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Dupilumab, a human monoclonal antibody blocking interleukin-4/13 signaling, reduces severe exacerbation rates and improves lung function and asthma control in patients with moderate-to-severe asthma. This analysis assessed the impact of using different cutoffs of 5-item Asthma Control Questionnaire (ACQ-5) score: <1.5 (controlled asthma) vs <0.75 (well-controlled asthma) on the multicomponent outcome of clinical remission in patients who completed TRAVERSE (NCT02134028).

Dupilumab reduces asthma exacerbation rates and improves lung function in children (VOYAGE, NCT02948959) and adults/adolescents (QUEST, NCT02414854) with uncontrolled, moderate-to-severe asthma. Previous data have demonstrated that FeNO is a valid prognostic biomarker, a predictor of response to dupilumab. The aim of this post hoc analysis was to evaluate the stability of FeNO over time following the American Thoracic Society (ATS) and European Respiratory Society (ERS) FeNO guidelines, in placebo patients from the QUEST and VOYAGE studies.

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TRAVERSE (NCT02134028) assessed dupilumab long-term safety and efficacy in patients ≥12 years who previously completed a dupilumab asthma study. Safety was consistent with the known dupilumab safety profile. This analysis of TRAVERSE evaluated dupilumab long-term efficacy in patients who previously participated in QUEST (NCT02414854) and had type 2 asthma (blood eosinophils ≥150cells/µL or fractional exhaled nitric oxide [FeNO] ≥20ppb) with or without an allergic phenotype (serum total IgE ≥30IU/mL and ≥1 perennial aeroallergen-specific IgE ≥0.35kU/L) at parent study baseline and history of ≥2 exacerbations in the year prior to QUEST.

BackgroundPatients presenting with an acute exacerbation of COPD (AECOPD) and a peripheral blood eosinophil count≥=2% of the total white cell count have a better response to oral cortico-steroids, suggesting that stratification by this biomarker identifies a pathologically distinct phenotype and has clinical value.1We have tested the hypothesis that the eosinophilic and non-eosinophilic exacerbations of COPD have different seasonality using a dataset of patents admitted to an inner London teaching hospital with AECOPD over 9 years.MethodsAll admissions with AECOPD were recorded between 2004 and 2012. We recorded the first blood test result within 24 hours of admission. The month of admission was recorded. Seasons were defined as per figure 1 and the distribution of eosinophilic (blood eosinophil count≥=2%) and non-eosinophilic events compared.[Figure]Results2793 admissions with AECOPD were recorded, of which 2416 (86.5%) had a FBC result available and 750 (31.0%) were eosinophilic. The mean age of the entire population was 70 with 44.3% female. Eosinophilic admissions had a median age 69.3 of which 40.5% were female. Non-eosinophilic admissions had a median age 70.9 of which 46.9% were female. There were no significant differences between the number of eosinophilic exacerbations across seasons. In contrast, non-eosinophilic exacerbations occurred more commonly in winter compared to summer. The proportion of eosinophilic events was 36.5 vs 28.1% in summer and winter respectively (mean difference 9%; 95% CI 4%–14%; p=0.003).Figure 1 – Admissions via A and E for patients with Acute Exacerbations of COPD between 2004 and 2012 stratified by season and peripheral blood eosinophil percentage.DiscussionExacerbations of COPD associated with a higher blood eosinophil count do not vary according to season whereas non-eosinophilic exacerbations occur more commonly in winter and account for a significantly higher proportion of winter events.ReferenceBafadhel M, McKenna S, Terry S, et al. Blood eosinophils to direct corticosteroid treatment of exacerbations of chronic obstructive pulmonary disease: A randomised placebo-controlled trial. Am J Respir Crit Care Med2012;186(1):48–55. doi:10.1164/rccm.201108-1553OC

The goals of asthma management are the accurate diagnosis and effective control of symptoms, prevention of exacerbations and the achievement and preservation of best pulmonary function. Despite improvements in asthma care patients are still misdiagnosed or undertreated. The reason for this is simple, asthma is a heterogeneous disease, but in most primary and secondary care settings only one facet, variable airflow obstruction, is addressed. The two other main aspects of asthma, airway inflammation and airway hyperresponsiveness, remain under-utilized in both diagnosis and treatment of asthma. Treatment algorithms based on airway hyperresponsiveness have been successfully used to reduce asthma exacerbations but at the expense of more corticosteroid use. Using a non-invasive marker of airway inflammation has also been shown to reduce exacerbations compared with a control group following current guidelines, but with similar steroid dose between both groups and with comparative symptom and quality of life measures. There are various non-invasive markers of airway inflammation (as opposed to bronchial biopsy and bronchoalveolar lavage). This article will concentrate on the use of the two most clinically important methods of assessing airway inflammation, namely induced sputum and exhaled nitric oxide. It will evaluate the indications, practicalities and use for each method and discuss future areas for research.

