was similar with simvastatin and placebo (median (IQR) 50 µg daily (0-100) for both, p=0.620). In those patients who reached 0 µg/day (n=18), Astma Control Questionnaire (ACQ) was lower (p=0.037), forced expiratory volume in 1 s (FEV(1)) higher (p<0.01) and sputum eosinophils lower with simvastatin compared with placebo (9.5% compared with 25.4%, p=0.033). CONCLUSIONS: Simvastatin does not have clinically important steroid-sparing effects in patients with eosinophilic asthma. In the absence of steroid, simvastatin is associated with minor improvements in symptoms and lung function, and a reduction in sputum eosinophils. Clinical trial number ACTRN12606000531516.

Effects of steroid therapy on inflammatory cell subtypes in asthma.

RATIONALE Airway inflammation in asthma is heterogeneous with different phenotypes. The inflammatory cell phenotype is modified by corticosteroids and smoking. Steroid therapy is beneficial in eosinophilic asthma (EA), but evidence is conflicting regarding non-eosinophilic asthma (NEA). OBJECTIVES To assess the inflammatory cell phenotypes in asthma after eliminating potentially confounding effects; to compare steroid response in EA versus NEA; and to investigate changes in sputum cells with inhaled corticosteroid (ICS). METHODS Subjects undertook ICS withdrawal until loss of control or 28 days. Those with airway hyper-responsiveness (AHR) took inhaled fluticasone 1000 microg daily for 28+ days. Cut-off points were > or = or <2% for sputum eosinophils and > or = or <61% for neutrophils. RESULTS After steroid withdrawal (n=94), 67% of subjects were eosinophilic, 31% paucigranulocytic and 2% mixed; there were no neutrophilic subjects. With ICS (n=88), 39% were eosinophilic, 46% paucigranulocytic, 3% mixed and 5% neutrophilic. Sputum neutrophils increased from 19.3% to 27.7% (p=0.024). The treatment response was greater in EA for symptoms (p<0.001), quality of life (p=0.012), AHR (p=0.036) and exhaled nitric oxide (p=0.007). Lesser but significant changes occurred in NEA (ie, paucigranulocytic asthma). Exhaled nitric oxide was the best predictor of steroid response in NEA for AHR (area under the curve 0.810), with an optimum cut-off point of 33 ppb. CONCLUSIONS After eliminating the effects of ICS and smoking, a neutrophilic phenotype could be identified in patients with moderate stable asthma. ICS use led to phenotype misclassification. Steroid responsiveness was greater in EA, but the absence of eosinophilia did not indicate the absence of a steroid response. In NEA this was best predicted by baseline exhaled nitric oxide.

Exercise-induced wheeze: Fraction of exhaled nitric oxide-directed management.

BACKGROUND AND OBJECTIVE: Exercise-induced wheeze (EIW) is common. Several treatment options exist. Patients with low fraction of exhaled nitric oxide (F(E)NO) are unlikely to be steroid-responsive and might benefit from non-steroidal therapies. We assessed: the efficacy of cromoglycate, formoterol and montelukast in patients with EIW and low F(E)NO (<35 ppb) in a randomized cross-over trial, and the efficacy of inhaled corticosteroid in a high F(E)NO (>35 ppb) group. METHODS: Patients had EIW and airway hyperresponsiveness (AHR) to mannitol and/or exercise. Those with low F(E)NO (n = 19) received cromoglycate (20 mg inh. bd + before challenge tests), formoterol (12 microg inh. bd + before challenge tests) and montelukast (10 mg p.o. od), each for 2 weeks. Those with high F(E)NO (n = 20) took inhaled fluticasone (500 microg) daily for 4 weeks. Primary end-points were: 50% reduction in maximum FEV(1) %fall (clinical protection) and decrease in AHR to mannitol. RESULTS: In patients with low F(E)NO, cromoglycate, formoterol and montelukast significantly decreased AHR to mannitol in 63%, 61% and 47% of patients, respectively. In this group, the magnitude of exercise-induced bronchoconstriction (EIB) was significantly reduced with montelukast and formoterol; between-treatment differences were not significant. Of 6/19 with low F(E)NO and EIB, protection occurred in 67% (cromoglycate), 83% (formoterol) and 50% (montelukast), respectively. In the high F(E)NO group, AHR to mannitol and EIB decreased significantly with fluticasone (P < 0.001, P = 0.005, respectively), and protection occurred in 7/8 (88%) with EIB. CONCLUSIONS: In patients with EIW and low F(E)NO, the number of 'responders' to cromoglycate, formoterol and montelukast was similar. In a high F(E)NO population the response to inhaled corticosteroid was highly significant and comparable to previous studies.

Asthma, obesity and targeted interventions: an update.

PURPOSE OF REVIEW: Obese asthma is now widely recognized as a phenotype of difficult asthma that is common and less responsive to traditional asthma treatments, so identifying specific treatments is increasingly important. RECENT FINDINGS: Obesity can lead to asthma through a complex relationship of causes including mechanical, inflammatory, metabolic and genetic factors. Exercise programmes including pulmonary rehabilitation, weight loss via dietary restriction, exercise and bariatric surgery, or combinations of all of these can improve quality of life, symptoms, and exercise capacity, with reductions in medication use and exacerbations, and represent tailored treatment for this phenotype of severe difficult to treat asthmatic patients. SUMMARY: Exercise programmes and pulmonary rehabilitation, weight loss programmes targeting 5-10% weight loss and bariatric surgery are effective treatments for the obese asthma phenotype.

