Risk factors for asthma-related hospital and intensive care admissions in children, adolescents and adults: a cohort study using primary and secondary care data.

BACKGROUND: Asthma remains a common cause of hospital admissions across the life course. We estimated the contribution of key risk factors to asthma-related hospital and intensive care unit (ICU) admissions in children, adolescents and adults. METHODS: This was a UK-based cohort study using linked primary care (Clinical Practice Research Datalink Aurum) and secondary care (Hospital Episode Statistics Admitted Patient Care) data. Patients were eligible if they were aged 5 years and older and had been diagnosed with asthma. This included 90 989 children aged 5-11 years, 114 927 adolescents aged 12-17 years and 1 179 410 adults aged 18 years or older. The primary outcome was asthma-related hospital admissions from 1 January 2017 to 31 December 2019. The secondary outcome was asthma-related ICU admissions. Incidence rate ratios adjusted for demographic and clinical risk factors were estimated using negative binomial models. Population attributable fraction (PAF) was estimated for modifiable risk factors. RESULTS: Younger age groups, females and those from ethnic minority and lower socioeconomic backgrounds had an increased risk of asthma-related hospital admissions. Increasing medication burden, including excessive use of short-acting bronchodilators, was also strongly associated with the primary outcome. Similar risk factors were observed for asthma-related ICU admissions. The key potentially modifiable or treatable risk factors were smoking in adolescents and adults (PAF 6.8%, 95% CI 0.9% to 12.3% and 4.3%, 95% CI 3.0% to 5.7%, respectively), and obesity (PAF 23.3%, 95% CI 20.5% to 26.1%), depression (11.1%, 95% CI 9.1% to 13.1%), gastro-oesophageal reflux disease (2.3%, 95% CI 1.2% to 3.4%), anxiety (2.0%, 95% CI 0.5% to 3.6%) and chronic rhinosinusitis (0.8%, 95% CI 0.3% to 1.3%) in adults. CONCLUSIONS: There are significant sociodemographic inequalities in the rates of asthma-related hospital and ICU admissions. Treating age-specific modifiable risk factors should be considered an integral part of asthma management, which could potentially reduce the rate of avoidable hospital admissions.

Biomarker Predictors of Clinical Efficacy of the Anti-IgE Biologic, Omalizumab, in Severe Asthma in Adults: Results of the SoMOSA Study.

BACKGROUND: The anti-IgE monoclonal, omalizumab, is widely used for severe asthma. This study aimed to identify biomarkers that predict clinical improvement during one year of omalizumab treatment. METHODS: 1-year, open-label, Study of Mechanisms of action of Omalizumab in Severe Asthma (SoMOSA) involving 216 severe (GINA step 4/5) uncontrolled atopic asthmatics (≥2 severe exacerbations in previous year) on high-dose inhaled corticosteroids, long-acting ß-agonists, ± mOCS. It had two phases: 0-16 weeks, to assess early clinical improvement by Global Evaluation of Therapeutic Effectiveness (GETE), and 16-52 weeks, to assess late responses by ≥50% reduction in exacerbations or dose of maintenance oral corticosteroids (mOCS). All participants provided samples (exhaled breath, blood, sputum, urine) before and after 16 weeks of omalizumab treatment. RESULTS: 191 patients completed phase 1; 63% had early improvement. Of 173 who completed phase 2, 69% had reduced exacerbations by ≥50%, while 57% (37/65) on mOCS reduced their dose by ≥50%. The primary outcome 2, 3-dinor-11-ß-PGF2α, GETE and standard clinical biomarkers (blood and sputum eosinophils, exhaled nitric oxide, serum IgE) did not predict either clinical response. Five breathomics (GC-MS) and 5 plasma lipid biomarkers strongly predicted the ≥50% reduction in exacerbations (receiver operating characteristic area under the curve (AUC): 0.780 and 0.922, respectively) and early responses (AUC:0.835 and 0.949, respectively). In independent cohorts, the GC-MS biomarkers differentiated between severe and mild asthma. Conclusions This is the first discovery of omics biomarkers that predict improvement to a biologic for asthma. Their prospective validation and development for clinical use is justified. This article is open access and distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).

Post-hospitalisation asthma management in primary care: a retrospective cohort study.

