Asthma Trials Research Articles

Bronchiectasis enters the inflammation era.

Bronchiectasis enters the inflammation era.

Is Inhaler Technique Adequately Assessed and Reported in Clinical Trials of Asthma and Chronic Obstructive Pulmonary Disease Therapy? A Systematic Review and Suggested Best Practice Checklist

Inhaled medications are central to treating asthma and chronic obstructive pulmonary disease (COPD), yet critical inhaler technique errors are made by up to 90% of patients. In the clinical research setting, recruitment of subjects with poor inhaler technique may give a false impression of both the benefits and the necessity of add-on treatments such as biologic therapies. To assess the frequency with which inhaler technique is assessed and reliably optimized before and during patient enrollment into randomized controlled trials (RCTs) addressing the efficacy of topical therapy, and the escalation of therapy for asthma and COPD. Systematic searches were conducted of PubMed and Embase for RCTs published in the past 10 years involving patients with a diagnosis of asthma or COPD undergoing escalation of baseline inhaled therapy (stepping up, changing, adding, switching, increasing, etc) or the introduction of biologic agents. Searches highlighted 1,014 studies, 118 of which were eligible after the removal of duplicates as well as screening and full text review. Of these, only 14 (11.9%) included accessible information in the methods section or referred to such information in online supplements or protocols concerning assessment of participants' inhaler technique. We therefore developed the proposed Best Practice Inhaler Technique Assessment and Reporting Checklist. Our study identifies a concerning lack of checking and correcting inhaler technique, or at least reporting that this was undertaken, before enrollment in asthma and COPD RCTs, which may affect the conclusions drawn. Mandating the use of a standardized checklist in RCT protocols and ensuring all published RCTs report checking and correcting inhaler technique before enrollment are important next steps.

Caregiver Experiences Managing Persistent Childhood Asthma During the COVID-19 Pandemic.

COVID-19 has adversely affected child wellness, but it is unclear whether the pandemic led to changes in home management of chronic diseases like asthma. We surveyed 93 caregivers of children with persistent asthma from 2 ongoing asthma trials to measure changes in home asthma management, stressors, access to health care, and caregivers' worry about COVID-19 affecting their child's health. We conducted descriptive analyses, and assessed whether caregiver worry about COVID-19 was associated with asthma management, stressors, health care access, or recent symptoms. Most (80%) caregivers worried that COVID-19 would affect their child's health, and >50% restricted their child's physical activity to avoid asthma symptoms. We observed a dose-dependent relationship between increasing worry about COVID-19 and activity restrictions, financial hardship, difficulty obtaining asthma medications, and nocturnal asthma symptoms. These findings raise concern that children with persistent asthma may be at particular risk for weight gain and obesity-associated asthma morbidity due to the pandemic.

Tezepelumab Reduces Inflammatory Biomarkers as Early as Week 2 and Maintains Reductions Until Week 52 in the Phase 3 NAVIGATOR Severe Asthma Trial

Tezepelumab, a human monoclonal antibody, blocks the actions of thymic stromal lymphopoietin (TSLP) and reduces downstream airway inflammation. To provide mechanistic insight into the clinical effects of tezepelumab in patients with severe asthma, we evaluated the effect of tezepelumab on levels of airway and circulating inflammatory cytokines and biomarkers during the phase 3, randomized, placebo-controlled NAVIGATOR study (NCT03347279).

Deprescribing montelukast in children with asthma: a systematic review

BackgroundNational and international asthma guidelines recommend adjusting asthma treatment based on levels of control, yet no guidance is given regarding the stepping-down of montelukast in children and young people (CYP).ObjectiveTo...

Role of Ipratropium bromide in management of Thunderstorm asthma

Epidemic thunderstorm asthma has been reported to have occurred around twenty times over the past three decades in locations around the world. Thunderstorm asthma events are characterized by a significant increase in asthma presentations, which on occasion can overwhelm local medical services and result in fatalities. Thunderstorm asthma (TA) typically presents during an aeroallergen season in individuals, sensitized to perennial rye grass pollen (RGP) in Australia, in combination with meteorological factors such as thunderstorms and lightning activity. Short acting beta agonist (SABA) only treatment is sub-optimal therapy for prevention of asthma exacerbations. The combined treatment includes inhaled corticosteroids (ICS) and SABA but is found to be contentious. So the present review focuses on suitable alternative, short acting muscarinic antagonist (SAMA), Ipratropium bromide and its efficacy on the management of allergic asthma. Salbutamol induces bronchodilation rapidly but it elicits profound cardiovascular event as the side effects. Meanwhile, ipratropium also has equivalent effect of salbutamol with low side effect profile. Ipratropium also minifies the asthmatic response to grass pollen, allergen induced bronchoconstriction. Further, it also reduces allergen induced early and late asthmatic response and also inhibits the response towards histamine inhalation. In this regard, ipratropium may be considered as a suitable agent in the management of thunderstorm asthma and future trials are highly warranted. Keywords: Thunderstorm asthma, grass pollen, rye grass, short acting beta agonist, Ipratropium bromide

