BACKGROUND:Exacerbations contribute significantly to the burden of asthma. Some individuals are predisposed to recurring exacerbations; however, the underlying mechanisms are not well understood. OBJECTIVE:Our aim was to generate a sputum protein signature associated with future exacerbations. METHOD:A total of 22 baseline sputum samples from the control (placebo control) arm of the AMAZES study were analyzed by using an optimized high-throughput mass spectrometry method. RESULTS:With use of a log fold change of at least 1.5 and a P value of .05 as cutoffs, univariate analysis identified 533 differentially abundant sputum proteins in participants with and without future exacerbations over the ensuing 48 weeks. A multivariate signature of 260 proteins for predicting future exacerbations was developed by using sparse partial least squares data analysis, which was partially able to predict (with an area under the receiver operating characteristic curve of 0.95 and an error rate of 0.41) those who would likely experience an exacerbation. Next, from sputum samples collected from an additional 123 participants, the 20 most influential proteins were selected for validation and quantification. After validation, 9 proteins were found to be linked to future exacerbation risk. The final model was able to predict future exacerbations with an area under the receiver operating characteristic curve of 0.77 and an error rate of 0.40. Pathway analysis revealed major themes associated with exacerbations, including inflammation, recruitment, and proliferation of immune cells. CONCLUSION:This study has identified, for what we believe is the first time, a sputum proteomic signature and pathways associated with future exacerbations, which will facilitate the discovery of new biomarkers and novel therapeutic targets in uncontrolled persistent asthma.

BackgroundSputum extracellular DNA (eDNA) is associated with disease severity in asthma and COPD and therefore emerging as a potential therapeutic target. The aim of this study was to investigate the effect of 10 days of recombinant human DNase (rhDNase) treatment of eDNA-high asthma and COPD on sputum eDNA levels, neutrophil-related inflammation, lung function and symptoms.MethodsAdults with asthma (n=80) or COPD (n=66) were screened for the presence of high (>20 µg·mL−1) sputum eDNA and those eligible (n=18 asthma, n=17 COPD) were randomised to a two-period crossover controlled trial consisting of daily nebulised rhDNase (2.5 mg/2.5 mL) or placebo (5 mL 0.9% saline) for 10 days, with a 2-week washout period. The primary outcome was sputum eDNA, and secondary outcomes included sputum neutrophil extracellular trap (NET)-related biomarkers, inflammatory cell counts, lung function and respiratory symptoms.ResultsAt screening, high eDNA was associated with significantly higher sputum total cell count, sputum colour score and inflammation (HNP1-3, LL-37 and interleukin-1β) in both asthma and COPD compared to low eDNA groups. In asthma, participants with high eDNA were older and had poorer lung function and asthma control compared to low eDNA. Administration of nebulised rhDNase significantly reduced sputum eDNA levels in both asthma (median (Q1–Q3) Pre: 48.4 (22.1–74.1); Post: 17.0 (5.0–31.0) µg·mL−1; p=0.022) and COPD (median (Q1–Q3) Pre: 39.3 (36.7–55.6); Post: 25.4 (11.3–38.6) µg·mL−1; p=0.044) compared to placebo. Symptoms, lung function and NET biomarkers remained unchanged. In asthma, there was a reduction in banded blood neutrophils (3.2 (0–7.7) to 0.0 (0.0–1.5); p=0.044).ConclusionTargeted rhDNase treatment for 10 days effectively reduced sputum eDNA in eDNA-high asthma and COPD.