BACKGROUND: Clinical guidelines recommend that patients admitted to hospital for asthma attacks are reviewed in primary care following hospital discharge. AIM: To evaluate asthma management in primary care following a hospital admission for asthma and its associations with patient characteristics. DESIGN AND SETTING: A retrospective cohort study using English primary care data from the Clinical Practice Research Datalink Aurum database and linked Hospital Episode Statistics Admitted Patient Care data. METHOD: Patients with asthma aged ≥5 years who had at least one asthma-related hospital admission from 1 January 2017 to 31 December 2019 were included. The primary outcome was a composite of any of the following delivered in primary care within 28 days from hospital discharge: asthma review, asthma management plan, asthma medication prescriptions, demonstration of inhaler technique, or smoking cessation counselling. The association between patient characteristics and delivery of clinical care was assessed using logistic regression. RESULTS: The study included 17 457 patients. A total of 10 515 (60.2%) patients received the primary outcome within 28 days of hospital discharge. There were 2311 (13.2%) who received an asthma review, 1459 (8.4%) an asthma management plan, 9996 (57.3%) an asthma medication, 1500 (8.6%) a demonstration of inhaler technique, and 52 (1.2% of smokers) had smoking cessation counselling. Patients from Black ethnic minority groups received less of this care (27%-54% lower odds, depending on age). However, short-acting bronchodilator prescriptions in the previous year were associated with an increased likelihood of the primary outcome. CONCLUSION: A significant proportion of patients do not receive timely follow-up in primary care following asthma-related admissions to hospital, particularly among Black ethnic minority groups.

Ethnic variation in asthma phenotypic presentation and outcomes: a cross-sectional analysis of the UK Biobank.

Ethnic disparities exist within asthma; however, country of birth is rarely investigated. We described demographic and clinical characteristics by ethnicity and country of birth within the UK Biobank. Lung function and asthma hospitalisations were similar for white, black and North-East Asian participants, however, South-East (SE) Asians more commonly had an FEV1 below the lower limits of normal (LLN; 53.8% vs 32.3%, p<0.001), blood eosinophilia (38.6% vs 23.8%, p<0.001) and asthma hospitalisation (12.5% vs 8.3%, p<0.001) than white participants. First-generation SE Asian immigrants had poorer lung function (57.7% vs 27.7% FEV1 below LLN, p<0.001) than UK/Ireland born participants. These data demonstrate inter-ethnic and intra-ethnic disparities.

The clinical effectiveness of mepolizumab treatment in severe eosinophilic asthma; outcomes from four years cohort evaluation.

BACKGROUND: Clinical trials and real world studies demonstrated benefit of mepolizumab treatment in severe asthma but data on its effectiveness beyond 2 years remain limited. Herein, we provide mepolizumab treatment evaluation up to 4 years. METHODS: we studied all patients initiated on mepolizumab in our center from June 2017 to August 2018. Clinical outcomes data were retrieved from the local dendrite systems registry. Comparison analyses and logistic regression were conducted to explore longevity and predictors of response to mepolizumab treatment. RESULTS: a total of 66 patients initiated on mepolizumab with a median follow-up of 45.8 (42.4,48.1) months were included in the study [mean age 50.3 years (range 18-79), females 50 (73%) ]. At 20.7 months of treatment, 42 patients (63.6%) had positive response, 13 (19.7%) negative response, and 11 (16.7%) discontinued due to other factors. At 45.8 months, 35 (53%) patients were still on mepolizumab, 21 (31.8%) switched to a different biologic, and 10 (15.2%) discontinued biologics. Two deaths were recorded during the study period.The median blood eosinophil was reduced from 0.43x109/L (0.27, 0.75) to 0.04 (0.0, 0.1) (p < 0.00001)]. The median annual exacerbations were reduced from 6.0 (4,8) to 1.0 (0.0,3.0) (p < 0.00001), and mOCS use was reduced from59% to 29%, p = 0.001. The mean asthma control questionnaire-6 (ACQ6) improved from 3.1 ± 1.7 to 2.1 ± 1.3 (p < 0.00001). CONCLUSIONS: mepolizumab clinical benefit was sustained over 4 years. However, approximately half of the cohort discontinued the treatment prompting the need for further research into the treatment response longevity.

Difficult-to-treat asthma patients from ethnic minority groups in central England are at an enhanced risk of house dust mite sensitisation.

