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 hyperresponsiveness (AHR) took inhaled fluticasone 1000 mg daily for 28+ days. Cut-off points were $/<2% for sputum eosinophils and $/<61% for neutrophils. Results After steroid withdrawal (n¼94), 67% of subjects were eosinophilic, 31% paucigranulocytic and 2% mixed; there were no neutrophilic subjects. With ICS (n¼88), 39% were eosinophilic, 46% paucigranulocytic, 3% mixed and 5% neutrophilic. Sputum neutrophils increased from 19.3% to 27.7% (p¼0.024). The treatment response was greater in EA for symptoms (p<0.001), quality of life (p¼0.012), AHR (p¼0.036) and exhaled nitric oxide (p¼0.007). 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.

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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 ICS is variable. Objective We hypothesized that a panel of inflammatory biomarkers i.e. FENO, sputum eosinophils and urinary BromoTyrosine (BrTyr) might predict steroid responsiveness. Methods The original study, from which this analysis originates, comprised 2 phases: a steroid naïve phase 1 and a 28-day trial of ICS (phase 2) during which times, FENO, sputum eosinophils, and urinary BrTyr were measured. Response to ICS was based on clinical improvements including: ≥12% increase in FEV1; ≥0.5 point decrease in Asthma Control Questionnaire; and ≥2 doubling dose increase in provocation concentration of adenosine 5′-monophosphate causing a 20% fall in FEV1 (PC20 AMP). Healthy controls were also evaluated in this study for comparison of biomarkers to asthmatics. Results Asthmatics had higher than normal FENO, sputum eosinophils and urinary BrTyr at steroid naïve phase and after ICS. After 28-day trial of ICS, FENO decreased in 82% of asthmatics, sputum eosinophils decreased in 60% and urinary BrTyr decreased in 58%. Each of the biomarkers at steroid naïve phase had utility for predicting steroid- responsiveness, but the combination of high FENO and high urinary BrTyr had the best power (13.3 fold; p<0.01) to predict a favorable response to ICS. However, the magnitude of decrease of biomarkers was unrelated to the magnitude of clinical response to ICS. Conclusion A noninvasive panel of biomarkers in steroid naïve asthmatics predicts clinical responsiveness to ICS.

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). MethodsWe 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. FindingsPatients 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-protoco...