Volatile anesthetic agents for life-threatening pediatric asthma: A multicenter retrospective cohort study and narrative review.

Volatile anesthetic agents are described as rescue therapy for children invasively ventilated for critical asthma. Yet, data are currently limited to case series. Using the Virtual Pediatric Systems database, we assessed children admitted to a pediatric intensive care unit invasively ventilated for life-threatening asthma and hypothesized ventilation duration and mortality rates would be lower for subjects exposed to volatile anesthetics compared with those without exposure. We performed a multicenter retrospective cohort study among nine institutions including children 5-17years of age invasively ventilated for asthma from 2013 to 2019 with and without exposure to volatile anesthetics. Primary outcomes were ventilation duration and mortality. Secondary outcomes included patient characteristics, length of stay, and anesthetic-related adverse events. A subgroup analysis was performed evaluating children intubated ≥2days. Of 203 children included in study, there were 29 (14.3%) with and 174 (85.7%) without exposure to volatiles. No differences in odds of mortality (1.1, 95% CI: 0.3-3.9, p>.999) were observed. Subjects receiving volatiles experienced greater median difference in length of stay (4.8, 95% CI: 1.9-7.8days, p<.001), ventilation duration (2.3, 95% CI: 1-3.3days, p<.001), and odds of extracorporeal life support (9.1, 95% CI: 1.9-43.2, p=.009) than those without volatile exposure. For those ventilated ≥2days, no differences were detected in mortality, ventilation duration, length of stay, arrhythmias, or acute renal failure. However, the odds of extracorporeal life support remained greater for those receiving volatiles (7.6, 95% CI: 1.3-44.5, p=.027). No children experienced malignant hyperthermia or hepatic failure after volatile exposure. For intubated children for asthma, no differences in mechanical ventilation duration or mortality between those with and without volatile anesthetic exposure were observed. Although volatiles may represent a viable rescue therapy for severe cases of asthma, definitive, and prospective trials are still needed.

Management of dupilumab-associated ocular surface diseases in atopic dermatitis patients.

Atopic dermatitis is a chronic inflammatory skin disease characterised by eczematous skin lesions and intense pruritus. It is often associated with other atopic diseases such as allergic rhinitis and conjunctivitis, bronchial asthma and eosinophilic oesophagitis. Dupilumab is the first biologic approved for the treatment of moderate-to-severe atopic dermatitis in Switzerland. Dupilumab targets the interleukin (IL)-4/IL-13 receptor and thus inhibits the signalling of IL-4 and IL-13, two key mediators of type 2 inflammation, resulting in an improvement of clinical signs and symptoms of atopic dermatitis. Patients with atopic dermatitis present more often with ocular surface diseases (OSDs), such as allergic conjunctivitis, blepharitis and keratitis as well as infectious conjunctivitis and keratoconus compared with the general population. Upon dupilumab therapy, increased rates of ocular surface diseases have been reported in clinical trials. Interestingly, dupilumab-associated (da) OSD is restricted to atopic dermatitis patients and has not been observed in asthma and chronic rhinosinusitis trials. Fortunately, most cases of dupilumab-associated OSD are mild-to-moderate and transient. Thus, ocular surface disease presents a particular adverse event of treatment with dupilumab in dermatology. This article aims at providing a practical guide for physicians, with a special focus on dermatologists, allergists and ophthalmologists in Switzerland, to the diagnosis and management of dupilumab-associated OSD in atopic dermatitis patients.For this purpose, an expert group of dermatologists and ophthalmologists from university and cantonal hospitals in Switzerland reviewed data on ocular surface diseases published in clinical trial and real-life reports of dupilumab therapy, published case reports and case series on the management of dupilumab-associated OSD, as well as recent recommendations provided by experts of national and international boards. Based on the observations of dupilumab-associated OSD and practical experiences in identifying and treating OSD, an algorithm has been developed that is specific to the needs in Switzerland. Considering concomitant ocular diseases and differential diagnoses, the clinical presentation of dupilumab-associated OSD and its response to therapeutic measures, a stepwise approach is recommended. Mild dupilumab-associated OSD can be managed by dermatologists and allergists, whereas patients with moderate-to-severe OSD requiring corticosteroid or calcineurin inhibitor therapy should necessarily be referred to an ophthalmologist. The effects of preventive measures, such as artificial tears, are uncertain. The recommendations provided here should guarantee a prompt and effective treatment of OSD for patients under dupilumab therapy in order to prevent that an otherwise potent therapy has to be ceased because of ocular adverse events.