BACKGROUND: House dust mite (HDM) is the most common sensitising allergen in asthma. Ethnic minority groups (EMGs) in the UK are more likely to live in deprived conditionings with a greater exposure to HDM and other aero-allergens. AIM: To compare the ethnicity-based patterns of sensitisation to aero-allergens and the impact of ethnicity on clinical outcomes in patients with difficult-to-treat asthma (DTA). METHODS: Data of patients with DTA were extracted from the registry of the Birmingham Regional Severe Asthma Service (BRSAS), which have a catchment population of 7.3million from Central England. Patients from White and EMG backgrounds were compared in terms of the prevalence of atopy, total serum immunoglobulin E (IgE), specific serum IgE (ssIgE) and asthma related clinical outcomes. Logistic regression analysis was conducted to explore ethnicity-based risk factors for HDM sensitisation. RESULTS: A total of 1272 patients [White 1016 (79.9%), EMG 256 (20.1%) EMG] with a median age of 51 years (range 16-97) were included in the analysis. Patients from EMG were more likely (64%) to reside in the worst scale of index of multiple deprivation (IMD) than the White patients (25.5%), p < 0.0001. Positive HDM sensitisation was more prevalent in the EMG than in the White group [142/216 (66%) versus 375/842 (45%), p < 0.0001]. The median HDM ssIgE level was higher in the EMG than in the White group [3.0 KUA/L (IQR 0.06, 11.5) versus 0.1 (0.01, 3.0), p < 0.000001]. The odds ratio for positive sensitisation to HDM conveyed by the EMG status was 2.61 (95%CI, 1.8-3.8), p < 0.0001. Compared to the White group, the EMG had higher median total serum IgE [326 KU/L (115, 971) versus 114 (29.8, 434.8), p < 0.000001], higher blood eosinophil count (0.36 × 109 (0.18, 0.62) versus 0.23 (0.1,0.47), p < 0.000001), were marginally more atopic (79.2% vs. 75.6%, p = 0.098) and were less likely to being on maintenance oral corticosteroids (22% vs. 39.7%, p < 0.0001). CONCLUSION: In this DTA cohort, positive HDM sensitisation was greater amongst the EMG than the White patients. The EMG status was a significant risk factor for HDM sensitisation.

Clinical remission in severe asthma with biologic therapy: an analysis from the UK Severe Asthma Registry.

BACKGROUND: Novel biologic therapies have revolutionised the management of severe asthma with more ambitious treatment aims. Here we analyse the definition of clinical remission as a suggested treatment goal and consider the characteristics associated with clinical remission in a large, real-world severe asthma cohort. METHODS: This was a retrospective analysis of severe asthma patients registered in the UK Severe Asthma Registry (UKSAR) who met strict national access criteria for biologics. Patients had a pre-biologics baseline assessment and annual review. The primary definition of clinical remission applied included Asthma Control Questionnaire (ACQ)-5 <1.5 and no oral corticosteroids for disease control and forced expiratory volume in 1 s above lower limit of normal or no more than 100 mL less than baseline. RESULTS: 18.3% of patients achieved the primary definition of remission. The adjusted odds of remission on biologic therapy were 7.44 (95% CI 1.73-31.95)-fold higher in patients with type 2 (T2)-high biomarkers. The adjusted odds of remission were lower in patients who were female (OR 0.61, 95% CI 0.45-0.93), obese (OR 0.49, 95% CI 0.24-0.65) or had ACQ-5 ≥1.5 (OR 0.19, 95% CI 0.12-0.31) pre-biologic therapy. The likelihood of remission reduced by 14% (95% CI 0.76-0.97) for every 10-year increase in disease duration. 12-21% of the cohort attained clinical remission depending on the definition applied; most of those who did not achieve remission failed to meet multiple criteria. CONCLUSIONS: 18.3% of patients achieved the primary definition of clinical remission. Remission was more likely in T2-high biomarker patients with shorter duration of disease and less comorbidity. Further research on the optimum time to commence biologics in severe asthma is required.

Effect of monitoring adherence to regular inhaled corticosteroid (ICS) alone or in combination with a long-acting ß2-agonist (LABA) using electronic methods on asthma outcomes: a narrative systematic review.