A randomised pragmatic trial of corticosteroid optimization in severe asthma using a composite biomarker algorithm to adjust corticosteroid dose versus standard care: study protocol for a randomised trial.

BACKGROUND: Patients with difficult-to-control asthma consume 50-60% of healthcare costs attributed to asthma and cost approximately five-times more than patients with mild stable disease. Recent evidence demonstrates that not all patients with asthma have a typical type 2 (T2)-driven eosinophilic inflammation. These asthmatics have been called 'T2-low asthma' and have a minimal response to corticosteroid therapy. Adjustment of corticosteroid treatment using sputum eosinophil counts from induced sputum has demonstrated reduced severe exacerbation rates and optimized corticosteroid dose. However, it has been challenging to move induced sputum into the clinical setting. There is therefore a need to examine novel algorithms to target appropriate levels of corticosteroid treatment in difficult asthma, particularly in T2-low asthmatics. This study examines whether a composite non-invasive biomarker algorithm predicts exacerbation risk in patients with asthma on high-dose inhaled corticosteroids (ICS) (± long-acting beta agonist) treatment, and evaluates the utility of this composite score to facilitate personalized biomarker-specific titration of corticosteroid therapy. METHODS/DESIGN: Patients recruited to this pragmatic, multi-centre, single-blinded randomised controlled trial are randomly allocated into either a biomarker controlled treatment advisory algorithm or usual care group in a ratio of 4:1. The primary outcome measure is the proportion of patients with any reduction in ICS or oral corticosteroid dose from baseline to week 48. Secondary outcomes include the rate of protocol-defined severe exacerbations per patient per year, time to first severe exacerbation from randomisation, dose of inhaled steroid at the end of the study, cumulative dose of inhaled corticosteroid during the study, proportion of patients on oral corticosteroids at the end of the study, proportion of patients who decline to progress to oral corticosteroids despite composite biomarker score of 2, frequency of hospital admission for asthma, change in the 7-item Asthma Control Questionnaire (ACQ-7), Asthma Quality of Life Questionnaire (AQLQ), forced expiratory volume in 1 s (FEV1), exhaled nitric oxide, blood eosinophil count, and periostin levels from baseline to week 48. Blood will also be taken for whole blood gene expression; serum, plasma, and urine will be stored for validation of additional biomarkers. DISCUSSION: Multi-centre trials present numerous logistical issues that have been addressed to ensure minimal bias and robustness of study conduct. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02717689 . Registered on 16 March 2016.

Biomarkers and asthma management: an update.

PURPOSE OF REVIEW: Asthma is heterogeneous with different endotypes/phenotypes. Response to corticosteroids is variable and novel biological therapies are proving useful. Biomarkers allow individualization of treatment. This review provides an update on available data regarding asthma biomarkers with focus on their utility for prediction of response to steroidal and new biological therapies. RECENT FINDINGS: Blood eosinophils are a biomarker with acceptable accuracy as a surrogate for sputum eosinophilia, are associated with relevant outcomes, and are more readily measureable. New evidence supports fraction of exhaled nitric oxide (FENO)-based treatment algorithms for cost-effective maintenance of asthma control/quality of life. Serum and sputum-derived periostin are biomarkers of lung function decline and associated with eosinophilic airway inflammation. Transcriptomics show promise for endotyping; their role in management remains to be determined. Biomarker panels may improve predictive value as shown for the combination of FENO/urinary bromotyrosine in prediction of steroid responsiveness. Novel biological therapies are proving effective in biomarker-selected populations. SUMMARY: Biomarkers including blood eosinophils and FENO are proving to have utility for the effective administration of steroidal and novel biological therapies in asthma, allowing individualized treatment. Transcriptomics can discriminate subtypes of asthma and may have a role in delivery of individualized therapy.

Effects of older age and age of asthma onset on clinical and inflammatory variables in severe refractory asthma.

BACKGROUND: Asthma in the elderly as well as asthma of adult-onset has been associated with increased morbidity, but little is known specifically about the effects of age on clinical and inflammatory outcomes in severe refractory asthma. The aims of the study were to examine the effects of age [<65 versus ≥65 years] and age of onset of asthma [childhood-onset, <18 versus adult-onset, ≥18 years] on clinical and inflammatory variables in patients with severe asthma. METHODS: In 1042 subjects with refractory asthma recruited to the British Thoracic Society Severe Asthma Registry, we compared patient demographics, disease characteristics and biomarkers of inflammation in patients aged <65 years (n = 896) versus ≥65 years (n = 146) and onset at age <18 years (n = 430) versus ≥18 years (n = 526). RESULTS: Severe asthma patients aged ≥65 years had improved symptom control, better asthma quality of life and in the last year, less emergency visits and rescue oral steroid courses [3 (1-6) versus 5 (2-7), p < 0.001] than severe asthmatics aged <65 years. Blood eosinophils were lower in the elderly group. Patients with severe adult-onset asthma had similar symptom control, lung function and health-care utilization compared to severe childhood-onset asthma. Adult-onset asthmatics had higher blood eosinophils and were less atopic. CONCLUSIONS: Patients with severe refractory asthma aged ≥65 years exhibit better clinical and health care outcomes and have lower blood eosinophils compared to those aged <65 years. Severe refractory adult-onset asthma is associated with similar levels of asthma control, higher blood eosinophils and less atopy than severe refractory childhood-onset asthma.