Use of Health Related Quality of Life in Clinical Trials for Severe Asthma: A Systematic Review.

BackgroundAsthma Health Related Quality of Life (HRQoL) is an outcome important to patients with severe asthma and can provide clinicians with additional insight into the benefits of treatment. The aim of this systematic review is to examine the use and reporting of HRQoL questionnaires within randomised controlled trials (RCTs) of biologics, fevipiprant and bronchial thermoplasty.MethodsWe followed the guidelines on the Preferred Reporting Items for Systematic reviews and Meta-Analysis (PRISMA) statement. Of the 2380 retrieved articles, 52 studies were identified for inclusion.ResultsSixty-three percent included an asthma HRQoL questionnaire. It was a secondary outcome in the majority of cases (73%). The proportion of studies including an asthma HRQoL questionnaire did not change significantly over a 20-year period. While the Asthma Quality of Life Questionnaire (AQLQ) was used in 45% of studies, 55% used a variety of 4 questionnaires. Most (70%) of the studies that included a HRQoL questionnaire did not report its subscale scores. Approximately half (52%) of studies that used HRQoL reported this in the abstract of the paper. A higher proportion of studies used an asthma control questionnaire compared to a HRQoL questionnaire (71% vs 63%).ConclusionIn order to increase the use of asthma HRQoL questionnaires in RCTs of severe asthma treatments, the drivers and barriers to their use must first be understood. At present, the patients’ perspective is underrepresented in RCTs of biologics, fevipiprant and bronchial thermoplasty for severe asthma.

Complexity of design in early phase respiratory clinical trials; evaluating impact of primary endpoints and sponsor size

Asthma and COPD represent most of the clinical trials in the respiratory area. The Primary Endpoint (PE) defines how trials are conducted. We hypothesised that small and mid-sized pharmaceutical companies may be innovative in the selection of their trial endpoints, to be time- and cost-effective. To test this, a record of industry-sponsored phase II trials in asthma, COPD and Asthma/COPD over 11 years was obtained. The type of PE and the influence these had on length, number of subjects and investigational trial sites were evaluated for the different disease categories.Differences in the type of PE used by large versus small/mid-sized companies were found for both asthma and COPD trials (p = 0.011 and 0.025), with sponsorship influencing the conduction of these. In asthma, studies sponsored by large companies were significantly longer than those from smaller companies (p = 0.0001). Additionally, large companies intended to recruit more subjects (asthma: p = 0.0048, COPD: p ≤ 0.0001) and use more investigational sites (asthma: p = 1 × 10−7, COPD: p = 1 × 10−5) than those from small and mid-size companies. A sub-analysis of the time and subject requirements associated with each type of PE did not provide an explanation for the differences observed.In conclusion, this exploratory analysis indicates differences in study size, duration and type of PE used by small/mid-sized and large companies. For some types of endpoints, differences in length and study size were found. However, it wasn't possible to attribute these differences between sponsors solely to the choice of PE, pointing out to the complexity of running clinical trials.

Factors Associated with Persistence of Severe Asthma from Late Adolescence to Early Adulthood.

Asthma severity in children generally starts mild but may progress and stay severe for unknown reasons. Identify factors in childhood that predict persistence of severe asthma in late adolescence and early adulthood. The Childhood Asthma Management Program is the largest and longest asthma trial in 1041 children aged 5-12 years with mild to moderate asthma. We evaluated 682 participants from the program with analyzable data in late adolescence (age 17-19) and early adulthood (age 21-23). Severe asthma was defined using criteria from the American Thoracic Society and the National Asthma Education and Prevention Program to best capture severe asthma. Logistic regression with stepwise elimination was used to analyze clinical features, biomarkers, and lung function predictive of persistence of severe asthma. In late adolescence and early adulthood 12% and 19% of the patents had severe asthma, respectively; only 6% were severe at both time periods. For every 5% decrease in post bronchodilator FEV1/FVC in childhood, the odds of persistence of severe asthma increased 2.36-fold (95% CI: 1.70-3.28; p <0.0001), for participants with maternal smoking during pregnancy odds of persistence of severe asthma increased 3.17-fold (95% CI: 1.18-8.53, p=0.02). Reduced growth lung function trajectory was significantly associated with persistence of severe asthma compared to normal growth. Lung function and maternal smoking during pregnancy were significant predictors of severe asthma from late adolescence to early adulthood. Interventions to preserve lung function early may prevent disease progression.