OBJECTIVES: To evaluate through a systematic review the effectiveness of electronic methods in monitoring adherence to regular inhaled corticosteroids (ICS) alone or in combination with long-acting ß2-agonists (LABAs) and their effect on clinical outcomes. DESIGN: A narrative systematic review. DATA SOURCES: MEDLINE, EMBASE, Cochrane Database of Systematic Reviews and Web of Science were searched through up to 10 July 2022. ELIGIBILITY CRITERIA: We included peer-reviewed studies of qualitative and quantitative outcomes that compared the effect of electronic methods to routine non-electronic monitoring intervention or placebo among children and adults with asthma on medication adherence rates to regular ICS alone or in combination with LABA, asthma control and asthma exacerbations. DATA EXTRACTION AND SYNTHESIS: Data extraction was performed according to a predetermined sheet specific to the review objectives. The risk of bias was assessed using the Cochrane Risk of Bias Tool for randomised controlled trials and the Risk of Bias in Systematic Reviews tool for systematic reviews. Meta-analysis was not possible based on the findings of the scoping search; however, a narrative review was performed to allow for the grouping of results based on asthma inhaler adherence rates, asthma control and exacerbations. RESULTS: Six articles comprising 98 studies published from 1998 to 2022 in the USA, Canada and the UK were included. Compared with the control, electronic monitoring devices (EMDs) showed a 23% adherence improvement, mean difference (MD) of 23%, 95% CI 10.84 to 34.16, p=0.0002. Asthmatic children were 1.5 times more likely to be adherent using EMDs compared with non-EMD users (RR=1.5, 95% CI 1.19 to 1.9) (p<0.001). Mobile devices and text message reminders (MHealth) showed a 12% adherence improvement (MD 12%, 95% CI 6.22 to 18.03) (p<0.0001), alongside a small to medium improvement in asthma control (standardised mean difference (SMD) 0.31, 95% CI 0.17 to 0.44), small improvement in asthma-related quality of life (SMD 0.26) (p=0.007) and variable risk reduction in asthma exacerbations for digital health (risk ratio 0.53, 95% CI 0.32 to 0.91) (p=0.02) compared with EMDs, which showed insignificant differences (risk ratio 0.89, 95% CI 0.45 to 1.75) (p=0.72). Technologies combined yielded variable adherence effects, with an SMD for eHealth of 0.41, 95% CI 0.02 to 0.79, and MD for digital health was 14.66% higher than the control, 95% CI 7.74 to 21.57. Heterogeneity between studies was significant (eHealth I2=98%, digital I2=94%). CONCLUSION: Electronic methods improved adherence to inhaled medications in asthma. EMDs appear to be the most effective technology, followed by mHealth. The adherence improvement was associated with a small clinical improvement. There was inconsistent overlapping of terminology describing electronic methods that require standardisation. Data on the cost-effectiveness of electronic devices and their utilisation in severe asthma are lacking and require further research. PROSPERO REGISTRATION NUMBER: CRD42022303069.

Management of difficult-to-treat asthma in adolescence and young adults.

The period of adolescence and young adulthood (AYA) has been proposed to extend from 11 to 25 years of age as patients in this age group face similar challenges. AYA is a time of fast and great physiological and psychological growth, in which an individual transitions from a young dependent child to a mature independent adult. Behaviour patterns during adolescence, such as risk taking and desire for privacy, can challenge parents or healthcare professionals' (HCPs') ability to help adolescents to manage their asthma. Asthma itself tends to remit, become milder or worsen into a severe variant during adolescence. The pre-pubertal male predominance of asthma switches to a female predominance in late teen years. ∼10% of AYA with asthma have "difficult-to-treat asthma (DTA)", characterised by poor asthma control despite treatment with inhaled corticosteroids (ICS) and other controller medications. DTA management in AYA requires a multidisciplinary team approach and systematic assessment that can address the key questions of objective confirmation of diagnosis, severity assessment, phenotyping, comorbidities, asthma mimickers or other drivers of poor control such as non-adherence to treatment. A key task for HCPs is to establish the magnitude of the severe asthma component versus other non-asthma drivers of symptoms (e.g. inducible laryngeal obstruction or breathing pattern disorder). Severe asthma is a subset of DTA and is determined once asthma diagnosis and its severity have been confirmed and adherence to controller (ICS) treatment has been assured. Severe asthma is a heterogeneous disease and appropriate phenotyping is necessary for the management of treatable traits and consideration for biologic therapies. Finally, an important part of successful management of DTA in the AYA group is the provision of an effective transition of asthma care from paediatric to adult asthma services through setting up a well-designed asthma transition pathway tailored to the individual patient needs.