Objective To examine airway inflammatory cell profiles in Indigenous Australian adults with asthma and chronic obstructive pulmonary disease (COPD).Design/setting A retrospective, cross-sectional study on data from a tertiary referral respiratory outpatient clinic.Participants Indigenous (n=23) and non-Indigenous (n=71) adults were matched according to diagnosis, gender and age to the ratio of 1:3.Main outcome measures Participants were defined by self-determined identification as Indigenous (Aboriginal) or non-Indigenous. A relevant history was taken, and lung function was measured by spirometry. In those with a diagnosis of asthma, symptom control was assessed by the Asthma Control Questionnaire, six items (ACQ6). In those with a diagnosis of COPD, symptoms were assessed by the COPD assessment test (CAT). Airway cell counts were obtained in all groups from bronchial lavage (BL) cell count.Results Lung function and inhaled corticosteroid dose were similar between groups. Current smoking was three times more common in Indigenous people (35%) compared with non-Indigenous people (12%, p=0.009). In participants with asthma, ACQ6 scores were similar between Indigenous and non-Indigenous participants with asthma. In those with COPD, Indigenous participants had significantly higher total CAT scores as well as scores for cough and sputum with a score indicating a high impact on quality of life (CAT score ≥14, 85%–25%, p=0.017). There was no difference in BL cell differential counts.Conclusions Indigenous people with COPD had higher smoking rates, worsened CAT scores and more symptoms of cough and sputum production. There were no differences between the groups in airway inflammation, but neutrophilic inflammation was associated with poorly-controlled asthma.

Chronic airway disease (CAD) is characterized by chronic airway inflammation and colonization of the lungs by pro-inflammatory pathogens. However, while various other bacterial species are present in the lower airways, it is not fully understood how they influence inflammation. We aimed to identify novel anti-inflammatory species present in lower airway samples of patients with CAD. Paired sputum microbiome and inflammatory marker data of adults with CAD across three separate cohorts (Australian asthma and bronchiectasis, Scottish bronchiectasis) was analyzed using Linear discriminant analysis Effect Size (LEfSE) and Spearman correlation analysis to identify species associated with a low inflammatory profile in patients. We identified the genus Aggregatibacter as more abundant in patients with lower levels of airway inflammatory markers in two CAD cohorts (Australian asthma and bronchiectasis). In addition, the relative abundance of Aggregatibacter was inversely correlated with sputum IL-8 (Australian bronchiectasis) and IL-1β levels (Australian asthma and bronchiectasis). Subsequent in vitro testing, using a physiologically relevant three-dimensional lung epithelial cell model, revealed that Aggregatibacter spp. (i.e. A. actinomycetemcomitans, A. aphrophilus) and their cell-free supernatant exerted anti-inflammatory activity without influencing host cell viability. These findings suggest that Aggregatibacter spp. might act to reduce airway inflammation in CAD patients.

INTRODUCTION:Biomarkers are used to select biologic therapies for patients with severe asthma, but not to regularly adjust therapy, especially oral corticosteroids (OCS).OBJECTIVE:Our goal was to test the efficacy of an algorithm to guide the titration of OCS using blood eosinophil count and fraction of exhaled nitric oxide (FeNO) levels.DESIGN, PARTICIPANTS, INTERVENTIONS AND SETTING:This proof-of-concept prospective randomised controlled trial assigned adult participants with severe uncontrolled asthma (n=32) to biomarker-based management (BBM) where OCS dose was adjusted based on a composite biomarker score comprised of blood eosinophil count and FeNO, or a standard best practice (SBP) arm. The study was conducted at the Hunter Medical Research Institute, Newcastle, Australia. Participants were recruited from the local Severe Asthma Clinic and were blinded to their study allocation.MAIN OUTCOME:The coprimary outcomes were number of severe exacerbations and time to first severe exacerbation assessed over 12 months.RESULTS:There was a longer median time to first severe exacerbation with BBM, although not significant (295 vs 123 days, Adj. HR: 0.714; 95% CI: 0.25 to 2.06; p=0.533). The relative risk of a severe exacerbation in BBM (n=17) vs SBP (n=15) was 0.88 (Adj.; 95% CI: 0.47 to 1.62; p=0.675) with a mean exacerbation rate per year of 1.2 and 2.0, respectively. There was a significant reduction in the proportion of patients requiring an emergency department (ED) visit using BBM (OR 0.09, 95% CI: 0.01 to 0.91; p=0.041). There was no difference in the cumulative OCS dose used between the two groups.CONCLUSION:A treatment algorithm to adjust OCS using blood eosinophil count and FeNO is feasible in a clinical setting and resulted in a reduced odds of an ED visit. This warrants further study to optimise the use of OCS in the future.TRIAL REGISTRATION NUMBER:This trial was registered with the Australia and New Zealand Clinical Trials Registry (ACTRN12616001015437).