A Comprehensive Analysis of the Stability of Blood Eosinophil Levels.

Rationale: Blood eosinophil counts are used to inform diagnosis/management of eosinophilic asthma.Objectives: Examine blood eosinophil variability and identify factors affecting eosinophil levels to inform clinical interpretation.Methods: Post hoc analysis to understand eosinophil variability using data from four randomized controlled asthma trials. We examined 1) influence of intrinsic/extrinsic factors (comorbidities, medication, and patient history) using baseline data (n = 2,612); 2) monthly variation using placebo-treated patient data (n = 713); 3) stability of eosinophil classification (<150, 150–299, and ⩾300 cells/μl) in placebo-treated patients with monthly measurements over a 1-year period (n = 751); and 4) impact of technical factors (laboratory-to-laboratory differences and time from collection to analysis).Results: Of intrinsic/extrinsic factors examined, nasal polyps increased eosinophil levels by 38%, whereas current smoking decreased levels by 23%. Substantial seasonal differences in eosinophil counts were observed, with differences of ∼20% between July and January. Eosinophil levels between 150 and 299 cells/μl were least stable, with 44% of patients remaining in the same classification for seven of 10 measurements versus 59% and 66% of patients in the <150 and ⩾300 cells/μl subgroups, respectively. Measurements at different laboratories showed high association (Spearman’s correlation coefficient, R = 0.89); however, eosinophil counts were reduced, with longer time from collection to analysis, and variability increased with increasing eosinophil counts.Conclusions: Several intrinsic, extrinsic, and technical factors may influence, and should be considered in, clinical interpretation of eosinophil counts. Additionally, a single measurement may not be sufficient when using eosinophil counts for diagnosis/management of eosinophilic asthma.

Chlamydia pneumoniae and chronic asthma: Updated systematic review and meta-analysis of population attributable risk.

BackgroundChlamydia pneumoniae (Cp) is an obligate intracellular human respiratory pathogen producing persisting lung infection with a plausible link to asthma pathogenesis. The population attributable risk of potentially treatable Cp infection in asthma has not been reported.MethodsThe author searched from 2000 to 2020 inclusive for previously un-reviewed and new cross sectional and prospective controlled studies of Cp biomarkers and chronic asthma in both children and adults. Qualitative descriptive results and quantitative estimates of population attributable risk for selected biomarkers (specific IgG, IgA and IgE) are presented.FindingsNo large, long-term prospective population-based studies of Cp infection and asthma were identified. About half of case-control studies reported one or more significant associations of Cp biomarkers and chronic asthma. Heterogeneity of results by age group (pediatric v adult asthma), severity category (severe/uncontrolled, moderate/partly controlled, mild/controlled) and antibody isotype (specific IgG, IgA, IgE) were suggested by the qualitative results and confirmed by meta-analyses. The population attributable risks for Cp-specific IgG and IgA were nul in children and were 6% (95% confidence interval 2%-10%, p = 0.002) and 13% (9%-18%, p<0.00001) respectively in adults. In contrast to the nul or small population attributable risks for Cp-specific IgG and IgA, the population attributable risk for C. pneumoniae-specific IgE (children and adults combined) was 47% (39%-55%, p<0.00001). In the subset of studies that reported on asthma severity categories, Cp biomarkers were positively and significantly (P<0.00001) associated with asthma severity.InterpretationC. pneumoniae-specific IgE is strongly associated with asthma and asthma severity, suggesting a possible mechanism linking chronic Cp infection with asthma in a subset of individuals with asthma. Infection biomarkers should be included in future macrolide treatment trials for severe and uncontrolled asthma.

