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Background Several animal studies, and one inoculation study in adult asthmatics have shown that interleukin-33 (IL-33) is a major contributor to type-2 inflammation in acute asthma. However, the link between IL-33 and type-2 inflammation has not been shown in naturally occurring asthma exacerbations. Objectives To determine if airway IL-33 is associated with type-2 inflammation measured by type-2 cytokines, FeNO and sputum eosinophils in patients presenting to the Emergency Department with an asthma exacerbations. Methods Adult patients hospitalized due to acute asthma were enrolled. Upper airways were sampled with nasal swabs and lower airways with induced sputum. Cytokines were measured at protein level using a Luminex® assay and mRNA expression level using droplet-digital-PCR. Airway sampling was repeated four weeks after exacerbation. Results At the time of exacerbation, upper airway IL-33 correlated with upper airway IL-5 and IL-13 (R = 0.84, p, Highlights • IL-33 correlates to type 2 cytokines in hospitalized patients with acute asthma. • Airway IL-13 and IL-33 positively correlate with fractional exhaled nitric oxide. • Airway IL-5 correlates to blood eosinophils in naturally occurring acute asthma.

SummaryBackground The major trigger of asthma exacerbations is infection with a respiratory virus, most commonly rhinovirus. Type 2 inflammation is known to be associated with an increased risk of exacerbations in general. Whether type 2 inflammation at baseline increases the risk of future virus-induced exacerbations is unknown. Objective To assess whether type 2 inflammation is associated with an increased risk of virus-induced exacerbations of asthma. Methods Stable asthmatics had spirometry, skin prick test, measurement of FeNO and sputum induced for differential cell counts. Patients were followed up for 18 months, during which they were assessed at the research unit when they had symptoms of an exacerbation. Nasal swabs collected at these assessments underwent viral detection by PCR. Results A total of 81 asthma patients were recruited, of which 22 (27%) experienced an exacerbation during the follow-up period. Of these, 15 (68%) had a respiratory virus detected at exacerbation. Sputum eosinophils >1% at baseline increased the risk of having a subsequent virus-induced exacerbation (HR 7.6 95% CI: 1.6-35.2, P=.010) as did having FeNO >25 ppb (HR 3.4 95% CI: 1.1-10.4, P=.033). Conclusion and Clinical Relevance Established type 2 inflammation during stable disease is a risk factor for virus-induced exacerbations in a real-life setting. Measures of type 2 inflammation, such as sputum eosinophils and FeNO, could be included in the risk assessment of patients with asthma in future studies.

Background and objective Airway eosinophilia is associated with an increased risk of asthma exacerbations; however, the impact on the severity of exacerbations is largely unknown. We describe the sputum inflammatory phenotype during asthma exacerbation and correlate it with severity and treatment response. Methods Patients presenting to hospital with an asthma exacerbation were recruited during a 12-month period and followed up after 4 weeks. Induced sputum was collected at both visits. Patients underwent spirometry, arterial blood gas analysis, fractional exhaled nitric oxide analysis, white blood cell counts and a screening for common respiratory viruses and bacteria. An eosinophilic exacerbation (EE) was defined as having sputum eosinophils ≥ 3% and a non-eosinophilic exacerbation as < 3% (NEE). Results A total of 47 patients were enrolled; 37 (79%) had successful sputum induction at baseline, of whom 43% had sputum eosinophils ≥3% (EE). Patients with EE had a significantly lower forced expiratory volume in 1 s (FEV1 ) % predicted (70.8%, P = 0.03) than patients with NEE (83.6%). Furthermore, EE patients were more likely to require supplemental oxygen during admission (63% vs 14%, P = 0.002). The prevalence of respiratory viruses was the same in EE and NEE patients (44% vs 52%, P = 0.60), as was bacterial infection (6% vs 14%, P = 0.44). Fractional expiratory nitric oxide (FeNO) correlated with sputum %-eosinophils (ρ = 0.57, P < 0.001), and predicted airway eosinophilia with a sensitivity of 86% and a specificity of 70%. Conclusion Our findings suggest that eosinophilic asthma exacerbations may be clinically more severe than NEEs, supporting the identification of these higher risk patients for specific interventions.

INTRODUCTION Animal studies, and in vivo inoculation with rhinovirus, have shown that the epithelial-derived cytokine interleukin-33 (IL-33) is a major contributor to Th2-inflammation in acute asthma. However the link between IL-33 and Th2-inflammation has never been shown in naturally occurring cases of acute asthma. AIMS AND OBJECTIVES To determine whether IL-33 plays a role in driving Th2-inflammation in hospitalised acute asthma patients, we aimed to investigate whether the level of IL-33 in the nasal epithelium correlated with levels of Th2 cytokines in upper and lower airways. METHODS Patients admitted to hospital with an acute asthma exacerbation were recruited. Nasal swabs were used to sample nasal fluid representing upper airways, and induced sputum were collected, representing lower airways. Sampling was repeated after 4 weeks, and all samples analysed using Droplet Digital PCR for IL-33, IL-5 and IL-13. RESULTS Nineteen patients were recruited. Nasal IL-33 correlated with IL-5 in both upper and lower airways during acute asthma (0.75, p=0.008 and 0.74, p=0.010, respectively). Similar correlations were found with IL-13 (0.64, p=0.018 and 0.65, p=0.017, respectively). These associations were not significant at the 4-week follow-up. Sputum IL-33 was not associated with IL-5 or IL-13 in either sputum or in the nasal epithelium. CONCLUSION Nasal, but not sputum IL-33 is associated with Th2-promoting cytokines IL-5 and IL-13 in naturally occurring acute asthma cases. These findings support the role of IL-33 as an initiator of Th2-inflammation in acute asthma.