Asthma is common impacting over 5 million in UK. Inhaled corticosteroids (ICS) are universally recommended for disease control, not all respond or have asthma. FeNO is a test of corticosteroid responsive inflammation and could guide ICS use. Question: Is using FeNO in primary care practicable and effective in asthma management? Design Multi-centre study with cluster randomisation. Subjects recruited from Thames Valley GP practices. Subjects: new asthma and poorly controlled asthmatics. Day 0: full assessment symptoms, medication, history and FeNO. Trial visits: day 30 and 60 for assessment and correction of inhaler technique and adherence. FeNO driven treatment algorithm was followed vs standard care. Final visit d360. Goal: maintain FeNO <25 ppb. Primary outcome: ACT score. Data for the first 71 participants from 251 total. Results Poorly controlled cohort: Fifty-five adults completed trial using FeNO guidance. 76% non-smoking, mean age 56 years, with mild to moderate airflow obstruction. 87% were using ICS and 58% reported good asthma control at baseline (ACT>19). Baseline and D360 data shown in table 1. A FeNO of <25ppb was achieved and maintained in 54%, compared baseline, p<0.001. There was a modest increase in ICS dose from 400 mg to 800 mg daily, no change in exacerbation rate (p=0.823). ACT score improved from median 20 (16,23) at baseline, to 21 (19,24), p=0.020 at 12 months. FeNO levels were lower at study end, median 24ppb vs 28ppb at baseline (p=0.085) New Asthma Cohort: 16 enrolled, 11 completed, 63% female, mean age 40yrs. At study end ACT and MRC scores were improved, mean ICS dose: 400 mgc Bec. FeNO was unchanged. Conclusion This initial analysis demonstrates that asthmatics in primary care improve control when FeNO guides ICS dose adjustments This was both practicable and acceptable in the primary care setting. However, continued clinical support is required for continued improvement.

Purpose:This study sought to characterize transcriptional phenotypes of COPD through unsupervised clustering of sputum gene expression profiles, and further investigate mechanisms underlying the characteristics of these clusters.Patients and methods:Induced sputum samples were collected from patients with stable COPD (n = 72) and healthy controls (n = 15). Induced sputum was collected for inflammatory cell counts, and RNA extracted. Transcriptional profiles were generated (Illumina Humanref-8 V2) and analyzed by GeneSpring GX14.9.1. Unsupervised hierarchical clustering and differential gene expression analysis were performed, and gene alterations validated in the ECLIPSE dataset (GSE22148).Results:We identified 2 main clusters (Cluster 1 [n = 35] and Cluster 2 [n = 37]), which further divided into 4 sub-clusters (Sub-clusters 1.1 [n = 14], 1.2 [n = 21], 2.1 [n = 20] and 2.2 [n = 17]). Compared with Cluster 1, Cluster 2 was associated with significantly lower lung function (p = 0.014), more severe disease (p = 0.009) and breathlessness (p = 0.035), and increased sputum neutrophils (p = 0.031). Sub-cluster 1.1 had significantly higher proportion of people with comorbid cardiovascular disease compared to the other 3 sub-clusters (92.5% vs 57.1%, 50% and 52.9%, p < 0.013). Through supervised analysis we determined that degree of airflow limitation (GOLD stage) was the predominant factor driving gene expression differences in our transcriptional clusters. There were 452 genes (adjusted p < 0.05 and ≥2 fold) altered in GOLD stage 3 and 4 versus 1 and 2, of which 281 (62%) were also found to be significantly expressed between these GOLD stages in the ECLIPSE data set (GSE22148). Differentially expressed genes were largely downregulated in GOLD stages 3 and 4 and connected in 5 networks relating to lipoprotein and cholesterol metabolism; metabolic processes in oxidation/reduction and mitochondrial function; antigen processing and presentation; regulation of complement activation and innate immune responses; and immune and metabolic processes.Conclusion:Severity of lung function drives 2 distinct transcriptional phenotypes of COPD and relates to immune and metabolic processes.