Dupilumab‐associated hypereosinophilia in patients treated for moderate‐to‐severe atopic dermatitis

Trials assessing dupilumab in atopic dermatitis (AD) showed transient eosinophilia in less than 2% of patients (1). The frequency of hypereosinophilia (HE), defined as eosinophil blood count (EBC) ≥1500/mm3 (2), was higher (15.8%) in our previous real-life cohort of AD patients treated with dupilumab (3). Since symptomatic HE was reported in asthma trials, we aimed to assess the clinical impact of HE in AD patients receiving dupilumab.

Daily, Once-Weekly, or No Asthma Controller Therapy At All: The Annoying Issue with Disease Remission in Clinical Asthma Trials

Daily, Once-Weekly, or No Asthma Controller Therapy At All: The Annoying Issue with Disease Remission in Clinical Asthma Trials

Assessing efficacy in important subgroups in confirmatory trials: An example using Bayesian dynamic borrowing.

Assessment of efficacy in important subgroups – such as those defined by sex, age, race and region – in confirmatory trials is typically performed using separate analysis of the specific subgroup. This ignores relevant information from the complementary subgroup. Bayesian dynamic borrowing uses an informative prior based on analysis of the complementary subgroup and a weak prior distribution centred on a mean of zero to construct a robust mixture prior. This combination of priors allows for dynamic borrowing of prior information; the analysis learns how much of the complementary subgroup prior information to borrow based on the consistency between the subgroup of interest and the complementary subgroup. A tipping point analysis can be carried out to identify how much prior weight needs to be placed on the complementary subgroup component of the robust mixture prior to establish efficacy in the subgroup of interest. An attractive feature of the tipping point analysis is that it enables the evidence from the source subgroup, the evidence from the target subgroup, and the combined evidence to be displayed alongside each other. This method is illustrated with an example trial in severe asthma where efficacy in the adolescent subgroup was assessed using a mixture prior combining an informative prior from the adult data in the same trial with a non‐informative prior.

Editorial introductions

Editorial introductions

Conjunctivitis in Dupilumab Clinical Trials for Adolescents with Atopic Dermatitis or Asthma.

BackgroundConjunctivitis is a known comorbidity of atopic dermatitis. Dupilumab clinical trials for moderate-to-severe atopic dermatitis in adults showed a higher conjunctivitis incidence for dupilumab-treated patients than placebo-treated patients, whereas trials for uncontrolled asthma reported lower rates for both dupilumab and placebo.ObjectiveThe objective of this study was to evaluate the incidence and severity of conjunctivitis in dupilumab clinical trials in adolescents with moderate-to-severe atopic dermatitis or uncontrolled asthma.MethodsWe evaluated the incidence of conjunctivitis in adolescents (aged 12 to < 18 years) in three phase III trials. Ocular events were diagnosed and treated based on patient-reported symptoms and an external eye examination by study investigators, in most cases without an ophthalmologic referral. In LIBERTY AD ADOL (16-week, randomized, placebo-controlled, double-blinded trial), adolescents with moderate-to-severe atopic dermatitis were randomized to subcutaneous placebo, dupilumab 300 mg every 4 weeks, or dupilumab every 2 weeks (200 mg, patients < 60 kg at baseline; 300 mg, ≥ 60 kg at baseline). In LIBERTY AD PED-OLE (open-label extension), pediatric patients from previous dupilumab atopic dermatitis trials received dupilumab 2 mg/kg or 4 mg/kg weekly (up to 300 mg) or 300 mg every 4 weeks. In LIBERTY ASTHMA QUEST (randomized, double-blinded, placebo-controlled trial), patients with uncontrolled moderate-to-severe asthma were randomized to 52 weeks of add-on therapy with dupilumab 200 or 300 mg every 2 weeks or matched-volume placebo.ResultsIn ADOL, more dupilumab-treated (17/165; 10.3%) than placebo-treated patients (4/85; 4.7%) reported one or more conjunctivitis event. All events were mild to moderate in severity; 12 (7.3%) dupilumab-treated and 4 (4.7%) placebo-treated patients received treatment. Most patients with conjunctivitis (dupilumab, 12/17; placebo, 4/4) recovered/resolved during the treatment period. The risk of conjunctivitis showed no relationship with dupilumab serum concentration. In PED-OLE, 12/275 adolescents (4.4%) reported one or more conjunctivitis event. Most conjunctivitis events were mild to moderate. Ten patients received treatment for conjunctivitis. Ten patients recovered/resolved during the study. In QUEST, similar low proportions of dupilumab-treated (2/68, 2.9%) and placebo-treated (1/39, 2.6%) adolescents reported one or more conjunctivitis event. All events were mild to moderate. One dupilumab-treated patient received treatment for conjunctivitis. All cases recovered/resolved during the study. No patients in these trials discontinued study treatment temporarily or permanently because of conjunctivitis. In ADOL, one case of unspecified viral keratitis (specific viral etiology not known) in the dupilumab 300-mg every 4 weeks group and one case of allergic blepharitis in the placebo group were reported; both events resolved during the treatment period, and neither led to treatment discontinuation.ConclusionsDupilumab-treated adolescents in atopic dermatitis trials had a higher incidence of conjunctivitis than placebo-treated patients, whereas overall rates of conjunctivitis among adolescents in the asthma trial were lower than in atopic dermatitis trials and were similar for dupilumab- and placebo-treated patients. Most events were mild to moderate, most recovered/resolved, and none prompted study withdrawal. These results are similar to those reported in adult trials and support a drug–disease interaction.ClinicalTrials.gov IdentifiersNCT03054428, NCT02612454, NCT02414854. Conjunctivitis in Dupilumab Clinical Trials for Adolescents with Atopic Dermatitis or Asthma (MP4 18453 kb)Supplementary InformationThe online version contains supplementary material available at 10.1007/s40257-020-00577-1.