A Charter to Fundamentally Change the Role of Oral Corticosteroids in the Management of Asthma.

Asthma affects 339 million people worldwide, with an estimated 5-10% experiencing severe asthma. In emergency settings, oral corticosteroids (OCS) can be lifesaving, but acute and long-term treatment can produce clinically important adverse outcomes and increase the risk of mortality. Therefore, global guidelines recommend limiting the use of OCS. Despite the risks, research indicates that 40-60% of people with severe asthma are receiving or have received long-term OCS treatment. Although often perceived as a low-cost option, long-term OCS use can result in significant health impairments and costs owing to adverse outcomes and increased utilization of healthcare resources. Alternative treatment methods, such as biologics, may produce cost-saving benefits with a better safety profile. A comprehensive and concerted effort is necessary to tackle the continued reliance on OCS. Accordingly, a threshold for OCS use should be established to help identify patients at risk of OCS-related adverse outcomes. Receiving a total dose of more than 500 mg per year should trigger a review and specialist referral. Changes to national and local policies, following examples from other chronic diseases, will be crucial to achieving this goal. Globally, multiple barriers to change still exist, but specific steps have been identified to help clinicians reduce reliance on OCS. Implementing these changes will result in positive health outcomes for patients and social and economic benefits for societies.

A Randomized Trial of a Composite T2-Biomarker Strategy Adjusting Corticosteroid Treatment in Severe Asthma: A Post Hoc Analysis by Sex.

BACKGROUND: Approximately 5% to 10% of patients with asthma have severe disease, with a consistent preponderance in females. Current asthma guidelines recommend stepwise treatment to achieve symptom control with no differential treatment considerations for either sex. OBJECTIVE: To examine whether patient sex affects outcomes when using a composite T2-biomarker score to adjust corticosteroid (CS) treatment in patients with severe asthma compared with standard care. METHODS: This is a post hoc analysis, stratifying patient outcomes by sex, of a 48-week, multicenter, randomized controlled clinical trial comparing a biomarker-defined treatment algorithm with standard care. The primary outcome was the proportion of patients with a reduction in CS treatment (inhaled and oral corticosteroids). Secondary outcomes included exacerbation rates, hospital admissions, and lung function. RESULTS: Of the 301 patients randomized, 194 (64.5%) were females and 107 (35.5%) were males. The biomarker algorithm led to a greater proportion of females being on a lower CS dose versus standard care, which was not seen in males (effect estimate: females, 3.57; 95% CI, 1.14-11.18 vs males, 0.54; 95% CI, 0.16-1.80). In T2-biomarker-low females, reducing CS dose was not associated with increased exacerbations. Females scored higher in all domains of the 7-item Asthma Control Questionnaire, apart from FEV1, but with no difference when adjusted for body mass index/anxiety and/or depression. Dissociation between symptoms and T2 biomarkers were noted in both sexes, with a higher proportion of females being symptom high/T2-biomarker low (22.8% vs 15.6%; P = .0002), whereas males were symptom low/T2-biomarker high (22.3% vs 11.4%; P < .0001). CONCLUSIONS: This exploratory post hoc analysis identified that females achieved a greater benefit from biomarker-directed CS optimization versus symptom-directed treatment.

Biologic therapy practices in severe asthma; outcomes from the UK Severe Asthma Registry and survey of specialist opinion.