Introduction The significance of endoplasmic reticulum (ER) stress in asthma is unclear. Here, we demonstrate that ER stress and the unfolded protein response (UPR) are related to disease severity and inflammatory phenotype. Methods Induced sputum (n=47), bronchial lavage (n=23) and endobronchial biopsies (n=40) were collected from participants with asthma with varying disease severity, inflammatory phenotypes and from healthy controls. Markers for ER stress and UPR were assessed. These markers were also assessed in established eosinophilic and neutrophilic murine models of asthma. Results Our results demonstrate increased ER stress and UPR pathways in asthma and these are related to clinical severity and inflammatory phenotypes. Genes associated with ER protein chaperone ( BiP, CANX, CALR ), ER-associated protein degradation ( EDEM1, DERL1) and ER stress-induced apoptosis ( DDIT3, PPP1R15A ) were dysregulated in participants with asthma and are associated with impaired lung function (forced expiratory volume in 1 s) and active eosinophilic and neutrophilic inflammation. ER stress genes also displayed a significant correlation with classic Th2 (interleukin-4, IL-4/13) genes, Th17 (IL-17F/CXCL1) genes, proinflammatory (IL-1b, tumour necrosis factor α, IL-8) genes and inflammasome activation (NLRP3) in sputum from asthmatic participants. Mice with allergic airway disease (AAD) and severe steroid insensitive AAD also showed increased ER stress signalling in their lungs. Conclusion Heightened ER stress is associated with severe eosinophilic and neutrophilic inflammation in asthma and may play a crucial role in the pathogenesis of asthma.

Acute asthma remains an important unmet need for people living with asthma. It is a major cause of morbidity with a substantial impact on quality of life as well as leading to a significant consumption of healthcare resources. The frequency and severity of asthma exacerbations is a central determinant of asthma control and reducing the risk of exacerbations is now a major goal of asthma treatment (GINA, 2020). Our ability to offer targeted treatment and prevention will continue to improve with our increasing understanding of the factors that influence acute asthma, such as the predisposing clinico-pathological traits, and the complex interactions between the immune system and the environment. This chapter aims to summaries recent insights into the epidemiology, pathophysiology, and management of acute asthma.

BACKGROUND AND OBJECTIVE:Severe asthma (SA) is a heterogeneous disease. Transcriptomic analysis contributes to the understanding of pathogenesis necessary for developing new therapies. We sought to identify and validate mechanistic pathways of SA across two independent cohorts.METHODS:Transcriptomic profiles from U-BIOPRED and Australian NOVocastrian Asthma cohorts were examined and grouped into SA, mild/moderate asthma (MMA) and healthy controls (HCs). Differentially expressed genes (DEGs), canonical pathways and gene sets were identified as central to SA mechanisms if they were significant across both cohorts in either endobronchial biopsies or induced sputum.RESULTS:Thirty-six DEGs and four pathways were shared across cohorts linking to tissue remodelling/repair in biopsies of SA patients, including SUMOylation, NRF2 pathway and oxidative stress pathways. MMA presented a similar profile to HCs. Induced sputum demonstrated IL18R1 as a shared DEG in SA compared with healthy subjects. We identified enrichment of gene sets related to corticosteroid treatment; immune-related mechanisms; activation of CD4+ T cells, mast cells and IL18R1; and airway remodelling in SA.CONCLUSION:Our results identified differentially expressed pathways that highlight the role of CD4+ T cells, mast cells and pathways linked to ongoing airway remodelling, such as IL18R1, SUMOylation and NRF2 pathways, as likely active mechanisms in the pathogenesis of SA.