Asthma in pregnancy: An update.

AimTo update obstetric care providers about asthma management.SummaryAsthma is the most frequent comorbid chronic illness in pregnancy. Convincing evidence shows that uncontrolled asthma magnifies the risk of maternal, fetal and neonate complications. Unfortunately, one in four women take no inhaler during pregnancy, and it is likely that decreased adherence, rather than changes in pathology, explains uncontrolled maternal asthma. Patient surveys reveal a need for information and reassurance. Although some molecules are preferred in pregnancy, there is currently no basis to withhold any asthma medication – old or new. Biomarkers such as blood eosinophils and fractional exhaled nitric oxide are an effective way to assess the risk of asthma attacks and the likelihood of responding to inhaled steroids. Furthermore, practice-changing trials in mild asthma show that switching reliever-only regimens to as-needed ‘controller-and-reliever’ therapy is effective. We suggest that applying these changes can alleviate women’s concerns and improve outcomes.

Neutrophil Extracellular Traps are Increased in Severe Bronchiectasis and Reduced by Long-Term Azithromycin Treatment

Background: Bronchiectasis is predominantly a neutrophilic inflammatory disease. There are no established therapies that directly target neutrophilic inflammation because of a lack of understanding of the underlying mechanisms leading to severe disease. Neutrophil extracellular trap (NET) formation is a mode of host defence that has been implicated in multiple inflammatory diseases. Methods: We conducted a series of UK and international studies to investigate the role of NETs in disease severity and treatment response in bronchiectasis. Nano LC/MS-MS was used to identify proteomic markers associated with disease severity, defined using the bronchiectasis severity index (BSI) (n=40). These were validated in two cohorts (n=175 and n=275) using a validated immunoassay to measure NETs. 20 patients with acute exacerbations of bronchiectasis were treated with intravenous antibiotics for 14 days and proteomics used to identify proteins associated with treatment response. Two studies of long-term macrolide treatment, one in bronchiectasis and a post-hoc analysis of the AMAZES trial in asthma, investigated the effect of macrolide treatment on NETs. Findings: 96 proteins were differentially expressed in sputum between severe and mild bronchiectasis. The most abundant and most discriminating were proteins known to be NET proteins. This was validated in two observational cohorts where sputum NETs were associated with BSI, quality of life, lung function, future risk of hospital admissions and mortality. Antibiotic treatment in 20 patients was associated with 23 significantly down-regulated and 16 up-regulated proteins, with the “neutrophil degranulation” pathway being most strongly implicated in response. Patients with Pseudomonas aeruginosa infection had a blunted proteomic and clinical response to treatment. Treatment with low dose azithromycin was associated with a significant reduction in NETs in sputum over 12 months in both bronchiectasis and asthma. Interpretation: NETs are identified as a key marker of disease severity and treatment response in bronchiectasis. Funding: Supported by the Scottish Government Chief Scientist Office (Senior Clinical Fellowship to JDC) and British Lung Foundation through the BLF Chair of Respiratory Research. Supported by the European Bronchiectasis Network (EMBARC), a European Respiratory Society Clinical Research Collaboration. Declaration of Interests: None to declare Ethics Approval Statement: The studies were approved by local research ethics committees and patients provided informed consent.