BACKGROUND: several biological treatments have become available for management of severe asthma. There is a significant overlap in the indication of these treatments with lack of consensus on the first-line biologic choice and switching practice in event of treatment failure. AIMS: to evaluate outcomes of biologic treatments through analysis of the UK Severe Asthma Registry (UKSAR), and survey of the UK severe asthma specialists' opinion. METHODS: patients registered in the UKSAR database and treated with biologics for severe asthma in the period between January 2014 and August 2021, were studied to explore biologic treatments practice. This was complemented by survey of opinion of severe asthma specialists. RESULTS: a total of 2,490 patients from 10 severe asthma centres were included in the study (mean age 51.3 years, 61.1% female, mean BMI 30.9kg/m2 ). Biologics use included mepolizumab 1,115 (44.8%), benralizumab 925 (37.1%), omalizumab 432 (17.3%), dupilumab 13 (0.5%), and reslizumab 5 (0.2%). Patients on omalizumab were younger and had earlier age of onset asthma than those prescribed mepolizumab or benralizumab. Patients prescribed mepolizumab and benralizumab had similar clinical characteristics. Those on benralizumab were more likely to continue treatment at approximately one year follow up (93.9%), than those on mepolizumab (80%), or omalizumab (69.6%). The first choice biologic differed between centres and changed over the study time period. Experts' opinion also diverged in terms of biologic initiation choice and switching practice. CONCLUSION: We observed significant variation and divergence in the prescribing practices of biologics in severe asthma that necessitates further research and standardisation.

Preventing unscheduled hospitalisations from asthma: a retrospective cohort study using routine primary and secondary care data in the UK (The PUSH-Asthma Study)-protocol paper.

INTRODUCTION: Asthma is the most common chronic respiratory disease in children and adults. Asthma results in significant disease-related morbidity, healthcare costs and, in some cases, death. Despite efforts through implementation of national guidelines to improve asthma care, the UK has one of the highest asthma-related morbidity and mortality rates in the western world. New approaches are necessary to prevent asthma attacks in children and adults. The objectives of this study are to assess the association between demographic and clinical factors and asthma-related hospital admissions in children and adults, describe the epidemiology of asthma phenotypes among hospital attenders, and externally validate existing asthma risk prediction models. METHODS AND ANALYSIS: This is a retrospective cohort study of children and adults with asthma. Data will be extracted from the Clinical Practice Research Datalink (CPRD) Aurum database, which holds anonymised primary care data for over 13 million actively registered patients and covers approximately 19% of the UK population. The primary outcome will be asthma-related hospital admissions. The secondary outcomes will be prescriptions of short courses of oral corticosteroids (as a surrogate measure for asthma exacerbations), a composite outcome measure including hospital admissions and prescriptions of short courses of oral corticosteroids and delivery of asthma care management following hospital discharge. The primary analysis will use a Poisson regression model to assess the association between demographic and clinical risk factors and the primary and secondary outcomes. Latent class analysis will be used to identify distinct subgroups, which will further our knowledge on potential phenotypes of asthma among patients at high risk of asthma-related hospital admissions. A Concordance statistic (C-statistic) and logistic regression model will also be used to externally validate existing risk prediction models for asthma-related hospitalisations to allow for the optimal model to be identified and evaluated provide evidence for potential use of the optimal performing risk prediction model in primary care. ETHICS AND DISSEMINATION: This study was approved by the CPRD Independent Scientific Advisory Committee (reference number: 21_000512). Findings from this study will be published in a peer-reviewed journal and disseminated at national and international conferences.

Relationship between inflammatory status and microbial composition in severe asthma and during exacerbation.

BACKGROUND: In T2-mediated severe asthma, biologic therapies, such as mepolizumab, are increasingly used to control disease. Current biomarkers can indicate adequate suppression of T2 inflammation, but it is unclear whether they provide information about airway microbial composition. We investigated the relationships between current T2 biomarkers and microbial profiles, characteristics associated with a ProteobacteriaHIGH microbial profile and the effects of mepolizumab on airway ecology. METHODS: Microbiota sequencing was performed on sputum samples obtained at stable and exacerbation state from 140 subjects with severe asthma participating in two clinical trials. Inflammatory subgroups were compared on the basis of biomarkers, including FeNO and sputum and blood eosinophils. ProteobacteriaHIGH subjects were identified by Proteobacteria to Firmicutes ratio ≥0.485. Where paired sputum from stable visits was available, we compared microbial composition at baseline and following ≥12 weeks of mepolizumab. RESULTS: Microbial composition was not related to inflammatory subgroup based on sputum or blood eosinophils. FeNO ≥50 ppb when stable and at exacerbation indicated a group with less dispersed microbial profiles characterised by high alpha-diversity and low Proteobacteria. ProteobacteriaHIGH subjects were neutrophilic and had a longer time from asthma diagnosis than ProteobacteriaLOW subjects. In those studied, mepolizumab did not alter airway bacterial load or lead to increased Proteobacteria. CONCLUSION: High FeNO could indicate a subgroup of severe asthma less likely to benefit from antimicrobial strategies at exacerbation or in the context of poor control. Where FeNO is <50 ppb, biomarkers of microbial composition are required to identify those likely to respond to microbiome-directed strategies. We found no evidence that mepolizumab alters airway microbial composition.