Abstract. Objectives and Design: Cough is a common symptom in idiopathic pulmonary fibrosis that is difficult to treat and has a major impact on quality of life. We tested the hypothesis that the cough and increased cough reflex sensitivity seen in patients with idiopathic pulmonary fibrosis may be due to airway inflammation in a prospective, cross-sectional study.

A hallmark of allergic disease is infiltration of the tissues with increased numbers of eosinophils. This is the result of the co-ordinated action of cytokines, particularly IL-5, CCR3 binding chemokines and the adhesion molecules P-selectin and VCAM-1, acting in concert to cause selective trafficking of eosinophils into allergic tissue. This process is orchestrated by the Th-2 allergen specific lymphocyte. While there is little data to support the view that eosinophils ameliorate the allergic process, although they could have an important role in the disordered repair that leads to permanently impaired function in some allergic diseases, the evidence that they cause many of the pathophysiological features of allergic disease, while strong, remains circumstantial. Much of the data could be interpreted just as easily to suggest that eosinophils are bystander cells; markers of a certain type of pathological process, but not impinging upon it. The most direct evidence for a pathological role rests on the toxicity of the eosinophil granule proteins for bronchial epithelium and the bronchoconstrictor actions of the sulphidopeptide leukotrienes. The actions of LT antagonists in asthma which are certainly beneficial, but in most cases are not as effective as glucocorticoids, could be interpreted both for and against the eosinophil. In this paper we have focused on the studies that ask most directly the question of whether eosinophils are important effector cells in the pathogenesis of allergic disease. We conclude with a qualified affirmative. Even if they are only bystander cells they remain clinically important as diagnostic markers and a guide to the management of allergic disease.

Abstract Background Inhaled adenosine monophosphate (AMP) is thought to cause bronchoconstriction in asthmatic patients indirectly through mast cell mediator release. It may therefore be a more sensitive marker of airway inflammation in asthma and hence more specific for epidemiological surveys of asthma than challenges that act directly on airway smooth muscle such as histamine. There is some uncertainty as to how repeatable the measurement is and this is important if it is to be used for epidemiological studies. Methods The response to histamine and AMP challenges and the protection afforded by terbutaline (500 μg) against these two challenges was measured on two occasions two weeks apart in 20 subjects with asthma (19 completed the study). The response to histamine and AMP was measured as the provocative dose causing a 20% fall in forced expiratory volume in one second (PD₂₀) and the protection afforded by terbutaline in doubling doses (DD). Repeatability was assessed as the limits of agreement. Results Although terbutaline had a slightly greater protective effect against AMP than histamine on both the first (ΔPD₂₀ =2.66 versus 2.11 DD) and second occasion (2.56 and 2.15 DD), the differences were not statistically significant. The limits of agreement for the two histamine and two AMP challenges after placebo were from 3.06 to −3.5 and from 3.78 to −4.54 DD respectively, and these values did not differ significantly. The agreement limits between the first PD₂₀ histamine and PD₂₀ AMP values after placebo were similar, being from 3.73 to −3.72 DD after allowing for the 17.8-fold higher PD₂₀ values for AMP compared with histamine. Conclusions Terbutaline caused a slightly greater inhibition of the bronchoconstrictor response to AMP than histamine but the differences were small and non-significant. Any differences in repeatability between AMP and histamine challenges are small and in this study were not significant. The fact that the agreement between histamine and AMP PD₂₀ values was similar to the agreement between repeat histamine or repeat AMP PD₂₀ values suggests that, within an asthmatic population, PD₂₀ AMP may not be providing different information from that provided by PD₂₀ histamine.

Dupilumab, a fully human interleukin (IL)-4 receptor-α monoclonal antibody inhibiting IL-4/IL-13 signaling pathways, key drivers of Type 2 inflammation, is approved for treating adults with inadequately controlled moderate-to-severe atopic dermatitis. In the phase 3 LIBERTY ASTHMA QUEST study (NCT02414854), dupilumab 200mg and 300mg administered every 2 weeks versus matched placebo reduced annualized severe exacerbation rates and improved pre-bronchodilator forced expiratory volume in 1 second (FEV1) and quality-of-life measures, and was generally well tolerated in patients with uncontrolled, moderate-to-severe asthma (≥12 years, without minimum baseline Type 2 inflammatory biomarkers). This post-hoc analysis assessed the efficacy of dupilumab in patients with and without allergic asthma.