BACKGROUND:Community-based clinical trials of the inhaled corticosteroid budesonide in early COVID-19 have shown improved patient outcomes. We aimed to understand the inflammatory mechanism of budesonide in the treatment of early COVID-19. METHODS:The STOIC trial was a randomised, open label, parallel group, phase 2 clinical intervention trial where patients were randomly assigned (1:1) to receive usual care (as needed antipyretics were only available treatment) or inhaled budesonide at a dose of 800 μg twice a day plus usual care. For this experimental analysis, we investigated the nasal mucosal inflammatory response in patients recruited to the STOIC trial and in a cohort of SARS-CoV-2-negative healthy controls, recruited from a long-term observational data collection study at the University of Oxford. In patients with SARS-CoV-2 who entered the STOIC study, nasal epithelial lining fluid was sampled at day of randomisation (day 0) and at day 14 following randomisation, blood samples were also collected at day 28 after randomisation. Nasal epithelial lining fluid and blood samples were collected from the SARS-CoV-2 negative control cohort. Inflammatory mediators in the nasal epithelial lining fluid and blood were assessed for a range of viral response proteins, and innate and adaptive response markers using Meso Scale Discovery enzyme linked immunoassay panels. These samples were used to investigate the evolution of inflammation in the early COVID-19 disease course and assess the effect of budesonide on inflammation. FINDINGS:146 participants were recruited in the STOIC trial (n=73 in the usual care group; n=73 in the budesonide group). 140 nasal mucosal samples were available at day 0 (randomisation) and 122 samples at day 14. At day 28, whole blood was collected from 123 participants (62 in the budesonide group and 61 in the usual care group). 20 blood or nasal samples were collected from healthy controls. In early COVID-19 disease, there was an enhanced inflammatory airway response with the induction of an anti-viral and T-helper 1 and 2 (Th1/2) inflammatory response compared with healthy individuals. Individuals with COVID-19 who clinically deteriorated (ie, who met the primary outcome) showed an early blunted respiratory interferon response and pronounced and persistent Th2 inflammation, mediated by CC chemokine ligand (CCL)-24, compared with those with COVID-19 who did not clinically deteriorate. Over time, the natural course of COVID-19 showed persistently high respiratory interferon concentrations and elevated concentrations of the eosinophil chemokine, CCL-11, despite clinical symptom improvement. There was persistent systemic inflammation after 28 days following COVID-19, including elevated concentrations of interleukin (IL)-6, tumour necrosis factor-α, and CCL-11. Budesonide treatment modulated inflammation in the nose and blood and was shown to decrease IL-33 and increase CCL17. The STOIC trial was registered with ClinicalTrials.gov, NCT04416399. INTERPRETATION:An initial blunted interferon response and heightened T-helper 2 inflammatory response in the respiratory tract following SARS-CoV-2 infection could be a biomarker for predicting the development of severe COVID-19 disease. The clinical benefit of inhaled budesonide in early COVID-19 is likely to be as a consequence of its inflammatory modulatory effect, suggesting efficacy by reducing epithelial damage and an improved T-cell response. FUNDING:Oxford National Institute of Health Research Biomedical Research Centre and AstraZeneca.

New interventions are needed for non-T2 asthma phenotypes. Although the AMAZES study (Lancet 2017) showed that azithromycin (AZM) reduces asthma exacerbations, the involved mechanisms are not well understood. This study aimed to identify a unique AZM-sensitive protein signature in sputum from AMAZES participants, comparing sputum obtained before and after 48 weeks of AZM or placebo, added to optimal inhaler therapy. Using a robust high throughput method (mass spectroscopy) for the global analysis of the sputum proteome, 52 samples (representative of entire AMAZES cohort) were selected. Protein intensities were extracted for external statistical analyses using R studio. Differentially enriched proteins were identified by a log-fold change of 1.5 and a p-value of 0.05. Findings were validated in a larger cohort of participants. Univariate modelling identified 240 proteins uniquely expressed at week 48 in AZM-treated patients and 214 proteins in placebo-treated patients. An additional 32 proteins were differentially expressed in AZM-treated patients, comparing week 48 to baseline. Finally, 90 proteins were differentially expressed at week 48 between AZM and placebo-treated samples. Multivariate modelling identified a unique 60 protein signature that distinguished AZM from placebo in comparison to the baseline proteome. Protein interactions and pathway analysis identified several overrepresented pathways independent of asthma phenotype: including apoptosis, phagocytosis, IL-5 pathway, endogenous TLR/chemokine signalling and bacterial invasion. Analysis of the proteome provides unique insight into AZMs mechanism and facilitates development of novel treatment options for severe asthma