Background: Overweight both in childhood and adolescence is an increasing challenge word-wide and associated with an increased incidence of asthma. However, the mechanisms underlying this association are incompletely understood. In the present study, we investigated if overweight in childhood and adolescence is associated with an increased risk of airway hyperresponsiveness (AHR), a hallmark of asthma, in adulthood. Methods: Of 537 subjects from a random population sample of children and adolescents (7 to 17 years) examined in 1986 (baseline visit), 189 completed a follow-up visit in 2006. Both visits included assessment of height and weight, spirometry and case history, including asthma and allergic diseases. At both visits, bronchial provocation tests were performed using either histamine (baseline visit) or metacholine (follow-up visit). Results: Subjects who were overweight or obese at baseline visit (n=26) (paediatric definition, body mass index (BMI) ≥85%percentile), had a significant higher BMI at follow-up visit, compared with participants of normal weight at baseline visit (n=163) (mean (SD) 30.9 (7.0) vs. 24.8 (3.1), respectively, p Conclusion: In children and adolescence, being obese or overweight seems not to be associated with an increased risk of having airway hyperresponsiveness to metacholine in adulthood.

INTRODUCTION: Pro-inflammatory signalling by the receptor for advanced glycation end products (RAGE), has been described in stable asthma, and a protective role of soluble RAGE (esRAGE) is well established, but the role of esRAGE and RAGE ligands (including enRAGE) is unknown in acute asthma. We aimed to determine whether RAGE signalling is involved in the increased inflammation seen during asthma exacerbations. METHODS: Adult asthmatics were recruited on presentation with acute asthma to Bispebjerg University Hospital during a one-year period. Spirometry and blood samples were collected within 24 hours of admission and repeated after 12 weeks. RESULTS: Patients (n=47) were 16-45 years old and 70% were females. Serum enRAGE was higher (78 ng/ml 95%CI 62-99, p = 0.001) at exacerbation than follow-up (41 ng/ml 95%CI 29-57), while serum esRAGE was lower (96 pg/ml 95%CI 79-115 vs. 158 pg/ml 95%CI 134-187, respectively, p Both enRAGE and the ratio of enRAGE to esRAGE correlated negatively with FEV 1 at exacerbation adjusting for age, gender, ICS usage, blood neutrophil count and detection of respiratory pathogens (p=0.012, R 2 =0.26 and p=0.014, R 2 =0.26, respectively). Patients with a severe or life threatening exacerbation, as defined by BTS guidelines (n=23), had higher enRAGE (83.9 95%CI 56.8-123.8, p=0.046) than patients with a mild to moderate exacerbation (52.1 95%CI 39.1-69.5). CONCLUSION: A systemic, pro-inflammatory response mediated by RAGE, is increased during acute asthma and correlates with the severity of symptoms.

Background and objective Airway eosinophilia is associated with an increased risk of asthma exacerbations; however, the impact on the severity of exacerbations is largely unknown. We describe the sputum inflammatory phenotype during asthma exacerbation and correlate it with severity and treatment response. Methods Patients presenting to hospital with an asthma exacerbation were recruited during a 12‐month period and followed up after 4 weeks. Induced sputum was collected at both visits. Patients underwent spirometry, arterial blood gas analysis, fractional exhaled nitric oxide analysis, white blood cell counts and a screening for common respiratory viruses and bacteria. An eosinophilic exacerbation (EE) was defined as having sputum eosinophils ≥ 3% and a non‐eosinophilic exacerbation as < 3% (NEE). Results A total of 47 patients were enrolled; 37 (79%) had successful sputum induction at baseline, of whom 43% had sputum eosinophils ≥3% (EE). Patients with EE had a significantly lower forced expiratory volume in 1 s (FEV1) % predicted (70.8%, P = 0.03) than patients with NEE (83.6%). Furthermore, EE patients were more likely to require supplemental oxygen during admission (63% vs 14%, P = 0.002). The prevalence of respiratory viruses was the same in EE and NEE patients (44% vs 52%, P = 0.60), as was bacterial infection (6% vs 14%, P = 0.44). Fractional expiratory nitric oxide (FeNO) correlated with sputum %‐eosinophils (ρ = 0.57, P < 0.001), and predicted airway eosinophilia with a sensitivity of 86% and a specificity of 70%. Conclusion Our findings suggest that eosinophilic asthma exacerbations may be clinically more severe than NEEs, supporting the identification of these higher risk patients for specific interventions., Patients with airway eosinophilia during an exacerbation of asthma had lower forced expiratory volume in 1 s (FEV1) and were more likely to require supplemental oxygen during admission than those without eosinophilia. This suggests that eosinophilic asthma exacerbations are more severe than non‐eosinophilic exacerbations.