IntroductionPost-mortem studies of patients who have died from asthma show that mucus plugging of the airways is a prominent feature. We have investigated whether this can be identified and quantified on CT scans taken at the time of a severe asthma attack and tested the hypothesis that mucus plugging is specific to attacks associated with a raised blood eosinophil count.MethodsWe developed a scoring system based on features on CT scans of asthmatic patients potentially associated with mucus plugging (see Table 1). We used this scoring system to retrospectively score CT scans of 6 patients admitted to the John Radcliffe Hospital, Oxford, with acute attacks of asthma. CT scans were performed within three days of admission to investigate whether there was an alternative cause for the patients’ presenting symptoms. Two radiologists, blinded to clinical measures for the patients, independently scored the CT scans.Abstract P227 Table 1CT scoring protocol for patients admitted secondary to asthma. Scans were interpreted by a specialist chest radiologist from slices at three locations on each lung: at the level of the inferior pulmonary vein, at the origin of the lingular bronchus, and at the aortic arch. This gives a score between 0 and 54.0123Bronchial wall thickeningNoneSomeProminentMucus pluggingNoneSomeProminentMosiacismNoneMinorMajorAtelectasisNoneLinearSegmentalLobarResultsFour patients had a blood eosinophil count ≥0.3 × 109/litre at the time of admission. The mean (range) CT score was 18 (17) in these patients and 6 (4) in the non-eosinophilic patients. The intraclass correlation coefficient between the two radiologists’ scores was 0.823. The largest contributors to the difference between the eosinophilic and non-eosinophilic patients’ scores was bronchial wall thickening (6 v 1) and mucus plugging (3 v 0).ConclusionOur scoring system was repeatable between observers and might potentially identify a pathophysiological mechanism particularly associated with eosinophilic asthma attacks.

Introduction and ObjectivesBlood eosinophil counts (Bl–Eos) and fractional exhaled nitric oxide concentrations (FeNO) are established biomarkers in asthma. While patients with raised Bl–Eos are at increased risk of asthma exacerbations, it is unclear whether raised FeNO is associated with further increased risk. We sought to determine if raised Bl–Eos combined with raised FeNO was associated with increased frequency of asthma exacerbations.MethodsThis was a cross-sectional study of data from the Optimum Patient Care Research Database. Patients included were aged 18–80 years with ≥1 year of continuous electronic health records prior to their most recent FeNO readings, had evidence of asthma, had received ≥1 inhaled corticosteroid prescription, and had Bl–Eos recorded within 5 years of FeNO reading. Cohorts were determined by: Bl–Eos raised (≥0.25×109/L, a cutoff representing the sample mean) and not raised (<0.25×109/L) and, FeNO raised (≥35 ppb) and not raised (<35 ppb). Patients were directly matched on age, sex, and smoking status. Patients with (i) raised Bl–Eos and not raised FeNO, (ii) raised FeNO and not raised Bl–Eos, or (iii) both biomarkers raised were compared with reference patients (neither biomarker raised). Comparison of exacerbations (evidenced by acute oral corticosteroid prescription or unplanned asthma-related hospital attendance) was conducted using conditional Poisson regression.ResultsThe unmatched study population consisted of 610 patients (mean age 52, 38% male, 46% non-smokers). With 1:1 matching, both the (i) raised Bl–Eos and not raised FeNO cohort (n=186) and the (ii) raised FeNO and not raised Bl–Eos cohort (n=98) demonstrated a trend toward greater exacerbation rates (unadjusted rate ratio: 1.41 [95% CI 0.91, 2.19] and 1.35 [95% CI 0.99 1.84], respectively) vs. reference group. Importantly, however, when both biomarkers were raised (n=53), a significantly greater exacerbation rate was observed (1.72 [95% CI 1.00, 2.93]).ConclusionThe combination of raised FeNO and raised Bl–Eos was associated with a greater exacerbation rate compared with neither biomarker raised. FeNO and Bl–Eos are simple primary care measurements that could reliably predict exacerbation risk for asthma patients. This should be confirmed prospectively in larger populations.Please refer to page A258 for declarations of interest in relation to abstract P198.