BACKGROUND:Low-dose long-term azithromycin is recommended in clinical practice guidelines for obstructive airway diseases (OAD); however, an optimal therapeutic regimen is not yet established.AIM:To understand the patterns of azithromycin use in OAD, characterise the patients who received it and evaluate its safety and efficacy using real-world data.METHODS:We audited 91 patients who had received azithromycin for at least 4 weeks for the management of asthma, chronic obstructive pulmonary disease (COPD) or non-cystic fibrosis bronchiectasis.RESULTS:The mean age was 65 ± 18 years, 60% were female and 48% were ex-smokers. The majority had asthma (75%), either alone (50%) or in combination with COPD (12%) or bronchiectasis (13%). Most (64%) reported cough or sputum at baseline. The most common treatment regimen was azithromycin 250 mg daily (73%) for more than 1 year (57%), with only seven adverse events. There was a significant reduction in the proportions of patients requiring emergency department visits (48% vs 32%; P < 0.001) and hospital admissions (35% vs 31%; P < 0.001) after starting azithromycin. In 88% of cases, physicians favoured the use of azithromycin.CONCLUSION:Physicians are currently using low-dose azithromycin for a long duration of more than 1 year for the management of OAD. The typical case definition is an older non-smoking adult with persistent asthma, often in combination with another OAD and presenting with bothersome cough or sputum. Azithromycin was well tolerated and led to reduced healthcare utilisation. Further research is required to establish an optimal dosage regimen of azithromycin in OAD.

Introduction: CYP with PCD have an annual clinical assessment as part of the National PCD Management service and an MSK assessment is part of this for all CYP over 8yrs of age. This enables us to have a proactive approach in preventing possible MSK issues that can be seen in adolescence and adulthood. We describe our experience with MSK assessment in PCD patients. Methods: Data was prospectively collected at annual review for all CYP over 8 years of age over a 12-month period. MSK assessment was completed using the ACPCF Manchester Musculoskeletal Screening Tool (Ashbrook-JCysticfibrosis-2011) which assesses posture, thoracic mobility, presence of urinary incontinence and incidence of MSK pain. Results: 26 CYP (M13:F13) (9-16years) had an MSK assessment, 13 had no abnormality detected. Of the remaining 13, 10 (M3:F7) had some thoracic limitation, 6 reported MSK pain and 2 symptoms of stress urinary incontinence. Loss of thoracic extension was seen in 7 CYP, 5 also had a loss of side flexion, 4 of which reported MSK pain. 2 CYP reporting non spine specific MSK pain and had no thoracic limitation. There was no difference in the mean FEV1 and FVC predicted values between those with normal and abnormal findings and no clear correlation with ethnicity. Conclusions: Our findings show that an MSK assessment is an essential element of PCD clinical review and MSK problems appear to be common. The majority of those with thoracic limitation were female and the presence of limitation in both thoracic extension and side flexion appears to increase the risk of MSK pain. Further assessment and investigation in this area would be valuable in our understanding and management of this patient group.

BACKGROUND:Chronic airway inflammation is the main driver of pathogenesis in respiratory diseases such as severe asthma, chronic obstructive pulmonary disease, cystic fibrosis (CF) and bronchiectasis. While the role of common pathogens in airway inflammation is widely recognised, the influence of other microbiota members is still poorly understood.METHODS:We hypothesised that the lung microbiota contains bacteria with immunomodulatory activity which modulate net levels of immune activation by key respiratory pathogens. Therefore, we assessed the immunomodulatory effect of several members of the lung microbiota frequently reported as present in CF lower respiratory tract samples.RESULTS:We show that Rothia mucilaginosa, a common resident of the oral cavity that is also often detectable in the lower airways in chronic disease, has an inhibitory effect on pathogen- or lipopolysaccharide-induced pro-inflammatory responses, in vitro (three-dimensional cell culture model) and in vivo (mouse model). Furthermore, in a cohort of adults with bronchiectasis, the abundance of Rothia species was negatively correlated with pro-inflammatory markers (interleukin (IL)-8 and IL-1β) and matrix metalloproteinase (MMP)-1, MMP-8 and MMP-9 in sputum. Mechanistic studies revealed that R. mucilaginosa inhibits NF-κB pathway activation by reducing the phosphorylation of IκBα and consequently the expression of NF-κB target genes.CONCLUSIONS:These findings indicate that the presence of R. mucilaginosa in the lower airways potentially mitigates inflammation, which could in turn influence the severity and progression of chronic respiratory disorders.