Exacerbation Profile and Risk Factors in a Type-2-Low Enriched Severe Asthma Cohort: A Clinical Trial to Assess Asthma Exacerbation Phenotypes.

Rationale: The past 25 years have seen huge progress in understanding of the pathobiology of type-2 (T2) asthma, identification of measurable biomarkers, and the emergence of novel monoclonal antibody treatments. Although present in a minority of patients with severe asthma, very little is known about the mechanisms underlying T2-low asthma, making it a significant unmet need in asthma research. Objectives: The objective of this study was to explore the differences between study exacerbators and nonexacerbators, to describe physiological changes at exacerbation in those who are T2HIGH and T2LOW at the time of exacerbation, and to evaluate the stability of inflammatory phenotypes when stable and at exacerbation. Methods: Exacerbation assessment was a prespecified secondary analysis of data from a 48-week, multicenter, randomized controlled clinical study comparing the use of biomarkers and symptoms to adjust steroid treatment in a T2-low severe asthma-enriched cohort. Participants were phenotyped as T2LOW (fractional exhaled nitric oxide ⩽ 20 ppb and blood eosinophil count ⩽ 150 cells/µl) or T2HIGH (fractional exhaled nitric oxide > 20 or blood eosinophil count > 150) at study enrollment and at each exacerbation. Here, we report the findings of the exacerbation analyses, including comparison of exacerbators and nonexacerbators, the physiological changes at exacerbation in those who had evidence of T2 biology at exacerbation versus those that did not, and the stability of inflammatory phenotypes when stable and at exacerbation. Measurements and Main Results: Of the 301 participants, 60.8% (183) had one or more self-reported exacerbations (total of 390). Exacerbators were more likely to be female, have a higher body mass index, and have more exacerbations requiring oral corticosteroid and unscheduled primary care attendances for exacerbations. At enrollment, 23.6% (71) were T2LOW and 76.4% (230) T2HIGH. The T2LOW group had more asthma primary care attendances, were more likely to have a previous admission to HDU (high dependency unit)/ICU and to be receiving maintenance oral corticosteroids. At exacerbation, the T2LOW events were indistinguishable from T2HIGH exacerbations in terms of lung function (mean fall in T2LOW FEV1, 200 [400] ml vs. T2HIGH 200 [300] ml; P = 0.93) and symptom increase (ACQ5: T2LOW, 1.4 [0.8] vs. T2HIGH, 1.3 [0.8]; P = 0.72), with no increase in T2 biomarkers from stable to exacerbation state in the T2LOW exacerbations. The inflammatory phenotype within individual patients was dynamic; inflammatory phenotype at study entry did not have a significant association with exacerbation phenotype. Conclusions: Asthma exacerbations demonstrating a T2LOW phenotype were physiologically and symptomatically similar to T2HIGH exacerbations. T2LOW asthma was an unstable phenotype, suggesting that exacerbation phenotyping should occur at the time of exacerbation. The clinically significant exacerbations in participants without evidence of T2 biology at the time of exacerbation highlight the unmet and pressing need to further understand the mechanisms at play in non-T2 asthma. Clinical trial registered with www.clinicaltrials.gov (NCT02717689).

Airway remodelling rather than cellular infiltration characterizes both type2 cytokine biomarker-high and -low severe asthma.

BACKGROUND: The most recognizable phenotype of severe asthma comprises people who are blood eosinophil and FeNO-high, driven by type 2 (T2) cytokine biology, which responds to targeted biological therapies. However, in many people with severe asthma, these T2 biomarkers are suppressed but poorly controlled asthma persists. The mechanisms driving asthma in the absence of T2 biology are poorly understood. OBJECTIVES: To explore airway pathology in T2 biomarker-high and -low severe asthma. METHODS: T2 biomarker-high severe asthma (T2-high, n = 17) was compared with biomarker-intermediate (T2-intermediate, n = 21) and biomarker-low (T2-low, n = 20) severe asthma and healthy controls (n = 28). Bronchoscopy samples were processed for immunohistochemistry, and sputum for cytokines, PGD2 and LTE4 measurements. RESULTS: Tissue eosinophil, neutrophil and mast cell counts were similar across severe asthma phenotypes and not increased when compared to healthy controls. In contrast, the remodelling features of airway smooth muscle mass and MUC5AC expression were increased in all asthma groups compared with health, but similar across asthma subgroups. Submucosal glands were increased in T2-intermediate and T2-low asthma. In spite of similar tissue cellular inflammation, sputum IL-4, IL-5 and CCL26 were increased in T2-high versus T2-low asthma, and several further T2-associated cytokines, PGD2 and LTE4 , were increased in T2-high and T2-intermediate asthma compared with healthy controls. CONCLUSIONS: Eosinophilic tissue inflammation within proximal airways is suppressed in T2 biomarker-high and T2-low severe asthma, but inflammatory and structural cell activation is present, with sputum T2-associated cytokines highest in T2 biomarker-high patients. Airway remodelling persists and may be important for residual disease expression beyond eosinophilic exacerbations. Registered at ClincialTrials.gov: NCT02883530.

Burden of allergic disease among ethnic minority groups in high-income countries.

The COVID-19 pandemic raised acute awareness regarding inequities and inequalities and poor clinical outcomes amongst ethnic minority groups. Studies carried out in North America, the UK and Australia have shown a relatively high burden of asthma and allergies amongst ethnic minority groups. The precise reasons underpinning the high disease burden are not well understood, but it is likely that this involves complex gene-environment interaction, behavioural and cultural elements. Poor clinical outcomes have been related to multiple factors including access to health care, engagement with healthcare professionals and concordance with advice which are affected by deprivation, literacy, cultural norms and health beliefs. It is unclear at present if allergic conditions are intrinsically more severe amongst patients from ethnic minority groups. Most evidence shaping our understanding of disease pathogenesis and clinical management is biased towards data generated from white population resident in high-income countries. In conjunction with standards of care, it is prudent that a multi-pronged approach towards provision of composite, culturally tailored, supportive interventions targeting demographic variables at the individual level is needed, but this requires further research and validation. In this narrative review, we provide an overview of epidemiology, sensitization patterns, poor clinical outcomes and possible factors underpinning these observations and highlight priority areas for research.

Effect of benralizumab in a patient with uncontrolled severe eosinophilic asthma and comorbid chronic rhinosinusitis with nasal polyps refractory to mepolizumab treatment.

Severe eosinophilic asthma is associated with a high corticosteroid burden, particularly in patients with comorbid chronic sinusitis/nasal polyps. This case study reports a 33-year-old woman who presented to the severe asthma center with uncontrolled severe eosinophilic asthma and chronic rhinosinusitis with nasal polyps (CRSwNP). Despite maximized asthma treatment, including maintenance oral corticosteroids (OCS) for 7 years, the patient experienced one to two hospitalizations per year, had daily symptoms that substantially impacted her quality of life, and elevated type 2 inflammatory markers (blood eosinophils, 0.72 × 109/L; fractional exhaled nitric oxide, 134 to 300 parts per billion). Her asthma worsened during her first pregnancy, in which she required five hospital admissions despite treatment with maintenance OCS. Mepolizumab treatment was commenced after pregnancy but showed limited efficacy (blood eosinophil levels up to 0.94 × 109/L); treatment was discontinued because of a second pregnancy. The patient's asthma worsened and resulted in four hospitalizations and an increase in monthly OCS dose. Mepolizumab was recommenced after pregnancy, but her asthma remained uncontrolled, symptoms persisted, and one hospitalization and nine OCS courses were required. The patient was switched to benralizumab treatment when it became available. Although her CRSwNP symptoms remained, benralizumab treatment resulted in a marked improvement in asthma control, zero hospitalizations, and suppressed blood eosinophil levels. Notably, the patient was successfully weaned off maintenance OCS after >11 years of treatment. In summary, these findings support the use of benralizumab as a corticosteroid-sparing treatment option in difficult-to-treat severe eosinophilic asthma refractory to mepolizumab treatment.