Airway inflammation plays a key role in asthma pathogenesis but is heterogeneous in nature. There has been significant scientific discovery with regard to type 2-driven, eosinophil-dominated asthma, with effective therapies ranging from inhaled corticosteroids to novel biologics. However, studies suggest that approximately 1 in 5 adults with asthma have an increased proportion of neutrophils in their airways. These patients tend to be older, have potentially pathogenic airway bacteria and do not respond well to classical therapies. Currently, there are no specific therapeutic options for these patients, such as neutrophil-targeting biologics. Neutrophils comprise 70% of the total circulatory white cells and play a critical defence role during inflammatory and infective challenges. This makes them a problematic target for therapeutics. Furthermore, neutrophil functions change with age, with reduced microbial killing, increased reactive oxygen species release and reduced production of extracellular traps with advancing age. Therefore, different therapeutic strategies may be required for different age groups of patients. The pathogenesis of neutrophil-dominated airway inflammation in adults with asthma may reflect a counterproductive response to the defective neutrophil microbial killing seen with age, resulting in bystander damage to host airway cells and subsequent mucus hypersecretion and airway remodelling. However, in children with asthma, neutrophils are less associated with adverse features of disease, and it is possible that in children, neutrophils are less pathogenic. In this review, we explore the mechanisms of neutrophil recruitment, changes in cellular function across the life course and the implications this may have for asthma management now and in the future. We also describe the prevalence of neutrophilic asthma globally, with a focus on First Nations people of Australia, New Zealand and North America.

PURPOSE:Systemic inflammatory biomarkers can improve diagnosis and assessment of chronic obstructive pulmonary disease (COPD) and asthma. We aimed to validate an airway disease biomarker panel of 4 systemic inflammatory biomarkers, α2-macroglobulin, ceruloplasmin, haptoglobin and hemopexin, to establish their relationship to airway disease diagnosis and inflammatory phenotypes and to identify an optimized biomarker panel for disease differentiation.METHODS:Participants with COPD or asthma were classified by inflammatory phenotypes. Immunoassay methods were used to measure levels of validation biomarkers in the sera of participants with disease and non-respiratory disease controls. Markers were analyzed individually and in combination for disease differentiation and compared to established biomarkers (C-reactive protein, interleukin-6, and white blood cell/blood eosinophil count).RESULTS:The study population comprised of 141 COPD, 127 severe asthma, 54 mild-moderate asthma and 71 control participants. Significant differences in ceruloplasmin, haptoglobin and hemopexin levels between disease groups and between systemic inflammatory phenotypes were observed. However, no differences were found between airway inflammatory phenotypes. Hemopexin was the best performing individual biomarker and could diagnose COPD versus control participants (area under the curve [AUC], 98.3%; 95% confidence interval [CI], 96.7%-99.9%) and differentiate COPD from asthmatic participants (AUC, 97.0%; 95% CI, 95.4%-98.6%), outperforming established biomarkers. A biomarker panel, including hemopexin, haptoglobin and other established biomarkers, could diagnose asthma versus control participants (AUC, 87.5%; 95% CI, 82.8%-92.2%).CONCLUSIONS:Hemopexin can be a novel biomarker with superior diagnostic ability in differentiating COPD and asthma. We propose an anti-inflammatory axis between the airways and systemic circulation, in which hemopexin is a protective component in airway disease.